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10.1101/2025.03.13.643134
|
Continuous FACS sorting of double emulsion picoreactors with a 3D printed vertical mixer.
|
Yang, Z.; Thompson, S.; Zhang, Y.; Rutten, I.; Van Duyse, J.; Van Isterdael, G.; Nichols, L.; Lammertyn, J.; Soh, H. T.; Fordyce, P. M.
|
Samuel Thompson
|
Stanford University
|
2025-03-15
|
1
|
new results
|
cc_by_nc_nd
|
bioengineering
|
https://www.biorxiv.org/content/early/2025/03/15/2025.03.13.643134.source.xml
|
High-throughput screening and directed evolution using microfluidic picoreactors have produced high-activity enzymes. In this approach, a substrate is co-encapsulated with a candidate enzyme and individual picoreactors are sorted based on an activity reporter. While many approaches use water-in-oil droplets (single emulsions) for fluorescence-activated droplet sorting (FADS) on custom-fabricated microfluidic devices that require integrated optics and electronics, recent approaches have lowered the engineering barriers to adoption by using simple microfluidic droplet generators to produce water-in-oil-in-water droplets (double emulsion picoreactors, DEs) that can be sorted with commercial FACS (fluorescence-activated cell sorting). Despite the simplified engineering requirements, high variability in loading rates and low yield during loading are barriers to efficient DE FACS sorting. Here, we optimized surfactants to enhance DE stability and demonstrated that a 3D-printed cork-screw on the sample line acts as a vertical mixer to enable more continuous loading. With these optimized loading conditions, we analyzed 1.17 million DEs in four 10-minute sorting rounds with a mean frequency of 480 Hz (390 Hz including sample exchanges); in a mock sort of 10% fluorescent DEs, we achieved 89.2+/-1.1% accuracy and 78+/-0.9% recovery with our optimized loading protocol. Overall, improved ease-of-use and throughput for FACS sortable DEs should expand the accessibility of directed evolution in controlled in vitro environments.
|
NA
|
biorxiv
| 2,339 |
10.1101/2025.03.14.643263
|
C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC- Derived Microglia and Modulates Glial-Neuronal Crosstalk
|
Mearelli, M.; Hirschberg, I.; Provenzano, F.; Weissleder, C.; Rizzuti, M.; Ottoboni, L.; Corti, S.; Deleidi, M.
|
Michela Deleidi
|
Mechanisms and Therapy of Genetic Brain Diseases, Institut Imagine, Paris, France
|
2025-03-15
|
1
|
new results
|
cc_no
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/15/2025.03.14.643263.source.xml
|
The C9orf72 hexanucleotide repeat expansion mutation is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, but its cell type-specific effects on energy metabolism and immune pathways remain poorly understood. Using induced pluripotent stem cell (iPSC)-derived motor neurons, astrocytes and microglia from C9orf72 patients and their isogenic controls, we investigated metabolic changes at the single-cell level under basal and inflammatory conditions. Our results showed that microglia are particularly susceptible to metabolic disturbances. While C9orf72 motor neurons exhibited impaired mitochondrial respiration and reduced ATP production, C9orf72 microglia presented pronounced increases in glycolytic activity and oxidative stress, accompanied by the upregulation of the expression of key metabolic enzymes. These metabolic changes in microglia were exacerbated by inflammatory stimuli. To investigate how these changes affect the broader cellular environment, we developed a human iPSC-derived triculture system comprising motor neurons, astrocytes and microglia. This model revealed increased metabolic activity in all cell types and highlighted that microglia-driven metabolic reprogramming in astrocytes contributes to the vulnerability of motor neurons under inflammatory conditions. Our findings highlight the central role of microglia in driving metabolic dysregulation and intercellular crosstalk in ALS pathogenesis and suggest that targeting metabolic pathways in immune cells may provide new therapeutic avenues.
|
NA
|
biorxiv
| 2,340 |
10.1101/2025.03.14.643280
|
Steering fatty acid composition of yeast microbial oil via genetic modification and bioprocess adjustment
|
Duman-Özdamar, Z. E.; Saccenti, E.; Martins dos Santos, V. A. P.; Hugenholtz, J.; Suarez-Diez, M.
|
Maria Suarez-Diez
|
Wageningen University & Research
|
2025-03-15
|
1
|
new results
|
cc_by
|
microbiology
|
https://www.biorxiv.org/content/early/2025/03/15/2025.03.14.643280.source.xml
|
The increasing demand for palm oil has drastic effects on the ecosystem as its production is not sustainable. To that end, developing a sustainable alternative to fatty acids and oils is urgent and of utmost interest. Oils produced by oleaginous yeasts present a promising solution, particularly because the fatty acid profile of the oil produced by these yeasts is comparable to that of plant-based oils and fats. The fatty acid composition of the oil determines its physiological properties, thereby determining its potential applications. Accordingly, the production of microbial oil with an optimal composition profile for a specific application is of great importance. In this study, we evaluated the variation that occurred in fatty acid composition due to different cultivation parameters (temperature, C/N ratio, carbon, and nitrogen sources) and applied genetic modifications to improve the lipid accumulation of Cutaneotrichosporon oleaginosus and Yarrowia lipolytica. We showed that specific fatty acid profiles associated with a particular application can be obtained by carefully selecting the microorganism and cultivation conditions.
|
NA
|
biorxiv
| 2,341 |
10.1101/2025.03.14.643292
|
Pseudogenization of the cntQ permease confers distinct yersinopine-metal uptake selectivity in Yersinia species
|
Laffont, C.; Pradel, E.; Ouerdane, L.; Brodel, A.; Gomez, N. O.; Hujeux, A.; Tribout, M.; Brutesco, C.; Voulhoux, R.; Lobinski, R.; Sebbane, F.; Arnoux, P.
|
Pascal Arnoux
|
CEA
|
2025-03-15
|
1
|
new results
|
cc_no
|
microbiology
|
https://www.biorxiv.org/content/early/2025/03/15/2025.03.14.643292.source.xml
|
Yersinopine is a nicotianamine-like metallophore recently inferred from a biochemical study, however its production in vivo and functional role have not been evaluated. Intriguingly, the Yersinia pestis cnt operon (cntPQRLMI) encoding yersinopine biosynthesis and transport (with cntPQR encoding a predicted ABC transport system, cntLM the two biosynthetic enzymes and cntI the predicted yersinopine exporter) shows two frameshift mutations in the cntQ gene encoding the permease, whereas this gene appears intact in Yersinia pseudotuberculosis. This pseudogenization, which occurred during the emergence of Y. pestis from Y. pseudotuberculosis, questions the role of yersinopine (if any) in both species. Here we show that yersinopine is secreted by both Y. pestis and Y. pseudotuberculosis in metal scarce conditions, and expression of the operon is repressed by the zinc uptake regulator (Zur). Surprisingly, the cnt operon was found to be involved in iron uptake in Y. pseudotuberculosis whereas it played a role in zinc acquisition in Y. pestis. Furthermore, mutation of cntQ in Y. pseudotuberculosis triggered a switch from iron import to zinc import, therefore recapitulating the phenotype observed in Y. pestis. This work demonstrates the production of yersinopine in two closely related bacteria in zinc scarce conditions, and highlights the effect of a pseudogenization event triggering a global change in metal uptake specificity.
|
NA
|
biorxiv
| 2,342 |
10.1101/2025.03.15.643420
|
A rapid non-traditional approach for developing biologicals against drug- resistant bacteria and yeasts.
|
BANERJEE, S. K.; Patil, P.; Suresh, A.; Nada, R.; Naik, G.; Shukla, M.
|
SANJIBAN K BANERJEE
|
AbGenics LifeSciences P Ltd
|
2025-03-15
|
1
|
new results
|
cc_no
|
microbiology
|
https://www.biorxiv.org/content/early/2025/03/15/2025.03.15.643420.source.xml
|
Development of effective, long-lasting antibiotics is a challenge due to the rate at which the pathogens acquire resistance, prompting the major pharma players to omit them from their portfolio. We present a non-traditional approach for rapidly developing anti-infective biologicals that is resilient to resistance. Antibody-drug conjugates were developed against three different pathogens Pseudomonas aeruginosa (ABG 14), Staphylococcus aureus (ABG 16) and Candida. albicans (ABG 07) that were extremely specific and effective in neutralising them irrespective of their drug resistance profiles. Neutralising camelid antibody fragment (VHH) were isolated from immunised camel libraries by phage display that effectively neutralised the pathogens at a MIC 99 of 125 ug mL-1 in vitro. Antimicrobial peptides (AMP) were then conjugated to them by pathogen-specific cleavable linkers and the resultant molecules were 10 -20 times more effective due to a dual mode of action-the inhibitory action of the VHH on surface transporters and enzymes and the activity of the AMPs released by the pathogen surface proteases. Called AbTids, these molecules were extremely specific, stable in plasma and were activated in the presence of 104 to 105 CFU mL-1 of the pathogens and had an efficacy in the sub-micromolar range (6.25-12.5 ug mL-1, 250 nM) inhibiting their growth within 2 hrs. of administration. They were economically and efficiently produced in microbial production system as a single chain fusion protein. One of the molecules ABG 14 was characterized further and found to be pathogen specific with negligible frequency of resistance, was non-toxic, had the capability to destroy biofilms, and cleared a systemic infection in a mouse with a carbapenem resistant strain of P. aeruginosa at a dose of 5 mg kg-1. This strategy can be used to generate new hits against medically important pathogens in a matter of weeks by simply shuffling the components, using different VHHs and AMPs, bypassing years of expensive drug development efforts that can potentially rejuvenate drug discovery efforts against emerging superbugs.
|
NA
|
biorxiv
| 2,343 |
10.1101/2025.03.14.643217
|
Nucleosome binding relinquishes the association of the BAH domain of Orc1 with Sir1
|
Jiang, H.; Yu, C.; Liu, C.-P.; Han, X.; Chen, J.; Yu, Z.; Xu, R.-M.
|
Zhenyu Yu
|
Institute of Biophysics, Chinese Academy of Sciences
|
2025-03-15
|
1
|
new results
|
cc_by
|
molecular biology
|
https://www.biorxiv.org/content/early/2025/03/15/2025.03.14.643217.source.xml
|
Mating-type switching in S. cerevisiae requires silencing of the homothallic mating (HM) loci through formation of position-dependent, gene-independent repressive chromatin domains, resembling heterochromatic regions in higher eukaryotes. Genetic and biochemical studies have identified cis-acting DNA elements, called silencers, and trans-acting protein factors important for the establishment and maintenance of the silent chromatin. Yet, the molecular mechanism governing the position-dependence of gene silencing is not fully understood. Here we report that the BAH domain of Orc1, which is responsible for recruiting Sir1 to the Orc1-bound silencers, ceases to bind Sir1 in the presence of nucleosome. This finding suggests a unified role of sensing the chromatin environment by Orc1's BAH domain in transcriptional silencing and specification of replication origins. We further dissected the structural determinants of the BAH domain required for binding Sir1. These results expanded the understanding of Orc1's functions in epigenetic silencing of the HM loci.
|
NA
|
biorxiv
| 2,344 |
10.1101/2025.03.14.643198
|
Spatial relationship of urban carbon neutrality in Yangtze River Basin
|
Li, Q.; Meng, X.; Chen, X.; Liu, Y.
|
Xiaohe Meng
|
University Chinese Academy of Social Sciences
|
2025-03-15
|
1
|
new results
|
cc_by
|
ecology
|
https://www.biorxiv.org/content/early/2025/03/15/2025.03.14.643198.source.xml
|
Carbon neutrality needs to be implemented spatially in order to be realized concretely. The distribution of carbon sources and sinks across the national territory is closely related to many factors, such as natural geographical resources, levels of economic and social development, and cultural and historical heritage. It is difficult for many regions to achieve carbon neutrality through their own efforts alone. This article believes that only by achieving local optimal carbon neutrality through a reasonable spatial organization can emissions be ultimately reduced to zero on a national scale. Under the connection of rivers, the basin forms an ecosystem and an economic system with independent characteristics. Carbon sources and sinks within the basin exist within the ecological and economic space of the basin, forming a unique carbon neutrality spatial pattern. This study starts with the spatial distribution status, features and relationships of carbon neutrality elements in the cities of the Yangtze River Basin, and divides the cities into eight types based on their development level, emission level and forest resources, such as high-emission and low-carbon sink developed cities and low-emission and high-carbon sink underdeveloped cities. Different types of cities are proposed with carbon neutrality paths and spatial organization schemes, and it is suggested that the spatial organization demonstration of carbon neutrality in the cities of the Yangtze River Basin can provide a reference for carbon neutrality on a national scale.
|
NA
|
biorxiv
| 2,345 |
10.1101/2025.03.13.643148
|
Mitochondrial DNA variation of the striped hyena (Hyaena hyaena) in Algeria and further insights into the species' evolutionary history
|
Derouiche, L.; Rodrigues, M.; Benameur-Hasnaoui, H.; Aissa, R. H.; Hassan-Beigi, Y.; Madjdzadeh, S. M.; Amr, Z.; Cokayne, A.; Vercammen, P.; Fernandes, C.
|
Carlos Fernandes
|
CE3C - Centre for Ecology, Evolution and Environmental Changes & CHANGE - Global Change and Sustainability Institute, Departamento de Biologia Animal, Faculdade
|
2025-03-15
|
1
|
new results
|
cc_no
|
evolutionary biology
|
https://www.biorxiv.org/content/early/2025/03/15/2025.03.13.643148.source.xml
|
The striped hyena (Hyaena hyaena) occurs in a wide range from north and east Africa, through southwest Asia to India, but its distribution is increasingly patchy and many of its populations are in decline due to intense human pressure. Its genetic diversity and structure, phylogeography, and evolutionary history, remain poorly understood. In this study, we investigated mitochondrial DNA variation in Algerian striped hyenas, by sequencing a fragment of the cytochrome b gene encompassing the one used in a pioneering study that remains the only one in which individuals from across the range of the species were analysed, to allow for comparisons. With the aim of contributing to our understanding of the evolutionary history of the species, we also examined samples from geographic regions not included in that study, and using a larger global dataset we performed a wide range of analyses of demographic history and estimation of the age of the extant mitochondrial DNA variation. The Algerian population sample was monomorphic. Overall, the global patterns of genetic diversity and the results of some demographic history analyses supported a scenario of population growth in the species, estimated to have occurred in the Late Pleistocene, but many of the analyses did not detect a significant signal of growth, most likely a result of the limited power provided by a small number of segregating sites. The estimates, from three different methods, for the time to the most recent common ancestor (TMRCA) of the mitochondrial DNA variation hovered around 400 ka, coinciding with one of the longest and warmest interglacials of the last 800,000 years, with environmental conditions similar to the Holocene.
|
NA
|
biorxiv
| 2,346 |
10.1101/2025.03.13.643185
|
Macrocyclic phage display for identification of selective protease substrates
|
Faucher, F. F.; Lovell, S.; Bertolini, M.; Blazkova, K.; Cosco, E. D.; Bogyo, M.; Barniol-Xicota, M.
|
Matthew Bogyo
|
Stanford University
|
2025-03-15
|
1
|
new results
|
cc_by_nc
|
biochemistry
|
https://www.biorxiv.org/content/early/2025/03/15/2025.03.13.643185.source.xml
|
Traditional methods for identifying selective protease substrates have primarily relied on synthetic libraries of linear peptides, which offer limited sequence and structural diversity. Here, we present an approach that leverages phage display technology to screen large libraries of chemically modified cyclic peptides, enabling the identification of highly selective substrates for a protease of interest. Our method uses a reactive chemical linker to cyclize peptides on the phage surface, while simultaneously incorporating an affinity tag and a fluorescent reporter. The affinity tag enables capture of the phage library and subsequent release of phages expressing optimal substrates upon incubation with a protease of interest. The addition of a turn-on fluorescent reporter allows direct quantification of cleavage efficiency throughout each selection round. The resulting identified substrates can then be chemically synthesized, optimized and validated using recombinant enzymes and cells. We demonstrate the utility of this approach using Fibroblast Activation Protein alpha (FAP) and the related proline-specific protease, dipeptidyl peptidase-4 (DPP4), as targets. Phage selection and subsequent optimization identified substrates with selectivity for each target that have the potential to serve as valuable tools for applications in basic biology and fluorescence image-guided surgery (FIGS). Overall, our strategy provides a rapid and unbiased platform for effectively discovering highly selective, non-natural protease substrates, overcoming key limitations of existing methods.
|
NA
|
biorxiv
| 2,347 |
10.1101/2025.03.13.643057
|
MyoBack: A Musculoskeletal Model of the Human Back with Integrated Exoskeleton
|
Walia, R.; Garzon, K.; Billot, M.; Subramanian, S.; WANG, H.; Refai, M. I.; Durandau, G.
|
HUIYI WANG
|
McGill University
|
2025-03-15
|
1
|
new results
|
cc_by_nc_nd
|
bioengineering
|
https://www.biorxiv.org/content/early/2025/03/15/2025.03.13.643057.source.xml
|
Given the challenges of real-life experimentation, musculoskeletal simulation models could become essential in biomedical research. This is especially critical for the human back, a key structure involved in daily movements, where modeling and simulation could streamline design and support the development of treatments and robotic rehabilitation techniques, such as exoskeletons. However, musculoskeletal simulation engines are computationally demanding and lack contact dynamics, restricting current models' use in studying prolonged behaviors or optimizing system design while maintaining physiological accuracy. To overcome this limitation, this work proposes MyoBack, a human back model part of the MyoSuite framework relying on the physics engine MuJoCo. This model is derived from a physiologically accurate model built in the state-of-the-art musculoskeletal simulation software OpenSim and replicates the latter's kinematic properties accurately, with some discrepancies regarding muscle dynamics stemming from engine differences. The MyoBack model was also validated empirically by integrating a passive back exoskeleton in simulation and comparing forces exerted on the back with values from experimental trials. Over different tasks, the model reproduced measured force progressions well, resulting in RMSE = 11% for a stoop and RMSE = 16% for a squat motion pattern relative to peak forces.
|
NA
|
biorxiv
| 2,348 |
10.1101/2023.01.10.523479
|
How Occam's razor guides human decision-making
|
Piasini, E.; Liu, S.; Chaudhari, P.; Balasubramanian, V.; Gold, J. I.
|
Eugenio Piasini
|
International School for Advanced Studies (SISSA)
|
2025-03-16
|
4
|
new results
|
cc_by
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2023.01.10.523479.source.xml
|
Occam's razor is the principle that, all else being equal, simpler explanations should be preferred over more complex ones. This principle is thought to guide human decision-making, but the nature of this guidance is not known. Here we used preregistered behavioral experiments to show that people tend to prefer the simpler of two alternative explanations for uncertain data. These preferences match predictions of formal theories of model selection that penalize excessive flexibility. These penalties emerge when considering not just the best explanation but the integral over all possible, relevant explanations. We further show that these simplicity preferences persist in humans, but not in certain artificial neural networks, even when they are maladaptive. Our results imply that principled notions of statistical model selection, including integrating over possible, latent causes to avoid overfitting to noisy observations, may play a central role in human decision-making.
|
NA
|
biorxiv
| 0 |
10.1101/2023.11.15.567174
|
Idiosyncrasies unveiled: examining the pace, patterns and predictors of biotic diversification in peninsular India
|
Roy, P.; Joshi, J.
|
Jahnavi Joshi
|
CSIR-Centre for Cellular and Molecular Biology, Hyderabad; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
|
2025-03-16
|
4
|
new results
|
cc_no
|
evolutionary biology
|
https://www.biorxiv.org/content/early/2025/03/16/2023.11.15.567174.source.xml
|
The Peninsular Indian Plate (PIP), one of the oldest regions of diversification in tropical Asia, harbours highly diverse and endemic biota. However, our understanding of the diversification dynamics of its biota within a quantitative framework remains limited. To address this, we used time-calibrated molecular phylogenies and birth-death models to examine the tempo, mode, and drivers of diversification across 33 well-studied endemic lineages (~770 species). Among PIP lineages, angiosperms diversified the fastest, invertebrates the slowest and younger lineages of Asian origins diversified more rapidly than the older relictual Gondwanan lineages. Evolutionary relatedness explained the disparities in diversification rates across taxonomic groups and biogeographic origins. A gradual accumulation of diversity was supported in 17 lineages, suggesting that the historical stability of their habitat was an important driver. Miocene intensification of monsoons and aridification and fluctuations in paleotemperature explained diversification patterns in the remaining 16 lineages. Our results highlight the role of regional biogeography, geoclimatic processes, and phylogenetic history in governing diversification dynamics in the tropics.
|
NA
|
biorxiv
| 1 |
10.1101/2024.03.01.583057
|
Cyclin A2 Induces Human Adult Cardiomyocyte Cytokinesis and Elicits Cardiomyocyte Reprogramming and Dedifferentiation
|
Bouhamida, E.; Vadakke-Madathil, S.; Mathiyalagan, P.; Ranjan, A.; Khan, A.; Sherman, C.; Miller, P. E.; Ghetti, A.; Abi-Gerges, N.; Chaudhry, H. W.
|
Hina W Chaudhry
|
Icahn School of Medicine at Mount Sinai
|
2025-03-16
|
4
|
new results
|
cc_no
|
cell biology
|
https://www.biorxiv.org/content/early/2025/03/16/2024.03.01.583057.source.xml
|
Background: Cyclin A2 (CCNA2), the master regulatory gene of the cell cycle is commonly silenced in postnatal mammalian cardiomyocytes. We have previously demonstrated that it can induce significant cardiac repair in both small and large animals when delivered to the heart via a viral vector. To date, whether CCNA2 gene delivery can induce cytokinesis in isolated cardiomyocytes from adult human hearts has not been investigated. Here we report that CCNA2 delivery can induce cytokinesis in cardiomyocytes isolated from adult human hearts. Methods: We designed a human gene therapy vector featuring a replication-deficient, E1/E3-deleted human adenovirus five encoding human CCNA2 driven by the cardiac Troponin T promoter to enable the expression of CCNA2 in freshly isolated human cardiomyocytes. We utilized time-lapse microscopy with live imaging to study cultured adult human cardiomyocytes isolated from a 21-year-old male, a 41-year-old female, and a 55-year-old male. To elucidate the mechanistic underpinnings of CCNA2-dependent gene regulation in governing cardiomyocyte cytokinesis, we conducted single nucleus transcriptomics (snRNA-seq, 10X Genomics) analysis of hearts isolated from adult transgenic mice that constitutively express CCNA2 in cardiomyocytes (CCNA2-Tg) and non-transgenic mice (nTg). Results: We now report that human adult cardiomyocytes can be induced to undergo complete cytokinesis in response to CCNA2 gene delivery with preservation of sarcomere integrity in the resulting daughter cells and maintaining active calcium mobilization in redifferentiated cardiomyocytes. Remarkably, snRNA-seq analysis revealed a subpopulation of cardiomyocytes enriched with cytokinesis, proliferative and reprogramming genes in hearts obtained from CCNA2-Tg mice as compared to hearts obtained from nTg mice. Additionally, bulk RNA sequencing of human adult and fetal hearts identified key reprogramming genes relevant for understanding the mechanisms of CCNA2-induced effects observed in our experimental models. Conclusion: These results provide a compelling path forward for the clinical development of cardiac regenerative therapy based on strategic manipulation of CCNA2 in cardiomyocytes.
