Biology subjects

Chang, L.

Publications and source records attributed to Chang, L..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Geometric structure of features underlies human VTC object recognition.

The ventral temporal cortex (VTC) plays a crucial role in human object recognition. Within VTC neural space, object-specific domains align with domain-general features, e.g. face- and scene-domain align with the feature distribution of animacy, generating a hierarchical knowledge structure for categorization. However, the neural process of integrating information from VTC to distinguish different objects remains unclear. Here, we employed a combination of ANN modeling, functional MRI, and MEG to investigate how VTC features affect object manifold separability. The representational geometry analysis shows that domain-general features in VTC form a unique structure, different from ANN, to assist object classification. Moreover, VTC dynamically adjusts the geometrical relationship of these features during object recognition, influencing the geometrical properties of object manifolds and, consequently, their separability. These findings advance our understanding of the neural computation involved in VTC object recognition, revealing how downstream neurons can flexibly access category information in diverse recognition tasks.

neuroscience↗

bioRxiv2025

Computational design of metalloproteases

Although significant progress has been made in creating de novo metalloenzymes that hydrolyze activated esters, the energetically demanding cleavage of amide bonds has remained a major challenge for enzyme design: amide bonds are significantly more stable than ester bonds, the amine leaving groups in proteins are not activated, and peptide substrates are flexible making them difficult to bind precisely. Here, we report the de novo design of zinc proteases from minimal catalytic motifs using RoseTTAFold Diffusion 2 for Molecular Interfaces, optimized for both enzyme and protein-protein interaction design. Of 135 computational designs experimentally tested, 36% had activity and cleaved precisely at the intended site. The most active design accelerates peptide bond hydrolysis by more than 10^8-fold relative to the uncatalyzed reaction, and by over 10^10-fold following the introduction of four point mutations that enhanced active-site preorganization4. Building on these capabilities, we designed metalloproteases that specifically cleave human TDP-43, the amyloid-{beta} peptide, and serum amyloid A with rate accelerations up to 9.2x10^8-fold over background. We illustrate the potential of our approach for bio-orthogonal control over cell state by generating caged cytokines and caged receptor antagonists that are selectively unmasked by our designed proteases. These results demonstrate that de novo enzyme design has advanced well beyond model reactions with activated substrates and open the door to design of proficient metallohydrolases for a wide range of applications in medicine and bioremediation.

biochemistry↗

bioRxiv2025

Direct cell reprogramming by a designed agonist inducing HER2-FGFR proximity

Growth factor induced receptor dimerization and activation of downstream pathways can modulate cell fate decisions. Here, we investigate the potential of de novo designed synthetic ligands, termed Novokines, to reprogram cell identity by inducing proximity of novel pairs of receptor subunits. We find that a design, H2F, that brings together HER2 (which has no known natural ligand) and the FGF receptor has potent signaling activity. H2F induces robust signaling and reprograms fibroblasts into myogenic cells. Unlike native FGF ligands, H2F selectively activates the MAPK pathway without engaging PLC{gamma}-mediated Ca{superscript 2} signaling. FRET assays confirm H2F-mediated HER2-FGFR proximity, and phosphoproteomic analysis reveals activation of MAPK effectors. H2F-induced ERK phosphorylation is abolished in cells expressing a kinase-dead FGFR1 (K514M) mutant, confirming the requirement for FGFR catalytic activity. H2F treatment significantly increases myofiber formation from adult patient-derived primary myoblasts, demonstrating its capacity to promote myogenic regeneration. Our findings demonstrate that synthetic receptor pairings can rewire signaling outputs to drive regeneration, providing a programmable platform for cell fate engineering.

biochemistry↗

bioRxiv2025

The immune and genetic heterogeneity of Hepatocellular Carcinoma, with a focus on multifocal disease

