Biology subjects

Dong, D.

Publications and source records attributed to Dong, D..

At least 19 recordsLinked to original sources

bioRxiv2026

Sequential vaccination matures VRC01-class HIV-1 neutralizing antibodies in humans

Inducing a broadly neutralizing antibody (bnAb) response is a key goal of HIV-1 vaccine development. Despite significant progress, it is unknown whether vaccine-primed B cells can be reactivated and matured to secrete bona fide bnAbs. In the IAVI C107/C110 single-arm, open-label human trial, VRC01-class memory B cells previously primed by the GT1.1 germline-targeting envelope glycoprotein (Env) trimer were reactivated by a BG505 SOSIP.664 trimer boost. Somatic hypermutation in the activated B cells drove higher antibody affinity for the CD4-binding site on fully glycosylated, heterologous Env trimers. Three VRC01-class monoclonal antibodies derived from independent B cell lineages neutralized 18-31% of 119 viruses in a globally diverse panel. This work advances the HIV-1 germline-targeting vaccination concept from proof-of-priming towards proof-of-breadth and defines a benchmark for bnAb induction.

immunology↗

bioRxiv2026

Mapping the Fragment-Binding Landscape of SARS-CoV-2 nsp14 for Antiviral Drug Discovery

Non-structural protein 14 (nsp14) is a bifunctional coronavirus drug target, combining a 3'-to-5' exoribonuclease domain with an N7-methyltransferase domain. Proof-of-concept data have demonstrated beneficial effects in animal models upon inhibition. Using microscale thermophoresis and X-ray crystallography, we screened full-length nsp14 for fragment hits and developed SAR-by-catalogue analogues with five- to eight-fold improved affinity. Several scaffolds showed pronounced overlap between distinct pockets, complicating structure-based optimisation. Analysis of mutational frequencies across over 14 million SARS-CoV-2 genome sequences identified nsp14 residues with markedly high and very low mutation rates, highlighting sites best suited to pan-coronavirus inhibitor design. Combining these data with all 19 publicly known fragment- and ligand-binding regions on nsp14, most of which have never been directly compared, we introduce a systematic site-naming system and rank every site by its potential for future structure-based development. Weighing criteria include proof-of-principle inhibitor data, cross-coronavirus conservation, mutation frequency, the number of fragments bound per site, and susceptibility to crystallographic artefacts from symmetry mates. This ranked, unified binding-site atlas resolves which of the many previously reported nsp14 sites merit prioritisation, providing a practical resource for future coronavirus antiviral drug development.

biochemistry↗

bioRxiv2026

MetExPred: A Comprehensive Prediction Framework with Protein-Context-Aware Multi-view Learning for Drug Metabolism and Excretion

Within the ADMET continuum, metabolism and excretion (ME) form a critical bridge between drug exposure established by absorption and distribution and downstream efficacy and toxicity. However, no existing framework for drug ME prediction has simultaneously achieved broad coverage of endpoints and robust data recency and completeness. Here, we developed MetExPred, a multi-view prediction framework that comprises 17 classification endpoints and two regression endpoints, covering the overall drug ME process. The framework combines sequence-based and graph-based molecular representations, while optionally incorporating ESM-2 protein representations when experimentally annotated targets are available. A protein-aware masking strategy enables the same architecture to operate in both molecular-only and target-enhanced settings, and multi-view attention adaptively integrates the available representations. Across the classification tasks, MetExPred achieved mean AUROC, AUPRC and F1 scores of 0.844, 0.734 and 0.697, respectively. For clearance and half-life prediction, the model achieved RMSE values of 0.686 and 0.668. MetExPred showed the strongest average performance among the evaluated baselines, while ablation studies confirmed the complementary contributions of molecular sequence, graph and protein information. These results provide a unified and flexible modeling framework for systematic ME prediction of drug compounds, enabling early-stage virtual screening and pharmacokinetic assessment during lead optimization.

