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This feed contains articles for bioRxiv Subject Collection "All"
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<title>bioRxiv</title>
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<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.11.724285v1?rss=1">
<title>
<![CDATA[
Mutational and bioinformatic analysis of the binding site for the ribonucleotide reductase-specific transcriptional repressor NrdR 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.11.724285v1?rss=1
</link>
<description><![CDATA[
The prevalent transcriptional repressor NrdR binds to highly conserved prokaryotic sequences in the promoter regions of operons encoding the essential enzyme ribonucleotide reductase. The NrdR binding sites consist of two partially palindromic 16 bp sequences (NrdR boxes) separated by a 15-16 bp linker sequence. We have assessed the requirement of both boxes for binding, the propensity of different NrdRs to bind to heterologous binding sites, and that the linker sequence is only limited to length and not sequence conservation. As we have observed several deviations from the conserved sequences of the NrdR boxes, we here test the conservation requirements of individual basepairs in the NrdR boxes using a synthetic DNA fragment (Synt DNA) to which the NrdR proteins from the actinomycete Streptomyces coelicolor and the gammaproteobacterium Escherichia coli bind equally well as to their homologous binding sites. By introducing isolated mutations to Synt DNA and testing the binding capacity of NrdR from S. coelicolor and E. coli we expand our understanding of what criteria are needed to build a functional binding site for the NrdR repressor.
]]></description>
<dc:creator><![CDATA[ Shahid, S., Lundin, D., Rozman Grinberg, I., Sjöberg, B.-M. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.11.724285</dc:identifier>
<dc:title><![CDATA[Mutational and bioinformatic analysis of the binding site for the ribonucleotide reductase-specific transcriptional repressor NrdR]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.11.724226v1?rss=1">
<title>
<![CDATA[
Context-dependent tonic signaling shapes the performance and manufacturability of a 4-1BB- based HER2 CAR-T cell therapy 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.11.724226v1?rss=1
</link>
<description><![CDATA[
The development of clinically effective CAR-T cell therapies for solid tumors requires careful optimization of receptor design, functional fitness, and manufacturability. While advancing low-affinity HER2-targeting CAR-T cells toward clinical application, we found that the candidate with the strongest in vivo antitumor activity--comprising a CD8 hinge and transmembrane region and a 4-1BB co-stimulatory domain--exhibited measurable tonic signaling. This basal antigen-independent signaling, likely driven by high CAR surface expression, was associated with increased apoptosis and reduced ex vivo expansion under research-grade manufacturing conditions. Modification of the transmembrane domain reduced CAR surface expression but did not alleviate tonic signaling and instead impaired antitumor activity. By contrast, transient pharmacologic inhibition of CAR signaling with dasatinib rescued expansion and reduced apoptosis in small-scale research cultures. Notably, these tonic-signaling-associated defects were largely absent during large-scale, GMP-compliant manufacturing, which enabled robust CAR-T cell expansion without additional benefit from dasatinib supplementation. Together, these findings show that tonic signaling is not inherently detrimental to CAR-T cell performance and that its functional consequences are highly dependent on manufacturing context. Our study underscores the importance of evaluating CAR candidates within clinically relevant production platforms and supports the advancement of this 4-1BB-based HER2-specific CAR-T cell product toward clinical testing.
]]></description>
<dc:creator><![CDATA[ Angelats, L., Marzal, B., Rodriguez-Garcia, A., Espanol-Rego, M., Lobo-Jarne, T., Hernandez-Sanchez, M., Cascallo, G., Colell, S., Gimenez-Alejandre, M., Colell, G., Castellsague, J., Andreu-Saumell, I., Calderon, H., Galvan, P., Urbano-Ispizua, A., Delgado, J., Gonzalez-Navarro, E. A., Prat, A., Juan, M., Guedan, S. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.11.724226</dc:identifier>
<dc:title><![CDATA[Context-dependent tonic signaling shapes the performance and manufacturability of a 4-1BB- based HER2 CAR-T cell therapy]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.11.724393v1?rss=1">
<title>
<![CDATA[
Spatial proteomics reveals CD8+ T cell signatures and cellular niches associated with active HIV-1 replication in lymph nodes 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.11.724393v1?rss=1
</link>
<description><![CDATA[
Despite its effectiveness in suppressing active HIV-1 replication, antiretroviral therapy (ART) does not eliminate the persistent long-lived pool of HIV-1-infected reservoir cells, preventing the eradication of the infection. Lymphoid tissues are key anatomical sites where these reservoirs persist even in the presence of ART, but the mechanisms that are associated with viral persistence in lymphoid tissues and how tissue networks are reshaped in the setting of viral replication remain incompletely understood. Advances in tissue imaging offer a unique opportunity to characterize immune correlates of viral persistence. Here, we used a spatial proteomic method to map immune microenvironments in HIV-1-infected lymph nodes (LNs) at different stages of infection, including with or without ART. LNs from people with HIV-1 (PWH) were characterized by lower CD4+ T cell counts and higher CD8+ T cell counts in both the whole tissue and within follicles compared to people without HIV (PWOH). CD8+ T cells were more abundant in LN samples with active viral replication, defined by detection of the viral protein p24. Further characterization of p24+ LNs showed that CD8+ T cells located inside of B cell follicles exhibited higher levels of markers associated with immune activation and exhaustion, in addition to the inflammasome protein caspase-1. Using a spatial niche detection method, we found that LNs from PWH with varying levels of viral replication were differentially enriched for CD8+ T cells near antigen-presenting cells, myeloid cells, and fibroblasts. Notably, we found that p24+ cells were less enriched near CD8+ T cells but closer to follicular dendritic cells. Finally, comparing LNs from viremic and aviremic donors, where viremia was defined by detectable plasma viral load, we found low levels of activation markers in CD11c+ cells in aviremic donors, including NLRP3 inflammasome activation. Thus, using spatial proteomics to map the immune landscape in LNs, we identified novel markers characterizing immune cell subsets and tissue microenvironments that were differently enriched in PWH with varying levels of viremia, implying that HIV-1 infection confers long-term changes on the immune landscape in LN tissue. Collectively, these data provide new insights into the complex cell networks associated with viral replication at a key tissue reservoir site, which could be relevant for future HIV-1 cure strategies.
]]></description>
<dc:creator><![CDATA[ Liu, C. C., Calvet-Mirabent, M., Spence, A., Goldston, M., Adrados de Llano, M., Bendall, S. C., Angelo, M., Martin-Gayo, E. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.11.724393</dc:identifier>
<dc:title><![CDATA[Spatial proteomics reveals CD8+ T cell signatures and cellular niches associated with active HIV-1 replication in lymph nodes]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.11.724235v1?rss=1">
<title>
<![CDATA[
foxQ2 marks fast-acting brain interneurons including a subset of dopaminergic neurons innervating mushroom bodies and central complex in the beetle Tribolium castaneum 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.11.724235v1?rss=1
</link>
<description><![CDATA[
The brain is one of the most complex animal organs but the development of the many different neuron types remains enigmatic. A set of brain-specific transcription factors is known to be involved in brain patterning but their specific contributions remain to be elucidated in most cases, including foxQ2II. This transcription factor is known to be conserved in anterior neuroectodermal patterning of most animals while it has been lost from vertebrates. However, the contribution of foxQ2II-positive neurons to the adult brain has remained enigmatic. Here, we use an enhancer trap, immunostainings and our newly established beetle brainbow system to categorize Tc-foxQ2II-positive neurons into nine clusters with different projection patterns. All clusters contain neurons with the fast activating neurotransmitters acetylcholine and glutamate while no Tc-foxQ2II positive neuron is GABA-ergic or serotonin-positive. Interestingly, we found that many dopaminergic neurons were Tc-foxQ2II positive and we homologize them with dopaminergic neurons of the PPL2c, PPM1 and PPL1 cluster described in the Drosophila brain. Our results show that Tc-foxQ2II marks subsets of fast-acting interneurons contributing to the higher order brain centers mushroom bodies and central complex. Taken together, our work expands the known functional range of foxQ2 genes from sensory and neurosecretory cell specification to interneurons involved in the function of higher order brain centers.
