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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 19 recordsLinked to original sources
bioRxiv2026

Structures of MyD88 and its oncogenic mutant reveal DNA binding with implications for cytosolic DNA sensing

MyD88 is a universal adaptor that connects to Toll-like receptors and interleukin-1 receptors through its Toll/IL-1R homology (TIR) domain and activates inflammatory signaling via its death domain (DD). However, how MyD88TIR serves as the platform for these functions and if it has additional functions remain unclear. Here, we report cryogenic electron microscopy (cryo-EM) structures of MyD88TIR and its cancer-specific mutant L252P (previously L265P) mainly in ring and spiral forms, respectively. Both assemblies are formed by antiparallel double-filaments, using canonical TIR interfaces within each strand but unique surfaces between the strands, and position MyD88DD at the same sides of the assemblies for self-oligomerization and pathway activation. Surprisingly, these WT or L252P filaments are bound to dsDNA using the concave sides of the rings and the spirals. In vitro assays and cellular studies establish that MyD88 directly binds dsDNA and promotes inflammatory cytokine expression, particularly pro-IL-1{beta}, following dsDNA transfection or viral infection. Notably, these responses are unaffected by deficiency of UNC93B1, the essential chaperone required for trafficking endosomal nucleic acid-sensing TLRs. Structure-guide MyD88 mutant that disrupts dsDNA binding specifically compromises dsDNA-induced transcriptional program while maintaining TLR signaling. RNA-seq further reveals that MyD88 plays a crucial role in inducing gene expression upon dsDNA sensing and that about half of cGAS-dependent genes are also MyD88-dependent. Together, our structural, biochemical and genetic data support the findings that MyD88 directly engages with cytosolic dsDNA and cooperates with cGAS to promote the full innate immune transcriptional response.

immunology↗
bioRxiv2026

Human infection with an ape Plasmodium vivax-like parasite

An unusually divergent Plasmodium vivax parasite was reported in a Swedish patient with recent travel. Using whole-genome sequencing, we show that the infection was caused by a strain of ape P. vivax-like, providing evidence of the zoonotic potential of these parasites that infect wild gorillas and chimpanzees in central Africa.

genetics↗
bioRxiv2026

Revealing multiscale architecture of the intact human spine using hierarchical phase contrast tomography

Background: Computed tomography (CT) and magnetic resonance imaging (MRI) provide detailed clinical assessment of the human spine; however, their millimeter-scale spatial resolution limits direct visualization of tissue microarchitecture and interfaces. Hierarchical phase-contrast tomography (HiP-CT) enables ex vivo non-destructive, micron-resolution imaging of intact human organs without exogenous contrast agents, extending anatomical assessment to spatial scales inaccessible to conventional clinical imaging. Purpose: To evaluate the capability of HiP-CT to visualize macro- to microanatomy of an intact adult human spine ex vivo. Methods: An intact spine (C1-L5) from a 62-year-old male donor without known skeletal disease was formalin-fixed and imaged by HiP-CT at the European Synchrotron. Whole-spine imaging was performed at 16.26 m isotropic voxels, with selected regions of interest imaged using 2.2 m voxels. Ex vivo MRI using clinical sequences was performed for anatomical comparison. Three-dimensional segmentation and quantitative analyses included intervertebral disc (IVD) grading, annulus fibrosus fiber tracing, and vertebral trabecular micro-morphometry. Results: HiP-CT enabled high spatial-resolution, multiscale imaging of the intact human spine, simultaneously visualizing vertebral bone and endplate, IVDs, spinal cord and meninges, nerve roots and ganglia, vasculature, ligaments, and musculature. Three-dimensional segmentation and virtual sectioning mapped neurovascular anatomy and vertebral vascular supply, without exogenous contrast enhancement, while preserving their relationships with surrounding tissues. Whole-spine images enabled quantitative analysis of annulus fibrosus fiber organization and vertebral trabecular microarchitecture, permitting the detection of focal posterolateral fiber disruption at the L4-L5 IVD and regional differences in trabecular architecture between cervical and lumbar vertebral bodies. Local tomography resolved annulus fibrosus lamellae, vertebral endplate Haversian systems, and facet joint hyaline cartilage at micron resolution. Conclusions: HiP-CT enables non-destructive, multiscale three-dimensional imaging of the intact human spine while preserving tissue relationships across spatial scales and hard-soft tissue boundaries. HiP-CT could provide an ex vivo microanatomical reference for future correlation with clinical imaging investigations of spinal disease and in the development and validation of imaging biomarkers.

