Search bioRxiv⌕ Search

resource

Preprint

Preprint: explore 300 source-linked works published from 2026 to 2026, with original documents and citations.

Search within this collectionFollow this collection with RSS

Coverage and selection

Includes records with this source-supplied label or an explicit phrase match in their metadata. Matches indicate a mention, not proof that a paper uses a method or tests a material. Source versions are consolidated by DOI.

Sources: biorxiv. Collection updated 2026-09-15. Counts describe this index, not the complete source archives.

bioRxiv2026

Differential expression of NEAT1 in the corneal endothelium increases susceptibility to oxidative stress in Fuchs Endothelial Corneal Dystrophy

Fuchs endothelial corneal dystrophy (FECD) is a disease of the corneal endothelium (CE) characterized by the loss of corneal endothelial cells (CECs) and guttae formation, ultimately resulting in corneal edema and vision loss. FECD primarily affects the central CE while sparing the peripheral CE, however the underlying mechanism contributing to the spatial differences remain unknown. Oxidative stress has been increasingly recognized as a key contributor to the pathogenesis of FECD, with CECs being particularly susceptible to damage from reactive oxygen species (ROS), high metabolic activity and ultraviolet induced DNA damage. The non-proliferative nature of CECs, along with the accumulation of oxidative damage can ultimately lead to CEC loss, a key feature of FECD. In this study, we induced oxidative stress with hydrogen peroxide (H2O2) on ex-vivo corneal specimens and observe increased cell death in the central region compared to the peripheral CE. To investigate these underlying differences, we performed bulk RNA sequencing (RNA-seq) on the central and peripheral regions of CE from FECD and normal cadaveric donors. Pathway analysis identified an enrichment of genes involved in collagen and extracellular matrix between the central and peripheral regions of CE in both normal and FECD, as well as between normal and FECD CE. Intriguingly, we identified the long non-coding RNA (lncRNA), NEAT1 as a top differentially expressed gene, with reduced expression in the central CE compared to the peripheral CE and lower expression in FECD compared with normal CE. Using corneal endothelial cell lines and ex-vivo specimens from FECD patients and normal cadavers, we found decreased NEAT1 expression levels in FECD and increased susceptibility to H2O2-induced oxidative stress. We observed that NEAT1 knockdown in normal and FECD cells exacerbated H2O2-mediated oxidative stress, and that NEAT1 overexpression protected FECD cells. We report in this study, a novel insight in the spatial differences in gene expression in the CE and identify reduced expression of NEAT1 in the central CE as a potential contributor to oxidative stress-related cell death in FECD. These findings provide novel insight into FECD pathogenesis and why FECD pathology preferentially affects the central CE. Antioxidants targeting NEAT1 signaling could be developed into novel therapeutics aimed at preventing FECD pathogenesis.

cell biology↗
bioRxiv2026

A transition state-like acylenzyme conformation distinguishes carbapenemase activity in class A β-lactamases

Carbapenems are the most potent {beta}-lactams, key antibiotics for healthcare-associated infections by Gram-negative bacteria and evade hydrolysis by most {beta}-lactamases, but are increasingly threatened by emergence of enzymes exhibiting hydrolytic activity towards them. Of the four recognised {beta}-lactamase subclasses, class A (active-site serine enzymes that hydrolyse {beta}-lactams via a covalent acylenzyme intermediate) is the most widely disseminated and, while the majority of such enzymes react with carbapenems to form long-lasting acylenzyme complexes, several possess carbapenem-hydrolyzing activity (carbapenemases). Here, we investigate the basis for these differences in a panel of class A {beta}-lactamases using molecular dynamics (MD) simulations of the respective acylenzyme complexes and tetrahedral intermediates (TI). The simulations reveal multiple features associated with catalytic activity across the spectrum of enzymes tested, including more extensive interactions of the carbapenem acylenzyme carbonyl and generally increased lifetimes of active site water molecules positioned for deacylation. Analysis of the dynamic trajectories shows carbapenemases to have reduced root mean-squared fluctuation (RMSF) differences between the acylenzyme and TI, that are not limited to the active site, indicating that the acylenzyme complex is pre-organised for reaction in carbapenemases but not in carbapenem-inhibited enzymes. Similarly, Principal Component Analysis (PCA) of acylenzyme and TI dynamics shows greater overlap between the two states in carbapenemases, providing further evidence for acylenzyme pre-organisation. Such simulations may represent an effective computational assay able to identify enzymes with carbapenemase activity at relatively modest computational cost.