]]></description>
<dc:creator><![CDATA[ Pang, Y., Klussmann-Fricke, B., Cedden, D., Zhang, J., Schinko, J. B., Averof, M., Riemensperger, T. D., Bucher, G. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.11.724235</dc:identifier>
<dc:title><![CDATA[foxQ2 marks fast-acting brain interneurons including a subset of dopaminergic neurons innervating mushroom bodies and central complex in the beetle Tribolium castaneum]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.724352v1?rss=1">
<title>
<![CDATA[
Molecular and Structural Characterization Reveals Divergent Extracellular Vesicle Profiles Between Wild Type and Alzheimer's Disease Cerebrocortical Organoids 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.724352v1?rss=1
</link>
<description><![CDATA[
Alzheimer's disease (AD) is a neurodegenerative disorder affecting millions of patients globally. Despite significant efforts from researchers in recent decades, there are still many unanswered questions about AD pathogenesis. AD patient brains manifest changes in extracellular vesicles (EVs) secreted from diseased neurons, and the effect of this phenomenon remains poorly understood. EVs contain a variety of biomolecules and play a critical role in cell-to-cell communication in all eukaryotic organisms. Here, we report a thorough characterization of small EVs purified from cultures of human cerebrocortical organoids. These organoids are differentiated from human patient-derived stem cells that bear a familial AD mutation in the presenilin 1 (PSEN1) gene, or from an isogenic wildtype (WT) control. The organoid conditioned media was aspirated from cultures and processed for EV enrichment using a non-invasive technique that requires no cellular disruption. EVs purified from AD organoid conditioned media have a wider size distribution and show differential expression of tetraspanins CD63, CD9, and CD81 when compared to WT organoid-derived EVs. AD organoid-derived EVs can have single, double, and even triple membranes and display luminal fibrillar material. A deep proteomic profiling of the EVs reveals several statistically significant differences, including evidence for modifications in secretory autophagy. EV isolates from both WT and AD organoids show strong binding to amyloid detecting dyes, both in bulk fluorescence and fluorescence microscopy assays. After a 1-week co-culture of AD organoids with WT organoids, there is evidence of endosomal membrane transfer between the isogenic cultures with an increase in amyloid-{beta} peptides in the WT organoids. These observations support the notion that non-cell-autonomous spread of amyloid-containing EVs in human AD brains can be modeled in a cerebral organoid system.
]]></description>
<dc:creator><![CDATA[ Balistreri, A., Turner, N., Compher, J., Almaraz, M., Prabhavalkar, A., Chittal, S., Labra, S. R., Ezekiel, K., Baal, C., Cedeno Kwong, C., Ghatak, S., Schaefer, J.-H., Vanderpool, K., Spencer, K., Yates, J. R., Nolan, J. P., Henderson, S., Lipton, S. A., Kelly, J. W. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.724352</dc:identifier>
<dc:title><![CDATA[Molecular and Structural Characterization Reveals Divergent Extracellular Vesicle Profiles Between Wild Type and Alzheimer's Disease Cerebrocortical Organoids]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.11.724258v1?rss=1">
<title>
<![CDATA[
Global quantification of mammalian gene expression noise 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.11.724258v1?rss=1
</link>
<description><![CDATA[
Even cells of the same type growing in the same environment show cell-to-cell differences in protein abundance, a phenomenon known as gene expression noise. This variability can be decomposed into intrinsic components, reflecting molecular randomness, and extrinsic components, arising from differences in cellular state. While gene expression noise has been studied genome-wide in microbes, its global organization remains largely unknown in mammalian cells. Here, we develop a spike-in-based stable isotope single-cell proteomics approach that enables robust quantification of protein-level gene expression noise across thousands of human proteins. We find that protein noise scales inversely with abundance until reaching a plateau, consistent with an extrinsic noise floor and conserved scaling principles observed in bacteria and yeast. Cell cycle stage and cell size contribute substantially to protein variability but do not fully account for the observed heterogeneity. Gene-specific features such as mRNA and protein half-lives and translation efficiency show only weak associations with protein noise, and variability at the mRNA level is a weak predictor of protein variability. Instead, protein noise is largely extrinsic, with coordinated variation across proteins encoding biologically organized cellular states. Consistently, coordinated proteome programs predict intercellular differences in proteome dynamics, linking protein variability to cellular function. Together, these results provide a proteome-wide view of gene expression noise in mammalian cells, establishing that protein-level variability encodes structured and functionally relevant differences in cellular state.
]]></description>
<dc:creator><![CDATA[ Welter, A. S., Mutschler, F., Simon, M., Giacomelli, C., Branscheid, A.-C., Manukyan, A., Teixeira Alves, L. G., Gerwien, M., Kerridge, R., Landthaler, M., Wolf, J., Selbach, M. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.11.724258</dc:identifier>
<dc:title><![CDATA[Global quantification of mammalian gene expression noise]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.12.724622v1?rss=1">
<title>
<![CDATA[
LOCOPOTS: a low-cost high-throughput screening platform for in vitro potato phenotyping under abiotic stress 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.12.724622v1?rss=1
</link>
<description><![CDATA[
Potato crop is highly vulnerable to abiotic stresses like salinity and low nutrient availability. Rapid identification of stress-resilient genotypes is therefore essential for breeding, yet conventional phenotyping is often slow, space-demanding and expensive. We present LOCOPOTS--a LOw-COst high-throughput screening platform for in vitro POTatoes under abiotic Stress--which combines individual in vitro plant culture, low-cost RGB imaging and machine-learning-based automatic segmentation using a trained model of a convolutional neural network, based on U-Net architecture. LOCOPOTS enabled the automated extraction of growth, colour, and vegetation-index traits and demonstrated robust performance across independent phenotyping rounds. We screened 30 potato varieties under control, low-nutrient and saltinity conditions, identifying contrasting growth and physiological responses. Integrated traits such as final area and height, Area_AUC and height_AUC, together with GLI, Chol, cive and chlorophyll fluorescence parameters, discriminated genotype performance under stress. Metabolic profiling further revealed genotype-specific reprogramming in carbon and nitrogen metabolism under low nutrition and salt stress, including changes in fructose, myo-inositol, {beta}-aminobutyric acid, gamma-aminobutyric acid, proline, and certain polyamines, identifying them as specific chemical biomarkers of plant stress responses. LOCOPOTS provides a scalable, affordable and space-efficient platform for early screening of potato genetic diversity and identification of candidate traits associated with stress resilience.