bioinformatics↗

bioRxiv2026

Solution structure, dynamics and fragment binding of unbound MERS-CoV nsp10

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) poses a significant public health threat, with a fatality rate of 37% and no approved therapeutics. Non-structural protein 10 (nsp10) is an essential cofactor that activates both the nsp14 3'-5' exoribonuclease (ExoN) activity required for RNA proofreading and the nsp16 2'-O-methyltransferase (2'-O-MTase) implicated in viral RNA cap formation. Despite its functional importance, the unbound structure and dynamics of MERS-CoV nsp10 in solution remain uncharacterised. Here we report a near-complete NMR backbone and sidechain assignment and characterise the solution structure and dynamics of the protein by NMR. In contrast to the folded 1 helix observed in crystal structures of coronavirus nsp10, we find that this region is intrinsically disordered in solution, with residues 10-22 undetectable under standard conditions and further evidenced by pH titration, temperature-dependent NMR, and CLEANEX-PM experiments. Analysis of NOE contacts confirmed that the core adopts the conserved coronavirus nsp10 fold, consistent with the AlphaFold-predicted structure. 15N backbone relaxation measurements indicated a rigid, well-ordered core with only localised flexibility, despite a relatively low proportion of secondary structure elements, and CPMG and CEST experiments detected no conformational exchange on the s-ms timescale. Building on this structural and dynamic characterisation, we explored the ligandability of nsp10 by 19F NMR fragment screening. Screening of a 463-compound library identified 23 initial hits (4.97% hit rate), of which 20 were confirmed by 15N SOFAST-HMQC and eight gave quantifiable affinities by MST (Kd 0.5-6.9 mM), the remainder being too weak for reliable determination. Chemical shift perturbations clustered near functional surfaces of the folded core, indicating that MERS-CoV nsp10 is ligandable and providing chemical starting points for antiviral development.

biochemistry↗

bioRxiv2026

DNA double-strand break signaling induces aberrant neuronal activity

Aberrant neuronal activity is an early pathological feature of numerous neurodegenerative disorders, including tauopathy, and is thought to play a role in disease progression. However, the mechanism underlying abnormal neuronal activity remains elusive. Here, we reveal a relationship between DNA double-strand break (DSB)/p53 pathway activation and aberrant neuronal activity. Activating p53 as part of the DNA damage response via DSB induction, or by preventing MDM2-mediated p53 degradation, causes aberrant activity in both mouse and human neurons. p53 activation induces the expression of genes regulating synaptic transmission, and p53-responsive gene upregulation is overrepresented in postmortem human Alzheimers disease neurons burdened with neurofibrillary tangles (NFTs). Using a human iPSC-based cerebral organoid model of frontotemporal dementia that exhibits relevant pathologies including elevated DSBs, aberrant neuronal activity, and NFTs, we show that inhibiting p53 transcriptional activity with a small molecule ameliorates aberrant calcium fluctuations in neurons. Together, our findings highlight p53 inhibition as a novel therapeutic strategy to counter aberrant neuronal activity in neurodegenerative diseases characterized by tauopathy.

neuroscience↗

bioRxiv2026

Microglia-derived extracellular vesicles attenuate acute α-synuclein induced astrocyte inflammation

Aggregates of misfolded -synuclein (Syn) and neuroinflammation are pathological features of Parkinsons disease (PD). These, misfolded conformations of Syn promote cytokine and chemokine signaling in the surrounding microenvironment by triggering activation of glial cells through pattern recognition receptors. Microglia and astrocytes act as innate mediators of the neuroimmune response in the brain by regulating inflammatory signaling via paracrine and autocrine forms of cell communication. Extracellular vesicles (EVs) represent a form of glial cell to cell communication that can regulate the glial neuroimmune responses depending on the phenotype of the donor cell. Research has shown that the contents of EVs can be altered via pharmacologically altering the donor cell which offers a potential avenue for the regulation of inflammation. As such, we analyzed enriched mouse cortical primary astrocytes and characterized their response to Syn exposure in the absence and presence of microglia-derived EVs. Using trans-resveratrol, a naturally occurring polyphenol implicated for its anti-inflammatory properties, as our pharmacological agent to generate an anti-inflammatory microglial-derived EV phenotype we found that EVs derived from resveratrol-treated microglia decreased the production of proinflammatory molecules in enriched astrocytes exposed to Syn. Sequencing of EV miRNAs revealed two miRNAs (miR-5099 and miR-115) with significant up-regulation in resveratrol EVs compared to control EVs. Astrocytes transfected with corresponding miRNA mimics prior to Syn exposure showed a dramatic decrease in inflammatory biomarker production. These findings show that microglia-derived EVs and their specific miRNA cargo can attenuate Syn-directed inflammation in astrocytes and may serve as a novel therapeutic for proteinopathies like PD.

