Biology subjects

Ma, X.

Publications and source records attributed to Ma, X..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Atypical Chemokine Receptor DARC/ACKR1 Is Expressed Selectively by Neurons with Regional Heterogeneity and Protects against Neuroinflammation and Cognitive Impairment

Atypical chemokine receptors (ACKRs) regulate inflammatory responses by scavenging and sequestering chemokines. The Duffy antigen receptor for chemokines (DARC), also known as ACKR1, binds multiple inflammatory chemokines and regulates inflammation in peripheral tissues. However, the distribution and functional role of DARC/ACKR1 in the brain remain to be defined. Here, we show that DARC/ACKR1 is widely expressed throughout the mouse brain, with marked regional heterogeneity. DARC/ACKR1 is predominantly expressed by neurons and is not detected in microglia or astrocytes. Importantly, this neuronal expression pattern was also observed in the human brain. Furthermore, DARC/ACKR1 deficiency resulted in enhanced neuroinflammation, characterized by increased microglial activation and astrogliosis across multiple brain regions, particularly the hippocampus, and was accompanied by cognitive deficits. Together, these findings identify DARC/ACKR1 as a previously unrecognized neuron-specific atypical chemokine receptor that plays an important role in restraining neuroinflammation and preserving cognitive function.

neuroscience↗

bioRxiv2026

A hypothalamic dynorphin-KOR pathway that orchestrates male sexual behavior under sexual competition

In nature, males often attack rivals before mating, yet how aggression shapes mating strategies remains unclear. Using a laboratory sexual competition model with optogenetics, calcium imaging, and pharmacology, we found that aggressive male mice attack competitors before mating, whereas social males mate promptly. This delay is mediated by Gi-coupled kappa-opioid receptor-expressing GABAergic interneurons in the medial preoptic area (MPOAKOR), recruited by estrogen receptor 1-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvlEsr1), which inhibit MPOAEsr1 mating neurons. VMHvlEsr1 neurons activate MPOAKOR neurons through direct glutamatergic transmission and indirect disinhibition by suppressing dynorphin release from prodynorphin-expressing arcuate nucleus terminals (ArcPdyn). During rival encounters, aggressive males show a greater MPOA dynorphin decline and stronger MPOAKOR activity than social males. Thus, a VMHvlEsr1/ArcPdyn[->]MPOAKOR[->]MPOAEsr1 circuit gates mating according to prior aggressive experience, explaining how social competition shapes reproductive strategies.

neuroscience↗

bioRxiv2026

A Hymenoptera-restricted gene mediating ant castes co-opts deeply conserved machinery to control organ size

Lineage-specific genes are widespread and have been implicated as phenotypic innovation inducers, but how they acquire complex developmental functions remains poorly understood. Ant queens and workers develop dramatically different organ sizes from identical genomes under juvenile hormone (JH) control, yet the molecular effectors translating JH signalling into caste-specific organ growth remain unknown. Here we identify torch, a Hymenoptera-restricted gene, as the most consistently gyne-biased and JH-responsive gene across 68 ant species. Knockdown of torch in virgin queens of Monomorium pharaonis produces a worker-like, multi-organ growth-restricted phenotype. Mechanistically, torch harbours an E-box-like motif activated by the JH receptor Gce-Tai and acts as a GA-repeat-binding transcription factor that regulates Hippo signalling, the deeply conserved organ-size control pathway in animals. Expressing torch heterologously in mice and a growth-restricted Drosophila background shows that the gene retained its general growth-promoting activity across more than 700 million years of animal evolution in lineages that lack the gene, establishing that its function is mediated through conserved rather than ant-specific machinery. A lineage-specific gene can therefore acquire complex morphogenetic function by co-opting ancient organ-size circuitry, providing a general route by which novel genes can drive phenotypic innovation.

evolutionary biology↗

bioRxiv2026

Patient-Derived Glioma Models Preserve Tumor Heterogeneity and Identify Stearoyl-CoA Desaturase1 (SCD1) as a Candidate Biomarker for Precision Immunotherapy