]]></description>
<dc:creator><![CDATA[ Saiz-Fernandez, I., Bastidas Parrado, L. A., Klimes, P., Cavar Zeljkovic, S., Ruiz de Galarreta, J. I., Leyva-Perez, M. d. l. O., Ortiz-Barredo, A., Spichal, L., De Diego, N. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.12.724622</dc:identifier>
<dc:title><![CDATA[LOCOPOTS: a low-cost high-throughput screening platform for in vitro potato phenotyping under abiotic stress]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.10.724169v1?rss=1">
<title>
<![CDATA[
Pulmonary Fibrosis Enhances Vasodilation to Calcitonin Gene-Related Peptide 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.10.724169v1?rss=1
</link>
<description><![CDATA[
Background: Calcitonin gene related peptide (CGRP) hyperpolarizes pulmonary arterial smooth muscle cells (SMCs) and endothelial cells (ECs) through PKA-dependent activation of KATP channels. CGRP can diminish the severity of pulmonary fibrosis (PF), however, the effects on vascular signaling were poorly defined. We hypothesized that hyperpolarization to CGRP would be augmented in a mouse model of PF. Methods: PF was induced in male and female C57BL/6 mice by intratracheal delivery of bleomycin (3 wk), with saline used as control (sham). Pulmonary arteries (PAs; 100-150 m diameter) were cannulated and pressurized to 16 cmH2O, and endothelial tubes were studied in complementary experiments to eliminate the influence of SMCs. Membrane potential (Vm) was recorded continuously using intracellular microelectrodes. Responses were also evaluated in isolated lungs preconstricted with U46619 (~10 mmHg). Results: PF led to greater indices of PH in males vs. females. Isolated lungs and PAs from male PF mice had enhanced vasodilation and hyperpolarization of Vm to CGRP, although no effect was observed in females. The greater vasodilation and hyperpolarization of SMCs to CGRP in males persisted in endothelium-disrupted PAs and during treatment with L-NAME indicating that ECs are not required for greater responsiveness to CGRP. With no effect on resting Vm, inhibition of KATP channels or PKA significantly attenuated hyperpolarization of SMCs and ECs, attenuated vasodilation to CGRP in PAs, and eliminated differences between groups in males. Direct activation of PKA, but not KATP, evoked greater Vm hyperpolarization and vasodilation in PF vs. sham PAs and lungs. Although no difference in sensory nerves was observed in fibrotic mice, perivascular nerve stimulation evoked greater vasodilation in PAs. Conclusions: In a mouse model of PF, CGRP-dependent hyperpolarization of pulmonary arterial SMCs and ECs is augmented through increased PKA-dependent activation of KATP channels leading to increased vasodilator sensitivity.
]]></description>
<dc:creator><![CDATA[ Norton, C. E. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.10.724169</dc:identifier>
<dc:title><![CDATA[Pulmonary Fibrosis Enhances Vasodilation to Calcitonin Gene-Related Peptide]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.11.723846v1?rss=1">
<title>
<![CDATA[
Profilin-1 Promotes Chromophobe Renal Cell Carcinoma Malignancy 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.11.723846v1?rss=1
</link>
<description><![CDATA[
Chromophobe renal cell carcinoma (ChRCC) accounts for 5% of all renal cancer cases. Despite its generally indolent behavior and low mutational burden, there is no targeted therapy for metastatic ChRCC. Profilin-1 (Pfn1), a cytoskeletal regulator of actin and tubulin dynamics, has emerged as a potential oncogenic driver in several cancers including RCC, but its role in ChRCC, remains undefined. We observed elevated Pfn1 expression in stage IV ChRCC patients, implicating Pfn1 in advanced disease progression. To investigate this, we manipulated Pfn1 expressions in two ChRCC cell lines UOK276 and RCJ41M. Pfn1 knockdown (KD) significantly reduced proliferation, invasion, and colony formation, whereas Pfn1 overexpression (OE) in UOK276 enhanced ChRCC aggressive phenotypes. Pharmacological inhibition of Pfn1 significantly suppressed proliferation and clonogenic growth in both cell lines. Additionally, Pfn1 KD increased intracellular ROS accumulation, while overexpressed reduced ROS levels, linking cytoskeletal regulation to oxidative stress control. Together, these findings position Pfn1 as a critical mediator of ChRCC progression, linking cytoskeletal remodeling to aggressive tumor behavior. This work highlights Pfn1 as a potential therapeutic target and establishes a framework for cytoskeletal-focused strategies in advanced ChRCC.
]]></description>
<dc:creator><![CDATA[ Montanari, K., Acharya, A., Vo, C., Shah, D., Henske, E. P., Gau, D. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.11.723846</dc:identifier>
<dc:title><![CDATA[Profilin-1 Promotes Chromophobe Renal Cell Carcinoma Malignancy]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.11.724259v1?rss=1">
<title>
<![CDATA[
TumorArchetypeR: A modular framework to derive signature-based tumor subtypes 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.11.724259v1?rss=1
</link>
<description><![CDATA[
Motivation: The tumor microenvironment (TME) dictates cancer progression and therapeutic response, yet translating TME subtypes into robust clinical biomarkers remains a significant challenge. Existing classification models typically rely on static gene signatures and cohort-dependent normalization, making them ill-suited for application to the small, unbalanced datasets common in early-phase clinical trials. To better guide drug development, methods are required that offer the flexibility to target specific biological contexts and bridge the gap between the discovery of tumor archetypes and their robust translation to individual patient samples. Results: We developed TumorArchetypeR, a modular R package that unifies unsupervised subtype discovery with the generation of rank-based, single-sample classifiers. By leveraging a systematic parameter grid search, the framework identifies stable, data-driven subtypes rather than relying on arbitrary defaults. Crucially, to ensure clinical translatability, the package includes a module to train a robust classifier using binary gene-pair rules, enabling prediction without cohort-level preprocessing. Applying TumorArchetypeR to colorectal cancer, we resolved the heterogeneity of fibrotic tumors, distinguishing an immunosuppressive "Immune-enriched/Fibrotic" state from an immune-excluded "Fibrotic/Myeloid" phenotype. Furthermore, we identified a distinct "Th/B-cell enriched" archetype associated with superior survival, a group largely obscured by existing pan-cancer models. With our rank-based classifier demonstrating robust performance on previously unseen samples, these findings highlight TumorArchetypeR as a scalable, end-to-end solution for refining patient stratification and optimizing precision oncology strategies. The TumorArchetypeR package and documentation are openly available on GitHub at https://github.com/lutgem/TumorArchetypeR.
]]></description>
<dc:creator><![CDATA[ Luetge, M., Nassiri, S. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.11.724259</dc:identifier>
<dc:title><![CDATA[TumorArchetypeR: A modular framework to derive signature-based tumor subtypes]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.12.724524v1?rss=1">
<title>
<![CDATA[
A workflow for the identification of oligomeric structures on tilted sample planes in Cryo-SMLM 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.12.724524v1?rss=1
</link>
<description><![CDATA[
We introduce a workflow to identify oligomeric structures that are recorded with single-molecule localization microscopy (SMLM) under cryogenic conditions. Typically, these oligomers are assumed to consist of protomers arranged as equilateral two-dimensional polygons and every protomer is labeled with a dye molecule for visualization. Unlike previous work, we consider scenarios in which the sample plane has an unknown orientation relative to the focal plane. Our contribution is a high-precision plane-fitting algorithm to determine the sample plane, combined with geometrical transformations and two circle-fitting algorithms to identify the oligomeric structures. Our simulations on synthetic data demonstrate that the proposed workflow achieves high accuracy in estimating both the unknown tilted plane and the oligomer size.