|
NA
|
biorxiv
| 2 |
10.1101/2024.03.28.587237
|
Trauma Under Psychedelics: How Psychoactive Substances Impact Trauma Processing
|
Netzer, O.; Magal, N.; Stern, Y.; Polinsky, T.; Gross, R.; Admon, R.; Salomon, R.
|
Roy Salomon
|
University of Haifa
|
2025-03-16
|
2
|
new results
|
cc_by_nc_nd
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2024.03.28.587237.source.xml
|
Traumatic events play a causal role in the etiology of stress-related psychopathologies such as depression and posttraumatic stress disorder (PTSD). Recent research highlighted the therapeutic potential of psychoactive substances in alleviating trauma symptoms among chronic stress-related patients. This study is the first to investigate the impact of psychoactive substances consumed during actual trauma exposure. Our cohort includes 772 adult survivors (487 males, Mean[SD] Age: 26.96[6.55]) of the high-casualty attack that occurred at the Supernova festival in Israel on October 7th, 2023. Survivors completed the study during the peritraumatic period of one to four months following the attack. Primary outcomes include the PTSD Checklist for DSM-5 (PCL-5), the Kessler Psychological Distress Scale (K6), and a self-reported rating of feeling overwhelmed. Secondary outcomes include subjective experiences during the attack and reports on social interactions and sleep quality. All survivors reported being in direct danger of death during the attack. Approximately two-thirds of the sampled survivors were under the influence of psychoactive substances at the time of the attack, including LSD, MDMA, Ketamine, Cannabis, and Alcohol, creating a tragic and unique natural experiment to study the impact of psychoactive compounds on trauma processing. Analysis revealed that participants that were under the influence of MDMA during the attack (n=99) reported feeling less overwhelmed, having more social interactions, improved sleep quality, and reduced psychological distress compared to those not under the influence of any substance during the attack (n=216). In contrast, those consuming Cannabis and/or Alcohol during the attack (n=68) showed higher psychological distress, more PTSD symptoms, and worse sleep quality compared to those not under the influence of any substance during the attack. Together, these novel findings suggest that trauma exposure under the influence of MDMA is associated with reduced psychological distress and higher sociality, possibly mediated through MDMA's known effects of reducing negative emotions and elevating prosociality, while Cannabis and/or Alcohol consumption produces deleterious effects. Further research is needed to explore the cognitive and physiological mechanisms linking psychoactive substances to trauma recovery and establish the putative protective role of MDMA.
|
NA
|
biorxiv
| 3 |
10.1101/2024.05.15.594435
|
A linear perception-action mapping accounts for response range-dependent biases in heading estimation from optic flow
|
Sun, Q.; Xu, L.-H.; Stocker, A. A.
|
Qi Sun
|
Zhejiang Normal University
|
2025-03-16
|
3
|
new results
|
cc_by_nc_nd
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2024.05.15.594435.source.xml
|
Accurate estimation of heading direction from optic flow is a crucial aspect of human spatial perception. Previous psychophysical studies have shown that humans are typically biased in their estimates of heading directions, but the reported results are inconsistent. While some studies found that humans generally underestimate heading direction (central bias), others find the opposite, an overestimation of heading direction (peripheral bias). We conducted three psychophysical experiments showing that these conflicting findings do not reflect inherent differences in heading perception but are caused by the different sizes of the response range that participants were allowed to utilize when reporting their estimates. Notably, we show that participants' heading estimates monotonically scale with the size of the response range, leading to underestimation for small and overestimation for large response ranges. Additionally, neither the speed profile of the optic flow pattern nor the response method (mouse vs. keyboard) significantly affected participants' estimates. Furthermore, we introduce a Bayesian heading estimation model that can quantitatively account for participants' heading reports. The model assumes an efficient sensory encoding of heading direction according to a prior inferred from human heading discrimination data. In addition, the model assumes a response mapping that linearly scales the perceptual estimate with a scaling factor that monotonically depends on the size of the response range. This simple perception-action model accurately predicts participants' estimates both in terms of mean and variance across all experimental conditions. Our findings underscore that human heading perception follows efficient Bayesian inference; differences in participants reported estimates can be parsimoniously explained as differences in mapping percept to probe response.
|
NA
|
biorxiv
| 4 |
10.1101/2024.05.27.595705
|
Impact of symmetry in local learning rules on predictive neural representations and generalization in spatial navigation
|
Keck, J. S.; Barry, C.; Doeller, C. F.; Jost, J.
|
Janis Samuel Keck
|
Max Planck Institute for Mathematics in the Sciences
|
2025-03-16
|
3
|
new results
|
cc_by_nc
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2024.05.27.595705.source.xml
|
In spatial cognition, the Successor Representation (SR) from reinforcement learning provides a compelling candidate of how predictive representations are used to encode space. In particular, hippocampal place cells are hypothesized to encode the SR. Here, we investigate how varying the temporal symmetry in learning rules influences those representations. To this end, we use a simple local learning rule which can be made insensitive to the temporal order. We analytically find that a symmetric learning rule results in a successor representation under a symmetrized version of the experienced transition structure. We then apply this rule to a two-layer neural network model loosely resembling hippocampal subfields CA3 - with a symmetric learning rule and recurrent weights - and CA1 - with an asymmetric learning rule and no recurrent weights. Here, when exposed repeatedly to a linear track, neurons in our model in CA3 show less shift of the centre of mass than those in CA1, in line with existing empirical findings. Investigating the functional benefits of such symmetry, we employ a simple reinforcement learning agent which may learn symmetric or classical successor representations. Here, we find that using a symmetric learning rule yields representations which afford better generalization, when the agent is probed to navigate to a new target without relearning the SR. This effect is reversed when the state space is not symmetric anymore. Thus, our results hint at a potential benefit of the inductive bias afforded by symmetric learning rules in areas employed in spatial navigation, where there naturally is a symmetry in the state space.
|
NA
|
biorxiv
| 5 |
10.1101/2024.07.09.602634
|
Serum amyloid A3 deficiency modulates aortic immune composition and attenuates murine atherosclerosis progression
|
Chou, T.-Y.; Ye, Y.-Z.; Lien, C.-J.; Wang, J.-C.; Yang, C.-H.; Chen, Y.-T.; Chao, P.-A.; Lin, J.-D.
|
Jian-Da Lin
|
Department of Biochemical Science and Technology, National Taiwan University, Taiwan
|
2025-03-16
|
3
|
new results
|
cc_by_nc_nd
|
immunology
|
https://www.biorxiv.org/content/early/2025/03/16/2024.07.09.602634.source.xml
|
Atherosclerosis is a growing concern in developed nations, necessitating the identification of therapeutic targets for advancing personalized medicine. Serum amyloid A3 (Saa3) has been linked to accelerated plaque progression by affecting cholesterol metabolism and modulation of inflammation. We hypothesize that knocking out Saa3 (Saa3-/-) could mitigate plaque development by regulating aortic immune cell compositions during atherosclerosis progression. Using a murine model, we induced atherosclerosis via a gain-of-function mutant PCSK9-encoding adeno-associated viral vector (AAVmPCSK9) in female wild-type (WT) and Saa3-/- mice. Saa3-/- mice developed smaller plaques than WT mice, and single-cell RNA sequencing revealed significant differences in aortic immune cell populations, particularly among aortic macrophages. Aortic macrophages in atherosclerotic Saa3-/- mice represent an anti-inflammatory and tissue-repairing phenotype and the Trem2hi macrophages, characterized by high Gpnmb, Lpl, and Spp1 expressions, predominated over the typical foamy macrophages in Saa3-/- compared to WT mice. Notably, SAA3 regulates cholesterol metabolism and inflammatory responses in foamy macrophages. Our study highlights Saa3 as a key modulator of aortic immune cells that impact atherosclerosis progression.
|
NA
|
biorxiv
| 6 |
10.1101/2024.08.11.607487
|
AmygdalaGo-BOLT3D: A fast and valid transformer tracing boundaries of amygdala from brain images
|
Dong, B.; Zhou, Q.; Gao, P.; Jintao, W.; Xiao, J.; Wang, W.; Liang, P.; Lin, D.; He, H.; Zuo, X.-N.
|
Xi-Nian Zuo
|
Beijing Normal University
|
2025-03-16
|
2
|
new results
|
cc_by_nc_nd
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2024.08.11.607487.source.xml
|
Tracing boundaries of amygdala from brain images is one of the most fundamental steps in human neuroscience research. However, due to its small volume and complex anatomy, especially in developing brains, the precision and consistency of the tracing outcomes are highly affected by individual differences and methodological inconsistencies between different tools. To address these challenges, we propose an algorithm for learning boundary contrast of 427 manually traced amygdalae in children and adolescents to generate a transformer, AmygdalaGo-BOLT3D, for automatically tracing human amygdala. This method focuses on the boundary to effectively address issues with false positive recognition and inaccurate edges due to small but complex amygdala. AmygdalaGo-BOLT3D first develops the basic architecture of an adaptive cooperation network with multiple granularities. A self-attention-based consistency module is then constructed to improve generalizability by adapting the three-module sample-mask model for the amygdala scene: a lightweight volumetric feature encoder, a 3D cue encoder, and a volume mask decoder. Finally, AmygdalaGo-BOLT3D implements a boundary contrastive learning framework that utilizes the interaction mechanisms between a prior cue and the embedded magnetic resonance images to achieve their effective integration. Our results confirmed that predictions of the overall structure and boundaries of the human amygdala exhibited highly improved precision as the golden-standard - manual tracing, while further achieve high stability across multiple age groups and imaging centers and more efficient for large-scale studies than manual tracing. Open source code for AmygdalaGo-BOLT3D is available at Science Data Bank (SciDB\_LINK).
|
NA
|
biorxiv
| 7 |
10.1101/2024.09.02.610785
|
Continuous self-repair protects vimentin intermediate filaments from fragmentation
|
Tran, Q. D.; Lenz, M.; Lamour, G.; Paty, L.; Varela-Salgado, M.; Campillo, C.; Wioland, H.; JEGOU, A.; Romet-Lemonne, G.; Leduc, C.
|
Cecile Leduc
|
Institut Jacques Monod - CNRS
|
2025-03-16
|
2
|
new results
|
cc_by
|
biophysics
|
https://www.biorxiv.org/content/early/2025/03/16/2024.09.02.610785.source.xml
|
Intermediate filaments are key regulators of cell mechanics. Vimentin, a type of intermediate filament expressed in mesenchymal cells and involved in migration, forms a dense network in the cytoplasm that is constantly remodeling through filament transport, elongation/shortening, and subunit exchange. While it is known that filament elongation involves end-to-end annealing, the reverse process of filament shortening by fragmentation remains unclear. Here, we use a combination of in vitro reconstitution, probed by fluorescence imaging and AFM, with theoretical modeling to uncover the molecular mechanism involved in filament breakage. We first show that vimentin filaments are composed of two populations of subunits, half of which are exchangeable and half immobile. We also show that the exchangeable subunits are tetramers. Furthermore, we reveal a mechanism of continuous filament self-repair, where a soluble pool of vimentin tetramers in equilibrium with the filaments is essential to maintain filament integrity. Filaments break due to local fluctuations in the number of tetramers per cross-section, induced by the constant subunit exchange. We determine that a filament tends to break if approximately four tetramers are removed from the same filament cross-section. Finally, we analyze the dynamics of association/dissociation and fragmentation to estimate the binding energy of a tetramer to a complete versus a partially disassembled filament. Our results provide a comprehensive description of vimentin turnover and reveal the link between subunit exchange and fragmentation.
|
NA
|
biorxiv
| 8 |
10.1101/2024.11.26.625404
|
Neurogenetic evidence that Dilp8 promotes developmental-stability via Lgr3-neuron oscillation
|
Zanini, R.; Pereirinha, J.; Fernandez-Acosta, M.; Casimiro, A. P.; Pinho, M.; Lage, L.; Garelli, A.; Heredia, F.; Gontijo, A. M.
|
Alisson M. Gontijo
|
fdheredia@ciencias.ulisboa.pt 1 cE3c, Department of Animal Biology, Faculty of Sciences, University of Lisbon, Lisbon, Portugal. 2 iNOVA4Health, Nova Medical Sc
|
2025-03-16
|
2
|
new results
|
cc_no
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2024.11.26.625404.source.xml
|
The ability to achieve a species-specific size and proportion despite developmental or environmental perturbations is termed developmental stability. The molecular and cellular processes behind this are best understood in insects. In Drosophila, a peripheral-tissue stress signal, the relaxin/insulin-like peptide Dilp8, promotes developmental stability during larval development via its neuronal receptor, Lgr3, an ortholog of vertebrate relaxin receptors. Lgr3 signaling is widely accepted to occur in--and to activate (depolarize)--the central brain growth-coordinating interneurons (PIL/GCL neurons). Here, using neurogenetic approaches, we confirm the requirement of Lgr3 in PIL/GCL neurons, but unexpectedly find that they require both silenced (hyperpolarized) and active (depolarized) states for an appropriate response to Dilp8. These results are most simply explained if Lgr3 activation by Dilp8 triggers PIL/GCL-neuron oscillatory activity, and such oscillations promote developmental stability. PIL/GCL neurons express and require Cyclin A--which can form cell-cycle oscillator complexes with cyclin-dependent kinases--for their response to Dilp8, independently of Rca1 (regulator of CycA)/Emi1 (early mitotic inhibitor). This opens the possibility that cell-cycle machinery can be co-opted for postmitotic neuron oscillations, adding to an increasing list of postmitotic roles for cyclins. Neuroanatomically, we show that PIL/GCL neurons form reciprocally-innervating loops, which are common architectures in oscillating circuits and central pattern generators. The role of PIL/GCL neurons in developmental stability mirrors other homeostasis-regulating, peptide-driven oscillatory circuits found in the vertebrate hypothalamus, a developmentally-homologous region to the one occupied by PIL/GCL neurons in the fly brain.
|
NA
|
biorxiv
| 9 |
10.1101/2025.01.10.632449
|
Decoding gene regulatory networks controlling hypothalamic and prethalamic development.
|
Kim, D. W.; Duncan, L.; Xu, J.; Chang, M.; Sorensen, S. S.; Terrillin, C.; Kanold, P.; Place, E. S.; Blackshaw, S.
|
Seth Blackshaw
|
Johns Hopkins University School of Medicine
|
2025-03-16
|
2
|
new results
|
cc_by_nc_nd
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2025.01.10.632449.source.xml
|
Neuronal subtypes derived from the embryonic hypothalamus and prethalamus regulate many essential physiological processes, yet the gene regulatory networks controlling their development remain poorly understood. Using single-cell RNA- and ATAC-sequencing, we analyzed mouse hypothalamic and prethalamic development from embryonic day 11 to postnatal day 8, profiling 660,000 cells in total. This identified key transcriptional and chromatin dynamics driving regionalization, neurogenesis, and differentiation. This identified multiple distinct neural progenitor populations, as well as gene regulatory networks that control their spatial and temporal identities, and their terminal differentiation into major neuronal subtypes. Integrating these results with large-scale genome-wide association study data, we identified a central role for transcription factors controlling supramammillary hypothalamic development in a broad range of metabolic and cognitive traits. Recurring cross-repressive regulatory relationships were observed between transcription factors that induced prethalamic and tuberal hypothalamic identity on the one hand and mammillary and supramammillary hypothalamic identity on the other. In postnatal animals, Dlx1/2 was found to severely disrupt GABAergic neuron specification in both the hypothalamus and prethalamus, resulting in a loss of inhibition of thalamic neurons, hypersensitivity to cold, and behavioral hyperactivity. By identifying core gene regulatory networks controlling the specification and differentiation of major hypothalamic and prethalamic neuronal cell types, this study provides a roadmap for future efforts aimed at preventing and treating a broad range of homeostatic and cognitive disorders.
|
NA
|
biorxiv
| 10 |
10.1101/2025.02.06.636115
|
Deep origins and distinct adaptations indicated for a glacial relict seal
|
Loytynoja, A.; Pohjoismaki, J.; Valtonen, M.; Laakkonen, J.; Morita, W.; Kunnasranta, M.; Vainola, R.; Olsen, M. T.; Auvinen, P.; Jernvall, J.
|
Jukka Jernvall
|
University of Helsinki
|
2025-03-16
|
2
|
new results
|
cc_by_nc_nd
|
zoology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.02.06.636115.source.xml
|
Isolated populations of postglacial relicts are known from many regions and are typically found on mountains for terrestrial species and in lakes for aquatic species. Among the few aquatic mammalian relicts, the Saimaa ringed seal (Pusa hispida saimensis) has been land-locked in Lake Saimaa, Finland, for the last 10,000 years. Saimaa ringed seals show genetic, behavioral, and morphological differences to the other ringed seal subspecies, but the extent these differences stem from the end of the last glacial period remains unclear. Here, we demonstrate with comprehensive sampling and state-of-the-art genomic methods that the Saimaa ringed seals are much older than the lake they inhabit, having formed a separate evolutionary branch for at least 60,000 years ago. This deep evolutionary origin of the Saimaa ringed seals is further underscored by our ecomorphological analyses revealing adaptively distinct features in their dentition and tongue. Overall, glacial relicts, many threatened by extinction, may harbor a richer selection of evolutionary history than might be expected from their recent isolation history alone.
|
NA
|
biorxiv
| 11 |
10.1101/2025.02.14.638244
|
Sex-related gut microbiota in three geographically separated Norway lobster (Nephrops norvegicus) populations
|
Rusanova, P.; Nikouli, E.; Casini, M.; Bono, G.; Mente, E.; Meziti, A.; Kormas, K.
|
Konstantinos Kormas
|
University of Thessaly
|
2025-03-16
|
2
|
new results
|
cc_by_nc_nd
|
microbiology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.02.14.638244.source.xml
|
Despite the ecological and economic interest of the Norway lobster (Nephrops norvegicus), its gut microbiota remains largely understudied. The current study aimed at investigating the gut bacterial microbiota in three geographically separated N. norvegicus populations from the Mediterranean and the North Sea and detecting any potential sex-related microbiota differences, by high-throughput sequencing of the V3-V4 16S rRNA gene diversity of the gut tissue. From the Greek population, egg-bearing females were also caught. A total of 2,385 operational taxonomic units (OTUs) were identified and between 417 and 1290 occurred in each population/sex group. The dominant OTUs belonged to the Fusobacteriia and Bacteroidia (Sweden), Bacilli and Gammaproteobacteria (Italy) and Spirochaetia and Bacilli (Greece) bacterial classes. In the eggs, the Actinobacteria, Alphaproteobacteria and Gammproteobacteria prevailed. Four OTUs related to the Oceanispirochaeta, Kordiimonas, Desulfovibrio, Carboxylicivirga genera and one unafilliated OTU were positively correlated (p values between 0.001 and 0.04) to body size indicating their potential role in the animal's nutrition and growth. No statistically significant differences were found between males-females in each of the three populations. However, statistically significant differences between populations for each sex, were found for all females (p values between 0.008 and 0.032) and for the males between the most distant populations, i.e. Italy-Sweden (p=0.021) and Greece-Sweden (p=0.015). The eggs microbiota was statistically different from both the adult females (p=0.027) and males (p=0.046) gut microbiota. Overall, this study showed that N. norvegicus gut microbiota are differentiated between geographically distant populations and that sex-related differences are not significant.
|
NA
|
biorxiv
| 12 |
10.1101/2025.02.16.638517
|
TinkerHap - A Novel Read-Based Phasing Algorithm with Integrated Multi-Method Support for Enhanced Accuracy
|
Hartmann, U.; Shaham, E.; Nathan, D.; Blech, I.; Zeevi, D.
|
Uri Hartmann
|
Jerusalem Multidisciplinary College
|
2025-03-16
|
2
|
new results
|
cc_by
|
genomics
|
https://www.biorxiv.org/content/early/2025/03/16/2025.02.16.638517.source.xml
|
Phasing, the assignment of alleles to their respective parental chromosomes, is fundamental to studying genetic variation and identifying disease-causing variants. Traditional approaches, including statistical, pedigree-based, and read-based phasing, face challenges such as limited accuracy for rare variants, reliance on external reference panels, and constraints in regions with sparse genetic variation. To address these limitations, we developed TinkerHap, a novel and unique phasing algorithm that integrates a read-based phaser, based on a pairwise distance-based unsupervised classification, with external phased data, such as statistical or pedigree phasing. We evaluated TinkerHap's performance against other phasing algorithms using 1,040 parent-offspring trios from the UK Biobank (Illumina short-reads) and GIAB Ashkenazi trio (PacBio long-reads). TinkerHap's read-based phaser alone achieved higher phasing accuracies than all other algorithms with 95.1% for short-reads (second best: 94.8%) and 97.5% for long-reads (second best: 95.5%). Its hybrid approach further enhanced short-read performance to 96.3% accuracy and was able to phase 99.5% of all heterozygous sites. TinkerHap also extended haplotype block sizes to a median of 79,449 base-pairs for long-reads (second best: 68,303 bp) and demonstrated higher accuracy for both SNPs and indels. This combination of a robust read-based algorithm and hybrid strategy makes TinkerHap a uniquely powerful tool for genomic analyses.
