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<title>bioRxiv</title>
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<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.17.759802v1?rss=1">
<title>
<![CDATA[
Dietary phosphorus restriction enables multigenerational breeding of α-Klotho-deficient rats 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.17.759802v1?rss=1
</link>
<description><![CDATA[
Severe -Klotho deficiency causes early mortality and reproductive impairment, limiting the maintenance and physiological analysis of rat models. We generated rats carrying a CRISPR/Cas9-mediated -Klotho deletion spanning exons 1-5 and evaluated dietary phosphorus restriction primarily in the Wistar-Imamichi background. Maternal low-phosphorus (LP) feeding from mating through lactation was associated with higher overall survival to weaning (92.6% versus 85.8% under normal-phosphorus conditions) and a higher proportion of KO animals among weaned survivors (34/113 versus 23/145). Maternal LP feeding also reduced plasma phosphorus in KO pups. Continued LP feeding after weaning supported growth, gonadal development, and natural KO x KO breeding. Across 15 litters, 74 of 85 offspring survived to weaning, and KO colonies were maintained to at least the fifth generation. We additionally characterized 24-h metabolic rhythms in LP-maintained KO animals using indirect calorimetry. These profiles remained heterogeneous under a light-dark cycle. In conclusion, dietary phosphorus restriction provides a reliable strategy for the multigenerational maintenance of severe -Klotho-deficient rats, establishing a maintainable model to investigate residual metabolic and physiological phenotypes.
]]></description>
<dc:creator><![CDATA[ Sarai, C., Totsuka, Y., Horii, T., Tamura, S., Gouda, E., Kojima, S., Kouki, T., Ohno, N., Yoshiki, A., Ohmori, T., Kurosu, H., Endo, H., Tominaga, K., Hatada, I., Yamamoto, T., Kuro-o, M., Nagao, Y. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.17.759802</dc:identifier>
<dc:title><![CDATA[Dietary phosphorus restriction enables multigenerational breeding of α-Klotho-deficient rats]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.12.758406v1?rss=1">
<title>
<![CDATA[
CAPO: Compute-Aware Automated Protein-Model Optimization 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.12.758406v1?rss=1
</link>
<description><![CDATA[
Protein models such as Evolutionary Scale Modeling (ESM), AlphaFold and Boltz have transformed computational protein science, yet a pretrained model rarely transfers to a particular laboratory's assay without adaptation to its data and experimental setting, and that adaptation is technically demanding and spends real compute budget. Existing agentic systems can automate model training, yet typically treat fine-tuning as a reliable tool call: feasibility and cost are estimated rather than measured, and infeasibility is discovered only after compute has been spent. We formulate protein-model adaptation as a gated decision problem: given a task, raw data and a compute budget c_max, a system should decide whether and how to adapt a model before committing expensive computation. We introduce CAPO (Compute-Aware Automated Protein-Model Optimization), a multi-agent system built around one rule: gate before you train. CAPO measures feasibility on the target accelerator, projects cost against the available budget, runs a canary inside the actual training loop and maintains an auditable artifact trail; critically, it can decline an unaffordable adaptation and select a cheaper alternative. We evaluate CAPO, without system changes, on three protein-modeling tasks: (i) SARS-CoV-2 host-range prediction, (ii) hit-to-lead affinity ranking and (iii) temporal variant-effect reclassification. On host range, CAPO partially fine-tuned an 8-million-parameter ESM-2 model to a species-averaged MCC of 0.826, compared with 0.743 for a hand-designed expert transformer; it matched a general coding agent while using 57.4% less GPU time and reduced failed training trials from four to zero. For hit-to-lead affinity ranking, CAPO rejected Boltz-2 fine-tuning and instead trained an assay-calibrated lightweight head over frozen representations, improving ranking on 11 of 15 held-out targets in 1.68 GPU-hours. On temporally held-out ClinVar variants, rank-4 low-rank adaptation of ESM-2 reached an MCC of 0.478, compared with 0.252 for a one-hot baseline and 0.000 for the frozen zero-shot score. These results come from single runs, without a gate ablation and with one generalist-agent comparison. Within those limits, they show that measured admission control can make protein-model adaptation not only automated but selective: deciding what to compute, what not to compute and why.
]]></description>
<dc:creator><![CDATA[ Schifferli, T., Garcia Pardinas, J., B. Irvine, E., Hartley, M.-A., Bikias, T. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.12.758406</dc:identifier>
<dc:title><![CDATA[CAPO: Compute-Aware Automated Protein-Model Optimization]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.12.758456v1?rss=1">
<title>
<![CDATA[
Beyond Better Models: Barriers and a Path Forward in Generalisable TCR Antigen Specificity Prediction 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.12.758456v1?rss=1
</link>
<description><![CDATA[
T cells are at the centre of adaptive immunity, protecting the organism against infection and cancer. T cell receptors (TCRs), expressed on the surface of T cells, enable the recognition of target cells through interactions with peptides presented by major histocompatibility complex (pMHC) molecules. Reliable, large-scale mapping of TCRs to their cognate pMHCs remains a holy grail of modern systems immunology, with far-reaching implications for cancer immunotherapy, vaccine development, and the understanding and treatment of autoimmune diseases. While exhaustive experimental mapping remains intractable due to the enormous combinatorial sequence space of TCRs and pMHCs, computational approaches offer a promising alternative. Consequently, we have witnessed increasingly sophisticated computational models of TCR antigen specificity, from small neural networks to deep generative models and large protein language models. However, several independent benchmarks have shown that these models, despite their size and sophistication, largely fail to generalise to TCRs or pMHCs not present in the data available during model development. Here, we investigate possible reasons for this and suggest a path forward to generalisable TCR:pMHC prediction. First, our analysis of the largest public repositories of TCR:pMHC data reveals significant biases towards a small number of antigens and MHC molecules, sparse sampling of TCR sequence space per pMHC, as well as inconsistencies and inaccuracies in data collation. Second, we show the importance of carefully setting up model evaluation to measure discrimination based on antigen specificity instead of confounding factors present in the evaluation data. Finally, we highlight the need for and propose how best to match the evaluation metric with the specific downstream application of the predictions. Our investigation suggests that we, as a community, need more representative and better curated data, and a robust set of metrics and benchmarks to guide future model development towards generalisable TCR:pMHC specificity prediction.
]]></description>
<dc:creator><![CDATA[ Koohy, H., Ilievski, I., Antanaviciute, A., Ogg, G. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.12.758456</dc:identifier>
<dc:title><![CDATA[Beyond Better Models: Barriers and a Path Forward in Generalisable TCR Antigen Specificity Prediction]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.12.758592v1?rss=1">
<title>
<![CDATA[
A Humanized Mouse Model of DRPLA Recapitulates Epilepsy and Demonstrates Antisense Oligonucleotide-Mediated Disease Modification 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.12.758592v1?rss=1
</link>
<description><![CDATA[
Dentatorubral-pallidoluysian atrophy (DRPLA) is an ultra-rare progressive myoclonus epilepsy caused by a glutamine-coding CAG repeat expansion in atrophin-1 (ATN1). Mutant ATN1 (mATN1) expression results in symptoms that inversely correlate to CAG-expansion size: young-onset cases have the most CAG repeats and developmental delay, high-frequency treatment-resistant seizures, and early mortality. We sought to characterize the seizure susceptibility of a fully humanized ATN1 mouse expressing human mATN1 with 112 CAG repeats to then assess therapeutic antisense oligonucleotide (ASO) intervention on seizure-related outcomes. Atn1Q112/+ or wild-type (WT) mice were treated with investigational ASO targeting human, CAG-expanded, ATN1 or saline (P2 and then again at 4 weeks-old) before acute seizure testing, ataxia profiling, and chronic in vivo video-EEG recording for spontaneous seizures up to 8 weeks-old. Saline-treated Atn1Q112/+ mice were more seizure prone with early death. However, ASO administration to Atn1Q112/+ mice normalized seizure threshold, decreased ataxia, and protected against early death. Atn1Q112/+ mice exhibited spontaneous behavioral seizures recorded over 2 weeks, which were absent in ASO-treated Atn1Q112/+ and WT mice, with a specific mATN1 expression-driven decrease in delta and theta EEG frequencies. Atn1Q112/+ mice are highly seizure prone, validating this model for DRPLA epilepsy. ATN1 represents a novel epilepsy-related risk factor for therapeutic investigation.
