Biology subjects

Wang, R.

Publications and source records attributed to Wang, R..

At least 19 recordsLinked to original sources

bioRxiv2026

High-resolution HLA and MICA/MICB typing of the 1000 Genomes panel: a resource for precision medicine

High-resolution characterization of human leukocyte antigen (HLA) and MICA/MICB variation is important for transplantation, immunogenetics, and the interpretation of disease associations within the major histocompatibility complex (MHC). However, publicly available population reference datasets remain limited in their resolution and coverage of these loci. We performed high-resolution typing of the 1000 Genomes Phase 3 panel across 13 HLA and MIC loci, generating HLA genotypes for 2,486 individuals, extended HLA-A, -B, and -C allele assignments, and MICA/MICB genotypes for 2,393 individuals representing 25 populations and five continental super-populations. Concordance with previously reported HLA genotypes was 96.2-97.4% at two-field resolution, and independent retyping confirmed the present assignments for samples exhibiting reciprocal genotype discrepancies with an earlier dataset. Analysis of extended class I variation within defined assay boundaries revealed that most of the 78 common three-field HLA lineages were dominated by a single extended sequence group. However, eleven lineages exhibited substantial heterogeneity, with the predominant group accounting for less than 80% of observed copies. The distinguishing sequence differences were noncoding, involving intronic and 3' untranslated regions, and their distributions varied among ancestral populations. These findings identify recurrent, population-relevant variants for which functional consequences remain to be established. Population analyses demonstrated extensive allelic diversity at classical class I loci and DRB1, whereas the greatest between-population differentiation occurred at selected class II and DRB-linked loci. Most common alleles were shared among populations but differed substantially in frequency. Multilocus haplotypes revealed characteristic population-associated combinations of HLA and MIC alleles and provided the basis for predicting MIC genotypes from existing HLA typing. Using two-field HLA-B and HLA-C genotypes, five-fold cross-validation achieved exact genotype prediction accuracies of 77.3% for MICA and 53.6% for MICB, compared with 4.6% and 21.6%, respectively, without HLA information. Together, these results provide an extended-resolution HLA and MIC reference resource, demonstrate the limited routine utility of universal fourth-field typing while identifying specific variants for functional investigation, and establish the potential for recovering MIC variation from existing HLA-typed cohorts. The resource also supports future investigations of MHC variation underlying disease associations and transplantation outcomes.

genetics↗

bioRxiv2026

Technology solutions for immune loci: integrated high-resolution KIR genotyping reveals allelic, structural, and KIR-HLA diversity across 24 human populations

High-resolution genotyping of killer cell immunoglobulin-like receptor (KIR) genes remains challenging because of extensive sequence homology, copy-number variation, and complex haplotype structures. Although KIR allelic variation influences receptor expression and function, routine typing has largely been limited to gene presence or absence. Here, we evaluated an integrated short-read sequencing system combining a four-reaction, two-stage multiplex PCR assay (ScisGo-KIR-v3), centralized cloud-based copy-aware allele analysis, and interactive genotype review. The system was applied to 2,298 individuals representing 24 populations from the 1000 Genomes Project, with matched high-resolution HLA class I genotypes. Independent validation against complete, phased PacBio KIR sequences from 48 samples demonstrated 98.6% automated copy-number concordance and 92.8% combined copy-number and allele concordance across 768 gene-sample comparisons. Following desktop review, all evaluated assignments were concordant with the reference sequences. In a separate comparison of four computational genotyping methods involving 311 shared samples, the automated Scisco pipeline showed the lowest overall mismatch with the four-method consensus (1.62%). Population analyses identified substantial allele diversity and distinct centromeric and telomeric haplotype-motif distributions. Although exact haplotype pairs were frequently ambiguous, structural assignments became increasingly resolvable at the motif level, and motif backgrounds exhibited characteristic allele compositions. Paired KIR and HLA analysis revealed inherited receptor-ligand configurations concealed by gene-content typing. Among 1,401 KIR3DL1/HLA-B Bw4 co-carriers, 57 lacked an allele annotated for ordinary surface expression, while 457 of 1,175 KIR2DS4 co-carriers of six specified HLA-C allotypes carried only truncated receptor forms. Allele-specific KIR2DL1 and KIR2DS5 classifications further distinguished receptor properties and published ligand-binding annotations that varied among populations. Although potential receptor-ligand repertoire composition differed across populations, analyses did not establish preferential KIR-HLA genetic association after accounting for population structure and multiple testing. Together, these findings demonstrate that integrated short-read KIR genotyping can provide scalable, high-resolution allele and copy-number information while explicitly retaining uncertainty in inferred haplotype structures. Compatibility with established HLA laboratory workflows provides a practical foundation for incorporating allele-resolved KIR analysis into immunogenetic research and future clinical investigations.