Understanding the genetic and immune heterogeneity in hepatocellular carcinoma (HCC) is crucial as treatments advance towards personalisation. This study characterises the genetic and immune heterogeneity within a population of 56 tumours from 28 patients, 10 of whom have multifocal disease, obtained from patients undergoing surgery at the Leeds Teaching Hospital NHS Trust. These samples represent the most common aetiological groups found in the UK: alcohol-related liver disease, non-alcoholic fatty liver disease and hepatitis C. Whole exome sequencing was performed on DNA from these tumour alongside matched background liver samples to determine tumour-specific variants. Tissue sections were stained for both proliferation and immune cell markers. Tumours across aetiological groups showed significant levels of variation, with high inter-individual variation. Analyses of multifocal tumours revealed significant discordance in genetic and immune cell profiles, both between multi-centric primary and metastatic tumours. This work emphasises the genetic and immuneheterogeneity in HCC across HCC subtypes, between and within individuals, highlighting mechansisms for therapeutic resistance and the need for personalised medicine.

cancer biology↗

bioRxiv2025

Genomic insights into adaptation strategies and microevolutionary forces of novel non-AOA Nitrososphaeria in acid mine drainage ecosystems

The class Nitrososphaeria is best known for ammonia-oxidizing archaea (AOA), yet deeply branching non-AOA lineages remain poorly characterized, leaving a critical gap in our understanding of the groups early evolution and ecological diversification. Herein, we recovered 44 non-AOA Nitrososphaeria metagenome-assembled genomes (MAGs) from acid mine drainage (AMD) sediments in diverse metal mines, representing two novel genera within the family UBA164, Acidarchaeum and Thermosulfuris. A meta-analysis of 251 AMD-associated metagenomes showed that these potentially thermophilic lineages are globally distributed but typically rare, with local peaks ([~]6.6%) at sites such as Fankou. Metabolic reconstruction suggested a facultatively anaerobic, mixotrophic lifestyle capable of CO oxidation and sulfur reduction, and extensive acid- and heavy-metal resistance mediated primarily by ether-linked archaeal lipids, ion efflux systems, and enzymatic reduction. Genus-specific traits include dissimilatory sulfate reduction in Thermosulfuris and urea utilization in Acidarchaeum, illuminating distinct ecological niches for them. Population-genomic analyses reveal low homologous recombination and pervasive purifying selection in these non-AOA populations, together with local relaxation of selection and elevated diversity, the former being correlated with geochemical stressors (notably copper), pointing to long-term, geochemically driven adaptation. Overall, these findings provide insights into the biodiversity, ecophysiology, and evolutionary dynamics of non-AOA Nitrososphaeria. IMPORTANCEMembers of the class Nitrososphaeria that oxidize ammonia are central to the global nitrogen cycle, yet deep-branching lineages that lack this metabolism remain poorly explored, obscuring their early evolutionary trajectory. Here, we identify two new genera of non-ammonia-oxidizing Nitrososphaeria from acid mine drainage ecosystems and show that they recur globally in these acidic, metal-rich, oligotrophic habitats. Genomic analyses reveal adaptations for survival in harsh environments and genus-specific metabolic traits, suggesting distinct ecological strategies. Evolutionary analyses further indicate that these lineages are highly specialized, with population-genomic patterns consistent with long-term adaptation to geochemical conditions. This work sheds light on the biodiversity and evolutionary constraints of early-diverging lineages of Nitrososphaeria.

microbiology↗

bioRxiv2025

Bodily Self in Macaque Monkeys and Human Infants

Whether monkeys possess the concept of bodily self remains controversial. We found that macaque monkeys trained for mirror self-recognition (MSR) could spontaneously recognize themselves when viewing video images of their back from a third-person perspective (3PP), but this generalization required a few minutes of "exploration". In contrast, through visual-tactile synchronization training similar to that used in human out-of-body studies, naive monkeys could recognize themselves from 3PP back images and demonstrated MSR within seconds. Interestingly, in human infants, we found that 3PP back self-recognition developed spontaneously several months after MSR. These results demonstrate the existence of hierarchical bodily self in macaques and similar stepwise development of bodily self in human infants, offering insights into the emergence and manifestation of bodily self in natural and artificial intelligence.