neuroscience↗

bioRxiv2026

A distributed neural architecture of sustained affect across external and internal experience

AO_SCPLOWBSTRACTC_SCPLOWSustained affect shapes well-being, yet its neural architecture across externally elicited and internally generated experience remains unclear. Using whole-brain functional connectivity during minutes-long naturalistic movie viewing, we derived positive and negative affective experience signatures and their underlying neural architecture. These signatures predicted valence-specific affective intensity and generalized to independent movie-viewing data and internally generated affect, discriminating sad memory and rumination from neutral distraction while tracking subjective experience. Importantly, their expression showed little relation to vigilance or cognitive demand. Characterization of these signatures revealed coherent community structure and a shared distributed backbone, alongside valence-preferential components, consistent with a partially separable architecture. Extending beyond experimentally evoked states, in four resting-state depression cohorts, these signatures distinguished patients from controls with reduced positive and elevated negative signature expression, and predicted symptom burden and anhedonia. These findings identify a generalizable distributed architecture bridging external and internal affective experience and extending to clinically relevant affective dysregulation.

neuroscience↗

bioRxiv2026

Proteomic identification and validation of novel neuronal EV-based markers for Alzheimers disease biomarker discovery

Extracellular vesicles (EVs) circulate in biofluids and carry tissue-specific molecular cargo, offering significant potential for the discovery of minimally invasive biomarkers. However, translation in neurodegenerative diseases has been hindered by the lack of validated neuronal EV surface markers that enable selective isolation from plasma. We hypothesized that proteomic profiling of EVs released from human induced pluripotent stem cell (hiPSC)-derived neurons would identify 1. robust Alzheimers disease (AD)-associated signatures that reflect disease pathogenesis, and 2. surface-accessible neuronal markers capable of enriching disease-relevant cargo. Neurons differentiated from AD patients and age-matched cognitively normal (CN) individuals were used to isolate EVs, which were characterized and analyzed by LC-MS proteomics in both total and membrane-enriched fractions. Proteomic profiling identified numerous dysregulated proteins, with a subset validated across independent AD datasets. We identified CNTNAP2 and STX1B as neuronal, brain-enriched EV surface proteins accessible for selective capture and confirmed their presence in EVs from post-mortem human brain, supporting them as bona fide brain-derived EV markers. Immuno-isolation of plasma EVs showed that CNTNAP2-positive EVs had a robust AD-associated increase in phosphorylated tau, identifying CNTNAP2 as a highly discriminative brain-derived EV marker and supporting its potential for blood-based AD diagnostics. Graphical AbstractPrevious studies indicate that extracellular vesicles (EVs) released from neurons carry disease-relevant cargo, yet the search for the optimal neuronal surface markers for the selective isolation of EVs pertinent to Alzheimers disease (AD) from blood is ongoing. To address this need, we performed proteomic profiling of EVs derived from hiPSC-neurons (iNEVs) of AD patients and cognitively normal individuals (CN). LC-MS analysis of whole and membrane-enriched EV fractions revealed robust protein dysregulation and identified CNTNAP2 and STX1B as surface-exposed neuronal EV proteins, confirmed in human brain-derived EVs (BDEVs). Immuno-isolation of plasma EVs demonstrated that CNTNAP2-positive EVs are enriched for phosphorylated tau in AD, whereas the previously used markers; NrCAM and ATP1A3-positive EVs showed limited discrimination. These findings establish a robust framework for proteomic discovery and nominate CNTNAP2 as a promising EV selection marker for blood-based AD diagnostics. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/720870v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@754b45org.highwire.dtl.DTLVardef@a0a566org.highwire.dtl.DTLVardef@cb0134org.highwire.dtl.DTLVardef@1bc0275_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