biochemistry↗
bioRxiv2026

Absence of a spindle position checkpoint in the fungal pathogen Cryptococcus neoformans

To maintain genome stability, it is crucial that cells do not initiate cytokinesis until chromosomes have been properly segregated. In the model budding yeast Saccharomyces cerevisiae, a surveillance mechanism called the Spindle Position Checkpoint (SPoC) ensures this coordination by regulating the Mitotic Exit Network (MEN) to couple exit from mitosis and cytokinesis to spindle position. The MEN is conserved in Ascomycota where the orthologous pathway in the fission yeast Schizosaccharomyces pombe, the Septation Initiation Network (SIN), regulates cytokinesis in response to defects in spindle elongation. Here, we show that the MEN/SIN pathway is conserved in the basidiomycetous budding yeast and human pathogen, Cryptococcus neoformans, and controls cytokinesis. However, spindle position or elongation does not regulate pathway activation or cell cycle progression in C. neoformans. In essence, there appears to be no SPoC in this organism to delay cytokinesis upon defects in mitosis. We speculate that while increasing the risk of genome instability, the lack of a SPoC might facilitate C. neoformans's ability to change ploidy in the host.

cell biology↗
bioRxiv2026

DNA Sequence-Programmed Protein Coronas Determine Intracellular Fate and Proteostatic Stress of Carbon Nanotubes

Single-walled carbon nanotubes (SWCNTs) show promise for optical biosensing, imaging, and drug delivery, but turning them into safe, precision nanomedicine tools requires understanding how nanotube surface chemistry dictates recognition and processing by cells. Like other nanomaterials, carbon nanotubes acquire a biomolecular corona on contact with biological fluids, and corona identity is increasingly recognized as central to sensor performance and drug delivery efficacy. However, whether corona identity also governs the intracellular fate of carbon nanotubes remains largely unknown. Here, we show that the single-stranded DNA wrapping of (6,5)-enriched single-walled carbon nanotubes reprograms their protein corona, intracellular trafficking, and macrophage response. By profiling (AT)15, (GT)15, and (CT)15 wrapped SWCNTs, we show that the wrapping sequence programs both the protein corona and the resulting proteostatic stress on macrophages. Photoluminescence imaging and confocal Raman measurements reported that (AT)15 is internalized the most yet leaves the proteome and nanotube structure largely undisturbed, whereas (CT)15, taken up the least, undergoes the most aggressive intracellular degradation and drives the highest oxidative and proteostatic stress. Corona proteomics indicated that all three tested nanotubes form coronas with distinct functional identities that are responsible for divergent intracellular routes. Time-resolved intracellular proteomics combined with functional assays resolved how the host cell reorganizes its biomolecular complexity over time, including oxidative outputs, aside from a sequence-independent core response involving particle engagement, phagosomal sorting, and lysosomal processing. These findings provide mechanistic insight into nanomaterial-cell interactions and the wrapping sequence as a tunable, nucleotide-level design handle for controlling the intracellular fate of carbon nanomaterials, with potential implications for safe and effective nanomedicine platforms.

bioengineering↗
bioRxiv2026

Nitrate regulates anchor root development

Nitrogen is a critical nutrient necessary for plant growth and survival. Plasticity in root architecture helps adapt to soil nitrogen levels for optimal nitrogen uptake; the nitrate form of soil nitrogen is a major modulator of root architecture. Although details of nitrate-regulated primary and lateral root growth are known, nitrate-regulated formation of anchor roots, which arise from the collet, is not understood. In this work, we uncover a role for nitrate in the regulation of anchor root formation. We find that cytokinin inhibits anchor root formation with rising nitrate. These cytokinin effects on anchor root formation rely on regulated indole-3-butyric acid (IBA) to indole-3-acetic acid (IAA) conversion. These data point toward a mechanism by which nitrate controls a previously underappreciated aspect of nitrate-dependent root architecture driven by anchor roots.

plant biology↗
bioRxiv2026

DIFFERENTIAL PHOTOSYNTHETIC RESPONSES TO GLUFOSINATE AMMONIUM IN TWO GRASS WEEDS: Lolium multiflorum AND Echinochloa crus-galli.