bioengineering↗
bioRxiv2026

A preclinical platform for focused ultrasound delivery from microplate to awake brain

Background. Focused ultrasound (FUS) has broad therapeutic potential, but its mechanisms of action are poorly understood. Preclinical FUS research enables rigorous interrogation of understudied parameters, but fragmented, single-purpose benchtop devices prevent standardized acoustic exposure across models. Objective. To describe a unified preclinical FUS platform for cell culture, ex vivo tissue, and awake stereotaxic in vivo delivery in one lightweight system, validated using glioblastoma as a disease model. Methods. We performed single-well FUS delivery to 96-well microplates, single-well delivery to freshly resected human glioblastoma tissue, and stereotaxic transcranial delivery to awake, head-fixed mice ambulating freely on a floating cage. Output was independently calibrated in free field, with measured microplate insertion loss. Pulsed low-intensity focused ultrasound (pLIFU) was applied to GL261-bearing mice, resected human glioblastoma, and macrophage cell lines. Results. Awake stereotaxic pLIFU produced acute tumor signal attenuation in GL261-bearing mice (mean log2 fold-change -1.66 versus +5.20 controls, p = 0.016) with bioluminescence evidence consistent with focal targeting. Ex vivo pLIFU produced directionally consistent immunophenotypic shifts in human glioblastoma (increased iNOS+, decreased Arg1+ populations). In vitro, pLIFU reduced CD80 on immunosuppressive macrophages to 73% of baseline in RAW 264.7 cells (p = 0.0008, n = 5) and 64% in THP-1 cells (p = 0.0006, n = 2), with MHC II upregulation in RAW 264.7 (ratio 1.65, p = 0.004) and ARG1 reduction in THP-1 (ratio 0.52, p = 0.0025). Conclusions. A unified preclinical FUS platform validated across in vitro, ex vivo, and awake in vivo applications enables stereotaxically guided transcranial FUS in awake, head-fixed mice ambulating in an exploratory manner during sonication, and single-well microplate treatments.

neuroscience↗
bioRxiv2026

CellMethMarker provides an integrated database of human cell- and tissue-type-specific DNA methylation markers

Cell- and tissue-type-specific DNA methylation markers provide epigenetic signatures of cellular identity and are widely used to infer cellular origin from bulk and single-cell methylomes. Existing resources mainly emphasize disease-associated biomarkers, methylome atlases, genomic annotations or RNA-based cell markers, leaving an unmet need for an integrated region-level resource dedicated to such markers. Here we present CellMethMarker (http://gu-zhanglab.hfcas.ac.cn/CellMethMarker), a curated database integrating 347,514 de novo markers derived from uniformly processed whole-genome and reduced-representation bisulfite sequencing datasets, 2,203,507 literature-derived marker records and harmonized metadata for 2,810 samples. CellMethMarker enables cell- and tissue-centered marker retrieval, coordinate-based search, genome-browser visualization, interactive methylation analysis and data download. In an independent single-cell methylome atlas, these markers recover the expected cell-type-associated methylation patterns, and a platform-matched reference built from them lowers the mean deconvolution error from 0.365 to 0.144. CellMethMarker therefore links region-level DNA methylation variation to cellular identity and supports methylome-based cell-type annotation and deconvolution.

bioinformatics↗
bioRxiv2026

A comprehensive identification protocol for postcranial bones of Southeast Asian Ruminantia. Part 2: Morphological criteria for small and medium-sized species