genetics↗

bioRxiv2026

Xenograft supervision and joint methylation-fragment-end encoding define a reusable molecular scoring layer for cell-free tumor DNA

Circulating tumor DNA is often scarce in plasma, and regional methylation summaries can obscure informative differences between individual molecules. Here we present ctDNA-BERT, a Transformer that scores individual bisulfite reads without predefined differentially methylated regions by jointly encoding CpG methylation state, nucleotide context and the fragment 3' end. Xenografts provide molecule-level tumor supervision. The resulting frozen scorer supported tumor-fraction estimation in synthetic and patient-derived xenograft mixtures and enriched tumor-concordant methylation and chromatin-accessibility signals in independent hepatocellular carcinoma and stage III pan-cancer plasma without cohort-specific retraining. Features derived from selected reads discriminated stage I cancers from healthy controls in a retrospective cohort of 1,477 specimens, achieving an out-of-fold area under the receiver operating characteristic curve of 0.884. By separating molecular scoring from sample-level inference, ctDNA-BERT provides a reusable read-level scoring layer for cell-free DNA methylation analysis.

bioinformatics↗

bioRxiv2026

Daytime Napping and Associative-Memory Retrieval Speed: An Exploratory Behavioral and EEG Study

Purpose: To test whether a daytime nap was associated with improved associative-recognition performance relative to monitored wakefulness and to determine where any response-time (RT) difference occurred in the RT distribution. Methods: Fifteen healthy students completed nap and wake sessions in a within-participant design. Each session included word-pair learning, immediate recognition, a 60-min interval, and delayed recognition without additional study. Trial-level log RT was the focal outcome; accuracy and electroencephalography (EEG) were complementary outcomes. Results: The RT Condition-by-Time interaction was significant (b = -0.063, 95% CI [-0.117, -0.009], p = .027). Responses were 6.7% faster after the nap (p = .010) but did not change after wakefulness (p = .704), with the difference concentrated among slower responses. Accuracy showed no condition-specific change (p = .401). Nap EEG showed aperiodic spectral slowing and stronger periodic sigma activity, but no EEG measure explained the RT effect. Conclusions: Daytime napping was associated with faster delayed associative recognition, primarily through attenuation of the slowest responses. The exploratory findings warrant larger confirmatory studies.

neuroscience↗

bioRxiv2026

Benchmarking the Performance of a Commercial Electrostatic Linear Ion Trap (ELIT) Charge Detection Mass Spectrometer For Higher-Order Antibody Aggregate Analysis

Higher-order antibody aggregates remain challenging to characterize using conventional mass spectrometry because of their low abundance, broad mass distributions, and extensive heterogeneity. Here, the practical performance of a commercial electrostatic linear ion trap charge detection mass spectrometer (XevoTM CDMS) was evaluated for therapeutic antibody analysis. The platform provided reproducible mass and charge measurements, with repeatability and intermediate-precision RSDs below 1%, and maintained consistent mass determination across the concentration and solution conditions examined. Controlled mixtures of antibody-derived species showed a linear molar-ratio-dependent ion response, supporting semi-quantitative estimation of relative species abundance under defined conditions. For heat-stressed trastuzumab, CDMS measurements were qualitatively consistent with SEC-MALS, mass photometry, and conventional native MS, while enabling direct mass determination of individual ions within highly heterogeneous high-molecular-weight (HMW) populations that exhibited extensive charge-state overlap and could not be reliably deconvoluted by conventional native MS. High-duty-cycle acquisition increased sampling of low-abundance, high-m/z ions and improved access to higher-order aggregate signals. Joint single ion mass-charge analysis further differentiated statistical ion families within the broad HMW fraction and related major mass differences to independently obtained compositional information. These results support commercial XevoTM CDMS as a practical multidimensional platform for antibody aggregate characterization.