]]></description>
<dc:creator><![CDATA[ Dong, Y., Yang, Z., Schneider, M., Scherzer, O., Schuetz, G. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.12.724524</dc:identifier>
<dc:title><![CDATA[A workflow for the identification of oligomeric structures on tilted sample planes in Cryo-SMLM]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.724805v1?rss=1">
<title>
<![CDATA[
Temperature-dependent ligand relocation reveals plasticity of TRPM4 inhibition 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.724805v1?rss=1
</link>
<description><![CDATA[
Transient receptor potential melastatin 4 (TRPM4) is a Ca2+-activated cation channel whose pharmacology is shaped by its molecular environment. It remains poorly understood how temperature and membrane context influence inhibitor recognition. Here we combine cryo-electron microscopy of membrane-derived vesicles and detergent-solubilized TRPM4 to investigate lipid-associated architecture and binding of the potent anthranilic anilide inhibitor PBA. We find that membrane vesicles preserve a native-like paralipid environment and reveal lipid binding patterns highly similar to those observed in GDN, supporting detergent-solubilized TRPM4 as a structurally relevant system for ligand analysis. Strikingly, PBA occupies distinct binding pockets at 8 {degrees}C and 37 {degrees}C. At low temperature, PBA binds in a previously described inhibitor pocket formed by S3, S4, the S4-S5 linker and the TRP helix, whereas at physiological temperature it relocates to a distinct site within the S1-S4 domain proximal to the Ca2+ regulatory region. These findings reveal temperature-dependent plasticity in TRPM4 ligand recognition.
]]></description>
<dc:creator><![CDATA[ Schneiter, D. M., Rougier, J.-S., Abriel, H., Stahlberg, H., Ekundayo, B. E. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.724805</dc:identifier>
<dc:title><![CDATA[Temperature-dependent ligand relocation reveals plasticity of TRPM4 inhibition]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.12.724695v1?rss=1">
<title>
<![CDATA[
Transthyretin amyloid fibrils adopt distinct folds in the brain 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.12.724695v1?rss=1
</link>
<description><![CDATA[
Amyloid deposition in the central nervous system is increasingly recognized in transthyretin (ATTR) amyloidosis, particularly in patients with prolonged survival following liver transplantation or disease-modifying therapies. However, the structural basis of transthyretin aggregation in the brain remains unknown. Here we determine cryo-electron microscopy (cryo-EM) structures of ex vivo brain-derived ATTR fibrils from patients carrying the ATTRv-V30M and ATTRv-V30G variants. Both fibrils adopt folds distinct from those previously reported in peripheral tissues and the vitreous humor. V30M fibrils exhibit a continuous ordered core spanning residues Pro11-Asn124, whereas V30G fibrils consist of a substantially reduced ordered core, revealing pronounced structural divergence even within the same tissue environment. Despite this diversity, comparative analyses identify conserved regions across ATTR fibrils, including a segment implicated in transthyretin aggregation and targeted for diagnostic and therapeutic development. These results provide direct evidence that local tissue context can shape amyloid fibril architecture in human disease.
]]></description>
<dc:creator><![CDATA[ Saelices, L., Afrin, S., Nguyen, B. A., Bassett, P. T., Fernandez Ramirez, M. d. C., Pedretti, R., Villalon, L., Kelly, C., Lopez, C., Madabushi, M., Zhou, A., Reis, I., Taipa, R., Evers, B. M. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.12.724695</dc:identifier>
<dc:title><![CDATA[Transthyretin amyloid fibrils adopt distinct folds in the brain]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.725025v1?rss=1">
<title>
<![CDATA[
Integrative host transcriptomic and mucosal microbiome profiling reveals region-specific host-microbiome associations across the human intestine 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.725025v1?rss=1
</link>
<description><![CDATA[
Host genetics shapes gut microbiome composition, yet the physiological mechanisms underlying this relationship remain poorly understood. Characterizing associations between host gene expression and the mucosal microbiome offers a promising route to identifying the host pathways and microbial taxa most likely to interact physiologically. However, existing investigations have been conducted primarily in acute disease contexts and within the colon, leaving host-microbiome associations outside of acute inflammatory contexts and those in undersampled regions such as the terminal ileum poorly characterized. To address these gaps, we profiled paired host gene expression from full-thickness resections and mucosal microbiome data, both from macroscopically non-inflamed tissue from Crohn's disease patients undergoing surgery across three intestinal sites: terminal ileum (n = 32), cecum (n = 35), and right colon (n = 30). Using a multi-level analytical framework including Procrustes analysis, sparse canonical correlation analysis, and elastic net regression, we identified significant associations between the mucosal transcriptome and microbiome. Intestine-wide, genes enriched in immune and intestinal barrier integrity pathways were associated with heritable taxa including Fusicatenibacter, consistent with patterns observed in microbiome genome-wide association studies. Region-specific analysis identified the terminal ileum as a distinct site of host-microbiome interaction, with associations involving metabolic and barrier-related pathways not observed in the large intestine. Notable terminal ileum-specific associations included PCDH20 with Faecalitalea and ACAT1 with Lactococcus, implicating epithelial barrier maintenance and host-microbiome metabolic interactions, respectively. These findings advance our understanding of the physiological basis of host-microbiome interactions across the intestine.
]]></description>
<dc:creator><![CDATA[ Ryu, E. P., Keller, C. A., Nichols, R. G., Tran, H. N., Brocious, P. R., Harris, L. R., Koltun, W. A., Yochum, G. S., Davenport, E. R. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.725025</dc:identifier>
<dc:title><![CDATA[Integrative host transcriptomic and mucosal microbiome profiling reveals region-specific host-microbiome associations across the human intestine]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.724994v1?rss=1">
<title>
<![CDATA[
Temporal Transcriptomics Identifies Isoform-specific Trans-regulation by Multiple lncRNAs in Human iPSCs 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.724994v1?rss=1
</link>
<description><![CDATA[
Some long non-coding RNAs (lncRNAs) are known to regulate gene expression. However, the underlying temporal dynamics of lncRNAs influencing gene and epigenetic regulation and mechanisms of lncRNA regulation in trans are less understood. To investigate this, we genetically engineered 17 doxycycline-inducible lncRNA transgenes for ectopic expression at the H11 safe harbor locus in human pluripotent stem cells (hiPSCs), and we generated high-density temporal RNA-seq and ATAC-seq profiles. Most lncRNA transgenes were induced at 2 hours and maintained expression through the 96-hour time course. Surprisingly, when we sought to identify gene expression changes due to the lncRNAs, we found that the global transcriptional landscape was dominated by a strong systemic response triggered by doxycycline exposure. We rigorously defined this cohort of genes as a Doxycycline-Responsive Gene Signature (DRGS). The DRGS was also present in at least 28 public datasets from dox-inducible transgene studies involving diverse cell types. Next, we determined which lncRNAs exhibited trans-regulatory events. We identified DANCR, FENDRR, LINC00667, LINC00847, LNCPRESS1, and PNKY as lncRNAs that regulate specific transcript expression in trans. The downstream target genes encoded 53 mRNAs and 10 lncRNAs. None of the target lncRNAs altered gene expression proximal to their own loci (i.e., triggering secondary cis-effects). Surprisingly, the target genes of LINC00847 (transcribed from chromosome 22) were substantially enriched on chromosome 19, with a preponderance of target genes encoding RNA metabolism and RNA splicing factors. Collectively, our study provides a resource to discern artifacts in the doxycycline-inducible system and identifies temporally regulated targets of 6 lncRNAs for future mechanistic studies.