|
NA
|
biorxiv
| 13 |
10.1101/2025.02.26.640189
|
Path2Omics: Enhanced transcriptomic and methylation prediction accuracy from tumor histopathology
|
Hoang, D.-T.; Shulman, E. D.; Dhruba, S. R.; Nair, N. U.; Barman, R. K.; Lalchungnunga, H.; Singh, O.; Nasrallah, M. P.; Stone, E. A.; Aldape, K.; Ruppin, E.
|
Eytan Ruppin
|
Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
|
2025-03-16
|
2
|
new results
|
cc0
|
bioinformatics
|
https://www.biorxiv.org/content/early/2025/03/16/2025.02.26.640189.source.xml
|
Precision oncology is becoming increasingly integral to clinical practice, demonstrating notable improvements in treatment outcomes. While molecular data provide comprehensive insights, obtaining such data remains costly and time-consuming. To address this challenge, we developed Path2Omics, a deep learning model that predicts gene expression and methylation from histopathology for 23 cancer types. Path2Omics was trained on 20,497 slides (9,456 formalin-fixed and paraffin-embedded (FFPE) and 11,041 fresh frozen (FF)) from 8,007 patients across 23 The Cancer Genome Atlas cohorts. When tested on FFPE slides, the most readily available format in clinical pathology practice, the integrated model outperformed its individual FF and FFPE components, robustly predicting nearly 5,000 genes on average, approximately five times more than our recently published DeepPT model. Externally evaluated on seven independent cohorts, Path2Omics robustly predicted the expression of approximately 4,400 genes, yielding a 30% increase over the FFPE model alone. Finally, we demonstrate that the inferred gene expression is nearly as effective as the actual values in predicting patient survival and treatment response. These results lay the basis for using Path2Omics to advance precision oncology from histopathology slides in a speedy and cost-effective manner.
|
NA
|
biorxiv
| 14 |
10.1101/2025.03.12.642906
|
Focal Infrared Neural Stimulation Propagates Dynamical Transformations in Auditory Cortex
|
Coventry, B. S.; Luu, C. P.; Bartlett, E. L.
|
Edward L Bartlett
|
Purdue University
|
2025-03-16
|
2
|
new results
|
cc_by_nc
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.12.642906.source.xml
|
Significance: Infrared neural stimulation (INS) has emerged as a potent neuromodulation technology, offering safe and focal stimulation with superior spatial recruitment profiles compared to conventional electrical methods. However, the neural dynamics induced by INS stimulation remain poorly understood. Elucidating these dynamics will help develop new INS stimulation paradigms and advance its clinical application. Aim: In this study, we assessed the local network dynamics of INS entrainment in the auditory thalamocortical circuit using the chronically implanted rat model; our approach focused on measuring INS energy-based local field potential (LFP) recruitment induced by focal thalamocortical stimulation. We further characterized linear and nonlinear oscillatory LFP activity in response to single-pulse and periodic INS and performed spectral decomposition to uncover specific LFP band entrainment to INS. Finally, we examined spike-field transformations across the thalamocortical synapse using spike-LFP coherence coupling. Results: We found that INS significantly increases LFP amplitude as a log-linear function of INS energy per pulse, primarily entraining to LFP {beta} and {gamma} bands with synchrony extending to 200 Hz in some cases. A subset of neurons demonstrated nonlinear, chaotic oscillations linked to information transfer across cortical circuits. Finally, we utilized spike-field coherences to correlate spike coupling to LFP frequency band activity and suggest an energy-dependent model of network activation resulting from INS stimulation. Conclusions: We show that INS reliably drives robust network activity and can potently modulate cortical field potentials across a wide range of frequencies in a stimulus parameter-dependent manner. Based on these results, we propose design principles for developing full coverage, all-optical thalamocortical auditory neuroprostheses.
|
NA
|
biorxiv
| 15 |
10.1101/2025.03.12.642768
|
Sub-second Fluctuation between Top-Down and Bottom-Up Modes Distinguishes Diverse Human Brain States
|
Park, Y.; Cha, Y.; Kim, H.; Kim, Y.; Woo, J. H.; Cho, H.; Mashour, G. A.; Xu, T.; Lee, U.; Hong, S.-J.; Honey, C.; Moon, J.-Y.
|
Joon-Young Moon
|
Sungkyunkwan University
|
2025-03-16
|
2
|
new results
|
cc_by_nc
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.12.642768.source.xml
|
Information continuously flows between regions of the human brain, exhibiting distinct patterns that dynamically shift across states of consciousness, cognitive modes, and neuropsychiatric conditions. In this study, we introduce Relative Phase Analysis (RPA), a method that leverages phase-lead/lag relationships to reveal the real-time dynamics of dominant directional patterns and their rapid transitions. We demonstrate that the human brain switches on a sub-second timescale between a top-down mode--where anterior regions drive posterior activity--and a bottom-up mode, characterized by reverse directionality. These dynamics are most pronounced during full consciousness and gradually become less distinct as awareness diminishes. Furthermore, we find from simultaneous EEG-fMRI recordings that the top-down mode is expressed when higher-order cognitive networks are more active while the bottom-up mode is expressed when sensory systems are more active. Moreover, comparisons of an attention deficit hyperactivity disorder (ADHD) inattentive cohort with typically developing individuals reveal distinct imbalances in these transition dynamics, highlighting the potential of RPA as a diagnostic biomarker. Complementing our empirical findings, a coupled-oscillator model of the structural brain network recapitulates these emergent patterns, suggesting that such directional modes and transitions may arise naturally from inter-regional neural interactions. Altogether, this study provides a framework for understanding whole-brain dynamics in real-time and identifies sub-second fluctuations in top-down versus bottom-up directionality as a fundamental mechanism underlying human information processing.
|
NA
|
biorxiv
| 16 |
10.1101/2025.03.11.642701
|
RNAhub - an automated pipeline to search and align RNA homologs with secondary structure assessment
|
Magnus, M.; Gao, W.; Dutta, N.; Vicens, Q.; Rivas, E.
|
Elena Rivas
|
Harvard University
|
2025-03-16
|
2
|
new results
|
cc_by
|
bioinformatics
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.11.642701.source.xml
|
The complexity in the generation of RNA multiple sequence alignments (MSAs) and assessment of the accuracy of such alignments contributes to the challenges in the utilization of RNA MSAs in diverse integrative methods. RNAhub is a freely available user-friendly web server for a reliable generation of RNA multiple sequence alignments and the detection of the presence of structural RNA utilizing evolutionary information. This web-based tool, developed by the integration of existing computational approaches, takes an RNA sequence as input and automatically retrieves and aligns sequences homologous to the input (query) RNA sequence through an iterative and structure-agnostic approach. Based on the alignment, this tool statistically assesses whether the query RNA sequence has a conserved RNA structure using covariation analysis. The web server allows the user to efficiently search the sequence of interest against carefully curated, ready-to-use genomic databases to produce a multiple sequence alignment. Using this alignment, our tool either detects the presence of a conserved structural RNA, finds evidence against the presence of a conserved structure, or cannot make any assessment due to a lack of sequence diversity in the alignment. The web server is freely available at https://rnahub.org.
|
NA
|
biorxiv
| 17 |
10.1101/2025.03.14.642691
|
Direct cell-to-cell transmission of retrotransposons
|
Voichek, M.; Bernhard, A.; Novatchkova, M.; Handler, D.; Möseneder, P.; Rafanel, B.; Duchek, P.; Senti, K.-A.; Brennecke, J.
|
Julius Brennecke
|
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC); Dr. Bohr-Gasse 3, 1030 Vienna, Austria
|
2025-03-16
|
2
|
new results
|
cc_by
|
genetics
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.642691.source.xml
|
Transposable elements are abundant in host genomes but are generally considered to be confined to the cell in which they are expressed, with the notable exception of endogenous retroviruses. Here, we identify a group of LTR retrotransposons that infect the germline from somatic cells within the Drosophila ovary, despite lacking the fusogenic Envelope protein typically required for retroviral entry. Instead, these elements encode a short transmembrane protein, sORF2, with structural features reminiscent of viral cell-cell fusogens. Through genetics, imaging, and electron microscopy, we show that sORF2 localizes to invasive somatic protrusions, enabling the direct transfer of retrotransposon capsids into the oocyte. Remarkably, sORF2-like proteins are widespread among insect retrotransposons and also occur in piscine nackednaviruses and avian picornaviruses. These findings reveal a noncanonical, Envelope-independent transmission mechanism shared by retrotransposons and non-enveloped viruses, offering important insights into host-pathogen evolution and soma-germline interactions.
|
NA
|
biorxiv
| 18 |
10.1101/2025.03.15.643458
|
Relative strength variability measures for brain structural connectomes and their relationship with cognitive functioning
|
Yeung, H. W.; Buchanan, C. R.; Moodie, J. E.; Deary, I.; Tucker-Drob, E. M.; Bastin, M. E.; Whalley, H. C.; Smith, K. M.; Cox, S. R.
|
Hon Wah Yeung
|
University of Edinburgh
|
2025-03-16
|
1
|
new results
|
cc_by
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.15.643458.source.xml
|
In this work, we propose a new class of graph measures for weighted connectivity information in the human brain based on node relative strengths: relative strength variability (RSV), measuring susceptibility to targeted attacks, and hierarchical RSV (hRSV), a first weighted statistical complexity measure for networks. Using six different network weights for structural connectomes from the UK Biobank, we conduct comprehensive analyses to explore relationships between the RSV and hRSV, and (i) other known network measures, (ii) general cognitive function ('g'). Both measures exhibit low correlations with other graph measures across all connectivity weightings indicating that they capture new information of the brain connectome. We found higher g was associated with lower RSV and lower hRSV. That is, higher g was associated with higher resistance to targeted attack and lower statistical complexity. Moreover, the proposed measures had consistently stronger associations with g than other widely used graph measures including clustering coefficient and global efficiency and were incrementally significant for predicting g above other measures for five of the six network weights. Overall, we present a new class of weighted network measures based on variations of relative node strengths which significantly improved prediction of general cognition from traditional weighted structural connectomes.
|
NA
|
biorxiv
| 19 |
10.1101/2025.03.15.643456
|
A hippocampal population code for rapid generalization
|
Tang, W.; Chang, H.; Liu, C.; Perez-Hernandez, S.; Zheng, W. Y.; Park, J.; Oliva, A.; Fernandez-Ruiz, A.
|
Antonio Fernandez-Ruiz
|
Department of Neurobiology and Behavior, Cornell University, Ithaca, NY, USA.
|
2025-03-16
|
1
|
new results
|
cc_no
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.15.643456.source.xml
|
Generalizing from experience and applying prior knowledge to new situations is essential for intelligent behavior. Traditional models attribute this generalization to gradual statistical learning in the neocortex. However, such a slow process cannot account for animals' rapid generalization from limited experience. Here, we demonstrate that the hippocampus supports rapid generalization in mice by generating disentangled memory representations, where different aspects of experience are encoded independently. This code enabled the transfer of prior knowledge to solve new tasks. We identify specific circuit mechanisms underlying this rapid generalization. We show that the seemingly random changes in individual neuronal activity over time and across environments result from structured circuit-level processes, governed by the dynamics of local inhibition and cross-regional cell assemblies, respectively. Our findings provide computational and mechanistic insights into how the geometric structure and underlying circuit organization of hippocampal population dynamics facilitate both memory discrimination and generalization, enabling efficient and flexible learning.
|
NA
|
biorxiv
| 20 |
10.1101/2025.03.14.643248
|
The evolution of gene regulation in mammalian cerebellum development
|
Sarropoulos, I.; Sepp, M.; Yamada, T.; Schaefer, P. S. L.; Trost, N.; Schmidt, J.; Schneider, C.; Drummer, C.; Missbach, S.; Taskiran, I. I.; Hecker, N.; Bravo Gonzalez-Blas, C.; Kempynck, N.; Froemel, R.; Joshi, P.; Leushkin, E.; Arnskoetter, F.; Leiss, K.; Okonechnikov, K.; Lisgo, S.; Palkovits, M.; Paabo, S.; Cardoso-Moreira, M.; Kutscher, L. M.; Behr, R.; Pfister, S. M.; Aerts, S.; Kaessmann, H.
|
Henrik Kaessmann
|
Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany
|
2025-03-16
|
1
|
new results
|
cc_by_nc
|
evolutionary biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643248.source.xml
|
Gene regulatory changes are considered major drivers of evolutionary innovations, including the cerebellum's expansion during human evolution, yet they remain largely unexplored. In this study, we combined single-nucleus measurements of gene expression and chromatin accessibility from six mammals (human, bonobo, macaque, marmoset, mouse, and opossum) to uncover conserved and diverged regulatory networks in cerebellum development. We identified core regulators of cell identity and developed sequence-based models that revealed conserved regulatory codes. By predicting chromatin accessibility across 240 mammalian species, we reconstructed the evolutionary histories of human cis-regulatory elements, identifying sets associated with positive selection and gene expression changes, including the recent gain of THRB expression in cerebellar progenitor cells. Collectively, our work reveals the shared and mammalian lineage-specific regulatory programs governing cerebellum development.
|
NA
|
biorxiv
| 21 |
10.1101/2025.03.14.643395
|
Genetic diversity and regulatory features of human-specific NOTCH2NL duplications
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Real, T. D.; Hebbar, P.; Yoo, D.; Antonacci, F.; Pacar, I.; Diekhans, M.; Mikol, G. J.; Popoola, O. G.; Mallory, B.; Vollger, M. R.; Dishuck, P. C.; Guitart, X.; Rozanski, A. N.; Munson, K. M.; Hoekzema, K.; Ranchalis, J. E.; Neph, S. J.; Sedeno-Cortes, A. E.; Paten, B.; Salama, S.; Stergachis, A.; Eichler, E. E.
|
Evan E Eichler
|
Univ. of Washington
|
2025-03-16
|
1
|
new results
|
cc_by
|
genomics
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643395.source.xml
|
NOTCH2NL (NOTCH2-N-terminus-like) genes arose from incomplete, recent chromosome 1 segmental duplications implicated in human brain cortical expansion. Genetic characterization of these loci and their regulation is complicated by the fact they are embedded in large, nearly identical duplications that predispose to recurrent microdeletion syndromes. Using nearly complete long-read assemblies generated from 67 human and 12 ape haploid genomes, we show independent recurrent duplication among apes with functional copies emerging in humans ~2.1 million years ago. We distinguish NOTCH2NL paralogs present in every human haplotype (NOTCH2NLA) from copy number variable ones. We also characterize large-scale structural variation, including gene conversion, for 28% of haplotypes leading to a previously undescribed paralog, NOTCH2tv. Finally, we apply Fiber-seq and long-read transcript sequencing to human cortical neurospheres to characterize the regulatory landscape and find that the most fixed paralogs, NOTCH2 and NOTCH2NLA, harbor the greatest number of paralog-specific elements potentially driving their regulation.
|
NA
|
biorxiv
| 22 |
10.1101/2025.03.14.643159
|
Ultra-fast and highly sensitive protein structure alignment with segment-level representations and block-sparse optimization
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Litfin, T.; Zhou, Y.; von Itzstein, M.
|
Thomas Litfin
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Institute for Biomedicine and Glycomics, Griffith University
|
2025-03-16
|
1
|
new results
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cc_by
|
bioinformatics
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643159.source.xml
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Deep learning models for protein structure prediction have given rise to extreme growth in 3D structure data. As a result, traditional methods for geometric structure alignment are too slow to effectively search modern structure libraries. In this study we introduce SPfast - a fully geometric method for structure-based alignment which accelerates search by more than 2 orders of magnitude while increasing sensitivity by 21% and 5% compared with foldseek and TMalign respectively. Using the significant speed of SPfast to conduct more than 100B pairwise comparisons between bona fide uncharacterized proteins and a large-scale, annotated structure library uncovers new biological insights relating to type III secretion in pathogenic bacteria and identifies novel toxin-antitoxin systems. Putative SPfast-based functional assignments are supported by orthogonal evidence including shared genomic context and high-confidence AlphaFold3 complex modelling.
|
NA
|
biorxiv
| 23 |
10.1101/2025.03.14.643196
|
Target deletion or holding on sections after enzyme digestion monitored with attenuation-of-sound images
|
Miura, K.; Iwashita, T.
|
Katsutoshi Miura
|
Hamamatsu Ika Daigaku
|
2025-03-16
|
1
|
new results
|
cc_by
|
pathology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643196.source.xml
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Tissues consist of various components and if these can be deleted or reserved, their location and proportion can be detected. Scanning acoustic microscopy (SAM) calculates the attenuation of sound (AOS) through tissue sections to obtain histological images without staining. AOS values are reduced as tissue components break down. Here, we digested specific components in tissues using enzymes and followed the process with AOS imaging over time. In addition, we applied specific dyes and antibodies to inhibit enzyme activity and maintain a specific component in the section. We used specific enzymes to degrade tissues that contain the enzymes substrate, such as collagenase for bone, elastase for skin and arteries, actinase for amyloid-positive cervical arteries and lymph nodes, amylase for the corpora amylacea (CA) of the brain and DNase and haematoxylin for adenocarcinomas. Collagenase digested bone and cartilage to clearly visualise the internal structure. The structural components had characteristic AOS values, which gradually decreased. Elastases break elastic fibres in the skin and arteries differently between young and old individuals. The dermis and tunica media of arteries in the elderly fracture more easily than those of younger individuals. Actinase digested the cervical artery except for amyloid deposits, which were preferentially detected by Congo red staining. Actinase-digested lymphoid cells remained horseradish peroxidase (HRP)-staining positive. Amylase digested some CAs, which became periodic acid-Schiff (PAS) staining negative and diminished in size by electron microscopy observation. Cell nuclei were digested and deleted by DNase except for those stained with HRP. Residual nuclear images of AOS matched those of light microscopy, and haematoxylin staining inhibited DNase digestion of the nucleus. Specific inhibition of enzymes preserved the target cells and materials. SAM observation can monitor the tissue breakdown process, which provides an advantage over light microscopy as no staining is required and exhibits higher sensitivity to detect fragile structures.
|
NA
|
biorxiv
| 24 |
10.1101/2025.03.14.643197
|
Impact of exercise intervention on IGF-1 signaling related to muscle regeneration and physical performance in aged mice
|
Kim, T.; Cho, J.; Kim, Y.; Kim, J.; Woo, S. W.; Kim, D.
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Donghyun Kim
|
Hanbat National University
|
2025-03-16
|
1
|
confirmatory results
|
cc_by
|
physiology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643197.source.xml
|
Aging encompasses the natural processes of birth, growth, and aging, during which the functional ability of muscles gradually decreases, leading to the loss of muscle size and reduced exercise performance known as sarcopenia. This condition is closely associated with weakness, osteoporosis, and degenerative diseases, increasing the risk of falls, fractures, metabolic diseases, and mortality due to limitations in physical performance among the elderly. This study investigated the effects of exercise intervention on biological markers related to skeletal muscle mass and functions in conjunction with aging. At age of four or twenty, the C57BL/6 mice were assigned to Young control (Y-Con, n = 10) or exercise training (Y--Exe, n = 10), and Aged control (A-Con, n=10) or exercise training (A-Exe, n = 10). Exercise intervention was performed on a rodent motor-driven treadmill with a frequency of 5 days per week for 8 weeks. As a consequence, exercise intervention in mice resulted in positive changes in IGF-1 signaling and muscle phenotype compared to mice that did not undergo exercise intervention, specifically showing prominent effects in the A-Exe group compared to the A-Con group. The mitigating effects of exercise intervention on age-related skeletal muscle dysfunction were accompanied by enhanced exercise performance and muscle function, as assessed by grip strength and the rotarod test. The current findings support previous studies that have reported the positive effect of exercise intervention in alleviating age-related declines in exercise performance and muscle function in older adults.
|
NA
|
biorxiv
| 25 |
10.1101/2025.03.14.643200
|
Wnt and Fgf signaling pharmacological inhibition affect posterior growth during Tribolium castaneum germband elongation
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Mundaca-Escobar, M.; Pardo, R. V.; Cepeda, R. E.; Sarrazin, A. F.
|
Andres F. Sarrazin
|
Pontificia Universidad Catolica de Valparaiso
|
2025-03-16
|
1
|
new results
|
cc_by
|
developmental biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643200.source.xml
|
Axial elongation and sequential segmentation are developmental processes that occur simultaneously and are highly conserved in vertebrates and most arthropods. These features rely on the dynamic expression of a genetic network that establishes the segmented patterning and regulates various cellular behaviors, including tissue rearrangements and cell divisions. In vertebrates, Wnt and Fgf signaling are essential for these processes. While some studies in arthropods have linked these pathways to segmentation, there is still much to discuss regarding their regulatory role in cellular processes. In this study, we pharmacologically inhibited Wnt and Fgf signaling pathways by exposing developing Tribolium castaneum embryos to IWP-3 and SU5402, respectively. We observed that both treatments resulted in a shortening of the embryos and a decrease in the number of cell divisions during a period characterized by high proliferation rates. Although the segmented patterning was not disrupted, the segments were smaller in the embryos treated with the Fgf inhibitor than in the controls. Additionally, time-lapse imaging revealed that cell movement along the anteroposterior axis was affected in the IWP-3-treated embryos. In contrast, Fgf inhibition primarily altered the direction of cell movements at the posterior end of the embryo. Our findings provide insight into the roles of Wnt and Fgf signaling pathways in regulating significant cellular behaviors during the posterior growth of Tribolium and possibly other arthropods.
|
NA
|
biorxiv
| 26 |
10.1101/2025.03.14.643209
|
Tree ring segmentation performance in highly disturbed trees using deep learning
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Zambrano-Suarez, J. D.; Perez-Martin, J.; Manchado, A. M.-T.; Ballesteros Canovas, J. A.