]]></description>
<dc:creator><![CDATA[ WU, Q., Erickson, I., Davidson, S., Shonka, S., Smith, V., Gidi, B., Knox, K., Yu, T. W., Khurana, V., Carroll, J., Korecka, J. A., Barker-Haliski, M. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.12.758592</dc:identifier>
<dc:title><![CDATA[A Humanized Mouse Model of DRPLA Recapitulates Epilepsy and Demonstrates Antisense Oligonucleotide-Mediated Disease Modification]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.13.755060v1?rss=1">
<title>
<![CDATA[
Vibrotactile stimulation on the upper back requires stronger vibration during goal-directed reaching but does not impede reaching performance 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.13.755060v1?rss=1
</link>
<description><![CDATA[
Vibrotactile stimulation is a promising method of biofeedback, with potential applications for ergonomic posture and balance, rehabilitation, and motor learning. These applications require balancing tactile perception with motor performance and cognitive workload. In this study, participants performed a detection task, a reaching task, and a concurrent reach-and-detect task, with vibrotactile signals delivered on the hand or upper back. Sensitivity to stimuli, motor performance, and cognitive workload were compared for each task. Sensitivity was suppressed during movement, but this suppression was greater on hand compared to the upper back. Movement time was slowed by vibration on the hand but not the upper back. Mental workload and task complexity increased for the reach-and-detect task compared to the individual tasks. We conclude that vibrotactile feedback devices worn on the upper back do not impede motor performance, with only minor tactile suppression. This could be overcome by presenting highly salient or personalized feedback.
]]></description>
<dc:creator><![CDATA[ Atkin, A. E., 't Hart, B. M., Whyne, C. M., Tomescu, S., Strauss, B. H., Li, Q., Henriques, D. Y. P. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.13.755060</dc:identifier>
<dc:title><![CDATA[Vibrotactile stimulation on the upper back requires stronger vibration during goal-directed reaching but does not impede reaching performance]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.13.758728v1?rss=1">
<title>
<![CDATA[
Functional characterization of the 26RFa/orexin neurons of the lateral hypothalamic area reveals their key role in the control of glucose homeostasis 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.13.758728v1?rss=1
</link>
<description><![CDATA[
Defining the nature and molecular mechanisms of the neurocircuitry controlling glucose homeostasis is crucial in understanding how alterations in these pathways promote the development of obesity and type 2 diabetes. Here, we functionally characterize a population of lateral hypothalamic neurons co-expressing the anti-hyperglycemic neuropeptides 26RFa and orexin. Using complementary chemogenetic, pharmacological and genetic approaches, including mice deficient for 26RFa, orexin or both neuropeptides, we investigated the respective contribution of each signaling system to glucose homeostasis. We found that lateral hypothalamic 26RFa neurons extensively co-express orexin, defining a distinct peptidergic population with convergent anti-hyperglycemic properties. Unexpectedly, chemogenetic activation of these neurons potentiated glucose-induced hyperglycemia despite the anti-hyperglycemic properties of both neuropeptides. To understand this paradox, we examined the transcriptional responses of the 26RFa and orexin peptidergic systems and found that neuronal activation was associated with coordinated, glycemic state-dependent downregulation of both signaling systems. Furthermore, genetic loss-of-function approaches revealed distinct contributions of the two neuropeptidergic systems, with orexin signaling mediating most of the metabolic consequences of neuronal activation, whereas 26RFa signaling is required for the dynamic regulation of orexin expression. Finally, our findings provide new insights into the functional organization of lateral hypothalamic 26RFa/orexin neurons and advance our understanding of how coordinated neuropeptidergic signaling contributes to systemic glucose homeostasis.
]]></description>
<dc:creator><![CDATA[ Devere, M., Lusurier, C., Takhlidjt, S., Cherifi, Y., Nedelec, E., Benani, A., Rosay, M., Godefroy, D., Arabo, A., Lefranc, B., Leprince, J., Prevost, G., chartrel, n., PICOT, M. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.13.758728</dc:identifier>
<dc:title><![CDATA[Functional characterization of the 26RFa/orexin neurons of the lateral hypothalamic area reveals their key role in the control of glucose homeostasis]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.17.759680v1?rss=1">
<title>
<![CDATA[
Diurnal Variations in the Cholinergic System of the Nucleus Accumbens 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.17.759680v1?rss=1
</link>
<description><![CDATA[
The nucleus accumbens (NAc) plays a critical role in reward-related behaviors, which exhibit diurnal variations. Cholinergic interneurons (CINs) are the primary source of acetylcholine within the NAc and regulate local dopamine (DA) signaling through nicotinic acetylcholine receptors (nAChRs). Although there are diurnal variations in NAc dynamics, little is known about whether CIN activity and nicotinic signaling also vary across the light/dark cycle. Here, we aimed to determine diurnal variations in the NAc cholinergic system using ex vivo fast-scan cyclic voltammetry and cell-attached electrophysiological recordings in male rodents. We examined time-of-day-dependent differences in nAChR-mediated modulation of DA release, spontaneous CIN firing frequency, and firing patterns. We found that spontaneous CIN firing varied across the light/dark cycle, with increased activity during the dark cycle. Additionally, bath application of nicotine (NIC), mecamylamine (MEC), and dihydro-{beta}-erythroidine (DH{beta}E) reduced CIN firing frequency during the dark cycle, with only MEC decreasing firing frequency in the light cycle. NIC and MEC also altered CIN firing patterns during the dark cycle, whereas DH{beta}E primarily affected firing frequency. Together, these findings demonstrate diurnal variations in NAc CIN activity and reveal time-of-day-dependent differences in the effects of nAChR modulation on spontaneous firing. These results suggest that nicotinic signaling may contribute to diurnal regulation of NAc cholinergic activity, providing insight into mechanisms underlying time-of-day-dependent changes in reward circuitry.