]]></description>
<dc:creator><![CDATA[ Liu, M., Mamede, I., Sofi, S., Pereira, I., Dostal, V., Pashos, A. R. S., McMahon, C., Waikar, A., Stephenson, G., Cech, T. R., Rinn, J. L. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.724994</dc:identifier>
<dc:title><![CDATA[Temporal Transcriptomics Identifies Isoform-specific Trans-regulation by Multiple lncRNAs in Human iPSCs]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.12.724633v1?rss=1">
<title>
<![CDATA[
A TSST 1 structural motif disrupts endothelial programs required for vascular regeneration. 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.12.724633v1?rss=1
</link>
<description><![CDATA[
Staphylococcus aureus causes profound vascular damage during infection, where it inflicts vascular injury across organs and generates lesions that fail to heal. Superantigens are major virulence factors in S. aureus infections, yet their direct effects on vascular repair remain unclear. We provide evidence that TSST 1 disrupts endothelial regeneration through coordinated mechanisms. TSST 1 interferes with collective directed migration, impairing endothelial cell directional persistence and preventing re-endothelialization in vitro. These defects stem from cytoskeletal disorganization, characterized by stress fiber accumulation and loss of lamellipodia, and broad suppression of motility associated secreted factors. In an ex vivo aortic ring assay, TSST 1 suppresses angiogenic sprouting and generates dysmorphic vascular networks. Proteomic profiling reveals a shift toward matrix rigidity, adhesion stabilization, and overall suppression of angiogenesis. These activities map to a conserved dodecapeptide motif. Hence, TSST 1 suppression of vascular repair may convert sites of tissue injury into persistently non healing niches suited for S. aureus persistence.
]]></description>
<dc:creator><![CDATA[ Tang, S. S., Babatunde, O. F., Tran, P. M., Wu, X.-J., Castiglione, A., Kinney, K. J., Suresh, D., Mehta, K. P. J., Salgado-Pabon, W. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.12.724633</dc:identifier>
<dc:title><![CDATA[A TSST 1 structural motif disrupts endothelial programs required for vascular regeneration.]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.12.724733v1?rss=1">
<title>
<![CDATA[
Nitazoxanide activates BMP9-ALK1-SMAD signaling cascade and improves HHT vascular pathology 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.12.724733v1?rss=1
</link>
<description><![CDATA[
Objective: Hereditary hemorrhagic telangiectasia (HHT) is a vascular genetic disorder caused by endothelial cell dysfunction and characterized by telangiectasias and arteriovenous malformations (AVMs). HHT results primarily from loss-of-function mutations affecting components of the BMP9-ALK1-ENG-SMAD signaling cascade, a pathway essential for endothelial quiescence and vascular homeostasis, and currently lacks a cure. Here, we investigated whether nitazoxanide, an orally bioavailable drug with extensive clinical use, can modulate endothelial signaling relevant to HHT. Approach and Results: Nitazoxanide treatment activated SMAD1/5/8 signaling and increased expression of the downstream target ID1 in endothelial cells, while concurrently inhibiting mTOR signaling, indicating a dual modulatory effect on pathways implicated in HHT pathogenesis. In vivo, nitazoxanide activated SMAD signaling in BMP9/10-immunoblocked mice and significantly reduced AVM formation and hypervascularization. Importantly, nitazoxanide restored SMAD1/5/8 activation and ID1 expression in patient-derived blood outgrowth endothelial cells harboring loss-of-function mutations in ALK1 or SMAD4, which exhibit impaired BMP signaling. Conclusion: These findings identify nitazoxanide as a pharmacological modulator capable of activating BMP?SMAD signaling while restraining mTOR activity, thereby overcoming key signaling defects in HHT endothelial cells. Collectively, our results highlight nitazoxanide as a promising therapeutic candidate to target endothelial dysfunction in HHT.
]]></description>
<dc:creator><![CDATA[ Ruiz, S., Chiesa, C., Perez-Torrado, V., Nada, L., Mezzano, R., Vazquez, C., Santos, L., Criscuolo, Z., Serra, M., Marambaud, P., Escande, C. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.12.724733</dc:identifier>
<dc:title><![CDATA[Nitazoxanide activates BMP9-ALK1-SMAD signaling cascade and improves HHT vascular pathology]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.724849v1?rss=1">
<title>
<![CDATA[
Motor Neuron Dysfunction in SORD Deficiency: Implications for Therapeutic Development in Peripheral Neuropathies 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.724849v1?rss=1
</link>
<description><![CDATA[
Biallelic mutations in the sorbitol dehydrogenase (SORD) gene have been identified as one of the most common causes of autosomal-recessive Charcot Marie Tooth disease type 2 (CMT2) and distal hereditary neuropathy, collectively referred to as SORD deficiency. These mutations result in loss of sorbitol dehydrogenase activity, a key enzyme in the polyol pathway that metabolizes glucose, leading to marked accumulation of sorbitol in patient derived fibroblasts. However, the mechanisms by which SORD dysfunction drives axonal degeneration remain poorly understood, and robust in vitro models of human SORD deficient motor neurons (MNs) are still lacking. To address this gap, we established a human in vitro model of SORD deficiency by generating induced pluripotent stem cells (iPSCs) from fibroblasts affected individual carrying biallelic SORD mutations (SORDc.757delG/c.316_425+165del), and unaffected heterozygous carriers (SORDc.757delG/wt and SORDwt/c.316_425+165del). These iPSCs were subsequently differentiated into motor neuron progenitors (MNPs) and MNs. Comprehensive analysis of SORD-deficient human cells, including fibroblasts, MNPs, and MNs, revealed pronounced structural and functional abnormalities in the mitochondrial compartment, characterized by mitochondrial fragmentation and increased proton leak. Importantly, fibroblasts derived from two additional unrelated patients carrying the SORD mutation (SORDc.757delG/ c.757delG) further confirmed that SORD deficiency is associated with a mitochondrial phenotype. At the molecular level, SORD deficiency led to upregulation of aldose reductase (AR), another key enzyme of the polyol pathway, resulting in disruption of cellular redox homeostasis and increased oxidative stress. Consistent with these alterations, MNs derived from CMT2/SORD patients exhibited clear neurodegenerative features, including severe defects in neurite branching and synaptic architecture, ultimately impairing neuronal connectivity. Notably, pharmacological inhibition of AR effectively rescued both mitochondrial dysfunction and neuronal structural defects, supporting the targeting of AR as a promising therapeutic strategy for polyol pathway associated neuropathies as CMT2/SORD and diabetic neuropathy.