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Joe David Zambrano-Suárez
|
National Museum of Natural Sciences
|
2025-03-16
|
1
|
new results
|
cc_by
|
ecology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643209.source.xml
|
Dendrogeomorphology has provided valuable insights for dating geomorphic events, but requires the challenging analyses of tree-ring records from highly disturbed trees. Deep learning algorithms have been successfully used to detect ring boundaries under normal tree growth conditions. Here, we test if deep learning can perform tree ring segmentation in highly abnormal growth patterns. To this end, this study explores the relation between the complexity of convolutional neural networks (CNN)-based architectures, cellular detail levels, and the capacity to segment ring borders in abnormal tissues. Increment cores were collected from a debris flow-affected area in the Pyrenees, while images were acquired using a digital camera with a high-resolution macro. We defined four sets of experiments, including varying image resolution through downsampling, applying different architectures, and using image filters. Moreover, we test if the inclusion of the growth direction into a patchify-based system applied to increment cores improves the performance of the system. Our results suggest that intelligent systems can recognize tree-rings boundaries, but their performance was lower with high abnormal growth patterns due to the significant differences in colors and textures from normal growth patterns. However, the proposed segmentation system was able to segment sets of narrow ring borders, spaced above 200 m, where the color remained unchanged. Interestingly, our results suggest that the model ignored cellular details and relied on color gradients to detect ring borders when analyzing at the macro level. This implies that the image resolution is only becoming critical for densely packed rings with minimal spacing. Finally, we observed that CNN-based segmentation systems were unable to infer growth direction based solely on tree ring convexity and cellular details within an increment core patch. Our results provide new insights into how deep learning could be used in tree-ring research, but they still reveal the existing challenges with disturbed trees.
|
NA
|
biorxiv
| 27 |
10.1101/2025.03.14.643068
|
New methods on the block: Taxonomic identification of archaeological bones in resin-embedded sediments through palaeoproteomics
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Fagernäs, Z.; Troche, G.; Goldberg, P.; Hublin, J.-J.; McPherron, S. P.; Murphree, W. C.; Olsen, J. V.; Sandgathe, D.; Sirakov, N.; Soressi, M.; Tsanova, T.; Turq, A.; Wierer, M.; Welker, F.; Aldeias, V.
|
Vera Aldeias
|
ICArEHB - Interdisciplinary Center for Archaeology and the Evolution of Human Behaviour, Universidade do Algarve, 8005-139 Faro, Portugal
|
2025-03-16
|
1
|
new results
|
cc_by_nc_nd
|
evolutionary biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643068.source.xml
|
The integration of biomolecular studies of past organisms with geoarchaeological studies can significantly improve our understanding of the relative chronology and context of archaeologically (in)visible behaviours. However, the complexity and sedimentological heterogeneity of archaeological deposits at a microscopic scale is often not taken into consideration in biomolecular studies. Here, we investigate the preservation and retrieval of palaeoproteomic data from bone fragments embedded in Pleistocene resin-impregnated sediment blocks. We show that resin impregnation has minimal effect on skeletal protein taxonomic identifications in modern skeletal material, but observe an increase in oxidation-related post-translational modifications. We then successfully retrieve proteins from resin-impregnated blocks from the Palaeolithic sites of Bacho Kiro Cave, La Ferrassie and Quincay. The taxonomic identifications of minute bones encased in resin are in line with previous analyses of the faunal communities of these sites, with a diversity of taxa (Bos sp./Bison sp., Equus sp., Ursus sp., and Caprinae) observed at a microscale in Bacho Kiro. This differs from results from La Ferrassie where most of the samples are identified as a single taxon (Bos sp./Bison sp.) across different areas of the site. The block from Quincay only provided taxonomic identification of two out of eleven bone-derived samples, likely due to diagenesis. Our work indicates that palaeoproteomes can be retrieved from bone fragments at a microstratigraphic resolution, enabling the detailed study of faunal community composition at a scale that more closely matches that of past human occupations.
|
NA
|
biorxiv
| 28 |
10.1101/2025.03.14.643399
|
A targeted LC MS/MS assay of a health surveillance panel and its application to chronic kidney disease
|
Fu, Q.; Johnson, C. C.; Inker, L. A.; Van Eyk, J. E.
|
Jennifer E. Van Eyk
|
Cedars-Sinai Medical Center
|
2025-03-16
|
1
|
new results
|
cc_by
|
biochemistry
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643399.source.xml
|
Robust and reproducible assays capable of specific and quantitative monitoring of multiple biologically important proteins amongst the thousands of human plasma proteins can potentially be used to distinguish health versus disease. In this study, we established an LC-MS assay to monitor a Health Surveillance Panel (HSP) comprising 60 circulating plasma proteins selected based on their broad biological functions and assay performance. Plasma samples were prepared for proteomic analysis in an automated process. A scheduled LC-MRM assay with a 30-minute 5% - 35% acetonitrile gradient and 50.5 minutes of total run time was used to quantify the 60 endogenous proteins by monitoring 364 transitions from 117 proteotypic peptides along with their stable isotopic labeled standard peptides in a single assay. For each proteotypic peptide, we selected a quantifier ion and at least two qualifier ions. The quantifier ions have a linear response over a 100-fold range, and the peak area ratios of the three peptide ions were consistent. As proof of concept, we evaluated the performance of our HSP assay in a case-control study of progressive chronic kidney disease (CKD). Reduced plasma concentrations of alpha-2-antiplasmin, antithrombin-III, and immunoglobulin heavy constant alpha 1 correlated with CKD indicated by reduced GFR with p values < 0.05. These results demonstrate that the HSP proteins can be accurately and reproducibly quantified with a high-quality multiplexed MRM assay and the HSP assay can detect disease-associated differences.
|
NA
|
biorxiv
| 29 |
10.1101/2025.03.16.643503
|
Analyzing Neural Response to Visual Stimuli: Firing Rates, Frequency Band Dynamics, and Synchrony in Near and Far Flanker Conditions
|
Kunwar, M.
|
Manjeet Kunwar
|
Central Department of Physics, TU
|
2025-03-16
|
1
|
confirmatory results
|
cc_by_nc_nd
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643503.source.xml
|
This study examines neural responses to visual stimuli under Near and Far flanker conditions using EEG. Fifty participants (25 per condition) completed a visual task with closely or distantly positioned distractors. EEG data were analyzed using spectrograms, wavelet transformation, and neural firing rate estimation. Standard preprocessing techniques ensured data quality and statistical tests assessed differences between conditions. Findings provide insight into how spatial stimulus configurations affect neural processing and attention.
|
NA
|
biorxiv
| 30 |
10.1101/2025.03.16.643530
|
Two-Phase Coding Strategy by CA1 Pyramidal Neurons: Linking Spatiotemporal Integration to Predictive Behavior
|
Heldman, R.; Pang, D.; Porter, C.; Zhao, X.; Roxin, A.; Wang, Y.
|
Yingxue Wang
|
Max Planck Florida Institute for Neuroscience
|
2025-03-16
|
1
|
new results
|
cc_no
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643530.source.xml
|
Space and time are fundamental components of memory, yet how the brain encodes these dimensions to guide behavior remains unclear. Using virtual-reality environments, we uncovered a two-phase neural code in hippocampus CA1 that represents time or distance through two functional pyramidal subpopulations, PyrUp and PyrDown. In Phase I, PyrUp activity synchronously increases to mark the initiation of encoding; In Phase II, their activity decays at heterogeneous, neuron-specific rates, creating a gradual divergence in across-population firing rates that scales with elapsed time. Conversely, PyrDown activity initially decreases before gradually rising. The crossover point, where rising PyrDown activity surpasses declining PyrUp activity, precedes predictive licking behavior. Combining optogenetics and computational modeling, we provided circuit-level evidence that PyrUp neurons primarily process locomotion-related inputs regulated by somatostatin-positive interneurons, whereas PyrDown neurons mainly receive reward-related inputs gated by parvalbumin-positive interneurons. These findings advance our understanding of how hippocampal circuits compute spatiotemporal information to inform behavior.
|
NA
|
biorxiv
| 31 |
10.1101/2025.03.16.643460
|
Experimental change in personality: Overexpression of GDNF in the rat striatum converts the low exploratory phenotype into highly explorative
|
Harro, J.; O'Leary, A.; Norden, M.; Liiver, K.; Kanarik, M.; Garcia-Horsman, A.; Sakson, S.; Kupper, P.; Laugus, K.; Korulu, S.; Teino, I.; Org, T.; Parkkinen, I.; Kaart, T.; Lindholm, P.; Imbeault, S.; Poska, H.; Harvey, B. K.; Airavaara, M. T.; Shimmo, R.; Saarma, M.
|
Jaanus Harro
|
University of Tartu
|
2025-03-16
|
1
|
new results
|
cc_no
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643460.source.xml
|
Major vulnerability factors for psychiatric disorders such as depression, that often prevent complete remission and lead to relapses, are temperamental. In a rat model of clustered persistent high anxiety/low motivation, we have found that overexpression of glial-cell-line-derived neurotrophic factor (GDNF) by intra-striatally administered adeno-associated virus vector strikingly converts the passive coping style of low exploratory rats into an active one, similar to high exploratory rats. This conversion of behavioural strategy developed gradually over repeated testing, and was associated with increased catecholamine metabolism in several brain regions and changes in the regulation of serotonin neurotransmission. An increase in in vivo dopamine transporter availability in the striatum was necessary for the phenotype conversion. Associated changes in striatal gene expression included key players in monoamine storage and epitranscriptomic regulation. The increase in GDNF signalling also caused alterations in levels and regional covariation of oxidative metabolism, indicative of persistent reorganization of neural activity throughout the brain. Thus, neurotrophic factors, GDNF in particular, may play a pivotal role in the development, persistence and alteration of personality traits, and therefore constitute a potential target for treatment of chronic, relapsing psychiatric disorders.
|
NA
|
biorxiv
| 32 |
10.1101/2025.03.14.643338
|
The major role of the REL2/NF-κB pathway in the regulation of midgut bacterial homeostasis in the malaria vector Anopheles gambiae
|
Zakovic, S.; Rivera, G. E.; Gomaid, R.; Graham Martinez, C.; Kappler, C.; Marois, E.; Levashina, E. A.
|
Elena A Levashina
|
MPIIB
|
2025-03-16
|
1
|
new results
|
cc_by_nc_nd
|
immunology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643338.source.xml
|
Multicellular organisms harbor diverse microbial communities that play essential roles in host physiology. While often beneficial, these interactions require tight regulation to prevent dysbiosis and disease. This study examines the tissue-specific immune responses of mosquitoes to blood feeding and Plasmodium falciparum infection in Anopheles females. We demonstrate that REL2 signaling regulates antimicrobial peptide (AMP) expression and shapes midgut bacterial composition post-blood meal. Loss of REL2 leads to midgut dysbiosis, characterized by the overgrowth of Serratia spp., and mosquito lethality within a day of feeding. Interestingly, Serratia-induced dysbiosis also reduces P. falciparum prevalence in surviving mosquitoes. Our findings highlight the critical role of immune system in maintaining midgut bacterial homeostasis and uncover complex interactions between mosquito immunity, gut microbiota, and malaria parasites.
|
NA
|
biorxiv
| 33 |
10.1101/2025.03.14.643082
|
NOD1 ligand FK565 promotes atherogenesis and accumulation of NOD1high smooth muscle cells in atherosclerotic lesions
|
Zhang, X.-Y.; Jiang, X.-T.; Gistera, A.; Ding, Y.; Basbous, L.; Olofsson, P.; Religa, P.; Hansson, G. K.; Yan, Z.-Q.; E Johansson, M.
|
Maria E Johansson
|
University of Gothenburg
|
2025-03-16
|
1
|
new results
|
cc_no
|
immunology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643082.source.xml
|
Aims Nucleotide-binding oligomerization domain-containing protein (NOD)1 is an intracellular pattern recognition receptor that initiates immune responses upon ligation of molecules such as bacterial peptidoglycan containing a D-glutamyl-meso-diaminopimelic acid (iE-DAP) moiety. NOD1 ligation has been shown to promote vascular inflammation and atherosclerosis. In this study, we investigate the functional role of NOD1 in atherosclerotic plaques and characterize the vascular cells responsible for NOD1 expression and function. Methods and results NOD1 was mainly expressed in a subtype of vascular smooth muscle cells (SMC) in human atherosclerotic lesions. In ex vivo cultures, human endarterectomy specimens reacted to NOD1 ligand by activation of mitogen-activated protein kinase (MAPK) pathways, leading to cytokine expression. Levels of NOD1 mRNA were higher in carotid endarterectomy specimens obtained from symptomatic patients compared to asymptomatic ones. NOD1high SMC were also found in arteries of atherosclerosis-prone Ldlr-/- mice. Challenging these mice with a NOD1 agonist resulted in transmural vascular inflammation, severe arterial damage, accelerated atherogenesis throughout the aorta, and evidence of occlusive coronary artery disease. In rats, mechanic injury to carotid arteries promoted NOD1high SMC expansion and neointima formation. In vitro, neointima derived NOD1high SMCs responded to NOD1 ligand exposure by enhanced migration, increased iNOS+ cells and amplified CCL5 production. Conclusion Our findings show that NOD1 promotes vascular inflammation, vascular injury responses and atherosclerosis by acting on a NOD1high subtype of SMC.
|
NA
|
biorxiv
| 34 |
10.1101/2025.03.16.643511
|
Heparanase attenuates Zika virus infection by destabilizing the viral envelope protein
|
Ling, J.; Morente, S. F.; Lundkvist, A.; Li, J.
|
Jinlin Li
|
Uppsala University
|
2025-03-16
|
1
|
new results
|
cc_by
|
microbiology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643511.source.xml
|
Heparanase (Hpa) is the only endoglycosidase enzyme in mammalian cells capable of cleaving heparan sulfate. In addition to its well-known functions in the regulation of glycosaminoglycans integrity, accumulating evidence indicates that Hpa plays vital roles in viral infection, while the mechanisms are not yet fully understood, especially in RNA virus infection. In this study, we report that Hpa functions as a restriction factor for Zika virus (ZIKV) infection. Our results demonstrated that Hpa, but not the enzymatic inactive mutant (Hpa-DM), resulted in degradation of the ZIKV envelope (E) protein, which could be rescued by treatment of the proteasome inhibitor (MG132) and the autophagy inhibitor (NH4Cl), separately. Additionally, the ubiquitination of ZIKV E did not show an significant change in the presence of Hpa. Overexpression of Hpa, but not Hpa-DM, dramatically decreased ZIKV infection in different cell models, evidenced by the reduction of viral proteins and a compromised production of infectious virions. This was further confirmed by the results in MEF cells, in which knockout Hpa enhanced ZIKV infection, while overexpression of Hpa suppressed the production of virions. In addition, ZIKV was found to downregulate the Hpa expression, which could counteract the inhibitory effects of Hpa. Altogether, our study discovers an unrecognized role of Hpa in virus infection and demonstrates that Hpa serves as a restriction factor for ZIKV infection.
|
NA
|
biorxiv
| 35 |
10.1101/2025.03.16.643505
|
Determining the core bacterial and fungal genera in table olive fermentations.
|
Ricciardi, A.; Lopez, F. N. A.; Giavalisco, M.; Pietrafesa, R.; Parente, E.
|
Eugenio Parente
|
University of Basilicata
|
2025-03-16
|
1
|
confirmatory results
|
cc_by_nc_nd
|
microbiology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643505.source.xml
|
Table olives are among the most ancient and important fermented foods of the Mediterranean basin. Their production is still strongly related to traditional practices, and the lack of thermal treatments, the reliance on natural contamination and on selective factors (NaCl, anaerobiosis, occurrence of food phenolics, etc.) determine the dynamics of the microbial community. Lactic acid bacteria (LAB) and yeasts have a pivotal role in table olive microbial communities, but several halophilic and alkalophilic microorganisms may also contribute, positively or negatively, to the quality. We have use metataxonomic data extracted from the FoodMicrobionet database to provide quantitative insights on the structure of bacterial and fungal microbial communities of table olvies and to identify core genera in different trade preparations. A set of bacterial genera may be representative of the dominating core microbiota in table olives, with Celerinatantimonas and Lactiplantibacillus as the most prevalent genera, followed by several LAB, halophilic and alkalophilic lactic acid bacteria (HALAB) and Gram negatives, including non-halophilic species. Similarly, 3 fungal genera (Pichia, Candida and Wickerhamomyces) were the most abundant and prevalent among those representing the core microbiota of table olives. The distribution of both bacteria and yeasts varied significantly in different olive varieties, among olives, brines and contact surfaces or materials, and at different production stages, and no clear grouping related to the combination of ripeness and trade preparation was found, although HALAB were characteristically abundant in Spanish style green olives. Addition of starter cultures affected the composition and dynamics of microbial communities to a variable extent.
|
NA
|
biorxiv
| 36 |
10.1101/2025.03.16.643526
|
Degradation of rutin and genistein and the effect on human bacterial fecal populations of obese and non-obese
|
Jensen-Kroll, J.; Demetrowitsch, T.; Sprotte, S.; Brix, F.; Beckmann, A.; Schlicht, K.; Brinks, E.; Laudes, M.; Waschina, S.; Franz, C. M. A. P.; Schwarz, K.
|
Karin Schwarz
|
Christian-Albrechts-University Kiel
|
2025-03-16
|
1
|
new results
|
cc_by
|
microbiology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643526.source.xml
|
This study re-evaluates the microbial degradation of rutin and genistein, emphasizing health-related metabotypes and novel degradation and transformation products of these compounds. In silico predictions and calculations were made to determine the molecular formulae of metabolites derived from precursor molecules by methylation, sulfation, and dehydroxylation. To validate these, anaerobic, ex vivo experiments were conducted with pooled fecal samples of obese and non-obese test persons (n=7 per group) over 48 hours, followed by 16S rRNA gene sequencing and semi-targeted high-resolution mass spectrometry analysis. We identified 46 rutin and 23 genistein metabolites, including novel methylated and sulfated derivatives. Microbial analysis revealed that the plant compounds influenced 34 bacterial families and 83 genera. Rutin inhibited obesity-associated genera while promoting butyrate-producing bacteria in BMI >40 samples, but reduced health-associated bifidobacteria and increased enterobacteria. Both compounds stimulated Eggerthella. These findings highlight significant microbial and metabolic shifts induced by plant-derived compounds, suggesting potential health implications.
|
NA
|
biorxiv
| 37 |
10.1101/2025.03.16.643443
|
The Chlamydia trachomatis secreted effector protein CT181 binds to Mcl-1 to prolong neutrophil survival
|
Faris, R.; Koch, R.; McCaslin, P.; Challagundla, N.; Steiert, B.; Andersen, S.; Smith, P.; Jabeena, C. A.; Yau, P.; Rudel, T.; Weber, M. M.
|
Mary M Weber
|
University of Iowa Carver College of Medicine
|
2025-03-16
|
1
|
new results
|
cc_by_nc
|
microbiology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643443.source.xml
|
Chlamydia trachomatis (C.t) infections can lead to severe complications due to the pathogens ability to evade the host immune response, often resulting in asymptomatic infections. The mechanisms underlying this immune subversion remain incompletely understood but likely involve specific bacterial effector proteins. Here, we identify CT181 as a novel effector that directly binds to Mcl-1, a key regulator of neutrophil survival. While a C.t. CT181 mutant exhibited only modest defects in epithelial cell replication and inclusion development, it was essential for C.t. survival in neutrophils, correlating with Mcl-1 stabilization. Using a murine infection model, we demonstrate that CT181 is required for C.t. colonization and cytokine production in vivo. Our findings establish CT181 as the first bacterial effector protein known to bind Mcl-1 to enhance neutrophil survival, revealing a critical strategy by which C.t. promotes immune dysregulation, facilitating bacterial persistence while driving C.t. pathogenesis.
|
NA
|
biorxiv
| 38 |
10.1101/2025.03.15.643426
|
SYNCAS-Mediated CRISPR-Cas9 Genome Editing in the Jewel Wasp, Nasonia vitripennis
|
Guerra, F.; De Rouck, S.; Verhulst, E. C.
|
Filippo Guerra
|
Wageningen University
|
2025-03-16
|
1
|
new results
|
cc_by_nc_nd
|
molecular biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.15.643426.source.xml
|
Genetic engineering is a formidable approach to study biology. The development of CRISPR-Cas9 has allowed the genetic engineering of insect species from several orders, and in some species, this tool is used routinely for genetic research. However, insect gene editing often relies on the delivery of CRISPR-Cas9 components via embryo injection. This technique has a limitation: some species lay their eggs inside hard substrates or living hosts, making embryo collection impossible or labour-intensive. Recently, a variety of techniques that exploit maternal injection of nucleases have been developed to circumvent embryo injection. Yet, despite this variety of maternal delivery techniques, some insects remain refractory to gene editing. One of these is the parasitoid wasp, Nasonia vitripennis, an important hymenopteran model species. In this study, a recently developed method termed SYNCAS was used to perform knock-out (KO) of the cinnabar gene in this wasp, obtaining KO efficiencies up to ten times higher than reported for other maternal injection approaches. We found up to 2.73% of all offspring to display a KO phenotype, and we obtained up to 68 KO offspring per 100 injected mothers. The optimal timing of injection and provision of hosts for egg laying was determined. With this protocol, routine applications of CRISPR-Cas9 become feasible in this species, allowing reverse genetics studies of genes with unknown associated phenotypes and paving the way for more advanced editing techniques.
|
NA
|
biorxiv
| 39 |
10.1101/2025.03.15.643383
|
Ferlin C2A-C2B linkers are alternatively spliced, intrinsically disordered, and interact with negatively charged membranes
|
Kwok, E.; Khuu, P.; Reardon, P. N. P.; Vanegas, J.; Johnson, C. P.
|
Colin P Johnson
|
Oregon State University
|
2025-03-16
|
1
|
new results
|
cc_by_nc_nd
|
molecular biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.15.643383.source.xml
|
Ferlins are vesicle trafficking proteins composed of folded C2 domains conjugated by linkers which are largely disordered. Although a role for the for the C2 domains as calcium sensors has been established it remains unclear whether the linkers function beyond acting as passive spacers. We examined the C2A-C2B linker of vertebrate ferlins and found both putative AP2 and SH3 binding short linear motifs (SLiMs) as well as membrane binding sequences for members of the protein family. Specifically for otoferlin we identified an arginine-rich region proximal to a AP2 binding dileucine motif which interacts with negatively charged lipid membranes. Further, the linker region dominated the liposome binding properties of a larger C2A-C2B two-C2 domain segment of otoferlin, suggesting a dominant role in mediating the membrane binding property of the N-terminus. We also found that alternative splicing of the otoferlin C2A-C2B linker adds and additional membrane binding segment and alters the affinity and kinetics of membrane binding. By contrast alternative splicing of the dysferlin linker is not predicted to alter membrane binding but rather alters the number of predicted short linear motifs (SLiMs). In addition we found the otoferlin linker-membrane interaction was sensitive to ionic strength, and simulations suggest positively charged residues including an arginine-rich region mediates binding. We conclude that the C2A-C2B linker of vertebrate ferlins encode both SLiMs which recruit endocytic proteins as well as membrane binding regions that would place the endocytic binding motif proximal to the membrane surface to facilitate endocytosis and synaptic vesicle resupply.