biochemistry↗

bioRxiv2026

Braintree: An agentic framework for in-silico vision neuroscience

Vision neuroscience has many of the ingredients needed to conduct experiments entirely in-silico. We need AI systems that can reason over scientific knowledge, generative methods for creating precisely controlled stimuli, image-computable models that can predict neural responses with increasing accuracy, and tools that can analyze and interpret data. Here we take the first step toward making a vision neuroscience experiment end-to-end computable. We introduce Braintree, an agentic framework that can autonomously run multi-experiment studies directly with in-silico models of human visual cortex. Given a hypothesis, Braintree can reason over the current literature, design an experiment, build a stimulus set from algorithmically manipulated or synthesized stimuli, run the experiment on candidate brain encoding models, analyze the responses and then use the results to design even stronger tests. The entire loop runs autonomously and can accept human input at any stage. We evaluated Braintree on three increasingly open-ended scientific problems. First, Braintree reproduced published findings using their original stimuli and then asked whether the same effects could be replicated with entirely new stimulus sets that it constructed. Second, it designed new experiments to find stimulus dimensions that could drive two brain regions differently, even when those regions otherwise had similar response profiles. Third, it searched for experiments that could tell competing models of the same brain region apart. Experiments discovered using just two models also exposed differences across a much broader set of models, suggesting that Braintree had found more general dimensions along which brain models disagree. Braintree can augment the capabilities of a vision neuroscientist as a verifier for existing hypotheses, a test-bed for new ideas, and/or a tool for generating stimuli that can discriminate between competing hypotheses or models of the brain. Braintree shows how AI agents and brain models can work together to make in-silico vision neuroscience experiment computable, allowing vision scientists to explore many more experiment conditions and identify the most informative ones to test on the human brain.

neuroscience↗

bioRxiv2026

Using Polycistronic gRNAs and a tRNA Cleavage System in CRISPR-Based Genome Editing of Toxoplasma gondii

CRISPR/Cas9 is widely used for genetic manipulation in Toxoplasma gondii, but optimizing gRNA expression and multiplexed editing remains challenging. Here, we evaluated alternative promoters, gRNA scaffolds, and a tRNA-based polycistronic system to improve editing efficiency and reduce synthetic DNA costs. Four constructs targeting the SAG1 locus were used to compare the U6 and H1 promoters, as well as standard and modified gRNA scaffolds. U6-driven constructs supported robust gRNA-targeted Cas9 activity, whereas H1-driven constructs failed to produce detectable phenotypes. The alternative gRNA scaffold, modified by a number of base changes and insertions, increased knockout efficiency compared to the standard scaffold. To simplify dual gRNA-based methods, we establish a tRNA-based polycistronic system to simultaneously target two independent loci. Targeting the SAG1 and UPRT locus for proof-of-concept, all U6-driven polycistronic constructs conferred efficient SAG1 knockout and 5-fluorodeoxyuridine resistance, whereas H1-driven constructs exhibited position-dependent activity, with only the 3' gRNA being functional. These results demonstrate that U6-driven, tRNA-based polycistronic gRNA expression enables reliable multiplexed genome editing in T. gondii, with the minimal H1 promoter being insufficient for consistent multi-gRNA activity. This optimized system provides a scalable framework for dual-gRNA CRISPR strategies in this organism.

molecular biology↗

bioRxiv2026

Proteomic Characterization of Prostate Cancer Bone Metastasis Subtypes Defines Progressive Remodeling States of the Bone-Tumor Microenvironment