]]></description>
<dc:creator><![CDATA[ Divisato, G., Tozza, S., Cascone, E., Polishchuk, E., Zizolfi, M. C., Giannino, E., Marsella, F., Di Girolamo, D., Menale, C., Perone, L., Gianfico, P., Cuda, G., Bucci, C., Maiuri, P., Polishchuk, R., Manganelli, F., Parisi, S. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.724849</dc:identifier>
<dc:title><![CDATA[Motor Neuron Dysfunction in SORD Deficiency: Implications for Therapeutic Development in Peripheral Neuropathies]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.11.724452v1?rss=1">
<title>
<![CDATA[
The Cappuccino interactome reveals an intracellular role for Semaphorin-2a in Drosophila oogenesis 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.11.724452v1?rss=1
</link>
<description><![CDATA[
The spatiotemporal regulation of an actin mesh during Drosophila oogenesis is essential for proper localization of cell polarity determinants that establish the future patterning of the embryo. Here, we reveal an unexpected role for Semaphorin-2a (Sema2a) in actin mesh regulation and oogenesis. Sema2a classically functions as a secreted guidance cue that binds its cognate Plexin-B (PlexB) receptor to establish neural circuits. In contrast, we find that Sema2a is expressed inside the germarium, germline, and follicle cells of the developing ovary. Sema2a mutants possess small ovaries that fail to develop past mid-oogenesis. We demonstrate that Sema2a interacts with Cappuccino (Capu), a key actin nucleator crucial for building the actin mesh in Drosophila oocytes. Sema2a inhibits the actin assembly activity of Capu in vitro. Furthermore, genetic interaction between Sema2a and Capu influences mesh density and disrupts oskar mRNA localization. PlexB mutants, however, exhibit wild-type size ovaries with oskar mRNA localization distinct from Sema2a mutants, confirming the non-canonical role of Sema2a in oogenesis.
]]></description>
<dc:creator><![CDATA[ Wu, C., Rajan, S., Rixen, M., Wohlschlegel, J., Quinlan, M. E. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.11.724452</dc:identifier>
<dc:title><![CDATA[The Cappuccino interactome reveals an intracellular role for Semaphorin-2a in Drosophila oogenesis]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.724776v1?rss=1">
<title>
<![CDATA[
Caregiver-infant interactions selectively shape emerging functional connectivity in the neonatal brain 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.724776v1?rss=1
</link>
<description><![CDATA[
From birth, human infants engage in multi-modal social exchanges with caregivers that involve the coordination of gaze and touch to guide attention and support neurodevelopment. However, little is known about the association between these first interactive experiences and the functional organisation of the developing brain during the first postnatal month, a window of remarkable brain growth in humans. We address this gap by combining microanalytic coding of caregiver-infant interactions with task-free functional connectivity (FC), measured using high-density diffuse optical tomography (HD-DOT) in infants' homes during the first postnatal month. Task-free FC measures the intrinsic functional organisation of the developing brain, shedding light on the early development of neural systems supporting perception, regulation, and social interactions. Infants were assessed up to three times (1 week, 2 weeks, 1 month), enabling characterisation of both early FC and its rapid developmental change. Caregiver-infant interactions were associated with both concurrent organisation and rapid longitudinal change in FC. Dyadic engagement in the context of face-to-face interaction was associated with the refinement of short-range connectivity and the integration of long-range connectivity particularly between social brain regions, while affectionate touch was associated with general increases in long-distance connectivity. These results demonstrate that caregiving experiences influence the development of the brain's functional architecture in the first postnatal month, highlighting a critical window for shaping infant brain function.
]]></description>
<dc:creator><![CDATA[ Carnevali, L., Blanco, B., Rozhko, M., Weatherhead, M., Johnson, M. H., Lloyd-Fox, S., The PIPKIN Study Team ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.724776</dc:identifier>
<dc:title><![CDATA[Caregiver-infant interactions selectively shape emerging functional connectivity in the neonatal brain]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.722865v1?rss=1">
<title>
<![CDATA[
Neural Tracking of Linguistic Predictors in Spontaneous Conversational Speech 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.722865v1?rss=1
</link>
<description><![CDATA[
This study investigates whether neural tracking of linguistic information extends from read speech to spontaneous conversation. Using the temporal response function (TRF) framework, we validate our approach on a read-speech EEG dataset and then apply it to EEG recordings from natural conversations. We observe reliable neural tracking of key linguistic predictors, including word onset, part-of-speech surprisal, and lexical surprisal, in spontaneous speech, with effects around 200, 400, and 600 ms. These results provide new evidence that linguistic neural tracking operates in natural conversational settings and confirm the feasibility of EEG studies in ecologically valid contexts.
]]></description>
<dc:creator><![CDATA[ Fleig, M., Wang, S., Dudek, A. E., Freyermuth, J.-M., Becerra, L., Blache, P. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.722865</dc:identifier>
<dc:title><![CDATA[Neural Tracking of Linguistic Predictors in Spontaneous Conversational Speech]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.12.724564v1?rss=1">
<title>
<![CDATA[
Neural Substrates of Duration Serial Dependence: Opposing Modulation in Basal Ganglia and Posterior Medial Cortex 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.12.724564v1?rss=1
</link>
<description><![CDATA[
Perceptual judgments are systematically biased toward recent experience, a phenomenon called serial dependence. The brain circuits underlying this effect in time perception remain unknown. Using fMRI, we identified the neural substrates of duration serial dependence and tested whether they overlap with those for motion direction. Twenty-seven participants reproduced either the duration or direction of a visual stimulus; a retro-cue revealed which feature to report 3-s after stimulus onset, separating memory-trace signals from task-switching signals. Duration serial dependence was robust and roughly four times stronger on task-repeat than task-switch trials; direction serial dependence was near zero. The previous duration produced opposing responses in the bilateral putamen (suppression) and in the posterior cingulate cortex and precuneus (reinstatement); no analogous signal emerged for direction. Task switching from direction to time task engaged the inferior frontal junction and the dorsolateral prefrontal cortex, which carried no serial dependence signal. The anatomical dissociation resolves the behavioral pattern: the duration trace is encoded in the putamen and posterior medial cortex on every trial, but task-set reconfiguration by the frontoparietal network gates its read-out into behavior, explaining the task repetition effect. These results reveal a dissociation between two functionally distinct circuits: the putamen and posterior cingulate/precuneus carry signals from the previous trial, whereas frontoparietal regions support task switching but carry little serial dependence information.
]]></description>
<dc:creator><![CDATA[ Cheng, S., Chen, S., Wu, J., Qu, C., Shi, Z. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.12.724564</dc:identifier>
<dc:title><![CDATA[Neural Substrates of Duration Serial Dependence: Opposing Modulation in Basal Ganglia and Posterior Medial Cortex]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.724774v1?rss=1">
<title>
<![CDATA[
Distinct yet neighboring neural populations encode past, future, and surrounding speech context in the human temporal lobe 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.724774v1?rss=1
</link>
<description><![CDATA[
Context is critical for both human and artificial speech comprehension systems. While the role of preceding context in speech processing has been well documented, the neural mechanisms supporting the integration of subsequent input -- phonemes and words that occur in the future -- remain poorly understood. Here, we leverage advances in artificial speech systems to model the contribution of different sources of context on the neural encoding of speech in the human brain. For neural encoding, context-informed but not context-uninformed speech model embeddings explain unique variance in human neural activity beyond acoustics, including in early speech processing regions. In particular, model embeddings informed by past, future, and surrounding context explain activity in distinct intracranial electrodes. These electrodes are left-lateralised, and spatially intermixed in the temporal lobe. We find that beyond-word context is crucial for the representational quality of speech model embeddings, and in particular for the encoding of abstract linguistic information. Our finding that spatially neighboring yet distinct neural populations in the temporal lobe encode representations shaped by different contextual sources (past, future, and surrounding input) provides key insight into the neural circuitry that integrates multiple forms of contextual information. Furthermore, our results may inform the downstream use of self-supervised speech representations in language technology tasks, and in models of speech comprehension in the human brain.