|
NA
|
biorxiv
| 40 |
10.1101/2025.03.15.643469
|
Non-coding RNA Repertoire in Reef-Building Corals
|
Ashey, J.; Rodriquez-Casariego, J. A.; Durkin, K. M.; Bengtsson, Z.; Huffmyer, A. S.; White, S. J.; Becker, D. M.; Eirin-Lopez, J. M.; Putnam, H. M.; Roberts, S.
|
Jill Ashey
|
University of Rhode Island
|
2025-03-16
|
1
|
new results
|
cc_by_nd
|
molecular biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.15.643469.source.xml
|
Non-coding RNAs (ncRNAs) play critical regulatory roles in gene expression regulation that influences diverse biological processes in response to environmental change. Yet their characterization in non-model organisms, particularly sessile, benthic ecosystem engineers such as reef-building corals that are sensitive to climate change, remains limited. This study provides the first comprehensive analysis of the ncRNA repertoire of species from three ecologically important coral genera from Moorea, French Polynesia: Acropora pulchra, Pocillopora tuahiniensis, and Porites evermanni. These species demonstrate differing symbiotic partners, life history strategies, and physiological traits, offering a broad framework for documenting ncRNA variation in corals. We identified homologs for ncRNA biogenesis and functional machinery, characterized long ncRNAs (lncRNAs), microRNAs (miRNAs), and piwiRNAs (piRNAs), and assessed their genomic context and potential targets. Our findings reveal the presence of conserved ncRNA machinery across these coral species, indicating their capability to generate and utilize ncRNAs for the regulation of gene expression. We identified only a single miRNA conserved with corals and Eumetazoans (miR-100), four miRNAs shared across all three species, previously identified in other cnidarian taxa (miR-100, miR-2023, miR-2025, miR-2036), as well as several species-specific miRNAs. Predicted gene targets of the characterized miRNAs included immune response regulation in A. pulchra and P. tuahiniensis and signal transduction pathways in P. evermanni and P. tuahiniensis. Proximity analysis indicated >71-99% of piRNAs overlapped with genes, with genomic maintenance and stability identified as the primary functional enrichment of those genes. Our characterization of lncRNAs found little sequence overlap across each species (<2%), although lncRNAs in all three species were often in proximity to immune-related genes. This study lays the groundwork for the repertoire and regulatory roles of ncRNAs in reef-building corals, thereby expanding our understanding of epigenetic regulation in environmentally sensitive marine invertebrates and its potential implications in acclimatization and adaptation to environmental change.
|
NA
|
biorxiv
| 41 |
10.1101/2025.03.14.643362
|
Calcium signals shape metabolic control of H3K27ac and H3K18la to regulate EGA
|
Savy, V.; Stein, P.; Delker, D.; Estermann, M. A.; Papas, B. N.; Xu, Z.; Radonova, L.; Williams, C. J.
|
Virginia Savy
|
National Institute of Environmental Health Sciences
|
2025-03-16
|
1
|
new results
|
cc0
|
developmental biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643362.source.xml
|
The use of assisted reproductive technologies (ART) has enabled the birth of over 9 million babies; but it is associated with increased risks of negative metabolic outcomes in offspring. Yet, the underlying mechanism remains unknown. Calcium (Ca2+) signals, which initiate embryo development at fertilization, are frequently disrupted in human ART. In mice, abnormal Ca2+ signals at fertilization impair embryo development and adult offspring metabolism. Changes in intracellular Ca2+ drive mitochondrial activity and production of metabolites used by the epigenetic machinery. For example, acetyl-CoA (derived mainly from pyruvate) and lactyl-CoA (derived from lactate) are used for writing H3K27ac and H3K18la marks that orchestrate initiation of development. Using both a genetic mouse model and treatment with ionomycin to raise intracellular Ca2+ of wild-type fertilized eggs, we found that excess Ca2+ at fertilization changes metabolic substrate availability, causing epigenetic changes that impact embryo development and offspring health. Specifically, increased Ca2+ exposure at fertilization led to increased H3K27ac levels and decreased H3K18la levels at the 1-cell (1C) stage, that persisted until the 2-cell (2C) stage. Ultralow input CUT&Tag revealed significant differences in H3K27ac and H3K18la genomic profiles between control and ionomycin groups. In addition, increased Ca2+ exposure resulted in a marked reduction in global transcription at the 1C stage that persisted through the 2C stage due to diminished activity of RNA polymerase I. Excess Ca2+ following fertilization increased pyruvate dehydrogenase activity (enzyme that converts pyruvate to acetyl-CoA) and decreased total lactate levels. Provision of exogenous lactyl-CoA before ionomycin treatment restored H3K18la levels at the 1C and 2C stages and rescued global transcription to control levels. Our findings demonstrate conclusively that Ca2+ dynamics drive metabolic regulation of epigenetic reprogramming at fertilization and alter EGA.
|
NA
|
biorxiv
| 42 |
10.1101/2025.03.14.643329
|
Short-term exposure to Cook, Vitrolife, and KSOM media shapes early calcium oscillations in ICSI-fertilized mouse oocytes and impacts adult phenotype
|
Banrezes, B.; Sainte-Beuve, T.; Frambourg, A.; Jouneau, A.
|
Bernadette Banrezes
|
Universite Paris-Saclay, UVSQ, INRAE, BREED, 78350 Jouy-en-Josas, France
|
2025-03-16
|
1
|
new results
|
cc_no
|
developmental biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643329.source.xml
|
The influence of culture media used during in vitro fertilization (IVF) on the offspring phenotype remains controversial and not subject to consensus. However, the specific effects of short exposure time and duration immediately after fertilization remain underexplored. In this study, we investigated Ca2+; oscillatory responses in mouse oocytes fertilized by intracytoplasmic sperm injection (ICSI) as an indicator of early metabolic activity. We evaluated the long-term effects of a short but critical 4-hour exposure to three different culture media: Cook and Vitrolife - commonly used in human IVF - and KSOM, a standard mouse embryo culture medium. Our results indicate that culture media significantly modulate Ca2+; oscillations during oocyte activation. ICSI-fertilized oocytes cultured in Cook and Vitrolife exhibited fewer oscillations, lower frequency, and reduced inter-individual variability compared to KSOM, which produced a more diverse oscillation pattern. Notably, these early differences correlated with long-term developmental outcomes: females derived from Cook and Vitrolife embryo cultures exhibited were heavier throughout their growth period and had larger adult organ sizes compared to those derived from KSOM. These findings highlight the critical influence of this short post-fertilization window in shaping Ca2+; dynamics, which serve as biomarkers of metabolic variation and ultimately influence adult phenotype. Further research is needed to explore additional IVF media and refine culture conditions to better understand the metabolic pathways linking fertilization environment to offspring development. Optimization of embryo culture protocols in assisted reproductive technologies may improve developmental outcomes in IVF.
|
NA
|
biorxiv
| 43 |
10.1101/2025.03.15.643479
|
Myc and Tor drive growth and cell competition in the regeneration blastema of Drosophila wing imaginal discs
|
Hsu, F. T.-Y.; Smith-Bolton, R.
|
Rachel Smith-Bolton
|
University of Illinois at Urbana-Champaign
|
2025-03-16
|
1
|
new results
|
cc_by_nc
|
developmental biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.15.643479.source.xml
|
During the regeneration of injured or lost tissues, the regeneration blastema serves as a hub for robust growth. Drosophila imaginal discs are a genetically tractable and simple model system for the study of regeneration and organization of this regrowth. Key signals that contribute to regenerative growth in these discs, such as ROS, Wnt/Wg, JNK, p38, JAK/STAT, and the Hippo pathway, have been identified. However, a detailed exploration of the spatial organization of regrowth, the factors that directly drive this growth, and the consequences of activating drivers of regeneration has not been undertaken. Here we find that regenerative growth in imaginal discs is controlled by the transcription factor Myc and by Tor signaling, which additively drive proliferation and translation in the regeneration blastema. The spatial organization of growth in the blastema is arranged into concentric growth zones defined by Myc expression, elevated Tor activity, and elevated translation. In addition, the increased Myc expression in the innermost zone induced Xrp1-independent cell competition-like death in the adjacent zones, revealing a delicate balance between driving growth and inducing death in the regenerating tissue.
|
NA
|
biorxiv
| 44 |
10.1101/2025.03.14.643210
|
The influence of larval retention on coral recruitment
|
Gouezo, M.; Harrison, P.; Roff, G.; Chai, A.; Thomson, D.; Guglielmo, M.; Hardiman, L.; Forbes, A.; Gardner, B.; Doropoulos, C.
|
Marine Gouezo
|
Southern Cross University
|
2025-03-16
|
1
|
new results
|
cc_by
|
ecology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643210.source.xml
|
Marine broadcast spawners typically exhibit bipartite life-histories with distinct pelagic larvae and benthic phases. The transition between phases shapes benthic populations, but the rate of larval arrival to a reef is largely unknown due to challenges in accurately measuring supply. Once larvae arrive to a reef, reduced current flow and velocity, facilitate the transition from the water column to the benthos for inefficient swimming larvae. Yet, for coral reefs characterised by complex hydrodynamics and tides, slack current conditions typically last 1.5-3 hours and it remains unclear if such short retention periods drive significant recruitment. This study mechanistically examined the effects of water retention on the settlement of coral larvae from the water column to the benthos and subsequent longer-term recruitment over 15-months. Brief periods of slack currents (<3-hours) retained larvae in unconstrained larval supply treatments, resulting in settlement rates 40-times higher than natural, background rates. Constrained and longer retention of larvae under nets for 2.5- and 24-hours resulted in 4-7-times higher initial settlement than the unconstrained treatment and 305-times higher than background rates. However, after 15-months, similar numbers of surviving recruits were observed across all larval supply treatments, highlighting the effects of density-dependent population regulation. Observations from recruitment tiles show survival rates of coral recruits after 15-months were low (<0.25), even though gregarious settlement behaviour and settlement close to tile edges improved survival. In contrast, observations from the natural substrate show survival rates were 2.5-3.5-times higher than tiles after 15-months, indicating density-independent survival due to optimal niche space and less space limitation. Therefore, when larval supply is high and gregarious behaviour prominent, key vital rates including recruitment and mortality derived from settlement tiles are likely overestimated, as substrate and microhabitat properties between tiles and natural reef environment vary. Overall, our study highlights the prominent role of slack current conditions and local retention of larvae in facilitating the supply-to-settlement transition, and how this interacts with density-dependent processes post-settlement. Our findings underscore the need to investigate how the interaction strengths of pre- and post-settlement processes modulate early coral recovery to best model recovery trajectories for conservation and restoration prioritisation.
|
NA
|
biorxiv
| 45 |
10.1101/2025.03.14.643238
|
Experimental reduction of land use increases invertebrate abundance but not diversity in grasslands
|
Staab, M.; Keller, A.; Achury, R.; Hilpert, A.; Hoelzel, N.; Prati, D.; Weisser, W. W.; Bluethgen, N.
|
Michael Staab
|
Leuphana University of Lueneburg
|
2025-03-16
|
1
|
new results
|
cc_by_nc
|
ecology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643238.source.xml
|
Grasslands are diverse ecosystems that are increasingly threatened by intensive land use. Restoring grasslands by reducing land-use intensity may support insect abundance and diversity, helping to halt insect declines. To test for the effect of reduced land use on invertebrates, we studied an experiment (established 2020) at 45 sites across three regions of Germany. We hypothesized that reduced land use increases invertebrate abundance and diversity, with larger effects in less intensively used grasslands. Using suction sampling, invertebrates were quantitatively sampled in May 2021 and May 2023, with 2021 samples identified by DNA meta-barcoding. Reducing land use to a single late mowing increased invertebrate abundance by 41% after one year and 99% after three years. However, species richness, Shannon diversity, and Simpson diversity did not differ between treatments and controls. Finding more individuals in grasslands with reduced land use suggests that species already present benefit, rather than additional species being recruited from the surrounding area. The effect of land-use reduction on abundance was consistently influenced by land use in the surrounding matrix, with larger positive effect sizes at grasslands with lower mowing frequency but higher fertilization. In spite of these local differences in the magnitude of restoration effects, the consistent increase in invertebrate abundance suggests that reducing land-use intensity can enhance invertebrate populations with potential benefits for ecosystem functions. It will be important to study how outcomes of land-use reduction develop over time, as land-use reduction is likely more successful when implemented permanently.
|
NA
|
biorxiv
| 46 |
10.1101/2025.03.14.643063
|
Deciphering lung adenocarcinoma evolution and the role of LINE-1 retrotransposition
|
Zhang, T.; Zhao, W.; Wirth, C.; Diaz-Gay, M.; Yin, J.; Cecati, M.; Marchegiani, F.; Hoang, P. H.; Leduc, C.; Baine, M. K.; Travis, W. D.; Sholl, L. M.; Joubert, P.; Sang, J.; McElderry, J. P.; Klein, A.; Khandekar, A.; Hartman, C.; Rosenbaum, J.; Colon-Matos, F. J.; Miraftab, M.; Saha, M.; Lee, O. W.; Jones, K. M.; Caporaso, N. E.; Wong, M. P.; Leung, K. C.; Hsiung, C. A.; Chen, C.-Y.; Homer, R.; Yang, S.-R.; Pesatori, A. C.; Consonni, D.; Yang, L.; Zhu, B.; Edell, E. S.; Santamaria, J. M.; Schabath, M. B.; Yendamuri, S. S.; Manczuk, M.; Lissowska, J.; Swiatkowska, B.; Mukeria, A.; Shangina, O
|
Maria Teresa Landi
|
National Cancer Institute
|
2025-03-16
|
1
|
new results
|
cc_by
|
genomics
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643063.source.xml
|
Understanding lung cancer evolution can identify tools for intercepting its growth. In a landscape analysis of 1024 lung adenocarcinomas (LUAD) with deep whole-genome sequencing integrated with multi-omic data, we identified 542 LUAD that displayed diverse clonal architecture. In this group, we observed an interplay between mobile elements, endogenous and exogenous mutational processes, distinct driver genes, and epidemiological features. Our results revealed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry, and sex. LUAD from smokers showed an abundance of tobacco-related C:G>A:T driver mutations in KRAS plus short subclonal diversification. LUAD in never smokers showed early occurrence of copy number alterations and EGFR mutations associated with SBS5 and SBS40a mutational signatures. Tumors harboring EGFR mutations exhibited long latency, particularly in females of European-ancestry (EU_N). In EU_N, EGFR mutations preceded the occurrence of other driver genes, including TP53 and RBM10. Tumors from Asian never smokers showed a short clonal evolution and presented with heterogeneous repetitive patterns for the inferred mutational order. Importantly, we found that the mutational signature ID2 is a marker of a previously unrecognized mechanism for LUAD evolution. Tumors with ID2 showed short latency and high L1 retrotransposon activity linked to L1 promoter demethylation. These tumors exhibited an aggressive phenotype, characterized by increased genomic instability, elevated hypoxia scores, low burden of neoantigens, propensity to develop metastasis, and poor overall survival. Re-activated L1 retrotransposition-induced mutagenesis can contribute to the origin of the mutational signature ID2, including through the regulation of the transcriptional factor ZNF695, a member of the KZFP family. The complex nature of LUAD evolution creates both challenges and opportunities for screening and treatment plans.
|
NA
|
biorxiv
| 47 |
10.1101/2025.03.14.643405
|
Evaluation of Alphafold modeling for elucidation of nanobody-peptide epitope interactions
|
Cheloha, R. W.; Sachdev, S.; Roy, S.; Saha, S.; Zhao, G.; Kumariya, R.; Creemer, B. A.; Yin, R.; Pierce, B.; Bewley, C. A.
|
Ross W. Cheloha
|
National Institutes of Health
|
2025-03-16
|
1
|
new results
|
cc0
|
biochemistry
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643405.source.xml
|
Models of Ab-antigen complexes can be used to understand interaction mechanisms and to improve affinity. This study evaluates the use of the protein structure prediction algorithm AlphaFold (AF) for exploration of interactions between peptide epitope tags and the smallest functional antibody fragments, nanobodies (Nbs). Although past studies of AF for modeling antibody-target (antigen) interactions suggested modest algorithm performance, those were primarily focused on Ab-protein interactions, while the performance and utility of AF for Nb-peptide interactions, which are generally less complex due to smaller antigens, smaller binding domains, and fewer chains, is less clear. In this study we evaluated the performance of AF for predicting the structures of Nbs bound to experimentally validated, linear, short peptide epitopes (Nb-tag pairs). We expanded the pool of experimental data available for comparison through crystallization and structural determination of a previously reported Nb-tag complex (Nb127). Models of Nb-tag pair structures generated from AF were variable with respect to consistency with experimental data, with good performance in just over half (4 out of 6) of cases. Even among Nb-tag pairs successfully modeled in isolation, efforts to translate modeling to more complex contexts failed, suggesting an underappreciated role of the size and complexity of inputs in AF modeling success. Finally, the model of a Nb-tag pair with minimal previous characterization was used to guide the design of a peptide-electrophile conjugate that undergoes covalent crosslinking with Nb upon binding. These findings highlight the utility of minimized antibody and antigen structures to maximize insights from AF modeling.
|
NA
|
biorxiv
| 48 |
10.1101/2025.03.14.643254
|
Structural basis for DNA double-strand break sensing by human MRE11-RAD50-NBS1 and its TRF2 complex
|
Fan, Y.; Kuybu, F.; Cui, H.; Lammens, K.; Chen, J.-X.; Kugler, M.; Jung, C.; Hopfner, K.-P.
|
Karl-Peter Hopfner
|
Gene Center LMU
|
2025-03-16
|
1
|
new results
|
cc_by_nc_nd
|
biochemistry
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643254.source.xml
|
The MRE11-RAD50-NBS1 (MRN) complex is a central, multifunctional factor in the detection, signaling and nucleolytic processing of DNA double-strand breaks (DSBs). To clarify how human MRN binds generic and telomeric DNA ends and can separate DNA end sensing from nuclease activities, we determined cryo-electron microscopy structures of human MRN bound to DNA and to DNA and the telomere protection factor TRF2. MRN senses DSBs through a tight clamp-like sensing state with closed coiled-coil domains, but auto-inhibited MRE11 nuclease. NBS1 wraps around the MRE11 dimer, with NBS1's ATM recruitment motif sequestered by binding to the regulatory RAD50 S site, necessitating an allosteric switch underlying ATM activation. At telomeric DNA, TRF2 blocks the second S site via the iDDR motif to prevent nuclease and ATM activation. Our results provide a structural framework for topological DNA sensing and separation of sensing, signaling and processing activities of mammalian MRN.
|
NA
|
biorxiv
| 49 |
10.1101/2025.03.14.643079
|
Targeted Tumor Microenvironment Delivery of Floxuridine Prodrug via Soluble Silica Nanoparticles in Malignant Melanoma as a Model for Aggressive Cancer Treatment
|
Ramos-Valle, A.; Dominguez, A.; Navarro, N.; Marquez-Lopez, A.; Avino, A.; Eritja, R.; Fabrega, C.; Garcia-Hevia, L.; Fanarraga, M. L.
|
Andres Ramos-Valle
|
The Nanomedicine Group, Institute Valdecilla-IDIVAL, 39011 Santander, Spain / Molecular Biology Department, Faculty of Medicine, Universidad de Cantabria, 39011
|
2025-03-16
|
1
|
new results
|
cc_no
|
bioengineering
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643079.source.xml
|
Malignant melanoma presents a significant challenge in oncology due to its aggressive nature and high metastatic potential. Conventional systemic treatments often fail to effectively reach tumor sites, limiting their therapeutic impact. This study introduces a groundbreaking triple-strategy approach for treating malignant melanoma. We developed a novel prodrug, an oligonucleotide, comprising 10 units of Floxuridine (5-fluoro-2'-deoxyuridine) (FdU) nucleoside antimetabolites, to enhance half-life and reduce rapid metabolism. Encapsulated in soluble colloidal silica nanoparticles, this compound is protected and directed towards tumor neovasculature precursor endothelial cell receptors, ensuring local delivery. The strategy focuses on releasing the prodrug in the tumor microenvironment, aiming to eradicate both melanoma cells and their supportive structures. Efficacy was demonstrated in cell culture studies and preclinical models of malignant melanoma, showing a remarkable 50% reduction in tumor size after just three intravenous treatments. These findings underscore the transformative potential of targeting endothelial cell membrane proteins for drug delivery. Our study paves the way for innovative targeted therapies, promising significant advancements in treatment strategies and improved outcomes for patients with metastatic cancers.
|
NA
|
biorxiv
| 50 |
10.1101/2025.03.14.643160
|
Segger: Fast and accurate cell segmentation of imaging-based spatial transcriptomics data
|
Heidari, E.; Moorman, A.; Unyi, D.; Pasnuri, N.; Rukhovich, G.; Calafato, D.; Mathioudaki, A.; Chan, J.; Nawy, T.; Gerstung, M.; Pe'er, D.; Stegle, O.
|
Oliver Stegle
|
EMBL Heidelberg
|
2025-03-16
|
1
|
new results
|
cc_by
|
bioinformatics
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643160.source.xml
|
The accurate assignment of transcripts to their cells of origin remains the Achilles heel of imaging-based spatial transcriptomics, despite being critical for nearly all downstream analyses. Current cell segmentation methods are prone to over- and under-segmentation, misassign transcripts to cells, require manual intervention, and suffer from low sensitivity and scalability. We introduce segger, a versatile graph neural network based on a heterogeneous graph representation of individual transcripts and cells, that frames cell segmentation as a transcript-to-cell link prediction task and can leverage single-cell RNA-seq information to improve transcript assignments. On multiple Xenium dataset benchmarks, segger exhibits superior sensitivity and specificity, while requiring orders of magnitude less compute time than existing methods. The user-friendly open-source software implementation has extensive documentation (https://elihei2.github.io/segger_dev/), requires little manual intervention, integrates seamlessly into existing workflows, and enables atlas-scale applications.