Prostate cancer (PC) bone metastases (PCBM) are a debilitating disease morbidity that primarily affects the axial skeleton. PCBM are predominantly osteosclerotic with mixed osteosclerotic/osteolytic features, including irregular bone deposition, loss of collagen alignment and increased porosity that mimic features of woven bone formed during development and repair. We hypothesize that progression of PCBM is driven by interactions between tumor cells and the bone microenvironment and is associated with changes in the stromal compartment. We performed tandem mass tag mass spectrometry proteomics on lumbar vertebral specimens from 32 cadaveric PCBM specimens and 3 age-matched controls. Unsupervised clustering segregated specimens into three clusters associated with benign, mixed, and osteosclerotic lesion states, characterized by distinct immune-, tumor-, and osteogenic-associated protein signatures. Histological analysis showed tumor infiltration was accompanied by marrow fibrosis and increased collagen III deposition. We identified a marker signature associated with osteosclerotic remodeling and mapped this signature to independent metastatic PC transcriptomic datasets. The proteomics-derived markers reproduced similar molecular groupings at RNA level, and robustly segregated bone PCBMs from soft tissue metastases PC in RNA data. Together, these findings define molecularly distinct states of tumor-driven changes in PCBM that extend beyond histological classification and may inform biomarker development and therapeutic stratification.

cancer biology↗

bioRxiv2026

SpatialOmicsLab: an integrated research environment for AI co-scientists in spatial transcriptomics

Spatial profiling is moving from method development into a central platform for biological discovery and clinical translation, but analyzing such complex data has become the bottleneck of scientific discovery. Translating spatial transcriptomic measurements into biological insight requires reproducible workflows that integrate diverse analytical methods. Although language-model agents can plan and execute multistep analyses, fragmented data and software ecosystems hinder their use as reliable research assistants. In this study, we introduce SpatialOmicsLab, an integrated research environment for spatial transcriptomics comprising 113 curated computational tools, 63 reference datasets and 4,614 task specifications. We also introduce ST-Coscientist, an AI co-scientist that uses this environment to assemble, execute and refine spatial transcriptomic analyses. Within SpatialOmicsLab, ST-Coscientist outperformed expert-led workflows and other scientific agents across six benchmark settings spanning spatial clustering, cell-type deconvolution and spatially variable gene detection. It constructed alignment-aware workflows for three-dimensional MERFISH data and addressed biological questions by selecting and analysing relevant reference datasets. Procedural memory increased the success rate of integrating and validating additional analytical tools from 48% to 95%. Together, SpatialOmicsLab and ST-Coscientist establish an extensible ecosystem for reproducible spatial transcriptomic research, enabling AI co-scientists to address evolving biological questions with an expanding analytical repertoire.

bioinformatics↗

bioRxiv2026

Environmental correlates of understory plant diversity and distribution in a temperate climate-change refugium

Aim Regional climate-change refugia - areas where abiotic conditions related to hydrology and topography sustain unique plant communities despite an otherwise unsuitable regional macroclimate - have been essential for maintaining biodiversity through past climatic transitions. At fine spatial scales, regional refugia can also contain microrefugia, where canopy structure and topography strongly buffer understory microclimate. We tested whether such microrefugia structure understory plant communities within a regional climate-change refugium, where sheltered, groundwater-fed canyons have sustained a biogeographically distinctive flora since the Last Glacial Maximum. Location Temperate forest in the North American Great Plains, Nebraska, USA. Methods In a 20.2-ha forest inventory plot spanning a sharp topographic gradient, we quantified diversity, composition, and distributions and of understory woody and herbaceous plants across seven functional groups along fine-scale topographic, light, and soil moisture gradients. Results Woody species density and richness were significantly higher within sheltered microrefugia in canyon bottoms and on forested slopes and strongly decreased with increasing canopy openness, whereas C4 grass richness was highest along the exposed, high-light forest-prairie ecotone, reflecting divergent functional group responses to microclimate buffering. Soil moisture structured richness across functional groups: woody plant and C3 grass richness peaked at moisture extremes, sedge richness at intermediate moisture variability, and C4 grass richness declined with increasing moisture variability. Both woody and herbaceous understory plants showed strong variation in composition with topography; in particular, woody seedlings and graminoids exhibited strong species turnover with increasing elevation. Main Conclusions These results demonstrate that topographically driven microrefugia support disproportionate understory biodiversity and suggest that protecting both regional refugia and finer-scale microrefugia will be critical for conserving plant communities, including species documented exclusively in microrefugia, as macroclimate continues to change.