]]></description>
<dc:creator><![CDATA[ Stowe, T. A., Huang, Y., Ferris, M., McClung, C. A. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.17.759680</dc:identifier>
<dc:title><![CDATA[Diurnal Variations in the Cholinergic System of the Nucleus Accumbens]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.12.758495v1?rss=1">
<title>
<![CDATA[
Sex shapes capillary flows and oxygen extraction in the middle-aged mouse brain 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.12.758495v1?rss=1
</link>
<description><![CDATA[
Sex differences in brain aging are well documented, but their origin within the cerebrovascular hierarchy remains unclear. Here we show that cortical blood flow is higher in female than male mice at 15 months of age, at a point when an earlier sex difference in pulsatility and resistance indices has already converged, pial vessel diameter shows no difference between sexes, and estrogen levels are similar between sexes. Using an indicator-dilution and intravascular oxygen measurements using two-photon microscopy, we found that capillary transit-time heterogeneity (CTH) scales more steeply with mean transit time in females, consistent with a passively regulated capillary network, and that this is accompanied by reduced oxygen extraction fraction (OEF) without deficit in arterial oxygen delivery. Spatial transcriptomics reveals that sex differences are organized into distinct regional programs, most prominently in white matter, where a male-associated myelin and axonogenesis signature accompanies reduced white matter volume in females. These molecular and structural differences coincide with elevated hippocampal microglial reactivity and an altered spatial search strategy in females, without any detectable differences in circulating markers of stress, blood-brain barrier integrity, or immunity. Together, these findings indicate that sex differences in the aging brain are expressed at the level of capillary flow regulation and regional tissue programs rather than through bulk cerebral blood flow alone, and that elevated blood flow in females can mask, rather than reflect, adequate tissue oxygenation.
]]></description>
<dc:creator><![CDATA[ Gutierrez-Jimenez, E., Wied, B., Lindhardt, T. B., Mikkelsen, S. H., Knopper, R. W., Skoven, C. S., Christensen, O. B., Dashkovskyi, V., Mrotek, F., Rasmussen, P. M., Andresen, M. H., Krmpot, A., Khatib, M. E., Vinogradov, S. A., Sakadzic, S., Jensen, M. F., Pedroza-Pacheco, I., Postnov, D. D., Lin, L., Just, J., Hansen, B., Ostergaard, L. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.12.758495</dc:identifier>
<dc:title><![CDATA[Sex shapes capillary flows and oxygen extraction in the middle-aged mouse brain]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.17.759799v1?rss=1">
<title>
<![CDATA[
Temporal tuning of actin nucleation by the repurposed DNA repair complex RAD51/fignl1 encodes distinct axon guidance decisions 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.17.759799v1?rss=1
</link>
<description><![CDATA[
Axon guidance is essential for neural circuit assembly and function. While much of the repertoire of guidance cues and receptors is known, its limited diversity cannot fully explain the remarkable complexity of the brain connectome. How temporally ordered, context-dependent intrinsic programs shape the diversity of axonal responses to guidance signals remains poorly understood. We reveal how non-canonical Wnt5a signalling repurposes the DNA repair complex RAD51/fignl1 as a downstream integrator to control retinal ganglion cell axon decision-making at the midline. We demonstrate that differential RAD51/fignl1 expression and interaction dynamics between ipsilateral and contralateral axons tunes the magnitude and temporal dynamics of F-actin nucleation, thereby encoding their trajectory choice. Our findings establish temporal control of cytoskeletal dynamics as a key determinant of axon decision-making and thereby a fundamental layer of circuit wiring. They provide a potential mechanistic framework linking mutations in the DNA repair gene RAD51 to neurodevelopmental disorders with midline guidance defects.
]]></description>
<dc:creator><![CDATA[ Zerkoune, S., Zagar, Y., Delaroche, J., Danicka, J., Vougny, J., Uthayasuthan, S., Aureille, J., Roche, F., Haantjes, R., Gomez-Bravo, C., Baudet, S., Denarier, E., Zainu, A., Bun, P., Guillonneau, X., Debant, A., Baudat, F., Nicol, X., Pietrancosta, N., Boudeau, J., Andrieux, A., Arnal, I., Antkowiak, A., Fassier, C. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.17.759799</dc:identifier>
<dc:title><![CDATA[Temporal tuning of actin nucleation by the repurposed DNA repair complex RAD51/fignl1 encodes distinct axon guidance decisions]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.12.758423v1?rss=1">
<title>
<![CDATA[
DNA-Encoded Library-Guided Discovery of a First-in-Class Molecular Glue of the NOS1AP-SCRIB Complex in Alzheimer's Disease Patient-Derived Neurons 
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</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.12.758423v1?rss=1
</link>
<description><![CDATA[
NOS1AP is an adaptor for neuronal nitric oxide synthase that engages several partner proteins and is implicated in Alzheimer's disease. Efforts to drug NOS1AP have sought to disrupt these; we instead report pharmacological stabilization of one interaction. Affinity selection of a 1.4-billion-member DNA-encoded library identified a benzimidazole-5-carboxamide chemotype, optimized by fragment-directed SAR to NOSTRA with submicromolar NOS1AP binding affinity. Of six interactions, NOSTRA enhanced only SCRIB binding, with a cooperativity factor of 30, predominantly through a 14-fold slowing of dissociation; native mass spectrometry resolved a NOS1AP:NOSTRA:SCRIB ternary complex. In healthy human iPSC-derived cortical neurons, NOSTRA engaged the endogenous complex and activated Rac1 without cytotoxicity; in Alzheimer's patient-derived neurons, it lowered the A{beta}42/A{beta}40 ratio and p-tau217, reduced neurofilament light and improved network activity. With an in vitro ADME profile consistent with CNS exposure, NOSTRA is the first molecular glue for a NOS1AP complex, establishing interaction stabilization as a viable NOS1AP pharmacology.
]]></description>
<dc:creator><![CDATA[ Kaur, B., Abdo, A., Cho, S., Gabr, M. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.12.758423</dc:identifier>
<dc:title><![CDATA[DNA-Encoded Library-Guided Discovery of a First-in-Class Molecular Glue of the NOS1AP-SCRIB Complex in Alzheimer's Disease Patient-Derived Neurons]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.12.758449v1?rss=1">
<title>
<![CDATA[
Pathological musculoskeletal characterisation of a new model of spontaneous OA in CD1 mice. 
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</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.12.758449v1?rss=1
</link>
<description><![CDATA[
Osteoarthritis (OA) is a whole joint disease involving pathological changes in cartilage, synovium, ligaments, menisci and periarticular muscle. This study provides a comprehensive musculoskeletal characterisation of spontaneous OA in male CD1 mice to evaluate their suitability as a model of naturally occurring disease. Knee joints from 3-4 and 6-8 month old mice were analysed histologically, OARSI scoring and immunohistochemistry for markers of chondrogenesis and endochondral ossification. Quadriceps and gastrocnemius muscles were examined for fibre cross sectional area. CD1 mice displayed mild OA at 3-4 months, progressing to moderate to severe disease by 6-8 months. Cartilage loss, synovial hyperplasia and fibrosis increased across compartments. Anterior cruciate and collateral ligaments, and medial meniscus exhibited marked pathological remodelling, including proteoglycan rich rounded cell regions and evidence of endochondral ossification with increased COL2, SOX9, RUNX2 and ASPN expression. Gastrocnemius muscle showed significant atrophy at 6-8 months, correlating with OA severity, whereas quadriceps atrophy was not significant. These findings establish CD1 mice as a robust spontaneous OA model that recapitulates the multi-tissue complexity of human disease. Because CD1 mice are globally available, cost-effective, genetically diverse and frequently, this model offers a practical and translationally relevant platform for investigating whole-joint organ mechanisms of OA progression and for evaluating therapies aimed at modifying disease across the entire joint.