]]></description>
<dc:creator><![CDATA[ de Heer Kloots, M., Kazemian, A., Turner, W., Parvizi, J., Gwilliams, L. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.724774</dc:identifier>
<dc:title><![CDATA[Distinct yet neighboring neural populations encode past, future, and surrounding speech context in the human temporal lobe]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.724991v1?rss=1">
<title>
<![CDATA[
Intrinsic coordination of dynamic molecular signatures shape the human prefrontal cortex 
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</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.724991v1?rss=1
</link>
<description><![CDATA[
The cerebral cortex drives human cognition through the coordinated activity of discrete cortical areas, each harboring specialized molecular, structural and functional characteristics. Central to this organization is the prefrontal cortex (PFC), a hub for executive function that displays disproportionate expansion in humans and selective vulnerability to neurodevelopmental disorders. Previous work has identified a collection of PFC-enriched marker genes with dynamic expression trajectories, and re-analysis of these datasets converge these markers into 18 distinct molecular signatures of spatiotemporal PFC identity. However, the intrinsic gene networks that coordinate these molecular signatures to shape the human PFC remains unclear. Through pooled CRISPR activation screens in human primary cortical tissues, we have evaluated the ability of PFC-enriched transcription factors to intrinsically pattern PFC molecular identity. Our screens identify novel roles for the neurogenesis regulator, YBX1, in the activation of human PFC fate. In parallel screens and knock-down experiments in human cortical organoids, we define how YBX1 acts in concert with other PFC determinants to activate molecular signatures of PFC identity. Our findings support a model in which PFC patterning is orchestrated by cohorts of intrinsic determinants that initiate, potentiate, and modulate PFC gene signatures, conferring robustness to the development of the human PFC.
]]></description>
<dc:creator><![CDATA[ Nano, P. R., Jaklic, D. C., Giang, V., Soto, J. A., Mil, J., Wang, S., Martija, A., Wick, B., Haeussler, M., Bhaduri, A. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.724991</dc:identifier>
<dc:title><![CDATA[Intrinsic coordination of dynamic molecular signatures shape the human prefrontal cortex]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.12.724557v1?rss=1">
<title>
<![CDATA[
Transcriptional plasticity of melanin-concentrating hormone neurons in the medial preoptic area of lactating mouse dams 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.12.724557v1?rss=1
</link>
<description><![CDATA[
The medial preoptic area (MPOA) is a central hub for maternal behavior, integrating hormonal and sensory signals to coordinate adaptive postpartum responses. Although melanin-concentrating hormone (MCH) neurons are well characterized in the lateral hypothalamus, their identity and functional engagement within MPOA circuits remain poorly defined. Here, through integrative reanalysis of a publicly available single-cell RNA sequencing dataset of the mouse MPOA (GSE295610), we identify two transcriptionally distinct Pmch-expressing neuronal populations. Both populations are GABAergic and emerge prominently during mid to late lactation. Lactation is characterized by significant upregulation of Pmch and coordinated enrichment of neuropeptidergic and hormone-responsive genes, including islet amyloid polypeptide (Iapp), prodynorphin (Pdyn), and prolactin receptor (Prlr). Independent single-cell gene expression profiling of FACS-isolated GAD67-GFP neurons from the MPOA further corroborated these findings, confirming the selective emergence of Pmch expression during lactation and its co-expression with neuropeptidergic and hormone-responsive genes. NeuroEstimator-based activity inference demonstrates increased predicted neuronal activity in lactating females, while pseudotime reconstruction reveals a lactation-associated transcriptional shift toward later trajectory states. hdWGCNA analysis identified gene co-expression modules significantly enriched during lactation. Regulatory network inference using SCENIC further revealed activation of activity-dependent transcriptional regulons, including cyclic AMP-responsive element-binding protein 3-like 1 (Creb3l1), early growth response 1 (Egr1), and FBJ osteosarcoma oncogene (Fos). These transcriptional programs converge on gene networks associated with synaptic plasticity, regulation of neurogenesis, and broader mechanisms of neuronal plasticity. Notably, these Pmch populations were not annotated in the original study, underscoring the power of systems-level reanalysis to uncover previously unrecognized components of maternal circuitry. Together, our findings provide single-cell evidence that MCH-expressing neurons in the MPOA undergo state-dependent transcriptional reorganization during lactation, suggesting a dynamic role for MCH signaling in postpartum neuroendocrine plasticity.
]]></description>
<dc:creator><![CDATA[ Anjos-Monteiro, A. d., Ferreira, J. G. P., Santos-Affonso, V. H. d., Chamiec-Case, E., Mickelsen, L. E., Abbasabadi, B. M., Elias, C. F., Jackson, A. C., Bittencourt, J. C. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.12.724557</dc:identifier>
<dc:title><![CDATA[Transcriptional plasticity of melanin-concentrating hormone neurons in the medial preoptic area of lactating mouse dams]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.12.724401v1?rss=1">
<title>
<![CDATA[
Engineering high-titer lentiviral vectors for robust expression of RNA-based gene circuits 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.12.724401v1?rss=1
</link>
<description><![CDATA[
Lentiviral vectors enable efficient delivery of genetic cargoes for gene and cell therapies. With their ~10-kb packaging limit, lentiviral vectors can encode multiple transcription units, supporting delivery of compact gene circuits. RNA-based devices offer highly compact control including ligand-responsive induction and closed-loop regulation. However, RNA devices such as ribozymes and splicing switches may interfere with vector production via activity on the single-stranded RNA genome. Here, we examine the impact of gene syntax and genetic parts to define design strategies for two-gene vectors encoding RNA devices. We find that titer decreases with genetic parts that interfere with transcription or processing of the viral transcript during production. Compared to initial vectors, our best-performing design boosts titer more than 30-fold, enabling fine-scale tuning of expression to optimize cell-fate conversion within a non-monotonic landscape. Together, this work illuminates principles for constructing two-gene lentiviral vectors with both high titer and robust expression, enhancing efficacy for downstream applications.