ecology↗

bioRxiv2026

Extracellular cGAMP transmission exacerbates neuroinflammation in aging and multiple sclerosis

Neuroinflammation drives neurodegeneration and cognitive decline in aging, but the signals that spread this inflammation across the CNS remain unclear. Here, we show in mice that advanced age and experimental autoimmune encephalomyelitis (EAE) both result in elevated cytosolic mtDNA in microglia, which stimulates the production and export of cGAMP from these cells. Meanwhile, ENPP1, the dominant cGAMP hydrolase in the brain and spinal cord, is downregulated in both EAE mice and MS patients, releasing the brake on extracellular cGAMP accumulation. In Enpp1H362A mice, which selectively lack cGAMP hydrolysis activity, unrestrained extracellular cGAMP worsens EAE-associated paralysis and drives premature aging phenotypes including impaired motor coordination (rotarod, pole test) and reduced exploration (open field test) in a manner dependent on STING. Single-cell RNA sequencing pinpoints microglia, astrocytes, and inhibitory neurons as the principal cGAMP responders that activate STING-dependent interferon-stimulated gene induction in response to elevated extracellular cGAMP. Mechanistically, microglia import cGAMP through the LRRC8A:C channel, while astrocytes and neurons import cGAMP via the glutamate antiporter system xc-, reinforced by SLC1A2-mediated glutamate uptake in astrocytes and SLC38A1/2-fueled glutamine-to-glutamate synthesis in neurons. In isolated primary astrocytes and neurons, high intracellular glutamate and system xc--driven redox demands favor cGAMP uptake, raising the possibility that neurotransmitter cycling and redox burden shape cellular vulnerability to cGAMP immunotransmission in vivo. Together, these findings position ENPP1 as a protective brake on neuroinflammation in aging and MS, nominating cGAS inhibition and CNS ENPP1 enhancement as therapeutic strategies.

cell biology↗

bioRxiv2026

A synaptic wiring diagram underlying modality-specific ascending pathways of the superficial spinal dorsal horn

The spinal cord dorsal horn transforms tactile, thermal, pruritic, and nociceptive signals from peripheral somatosensory neurons into outputs to the brain, but how dorsal horn circuits organize diverse inputs into modality-selective ascending pathways is poorly understood. Using dSC1, a large-scale electron microscopy dataset of the mouse dorsal horn, we mapped the circuitry connecting primary sensory afferents to projection neurons of the anterolateral tract (ALT), a principal pathway conveying somatosensory information to the brain. We find that afferents encoding distinct modalities are routed onto connectivity-defined populations of ALT projection neurons. Nociceptors and cold thermoreceptors directly innervate distinct lamina I ALT projection neuron populations specialized for conveying noxious and cooling signals, respectively, whereas tactile and pruritic signals instead pass through a recurrent, multilayered network involving interneurons called vertical cells before reaching a separate ALT projection population. This distinction, direct versus polysynaptic wiring, underlies marked differences in sensory convergence and establishes segregated ascending channels for conveying signals encoding the principal somatosensory modalities. Together, our findings define an architectural logic by which the dorsal horn integrates and routes tactile, thermal, pruritic, and nociceptive information into distinct ALT output pathways to the brain.

neuroscience↗

bioRxiv2026

Loss of DNA Demethylase Enhances Arsenic Resistance Via Reducing of PIN2 Antisense Long Noncoding RNA

DNA methylation dynamics regulate diverse plant stress responses, but the mechanisms governing arsenic (As) tolerance through epigenetic pathways remain largely unknown. Here we report that Arabidopsis mutants lacking the DNA demethylase, REPRESSOR OF SILENCING (ROS1), show substantially enhanced As resistance. Integrating transcriptome and methylome data, we found that PIN-FORMED 2 (PIN2), encoding an auxin efflux carrier that also transports As out of cells, represents a key ROS1 target. In ros1, we observed increased methylation in the last exon of PIN2, a region functioning as the promoter for an antisense long non-coding RNA (lncRNA). Hypermethylation of the promoter suppresses the antisense lncRNA, which follows reduction of sense PIN2 transcription. As a result, PIN2 expression increases in ros1 mutants during As exposure, enhancing As tolerance. Analysis of ros1 pin2 double mutants confirmed that PIN2 acts downstream of ROS1 in As tolerance. Our study demonstrates an epigenetic pathway in which ROS1 regulates As tolerance by controlling PIN2 expression through antisense lncRNA-mediated transcriptional interference, offering new epigenetic strategies using plants in heavy metal contaminated environments.

