- BioRxiv Biochemistry
- BioRxiv Bioinformatics
- BioRxiv Biophysics
- BioRxiv Cancer Biology
- BioRxiv Pharmacology and Toxicology
- BioRxiv Systems Biology
- BioRxiv Zoology
- by Long, W., Hou, Y., Zhang, Y.Motivation: Reliable topologically associating domain (TAD) calling from Hi-C contact maps remains difficult at high resolution and realistic sequencing depth. A central reason is that many callers learn boundary evidence largely from local signals, while domain compatibility is handled mainly during downstream decoding, so the learned boundary scores are not explicitly optimized for the TAD assembly step that ultimately determines the final calls. Results: We present ContextTAD, a deep-learning TAD caller that learns boundary evidence from broader local Hi-C windows […]
- by Garcia-Guillen, J., Ahmadi, M., Frimpong, T., Pacheco, K., Ambuehl, I., Mau, C., Duah, G., Oraby, T., El-Sherif, E.How spatial patterns arise during embryonic development is classically explained by the French Flag model, in which cells acquire positional identities by interpreting morphogen concentration thresholds. However, in many developmental systems, spatial patterns instead emerge progressively through temporal programs of gene expression that are transformed into spatial organization. In the short-germ insect Tribolium castaneum, both periodic pair-rule gene expressions that generate body segments and non-periodic gap gene expressions that establish regional identities arise sequentially at the posterior and propagate anteriorly […]
- by Clement, M., Gibbs, A., Begum, A., Siebzehnrubl, D., Kaushik, S., Singh, N., Gupta, B., Eftychidis, V., Siebzehnrubl, F. A.Glioblastomas are incurable and lethal brain cancers. Immunotherapies offer new and promising treatment options for glioblastoma patients, but the highly immunosuppressive nature of these cancers presents a challenging clinical obstacle. Glioblastoma immune evasion is driven by cell-cell interactions in the tumor microenvironment and recent studies have identified astrocytes as important contributors to immune silencing [1, 2]. Cell plasticity is a key feature of reactive astrocytes that drives heterogeneous, pro- or anti-inflammatory states [3], but the molecular regulators of astrocyte-immune interactions […]
- by Wang, Y., Tushar, M. A. K., Lucero, O., Zimmern, P. E., Li, Z.Objective: Neurogenic lower urinary tract dysfunction (NLUTD) impairs bladder control and remains difficult to treat. We aim to define how electrical stimulation (ES) parameters of the external urethral sphincter (EUS) affect urinary leakage thresholds to guide neuromodulation strategies for NLUTD. Methods: We performed direct EUS stimulation in anesthetized rats using charge-balanced biphasic pulses while systematically varying current amplitude (0.5-3.0 mA), frequency (20-100 Hz), and pulse duration (0.5-3 ms). Urine leakage thresholds were mapped across the multidimensional parameter space. Results: Stimulation […]
- by Zivkovic, L., Sumarac, S., Crompton, D., Hutchison, W. D., Lozano, A. M., Kalia, S. K., Milosevic, L.Introduction Stimulation-evoked potentials (SEPs), recorded both during and after deep brain stimulation (DBS) surgery, have shown promise for guiding DBS targeting and programming. However, filtering protocols applied to stimulation trains produce an artifact we call a filter-induced oscillation (FIO) which closely mimics physiological SEPs. Hence, we outline the mechanistic origins of this distortion and describe a means of differentiating it from valid SEP activity. Methods We recorded in 18 patients undergoing DBS surgery targeting the subthalamic nucleus or globus pallidus […]
- by Dannen, K. E., Yang, J., Bernholtz, J., Glebov-McCloud, A., Strack, S., Koland, J. G., Fisher, R. A., Stewart, A.Regulator of G protein Signaling 6 (RGS6), heavily implicated in neurological and neuropsychiatric disorders, is enriched in mouse and human brain. Our initial cloning effort identified 36 RGS6 mRNAs in human brain. However, we recently identified an additional RGS6 protein isoform that is larger (~69kDa) than the ubiquitously expressed ~56kDa RGS6L(+GGL) isoforms. Notably, this isoform, named RGS6B for brain-specific, is selectively expressed in the nervous system of mice and humans. Here, we report the cloning of a new RGS6-encoding mRNA, […]
- by Zhang, Y., Yang, X., Kang, Y., Zhu, W., Sun, Y., Qi, S., Chen, Y., Zhuang, G., Sun, A.-J.Infectious bursal disease virus (IBDV) and H9N2 avian influenza virus (AIV) are significant global threats to poultry health and production. While IBDV induces severe immunosuppression, undermining host defense and vaccine efficacy, H9N2 AIV is characterized by widespread prevalence, persistent shedding, and substantial economic losses. Conventional inactivated vaccines often fail to elicit robust cellular immunity and necessitate multiple booster doses, underscoring the urgent requirement for advanced multivalent vaccination platforms. To address this, we developed a recombinant herpesvirus of turkey (rHVT BAC-VP2-HA) […]