]]></description>
<dc:creator><![CDATA[ Ramos-Mucci, L., Shorter, E., Dikmen, T., Keenan, C., Wen, Y., Wang, Y., Comerford, E., Goljanek-Whysall, K., Poulet, B. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.12.758449</dc:identifier>
<dc:title><![CDATA[Pathological musculoskeletal characterisation of a new model of spontaneous OA in CD1 mice.]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.11.758397v1?rss=1">
<title>
<![CDATA[
PlasmoRhythm: A comprehensive database for malaria-associated rhythmic transcripts, proteins, and metabolites 
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</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.11.758397v1?rss=1
</link>
<description><![CDATA[
Abstract: Motivation: The malaria transmission cycle is temporally organized across three interacting biological systems: the parasite, vertebrate host, and mosquito vector. Rhythms in parasite development, host physiology, and vector behavior govern infection dynamics, transmission, and the efficacy of stage-specific antimalarial interventions. However, the molecular architecture connecting these rhythms remains difficult to interrogate because time-resolved omics datasets are distributed across species, experimental paradigms, and analytical frameworks, with no unified resource for comparative analysis. Results: We developed PlasmoRhythm, a curated database integrating 67 transcriptomic, proteomic, and metabolomic datasets from 15 studies, encompassing 1,126 sampling events across Plasmodium species, mammalian hosts, and Anopheles vectors. Harmonized metadata and rhythmicity outputs from JTK_CYCLE, ARSER, Lomb-Scargle, and the meta2d function support interactive cross-study interrogation of molecular profiles. Dedicated modules enable the exploration of rhythmic virulence factors and antimalarial drug interactors, providing a unified framework for hypothesis generation across the malaria transmission cycle. Availability: PlasmoRhythm is freely accessible at https://project.iith.ac.in/cgntlab/PlasmoRhythm/.
]]></description>
<dc:creator><![CDATA[ Rankawat, S., Kundal, K., Singh, S., Das, S., Parisi, B., Korra, B. T., Rijo-Ferreira, F., Kumar, R., Ray, S. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.11.758397</dc:identifier>
<dc:title><![CDATA[PlasmoRhythm: A comprehensive database for malaria-associated rhythmic transcripts, proteins, and metabolites]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.12.758417v1?rss=1">
<title>
<![CDATA[
Pan-cancer nucleosome landscapes reveal tumor heterogeneity and inform cell-free DNA-based detection 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.12.758417v1?rss=1
</link>
<description><![CDATA[
Background: Nucleosome positioning and occupancy are fundamental features of chromatin organization, yet their variation across human cancers and potential utility for noninvasive cancer detection remain poorly characterized. Methods: We systematically characterized nucleosome organization across 410 primary tumors spanning 23 cancer types using ATAC-seq, establishing a high-confidence pan-cancer nucleosome atlas validated by independent MNase-seq data. We characterized shared and cancer-type-enriched nucleosome patterns, investigated their associations with tumor heterogeneity and regulatory alterations, and evaluated tissue-derived nucleosome signatures for cancer classification and detection using circulating cell-free DNA (cfDNA). Results: The atlas identified shared and cancer-type-enriched nucleosomes associated with distinct regulatory programs. Notably, nucleosome occupancy provided information complementary to chromatin accessibility for tumor stratification and revealed molecular heterogeneity within individual cancers, including subgroups associated with Basal-like breast cancer. In hepatocellular carcinoma, differential nucleosome analysis revealed cancer-associated chromatin remodeling involving regulatory pathways, transcription factor motifs, and candidate genes. Importantly, tissue-derived nucleosome signatures were detectable in cfDNA, enabling classification among three cancer types (AUROC = 0.877) and colorectal cancer detection (AUROC = 0.930), with an AUROC of 0.773 in an independent validation cohort. We also developed OncoNucAtlas, a publicly accessible database facilitating exploration of these nucleosome landscapes. Conclusions: Our study cancer-associated nucleosome organization as a complementary source of epigenomic information and demonstrates the potential of tissue-derived nucleosome signatures for cfDNA-based cancer detection. The pan-cancer atlas provides a resource for investigating tumor heterogeneity and developing noninvasive cancer detection approaches.
]]></description>
<dc:creator><![CDATA[ Yang, S., Ye, J., Yuan, J., Huang, X., Yin, Y., Liu, Z., Li, W., Li, Y. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.12.758417</dc:identifier>
<dc:title><![CDATA[Pan-cancer nucleosome landscapes reveal tumor heterogeneity and inform cell-free DNA-based detection]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.12.758266v1?rss=1">
<title>
<![CDATA[
RiboGRAM learns multi-scale non-coding RNA grammar for structural and regulatory inference 
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</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.12.758266v1?rss=1
</link>
<description><![CDATA[
Protein-coding sequences are read through the triplet genetic code, whereas the organization of molecular information within non-coding RNA sequences remains elusive. Here, we identify a non-coding RNA grammar defined by multi-scale motif usage and 5'-to-3' positional gradients, and develop RiboGRAM to learn this organization. Across nine organisms, non-coding RNAs showed scale-dependent divergence from coding sequences, with directional U-rich and AU-rich gradients. Integrating multi-scale sequence encoding with contextual modeling, RiboGRAM organized RNA families, revealing motif-associated and pair-like patterns across layers. Without structural supervision, non-coding RNA pretraining improved base-pair recovery over coding or messenger RNA pretraining, with representations supporting alignment-free diffusion-based 3D modeling of short RNAs. In human RNA-protein binding profiles, RiboGRAM identified position-resolved motif organization across protein targets and cell types, with sequence-preference shifts associated with reduced cross-cell transferability. Together, these results establish a learnable grammar of non-coding RNA sequence organization for structural and regulatory inference.
]]></description>
<dc:creator><![CDATA[ Wang, H., Chen, Z., Huang, H., Li, S., Jäschke, A., Ye, Q., Zhang, Y. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.12.758266</dc:identifier>
<dc:title><![CDATA[RiboGRAM learns multi-scale non-coding RNA grammar for structural and regulatory inference]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.12.758511v1?rss=1">
<title>
<![CDATA[
N-terminal truncation diversifies USP18 function during early myogenesis 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.12.758511v1?rss=1
</link>
<description><![CDATA[
Ubiquitin-specific protease 18 (USP18) is primarily studied for its dual role in type-I interferon (IFN-I) signaling. At basal levels, however, USP18 also regulates muscle cell development, independently of IFN-I signaling. USP18 exists as a canonical long isoform (LF) and a short isoform (SF) generated by N-terminal truncation. Endogenous SF accumulates in the nucleus during muscle differentiation, but its cellular functions remain poorly understood. Here, we compared USP18 SF and LF in muscle cells stably overexpressing each isoform. We show that their distinct N-termini are associated with marked differences in protein stability, subcellular localization, and protein-protein interactions. SF displayed a substantially expanded interactome, with increased association with nuclear proteins, chaperones, and regulators of protein homeostasis. Functionally, SF enhanced an early stage of myogenic differentiation and was associated with changes in alternative splicing, including key sarcomere genes. Together, these findings identify the SF USP18 proteoform as a potential regulator of muscle differentiation and highlight the N-terminus as a determinant of non-canonical USP18 functions and proteoform diversity.