neuroscience↗

bioRxiv2025

Evidence for hierarchical representations of written and spoken words from an open-science human neuroimaging dataset

Reading and speech recognition rely on multi-level processing that builds from basic visual or sound features to complete word representations, yet details of these processing hierarchies (in particular those for spoken words) are still poorly understood. We re-analyzed the functional magnetic resonance imaging (fMRI) data provided in the Mother Of all Unification Studies (MOUS) open-science dataset by using parametric regressions of word frequency and sublexical unit (bigram or syllable) frequency during reading and speech listening tasks in order to elucidate lexical processing hierarchies in the visual and auditory modalities. We first validated our approach in the written word domain, where the technique identified significant correlations for word frequency in the left mid-fusiform cortex (at the location of the Visual Word Form Area) with a left occipital region tracking bigram frequency, compatible with prior reports. During listening, low-frequency spoken words elicited greater responses in a left mid-superior temporal region consistent with the recently-described Auditory Word Form Area (AWFA), while a more posterior region of the superior temporal gyrus was sensitive to syllable frequency. Activation in the left inferior frontal gyrus correlated with both written and spoken word frequency. These findings demonstrate parallel hierarchical organizations in the anteroventral visual and auditory streams, with modality-specific lexica and upstream sublexical representations that converge in higher-order language areas.

neuroscience↗

bioRxiv2025

Subtype-Specific Roles of Nigrostriatal Dopaminergic Neurons in Motor and Associative Learning

Nigrostriatal dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNc) comprise distinct subtypes defined by unique gene expression profiles and anatomical characteristics. However, their specific contributions to motor and non-motor functions remain elusive. Using Calbindin 1 (Calb1) and Aldehyde dehydrogenase 1a1 (Aldh1a1) as molecular markers, we investigated the functions of these nigrostriatal DAN subtypes in mice. Through intersectional genetics and chemogenetic manipulation, we selectively inhibited Calb1+ or Aldh1a1+ DANs by stereotactically delivering an adeno-associated viral vector (AAV-CreOn-FlpOn-hM4Di-P2A-mCherry) into the SNc of ThFlp; Calb1IRESCre or ThFlp; Aldh1a1CreERT2 double knock-in (KI) mice. This approach enabled subtype-specific neuronal inhibition via designer receptors exclusively activated by designer drugs (DREADD). Following DREADD ligand administration, both Calb1+ and Aldh1a1+ DAN-inhibited mice exhibited significant reduction in voluntary movement and impaired motor skill learning, demonstrating their essential roles in motor function. However, only Calb1+ DAN inhibition affected early associative-learning behavior, suggesting a unique role in reinforcement learning. These findings establish Calb1+ and Aldh1a1+ nigrostriatal DANs as key regulators of movement and motor learning, with Calb1+ neurons additionally modulating reward-based associative learning. This study advances our understanding of the functional heterogeneity of nigrostriatal DAN subtypes and identifies potential therapeutic targets for addressing motor and non-motor deficits in Parkinsons disease.

neuroscience↗

bioRxiv2025

The anaerobic WOR-3 Bacteria: Hydrogenotrophic metabolism and unique carbon fixation via Archaeal form III RuBisCO