|
NA
|
biorxiv
| 51 |
10.1101/2025.03.14.643229
|
Differential interfacial tension between oncogenic and wild-type populations forms the mechanical basis of tissue-specific oncogenesis in epithelia
|
Datta, A.; Dewan, P.; Anto, A.; Chhabra, T.; Tejaswi, T.; Muthukrishnan, S.; Rao, A.; Sarkar, S.; Vishwakarma, M.
|
Medhavi Vishwakarma
|
Department of Bioengineering, Indian Institute of Science, Bangalore, India
|
2025-03-16
|
1
|
new results
|
cc_no
|
biophysics
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643229.source.xml
|
Why does the same oncogenic mutation drive tumor formation in some tissues but not in others? While cancer driver mutations are well documented, their tissue specific effects remain largely attributed to genetic factors, leaving the biophysical aspects underexplored. Here, we demonstrate that mechanical interactions, specifically interfacial tension between newly transformed and wildtype epithelial cells are critical in determining survival and growth of HRasV12 oncogenic mutants in human mammary and bronchial epithelia, leading to contrasting outcomes in the two tissues. In mammary epithelium, isolated oncogenic cells are extruded, a typical mechanism of defense against cancer in epithelia while oncogenic groups become spatially confined in a kinetically arrested, jammed state, marked by an actomyosin belt at the interface. In contrast, bronchial epithelium permits persistent spreading of the same oncogenic cells, which form long protrusions regardless of colony size. Furthermore, oncogenic clusters in these two tissues exhibit distinct biophysical properties, including variations in cell shapes, intracellular pressure, cell to cell tension, and cellular motility. Using a cell shape tension coupled bidisperse vertex model, we reveal that differences in interfacial tension at mutant wildtype boundaries dictate whether oncogenic cells are eliminated, restrained, or expanded and that modulating interfacial tension alters mutant cell fate within the epithelium. Together, our findings uncover a mechanical basis for tissue specific oncogenesis by highlighting how differential cellular mechanics at the oncogenic host cell interface regulate tumor initiation and progression.
|
NA
|
biorxiv
| 52 |
10.1101/2025.03.14.643237
|
A novel immunogene therapy to cancer with high tumor selectivity and safety
|
Wang, J.
|
Jinke Wang
|
Southeast University
|
2025-03-16
|
1
|
new results
|
cc_by_nc_nd
|
cancer biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643237.source.xml
|
Cancer immunotherapy has made significant advancements over the past few decades, with immune checkpoint and cytokine-based drugs being successfully implemented in clinical settings. Nonetheless, the effective and safe clinical application of these therapies is hindered by critical issues, such as severe toxicity to healthy tissues due to on-target off-tumor effects. In this study, we have developed a novel immunogene therapy characterized by high tumor selectivity and safety in vivo, effectively mitigating the off-tumor effects associated with current antibody-based immune checkpoint therapies. We engineered a gene expression vector that is specifically activated by NF-{kappa}B activity to co-express artificial microRNAs targeting two key immune checkpoints (PD-L1 and CD47) and cytokine IL-15. This vector is capable of selectively and effectively down regulating the expression of PDL1 and CD47 while over expressing IL-15 just exclusively in cancer cells, both in vitro and in vivo. Through this mechanism, both adaptive and innate immune responses can be simultaneously activated and enhanced via the transfection of this vector. The in vivo administration of this vector via recombinant adeno-associated virus (AAV) demonstrated significant antitumor activity, high tumor selectivity, and safety in murine models. Consequently, this vector may offer a potential more effective and safer alternative to the current immune checkpoint inhibitors in future clinical applications.
|
NA
|
biorxiv
| 53 |
10.1101/2025.03.16.643552
|
Discovery, characterization, and application of chromosomal integration sites in the hyperthermophilic crenarchaeon Sulfolobus islandicus
|
Boob, A. G.; Zhang, C.; Pan, Y.; Zaidi, A.; Whitaker, R.; Zhao, H.
|
Huimin Zhao
|
University of Illinois Urbana-Champaign
|
2025-03-16
|
1
|
new results
|
cc_no
|
synthetic biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643552.source.xml
|
Sulfolobus islandicus, an emerging crenarchaeal model organism, offers unique advantages for metabolic engineering and synthetic biology applications owing to its ability to thrive in extreme environments. Although several genetic tools have been established for this organism, the lack of well-characterized chromosomal integration sites has considerably limited its potential as a cellular factory. Here, we systematically identified and characterized 13 artificial CRISPR RNAs (crRNAs) targeting eight chromosomal integration sites in S. islandicus using the CRISPR-COPIES pipeline and a multi-omics-informed computational workflow. By leveraging the endogenous CRISPR-Cas systems, we integrated the reporter gene lacS into these sites and validated heterologous gene expression through a {beta}-galactosidase reporter assay, which revealed significant positional effects on expression levels. As a proof of concept, we utilized these characterized sites to genetically manipulate lipid ether composition by overexpressing GDGT (glycerol dibiphytanyl glycerol tetraether) ring synthase B (GrsB) in S. islandicus, a key enzyme in GDGT biosynthesis. This study expands the genetic toolbox for S. islandicus and highlights a concept that could be widely applicable to other Sulfolobales, advancing their potential as robust platforms for archaeal synthetic biology and industrial biotechnology.
|
NA
|
biorxiv
| 54 |
10.1101/2025.03.16.643390
|
Cell-Free production of soybean leghemoglobins and non-symbiotic hemoglobin
|
Rocha, A. P.; Palmeiras, M. A.; de Oliveira, M. A.; Florentino, L. H.; Cataldi, T. R.; Bittencourt, D. M. C.; Labate, C.; Rosinha, G.; Rech, E.
|
Elibio Rech
|
NIST Synthetic Biology/EMBRAPA
|
2025-03-16
|
1
|
new results
|
cc_by_nc_nd
|
synthetic biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643390.source.xml
|
Hemoglobins are heme proteins and are present in some microorganisms, higher plants and mammals. In legume nodules there are two types: leghemoglobin (LegH) or symbiotic and non-symbiotic (nsHb). LegHs are present in high amounts at legumes roots and are responsible together with bacteroides for the nitrogen fixation process. Non-symbiotic hemoglobins Class 1 protein have very high affinity for O2 and are found in monocotyledons and legumes. LegH has aroused great interest in the vegetable meat industry due to its organoleptic and nutritional properties. Here, we demonstrated that soybean LegH A, C1, C2, C3 and nsHb are produced by E. coli-based cell-free protein synthesis (CFPS) and correctly synthesized in its amino acids sequence. In addition, it was also possible to reproduce some post-translational modifications confirmed by LC/MS analysis. All LegHs produced in this system showed peroxidase activity and heme binding correlated with its concentration in the assays. Furthermore, all proteins were readily digested by pepsin within 1 minute in analog digestion conditions. Therefore, LegHs and nsHb proteins were synthesized using cell-free systems (CFSs), maintaining their functionality and being digestible. These findings suggest that they could serve as viable alternative food additives for plant-based meat.
|
NA
|
biorxiv
| 55 |
10.1101/2025.03.16.643551
|
Progressively reduced cerebral oxygen metabolism and elevated plasma NfL levels in the zQ175DN mouse model of Huntington disease
|
Wu, Q.; Yao, M.; Liu, H.; Kakazu, A.; Ouyang, Y.; Liu, C.; Li, R.; Yang, F.; Wang, A.; Surasinghe, S.; Gerochi, D.; Baldo, B.; Jahn, S.; Tang, H.; Lu, H.; Wei, Z.; Duan, W.
|
Wenzhen Duan
|
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of medicine, Baltimore, Maryland, USA.
|
2025-03-16
|
1
|
new results
|
cc_no
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643551.source.xml
|
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG-repeat expansion in exon-1 of the huntingtin gene. Currently, no disease-modifying therapies are available, with a significant challenge in evaluating therapeutic efficacy before clinical symptoms emerge. This highlights the need for early biomarkers and intervention strategies. Therefore, it is essential to develop and characterize accurate mouse models and identify early biomarkers for preclinical therapeutic development. In this study, we characterized the pathological progression of the heterozygous zQ175 neo-deleted knock in (zQ175DN) mouse model across four age groups: 3, 6, 10, and 16 months to identify human translatable outcome measures. T2-relaxation-under-spin-tagging (TRUST) MRI was used to assess global CMRO2, while T2-weighted MRI was used to analyze brain volumes. Significant brain volume loss was detected as early as 6 months of age, worsening progressively with age in the zQ175 DN mice, resembling HD brain volumetric changes. A decline in CMRO2 was observed in 6-month-old zQ175 DN mice, with significant and progressive reductions in 10- and 16- months old HD mice. Additionally, PHP1-positive mutant huntingtin (mHTT) aggregates were present in the striatum of zQ175 DN mice at all four age groups, with intranuclear localization prior to 6 months, transitioning to both intranuclear and neuropil aggregates in older zQ175 DN mice, suggesting that the localization of mHTT aggregates may reflect the severity of HD pathogenesis. Interestingly, plasma neurofilament light chain (NfL) protein concentrations were significantly elevated at 6 months of age and older zQ175DN mice. These findings provide valuable insights for selecting outcome measures in preclinical evaluations of HD therapies using the zQ175 DN mouse model.
|
NA
|
biorxiv
| 56 |
10.1101/2025.03.14.643317
|
Perimenopause promotes neuroinflammation in select hippocampal regions in a mouse model of Alzheimers disease
|
Marongiu, R.; Platholi, J.; Park, L.; Yu, F.; Sommer, G.; Woods, C.; Milner, T. A.; Glass, M. J.
|
Teresa A. Milner
|
Weill Cornell Medicine
|
2025-03-16
|
1
|
new results
|
cc_no
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643317.source.xml
|
Alzheimers disease (AD) is the most common neurodegenerative disorder characterized by age-dependent amyloid beta (A{beta}) aggregation and accumulation, neuroinflammation, and cognitive deficits. Significantly, there are prominent sex differences in the risk, onset, progression, and severity of AD, as well as response to therapies, with disease burden disproportionally affecting women. Although menopause onset (i.e., perimenopause) may be a critical transition stage for AD susceptibility in women, the role of early ovarian decline in initial disease pathology, particularly key neuroinflammatory processes, is not well understood. To study this, we developed a unique mouse model of perimenopausal AD by combining an accelerated ovarian failure (AOF) model of menopause induced by 4-vinylcyclohexene diepoxide (VCD) with the 5xFAD transgenic AD mouse model. To target early stages of disease progression, 5xFAD females were studied at a young age (~4 months) and at the beginning stage of ovarian failure analogous to human perimenopause (termed peri-AOF), and compared to age-matched males. Assessment of neuropathology was performed by immunohistochemical labeling of A{beta} as well as markers of astrocyte and microglia activity in the hippocampus, a brain region involved in learning and memory that is deleteriously impacted during AD. Our results show that genotype, AOF, and sex contributed to AD-like pathology. Aggregation of A{beta} was heightened in female 5xFAD mice and further increased at peri-AOF, with hippocampal subregion specificity. Further, select increases in glial activation also paralleled A{beta} pathology in distinct hippocampal subregions. However, cognitive function was not affected by peri-AOF. These findings align with the hypothesis that perimenopause constitutes a period of susceptibility for AD pathogenesis in women.
|
NA
|
biorxiv
| 57 |
10.1101/2025.03.16.643547
|
Subthreshold variability of neuronal populations driven by synchronous synaptic inputs
|
Taillefumier, T.; Becker, L. A.; Baccelli, F.
|
Thibaud Taillefumier
|
University of Texas
|
2025-03-16
|
1
|
new results
|
cc_by
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643547.source.xml
|
Even when driven by the same stimulus, neuronal responses are well-known to exhibit a striking level of spiking variability. In-vivo electrophysiological recordings also reveal a surprisingly large degree of variability at the subthreshold level. In prior work, we considered biophysically relevant neuronal models to account for the observed magnitude of membrane voltage fluctuations. We found that accounting for these fluctuations requires weak but nonzero synchrony in the spiking activity, in amount that are consistent with experimentally measured spiking correlations. Here we investigate whether such synchrony can explain additional statistical features of the measured neural activity, including neuronal voltage covariability and voltage skewness. Addressing this question involves conducting a generalized moment analysis of conductance-based neurons in response to input drives modeled as correlated jump processes. Technically, we perform such an analysis using fixed-point techniques from queuing theory that are applicable in the stationary regime of activity. We found that weak but nonzero synchrony can consistently explain the experimentally reported voltage covariance and skewness. This confirms the role of synchrony as a primary driver of cortical variability and supports that physiological neural activity emerges as a population-level phenomenon, especially in the spontaneous regime.
|
NA
|
biorxiv
| 58 |
10.1101/2025.03.16.643494
|
Rapid modulation of choice behavior by ultrasound on the human frontal eye fields
|
Farboud, S.; Kop, B. R.; Koolschijn, R. S.; Walstra, S. L. Y.; Marques, J. P.; Chetverikov, A.; Medendorp, W. P.; Verhagen, L.; den Ouden, H. E. M.
|
Soha Farboud
|
Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
|
2025-03-16
|
1
|
new results
|
cc_by
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643494.source.xml
|
A fundamental challenge in neuroscience is establishing causal brain-function relationships with spatial and temporal precision. Transcranial ultrasonic stimulation (TUS) offers a unique opportunity to modulate deep brain structures non-invasively with high spatial resolution, but temporally precise effects and their neurophysiological foundations have yet to be demonstrated in humans. Here, we develop a temporally precise TUS protocol targeting the frontal eye fields (FEFs), a well-characterized circuit critical for saccadic eye movements. We demonstrate that TUS induces robust excitatory behavioral effects. Importantly, individual differences in baseline GABAergic inhibitory tone predict response magnitude. These findings establish TUS as a reliable tool for chronometric circuit interrogation and highlight the importance of neurophysiological state in neuromodulation. This work bridges human and animal research, advancing targeted TUS applications in neuroscience and clinical settings.
|
NA
|
biorxiv
| 59 |
10.1101/2025.03.14.643227
|
Phase-synchronized 40 Hz transcranial electric and magnetic stimulation boosts gamma oscillations and working memory
|
Glinski, B.; Salehinehjad, M. A.; Takahashi, K.; Jamil, A.; Yavari, F.; Kuo, M.-F.; Nitsche, M.
|
Michael Nitsche
|
Leibniz Research Centre for Working Environment and Human Factors and Bielefeld University and German Centre for Mental Health
|
2025-03-16
|
1
|
new results
|
cc_by
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643227.source.xml
|
Gamma oscillations play a crucial role in core cognitive functions such as memory processes. Enhancing gamma oscillatory activity, which is reduced in Alzheimers Disease (AD), may have therapeutic potential, but effective interventions remain to be determined. This study applies novel noninvasive brain stimulation techniques, namely phase-locked 40-Hz intermittent theta-burst stimulation (iTBS) and transcranial alternating current stimulation (tACS), and explores gamma oscillations and working memory changes. In 300 experimental sessions conducted on 30 participants, the effects of 40-Hz tACS, 40-Hz iTBS, two combined interventions (phase-locked iTBS to tACS peak sine wave or tACS trough sine wave), and a sham condition were explored. Gamma oscillatory activity (for 2 hours after intervention), working memory (3-back and 1-back load), and brain functional connectivity were monitored following each intervention. All stimulation protocols enhanced 40-Hz oscillatory power, with the iTBS-tACS Peak showing the most significant and stable increase, followed by 40-Hz tACS and 40-Hz iTBS. These stimulation protocols improved functional connectivity during the 30 minutes post-intervention while participants performed a memory task. Only the 40-Hz tACS and iTBS protocols enhanced high-load working memory speed. Concurrent, peak-synchronized 40 Hz iTBS combined with tACS and 40-Hz tACS may be a reliable protocol to induce long-lasting oscillatory activity in the gamma frequency range. These protocols may have therapeutic effects in patients with Alzheimers disease.
|
NA
|
biorxiv
| 60 |
10.1101/2025.03.15.643485
|
Taxonomically different symbiotic communities of sympatric Arctic sponge species show functional similarity with specialization at species level
|
Rusanova, A.; Mamontov, V.; Ri, M.; Meleshko, D.; Trofimova, A.; Fedorchuk, V.; Ezhova, M.; Lyupina, Y.; Finoshin, A.; Isaev, A.; Sutormin, D.
|
Dmitry Sutormin
|
Center for Molecular and Cellular Biology
|
2025-03-16
|
1
|
new results
|
cc_by_nc
|
microbiology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.15.643485.source.xml
|
Marine sponges harbor diverse communities of associated organisms, including eukaryotes, viruses, and bacteria. Sponge associated microbiomes contribute to the health of the host organisms by defending them against invading bacteria and providing them with essential metabolites. Here we describe microbiomes of three sympatric species of cold-water marine sponges - Halichondria panicea, Halichondria sitiens, and Isodictya palmata - sampled over a period of six years at the White Sea. We identified the sponges as low microbial abundance species and detected stably associated bacteria that represent new taxa of sponge symbionts within Alpha- and Gammaproteobacteria. The sponges carried unique sets of unrelated species of symbiotic bacteria illustrating varying complexity of microbiomes. On a community level, sponge associated microbiomes shared common symbiotic features; they encoded multiple eukaryotic-like proteins, biosynthetic pathways, and transporters of amino acids and vitamins essential for sponges. On a species level, however, different classes of eukaryotic-like proteins and pathways were distributed between dominant and minor symbionts indicating specialization within microbiomes. Particularly, taurine and sulfoacetate metabolism pathways were associated exclusively with dominant symbionts in all three sponge species. Our study demonstrates strong functional convergence and co-evolution of microbiomes of sympatric cold-water sponge species with a distribution of functions between community members. Additionally, we observed dramatic shifts in compositions of sponge microbiomes coinciding with abnormally high water temperatures during the 2018 season, highlighting the vulnerability of cold-water ecosystems to global warming.
|
NA
|
biorxiv
| 61 |
10.1101/2025.03.16.643550
|
Replicative selfish genetic elements are driving rapid pathogenic adaptation of Enterococcus faecium
|
Grieshop, M. P.; Behr, A. A.; Bowden, S.; Lin, J. D.; Molari, M.; Reynolds, G. Z.; Brooks, E. F.; Doyle, B.; Rodriguez-Nava, G.; Salinas, J. L.; Banaei, N.; Bhatt, A. S.
|
Ami S Bhatt
|
Stanford University
|
2025-03-16
|
1
|
new results
|
cc_by_nc_nd
|
microbiology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643550.source.xml
|
Understanding how healthcare-associated pathogens adapt in clinical environments can inform strategies to reduce their burden. Here, we investigate the hypothesis that insertion sequences (IS), prokaryotic transposable elements, are a dominant mediator of rapid genomic evolution in healthcare-associated pathogens. Among 28,207 publicly available pathogen genomes, we find high copy numbers of the replicative ISL3 family in healthcare-associated Enterococcus faecium, Streptococcus pneumoniae and Staphylococcus aureus. In E. faecium, the ESKAPE pathogen with the highest IS density, we find that ISL3 proliferation has increased in the last 30 years. To enable better identification of structural variants, we long read-sequenced a new, single hospital collection of 282 Enterococcal infection isolates collected over three years. In these samples, we observed extensive, ongoing structural variation of the E. faecium genome, largely mediated by active replicative ISL3 elements. To determine if ISL3 is actively replicating in clinical timescales in its natural, gut microbiome reservoir, we long read-sequenced a collection of 28 longitudinal stool samples from patients undergoing hematopoietic cell transplantation, whose gut microbiomes were dominated by E. faecium. We found up to six structural variants of a given E. faecium strain within a single stool sample. Examining longitudinal samples from one individual in further detail, we find ISL3 elements can replicate and move to specific positions with profound regulatory effects on neighboring gene expression. In particular, we identify an ISL3 element that upon insertion replaces an imperfect -35 promoter sequence at a folT gene locus with a perfect -35 sequence, which leads to substantial upregulation of expression of folT, driving highly effective folate scavenging. As a known folate auxotroph, E. faecium depends on other members of the microbiota or diet to supply folate. Enhanced folate scavenging may enable E. faecium to thrive in the setting of microbiome collapse that is common in HCT and other critically ill patients. Together, ISL3 expansion has enabled E. faecium to rapidly evolve in healthcare settings, and this likely contributes to its metabolic fitness and may strongly influence its ongoing trajectory of genomic evolution.
|
NA
|
biorxiv
| 62 |
10.1101/2025.03.16.643542
|
Development of novel high-affinity nanobodies against EGFR for cancer therapy
|
Heitrich, M.; Fernandez, M.; Aguilar-Cortes, D. C.; Werbajh, S.; Canziani, G.; Zylberman, V.; Ripari, L. B.; Videla-Richardson, G. A.; Malchiodi, E. L.; Podhajcer, O. L.; Vinzon, S. E.
|
Sabrina E. Vinzon
|
Fundacion Instituto Leloir, IIBBA-CONICET
|
2025-03-16
|
1
|
new results
|
cc_no
|
molecular biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643542.source.xml
|
The epidermal growth factor receptor (EGFR) is a member of a family of transmembrane tyrosine kinase receptors that plays a pivotal role in regulating diverse cellular processes such as cell proliferation, survival, migration, and differentiation. Aberrant activation of EGFR signaling has been implicated in various pathological conditions, particularly cancer, making it an attractive target for therapeutic intervention. While several anti-EGFR monoclonal antibodies have been developed and demonstrated their clinical value for the treatment of various solid tumors, smaller antibody fragments such as nanobodies (Nb) offer distinct advantages over conventional antibodies, including reduced immunogenicity and enhanced tumor penetration. In this paper, we report the isolation and characterization of two novel high-affinity Nb targeting EGFR. These Nb were identified and characterized using ELISA, flow cytometry, microscopy, and SPR. Furthermore, these Nb and bivalent Nb engineered from them were tested for their effects on cancer cell proliferation. We demonstrate that the novel Nb exhibit high affinity and potent anti-tumor activity in vitro in their bivalent form, positioning them as promising candidates for cancer treatment.