Background: Weed control is one of the main challenges in agriculture today, particularly due to the increasing occurrence of herbicide-resistant populations. Among the most problematic species are Lolium multiflorum (L.) and Echinochloa crus-galli (L.) Beauv., for which glyphosate-resistant populations have been reported. In this context, glufosinate ammonium has emerged as an alternative for their control; however, its efficacy may vary depending on species and photosynthetic metabolism. Objective: The objective of this study was to evaluate the differential sensitivity of ryegrass (C3) and barnyardgrass (C4) to ammonium glufosinate by analyzing physiological responses associated with leaf senescence and photosystem II activity. Methods: Visual injury, chlorophyll fluorescence, and ammonium accumulation were assessed. Results: Results revealed a differential response between species. Barnyardgrass exhibited earlier symptom onset and a greater reduction in the quantum yield of photosystem II ({Phi}PSII), whereas ryegrass showed a slower senescence process. These differences indicate a higher sensitivity of barnyardgrass to glufosinate ammonium, possibly associated with its C4 photosynthetic metabolism. Conclusions: It is concluded that the effectiveness of glufosinate ammonium depends on the type of photosynthetic metabolism and on the ability of each species to cope with herbicide-induced oxidative stress. This information contributes to optimizing glufosinate ammonium use and to the development of management strategies aimed at delaying the evolution of herbicide resistance.

plant biology↗
bioRxiv2026

Spatial Mapping of the Lung Cancer Ecosystem Reveals Distinct Patterns of Intratumoral and Internodular Heterogeneity

The spatial organization of malignant and non-malignant cells within the tumor microenvironment (TME) critically influences tumor evolution and therapeutic response. However, the architecture of micro-niches remains incompletely understood. Leveraging Xenium-based spatial transcriptomics, we comprehensively mapped the spatial ecosystem of an orthotopic murine lung cancer model, identifying distinct spatial domains that form unique, organized cellular neighborhoods. These domains cluster into three major communities: (1) non-tumoral regions that recapitulate canonical normal lung structures; (2) a heterogeneous peri-tumoral region composed of spatial domains characterized by mesenchymal remodeling, active immune checkpoint signaling, and immunosuppressive myeloid populations; and (3) intra-tumoral regions that reveal marked tumor nodule heterogeneity, with unique tumor-specific domains exhibiting hallmark cancer pathways. Furthermore, our analytic approach was applicable to human lung cancer tissue. Notably, spatial domain analysis allowed us to resolve tumor nodules into multiple biologically distinct subtypes, defined by domain composition, hallmark cancer programs, and intercellular communication patterns within the TME.

cancer biology↗
bioRxiv2026

X-inactivation escapee domains are CTCF-cohesin independent chromatin compartments

X-chromosome inactivation involves chromosome-wide gene silencing accompanied by extensive chromatin changes, as well the loss of topologically associating domains. Yet discrete regions of the inactive X chromosome retain activity within localised 3D domains, which contain active genes that variably escape from X inactivation. The transcription factor and architectural protein CTCF has been proposed to be implicated in escape by insulating escape domains or sustaining their topology via cohesin-mediated loop extrusion. Here, we test the role of CTCF and cohesin in escape using acute degron-mediated depletion of CTCF and RAD21 in neural progenitor cells with established escape profiles. Although CTCF occupancy correlates with escape status on the inactive X chromosome, its removal - together with loss of loop extrusion - does not disrupt escapee gene expression, or domain organization, nor does it result in spreading of silencing or activation of genes in cis. Rather, we show that facultative escape regions are self-sustaining compartments of active chromatin enriched in H3K27 acetylation and depleted in H3K27 methylation, with the magnitude of compartment strength scaling up with the degree of transcriptional activity on the inactive X chromosome. These active escapee compartments are propagated independently of CTCF and RAD21-dependent 3D architecture. Our findings identify chromatin compartmentalization as the primary feature of facultative escapee domains.