- by Wibisono, P., Liu, Y., SUN, J.Understanding how the nervous system regulates immune responses requires insight into how individual neurons respond to infection. In Caenorhabditis elegans, sensory neurons such as ASH play important roles in modulating innate immunity; however, the molecular mechanisms operating within these neurons remain poorly defined. Previous transcriptomic studies have relied on whole-animal RNA sequencing, which lacks the cellular resolution needed to detect neuron-specific signaling programs. Here, we performed single-type neuron transcriptomic profiling to characterize gene expression in ASH neurons from infected and […]
- by Swain, B., Sahoo, R. K.Sex ratio is a key demographic parameter shaping population dynamics and evolutionary trajectories. In biocontrol agents, demographic bottlenecks during species introduction to a new habitat and subsequent mass rearing can elevate inbreeding, potentially biasing sex ratios through sex-specific mortality associated with inbreeding depression. Moreover, reproductive endosymbionts such as Wolbachia are known to manipulate host reproduction and further skew sex ratios. However, the relative contributions of these processes to sex-ratio variation remain poorly resolved. In this study, we evaluated the effects […]
- by Park, Y.-K., Lee, J.-E., Skoultchi, A. I., Picketts, D. J., Peng, W., Ge, K.The ISWI chromatin remodeler regulates nucleosome spacing using one of two ATPase subunits Snf2h (Smarca5) and Snf2l (Smarca1). While Snf2h stable knockout (KO) is known to markedly reduce genomic binding of CTCF, an architectural protein organizing the 3D genome, ISWI's role in regulating genomic binding and function of lineage-determining transcription factors (LDTFs) during cell fate transition remains largely unclear. Using conditional KO mice and derived cells, we show Snf2h and Snf2l are partially redundant and are required for embryonic development […]
- Climate Gradients and Habitat Discontinuity Structure Genetic Variation in a Spring-Specialist Plantby Weiss, M., Faske, T. M., Holeski, L. M.Groundwater-dependent ecosystems support disproportionate biodiversity in arid regions, yet the population genetics of spring-specialist plants remains poorly understood. Here, we present the first species-wide genetic dataset for crimson monkeyflower (Mimulus verbenaceus, Phrymaceae), a spring-specialist plant distributed in seeps, springs, and associated riparian areas across desert regions of North America.Using genome-wide reduced representation sequencing data consisting of 10,760 SNPs from 175 individuals across 17 populations, we characterized the patterns of genetic diversity using FST and Neis D. Population structure was assessed […]
- by Rallapalli, K. L., Ho, J., Nocedal, I., Tan, J. W., Ocampo, R. F., Thomas, N. C., Justice, B., Jirde, S., Gonzalez-Osorio, L., Castelle, C. J., Lin, J.-L., Wright, J. T., Toch, S., Shah, K., Freeman, B., Rehman, J., Muysson, J., Krudop, I., Alexander, L. M., Brooks, A. R., Brown, C. T., Goltsman, D. S. A., Hoff, K. G., Szymanski, P., Thomas, B. C., Taylor, D. W., Butterfield, C. N.Adenine base editors (ABEs) have emerged as a powerful gene-editing technology enabling precise and programmable adenine-to-guanine substitutions across the genome. However, their translation into in vivo therapeutics is limited by delivery challenges, as their size exceeds the packaging capacity of adeno-associated virus (AAV). Here, we report the discovery, structural characterization, and engineering of two compact, highly active ABEs built on novel deaminases and Cas9d nucleases, enabling all-in-one, single-vector AAV delivery. Applying these compact ABEs to Duchenne muscular dystrophy (DMD), we […]
- by Venkataraman, Y. R., Shapiro, S. K., Newbrey, M., Tepolt, C. K.Many marine invertebrates are characterized by broad and highly plastic thermal limits, though the dynamic molecular mechanisms that enable extended thermal acclimation remain poorly understood. A classic example is the green crab (Carcinus maenas), which is a prolific and damaging non-indigenous species. Using a 22-day thermal exposure to cold (5{degrees}C), ambient (13{degrees}C), or warm (30{degrees}C) temperatures, we characterized plastic shifts in C. maenas performance using respirometry and time-to-right. We then used untargeted metabolomics and lipidomics analysis of heart tissues from […]