Background: Pediatric and adult brain tumors, including glioblastoma, astrocytoma, ependymoma, and medulloblastoma, remain associated with poor prognosis despite advances in surgery, radiation, and chemotherapy. Therapeutic resistance, tumor heterogeneity, and treatment-related toxicity highlight the need for clinically relevant models that enable precision medicine and immunotherapy development. Methods: Freshly dispersed tumors (FDTs), low-passage patient-derived brain tumor (PBT) spheroid lines, and matched patient-derived xenograft (PDX) models were established from patients with primary brain tumors. Models were characterized using single-cell and bulk RNA sequencing, whole-exome sequencing, multiparameter flow cytometry, and immunohistochemistry. PBTs were compared with matched FDTs to evaluate model fidelity. Results: PBT lines were established in approximately 68% of cases and retained key patient-specific genomic alterations, including IDH1, MGMT, TP53, and PTEN, with expression of therapeutically relevant targets, including IL13R2, EGFR, HER2, WNT1, JAK1/2, and NOTCH1-4. Gene expression profiles of PBTs closely correlated with matched FDTs (R = 0.38, P = 0.0038). PBT and PDX models preserved intratumoral heterogeneity and non-clonal populations, enabling identification of therapy-resistant subclones during in vitro selection. Molecular analyses identified Stearoyl-CoA Desaturase1 (SCD1) as an overexpressed biomarker across glioma PBTs and matched patient tumors. Ingenuity Pathway Analysis identified SCD1 as an upstream regulator of EGFR-, TP53-, and CYCS-associated signaling networks implicated in tumor progression and immune suppression. Conclusions: Clinically relevant PBT and matched PDX models recapitulate molecular, transcriptional, and histopathological characteristics of primary brain tumors. These platforms provide tools for biomarker discovery, therapeutic testing, and precision immunotherapy development, while identifying SCD1 as a biomarker and therapeutic target in glioma.

cancer biology↗

bioRxiv2026

Impaired proteostasis is an early feature of the diabetic heart in humans and mice

Diabetes and obesity increase cardiac lipid levels leading to cardiomyopathy and heart failure. We hypothesized that intermittent fasting would reduce cardiac lipid levels. Surprisingly, intermittent fasting increased myocardial triglyceride content, but rescued mortality and attenuated cardiomyopathy in mice overexpressing cardiomyocyte acyl-CoA synthetase 1 (MHC-ACSL1). Lipid overload caused cardiomyocyte accumulation of polyubiquitinated protein aggregates containing desmin, a scaffolding intermediate filament protein, which intermittent fasting prevented. Furthermore, intermittent fasting reversed elevated myocardial C16:0 ceramide content, and knockdown of ceramide synthase CerS5 and CerS6 reduced palmitate-induced protein aggregation, highlighting a role for C16:0 ceramides in this pathology. Conversely, impairing aggrephagy with cardiomyocyte-specific p62 ablation induced heart failure in mice fed a high-fat diet, with paradoxically reduced cardiac lipid content. Crucially, non-failing diabetic human hearts also exhibited protein aggregate pathology. Taken together, these results demonstrate that impaired proteostasis characterizes cardiomyopathy from cardiac lipid overload and identify a promising new therapeutic target for this condition.

molecular biology↗

bioRxiv2026

What do satellite vegetation indices actually measure? Photosynthetic capacity rather than transient physiological function across 328 global FLUXNET sites