The uncultured WOR-3 phylum is widely distributed in anaerobic environments, including hot springs, marine ecosystems, and hydrothermal vents, yet its ecological roles and metabolic capabilities remain poorly understood. In this study, we analyzed 180 medium- to high-quality metagenome-assembled genomes (MAGs), including 59 newly reconstructed from environmental samples and 121 retrieved from the Genome Taxonomy Database (GTDB). Phylogenetic analyses resolved the WOR-3 lineage into four subgroups (subgroup 1-4). Metabolic reconstruction revealed significant divergence of the carbon, sulfur, nitrogen and hydrogen metabolism pathways among the different subgroups. Subgroup 1 was characterized by fermentative metabolism involving formate and ethanol, and uniquely exhibited potential for carbon fixation via Calvin cycle, as indicated by the presence of ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) gene. Notably, WOR-3 RuBisCO is phylogenetically affiliated with archaeal form III, although the carbon fixation pathway follows the canonical bacterial Calvin cycle--a feature of potential evolutionary significance. Subgroup 3 exhibits metabolic versatility, including genes for dissimilatory sulfate reduction, sulfur oxidation, partial denitrification, and fatty acid degradation. In addition, all subgroups harbored key components of hydrogen metabolism, including widespread NiFe hydrogenases and Rnf complexes, supporting H2-dependent electron transfer and energy conservation under anaerobic conditions. Featuring near-universal presence of complexes I and II and frequent occurrence of terminal oxidases (cydAB and coxABC)--suggests a facultative anaerobic lifestyle. Collectively, this study expands the genomic framework for the WOR-3 phylum and provides novel insights into the metabolic versatility and ecological functions of this previously uncharacterized lineage in biogeochemical cycles of carbon, nitrogen, and sulfur. IMPORTANCEThe WOR-3 phylum represents a widespread but poorly understood bacterial lineage inhabiting diverse anaerobic/microaerobic environments. By integrating 180 metagenome-assembled genomes, including 59 newly reconstructed, this study provides the most comprehensive genomic framework to date for WOR-3. Phylogenomic and metabolic analyses revealed four distinct subgroups with divergent capacities for carbon, sulfur, and nitrogen metabolism. Notably, subgroup 1 encodes a complete Calvin-Benson-Bassham (CBB) cycle featuring an archaeal-type form III RuBisCO, suggesting an unusual evolutionary trajectory for carbon fixation in this lineage. Subgroup 3 exhibits versatile metabolic potential, including dissimilatory sulfur metabolism, partial denitrification, and fatty acid degradation, highlighting its possible roles in multiple biogeochemical processes. The widespread presence of hydrogenases and respiratory complexes across all subgroups supports energy conservation under anaerobic or microaerobic conditions. These findings not only expand the taxonomic and functional landscape of the WOR-3 phylum but also offer key insights into its ecological roles in global element cycling.

microbiology↗

bioRxiv2025

Exapted CRISPR-Cas12f homologs drive RNA-guided transcription

Bacterial transcription initiation is a tightly regulated process that canonically relies on sequence-specific promoter recognition by dedicated sigma ({sigma}) factors, leading to functional DNA engagement by RNA polymerase (RNAP)1. Although the seven {sigma} factors in E. coli have been extensively characterized2, Bacteroidetes species encode dozens of specialized, extracytoplasmic function {sigma} factors ({sigma}E) whose precise roles are unknown, pointing to additional layers of regulatory potential3. Here we uncover an unprecedented mechanism of RNA-guided gene activation involving the coordinated action of {sigma}E factor in complex with nuclease-dead Cas12f (dCas12f). We screened a large set of genetically-linked dCas12f and {sigma}E homologs in E. coli using RIP-seq and ChIP-seq experiments, revealing systems that exhibited robust guide RNA enrichment and DNA target binding with a minimal 5'-G target-adjacent motif (TAM). Recruitment of {sigma}E was dependent on dCas12f and guide RNA (gRNA), suggesting direct protein-protein interactions, and co-expression experiments demonstrated that the dCas12f-gRNA-{sigma}E ternary complex was competent for programmable recruitment of the RNAP holoenzyme. Remarkably, dCas12f-RNA-{sigma}E complexes drove potent gene expression in the absence of any requisite promoter motifs, with de novo transcription start sites defined exclusively by the relative distance from the dCas12f-mediated R-loop. Our findings highlight a new paradigm of RNA-guided transcription (RGT) that embodies natural features reminiscent of CRISPRa technology developed by humans4,5.