genetics↗
bioRxiv2026

Trans-Allosteric Activation Releases Distinct Conformational Traps in Kinase Heterodimers

Protein kinases function as dynamic, mechanically coupled nodes, yet the conformational drivers of multimeric activation remain unclear. Here, we present AlloQuant, a computational suite that translates AlphaFold3 structural ensembles into quantitative metrics of kinase regulation, including internal network rigidity, metastable-state populations, and sub-angstrom conformational drivers. Applying AlloQuant to CDK1, we demonstrate that binding of the Cyclin B1 (CCNB1) cofactor mechanically decouples a hyper-rigid inactive kinase core, allowing activating phosphorylation (pT161) to subsequently re-impose localized tension on the catalytic machinery. Conversely, the C-terminal Src kinase (CSK) faces a distinct conformational trap. While nucleotide-free monomeric CSK spontaneously samples a pre-active geometry, ATP binding excludes the active C-In conformation in all but 1 of 225 models. We show that docking partner engagement overcomes this blockade. Autophosphorylation of SRC at the activation loop (Y419) redistributes SRC conformational states without altering bulk rigidity. This redistribution is structurally coupled to the conformational state of CSK via the regulatory spine, not the catalytic machinery. Rather than mechanically deforming CSK, SRC engagement acts by conformational selection, committing roughly a quarter of CSK molecules to a fully active state. Thus, trans-allosteric kinase activation operates by defining the accessible conformational landscape of the receiver kinase. That control is exerted through mechanical remodeling in cofactor-dependent complexes and through conformational selection in transient kinase-kinase heterodimers. These findings establish AlloQuant as a general framework for quantifying how a binding partner reshapes a kinase's conformational landscape, applicable across the kinome because it assigns landmarks by profile-HMM alignment.

biophysics↗
bioRxiv2026

A structural census links penultimate-residue class to N-terminal burial in human protein assemblies

Initiator-methionine excision is among the earliest protein modifications, yet its relationship to assembly geometry is unknown. Burial of the mature first residue was measured across 7,246 deposited human biological assemblies (22,291 chain-level observations; 1,191 proteins). Among 1,143 analyzable proteins, termini in MetAP-permissive penultimate-residue sequence classes were less often interface-engaged than termini in MetAP-nonpermissive classes (37.4% versus 47.4%; adjusted odds ratio 0.65, p = 7.2e-4). Curated processing annotations did not show a corresponding burial difference, and correlated residue properties preclude attributing the sequence-class association specifically to iMet removal. The analysis identified 264 interface-engaged MetAP-permissive candidates concentrated in cellular machines. In a fully recomputed conformer scan of deeply buried proteasome positions, modeled methionine accommodation was less favorable than at observed-methionine controls (median overlap -0.30 versus -1.12 angstrom, p = 0.0049), although most scoreable sites permitted a nonoverlapping placement. The census therefore reveals a graded structural constraint - not universal steric failure - and prioritizes complexes in which altered packing, assembly kinetics, lipidation or N-terminal methylation can be tested.

biochemistry↗
bioRxiv2026

The trade-off between parsimony and model complexity for understanding biomedical mechanisms from mathematical models

Mechanistic mathematical models have been used extensively to provide a deeper understanding of biological mechanisms, including unveiling the regulation of tumour growth and its response to various treatments. However, given the breadth of biological regulatory mechanisms, these models are frequently large and thus prone to potential issues with parameter identifiability. Statistical metrics like the Akaike and Bayesian information criteria can help identify a parsimonious model by balancing goodness of fit against model complexity. Yet simple models may fail to provide sufficient biological insight if they do not adequately capture known physiological processes or mechanisms. A modeller must therefore balance hypothesis generation and biological learning with model tractability. Here, we illustrate this balance using models of ovarian cancer growth and treatment response to cisplatin and immune checkpoint blockade in homologous recombination (HR)-deficient and HR-proficient immunocompetent mouse models. We develop a hierarchy of mathematical models of increasing complexity to describe tumour growth, treatment response, and immune dynamics. Our results highlight the limits of relying purely on statistical metrics for model selection, particularly when the goal is to obtain biological insight and underscore the importance of balancing model complexity to avoid overfitting and parameter unidentifiability.