A direct empirical relationship between gross primary productivity (GPP) estimated by the eddy covariance method and satellite vegetation indices (VIs) has been widely observed across diverse ecosystems globally. Building on this observed covariation, VIs are frequently utilized as critical parameters - such as the fraction of absorbed photosynthetically active radiation (fPAR) - within light use efficiency (LUE) and greenness-based models for carbon cycle monitoring. However, actual canopy carbon assimilation is jointly governed by slowly evolving structural parameters and highly dynamic functional traits, such as physiological efficiency. The extent to which the macro-scale VI-GPP covariance is driven by structural scaffolding, and how this structural signal decouples from physiological function under environmental stress, remains to be systematically quantified. Here, we synthesized half-hourly eddy covariance measurements from 328 globally distributed sites and paired them with a rigorously angle-normalized Enhanced Vegetation Index (nadir view and fixed solar zenith angle at 30 degrees, EVI_SZA30). By applying a nonlinear light-response curve model across 54,720 high-frequency temporal windows, we mechanistically disentangled observed actual GPP (GPP_EC) into baseline photosynthetic capacity (P_c) and intrinsic quantum yield (alpha). Our results demonstrate that the macroscopic covariance between EVI_SZA30 and GPP_EC (R^2=0.554) is primarily driven by the index's robust ability to track structural capacity (P_c, R^2=0.538). In contrast, EVI_SZA30 exhibits limited sensitivity to high-frequency variations in functional traits like physiological efficiency (alpha, R^2=0.038). Particularly in water-limited biomes (e.g., open shrublands and woody savannas), intense environmental stress triggers rapid stomatal regulation while the physical canopy structure remains relatively stable. Consequently, the correlation between EVI and P_c becomes notably stronger than its correlation with actual GPP_EC, highlighting a pronounced structural-physiological decoupling. Because discrete overpasses by sun-synchronous polar-orbiting satellites face intrinsic temporal constraints in capturing sub-daily physiological down-regulation (e.g., midday photosynthetic depression), future monitoring paradigms could greatly benefit from the continuous, high-frequency observations provided by next-generation geostationary (GEO) satellites to bridge the gap between structural parameters and transient ecosystem function.

ecology↗

bioRxiv2026

Genome-wide association study of grain iron and zinc concentrations in a diverse CIMMYT wheat panel across contrasting moisture environments

Micronutrient deficiencies remain a major public-health challenge, and genetic improvement of grain iron and zinc concentrations in wheat offers a sustainable biofortification strategy. We evaluated 563 CIMMYT advanced wheat lines and six checks under restricted irrigation (two irrigations) and well-watered conditions (five irrigations) at Ciudad Obregon, Mexico. Grain iron and zinc concentrations were quantified by energy-dispersive X-ray fluorescence spectrometry. Best linear unbiased estimates were calculated, and genome-wide association analyses were conducted using 8,687 high-quality single-nucleotide polymorphisms and a multi-locus mixed model that accounted for population structure. Five marker-trait associations were detected in at least two datasets. For grain zinc concentration, S3B_811421507 was detected under both irrigation regimes and in the combined analysis, whereas S3B_814372642 was detected under well-watered conditions and in the combined analysis. For grain iron concentration, S2B_73321328 and S4B_20679079 were associated with variation under restricted irrigation and in the combined analysis, while S2B_72162723 was detected under well-watered conditions and in the combined analysis. Individual loci explained 0.34% to 3.36% of phenotypic variance, consistent with the quantitative inheritance of grain micronutrient concentration. The identified alleles provide candidate targets for validation and marker-assisted biofortification breeding, while their environment-dependent effects emphasize the need to evaluate micronutrient traits across contrasting moisture conditions.

plant biology↗

bioRxiv2026

Epitope-Focused Immunogens Confer Broad Protection against Coronaviruses

Variable regions in coronavirus spike dominate antibody responses elicited by infection or conventional vaccination and limit induction of broad neutralization. In contrast, conserved S2 elements, including the stem helix (SH) and fusion peptide proximal region (FPPR), are promising but subdominant targets of protective immunity. Here, we employed computational design to generate de novo epitope-focused immunogens that precisely present the SH and FPPR epitopes. Formulated as combinatorial immunogens, this vaccine elicited consistent serum responses with broad reactivity across known human coronaviruses and induced epitope-specific antibodies with broad neutralizing activity. As a heterologous boost, epitope-focused immunogens protected mice against challenge with phylogenetically distinct coronaviruses, including bat SARS-related RsSHC014-CoV and MERS-CoV, establishing a generalizable strategy for precision immune focusing and advancing universal coronavirus vaccine development.

bioengineering↗

bioRxiv2026

Neuropil aggrecan, not perineuronal nets, closes the critical period for visual plasticity