The taxonomic identification of postcranial elements from small and medium-sized ruminants represents a significant challenge in zooarchaeological and Late Quaternary paleontological studies, particularly in biodiversity-rich regions such as continental Southeast Asia. This study presents a comprehensive osteological reference framework for the small and medium-sized Ruminantia of this region, based on a comparative sample of 228 specimens representing 14 species across three families (Bovidae, Cervidae, and Moschidae). Osteological characters were first described on a small initial specimen set and subsequently scored across the full sample. Although a small number of character states were found to be unique to specific taxa, most proved highly variable, limiting their individual identification potential. To address this, a Random Forest and a Naive Bayes classifier were applied to assess the discriminatory power of character combinations across four taxonomic ranks (Family, Subfamily, Genus, and Species) on independent bones. Both approaches performed similarly, achieving mean identification accuracies of 87-86% at the family level, 69% at the subfamily level, 50% at the genus level, and 35-33% at the species level. The Naive Bayes models were further deployed as an interactive web application, allowing users to perform bone identification based on any combination of observable character states from a single anatomical element. Our results highlight the limits of morphological identification of postcranial elements in this taxonomic and biogeographic context, while demonstrating that a transparent, reproducible, and statistically grounded approach can still represent a significant step forward for zooarchaeological and Late Quaternary paleontological studies in Southeast Asia and beyond.

zoology↗
bioRxiv2026

A comprehensive identification protocol for postcranial bones of Southeast Asian Ruminantia. Part 3: Morphological criteria for large-sized species

Postcranial remains of large-bodied ruminants are abundant in the Late Quaternary record of continental Southeast Asia, yet their taxonomic attribution remains one of the least resolved problems in the zooarchaeology of this biodiversity-rich region. We address it here with an osteological identification protocol covering the six large ruminant species of the mainland: Bubalus bubalis, Bos javanicus, Bos sauveli, Bos gaurus, Budorcas taxicolor and Rusa unicolor, built from a comparative sample of 109 skeletons. A total of 148 discrete characters over 27 skeletal elements representing 442 states were defined on a restricted set of individuals, then scored across the entire sample. Most proved remarkably stable within taxa with 80.0% of the character/taxon combinations showing a dominant state at a frequency above 95%, and a substantial number of states occurred in a single family, subfamily, genus or species. Character combinations for taxonomic identification were then evaluated by the use of two supervised machine learning methods, a random forest model and a naive Bayes classifier at each of four taxonomic ranks. The two behaved almost identically, with mean accuracies of 95-94% for families, 93% for subfamilies, 89% for genera and 76% for species; only the three closely related and unevenly sampled species of Bos resisted consistent separation. The weighted naive Bayes models are distributed as a standalone web application in which any combination of states observed on a single element returns attribution probabilities for every rank. Together these results offer a transparent and statistically explicit alternative to expert judgement for the identification of Late Quaternary postcranial mammal remains, in Southeast Asia and elsewhere.

zoology↗
bioRxiv2026

Metabolic and transcriptional responses reveal co-option of symbiotic processes during early soybean-soybean cyst nematode interaction

The biochemical mechanisms by which virulent populations of soybean cyst nematode (Heterodera glycines, SCN) overcome host resistance are critical to understanding this economically important pathogen. Here, we deployed metabolic and transcriptome profiling of soybean roots during the SCN infection and establishment process to investigate the molecular and biochemical mechanisms of pathogen establishment. Across samples from a time series spanning nematode invasion to syncytium maturation, we demonstrate that compatible SCN infection does not bypass host immunity but systematically remodels it. In a compatible interaction between soybean carrying the high-copy Rhg1 resistance locus challenged with HG Type 2.5.7 SCN virulent on this host, we identify a 72-metabolite defense signature spanning isoflavonoids, triterpenoid saponins, and phenylpropanoids that persist across all infection stages. Despite activation of this metabolic defense signature by the pathogen on infection, defense transcription is near silence by 3 days post-infection, while defense metabolites persist, revealing a critical decoupling of transcriptional and metabolic defense programs at the precise window of syncytium initiation. Suppression of phenylpropanoid accumulation occurs downstream of PAL transcription, indicating a block at the metabolic level invisible to transcriptomics alone. By 5 days post-infection, cytokinin accumulation coincides with nodulin gene induction and phospholipid remodeling consistent with activation of the legume symbiosis program during syncytium maturation. Together, these findings establish that compatibility arises not from failed recognition but from progressive immune dismantling, including suppression of defense chemistry and co-option of the legume-rhizobium symbiosis machinery.