plant biology↗

bioRxiv2026

The conserved function of bHLH121 and overexpression of N-terminal bHLH121 fragment suppresses iron deficiency response in Arabidopsis

Iron (Fe) homeostasis is fundamental to plant growth and development and is centrally regulated by a well-conserved network of basic helix-loop-helix (bHLH) transcription factors. In Arabidopsis thaliana, bHLH121 regulates the expression of FER-like iron deficiency-induced transcription factor (FIT) and clade Ib bHLH38/39/100/101 genes, among others. However, its functional conservation remains unexplored, and some contradictory results have been reported regarding the effects of bHLH121 overexpression. Here, we investigated the evolutionary conservation of bHLH121 through complementary tests in the Arabidopsis bhlh121 mutant created by CRISPR/Cas9 gene editing. We also investigated the effects of ectopically expressing full-length, N-terminal, and C-terminal fragments of bHLH121 on plant responses to Fe deficiency in Arabidopsis. Transgenic plants overexpressing the full-length bHLH121 driven by the cauliflower mosaic virus 35S promoter (bHLH121 ox) resulted in shorter roots and more severe leaf chlorosis compared to wild-type plants under Fe limiting conditions. Moreover, overexpression of the N-terminal fragment (N121 ox) rendered plants highly sensitive to Fe deficiency, whereas overexpression of the C terminal fragment (C121 ox) did not. Consistent with the phenotypic observations, N121 ox plants accumulated lower Fe content, and the ferric chelate reductase activity was significantly reduced. In N121 ox plants, the induction of key Fe regulatory genes, especially FIT, was significantly inhibited under Fe deficiency. Confocal imaging showed that both N121-GFP and C121-GFP fusion proteins could localize to the nucleus. Electrophoretic mobility shift assay showed that both full-length bHLH121 and N121 could effectively bind the probes derived from the promoter of FIT. The present work reveals a conserved function of bHLH121 in Fe homeostasis across several dicot species and demonstrates that the N121 may possess a dominant nature in Fe deficiency responses.

plant biology↗

bioRxiv2026

The gut-liver axis and the role of bacteria in severe dengue virus infection in mice

Patients with severe dengue virus (DENV) infection can experience hemorrhage, shock and organ damage that coincides with defervescence and declining viremia. In addition to vascular leak, published work has shown that gut barrier permeability and elevated serum lipopolysaccharide (LPS) levels correlate with DENV disease severity. We previously described profound gut pathology in a mouse model of infection. This led to the hypothesis that a loss of gut epithelial barrier integrity and the influx of microbial products contribute to exacerbated inflammation and severe dengue disease. Consistent with this, here we demonstrated that DENV2 infection of AG129 mice compromised the gut epithelial barrier, promoted bacterial translocation, and induced microbial changes indicative of dysbiosis, including a reduced abundance of putatively beneficial microbial taxa and disrupted microbial circadian oscillations. Depleting gut bacteria with antibiotics from 1-day post-infection sharply reduced gut pathology as well as viral RNA in the proximal colon and liver, and the number of infected Kupffer cells in the liver. There was no evidence for systemic suppression of viral replication. We propose that viral infection of intestinal macrophages leads to inflammatory damage and mucosal barrier breakdown, dysbiosis and gut leak, with gut bacteria-dependent products promoting the susceptibility of Kupffer cells to DENV infection. Given the importance of liver damage in severe and fatal dengue disease, therapies that protect the gut barrier may help reduce disease severity.

microbiology↗

bioRxiv2026

Morphological and biochemical evaluation of tolerance to water deficit identifies SlCLE9 as a novel regulator of drought stress