Perineuronal nets (PNNs) are widely reported to close developmental critical periods and restrict experience-dependent plasticity. Here we tested this model by selectively eliminating gene expression for aggrecan (Acan), an essential component of PNNs. In visual cortex, PNNs predominantly ensheath parvalbumin-positive (PV+) interneurons. Deletion of Acan in inhibitory neurons eliminated PNNs but did not prevent closure of the critical period. By comparison, deletion of Acan in all neurons, or only in excitatory forebrain neurons, sustained critical-period plasticity in adult mice. Visual plasticity in adults was associated with reduced cortical excitatory synaptic inputs onto layer 2/3 PV+ interneurons and increased expression of some immediate early genes in visual cortex but normal response strength and tuning properties of layer 2/3 excitatory neurons. These findings rectify long-standing models that misattribute closure of the critical period to PNNs and identify that aggrecan expressed by excitatory neurons resident in the surrounding neuropil limits visual plasticity.

neuroscience↗

bioRxiv2026

Mechanism of fatty acid uptake and inhibition in human FATP2

Fatty Acid Transport Protein 2 (FATP2) couples fatty acid uptake to intracellular activation and is associated with pathological lipid accumulation in cancer and nonalcoholic fatty liver disease. Here, we present cryo-electron microscopy structures of human FATP2 across its reaction cycle. Our structures suggest that FATP2 recruits fatty acids directly from the membrane interface through a hydrophobic tunnel. Catalysis involves a [~]130{degrees} rotation of the C-terminal domain, a transition trapped by the antihypertensive drugs isradipine and benidipine. Both drugs lock the enzyme in a thioester-forming state, but benidipine exhibits superior efficacy by extending a bulky moiety into the primary catalytic tunnel to sterically block substrate entry. Furthermore, we identify a product inhibition mechanism where excess acyl-CoA traps the enzyme, potentially limiting metabolic overload. These findings provide a structural framework for understanding vectorial fatty acid channeling and a scaffold for developing modulators of metabolic flux. HighlightsO_LICryo-EM structures of human FATP2 reveal a membrane-anchored lollipop topology C_LIO_LIEndogenous fatty acids within a hydrophobic tunnel delineate the fatty acid uptake pathway C_LIO_LIIsradipine and benidipine displace fatty acids to trap a non-productive conformation C_LIO_LIAcyl-CoA product inhibition may provide negative feedback via steric occlusion C_LI

biophysics↗

bioRxiv2026

PIP2 stabilizes Nav1.5 gating and links receptor signaling to cardiac late sodium current

The cardiac sodium channel NaV1.5 initiates each heartbeat by generating the rapid depolarizing upstroke of the action potential. Dysregulation of NaV1.5 gating can produce cardiac arrhythmias by slowing inactivation, increasing late sodium current (INa,L), and impairing electrical stability. Here, we show that phosphatidylinositol-4,5-bisphosphate (PIP2) is a critical membrane cofactor that stabilizes NaV1.5 gating. Acute PIP2 depletion in human iPSC-derived cardiomyocytes, produced by activation of endogenous AT1 receptors, activation of an engineered M3q-DREADD, or optogenetic recruitment of CRY2-pseudojanin, shifted voltage dependence, slowed fast inactivation, and increased INa,L. These effects were prevented by augmenting intracellular PIP2, required PLC activity when driven by Gq-coupled receptors, and were independent of downstream Ca{superscript 2} or PKC signaling. Unlike the skeletal-muscle isoform NaV1.4, NaV1.5 displayed PIP2-dependent shifts in both activation and steady-state inactivation, indicating isoform-specific lipid coupling. Induced-fit docking and molecular dynamics simulations identified a PIP2-interaction interface between the domain IV voltage sensor and pore that contains disease-linked residues. The disease-reported variant R1644C weakened and redistributed the predicted PIP2-contact network, produced elevated basal INa,L, showed enhanced sensitivity to PIP2 depletion, and caused an approximately 30-fold reduction in apparent functional PIP2 sensitivity in excised patches. These findings define a lipid-dependent mechanism that stabilizes NaV1.5 gating and reveal how physiological Gq signaling and inherited channel variants can converge on the channel-PIP2 axis to promote proarrhythmic late sodium current.