plant biology↗
bioRxiv2026

IG-28 enables identification and quantification of high-confidence isoforms from large bulk and single-cell full-length cDNA datasets

The technology to sequence full-length transcriptomes from bulk and single-cell samples has rapidly advanced. As a result, full-length cDNA datasets now reach billions of reads in size which is beyond the capability of most established isoform identification tools. Here, we introduce IG-28 which addresses this challenge with its capability to process and analyze large fl-cDNA datasets fast and using minimal computational resources. In contrast to its predecessor Mandalorion, IG-28 is not limited to bulk fl-cDNA but is capable of parsing, processing, and analyzing single-cell fl-cDNA datasets. It does so in a lightweight, flexible manner, integrating seamlessly with established scRNA-seq analysis workflows. We benchmarked IG-28 against a variety of established and new isoform identification tools using several bulk and a complex single-cell fl-cDNA dataset and found that IG-28 consistently outperformed the other tools by identifying high-confidence public isoforms.

bioinformatics↗
bioRxiv2026

Co-transcriptomic network analysis of host-parasite interactions reveals genes underpinning parasite fitness

Interactions between parasites and their host organisms generate continuous variation in infection outcomes. Although dual transcriptome studies have demonstrated extensive molecular dialogues between interacting species, it is still unclear how natural variation in host and parasite gene regulatory networks and coordination between them contribute to diverse disease phenotypes. Here, we re-contextualized co-transcriptomes from recombinant inbred lines of the plant-parasitic root-knot nematode Meloidogyne hapla infecting Medicago truncatula host plants with relative measures of infection intensity as a proxy for parasite load. We used infection intensity to estimate interaction gradients on gene expression by calculating its covariance with transcript levels. Quantitative analyses of interaction gradients for host and parasite transcriptomes identified major differences in development-related transcriptional programs along the infection continuum. In addition, integrated network analyses connected host cell wall remodeling with parasite protein production and secretion. Silencing of candidate root-knot nematode genes reduced host galling and parasite reproductive fitness, providing experimental support for our network-derived predictions. Together, our findings present an integrated systems genetics framework connecting naturally occurring genetic variation to quantitative disease phenotypes.

systems biology↗
bioRxiv2026

Individualized brain-body signatures of positive emotions revealed by large-scale multimodal neurophysiological recording

Using one of the most comprehensive multimodal biosensing datasets in affective research, densely sampled within individuals, we asked how emotions are instantiated in each person's brain and body. Four participants viewed 168 emotion-evoking videos during 128-channel EEG and 28 autonomic, ocular and facial recordings. Cross-validated elastic-net classifiers distinguished each of 15 positive and neutral emotions from baseline in every participant (mean accuracy 87-97%). We found that no emotion was predicted by a single marker and each reflected a multimodal ensemble of cortical and autonomic activity whose composition was largely person-specific. Yet physiology-derived groupings converged selectively with self-report; Interest-Awe-Amusement-Satisfaction and Entrancement-Aesthetic Appreciation recurred across individuals based on physiology. Across emotion groups, frontal and posterior delta, posterior alpha and electrodermal activity formed a shared backbone, plausibly reflecting affective and sensory engagement, whereas cardiovascular and facial signals varied between people. This framework yields individualized, objective neurophysiological indicators of emotion, potentially aiding personalized diagnosis.

neuroscience↗
bioRxiv2026

Arena3D 3.0: a web server for exploring, analyzing, annotating and sharing multilayered networks in 3D