]]></description>
<dc:creator><![CDATA[ Love, K. S., Lende-Dorn, B. A., Galloway, K. E. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.12.724401</dc:identifier>
<dc:title><![CDATA[Engineering high-titer lentiviral vectors for robust expression of RNA-based gene circuits]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.12.724125v1?rss=1">
<title>
<![CDATA[
Cellular Mechanisms of Transcranial Magnetic Stimulation in Climbing Fibers and Purkinje Neurons in the Cerebellum 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.12.724125v1?rss=1
</link>
<description><![CDATA[
Although transcranial magnetic stimulation (TMS) is widely used for brain stimulation, fundamental issues about its underlying mechanisms remain unresolved. We investigated some of these issues experimentally using an intact isolated turtle cerebellum in vitro, employing a novel chamber designed to deliver precisely calibrated induced electric fields along cortical depth. Our results show that single-pulse TMS can directly activate Purkinje cells and climbing fibers, and synaptically activate Purkinje cells via climbing fibers -- all within the first 1.2 ms. Specifically, current source density analysis showed that TMS directly (non-synaptically) activated (1) climbing fibers near the bend with intracellular current directed toward the axonal terminals and (2) Purkinje cells directly near the axon initial segment with intracellular current directed toward the distal dendrites. The thresholds for direct activation of climbing fibers and Purkinje cells were found to be very similar, 25 {+/-} 1 V/m. The climbing fibers synaptically activated Purkinje cells, as expected, with intracellular current originating in the proximal dendritic trunk and directed toward the distal dendrites. At higher electric fields (> 58 {+/-} 17 V/m), TMS synaptically activated dendritic currents in Purkinje cells. These results provide new insight into how TMS may activate afferent fibers and cell bodies of cortical neurons.
]]></description>
<dc:creator><![CDATA[ Okada, Y., Dong, C., Makaroff, S., Sundaram, P. ]]></dc:creator>
<dc:date>2026-05-14</dc:date>
<dc:identifier>doi:10.64898/2026.05.12.724125</dc:identifier>
<dc:title><![CDATA[Cellular Mechanisms of Transcranial Magnetic Stimulation in Climbing Fibers and Purkinje Neurons in the Cerebellum]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-14</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.11.724466v1?rss=1">
<title>
<![CDATA[
Stage-aware transcriptomics reveals selective haplotype persistence in short-term ex vivo cultured Plasmodium vivax 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.11.724466v1?rss=1
</link>
<description><![CDATA[
Plasmodium vivax (Pv) infections are developmentally asynchronous and often polyclonal, complicating interpretation of bulk parasite transcriptomes. Here, we analyzed paired in vivo and short-term ex vivo transcriptomes from Ethiopian clinical isolates using stage deconvolution and PvMSP1 haplotyping. Ex vivo maturation modestly increased inferred schizont representation while largely preserving the proportion of trophozoites and gametocytes. After adjustment for parasite stage composition, in vivo and ex vivo transcriptomes remained globally similar, with no genes significantly differentially expressed, indicating the absence of major culture-induced transcriptional response. In contrast, short-term culture reduced multiplicity of infection, contracted within-host haplotype diversity, and non-randomly depleted specific haplotypes, consistent with a clonal bottleneck. In a subset of low-complexity infections, residual expression patterns were clustered by dominant haplotype, suggesting genotype-associated transcriptional heterogeneity independent of developmental stage. Together, these findings indicate that short-term ex vivo culture enriches late asexual stages and selectively filters clones rather than inducing a common transcriptional program. These results shows that ex vivo cultures are reliable way to study gene expression, especially for late stages. However, these needs explicitly model developmental composition and infection complexity when interpreting Pv transcriptomes from natural infections.
]]></description>
<dc:creator><![CDATA[ Abagero, B. R., Dumetz, F., Ford, C. T., Tolosa, T., Tesefay, D., Lukas, B., Shenkutie, T., Popovici, J., Yewhalaw, D., Serre, D., Lo, E. ]]></dc:creator>
<dc:date>2026-05-13</dc:date>
<dc:identifier>doi:10.64898/2026.05.11.724466</dc:identifier>
<dc:title><![CDATA[Stage-aware transcriptomics reveals selective haplotype persistence in short-term ex vivo cultured Plasmodium vivax]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-13</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.12.724742v1?rss=1">
<title>
<![CDATA[
Glutamylated vimentin proteoform identified by a synthetic binder links to epithelial-mesenchymal plasticity 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.12.724742v1?rss=1
</link>
<description><![CDATA[
Cytoskeletal protein expression and filament dynamics change significantly during cell state transitions. However, post-translational modifications of cytoskeletal proteins during these transitions have rarely been described. Here, using a synthetic glutamylation-binder (SB2B49) selected against a bi-glutamylated peptide epitope, we identify a distinct pool of glutamylated vimentin filaments. We demonstrate that vimentin glutamylation is enzymatically added by tubulin tyrosine ligase-like (TTLLs) and removed by cytosolic carboxypeptidases (CCPs). Mass spectrometry and mutagenesis reveal that glutamylation occurs on specific vimentin residues. We find that glutamylated vimentin levels are dynamically modulated during epithelial-mesenchymal plasticity. During collective migration in scratch-wound assays, glutamylated vimentin filaments are transiently depleted at the wound edge, a process controlled by canonical glutamylation writer-erasers. Our findings reveal a new layer of vimentin regulation via glutamylation and establish the glutamylation-binder as a valuable tool for exploring the diversity of vimentin proteoforms and glutamylation modifications in both physiological and pathological contexts.
]]></description>
<dc:creator><![CDATA[ Ganie, R. A., Biswas, A., Sasi, S., Devarakonda, L. P., Kale, I., Mullick, S., Siddappa, G., Singh, N., Gadadhar, S., Sirajuddin, M. ]]></dc:creator>
<dc:date>2026-05-13</dc:date>
<dc:identifier>doi:10.64898/2026.05.12.724742</dc:identifier>
<dc:title><![CDATA[Glutamylated vimentin proteoform identified by a synthetic binder links to epithelial-mesenchymal plasticity]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-13</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.05.13.724962v1?rss=1">
<title>
<![CDATA[
Au_Sus: A tiered consensus census of human autophagy genes 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.05.13.724962v1?rss=1
</link>
<description><![CDATA[
Autophagy is a critical cellular process, yet its genomic definition remains inconsistent across digital repositories. This lack of standardisation hinders reproducibility in high-throughput studies and clinical research. Here, we present Au_Sus, a high-confidence human autophagy census established through a frequency-based majority consensus of seven primary databases and literature sources. After rigorous manual curation and nomenclature standardisation, we defined a tiered framework: Maxim_Au (2,581 genes), Au_Sus (the 201-gene core consensus), and Minim_Au (77 universal genes). Functional enrichment and protein-protein interaction analysis confirm that Au_Sus captures a highly integrated and purified autophagic machinery, with significant associations to neurodegeneration and oncology. Furthermore, an analysis of nearly 100 published cancer gene signatures revealed profound functional dilution, with 60% of signature genes absent from our consensus. These findings suggest that many of these models incorporate peripheral stress markers rather than core autophagic effectors. Hence, Au_Sus (freely accessible at ausis.uniovi.es) provides a reliable, ready-to-use benchmark to standardise the study of autophagy in health and disease.
]]></description>
<dc:creator><![CDATA[ Guerra-Andres, M., Piedra-Macias, A., Garcia-Lopez, I., Jimenez-Garcia, P., Marino, G., Fernandez, A. F. ]]></dc:creator>
<dc:date>2026-05-13</dc:date>
<dc:identifier>doi:10.64898/2026.05.13.724962</dc:identifier>
<dc:title><![CDATA[Au_Sus: A tiered consensus census of human autophagy genes]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-05-13</prism:publicationDate>
<prism:section></prism:section>
</item>
</rdf:RDF>