molecular biology↗

bioRxiv2025

Structural basis of RNA-guided transcription by a dCas12f-σE-RNAP complex

RNA-guided proteins have emerged as critical transcriptional regulators in both natural and engineered biological systems by modulating RNA polymerase (RNAP) and its associated factors1-3. In bacteria, di-verse clades of repurposed TnpB and CRISPR-associated proteins repress gene expression by blocking transcription initiation or elongation, enabling non-canonical modes of regulatory control and adaptive immunity1,4,5. Intriguingly, a distinct class of nuclease-dead Cas12f homologs (dCas12f) instead activates gene expression through its association with unique extracytoplasmic function sigma factors ({sigma}E)6, though the molecular basis has remained elusive. Here we reveal a novel mode of RNA-guided transcription initiation by determining cryo-electron microscopy structures of the dCas12f-{sigma}E system from Flagellimonas taeanensis. We captured multiple conformational and compositional states, including the DNA-bound dCas12f-{sigma}E-RNAP holoenzyme complex, revealing how RNA-guided DNA binding leads to {sigma}E-RNAP recruitment and nascent mRNA synthesis at a precisely defined distance downstream of the R-loop. Rather than following the classical paradigm of {sigma}E-dependent promoter recognition, these studies show that recognition of the -35 element is largely supplanted by CRISPR-Cas targeting, while the melted -10 element is stabilized through unusual stacking interactions rather than insertion into the typical recognition pocket. Collectively, this work provides high-resolution insights into an unexpected mechanism of RNA-guided transcription, expanding our understanding of bacterial gene regulation and opening new avenues for pro-grammable transcriptional control.

biochemistry↗

bioRxiv2025

Inhibiting RhoA Activation via GDP-state Stabilization to Relieve Heart Failure

High rates of heart failure (HF) morbidity and mortality have made targeting myocardial remodeling--particularly hypertrophy and fibrosis--a key therapeutic focus. RhoA, which regulates cytoskeletal reorganization and cell migration, plays a role in this process. However, RhoA has long been considered "undruggable", due to its strong binding to its endogenous substrates, GDP/GTP, and the lack of well-defined pockets for drug targeting. Here, we discovered a cryptic pocket proximate to GDP within RhoA and identified a natural product, AH001, binds here and interacts with GDP, stabilizing RhoAs interaction with its endogenous inhibitor, RhoGDI. AH001 reduced the downstream MRTFA nuclear translocation and downregulated fibrosis/hypertrophy proteins. Consequently, AH001 mitigated myocardial remodeling in multiple HF animal models, and in the 3D myocardial tissue model. Our findings highlight the therapeutic potential of inhibiting RhoA activation in myocardial remodeling, ultimately targeting HF, and offer a promising avenue for developing reversible inhibitors against undruggable GTPases.

pharmacology and toxicology↗

bioRxiv2025

RIP2 inhibits DOCK8-mediated platelet dense granule release and alleviates experimental myocardial infarction