systems biology↗
bioRxiv2026

Magnesium induces iron starvation and metabolic rewiring to support the viability of cell envelope mutants and antibiotic-stressed cells

Magnesium supplementation permits deletion of otherwise essential genes involved in cell envelope biogenesis in the Gram-positive model bacterium Bacillus subtilis. Yet, the specific underlying mechanism has remained elusive. To address this key knowledge gap, we made use of a mutant lacking ezrA and gpsB. Deletion of both of these genes involved in cell wall synthesis leads to severe growth inhibition which is ameliorated by magnesium addition. Our results indicate that, in the absence of magnesium, this mutant contains elevated levels of labile iron, is impaired in activating the oxidative stress response, and displays extreme sensitivity to iron and manganese intoxication. Intriguingly, we find that an ezrA single deletion, but not gpsB, exhibits heightened susceptibility to excess iron and manganese. This observation allowed us to investigate the source of toxicity and how EzrA may support metal homeostasis. Our data suggests that the major contributor of ROS is the electron transport system involved in cellular respiration. Both genetic and chemical means to reprogram the cells in favor of fermentation alleviate the metal toxicity in cells lacking ezrA. Collectively, our data shows that magnesium limits iron availability and redirects metabolism towards pathways that are preferred during iron scarcity. Consequently, these mechanisms result in reduced ROS production and oxidative stress mitigation. This explains why magnesium supplementation may render essential genes dispensable. In support of this model, we find that addition of magnesium helps cells to circumvent lysis typically caused by the treatment of an antibiotic that disrupts cell wall synthesis. Taken together, our results suggest that unmitigated oxidative stress fueled by labile iron is likely responsible for the detrimental effects of specific gene disruptions and certain antibiotic treatments. By reducing the pool of free iron and reprogramming cellular metabolism, magnesium mitigates oxidative damage and protects cells from ROS-mediated death.

microbiology↗
bioRxiv2026

Stop codon readthrough in Trichomonas is a mechanism for gene expression regulation and expanding protein function

Trichomonas vaginalis is the causative agent of trichomoniasis, a common sexually transmitted infection among women of reproductive and peri-menopausal age. The parasite has an unusually large genome, rich in complex repeats, including a vast repertoire of transposable elements and multi-copy gene families. Since very few T. vaginalis genes have introns, gene expression is usually straightforward, with ribosomal translational machinery proceeding from a start codon to the next in-frame stop codon of an unspliced poly(A)denylated mRNA. However, our previous studies raised the possibility of T. vaginalis gene expression involving stop codon readthrough (SCR), where transcription through in-frame stop codons produces longer-than-predicted mRNAs that translate to fully functional proteins. Here, we leverage long-read RNA-seq and new chromosome-scale assemblies of two T. vaginalis strains and two avian sister species to investigate and characterize ~1,400 long, mature mRNAs that contain more than one predicted protein-coding gene transcribed from what we call '' RT genes '', composites of adjacent predicted genes. We first identify RT genes in a second T. vaginalis strain and in close relatives T. vaginalis-like and T. stableri, indicating that this phenomenon is conserved among Trichomonas species and strains. Second, we find transcripts of RT genes to be more abundant by many orders of magnitude than monocistronic genes. Third, we found the distance between predicted genes within RT genes to be significantly shorter than between adjacent independent predicted genes. Fourth, functional annotation revealed that RT genes encode at least 50 distinct protein functions, suggesting that this unusual transcriptional mechanism has a role in an array of biological processes in Trichomonas. Our results from two Trichomonas species suggest that SCR is an important mechanism controlling gene expression and the diversity of protein function in this parasite.