]]></description>
<dc:creator><![CDATA[ Raz, V., Nijssen, T., Draganov, S., Shademan, M., Vendrell, I., Kessler, B. M., Pinto-Fernandez, A., flannery, S. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.12.758511</dc:identifier>
<dc:title><![CDATA[N-terminal truncation diversifies USP18 function during early myogenesis]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.13.758751v1?rss=1">
<title>
<![CDATA[
Targeting skin ageing at the source: a novel cellular reprogramming approach using natural extract combinations 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.13.758751v1?rss=1
</link>
<description><![CDATA[
Cellular senescence is a driver of skin ageing that leads to structural deterioration and aesthetic changes. This study evaluated a novel senomorphic strategy, using synergistic combinations of natural small molecules to target RNA splicing regulation via upstream ERK/AKT signaling pathways. Nature-identical synthetic molecules, and corresponding extracts were assessed for cytotoxicity, impact on senescent cell load, proliferation, DNA damage load and SASP markers in naturally aged human primary skin cells. A topical, simple formulation was evaluated for impact on senescence and skin structure using 3D human ex vivo full-thickness skin explants exposed to 1.5 J/cm2 UVC irradiation. Combination of H. lupulus and G. biloba extracts produced a dose-dependent senomorphic impact of up to 45% in aged dermal fibroblasts and 10% in aged human primary keratinocytes (p [&le;] 0.0001 & 0.001), without inducing cell proliferation. A 50% decrease in DNA damage load was also observed (p [&le;] 0.0001). Qualitatively, the simple formulation mitigated UV-induced epidermal hyperplasia, restored collagen fiber organization, and reduced markers of senescence and inflammation. Targeting cellular senescence is an emerging traction point to address the root biological causes of skin ageing. Targeting the splicing dysregulation/senescence axis using combinations of natural plant extracts may provide a novel mode of action to reprogram senescent cells for repair and protection of skin structure and function.
]]></description>
<dc:creator><![CDATA[ Perciato, M. L., Davies, M., Akhbari, P., Denise, H., Clauss, A., Cole, S. L., Haas, K. M., Lee, B., Jouy, C., Ballihaut, C., Lee, B. P., Harries, L. W. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.13.758751</dc:identifier>
<dc:title><![CDATA[Targeting skin ageing at the source: a novel cellular reprogramming approach using natural extract combinations]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.11.757684v1?rss=1">
<title>
<![CDATA[
Firing Without Wiring: How REM-like Sleep Reactivation Rebalances Excitation and Inhibition to Orthogonalize Memories 
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</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.11.757684v1?rss=1
</link>
<description><![CDATA[
The role of Rapid Eye Movement (REM) sleep in memory consolidation remains poorly understood. Several influential ideas propose that REM sleep serves to eliminate crosstalk between memories, thereby orthogonalizing representations of similar ones; however, mechanistic confirmation remains sparse. Here we used recurrent neural networks trained with Equilibrium Propagation (EP), a biologically plausible training algorithm, to investigate the role of REM-like sleep in memory consolidation. We found that REM-like sleep reduces memory interference by decorrelating task-specific neuronal populations, isolating individual memory traces. During sleep, reactivation was dominated by the population encoding the most recent memory. Net excitatory input onto this population decreased, most strongly that from older-memory populations, which allowed inputs of older memories to drive their own neurons again. Spreading the same total synaptic change evenly across all target populations abolished this recovery. We call this mechanism reactivation-targeted pruning: plasticity is confined to one population, whose neurons lose inputs that are silent when they fire. The mechanism held under Dale's law, and depression of excitatory synapses alone, without any inhibitory plasticity, was sufficient. These findings suggest mechanistic principles underlying REM sleep's role in memory consolidation and highlight the potential for integrating human-like learning behaviors into artificial neural networks.
]]></description>
<dc:creator><![CDATA[ Kubo, Y., Delanois, E., Bazhenov, M. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.11.757684</dc:identifier>
<dc:title><![CDATA[Firing Without Wiring: How REM-like Sleep Reactivation Rebalances Excitation and Inhibition to Orthogonalize Memories]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.11.758339v1?rss=1">
<title>
<![CDATA[
Adolescent prodromal phenotypes of psychiatric disorders: insights from a novel DISC1-perturbed monkey model 
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</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.11.758339v1?rss=1
</link>
<description><![CDATA[
Neurodevelopmental deficits frequently lead to mild but significant adolescent social and cognitive changes, representing prodromal manifestations of adult-onset psychiatric disorders in a cross-disease manner. Although experimental medicine utilizes animal models to address the mechanisms, rodent brains lack critical structures for human higher brain functions such as the dorsolateral prefrontal cortex. To fill this translational gap, we generated monkeys with an impaired DISC1 gene locus, targeting the multifunctional protein essential for neurodevelopment and involved in transdiagnostic mental health risks. Here we analyze the F0 animals by minimizing mosaicism. At ages equivalent to human adolescence, these monkeys exhibited blunted responsiveness to social stimuli and increased internal drives, mirroring altered social behaviors in the prodromal stage in humans. Resting-state functional MRI data indicated disrupted global functional connectivity and reorganization of network topology, marked by a shift in the dominance of brain hubs from prefrontal regions to sensory areas. This primate model provides a unique platform for studying psychiatric disorders, such as schizophrenia, across the developmental trajectory.
]]></description>
<dc:creator><![CDATA[ Lan, Z., Onoe, H., Tsukiyama, T., Iwatani, C., Chen, C.-Y., Okita, K., Ishizuka, K., Endo, R., Nakai, R., Imamura, K., Hikishima, K., Tsuchiya, H., Nakaya, M., Fang, Y., Kobayashi, A., Shinto, Y., Yamaguchi, R., Matsunaga, M., Oe, K., Omori, K., Ozeki, Y., Tomoda, T., Miura, K., Urayama, S.-i., Oishi, N., Okada, T., Tanaka, M., Inoue, H., Takahashi, J., Sawa, A., Isa, T. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.11.758339</dc:identifier>
<dc:title><![CDATA[Adolescent prodromal phenotypes of psychiatric disorders: insights from a novel DISC1-perturbed monkey model]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.12.758473v1?rss=1">
<title>
<![CDATA[
Real-Time Neurotransmitter Sensing in Midbrain Organoids Using 3D Carbon Cup Electrodes 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.12.758473v1?rss=1
</link>
<description><![CDATA[
Real time, chemically selective detection of neurotransmitter release in brain organoids remains a challenge due to their complex three dimensional architecture and limited optical accessibility. We introduce 3D printed carbon cup electrodes (CCEs) -pyrolyzed, multi level pillar structures - designed to confine a single organoid, increase electroactive surface area, and enable amperometric recordings of oxidizable neurotransmitters. The CCEs exhibit excellent electrochemical performance and reproducibility, supporting diffusion controlled dopamine redox behavior without interference from culture medium. Using ventral midbrain (vMB) organoids at two maturation stages (Day 30 and Day 90), we demonstrate real time detection of potassium evoked dopamine release directly from organoids. Mature organoids exhibit higher peak currents, correlating with increased tyrosine hydroxylase (TH) expression confirmed by immunocytochemistry. Embedding organoids in Matrigel significantly attenuates dopamine signals, indicating a diffusion barrier that limits stimulant access and/or dopamine transport to the electrode. Repetitive stimulations reveal progressive depletion of dopamine stores, consistent with diminished vesicular release. Chemical perturbations using 6 hydroxydopamine and verapamil further validate the platform by producing substantial reductions in dopamine release accompanied by loss of TH neurons. These results establish CCEs as a powerful tool for label free, real-time monitoring of neurotransmission in human organoids, with potential for multiplexed sensing and integration of enzymatic detection strategies for non electroactive neurotransmitters.