physiology↗

bioRxiv2026

Engineering of CAR-less lentiviral vectors via ER retention-mediated CAR blockade

Chimeric antigen receptor (CAR)-T cell therapies have transformed the treatment of various tumor types by redirecting and activating T cells against tumor cells. However, CAR-T cell manufacturing approaches remain challenging and limit their widespread use in clinical settings. In vivo CAR-T therapy bypasses ex vivo cell manufacturing and patient preconditioning limitations; however, it faces a significant safety concern as CAR proteins on viral packaging cells are incorporated into budding virions, leading to off-target transduction of tumor cells. Here, we address this risk by developing the CAR-Less ER-Anchor Vector (CLEAN-V) system. By exploiting endoplasmic reticulum (ER) retention, CLEAN-V prevents the CAR protein from trafficking to the cell surface during viral packaging, thereby blocking its incorporation into the viral envelope. CLEAN-V particles exhibit near-complete loss of CAR-mediated tumor cell transduction. Furthermore, CLEAN-V integrates seamlessly into existing third-generation LVV workflows in four- or five-plasmid formats and generates CAR-T cells with preserved phenotypic and functional integrity. These results establish CLEAN-V as a robust platform for developing safe, targeted lentiviral vectors for in vivo CAR-T therapy.

bioengineering↗

bioRxiv2026

A structure-derived contact-network responsiveness atlas of human proteins

Protein structures encode non-local contact organization, but static coordinates do not directly quantify how a contact network responds when effective stabilizing interactions are strengthened or weakened. Here we introduce Contact-Network Responsiveness (CNR), a structure-derived framework that converts residue-level protein coordinates into density-controlled and topology-corrected response descriptors. The method is structure-source agnostic and can be applied to experimentally determined PDB structures, AlphaFold models, or other predicted structures; here, human AlphaFold models serve as the high-coverage structural substrate. Across 22,167 valid human protein structures, hydrophobic non-local contact density defined a nearly exact Bethe mean-field baseline for the conformational susceptibility threshold. A graph-aware residue-level extension then revealed systematic topology-dependent deviations from this density-only prediction. We define a topology correction ratio, [Formula], which separates topology-facilitated, density-dominated and topology-suppressed contact-network response regimes. CNR descriptors were associated with curated DisProt disorder annotations and broad-coverage UniProt/MobiDB-lite disorder fractions, supporting the interpretation that CNR captures a structural organization axis related to non-local contact availability and responsiveness.

biophysics↗

bioRxiv2026

A multi-organ spatial metabolomic atlas of exercising mice reveals neuronal Complex I as a convergent and sufficient axis for tau pathology reduction in PS19

We constructed a spatially resolved metabolomic atlas of long-term exercise across six major organs in wild-type mice: brain, heart, lung, liver, kidney, and skeletal muscle, cataloguing 224 metabolic features and revealing coordinated inter-organ remodeling. Surprisingly, the brain showed particularly pronounced region-specific adaptation. Because pathological tau associates with synaptic mitochondria from early stages of tauopathy, we extended this multi-organ spatial metabolomic approach to PS19 mice and found that exercise reduced over 70% of observable tau pathology in PS19 hippocampus and restored the mitochondrial-related metabolome. Integrated proteomic and spatial metabolomic analyses identified NADH dehydrogenase Complex I as the convergent node. To test this finding biologically, we expressed the yeast NADH dehydrogenase, Ndi1, in PS19 neurons in the absence of exercise. This increased cerebral antioxidants, restored shuttle-linked metabolites, and reduced tau pathology. Increasing NADH dehydrogenase activity through NDI1 reproduces the core anti-tau and metabolic effects of exercise. These findings provide a molecular mechanism for how exercise may prevent or slow tau pathology accumulation, complementing the human-cohort literature linking exercise to delayed cognitive decline.

neuroscience↗

bioRxiv2026

Aging promotes inflammation and steatosis in alcohol-associated liver disease in mice