ObjectiveReceptor-interacting protein 2 (RIP2) is an essential mediator of inflammation and innate immunity downstream of pattern recognition receptors (PRRs). Platelets express RIP2, while its role in platelet activation, thrombosis, and myocardial infarction (MI) is unknown. Approach and ResultsHere we show that RIP2 deficiency enhances platelet dense granule secretion in response to GPIb and GPVI activation; platelet aggregation in whole blood and adhesion under arterial shear are also increased. Consistently, RIP2 inhibitor WEHI-345 potentiates human platelet dense granule secretion and inhibits RIP2 phosphorylation induced by thrombin and collagen. These phenotypes are translated into shorter bleeding time, accelerated FeCl3-induced arterial thrombosis. Importantly, platelets from patients with coronary artery disease and mice with atherosclerosis express lower RIP2, and RIP2 deficiency deteriorates MI and cardiac function in a mouse ischemia/reperfusion model. Mechanistically, we found that platelets express dedicator of cytogenesis protein 8 (DOCK8), which is sequestered by phosphorylated RIP2 (p-RIP2), causing inhibition of Cdc42 activation and subsequent dense granule release. ConclusionsIn conclusion, RIP2 inhibits platelet activation, thrombosis, and ameliorates MI. Our results also suggest that a novel PRR-independent pathway, p-RIP2-DOCK8-Cdc42, negatively regulates platelet activation downstream of GPIb and GPVI. Platelet RIP2 pathway may be promising for therapeutic intervention of atherothrombotic diseases from early atherosclerosis stage to arterial thrombosis and MI. HighlightsO_LIRIP2 inhibits platelet dense granule release NOD2-independenly via pRIP2-DOCK8-Cdc42. C_LIO_LIThe negative regulation of RIP2 on platelet activation is translated into enhanced thrombosis, exacerbated myocardial infarction (MI). C_LIO_LIRIP2 pathway booster may be an approach for therapeutic intervention of atherothrombotic diseases. C_LI

molecular biology↗

bioRxiv2025

Restoration of Susceptibility of blaNDM-bearing Escherichia. coli to Carbapenem Antibiotics by Exogenous N-acetylcysteine

The global spread of the New Delhi metallo-{beta}-lactamase (NDM) -producing carbapenem-resistant Enterobacteriaceae pose a serious threat to public health, as NDM and its variants enzymes efficiently hydrolyze almost {beta}-lactam antibiotics. The development of novel antibiotics or antibiotic adjuvants capable of eradicating antibiotic-resistance bacteria through multiple mechanisms represents a promising strategy for reversing antibiotic resistance and preventing the emergence of new resistance. In this study, we utilized high-performance liquid chromatography (HPLC) to demonstrate that N-acetylcysteine (NAC) is a prominent reducing metabolite in bacteria harboring NDM-5. Notably, NAC was able to restore carbapenem susceptibility in NDM-producing bacteria in vitro. Subsequently, we further investigated the underlying mechanisms involved. Our findings revealed that NAC exerts its effect through multiple mechanisms that collectively contribute to reversing meropenem resistance. Firstly, NAC may inhibit biofilm formation and reduces polysaccharide production in NDM-positive Escherichia coli. and this potential mechanism was verified by transcriptomic analysis, reverse transcription PCR (RT-PCR) and a biofilm restoration experiment involving the addition of citrate cycle intermediate metabolites. Secondly, RT-PCR analysis demonstrated that NAC significantly downregulates the expression of blaNDM-5. Additionally, NAC exhibited competitive inhibition of NDM activity in vitro. Thirdly, NAC was found to enhance the intracellular accumulation of meropenem, therapy increasing its bactericidal efficacy. These three independent mechanisms offer valuable insights for developing adjuvants. The discovery offers a promising prospect for combating the antibiotic resistance concern. This study paves the way for further exploration and potential clinical applications in the fight against antibiotic-resistant bacterial infections.

pharmacology and toxicology↗

bioRxiv2025

Lamin A/C safeguards replication initiation by orchestrating chromatin accessibility and PCNA recruitment

Lamin A/C, a nuclear lamina protein, is essential for maintaining nuclear architecture, organizing chromatin and preserving genomic stability. However, its role in regulating DNA replication remains unclear. This study investigates how Lamin A/C regulates proper activation of replication origins by orchestrating the chromatin structure and recruitment of proliferating cell nuclear antigen (PCNA). We demonstrate that Lamin A/C stabilizes replication domains (RDs) by restricting chromatin mobility, preserving spatial organization, and maintaining accessibility. Furthermore, Lamin A/C interacts with PCNA and sequesters a pool of PCNA, to regulate its recruitment to replication machinery. The loss of Lamin A/C leads to an increase in chromatin dynamics, RD accessibility, and PCNA availability at RDs, which together trigger excessive activation of replication origins, leading to replication stress and DNA damage. These disruptions prolong the S phase and compromise genome stability, highlighting Lamin A/C as a critical gatekeeper of balanced replication initiation. Our findings reveal Lamin A/Cs dual role in chromatin organization and replication machinery regulation, offering valuable insights into its involvement in replication-associated diseases and potential therapeutic opportunities through targeting replication dynamics.