]]></description>
<dc:creator><![CDATA[ Tavares da Silva Maraschin, S., Thongkorn, S., Kanakkottu, S., Rezaei, B., Scordo, G., Sozzi, E., Parmar, M., Heiskanen, A., Keller, S. S., Emneus, J. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.12.758473</dc:identifier>
<dc:title><![CDATA[Real-Time Neurotransmitter Sensing in Midbrain Organoids Using 3D Carbon Cup Electrodes]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.12.758476v1?rss=1">
<title>
<![CDATA[
LIF is a pro-algesic mediator in human and mouse models of arthritis-related pain 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.12.758476v1?rss=1
</link>
<description><![CDATA[
Purpose: Emerging clinical and experimental data suggest that JAK inhibitors (JAKi) are effective in reducing pain in Rheumatoid Arthritis (RA). We recently showed that JAK/STAT signalling cytokines, specifically IL-6, LIF and IL-11, are present in the RA joint and can act directly on human induced pluripotent stem cell (iPSC) derived sensory neurons by increasing their STAT3 phosphorylation (pSTAT3) levels and expression of select pain-relevant genes. In this study, we determined that LIF is the most consequential cytokine out of the three, altering neuronal signalling, outgrowth and pain-like behaviours in in vitro and in vivo models of arthritis. Methods: Human iPSC-derived sensory neurons were stimulated with RA synovial fluid (SF) or with cytokine-treated RA synovial fibroblast conditioned media (CM) in the absence or presence of anti-cytokine antibodies. pSTAT3 and pSTAT1 levels, and gene expression patterns, were assessed by Western blot and RNA-sequencing (RNA-seq). The immortalised dorsal root ganglion (DRG)-derived cell line (HD 10.6) was assessed for LIF-induced JAK/STAT signalling in addition to neurite outgrowth assays as a functional readout of the sensory neurons. Lastly, mouse models were used to assess pain-related behaviours in vivo. Results: LIF was found to be consistently present in the SF from painful joints from individuals with inflammatory arthritis. Western blotting revealed that the addition of RA SF to iPSC-derived sensory neurons led to LIF-dependent induction of pSTAT3 and pSTAT1, while RNA-seq demonstrated that LIF alters the transcriptome of sensory neurons more prominently than IL-6 and IL-11, up-regulating signature genes related to peripheral neuron sensitization, such as TRPV1, NTRK1, BDNF, HRH1 and SCN10A. Similarly, cytokine-treated fibroblast conditioned media was shown to induce neuronal pSTAT3 and pSTAT1 and upregulate expression of BDNF, HRH1 and VGF in a LIF-dependent manner. Additionally, the immortalised dorsal root ganglion (DRG)-derived cell line (HD 10.6), which also exhibited LIF-induced pSTAT1 and pSTAT3, showed increased neurite outgrowth after axotomy when treated with LIF. Finally, in a mouse model of inflammatory arthritis, LIF was shown to be significantly increased in the affected joint. Furthermore, intraarticular injection of LIF into a healthy mouse knee resulted in increased responsiveness to painful pressure stimuli in that joint. Conclusions: Our data indicate that LIF may be a pro-algesic mediator and a possible therapeutic target to improve pain management in individuals living with inflammatory arthritis.
]]></description>
<dc:creator><![CDATA[ Ross, R., Li, Y., Vlachaki Walker, J., Ali Awadelkareem, M., Zebochin, I., Goodwin, G. L., Marin, A.-C., Trendafilova, T., Montague, I., Rutter-Locher, Z., Ryan, S., Baldeweg, F., Freytag, K., Condor, R., Arridge, N., Buckley, C. D., Bennett, D., Humby, F., Kirkham, B., Denk, F., Taams, L. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.12.758476</dc:identifier>
<dc:title><![CDATA[LIF is a pro-algesic mediator in human and mouse models of arthritis-related pain]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.12.758429v1?rss=1">
<title>
<![CDATA[
Exposure to childhood adversity and adult alcohol, nicotine, and illicit drug use in Germany: a cross-sectional analysis of the German National Cohort (NAKO) 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.12.758429v1?rss=1
</link>
<description><![CDATA[
Rationale: Exposure to adversity in childhood and adolescence (i.e., "early-life stress"; ELS) is a well-established risk factor for substance use. Objectives: The aim of this study was to investigate associations between ELS exposure and substance use across subtypes of ELS, different substance classes, and behavioral profiles of substance use. Methods: In this cross-sectional study, we examined associations between ELS exposure and substance use in a population-based sample of 172,173 adults aged 19-74 years from the German National Cohort (NAKO). ELS exposure was assessed using the Childhood Trauma Screener. Substance use included nicotine, alcohol, and illicit drug use. Associations were examined using regression models evaluating overall ELS exposure, cumulative trauma load, and ELS subtypes. Latent class analysis (LCA) was conducted to identify substance use profiles. Results: ELS exposure was associated with higher odds of smoking, greater smoking severity, heavier alcohol consumption among drinkers, and higher odds of lifetime illicit drug use. Overall, the strongest associations were observed for opioid and stimulant use. Dose-response analyses revealed higher risk with increasing numbers of ELS subtypes. Abuse-related subtypes, particularly exposure to physical and sexual abuse, consistently showed strongest independent associations across substances, whereas neglect exhibited weaker, more variable associations. LCA identified four substance use profiles, with ELS exposure predicting membership in more severe polysubstance classes. Conclusions: ELS emerged as a robust risk factor for adult substance use, underscoring the need for trauma-informed approaches in clinical practice, public health, and policy to mitigate the long-term consequences of early adversity.
]]></description>
<dc:creator><![CDATA[ Boehmer, J., Meyer-Degering, K., Ghadami, A., Sreepada, A., Bohmann, P., Castell, S., Feuchtinger, M., Gottschick, C., Grabe, H. J., Karch, A., Lahmann, C., Lang, A., Leitzmann, M., Meinke-Franze, C., Meyerdierks, D., Mikolajczyk, R., Nimptsch, K., Obi, N., Peters, A., Pischon, T., Stein, M. J., Keil, T., Krist, L., Tost, H., Heim, C. C. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.12.758429</dc:identifier>
<dc:title><![CDATA[Exposure to childhood adversity and adult alcohol, nicotine, and illicit drug use in Germany: a cross-sectional analysis of the German National Cohort (NAKO)]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.12.758428v1?rss=1">
<title>
<![CDATA[
Cooperative processing of visual threat across collicular pathways 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.12.758428v1?rss=1
</link>
<description><![CDATA[
Rapid defensive actions require the transformation of sensory cues into appropriate motor responses. The superior colliculus is central to this transformation, containing defined cell-types that form parallel output pathways linking visual inputs to distinct behaviors. However, whether these pathways act independently or cooperate remains unclear. Here we combine cell-type-specific inhibition, large-scale electrophysiology, and functional ultrasound imaging to determine how these pathways contribute to visually evoked defensive behaviors. Inhibiting either narrow-field or wide-field neurons impaired escape to overhead visual threats, demonstrating that both pathways contribute to escape. Recordings from downstream targets revealed a compact representation in the deeper layers of the superior colliculus that selectively distinguished visual stimuli associated with escape, whereas the lateral posterior thalamus contained a broader representation of visual stimuli. The representation of visual threat in the deeper layers of the superior colliculus predicted escape initiation and vigor in freely moving animals. Across the brain, functional ultrasound imaging showed that visual stimuli recruited distinct patterns of activity that could not be explained by response magnitude alone or by the contribution of single cell-types. Together, these results reveal a cooperative circuit architecture in which parallel pathways carry distinct but complementary signals that jointly support visually evoked escape.