Background and AimsAs the older population (aged 65 years and older) continues to expand and more people drink alcohol, aging has been linked to the development of alcohol-associated liver disease (ALD) and to worse disease outcomes. The aim of this study was to explore the mechanisms by which advanced age and alcohol exacerbate alcohol-induced liver injury. MethodsTwo-to-three-month-old and twenty-to-twenty-two-month-old male C57BL/6N mice were subjected to chronic-on-binge alcohol feeding (the Gao-binge model). Serum alanine aminotransferase, aspartate aminotransferase, and triglyceride content were determined using biochemical assays. The levels of lipogenesis, fatty acid-metabolizing proteins, inflammatory markers, mitochondrial and autophagy-related proteins, and senescence-associated proteins were determined by immunoblotting, immunohistochemistry, and real-time quantitative polymerase chain reaction (RT-qPCR). Liver tissues were also subjected to RNA sequencing and metabolomics analyses. Proteomics analysis was performed on serum samples. Tail-vein adenovirus-TFEB was injected to overexpress hepatic TFEB in 22-month-old C57BL/6N male mice, followed by Gao-binge alcohol feeding. ResultsHepatic triglyceride content was significantly increased in aged, alcohol-fed mice, whereas serum ALT and AST levels remained relatively similar between alcohol-fed young and aged mice. Gao-binge alcohol increased the hepatic levels of diacylglycerol and acyl-carnitine species in both aged and young livers. RNA sequencing, proteomic analysis, and serum cytokine array analysis showed that inflammatory cytokines, including Ccr2, Cxcl1, and CCL6, and pro-inflammatory antibody fragments were increased in aged, alcohol-fed mice. Increased gene and protein expression of the senescent markers p21 and p27, along with increased senescent-associated (SA) {beta}-galactosidase activity in ethanol-fed aged mice compared to young mice. Gene and protein expression of TFEB was downregulated in ethanol-fed young and aged animals, along with decreased levels of lysosomal ATPases and hepatic dipeptide content. Overexpression of TFEB in the livers of aged, Gao-binge-fed mice was associated with reduced Ly6G-positive cells, reduced protein levels of the innate immune mediators cGAS, IRF-7, IRF3, and NLRP3, and reduced caspase-1 activity as well as serum ALT levels. ConclusionsOur findings indicate that advanced age perpetuates the detrimental effects of excessive alcohol consumption on various homeostatic processes and promotes steatosis and inflammation in the liver. Modulations in hepatic TFEB could be effective in mitigating pro-inflammatory signaling that occurs due to the synergistic effect of both heavy alcohol consumption and advanced age.

Molecular Biology↗

bioRxiv2026

OmicOS: A Comprehensive Omics Ecosystem Infrastructure and Agent System for the AI Era

Biology has accumulated a vast ecosystem of omics methods, but much of this ecosystem remains built for expert humans rather than scientific agents. Methods are scattered across Python packages, R/Bioconductor and CRAN workflows, command-line tools, incompatible data containers and implicit object states, making even routine analyses difficult for an AI system to choose, execute and verify reliably. Here we introduce OmicOS, a comprehensive omics ecosystem infrastructure and agent system that turns OmicVerse V2, an open-source omics community, into an executable foundation for agentic biology. OmicVerse V2 provides the community substrate: scalable AnnDataOOM-compatible rust backends, agent-friendly Python algorithms for single-cell, spatial, bulk and multi-omics analysis, interfaces to single-cell foundation models, and Python-native reconstructions of historically R-centred Bioconductor/CRAN-style workflows. OmicOS makes this substrate actionable by registering analytical functions as state-aware capability contracts, allowing agents to inspect live data objects, select valid methods, execute controlled workflows and record provenance. The result is not a fixed pipeline, but a programmable omics environment in which agents compose real analyses from verified community methods rather than inventing tools. Across external and purpose-built benchmarks, OmicOS ranked first among the evaluated systems, reaching 81.2% on BiomniBench. Adding OmicVerse to a minimal agent improved task completion by up to 34.2 percentage points with qwen-3.6-35b, and controlled ablations showed that the gains came from registry-grounded execution rather than from larger models, documentation retrieval or unrestricted tool exposure. The same infrastructure scaled to atlas-sized data, reproduced R-centred workflows in Python and converted external pathology software into agent-usable skills. In a discovery task starting from a whole-body spatial map and the term "Alzheimers disease", OmicOS composed a non-canonical workflow that integrated spatial expression, genetic association, eQTL and colocalization evidence to nominate a colon epithelial risk axis centred on PICALM, CD2AP and CR1. Together, OmicVerse and OmicOS define an open foundation for AI-era omics, showing how a community of biological methods can be transformed into a reliable, extensible and agent-operable system for discovery. HighlightO_LIOmicVerse 2.0 consolidates 694 methods spanning 11 omics domains into agent-callable high-level APIs. C_LIO_LIRebuildR automatically reconstructs and evolves R/Bioconductor methods as Python-native implementations under output-equivalence gates. C_LIO_LIOmicOS establishes a state-of-the-art omics agent harness, ranking first on general omics benchmarks across models and substantially improving the analytical capability of local open-source models. C_LIO_LICompositional use of ecosystem modules nominates a colon epithelial axis associated with Alzheimers disease risk. C_LIO_LIExternal algorithm packages supporting automatic iterative evolution can be integrated into the OmicOS ecosystem. C_LI