We performed a screening to evaluate the responses to water deficit before the flowering stage in a panel of 31 genotypes composed of one commercial hybrid, one wild species, multiple ex-PVP (vintage) lines, several commercial heirlooms from the Northeast USA, Mexican landraces from hot and humid environments and genome edited lines with altered flowering and inflorescence traits. We characterized 18 different morphological, physiological and biochemical traits to assess the response to 40% water deficit. We observed diverse morphological, physiological and biochemical responses across the 31 genotypes screened, suggesting the presence of useful variation for breeding for drought tolerance in cultivated tomato. Interestingly, some heirlooms exhibited superior performance under drought, suggesting they can be used as donors to discover novel genes involved in drought responses. Unexpectedly, we found mutants in SlCLE9, a paralog of the stem cell regulator SlCLV3 known to co-regulate meristem proliferation in tomato, exhibited enhanced drought tolerance. Notably, the slcle9 mutant also conferred drought tolerance when used as rootstock with grafted scions from our reference cultivar M82, suggesting SlCLE9 influence root architecture and drought response. Consistent with this, we found SlCLE9 is transcriptionally upregulated in roots and leaves during drought stress, and exogenous application of SlCLE9 modifies root growth and response to drought. Altogether, our screening uncovered new potential trait donors for breeding against drought stress and describes a novel role for SlCLE9 in drought tolerance.

plant biology↗

bioRxiv2026

Zero-shot evaluations expose structured generalization limits in predictive models of the brain

Artificial neural networks (ANNs) can predict neural responses to natural images with remarkable accuracy, making them promising models of human vision. However, prediction scores alone reveal little about what computations these models have captured or how well they generalize beyond the images on which they are trained. Here, we introduce a principled zero-shot model evaluation framework in which ANN-based encoding models are frozen before being tested on not just held out images but entirely new datasets. Our strongest tests repurpose decades of cognitive neuroscience experiments as diagnostic benchmarks for identifying which computations current models capture and where they fail. To implement this framework we built encoding models of human category-selective regions (FFA, PPA, and EBA) using several pretrained ANNs and evaluated these fixed models across 7 independent fMRI datasets and 31 cognitive experiments from 10 published studies. This framework revealed three broad patterns. First, zero-shot evaluations exposed systematic limits to model predictivity that were largely hidden by standard within-dataset cross-validation. These limits were structured varying across brain regions and model classes and depending strongly on the similarity between the images used to build and test the models. Second, current models reproduced some, but not all, classical findings from cognitive neuroscience, providing a diagnosis of the computations that current models have yet to capture. Finally, models that performed well on prediction tests also tended to succeed at reproducing cognitive neuroscience findings, suggesting that prediction and explanation are closely linked. Unlike prediction scores however, cognitive tests help diagnose where and why models fail. Together, the zero-shot evaluation framework provides a scalable and unified approach for evaluating brain models across prediction and cognitive neuroscience tests, which can help us better understand what current models capture and what still remains to be explained.

neuroscience↗

bioRxiv2026

Cyclin D-CDK4/6 couple proliferation to membrane and mitochondrial protein supply through a DeSI1 phospho-switch

Cyclin D-CDK4/6 complexes drive cell-cycle entry through an RB-E2F-dependent transcriptional program, but how they coordinate proliferation with the membrane and organelle protein supply required for growth is unclear. We identify DeSI1 as a cyclin D-CDK4/6 substrate whose phosphorylation at S25 converts a latent homodimer into an active monomeric deubiquitylase that recognizes hydrophobic proteins such as those bearing transmembrane domains and mitochondrial targeting sequences. Phosphorylated DeSI1 extends the lifetime of newly synthesized hydrophobic proteins that support membrane and mitochondrial capacity. Constitutive DeSI1 activation uncouples this proteostatic program from metabolic supply, creating a cytidine-nucleotide supply-demand imbalance associated with impaired CTP-dependent phospholipid homeostasis, cardiolipin depletion, and mitochondrial decompensation - defects that cytidine reverses. In mice, constitutive DeSI1 activation causes progressive cerebellar degeneration with membrane-protein accumulation, respiratory-chain loss, and phospholipid depletion. These findings define a post-translational mechanism coupling cell-cycle entry to membrane and mitochondrial capacity, and reveal the cost of uncoupling this program from its metabolic support.

cell biology↗