molecular biology↗
bioRxiv2026

HIF1A recruits primate-specific endogenous retroviruses into the human hypoxic and immune responses

Oxygen availability varies profoundly across the human body and changes further during inflammation, infection, tissue injury and disease. Immune cells must therefore continuously adapt their transcriptional and metabolic state based on the oxygen availability to them. Hypoxia-inducible factor 1 (HIF1A) is central to this adaptation and a marker of the cellular response to low oxygen, yet its genomic targets have been assembled from a non-repetitive fraction of the genome, leaving nearly half of the human genome largely unexplored. Here we define the gene and transposable-element (TE) landscape of the human hypoxic response across different human tissues, cell lines, and conditions. This directional TE response was reproduced in transformed cells and in primary immune cells isolated from blood and the physiologically oxygen-restricted tonsil. Single-cell profiling of peripheral blood mononuclear cells (PBMC) under hypoxia, pharmacological HIF stabilization, and interferon stimulation revealed a striking difference between the gene and retrotranscriptome responses. While gene responses were strongly cell-type dependent and in a bidirectional manner, TEs were overwhelmingly activated. This pattern extended to blood and tonsil immune cells, where ~70-90% of tested TE families were induced under hypoxia, with activated tonsil cells showing exclusively induced significant families, including THE1B, alongside increased LTR7 and HERVH. Integrating HIF1A ChIP-seq with transcriptional responses revealed that HIF1A does not engage repetitive DNA indiscriminately. Instead, its binding converged on LTR7, the promoter long terminal repeat of the HERVH endogenous retrovirus. Approximately 80% of HIF1A-bound LTR7 elements contained a canonical hypoxia-response element, and disruption of HIF1A DNA binding dramatically reduced the expression of occupied HERVH loci. CRISPR deletion of individual LTR7/HERVH loci altered the expression of distant and neighboring genes, demonstrating that hypoxia-responsive retroelements can participate directly in host gene regulation and contribute to overall physiology. Our findings reveal the repetitive genome as a previously underappreciated component of oxygen sensing. We propose that HIF1A recruits selected endogenous retroviral elements into the human hypoxic response, extending oxygen-dependent regulation beyond conventional gene promoters and providing an additional regulatory layer through which tissue oxygenation can shape immune-cell state and human physiology.

genomics↗
bioRxiv2026

BARCS: beta-binomial regression for multivariate CRISPR screen design

Pooled CRISPR screens increasingly use longitudinal, donor-adjusted, and factorial designs, but beta-binomial screen methods have largely remained limited to pairwise comparisons. BARCS extends the library-total-conditional beta-binomial model to guide-level regression with an arbitrary design matrix, enabling direct estimation of time, covariate, and interaction effects. In four replicate-complete Cas13 screens, adding the intermediate time point modestly improved essential-gene recovery. Applying the same non-targeting-control scaling rule to BARCS, MAGeCK-MLE, edgeR-QL, DESeq2, and limma--voom produced similar calibration across all five methods, while the four alternatives ranked essential genes more strongly than BARCS. In an ordered-bin IL2RA screen, donor-adjusted BARCS recovered more validated regulators with fewer total calls than the matched four-bin MAGeCK-MLE fit, and cross-fitted controls exposed excess guide-level significance. Simulations showed gains from dispersion moderation and control-based denominators, but seed-specific results exposed denominator sensitivity and a null grid localized substantial gene-level error to correlated-guide aggregation rather than dispersion alone. Aggregation-matched control scaling reduced but did not eliminate this error. An external audit prompted by concerns about beta-binomial false discoveries showed that the reported CB2 null-discovery count disappeared when full-library totals were restored. This corrected one denominator-dependent result but did not refute the broader calibration concern; nominal-level calibration remained unresolved. BARCS therefore contributes a multivariable extension of the library-total-conditional beta-binomial model together with an explicit account of where its inference is valid: guide-level coefficients are supported by independent biological libraries, whereas gene-level summaries and partitioned-bin designs require correlation-aware aggregation or joint modelling that the present implementation provides diagnostically rather than generatively. We report this boundary because complex pooled designs make it consequential, not because it is unique to the beta-binomial model.