FOXP-stabilization of the Il2ra super-enhancer structure augments Treg fitness

Gene expression in regulatory T cells (Tregs) is context-dependent and maintains peripheral immune homeostasis. FOXP3 is lineage defining but not sufficient for Treg function or persistence. To define the cell-intrinsic roles of the FOXP3 paralogs FOXP1 and FOXP4, we generated and studied mice with Treg-specific deletion of Foxp1 and/or Foxp4. FOXP1 and FOXP4 are required to maintain the peripheral Treg pool through enhancing Il2ra transcription, thereby promoting sustained high-level expression of IL-2R and thus of the high-affinity IL-2R{beta}{gamma} complex. Integrating RNA-seq and ATAC-seq with previously published ChIA-PET and publicly available data, we propose a model of Il2ra transcriptional regulation in which in which FOXP1 and FOXP4 anchor chromatin looping of the Il2ra locus in mature Tregs, augment super-enhancer activity, and drive sustained CD25 expression. Our results reveal a unique role of FOXP1, and to a lesser extent FOXP4, in controlling Treg homeostasis. One Sentence SummaryFOXP1 and FOXP4 regulate chromatin architecture at the Il2ra locus, promoting sustained CD25 expression and maintaining the peripheral Treg pool.

immunology↗

bioRxiv2026

IR-AMES uncovers structure and composition of Alzheimer' s tau oligomers

The structure and composition of biomolecular assemblies shape their biological functions and disease processes. Yet existing approaches either require homogeneous samples or lack chemical specificity and sensitivity, limiting the elucidation of transient oligomeric species under native conditions. Here we report infrared absorbance-modulated evanescent scattering (IR-AMES) that enables ultrasensitive structural and compositional profiling of individual biomolecular assemblies in aqueous environments. This capability is achieved by photothermally encoding mid-infrared vibrational absorption into scattering contrast using a total-internal-reflection geometry. Applying IR-AMES to recombinant tau assemblies, we resolve random-coil monomers and the emergence of heterogeneous oligomers beyond ensemble-averaged measurements. In Alzheimer's disease brain-derived tau, IR-AMES reveals enrichment of antiparallel {beta}-sheet structures and RNA components in oligomers. Using lipid nanodiscs as membrane mimics, we find that pathological tau oligomers exhibit enhanced interactions with anionic membranes. IR-AMES enables spectroscopic imaging of diverse biomolecular assemblies, opening opportunities to elucidate structure-function relationships in heterogeneous biomolecular systems.

biophysics↗

bioRxiv2026

Protein Phosphatase 2A Orchestrates Mitochondrial Dynamics via MAPK Signaling in heart

Heart as one high ATP consuming organ accounts for 5% of the total oxygen demands. The central question of heart health is how mitochondria fit its needs. Impaired mitochondrial dynamics (fission and fusion) have been observed in failing heart, but whether and how phosphorylation events involved in mitochondrial quality control are still imperceptive. The phosphatase 2A catalytic subunit (PP2A c) cardiac-specific knockout mouse (KO), which exhibited a hypertrophic cardiomyopathy phenotype, was studied. We profiled the pattern of morphological and functional alteration of cardiac mitochondria that appeared during postnatal development. Increased heterogeneity of mitochondria and a decreased ATP yield was displayed. Notably, a fission procedure escalated. To illustrate the protagonist of the mitochondrial dynamics, we applied a high-throughput spectrometry-based phosphoproteomic screening following by GO and KEGG pathway annotations for 788 phosphosites, accounting for 90 proteins. Results suggested that the MAPK signaling may be a predominant factor associated with those mitochondrial alternations in KO hearts. Furthermore, we identified hyperphosphorylated ERK2 accumulated into the nucleus regarding PP2Ac depletion. Consequently, Fis1 expression was accelerated at the transcriptional level which facilitated recruitment of Drp1 onto the outer mitochondrial membrane. The mitochondrial fission towards shifting led to excessed mitophagy and is considered the culprit in early mortality. These findings are indicative of the fundamental role of PP2A in mitochondrial dynamics regulation and cardiomyopathy progression. During the progression of heart failure, the phospho-regulation of ERK2 could be a novel therapeutic approach to prevent or attenuate adverse hypertrophic cardiomyopathy.

cell biology↗

bioRxiv2026

Brain Age in Conduct Disorder: A Mega-Analysis of the ENIGMA Antisocial Behavior Working Group