- by Yang, X., Huang, Y.-W. A.Oligodendrocyte precursor cells (OPCs) are essential for sustaining myelin plasticity and maintaining oligodendroglial homeostasis throughout life. However, the intrinsic signaling mechanisms that regulate OPC generation from neural progenitors remain incompletely understood. Here, we identify chitinase-3-like protein 1 (CHI3L1/YKL-40) as a stage-specific, intrinsic signaling regulator of oligodendroglial lineage progression. Using human iPSC-derived models, we show that CHI3L1 selectively targets a transient IL13R2-expressing pre-OPC population, where it induces ferroptosis through suppression of GPX4, thereby limiting OPC generation. In contrast, CHI3L1 does not […]
- by Toth, E. Z., Stelcz, R., Bod, R., Petik, A., Toth, K., Essam, N., Somogyi, F., Kovacs, B., Mojtahedzadeh, A., Bago, A. G., Eross, L., Szabo, J. P., Fabo, D., Hajnal, B., Racz, B., Hillier, D., Ulbert, I., Wittner, L.Human organotypic slice cultures provide experimental access to adult human neuronal circuits ex vivo, yet it remains unclear whether these networks preserve function or undergo fundamental reorganization following the profound perturbation of slice preparation. Here, we combined extracellular population and single-unit electrophysiology, longitudinal calcium imaging, and quantitative histology to track the changes of human cortical slice cultures over several weeks in vitro. Early phases were marked by pronounced variability and instability, with reduced firing rates, increased burst propensity in principal […]
- by Gautam, A. K., umarao, P., Gourinath, S.The Rho family of small GTPases plays a critical role in regulating actin cytoskeleton dynamics during endocytic processes in E. histolytica, including phagocytosis, pinocytosis, and trogocytosis. These proteins act as molecular switches, transitioning between inactive GDP-bound and active GTP-bound states, with guanine nucleotide exchange factors (GEFs) catalyzing this transition. Among the GEFs, EhFP10, a FYVE domain-containing protein harbouring Dbl homology (DH) and pleckstrin homology (PH) domain was observed in phagocytosis along with seven functionally characterized Rho GTPases (EhRho1, EhRho2, EhRho4, […]
- by Lamarins, A., Waples, R. S., Piironen, J., Primmer, C. R.Effective population size (Ne) is a critical parameter for evaluating the evolutionary and persistence potential of endangered populations and for designing sustainable conservation strategies. Captive breeding and release programs are widely used across taxa to reduce risk of extinction when natural reproduction is insufficient or no longer possible, making it essential to assess their consequences. We used the case study of the landlocked Saimaa salmon (Salmo salar), one of the most critically endangered salmonid populations in Europe, with unique evolutionary […]
- by Ke, C.-L., Xu, J., Frazer, C., Bennett, R. J.Here, we develop CandiChrome, a multiplex labeling toolkit for Candida albicans, through combined in vitro and in vivo characterization of fluorescent proteins in a standard strain background. To this end, we screened 13 candidate fluorophores across the visible spectrum and assessed their practical performance based on brightness, stability, and usability. This analysis identified a seven-fluorophore set that achieved the most effective balance of signal strength, robustness, and compatibility. We used this optimized panel to build a modular multicolor platform that […]
- by Roeles, J., Giesler, A., Schmitz, J., Koenig, J., Friedersdorff, F., Busch, J., Greite, R., Krappitz, M., Layne, I., Koettgen, M., Kuehn, W. E., Schmid, J., Schmidt, K., Hoeft, K., Kramann, R., Eckardt, K.-U., Kocks, C., Braesen, J. H., Halbritter, J., Schmitt, R., Haerteis, S., Hopp, K., Schmidt-Ott, K. M., Hinze, C.Autosomal dominant polycystic kidney disease (ADPKD) exhibits substantial interpatient variability in disease course and therapeutic response, but the cellular basis for this variability remains poorly understood. Here, we combine single-nucleus RNA sequencing of human cyst epithelia with machine learning-based histological analysis of >1,800 cysts to resolve three epithelial cyst types-proximal tubule-like, collecting duct-like, and mixed. These cyst types display distinct injury states, metabolic programs, and stromal microenvironments, including a mixed-cyst niche enriched for CCL2-associated inflammatory signaling. Expression of key therapeutic […]
- by He, L., Su, Y.-W. N., Zhang, F., Moustafa Abdelrady, I., Gohara, D. W., Ye, C., Martinez-Sobrido, L., Arnold, J. J., Cameron, C. E., Xiang, Y.Coronaviruses (CoVs) replicate unusually large RNA genomes that necessitate proofreading by the 3'-to-5' exoribonuclease (ExoN) formed by nonstructural proteins 14 (nsp14) and 10 (nsp10). Previous studies suggested that inactivation of the ExoN catalytic site in severe acute respiratory syndrome CoV 2 (SARS-CoV-2) is lethal, leaving unresolved whether the virus can tolerate impaired proofreading activity. Here, we investigated the functional requirement for ExoN in SARS-CoV-2 replication by combining a continuous fluorescence-based biochemical assay with an optimized single-bacmid reverse genetics system. Mutational […]