|
NA
|
biorxiv
| 63 |
10.1101/2025.03.15.643072
|
UMIche: A platform for robust UMI-centric simulation and analysis in bulk and single-cell sequencing
|
Sun, J.; Li, S.; Canzar, S.; Cribbs, A. P.
|
Jianfeng Sun
|
Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, National Institute of Health Research Oxford Biomedical
|
2025-03-16
|
1
|
new results
|
cc_by_nc
|
molecular biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.15.643072.source.xml
|
Unique molecular identifiers (UMIs) have actively been utilised by various RNA sequencing (RNA-seq) protocols and technologies to remove polymerase chain reaction (PCR) duplicates, thus enhancing counting accuracy. However, errors during sequencing processes often compromise the precision of UMI-assisted quantification. To overcome this, various computational methods have been proposed for UMI error correction. Despite these advancements, the absence of a unified benchmarking and validation framework for UMI deduplication methods hinders the systematic evaluation and optimisation of these methods. Here, we present UMIche, an open-source, UMI-centric computational platform designed to improve molecular quantification by providing a systematic, integrative, and extensible framework for UMI analysis. Additionally, it supports the development of more effective UMI deduplication strategies. We show that through its integration of a broad spectrum of UMI deduplication methods and computational workflows, UMIche significantly advances the accuracy of molecular quantification and facilitates the generation of high-fidelity gene expression profiles.
|
NA
|
biorxiv
| 64 |
10.1101/2025.03.16.643548
|
Degradation of the intestinal mucus layer by the ETEC protease EatA is species specific determined by the structure of the MUC2 mucin
|
Trillo-Muyo, S.; Dolan, B.; Svensson, F.; Vickers, T. J.; Arike, L.; Garcia-Bonete, M.-J.; Gustafsson, J. K.; Wandall, H. H.; Fleckenstein, J. M.; Hansson, G. C.; van der Post, S.
|
Sjoerd van der Post
|
University of Gothenburg
|
2025-03-16
|
1
|
new results
|
cc_by_nc_nd
|
molecular biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643548.source.xml
|
Enterotoxigenic Escherichia coli (ETEC) infections are a leading cause of diarrheal illness, responsible for an estimated 100,000 deaths annually. ETEC pathogenesis is driven by various virulence factors, including toxins, adhesins, and noncanonical factors such as the protease EatA. The first line of host defense against intestinal pathogenic bacterial infections is the protective intestinal mucus layer. Here, we demonstrate the mechanism by which EatA facilitates access to the epithelial cell surface by degrading the core mucus component MUC2, thereby aiding to the infection. We identify the specific cleavage site region localized at the C-terminal of MUC2. EatA's protease activity depends on the interaction between two distinct domains, which are uniquely spaced in human MUC2, contributing to species specificity. This was confirmed using a novel chimeric mouse model solely expressing human MUC2, which allowed us to study the role of the mucus layer in the infection of human intestinal pathogens. These findings highlight how ETEC has adapted to specifically degrade the mucus layer of its human host.
|
NA
|
biorxiv
| 65 |
10.1101/2025.03.15.643430
|
A spatio-temporal brain miRNA expression atlas identifies sex-independent age-related microglial driven miR-155-5p increase
|
Engel, A.; Wagner, V.; Hahn, O.; Foltz, A. G.; Atkins, M.; Beganovic, A.; Guldner, I. H.; Lu, N.; Saksena, A.; Fischer, U.; Ludwig, N.; Meese, E.; Wyss-Coray, T.; Keller, A.
|
Andreas Keller
|
Saarland University
|
2025-03-16
|
1
|
new results
|
cc_by
|
molecular biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.15.643430.source.xml
|
An in-depth understanding of the molecular processes composing aging is crucial to develop therapeutic approaches that decrease aging as a key risk factor for cognitive decline. Herein, we present a spatio-temporal brain atlas (15 different regions) of microRNA (miRNA) expression across the mouse lifespan (7 time points) and two aging interventions composed of 1009 samples. MiRNAs are promising therapeutic targets, as they silence genes by complementary base-pair binding of messenger RNAs and are known to mediate aging speed. We first established sex- and brain-region-specific miRNA expression patterns in young adult samples. Then we focused on sex-dependent and independent brain-region-specific miRNA expression changes during aging. The corpus callosum in males and the choroid plexus in females exhibited strong sex-specific age-related signatures. In this work, we identified three sex-independent brain aging miRNAs (miR-146a-5p, miR-155-5p and miR-5100). We showed for miR-155-5p that these expression changes are driven by aging microglia. MiR-155-5p targets mTOR signaling pathway components and other cellular communication pathways and is hence a promising therapeutic target.
|
NA
|
biorxiv
| 66 |
10.1101/2025.03.15.643483
|
Novel Probe Design for Multi-Gene Detection Enabled by Cleavage and Capillary Electrophoresis
|
Gong, Y.; Wu, Y.; Luo, Y.; Lu, X.; Niu, M.
|
Yangqing Gong
|
Department of Physiology, Zhejiang University School of Medicine
|
2025-03-16
|
1
|
new results
|
cc_no
|
molecular biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.15.643483.source.xml
|
Nucleic acid sequences carry the most fundamental information about life, and gene detection plays a crucial role in studying and applying gene function. Here, we present a novel probe design that utilizes probe cleavage and capillary electrophoresis for gene detection, termed ProbeCE which detects genes by measuring the relative fluorescence signal intensity. Through the evaluation of probes with varying lengths and modifications, ProbeCE is believed to support the simultaneous detection of hundreds of genes. Additionally, the assessment of low-concentration samples has demonstrated the high sensitivity of the ProbeCE method. Compared to the conventional amplification product capillary electrophoresis (AmpCE) method, this new approach significantly increases detection throughput while simplifying primer design and enhancing specificity. In addition, ProbeCE is less expensive than current medium- or high-throughput sequencing for detecting large numbers of known genes.
|
NA
|
biorxiv
| 67 |
10.1101/2025.03.15.643033
|
mclUMI: Markov clustering of unique molecular identifiers enables dynamic removal of PCR duplicates
|
Sun, J.; Li, S.; Canzar, S.; Cribbs, A. P.
|
Jianfeng Sun
|
Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, National Institute of Health Research Oxford Biomedical
|
2025-03-16
|
1
|
new results
|
cc_by_nc
|
molecular biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.15.643033.source.xml
|
Molecular quantification in high-throughput sequencing experiments relies on accurate identification and removal of polymerase chain reaction (PCR) duplicates. The use of Unique Molecular Identifiers (UMIs) in sequencing protocols has become a standard approach for distinguishing molecular identities. However, PCR artefacts and sequencing errors in UMIs present a significant challenge for effective UMI collapsing and accurate molecular counting. Current computational strategies for UMI collapsing often exhibit limited flexibility, providing invariable deduplicated counts that inadequately adapt to varying experimental conditions. To address these limitations, we developed mclUMI, a tool employing the Markov clustering algorithm to accurately identify original UMIs and eliminate PCR duplicates. Unlike conventional methods, mclUMI automates the detection of independent communities within UMI graphs by dynamically fine-tuning inflation and expansion parameters, enabling context-dependent merging of UMIs based on their connectivity patterns. Through in silico experiments, we demonstrate that mclUMI generates dynamically adaptable deduplication outcomes tailored to diverse experimental scenarios, particularly best-performing under high sequencing error rates. By integrating connectivity-driven clustering, mclUMI enhances the accuracy of molecular counting in noisy sequencing environments, addressing the rigidity of current UMI deduplication frameworks.
|
NA
|
biorxiv
| 68 |
10.1101/2025.03.16.643506
|
Functional profiling reveals a non-enzymatic role of NUDT5 in repressing purine de novo synthesis
|
Lin, J.-M. G.; Nguyen, T.-A.; Marques, A.-S. M. C.; Scrofani, L.; Daum, D.; Bauer, L. G.; Cheng, C.; D'Angelo, L.; Sanchez, J.; Bueschl, C.; Buphamalai, P.; Siklos, M.; Genger, J.-W.; Hofstaetter, G.; Runggatscher, K.; Guertl, B.; Liu, Y.; Hansen, J.; Koren, A.; Froese, D. S.; Rosenblatt, D. S.; Klavins, K.; Bergthaler, A.; Menche, J.; Hannich, J. T.; Sdelci, S.; Huber, K. V. M.; Kubicek, S.
|
Stefan Kubicek
|
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences; 1090 Vienna, Austria
|
2025-03-16
|
1
|
new results
|
cc_by_nc_nd
|
molecular biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643506.source.xml
|
Folate metabolism is intricately linked to purine de novo synthesis through the incorporation of folate-derived one-carbon units into the purine scaffold. Here, we investigate the chemical and genetic dependencies caused by mutations in the folate enzyme MTHFD1 and discover a key role for Nudix hydrolase 5 (NUDT5) in regulating purine de novo synthesis. Through genetic knockout and development of a selective chemical NUDT5 degrader, we uncover an unprecedented scaffolding role rather than NUDT5 enzymatic activity is responsible for this phenotype. We find that NUDT5 interacts with the rate-limiting enzyme of purine de novo synthesis, PPAT, to repress the pathway in response to elevated purine levels. Our findings establish NUDT5 as an important regulator of purine de novo synthesis and elucidate its role in mediating sensitivities to 6-thioguanine in cancer treatment and to adenosine in MTHFD1 deficiency.
|
NA
|
biorxiv
| 69 |
10.1101/2025.03.16.643546
|
Alzheimer's Disease Mutations Disrupt Neural Stem Cell Fate and Early Brain Development
|
Wang, Y.; Lorentz, J.; Mohammadi, E.; Yilmaz, D. E.; Sgouras, T.; Guo, Y.; Pizzirusso, G.; Demetriou, A.; Nalvarte, I.; Schultzberg, M.; Li, X.
|
Xiaofei Li
|
Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
|
2025-03-16
|
1
|
new results
|
cc_by_nc_nd
|
developmental biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643546.source.xml
|
Alzheimer's disease (AD) has been largely considered as an age-related disease, mainly affecting mature or aging adult brain. Recent studies show that AD-associated mutations could impair early life, even during neurodevelopment. However, due to the complex of AD mutations and neurodevelopmental regulations, how mutations in specific genes affect the origin of neurodevelopment is still largely under studied. In this study, we investigate how AD mutations in App gene impact neurodevelopment, with a focus on NSC dynamics and the balance between neurogenesis and gliogenesis. We employed the 5xFAD transgenic line and the APPNL-G-F knock-in model, RNA sequencing, neurosphere assay and histological analyses on the cortex and hippocampus across critical developmental timepoints. Our results reveal that the APPNL-G-F model exhibits early gene expression changes, with suppressed stem cell proliferation, impaired neurogenesis, upregulation of gliogenesis and enhanced neuroinflammatory pathways. In contrast, the 5xFAD model displays minimal embryonic differences, with pronounced postnatal alterations likely driven by both gene mutations and APP overexpression. These findings indicate that AD mutations can inherently impair NSC self-renewal and differentiation, resulting in a suboptimal brain structure that have potentially higher vulnerability towards AD pathology in later life.
|
NA
|
biorxiv
| 70 |
10.1101/2025.03.14.643309
|
TORC1-driven translation of Nucleoporin 44A promotes chromatin remodeling and germ cell-to-maternal transition in Drosophila
|
Kotb, N. M.; Ulukaya, G.; Ramamoorthy, A.; Park, L. S.; Tang, J.; Hasson, D.; Rangan, P.
|
Prashanth Rangan
|
Icahn School of Medicine at Mount Sinai
|
2025-03-16
|
1
|
new results
|
cc_by_nc_nd
|
developmental biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643309.source.xml
|
Oocyte specification is a critical developmental transition that requires the coordinated repression of germ cell-specific genes and activation of the maternal program to support embryogenesis. In Drosophila, the timely repression of germ cell and early oogenesis genes is essential for this transition, yet the mechanisms that coordinate this process remain unclear. Here, we uncover an unexpected translation-chromatin axis, where transient Target of Rapamycin Complex 1 (TORC1)-driven translation triggers chromatin remodeling, ensuring irreversible oocyte fate commitment. Through a screen, we identified ribosome biogenesis regulators, including Zinc finger protein RP-8 (Zfrp8) and TORC1 components, as key mediators of gene silencing. We show that TORC1 activity increases during oocyte specification, and disrupting ribosome biogenesis, translation, or TORC1 function prevents proper heterochromatin formation, leading to epigenetic instability. Polysome-seq analysis of zfrp8-depleted ovaries revealed that Zfrp8 is required for the translation of Nucleoporin 44A (Nup44A), a key nuclear pore complex (NPC) component. Given the role of the NPC in chromatin organization, independent disruption of Nup44A results in defective silencing of the germ cell and early oogenesis genes. Our findings reveal a mechanism in which translation-driven NPC remodeling coordinates heterochromatin establishment, facilitating the germ cell-to-maternal transition and ensuring proper oocyte fate commitment.
|
NA
|
biorxiv
| 71 |
10.1101/2025.03.15.643376
|
Adhesion to a common ECM mediates interdependence in tissue morphogenesis in Drosophila
|
Sanchez-Cisneros, L. E.; Barrera-Velazquez, M.; Kromm, D.; Bun, P.; Merchant-Larios, H.; Rios-Barrera, L. D.
|
Luis Daniel Ríos-Barrera
|
Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de
|
2025-03-16
|
1
|
new results
|
cc_by
|
developmental biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.15.643376.source.xml
|
For organs to be functional, the cells and tissues that constitute them must effectively interact with each other and coordinate their behaviours. Halfway during Drosophila embryogenesis, two lateral epidermal sheets stretch to fuse at the dorsal midline; concomitant with this, the main tubes of the respiratory system also shift towards the dorsal side of the embryo. Here, we show that these two processes occur simultaneously and are coordinated by the adhesion of the epidermal sheets and a subset of cells of the tracheal trunks to a common extracellular matrix (ECM) that separates them. We show that during dorsal closure, tracheal trunk cells extend protrusions towards the ECM underneath the epidermis. These protrusions are under tension, suggesting they have a mechanical function. Additionally, perturbing adhesion between tracheal cells and the epidermis affects the development of both tissues. Altogether, our findings uncover a novel mechanism used for tissue coordination during development, one that is based on tissue adhesion towards a common ECM capable of transmitting forces across the embryo.
|
NA
|
biorxiv
| 72 |
10.1101/2025.03.16.643512
|
Chronic morphine treatment leads to a global DNA hypomethylation via active and passive demethylation mechanisms in mESCs
|
Araolaza, M.; Munoa-Hoyos, I.; Urizar-Arenaza, I.; Calzado, I.; Subiran, N.
|
Nerea Subiran
|
Department of Physiology, Faculty of Medicine and Nursery, University of the Basque Country, Leioa, Bizkaia, Spain.
|
2025-03-16
|
1
|
new results
|
cc_no
|
developmental biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643512.source.xml
|
Epigenetic changes are essential for normal development and ageing, but there is still limited understanding of how environmental factors can cause epigenetic changes that leads to health problems or diseases. Morphine is known to pass through the placental barrier and impact normal embryo development by affecting the neural tube, frontal cortex and spinal cord development, and, as a consequence, delaying nervous system development. In fact, in-utero morphine exposure has shown alterations in anxiety-like behaviours, analgesic tolerance, synaptic plasticity and the neuronal structure of offspring. However, how morphine leads to abnormal neurogenesis and other physiological consequences during embryo development is still unknown. Considering that DNA methylation is a key epigenetic factor crucial for embryo development, our aim is to elucidate the role of methylation in response to morphine. Chronic morphine treatment (24h, 10M) induces a global hypomethylation in mESC. WGBSeq identifies 16,808 sensitive to morphine which are involved in embryo development, signalling pathways, metabolism and/or gene expression, suggesting that morphine might impact methylation levels at developmental genes. Integrative analyses between WGBSeq and RNASeq identified Tet1 as morphine-sensitive gene. Morphine increased the gene expression of Tet1, modifying the methylation levels at the promoter. On the other hand, RNASeq and qRT-PCR analyses revealed that Dnmt1 gene expression decreased after morphine treatment, without altering the methylation patter at its promoters. By MS/MS approaches confirms a decrease in DNA methylation after chronic morphine treatment, together with an increase in hydroxymethylation global levels in mESCs. In conclusion, morphine induces a global hypomethylation in mESC through different mechanisms that involves passive demethylation and a self-regulatory mechanism via active demethylation.
|
NA
|
biorxiv
| 73 |
10.1101/2025.03.16.643543
|
tMHG-Finder: Tree-guided Maximal Homologous Group Finder for Bacterial Genomes
|
Yin, Y.; Kille, B.; Ogilvie, H. A.; Treangen, T.; Nakhleh, L.
|
Luay Nakhleh
|
Rice University
|
2025-03-16
|
1
|
new results
|
cc_by
|
evolutionary biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643543.source.xml
|
A maximal homologous group, or MHG, as a group of sequences with a shared evolutionary ancestry, shifts the focus from a gene-centric view to a homology-centric view in comparative genomic studies. Each MHG is formed by identifying and grouping all homologous sequences, which ensures that evolutionary events, such as horizontal gene transfer, gene duplication and loss, or de novo sequence evolution, are encapsulated within the same MHG. However, the current MHG computation tool, MHG-Finder, faces challenges in scalability to handle large datasets and lacks the ability to provide detailed insights into intermediate MHGs involving subsets of input genomes. We present tMHG-Finder (https://github.com/yongze-yin/tMHG-Finder), a new method that improves our previous method, MHG-Finder, by utilizing a guide tree to significantly improve scalability and provide more informative biological results. We also introduce a new measure, fractionalization (available at https://github.com/yongze-yin/Fract-Calculator), to assess the accuracy of delineated MHGs compared to ground truth data. Our results show that tMHG-Finder scales linearly with the number of taxa, requiring a small fraction of the computational time of MHG-Finder. Furthermore, according to the fractionalization measure, tMHG-Finder outperforms four state-of-the-art whole-genome aligners on simulated data. Applying tMHG-Finder to a phylum of extreme-environment-resistant bacteria, we validated our results through the encapsulation of 16S rRNA sequences within MHGs. We further investigated how evolutionary rates change with phylogenetic distance and explored the functional roles of genes captured by conserved MHGs, demonstrating the broader utility of tMHG-Finder in uncovering evolutionary insights beyond MHG delineation and phylogenetic relationships.
|
NA
|
biorxiv
| 74 |
10.1101/2025.03.15.641049
|
PAF15-PCNA assembly exhaustion governs lagging strand replication and replisome integrity
|
Chhetri, G.; Badugu, S. B.; Petriman, N.-A.; Petersen, M. B.; Pitchai, G. P.; Guller, A. S.; Novotny, J.; Balarasa, B.; Ebbesen, M.; Larsen, F.; Ravnsborg, T.; Yadav, A. K.; Lunding, A.; Polasek-Sedlackova, H.; Jensen, O. N.; Ravnskjaer, K.; Brewer, J.; Madsen, J. G. S.; Andersen, J. S.; Somyajit, K.
|
Kumar Somyajit
|
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
|
2025-03-16
|
1
|
new results
|
cc_by_nc_nd
|
biochemistry
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.15.641049.source.xml
|
Genome replication in eukaryotic cells is surveyed by the S-phase checkpoint, which orchestrates sequential replication origin activation to avoid exhaustion of hitherto poorly defined rate-limiting replisome components. Here, we find that excessive activation of replication origins depletes chromatin-bound PCNA and lagging strand components, thereby limiting additional PCNA loading at new origins when checkpoint control is disrupted. PAF15 (PCNA-associated factor 15) emerges as a dosage-sensitive regulator of PCNA, delineating the dynamic range of global genome duplication and defining distinct roles for PCNA on the leading and lagging strands. Through its high-affinity PIP motif and interaction within the DNA encircling channel of PCNA, PAF15 stabilizes PCNA exclusively on the lagging strand, optimizing and rate-limiting lagging strand processing. On the other hand, misregulation of PAF15, whether by overexpression or mislocalization to the leading strand, impairs replication fork progression and leads to cell death. These defects are mitigated by TIMELESS and CLASPIN, which restrain PAF15-PCNA interactions beyond the lagging strand. E2F4-mediated repression orchestrates PAF15 expression in normal and cancer cells, maintaining its optimal dosage for lagging strand-specific interactions with PCNA. Thus, the S-phase checkpoint functions in concert to restrict origin activation when lagging strand PAF15-PCNA assembly is exhausted, linking a previously concealed strand-specific rate limitation to overall replication dynamics.
|
NA
|
biorxiv
| 75 |
10.1101/2025.03.14.643379
|
Small-molecule allosteric activator of ubiquitin-specific protease 7 (USP7)
|
Jaen Maisonet, I.; Sharafi, M.; Korchak, E. J.; Salazar-Chaparro, A.; Bratt, A.; Parikh, T.; Varca, A. C.; Shah, B.; Darnowski, M.; Chung, M.; Teh, W. P.; Che, J.; Bezsonova, I.; Buhrlage, S. J.
|
Sara J Buhrlage
|
Dana-Farber Cancer Institute, Department of Cancer Biology; Harvard Medical School, Department of Biological Chemistry and Molecular Pharmacology
|
2025-03-16
|
1
|
new results
|
cc_no
|
biochemistry
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643379.source.xml
|
Ubiquitin-specific protease 7 (USP7) is a deubiquitylase essential for cell homeostasis, DNA repair, and regulation of both tumor suppressors and oncogenes. Inactivating USP7 mutations have been associated with Hao-Fountain Syndrome (HAFOUS), a rare neurodevelopmental disorder. Although a range of USP7 inhibitors have been developed over the last decade, in the context of HAFOUS as well as oncogene regulation, USP7 activators may represent a more relevant approach. To address this challenge, we report the discovery and characterization of a small-molecule activator of USP7 called MS-8. We showed that MS-8 activates USP7 by engaging the allosteric C-terminal binding pocket of USP7, thus mimicking the allosteric autoactivation by the USP7 C-terminal tail. We observed that MS-8 engages and activates mutant USP7 in a cellular context, impacting downstream proteins. Taken together, our study provides validation of the USP7 activator that paves the way towards novel activation-driven USP7 pharmacology.