Conduct disorder (CD) is the leading global cause of mental health burden in children and adolescents and has recently been hypothesized to be a neurodevelopmental disorder. Although prior research has identified neuroanatomical differences associated with CD, it remains unclear whether these differences reflect atypical brain development. Here, we investigated the difference between an individuals brain age and chronological age as a proxy for variations in brain maturation. Using a pretrained model, we estimated brain age from structural neuroimaging data obtained from 1,119 youth with CD and 1,183 typically developing controls across 14 international cohorts participating in the ENIGMA-Antisocial Behavior Working Group. Youth with CD exhibited a statistically robust but small acceleration in brain age compared to typically developing youth (around 0.50 years), which was restricted to the adolescence-onset subtype of the disorder. Our large-scale, coordinated analysis provides the first evidence of accelerated neurodevelopment as a potential mechanism underlying CD.

neuroscience↗

bioRxiv2026

Microbial Antioxidants Reduce ROS In Human Skin Cells Under Oxidative Stress

Reactive oxygen species (ROS) play a dual role in cellular homeostasis, but excessive levels of ROS lead to oxidative stress, accelerating skin aging. Environmental stressors like UV radiation induce ROS overproduction, overwhelming endogenous antioxidant defenses and causing cellular damage. While the skin possesses an intrinsic antioxidant network that provides moderate protection, excessive oxidative stress can trigger inflammatory responses, thereby necessitating exogenous antioxidant intervention. Microbe-derived antioxidants (MA), produced via probiotic fermentation of sea buckthorn and chestnut rose, have shown promise in mitigating ROS-induced damage. In this study, we evaluated two MA formulations, MA1 and MA2, for their ability to scavenge free radicals and alleviate hydrogen peroxide (H2O2)-induced oxidative stress in human dermal fibroblasts (HDF) and dermal papilla cells (HDP). Both formulations displayed dose-dependent DPPH radical scavenging activity and enhanced cell viability at low concentrations. Under H2O2-induced oxidative stress, MA1 and MA2 effectively restored intracellular ROS to baseline levels, demonstrating significant cytoprotective effects. UHPLC-MS/MS profiling identified 12 compounds shared by both formulations, and Gene Ontology Biological Process enrichment analysis revealed that their associated target genes were significantly enriched in antioxidant-related pathways. Five compounds--adenosine, citric acid, 5-hydroxymethylfurfural, myricetin, and phenylalanine--emerged as key contributors to the observed antioxidative effects. Together, these findings highlight the potential of fermented microbial antioxidants to re-establish redox homeostasis in human skin cells and support their further development as therapeutic or cosmetic interventions targeting oxidative stress and skin aging. Given the heightened oxidative sensitivity of aged fibroblasts, MAs ability to alleviate ROS may offer novel therapeutic strategies against skin aging and related pathologies.

molecular biology↗

bioRxiv2025

Uncovering structural determinants of peptide recognition by public and private T-cell receptors

Public T cell receptors (TCRs) recurrently emerge across individuals in response to common pathogens, yet the structural and biophysical basis distinguishing public from private clonotypes remains incompletely defined. Here, we combine epitope mapping, single-cell TCR sequencing, and single-particle cryo-electron microscopy to dissect CD8+ T cell responses to the immunodominant SARS-CoV-2 ORF3a(207-215) epitope presented by HLA-A*01:01. Among responding clonotypes, we identify a shared public TCR (TCRpub) and an individual-specific private TCR (TCRpriv) that use nearly identical TRBV5-1 {beta} chains but distinct chains. Both clonotypes exhibit comparable micromolar affinity and functional avidity, yet their structures reveal different antigen-recognition modes. We determined cryo-EM structures of the TCRpub and TCRpriv in complex with ORF3a(207-215)/ HLA-A*01:01 at [~]3 [A] resolution. Despite targeting the same epitope, the two receptors engaged the peptide-MHC complex with distinct CDR-loop orientations and contact footprints: TCRpub engages the peptide through a peptide-centric AGDL CDR3{beta} motif and focuses interactions on the MHC 2-helix, whereas TCRpriv distributes contacts across both MHC -helices via a canonical CDR3{beta} configuration. These findings illustrate how near-identical {beta} chains can yield divergent recognition strategies to recognise the same pMHC ligand through alternative -chain pairing. More broadly, this work establishes cryo-EM as a robust approach for resolving physiological-affinity TCR/pMHC complexes, providing mechanistic insight into how public TCRs emerge and persist in antiviral immunity.