bioinformatics↗
bioRxiv2026

A replicated patient-specific component of tumour telomere length across two pan-cancer cohorts

Bulk telomere length measured from tumour sequencing is routinely interpreted as a property of the cancer cells. However, a tumour specimen is a mixture, and the patient who supplies it has a telomere length of their own. Here I re-analyse published pan-cancer telomere estimates and ask how much of a tumour's telomere length is patient-specific. A calibration step comes first. Whole-genome and low-pass estimates recover the known cross-sectional attrition of leukocyte telomeres with age, at 26.6 bp per year in blood normals, whereas whole-exome estimates do not. After adjustment for cancer type, sequencing centre and sex, the exome slope is minus 0.6 bp per year. In 684 blood-normal aliquots sequenced by both assays, the whole-genome estimate declines at 38.9 bp per year, whereas the exome estimate from the same DNA shows no detectable decline. The difference between assays is 41.5 bp per year, with P = 3 x 10^-10. Because exome data constitute 78.6% of the original resource, downstream analyses use only whole-genome and low-pass libraries. Within those data, tumour telomere length tracks the patient's matched-normal telomere length. The Spearman correlation is 0.395 in TCGA, with positive associations in 22 of 23 cancer types. This finding replicates in PCAWG using a different telomere estimator, with a correlation of 0.472 and positive associations in all 24 histologies examined. Adjustment for cancer type, sequencing centre and library type leaves a regression coefficient of 0.385. The association is also stable after adjustment for age, sex, tumour purity, leukocyte fraction, ploidy, sequencing coverage and continental ancestry, with coefficients ranging from 0.406 to 0.429. Pure normal-cell admixture is rejected as the sole explanation. Under a two-compartment mixture model, the coefficient for host telomere length is expected to equal 1 and the host-by-purity interaction to equal minus 1. These restrictions are jointly rejected with P = 0.001. Tumour purity, leukocyte fraction and age each explain only about 1 to 3% of within-cohort variance and do not alter the cross-cancer ranking. By contrast, the between-cohort coefficient is not directly interpretable. Its apparent near one-to-one relationship with tissue-associated telomere length depends strongly on which tissue supplies the matched-normal reference and on the statistical spread of that predictor, falling to 0.44 when organ-matched solid tissue is used. Bulk tumour telomere length is therefore a composite phenotype containing a replicated patient-specific component. Telomere biomarker studies should include matched-normal telomere length as a covariate rather than treating tumour telomere length as exclusively tumour-intrinsic.

cancer biology↗
bioRxiv2026

A human-derived two-antibody cocktail confers prophylactic and therapeutic protection against authentic Mpox virus.

With sustained human-to-human transmission worldwide, Mpox virus remains a significant global health burden. However, there are no licensed therapeutics against Mpox, with clinical management limited to supportive care and pain management. Given the virus complex life cycles, effective treatments require the inhibition of both mature intracellular virions (MV) and extracellular virions (EV). Here, we describe the isolation of human monoclonal antibodies (mAbs) from antigen specific memory B cell using flow cytometry-based cell sorting. We also characterize the therapeutic potential of 2-mAb cocktails targeting both MV and EV using an in vitro neutralization assay and a mouse challenge model. Several developed human 2-mAb cocktails neutralized authentic Mpox in vitro. When administered 24 hours before or after Mpox challenge, the lead 2-mAb cocktail inhibited viral loads in mouse tissues, with the exception of the testes. Overall, our study identifies several human 2-mAb cocktails with therapeutic potential for controlling Mpox disease.