|
NA
|
biorxiv
| 76 |
10.1101/2025.03.14.643242
|
Blocking IF3N delays bacterial translation initiation
|
Sanchez-Castro, A.; Penaranda, K.; Dallape, A.; Safdari, H.; Nakamoto, J. A.; Morici, M.; Vinogradova, D.; Paleskava, A.; Wilson, D.; Konevega, A. L.; Milon, P.
|
Pohl Milon
|
Universidad Peruana de Ciencias Aplicadas
|
2025-03-16
|
1
|
new results
|
cc_by_nc
|
biochemistry
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643242.source.xml
|
Bacterial translation initiation factor IF3 is composed of two distinct domains, a well-characterized C-terminal domain (IF3C), which enhances the speed and fidelity of translation initiation, and a less understood N-terminal domain (IF3N). In this study, we developed an aptamer (Apt343) that targets IF3N with the goal of elucidating its contribution to translation initiation. Rapid kinetics assays revealed that Apt343 reduces the rate of IF3 association with the 30S ribosomal subunit by 13-fold, while inducing a pronounced rearrangement of both IF3 domains on the 30S. These changes compromise IF2-, mRNA-, and fMet-tRNAfMet-dependent movements of IF3, delaying 30S initiation complex (30S IC) formation by up to two orders of magnitude. Cryo-EM analysis suggests that Apt343 may sterically clash with fMet-tRNAfMet, thereby perturbing the canonical pathway by which the initiator tRNA is accommodated after IF2-dependent recruitment and prior to start codon decoding. However, once the 30S IC is formed, blocking IF3N does not prevent 50S subunit joining or 70S IC assembly. Collectively, these findings support a role for IF3N in enhancing an efficient path for fMet-tRNAfMet accommodation towards the 30S IC and promoting IF3C displacement to unlock 50S recruitment. Moreover, this aptamer-based strategy offers a valuable tool for dissecting domain-specific activities of multidomain factors within complex environments such as the initiating ribosome.
|
NA
|
biorxiv
| 77 |
10.1101/2025.03.14.643190
|
Probability-based sequence comparison finds the oldest ever nuclear mitochondrial DNA segments in mammalian genomes
|
Huang, M.; Frith, M.
|
Martin Frith
|
The Department of Computational Biology and Medical Sciences, The Graduate School of Frontier Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 2
|
2025-03-16
|
1
|
new results
|
cc_no
|
bioinformatics
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643190.source.xml
|
The insertion of mitochondrial genome-derived DNA sequences into the nuclear genome is a frequent event in organismal evolution, resulting in nuclear-mitochondrial DNA segments (NUMTs), which serve as a significant driving force for genome evolution. Once incorporated into the nuclear genome, some NUMTs can be conserved for extended periods, adapting to perform novel cellular functions. However, current mainstream methods for detecting NUMTs are inefficient at identifying ancient and highly degraded NUMTs, leading to their prevalence and impact being underestimated. This study focuses on identifying ancient NUMTs in mammalian genomes using enhanced high-sensitivity sequence comparison methods. A sensitive and accurate NUMT-searching pipeline was established, predicting 1,013 NUMTs in the human reference genome, 398 (39\%) of which are newly detected compared to the UCSC reference human NUMTs database. Notably, 93 pre-Eutherian human NUMTs were identified, representing significantly older NUMTs than previously reported, with origins dating back at least 100 million years. The most ancient mammalian NUMTs could even date back over 160 million years, inserted into the nuclear genome of the common ancestor of therian mammals. This study provides a comprehensive exploration of the quantity and evolutionary history of mammalian NUMTs, paving the way for future research on endosymbiotic impact on the evolution of nuclear genomes.
|
NA
|
biorxiv
| 78 |
10.1101/2025.03.14.643213
|
Integration of Proxy Intermediate Omics traits into a Nonlinear Two-Step model for accurate phenotypic prediction
|
Yoshioka, H.; Mary-Huard, T.; Aubert, J.; Toda, Y.; Ohmori, Y.; Yamasaki, Y.; Tsujimoto, H.; Takahashi, H.; Nakazono, M.; Takanashi, H.; Fujiwara, T.; Tsuda, M.; Kaga, A.; Inaba, J.; Fuji, Y.; Hirai, M. Y.; Nose, Y.; Kumaishi, K.; Usui, E.; Kobori, S.; Sato, T.; Narukawa, M.; Ichihashi, Y.; Iwata, H.
|
Hiroyoshi Iwata
|
Graduate School of Agricultural and Life Sciences, Univ. of Tokyo, Tokyo, Japan
|
2025-03-16
|
1
|
new results
|
cc_by_nc
|
bioinformatics
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.14.643213.source.xml
|
Intermediate omics traits, which mediate the effects of genetic variation on phenotypic traits, are increasingly recognised as valuable components of genetic evaluation. In particular, rhizosphere microbiota play a crucial role in plant health and productivity; however, their complex interactions with host genetics remain challenging to model. Although two-step modeling frameworks have been proposed to integrate intermediate omics traits into phenotype prediction, existing approaches do not incorporate nonlinear relationships between different omics layers. To address this, we have proposed a two-step phenotype prediction framework that integrates genomic, rhizosphere microbiome, and metabolome (meta-metabolome) data, while explicitly capturing omics-omics nonlinearities. The first step is to predict meta-metabolome traits from genetic and microbial features, thus effectively isolating them from the environmental noise. In this process, intermediate ``proxy'' omics traits are generated as general biological information to provide robust models. The second step utilises this ``proxy'' to enhance the accuracy of the phenotype prediction. We compared the linear model (Best Linear Unbiased Prediction, BLUP) and the nonlinear model (Random Forest, RF) at each step, as demonstrated through simulations and empirical analysis of a multi-omics soybean dataset in which nonlinear modeling captures intricate omics interactions. Notably, our approach enables phenotype prediction without requiring the original meta-metabolome data used in model training, thereby reducing reliance on costly omics measurements. This framework integrates intermediate omics traits into genomic prediction to improve prediction accuracy and provide solutions for deeper insights into plant-microbiome interactions.
|
NA
|
biorxiv
| 79 |
10.1101/2025.03.16.643561
|
Atomic Protein Structure Modeling from Cryo-EM Using Multi-Modal Deep Learning and AlphaFold3
|
Giri, N.; Cheng, J.
|
Jianlin Cheng
|
University of Missouri - Columbia
|
2025-03-16
|
1
|
new results
|
cc_by
|
bioinformatics
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643561.source.xml
|
Cryo-electron microscopy (cryo-EM) has revolutionized structural biology by enabling near-atomic resolution visualization of protein structures. However, accurately modeling 3D atomic structures from cryo-EM density maps remains challenging, particularly for large multi-chain complexes and assemblies. Here, we present an automated pipeline that integrates multi-modal deep learning and advanced structure prediction techniques to improve model accuracy. Our approach leverages a deep learning model that combines sequence-based features from a Protein Language Model with cryo-EM density maps, enabling a richer feature representation across modalities. The deep learning-predicted voxels are utilized to build a Hidden Markov Model (HMM) and a tailored Viterbi algorithm is used to align sequences to generate an initial protein backbone structures. These backbone models then serve as templates for AlphaFold3, which refines the structures for improved accuracy. Our approach combines cryo-EM data with AlphaFold3 predictions, helping to refine and improve AlphaFold3's predicted structures. By integrating both methods, we can generate more accurate and reliable atomic models, particularly for large proteins with complex conformations.
|
NA
|
biorxiv
| 80 |
10.1101/2025.03.15.643005
|
Molecular insight toward efficient & robust design of vesiculated protein nano-cages
|
Rahnama, S.; Ejtehadi, M. R.
|
Mohammad Reza Ejtehadi
|
Sharif University of Technology
|
2025-03-16
|
1
|
new results
|
cc_by_nc_nd
|
biophysics
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.15.643005.source.xml
|
Recently, recapitulation of viromimetic function in non-viral protein nanocages (PNCs) has emerged as a strategy to successfully encapsulate them in membrane vesicles. This method successfully evaded immune system detection. The mechanism responsible for triggering membrane budding and vesiculation remains elusive, primarily because the membrane initially interacts with a flat arrangement of proteins from nanocages (whether their shape is pyramidal, dodecahedron or icosahedron) and it is unclear how these seemingly flat protein arrangements can overcome the inherent mechanical resistance of the lipid bilayer to induce curvature. In this study, we considered a trimeric interface of a dodecahedron nanocage and explored the energetic and molecular role of its viromimetic module on protein nanocage packaging. Using a combination of all-atom and Martini coarse-graining molecular dynamics, we show that stronger highly basic region (HBR) promotes electrostatic sequestration of PIP2 lipids, known for their larger headgroups, around trimer binding sites, forming a PIP2 depletion zone in the central region of the trimer interface. Such lipid-sorting event resulted in membrane-thickness distribution with taller lipids accumulating toward the margins and shorter at the center of the trimer and inducing curvature to the lipid bilayer due to stretching and contraction events at different lipid interfaces. Our findings give molecular-level mechanistic insights into curvature generation and propagation in membranes induced by engineered PNC interactions, as well as a generic molecular design approach for clathrin-independent nanoparticle exocytosis.
|
NA
|
biorxiv
| 81 |
10.1101/2025.03.15.643457
|
Deep-learning models of the ascending proprioceptive pathway are subject to illusions
|
Perez Rotondo, A.; Simos, M.; David, F.; Pigeon, S.; Blanke, O.; Mathis, A.
|
Alexander Mathis
|
EPFL
|
2025-03-16
|
1
|
new results
|
cc_by_nc
|
neuroscience
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.15.643457.source.xml
|
Proprioception is essential for perception and action. Like any other sense, proprioception is also subject to illusions. In this study, we model classic proprioceptive illusions in which tendon vibrations lead to biases in estimating the state of the body. We investigate these illusions with task-driven models that have been trained to infer the state of the body from distributed sensory muscle spindle inputs (primary and secondary afferents). Recent work has shown that such models exhibit representations similar to the neural code along the ascending proprioceptive pathway. Importantly, we did not train the models on illusion experiments and simulated muscle-tendon vibrations by considering their effect on primary afferents. Our results demonstrate that task-driven models are indeed susceptible to proprioceptive illusions, with the magnitude of the illusion depending on the vibration frequency. This work illustrates that primary afferents alone are sufficient to account for these classic illusions and provides a foundation for future theory-driven experiments.
|
NA
|
biorxiv
| 82 |
10.1101/2025.03.15.642095
|
Structural Basis of Pseudomonas FapC Biofilm-Forming Functional Amyloid Formation
|
Hansen, K. H.; Golcuk, M.; Byeon, C. H.; Tunc, A.; Plechinger, E. B.; Conway, J. F.; Andreasen, M.; Gur, M.; Akbey, U.
|
Umit Akbey
|
University of Pittsburgh
|
2025-03-16
|
1
|
new results
|
cc_no
|
microbiology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.15.642095.source.xml
|
Biofilm-protected Pseudomonas aeruginosa causes chronic infections that are difficult to treat. FapC, the major biofilm forming functional-amyloid in Pseudomonas, is essential for biofilm integrity, yet its structural details remain unresolved. Using an integrative structural biology approach, we combine solution NMR-based structural ensemble of unfolded monomeric FapC, a ~3.3A resolution CryoEM density map of FapC fibril, and all-atom MD simulations to capture transition from unfolded to folded monomer to fibrillar fold, providing a complete structural view of FapC biogenesis. CryoEM reveals a unique triple-layer beta-solenoid cross-beta fibril composed of a single protofilament. MD simulations initiated from monomeric and fibrillar FapC mapped structural transitions, offering mechanistic insights into amyloid assembly and disassembly. Understanding FapC reveals how Pseudomonas exploits functional amyloids for biofilm formation and establishes a structural and mechanistic foundation for developing therapeutics targeting biofilm-related infection and antimicrobial resistance.
|
NA
|
biorxiv
| 83 |
10.1101/2025.03.15.641804
|
Systematic comparison of dCas9-based DNA methylation epimodifiers over time indicates efficient on-target and widespread off-target effects
|
Pahlevan Kakhki, M.; Rangani, F.; Ewing, E.; Starvaggi Cucuzza, C.; Zheleznyakova, G.; Kalomoiri, M.; v, T. V. S.; Covacu, R.; Andreou, I.; Needhamsen, M.; Kular, L.; Jagodic, M.
|
Maja Jagodic
|
Karolinska Institutet
|
2025-03-16
|
1
|
new results
|
cc_by
|
molecular biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.15.641804.source.xml
|
CRISPR/dCas9-based epigenome editing systems, including DNA methylation epimodifiers, have greatly advanced molecular functional studies revolutionizing their precision and applicability. Despite their promise, challenges such as the magnitude and stability of the on-target editing and unwanted off-target effects underscore the need for improved tool characterization and design. We systematically compared specific targeting of the BACH2 gene promoter and genome-wide off-target effects of available and novel dCas9-based DNA methylation editing tools over time. We demonstrate that multimerization of the catalytic domain of DNA methyltransferase 3A enhances editing potency but also induces widespread, early methylation deposition at low-to-medium methylated promoter-related regions with specific gRNAs and, interestingly, also with non-targeting gRNAs. A small fraction of the methylation changes associated with transcriptional dysregulation and mapped predominantly to bivalent chromatin associating both with transcriptional repression and activation. Additionally, specific non-targeting control gRNA caused pervasive and long-lasting methylation-independent transcriptional alterations particularly in genes linked to RNA and energy metabolism. CRISPRoff emerged as the most efficient tool for stable targeting of the BACH2 promoter, with fewer and less stable off-target effects compared to other epimodifiers but with persistent transcriptome alterations. Our findings highlight the delicate balance between potency and specificity of epigenome editing and provide critical insights into the design and application of future tools to improve their precision and minimize unintended consequences.
|
NA
|
biorxiv
| 84 |
10.1101/2025.03.15.643474
|
N2B27 media formulations influence gastruloid development
|
Balayo, T.; Lunn, S.; Pascual-Mas, P.; Fiuza, U.-M.; Vasudevan, A.; Frenster, J. D.; Galloon, H. Y.; Peirats, R. F.; Martinez Arias, A.; Dias, A.; Turner, D. A.
|
Andre Dias
|
Universitat Pompeu Fabra
|
2025-03-16
|
1
|
new results
|
cc_by_nc_nd
|
developmental biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.15.643474.source.xml
|
Gastruloids are 3D aggregates of pluripotent stem cells grown in suspension culture that mimic many aspects of gastrulation and early axial elongation. The N2B27 basal medium in which mouse gastruloids are cultured can either be home-made (HM-N2B27) with materials of known origin, or commercially sourced (NDiff227), where the exact formulation is unknown. In this study we examined whether these formulations resulted in significant differences in gastruloid development. Our results reveal that while both media enable the standard gastruloid elongation, HM-N2B27 results in gastruloids that start the elongation process earlier, have higher number of cells and an increased anterior domain. RNAseq analysis showed significant differences in cell fate specification, with HM-N2B27 gastruloids exhibiting higher expression of spinal cord-related genes, while NDiff227 favours mesodermal differentiation. Furthermore, differential gene enrichment analysis suggests that changes in key signalling pathways underline the differences between HM-N2B27 and NDiff227 gastruloids. These findings highlight the importance of basal media composition for gastruloid development, underscoring the need for careful media selection during in vitro engineering of stem cell-based embryo models.
|
NA
|
biorxiv
| 85 |
10.1101/2025.03.15.643290
|
Human genetic studies and zebrafish models identify Plxna4 as a regulator of adiposity, somatic growth, and feeding behaviours
|
Tandon, P.; Lyall, Z.; Cowie, M.; Minchin, J. E.
|
James EN Minchin
|
Centre for Cardiovascular Science, University of Edinburgh
|
2025-03-16
|
1
|
new results
|
cc_by_nc_nd
|
developmental biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.15.643290.source.xml
|
Obesity is a major public health crisis, affecting billions worldwide and increasing the risk of metabolic and cardiovascular diseases. While lifestyle factors play a role, genetic variation is a key determinant of both obesity susceptibility and the efficacy of treatment strategies. Recent studies have implicated the Semaphorin 3 signalling pathway in obesity; however, specific roles for pathway components remain largely unexplored. Here, we focus on Class A Plexins and their potential contributions to body weight regulation. Using large-scale genetic association data, we identified that rare, predicted loss-of-function mutations in PLXNA4 were associated with body mass index (BMI) in females. Furthermore, common variant analysis revealed that genetic variation at PLXNA4 was linked to BMI, height, and various neuropsychiatric disorders. To investigate the biological role of Plxna4, we generated zebrafish plxna4 loss-of-function mutants, which exhibited an ~92% reduction in Plxna4 protein. Despite appearing morphologically normal, mutant zebrafish at juvenile stages were shorter, had increased body fat levels relative to size-matched wild-type siblings, and displayed hypertrophic subcutaneous adipose tissue. Feeding assays revealed that plxna4 mutants consumed more food than wild-type siblings and exhibited food-stimulated hyperactivity, characterised by increased swimming speed, higher speed variability, and frequent high-speed bursts. Together, these findings demonstrate a conserved role for Plxna4 in regulating feeding behaviour and body fat levels, providing new insights into the genetic basis of obesity and warranting further studies to elucidate the molecular mechanisms underlying these effects.
|
NA
|
biorxiv
| 86 |
10.1101/2025.03.16.643389
|
Two sites in the C-terminal β-chain tail mediate interactions of the chaperone clusterin with amyloid beta and other misfolded client proteins
|
Satapathy, S.; Shen, Y.; Proctor, E.; Vendruscolo, M.; Sormanni, P.; Wilson, M. R.
|
Mark Richard Wilson
|
University of Wollongong
|
2025-03-16
|
1
|
new results
|
cc_no
|
biochemistry
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643389.source.xml
|
Clusterin (CLU) is the best known constitutively secreted mammalian chaperone which binds in extracellular body fluids to misfolded client proteins to neutralise their toxicity and mediate their safe disposal by cell uptake and intracellular degradation. Previously, the regions of CLU critical for its interactions with misfolded proteins were unknown. To search for CLU client protein binding sites, we expressed a variety of CLU deletion and alanine-stretch mutants in a recently developed mammalian expression system. Mutant CLU molecules lacking detectable structural aberrations were subjected to functional analyses to compare their abilities with that of wild type CLU to bind to misfolded proteins and to inhibit protein aggregation. These analyses implicated two regions in the CLU {beta}-chain as being important in the interactions of the chaperone with misfolded proteins, including aggregating Alzheimer {beta}-peptide. Finally, we used in silico designed sequence-specific single-domain camelid nanobodies to confirm the function of two putative client protein binding sites located in regions of flexibility in the {beta}-chain C-terminal tail. On the basis of our experimental results and outputs from in silico binding site predictive algorithms, we suggest that the potent ability of CLU to promiscuously interact with many different misfolded proteins, regardless of their size or structure, arises from the location of multiple client protein binding sites in its flexible tail region. The location of cell receptor binding sites remain to be established but may be located distant from the misfolded protein binding sites to reduce steric hindrance when CLU-client protein complexes bind to cells prior to their uptake and degradation.
|
NA
|
biorxiv
| 87 |
10.1101/2025.03.16.643490
|
A rapid and efficient red-light-activated Cre recombinase system for genome engineering in mammalian cells and transgenic mice
|
Zhou, Y.; Wei, Y.; Yin, J.; Kong, D.; Li, W.; Wang, X.; Yao, Y.; Huang, Q.; Li, L.; Liu, M.; Qiao, L.; Li, H.; Zhao, J.; Zhong, T. P.; Li, D.; Duan, L.; Guan, N.; Ye, H.
|
Haifeng Ye
|
East China Normal University
|
2025-03-16
|
1
|
new results
|
cc_no
|
synthetic biology
|
https://www.biorxiv.org/content/early/2025/03/16/2025.03.16.643490.source.xml
|
The Cre-loxP recombination system enables precise genome engineering; however, existing photoactivatable Cre tools suffer from several limitations, including low DNA recombination efficiency, background activation, slow activation kinetics, and poor tissue penetration. Here, we present REDMAPCre, a red-light-controlled split-Cre system based on the {Delta}PhyA/FHY1 interaction. REDMAPCre enables rapid activation (1-second illumination) and achieves an 85-fold increase in recombination efficiency. We demonstrate its efficient regulation of DNA recombination in mammalian cells and mice, as well as its compatibility with other inducible recombinase systems for Boolean logic-gated DNA recombination. Using a single-vector adeno-associated virus (AAV) delivery system, we successfully induced REDMAPCre-mediated DNA recombination in mice. Furthermore, we generated a REDMAPCre transgenic mouse line and validated its efficient, light-dependent recombination across multiple organs. To explore its functional applications, REDMAPCre transgenic mice were crossed with the relative Cre-dependent reporter mice, enabling optogenetic induction of insulin resistance and hepatic lipid accumulation via Cre-dependent overexpression of ubiquitin-like with PHD and ring finger domains 1 (UHRF1), as well as targeted cell ablation through diphtheria toxin fragment A (DTA) expression. Collectively, REDMAPCre provides a powerful tool for achieving remote control of recombination and facilitating functional genetic studies in living systems.
|
NA
|
biorxiv
| 88 |
10.1101/2025.03.14.643233
|
A simple way to find related sequences with position-specific probabilities
|
Frith, M.
|
Martin Frith
|
University of Tokyo & AIST
|
2025-03-17
|
1
|
new results
|
cc_by
|
bioinformatics
|
https://www.biorxiv.org/content/early/2025/03/17/2025.03.14.643233.source.xml
|
One way to understand biology is by finding genetic sequences that are related to each other. Often, a family of related sequences has position-varying probabilities of substitutions, insertions, and deletions: we can use these to find distant and subtle relationships. There are popular software tools for this task, which all have limitations. They either do not use all probability evidence (e.g. PSI-BLAST, MMseqs2), or have excessive complexity and minor biases (e.g. HMMER). This complexity inhibits fertile development of alternative tools. This study describes a simplest reasonable way to find related sequences with position-specific probabilities, using all probability evidence. The algorithms likely use the fewest operations that such algorithms possibly could, so they are fast and simple. This study does not describe practical heuristics for large data, but rather a \"theory\" that can be used in practical tools.
|
NA
|
biorxiv
| 89 |
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