Multilayer networks describe biological entities linked by several kinds of relation or measured under several conditions. Arena3D 3.0, a complete reimplementation of Arena3Dweb, gives each layer its own place in an interactive 3D scene. Networks are uploaded or imported from STRING, IntAct, OmniPath, NDEx, Reactome and the Gene Ontology. Twelve layouts, seven in 3D, are available, and node copies can be aligned across layers. Layers are drawn as floors or 3D containers in thirteen arrangements, including 3D hive plots. Communities and annotated groups can be laid out apart and outlined as hulls or fog clouds, and edges can be bundled. Analyses cover node and multilayer metrics, distributions and perturbation, with chord, Sankey, heatmap, UpSet and UMAP views. Networks go to Cytoscape, Gephi Lite, NORMA and JBrowse 2, gene lists to Flame, and a REST API gives programmatic access. Arena3D 3.0 is free at www.arena3d.org without login.

bioinformatics↗
bioRxiv2026

AN INTEGRATED HEART-ON-A-CHIP NAM RESOLVES DISTINCT CLINICAL PHENOTYPES OF MYOCARDIAL ISCHEMIA-REPERFUSION INJURY

Background: Reperfusion is required for myocardial salvage yet itself injures the heart, and cardioprotective interventions that reduce infarct size experimentally have repeatedly failed to improve outcomes in patients. These interventions are evaluated against viability or infarct size alone, whereas ischemia-reperfusion (I/R) injury produces structural, biochemical, and contractile dysfunction in the same tissue. No in vitro new approach methodology (NAM), however, resolves all three within one system. Methods: A NAM was created within a heart-on-a-chip platform, which was constructed by culturing neonatal rat ventricular myocytes (NRVMs) on muscular thin films. Cardiomyocytes were subjected to normoxia, 2 hours of ischemia, and ischemia followed by 2 hours of reperfusion. Sarcomeric architecture was quantified by immunofluorescence, cardiomyocyte injury by LIVE/DEAD staining and cardiac troponin I release into conditioned media, while contractile stress and spontaneous beat frequency were recorded on the same films before and after each condition. Results: Under ischemia, z-line density decreased while architectural metrics were preserved, indicating cell loss rather than sarcomere disorganization. Furthermore, viability decreased, troponin elevated, and every contractile stress component declined, while spontaneous beat frequency was unchanged. Reperfusion fractured this uniform depression. Cell death and troponin release increased further, yet structure was unchanged from ischemia, so every functional change occurred on a depleted but architecturally intact cardiomyocyte population. Systolic stress recovered partially, whereas diastolic stress exceeded baseline, leaving active stress suppressed despite oxygen recovery. Beat frequency increased with pronounced variability. Conclusions: This heart-on-a-chip NAM resolved structural, biochemical, and contractile injury that global indices conflate, distinguishing ischemic from reperfusion pathophysiology. Interestingly, individual readouts corresponded to distinct clinical syndromes of ischemic injury, positioning this platform for future testing of cardioprotective candidates against the full injury phenotype.

physiology↗
bioRxiv2026

Iron sensing modules participate in rhizospheric pH perception in rice

Rhizospheric pH has emerged as one of the most important environmental factors regulating plant fitness in almost every aspect of plant physiology and development. Interestingly, the information on how plant perceive rhizospheric pH is still not well understood. In this report we have elucidated the intricate mechanism where rhizospheric pH mediated changes in relative Fe availability are sensed by the plants to initiate complex physiological responses. Using root specific RNA-seq, ICPMS, hormone quantification and physiological validation in rice, the study revealed Fe availability to be a critical determinant of rhizospheric pH where the relative Fe toxicity towards acidic pH and Fe deficiency towards alkaline pH is deduced by the plant in the form of JA-auxin crosstalk regulating the physiological responses against rhizospheric pH.

plant biology↗
bioRxiv2026

Executive and language systems competitively shape predictive processing during reading