]]></description>
<dc:creator><![CDATA[ Nuttin, B., Sans-Dublanc, A., Chrzanowska, A., Liu, C., Hanson, L., Drakaki, Z., Luyks, R., Bruystreen, A., Philipon, A., Grillet, M., Kuhn, N., Goncalves, P., Montaldo, G., Bonin, V., Urban, A., Farrow, K. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.12.758428</dc:identifier>
<dc:title><![CDATA[Cooperative processing of visual threat across collicular pathways]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.12.757951v1?rss=1">
<title>
<![CDATA[
The ovarian cycle and estradiol modulate cortical network state and auditory entrainment in mice and women 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.12.757951v1?rss=1
</link>
<description><![CDATA[
The human brain is remarkably dynamic, continuously adapting to internal and external signals across rapid and protracted timescales. While both male and female brains are influenced by sex hormones to drive adaptive behavioural and physiological changes, the ovarian cycle in female mammals represents a conserved naturalistic model to understand how hormones such as estradiol (E2) alter cellular and network states to shape brain function. To understand whether and how the ovarian cycle influences sensory cortical processing, we investigated cortical network activity at rest and upon auditory stimulation across the ovarian cycle in mice and human subjects. We recorded EEG activity in men and women and intracortical local field potentials in male and female mice. Female participants were tested during two phases of their ovarian cycle characterized by low E2 levels (early follicular phase in women; late estrus in mice) and high E2 levels (late follicular phase in women; proestrus in mice). Across species, high endogenous or exogenous estradiol was associated with a steeper aperiodic power spectral slope, indicating decreased excitatory/inhibitory drive and attenuated auditory entrainment following a 40Hz stimulation. At the single-cell level, high E2 selectively increased the baseline and sustained 40-Hz firing of putative fast-spiking interneurons while reducing their temporal coherence during both spontaneous and stimulus-evoked activity, suggesting that E2 enhances inhibitory tone, while disrupting the temporal coordination of inhibitory networks. Altogether, these findings demonstrate that estradiol dynamically modulates cortical network states and auditory responsiveness. This underscores the necessity of investigating hormone-brain coupling as an evolutionarily conserved model essential for yielding translational insights into sex-specific neurobiology.
]]></description>
<dc:creator><![CDATA[ Carreno Munoz, M. I., Chehrazi, P., Ciancone Chama, A., Knoth, I., Fernandes do Nascimento, S. A., Campbell, B., Csicsvari, J., Chattopadhyaya, B., Lippe, S., Di Cristo, G. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.12.757951</dc:identifier>
<dc:title><![CDATA[The ovarian cycle and estradiol modulate cortical network state and auditory entrainment in mice and women]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.11.758322v1?rss=1">
<title>
<![CDATA[
Pilifers provide rapid mechanosensory feedback during floral tracking in hawkmoths 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.11.758322v1?rss=1
</link>
<description><![CDATA[
Hawkmoths expertly hover over flowers during feeding, accurately tracking floral movements even as flowers gently sway in the wind. They use visual and mechanosensory feedback to adjust their position, while their long, flexible mouthpart, the proboscis, stays inserted inside the nectar spur. Although much is known about how hawkmoths detect and process visual motion, far less is understood about how hawkmoths detect mechanical motion cues. Pilifers are hair bundles at the proboscis-head joint, well-positioned to provide feedback about floral motion. Here, we tested if pilifers could provide mechanosensory feedback essential for successful floral tracking. We computed bending at the proboscis base during floral tracking in freely flying hawkmoths and found that floral movements induce small yet significantly correlated lateral bending. Recordings from pilifer afferents showed that they respond to lateral motions of amplitudes similar to those seen in natural floral tracking behaviors. They respond to different directions and speeds of proboscis motion with an average latency of 1.9 ms. Neural tracing revealed extensive sensory arborizations in the sub-esophageal ganglion of the brain and ventral nerve cord, indicating a feedback pathway to the neck and flight motor system that enables rapid coordination of appendages and body for successful feeding.
]]></description>
<dc:creator><![CDATA[ Anand, M., Torres, M., Brunton, B. W., Daniel, T. L., Weber, A. I., Deora, T. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.11.758322</dc:identifier>
<dc:title><![CDATA[Pilifers provide rapid mechanosensory feedback during floral tracking in hawkmoths]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.11.758333v1?rss=1">
<title>
<![CDATA[
Modeling Paralinguistic Features for Speech Neuroprostheses: A Systematic Review 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.11.758333v1?rss=1
</link>
<description><![CDATA[
Recent advances in brain-computer interface (BCI) technology have brought speech neuroprostheses closer to restoring naturalistic communication for individuals with severe motor or speech impairments. Although current systems can decode phonemic and lexical information from cortical activity, they often fail to capture paralinguistic dimensions such as intonation, prosody, loudness, and affect that are essential for conveying emotion and intent. This review synthesizes emerging research on modeling and incorporating paralinguistic features into speech neuroprosthetic design. Foundational studies have mapped the cortical organization of speech production, identifying articulatory somatotopy within the sensorimotor cortex and functional subdivisions across planning, phonological, and semantic representations. More recent work has characterized expressive encoding within the ventral precentral and supplementary motor areas, while peripheral and multimodal sensing approaches have demonstrated promising accuracy in decoding emotional states. Collectively, these findings signal a shift toward closed-loop neuroprosthetic systems that integrate affective modulation with linguistic decoding, enabling restoration of speech that is not only intelligible but expressively human. Keywords: Speech neuroprosthesis, paralinguistics, BCI, naturalistic communication
]]></description>
<dc:creator><![CDATA[ Yenikapati, M. S., Deshpande, S., Desai, S. P., Santine, D. D., Roghani, A. K. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.11.758333</dc:identifier>
<dc:title><![CDATA[Modeling Paralinguistic Features for Speech Neuroprostheses: A Systematic Review]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.11.758328v1?rss=1">
<title>
<![CDATA[
Action-related brain dynamics during leader-follower coordination 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.11.758328v1?rss=1
</link>
<description><![CDATA[
Leader-follower dynamics are essential for social interaction, enabling smooth inter-personal coordination. Although neuroimaging studies have identified brain networks associated with leading and following, the dynamical brain signatures supporting these roles remain poorly characterized. Here, sixteen dyads performed a joint-improvisation mirror-game task with predefined leader-follower roles while magnetoencephalography (MEG) and hand kinematics (acceleration) were simultaneously recorded. We investigated role-specific modulations of source-space MEG activity in delta (0.54 Hz), theta (4-8 Hz), alpha (8-13 Hz), beta (13-30 Hz), and gamma (40-90 Hz) frequency bands, as well as coherence between cortical activity and movement kinematics. Compared with leaders, followers exhibited stronger theta-band activity in a cluster comprising frontal, cingulate, and sensorimotor regions, and stronger coherence between movement kinematics and occipital cortical activity, consistent with enhanced monitoring, adaptation, and reliance on visual kinematic information. In contrast, leaders showed reduced alpha-band power in sensorimotor and premotor regions, and stronger beta-band activity in occipital cortices, likely reflecting greater demands for action planning and predictive control. Our results identify complementary spectral and action-related brain signatures associated with leader-follower coordination during joint improvisation, providing new insights into the neural underpinnings of real-time interpersonal coordination.