bioinformatics↗

bioRxiv2026

Cognitive function depends upon Satb2 gene dosage in cortical projection neurons

SATB2-associated syndrome (SAS) is a severe neurodevelopmental disorder caused by de novo heterozygous SATB2 mutations, yet how haploinsufficiency disrupts brain development remains poorly understood. While homozygous Satb2 loss causes profound embryonic cell-fate defects, we demonstrate using a heterozygous mouse model that SAS phenotypes emerge primarily during postnatal circuit maturation. Integrating chromatin profiling, transcriptomics, electrophysiology, and behavior, we show that SATB2 acts as a dose-sensitive chromatin regulator that binds conserved enhancer-promoter landscapes to orchestrate networks linked to human intelligence. Although excitatory neuron subtype specification is preserved, Satb2 heterozygotes adopt an intermediate epigenetic state that drives cell-type-specific dysregulation of genes enriched for intellectual disability risk variants. Consequently, mutant neurons exhibit simplified dendritic arborization, reduced intrinsic excitability, and weakened layer 2/3-to-layer 5 intracortical connectivity. These circuit deficits culminate in the disorganization of the somatosensory barrel cortex and severe impairments in whisker-dependent texture discrimination. Finally, by restricting Satb2 heterozygosity to the cortex, we decouple these cortical sensory deficits from subcortical vocalization phenotypes. Together, our work links SATB2 dosage to chromatin architecture and postnatal circuit maturation, revealing a critical, post-mitotic therapeutic window for intervention in SAS.

neuroscience↗

bioRxiv2026

Dehydration/1,6-addition-based Site-specific Bioconjugation Unveils Norepinephrinylation as a Widespread Post-translational Modification in the Cellular Proteome

Norepinephrine (NE) is a key neurotransmitter and hormone involved in diverse physiological and pathological processes. Beyond its canonical non-covalent signaling through binding adrenergic receptors, NE also induces protein post-translational modifications (PTMs), representing an emerging regulatory mechanism. Two major forms of NE-derived PTMs have been proposed: non-enzymatic norepinephrinylation (NEylation) of cysteine residues mediated by NE quinone and transglutaminase 2 (TG2)-catalyzed NEylation of glutamine residues. However, the cellular abundance, biochemical basis, and pathophysiological roles of NEylation remain poorly understood due to limited detection tools. Here, we report a novel bioconjugation chemistry for selective labeling and enrichment of the endogenous NEylation proteome in cell lines and tissues, which is based on acid-catalyzed dehydration and 1,6-addition to thiol probes. This strategy enables fluorescence imaging and chemical proteomic profiling, revealing NEylation as a widespread PTM that affects enzymatic activities of modified proteins, including protein tyrosine-protein phosphatase non-receptor type 11 (PTPN11). Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=75 SRC="FIGDIR/small/731782v3_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@406ac5org.highwire.dtl.DTLVardef@121d6b9org.highwire.dtl.DTLVardef@98354corg.highwire.dtl.DTLVardef@d312ef_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