biophysics↗

bioRxiv2025

Patchy Striatonigral Neurons Modulate Locomotor Vigor in Response to Environmental Valence

Spiny projection neurons (SPNs) in the dorsal striatum play crucial roles in locomotion control and value-based decision-making. SPNs, which include both direct-pathway striatonigral and indirect-pathway striatopallidal neurons, can be further classified into subtypes based on distinct transcriptomic profiles and cell body distribution patterns. However, how these SPN subtypes regulate spontaneous locomotion in the context of environmental valence remains unclear. Using Sepw1-Cre transgenic mice, which label a specific SPN subtype characterized by a patchy distribution of cell bodies in the dorsal striatum, we found that these patchy striatonigral neurons constrain motor vigor in response to valence differentials. In a modified light/dark box test, mice exhibited differential walking speeds between the light and dark zones. Genetic ablation of these patchy SPNs disrupted restful slowing in the dark zone and increased zone discrimination by speed. In vivo recordings linked the activity of these neurons to zone occupancy, speed, and deceleration, with a specific role in mediating deceleration. Furthermore, chemogenetic activation of patchy SPNs--and optical activation of striatonigral neurons in particular--reduced locomotion and attenuated speed-based zone discrimination. These findings reveal that a subtype of patchy striatonigral neurons regulates implicit walking speed selection based on innate valence differentials.

neuroscience↗

bioRxiv2024

Data- and knowledge-derived functional landscape of human solute carriers

Research on the understudied solute carrier (SLC) superfamily of membrane transporters would greatly profit from a comprehensive knowledgebase, synthesizing data and knowledge on different aspects of SLC function. We consolidated multi-omics data sets with selected curated information from the public domain, such as structure prediction, substrate annotation, disease association and subcellular localization. This SLC-centric knowledge is made accessible to the scientific community via a web portal, featuring interactive dashboards and a tool for family-wide, tree-based visualization of SLC properties. Making use of the systematically collected and curated data sets, we selected eight feature-dimensions to compute an integrated functional landscape of human SLCs. This landscape represents various functional aspects, harmonizing local and global features of the underlying data sets, as demonstrated by inspecting structural folds and subcellular locations of selected transporters. Based on all available data sets and their integration, we assigned a biochemical/biological function to each SLC, making it one of the largest systematic annotations of human gene function and likely acting as a blueprint for future endeavours.

systems biology↗

bioRxiv2024

Identification and catalogue of viral transcriptional regulators in human diseases

Viral genomes encode viral transcriptional regulators (vTRs) that manipulate host gene expression to facilitate replication and evade immune detection. Nevertheless, their role in non-cancerous diseases remains largely underexplored. Here, we unveiled 268 new candidate vTRs from 14 viral families. We mapped vTRs genome-wide binding profiles and identified their potential human targets, which were enriched in immune-mediated pathways, neurodegenerative disorders, and cancers. Through vTR DNA-binding preference analysis, 283 virus-specific and human-like motifs were identified. Prioritized Epstein-Barr virus (EBV) vTR target genes were associated with multiple sclerosis (MS), rheumatoid arthritis, and systemic lupus erythematosus. The partitioned heritability study among 19 diseases indicated significant enrichment of these diseases in EBV vTR-binding sites, implicating EBV vTRs roles in immune-mediated disorders. Finally, drug repurposing analysis pinpointed candidate drugs for MS, asthma, and Alzheimers disease. This study enhances our understanding of vTRs in diverse human diseases and identifies potential therapeutic targets for future investigation.

bioinformatics↗