]]></description>
<dc:creator><![CDATA[ Ruuskanen, S., Avendano-Diaz, J. C., Hari, R., Parkkonen, L. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.11.758328</dc:identifier>
<dc:title><![CDATA[Action-related brain dynamics during leader-follower coordination]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.15.759509v1?rss=1">
<title>
<![CDATA[
Scalable Enzyme Reaction Retrieval Enables Metagenomic Biocatalyst Discovery 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.15.759509v1?rss=1
</link>
<description><![CDATA[
Enzyme catalyzed reactions drive metabolism and enable diverse applications in biotechnology and sustainable synthesis, but assigning catalytic functions to uncharacterized enzymes and finding enzymes for target reactions remain major challenges. Despite recent advances in machine learning, translating enzyme function prediction into systematic discovery across the vast space of uncharacterized proteins and biochemical reactions remains challenging. Here we present EzHit, a lightweight framework for bidirectional enzyme reaction retrieval. Across enzyme annotation, orphan-reaction retrieval and family-specific fine-tuning benchmarks, EzHit achieved strong top-ranked performance and outperformed representative enzyme reaction matching baselines. We further show that Mahalanobis distance based geometric confidence provides more useful reliability estimates than probability-derived uncertainty metrics or evidential learning, enabling confidence-aware prioritization of high scoring candidates. Owing to its efficiency, EzHit was applied to a nearly trillion-scale OMG_Prot50 with RHEA screen, yielding 8.20 billion retained enzyme reaction associations across 30.27 million predicted enzyme sequences. Experimental validation further confirmed the activity of EzHit prioritized metagenomic enzyme candidates for a sparsely annotated reaction. Together, these results establish EzHit as a scalable framework for enzyme annotation, reaction-guided mining and biocatalyst discovery
]]></description>
<dc:creator><![CDATA[ Luo, D., Jiang, M., Wang, B. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.15.759509</dc:identifier>
<dc:title><![CDATA[Scalable Enzyme Reaction Retrieval Enables Metagenomic Biocatalyst Discovery]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.15.759271v1?rss=1">
<title>
<![CDATA[
Microbial Reductive Dechlorination of Hexachlorobutadiene by Dehalococcoides 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.15.759271v1?rss=1
</link>
<description><![CDATA[
Hexachlorobutadiene (HCBD), a persistent organic pollutant (POP), poses a significant threat to ecological environments and human health. While anaerobic microbial transformation is a promising remediation strategy, the specific microorganisms and metabolic mechanisms involved have remained poorly understood. This study demonstrates the successful enrichment of an anaerobic microbial consortium from river sediment, with lactate as an electron donor, capable of transforming HCBD. Within 240 days, 62.5 mol of HCBD was sequentially dechlorinated through pentachlorobutadiene (PCBD), tetrachlorobutadiene (TeCBD), trichlorobutadiene (TCBD), and dichlorobutadiene (DCBD) to chlorobutadiene (CBD). Co-amendment with HCBD and trichloroethene (TCE) resulted in complete removal of both compounds. 16S rRNA gene sequencing and quantitative PCR showed enrichment of Dehalococcoides, linking its population growth to HCBD and TCE dechlorination. This study demonstrates that Dehalococcoides growth was associated with HCBD transformation in the enrichment cultures, broadens our understanding of the metabolic capabilities of Dehalococcoides, and identifies a candidate gene for this important environmental process, offering valuable insights for the bioremediation of sites contaminated with HCBD.
]]></description>
<dc:creator><![CDATA[ Wang, X., Wang, H., Qian, X., Wei, H., Zhong, Y., Xiu, Z., Yu, L., Wang, S., Zhang, H., Yan, H., Sun, W., Yang, Y. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.15.759271</dc:identifier>
<dc:title><![CDATA[Microbial Reductive Dechlorination of Hexachlorobutadiene by Dehalococcoides]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.15.759513v1?rss=1">
<title>
<![CDATA[
Understanding Substrate Transport and Metabolism in Clostridium thermocellum to Improve Biofuel Production 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.15.759513v1?rss=1
</link>
<description><![CDATA[
As a cellulolytic specialist microbe, Clostridium thermocellum primarily ferments cellulose and its breakdown products. However, the full breadth of its substrate range remains poorly understood. In this work, we investigated the ability of C. thermocellum to transport and metabolize a diverse range of alternative carbon substrates. We performed tetrazolium dye assays to assess the ability of wild-type (WT) C. thermocellum (strain LL1004) to transport and metabolize 190 different substrates and identified 18 positive hits and 27 false positives. These findings guided the selection of 22 substrates for batch fermentations of WT on 10 g/L alternative substrate plus 1 g/L cellobiose. We identified eight substrates that were either fully or partially consumed (cellobiose, glucose, fructose, sorbitol, arbutin, turanose, pyruvate, glucose-6-phosphate), two that were interconverted (malate, fumarate), seven that may undergo conversion to unidentified fermentation products (xylose, sorbose, tagatose, galactose, mannose, rhamnose, fucose), and five that were not consumed (glycerol, acetate, lactate, propionate, xylitol). Sorbitol and pyruvate, which are more and less reduced than cellobiose, respectively, were selected for further analysis of their effects on redox balance and product formation. Batch fermentations on sorbitol and pyruvate demonstrated that ethanol production in C. thermocellum may be limited in part by the availability of reducing equivalents. Collectively, this work demonstrates the utility of alternative carbon substrates as a tool for perturbing metabolism, redox balance, and fermentation product distributions to further our understanding of the metabolism of anaerobic, thermophilic bacteria such as C. thermocellum for the production of biofuels and biochemicals of interest.
]]></description>
<dc:creator><![CDATA[ Richardson, I. D., Sharma, B. D., Ma, E. Y., Pilny, R. S., Olson, D. G. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.15.759513</dc:identifier>
<dc:title><![CDATA[Understanding Substrate Transport and Metabolism in Clostridium thermocellum to Improve Biofuel Production]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.10.14.759234v1?rss=1">
<title>
<![CDATA[
Sample overlap in genome-wide association meta-analysis: practical comparisons across significance thresholds 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.10.14.759234v1?rss=1
</link>
<description><![CDATA[
Meta-analysis is widely used in genome-wide association studies (GWAS) to combine evidence across studies without requiring individual-level data. However, as both the number of studies included in meta-analyses and their sample sizes continue to grow, the same participant may be included in more than one study. Such sample overlap induces dependence across studies and violates the independence assumptions underlying standard meta-analysis methods. HostSeq is a Canadian initiative in which 15 clinical and epidemiological studies were assembled with DNA samples from approximately 10,000 Canadians infected by the SARS-CoV-2 virus. We observed duplicate samples across different participating studies. This observation raises an important practical question: what is the impact of sample overlap on association results, and when should such overlap be a concern? Motivated by this real problem, we sought to compare five meta-analysis methods and evaluate their performance against a reference mega-analysis in which the true sample overlap is known. We show that when the degree of sample overlap is relatively small, its impact on association results is minimal, even at the genome-wide significance threshold of  = 5*10 -8  . We demonstrate these findings through extensive simulation studies and an application to overlapping cohorts within HostSeq.
]]></description>
<dc:creator><![CDATA[ Xu, Z., Zhang, L., Elliott, L. T. ]]></dc:creator>
<dc:date>2026-10-18</dc:date>
<dc:identifier>doi:10.64898/2026.10.14.759234</dc:identifier>
<dc:title><![CDATA[Sample overlap in genome-wide association meta-analysis: practical comparisons across significance thresholds]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-10-18</prism:publicationDate>
<prism:section></prism:section>
</item>
</rdf:RDF>