microbiology↗
bioRxiv2026

Using sequence-to-function models to interpret archaic hominin introgression

Understanding the functional impact of archaic hominin introgression remains challenging due to the poor representation of global introgression in publicly available genomics resources. Sequence-to-function models can predict the effects of any possible variant in the human genome and may fill this gap. Here, we used AlphaGenome to predict the effects of 144,139 introgressed SNPs segregating in present-day individuals of Papuan genetic ancestry. AlphaGenome's chromatin accessibility predictions recapitulate experimentally observed effects, but gene expression performs no better than chance. Predictions correlate more strongly with an independent reporter assay of single-variant activity than with the same variants' effects in live cells, indicating that AlphaGenome captures the regulatory potential of individual variants more reliably. Predictions carry tissue specificity, allowing us to predict specific tissues potentially impacted by introgressed haplotypes. We identify genes, including JAK1 and TAB2, that are associated with haplotypes that contain an excess of variants predicted by AlphaGenome to have large impacts on chromatin accessibility. Finally, we highlight the challenges and limitations associated with using sequence-to-function models for introgressed variant effect prediction, and show that while AlphaGenome's chromatin accessibility predictions can aid in prioritising candidate functional regions, expression predictions and the assignment of variants to target genes remain as open challenges.

genomics↗
Compare source metadata on this page
WorkPublishedSource identifierSource
Differential expression of NEAT1 in the corneal endothelium increases susceptibility to oxidative stress in Fuchs Endothelial Corneal Dystrophy2026-09-0110.64898/2026.08.31.748332v1biorxiv
A transition state-like acylenzyme conformation distinguishes carbapenemase activity in class A β-lactamases2026-09-0110.64898/2026.08.31.748333v1biorxiv
Absence of a spindle position checkpoint in the fungal pathogen Cryptococcus neoformans2026-09-0110.64898/2026.08.31.748335v1biorxiv
DNA Sequence-Programmed Protein Coronas Determine Intracellular Fate and Proteostatic Stress of Carbon Nanotubes2026-09-0110.64898/2026.08.31.748348v1biorxiv
Nitrate regulates anchor root development2026-09-0110.64898/2026.08.31.748355v1biorxiv
DIFFERENTIAL PHOTOSYNTHETIC RESPONSES TO GLUFOSINATE AMMONIUM IN TWO GRASS WEEDS: Lolium multiflorum AND Echinochloa crus-galli.2026-09-0110.64898/2026.08.31.748356v1biorxiv
Spatial Mapping of the Lung Cancer Ecosystem Reveals Distinct Patterns of Intratumoral and Internodular Heterogeneity2026-09-0110.64898/2026.08.31.748358v1biorxiv
X-inactivation escapee domains are CTCF-cohesin independent chromatin compartments2026-09-0110.64898/2026.08.31.748372v1biorxiv
Trans-Allosteric Activation Releases Distinct Conformational Traps in Kinase Heterodimers2026-09-0110.64898/2026.08.31.748385v1biorxiv
A structural census links penultimate-residue class to N-terminal burial in human protein assemblies2026-09-0110.64898/2026.08.31.748389v1biorxiv
The trade-off between parsimony and model complexity for understanding biomedical mechanisms from mathematical models2026-09-0110.64898/2026.08.31.748397v1biorxiv
Magnesium induces iron starvation and metabolic rewiring to support the viability of cell envelope mutants and antibiotic-stressed cells2026-09-0110.64898/2026.08.31.748404v1biorxiv
Stop codon readthrough in Trichomonas is a mechanism for gene expression regulation and expanding protein function2026-09-0110.64898/2026.08.31.748405v1biorxiv
HIF1A recruits primate-specific endogenous retroviruses into the human hypoxic and immune responses2026-09-0110.64898/2026.08.31.748411v1biorxiv
BARCS: beta-binomial regression for multivariate CRISPR screen design2026-09-0110.64898/2026.08.31.748412v1biorxiv
A replicated patient-specific component of tumour telomere length across two pan-cancer cohorts2026-09-0110.64898/2026.08.31.748414v1biorxiv
A human-derived two-antibody cocktail confers prophylactic and therapeutic protection against authentic Mpox virus.2026-09-0110.64898/2026.08.31.748425v1biorxiv
Using sequence-to-function models to interpret archaic hominin introgression2026-09-0110.64898/2026.08.31.748430v1biorxiv

These are bibliographic comparisons, not experimental rankings. Follow the original document for methods and conditions.