When we read, our brains constantly generate predictions about upcoming words, which is thought to make comprehension faster and more efficient. Yet it remains unclear whether this predictive mechanism relies on the same domain-general executive resources the brain uses for other demanding cognitive tasks, or operates largely independently within the language system. Here we tested this question using transcranial magnetic stimulation (TMS) in twenty-five healthy adults, who performed self-paced naturalistic reading, an n-back task, and a dual task of concurrent reading and n-back, allowing us to place competing demands on cognitive resources. In three sessions, we stimulated the left angular gyrus alone, the angular gyrus together with dorsolateral prefrontal cortex, a hub of executive control, or delivered sham stimulation, and used computational modeling of decision-making to isolate how each brain state altered the underlying cognitive processes. Combined stimulation of the angular gyrus and prefrontal cortex selectively weakened the reading-time costs of unexpected words, but only when reading competed with the working-memory task, revealing that linguistic prediction draws on executive resources specifically under cognitive load. Computational models showed that the relationship was bidirectional: Unpredictable words also disrupted concurrent working-memory decisions, slowing the accumulation of evidence and increasing response caution. Together, these findings show that predictive language processing is not a fixed, encapsulated function but is dynamically coupled to executive control when cognitive demands compete. Our results provide evidence that prediction during language comprehension is embedded within a broader, demand-sensitive cognitive architecture that flexibly coordinates linguistic and executive resources.

neuroscience↗
bioRxiv2026

Preclinical Development and Safety of Laterally Spreading Dual AAV.SPR-MYO7A Vectors for the Treatment of Usher Syndrome Type 1B

Usher syndrome type 1B (USH1B), caused by mutations in MYO7A, is the most severe form of Usher syndrome and accounts for more than 50% of USH1 cases. Affected patients are born profoundly deaf with vestibular dysfunction and develop progressive retinitis pigmentosa, for which no approved treatment exists. The MYO7A coding sequence exceeds the packaging capacity of adeno-associated virus (AAV), the gold standard vector for retinal gene therapy. To overcome this, we developed dual AAV hybrid and overlap platforms to reconstitute full-length MYO7A expression in photoreceptors and retinal pigment epithelium. Modification of cDNA split points, and reduction of non-coding sequence yielded optimized vector pairs that produced higher full-length MYO7A levels with substantially reduced truncated protein. Packaging in the laterally spreading AAV.SPR capsid enabled supraphysiological MYO7A expression in cynomolgus macaques at macular and distal retinal sites without requiring foveal detachment, an important safety consideration for USH1B patients with remaining central vision. A six-month GLP toxicology study confirmed that ATSN-301, an AAV.SPR-based dual vector reconstituting MYO7A driven by the smCBA promoter, was well tolerated at all doses, with a No Observed Adverse Effect Level established at 1.2E11 vg/eye, supporting its clinical advancement for USH1B.

genetics↗
bioRxiv2026

Cancers relax selection on charge at the mitochondrial complex I quinone cavity

Mitochondrial complex I translocates protons through hydrated channels whose connectivity and electrostatics are both defined by structure, but whether they are distinctly constrained is unknown. From a 2.39 cryo-EM structure modelling 2,945 ordered waters, we built the proton wire of the seven mtDNA-encoded ND subunits and scored all 40,166 missense substitutions on two near-orthogonal axes (r = 0.17): electrostatic shift at proton-loading sites, and topological disruption of the wire. Across 858 germline variant sites, loading sites (0.51) and cut vertices (0.67) are both depleted. In tumours only loading sites are enriched (1.42 TCGA, 1.67 PCAWG, 1.29 MSK-IMPACT), a 3.06-fold difference tested as a wire class tissue-type interaction (P = 3.6 10-). It survives adjustment for conservation, burial and coverage, and is concentrated in ND1 within 15 of the quinone cavity, not spread along the proton path. Selection separates charge from connectivity, without establishing a fitness benefit.

biophysics↗
bioRxiv2026

Rugnux: from diffraction images to structure at synchrotrons and XFELs in one program

Rising data rates in macromolecular crystallography outpace multi-program pipelines on computing clusters. Rugnux, a single GPU-accelerated program, turns rotation or serial still diffraction images into merged data and an initial structure. At synchrotrons, results arrive seconds after the last image; on one workstation, 207 public datasets from 36 sources took a median of 15 s each, with deposition-quality. Serial XFEL data were processed faster than the collection rate, enabling real-time structure determination.

biophysics↗