immunology↗

bioRxiv2025

Ginkgolic acid attenuates e chinococcus granulosus infection-induced hepatic fibrosis by inhibiting Smad4 SUMOylation

BackgroundThe SUMOylation modification is closely linked to the progression of fibrotic diseases, yet its role in hepatic fibrosis associated with cystic echinococcosis (CE) remains unclear. This study aimed to investigate the function of SUMOylation in CE-related hepatic fibrosis and evaluate the anti-fibrotic effects and mechanisms of ginkgolic acid (GA) via regulation of the SUMOylation pathway. MethodologyPeri-lesional (PL) and adjacent normal (AN) liver tissues from CE patients were collected to examine histopathology and SUMO pathway proteins. A CE-infected mouse model was established and treated with GA to assess cyst burden, serum TGF-{beta}1 levels, hepatic fibrosis markers, and SUMO-related proteins. In vitro, macrophages and hepatic stellate cells (HSCs, LX-2 line) were stimulated with Echinococcus granulosus cyst fluid (EgCF) or TGF-{beta}1 to evaluate GAs effects on macrophage polarization (CD206/CD86), HSC activation (-SMA/PCNA), Smad4 SUMOylation, and nuclear translocation. Macrophage-HSC crosstalk was investigated via conditioned medium co-culture assays. ResultFibrosis was exacerbated in peri-lesional liver tissues of CE patients, accompanied by SUMO pathway activation. GA significantly alleviated hepatic fibrosis in CE mice and reversed SUMO pathway dysregulation. Mechanistically, GA inhibited EgCF-induced pro-fibrotic M2 macrophage polarization and blocked Smad4 SUMOylation and nuclear translocation by modulating SUMOylation. Furthermore, GA directly suppressed HSC activation and bidirectionally disrupted the pro-fibrotic crosstalk between macrophages and HSCs under EgCF stimulation, ultimately alleviating fibrosis. ConclusionThis study reveals the critical role of SUMOylation modification in CE-associated hepatic fibrosis and elucidates a novel anti-fibrotic mechanism whereby GA targets the SUMOylation-Smad4 axis to regulate the immune microenvironment. Author summaryThis study demonstrates aberrant activation of the SUMOylation pathway during hepatic fibrosis progression in cystic echinococcosis (CE), characterized by upregulated SUMO1/Ubc9 expression and downregulated SENP1 in peri-cystic liver tissue. Ginkgolic acid (GA) intervention significantly attenuated CE-associated liver fibrosis in mice, evidenced by reduced cyst volume, decreased TGF-{beta}1 levels, and suppressed expression of fibrotic markers (-SMA/COL1A1). GA concurrently reversed dysregulated SUMO pathway protein expression. Mechanistically, GA upregulates the deSUMOylating enzyme SENP1, thereby inhibiting Echinococcus granulosus cyst fluid (EgCF)-induced SUMOylation and nuclear translocation of Smad4. This blockade impedes macrophage polarization toward the pro-fibrotic M2 phenotype (CD206{downarrow}) and suppresses hepatic stellate cell (HSC) activation (-SMA/PCNA{downarrow}). Furthermore, GA disrupts the pro-fibrotic bidirectional crosstalk between HSCs and macrophages. Collectively, these findings indicate that GA ameliorates CE-induced hepatic fibrosis by targeting the SUMO-Smad4 axis to modulate the immune microenvironment, providing a novel therapeutic strategy.

molecular biology↗

bioRxiv2025

DeepADR: Multi-modal Prediction of Adverse Drug Reaction Frequency by Integrating Early-Stage Drug Discovery Information via Kolmogorov-Arnold Networks

Adverse drug reactions (ADRs) are a major cause of clinical trial failure and post-market withdrawal, posing significant risks to public health and impeding drug development. While computational methods offer an alternative to costly preclinical testing, existing models often fail with novel compounds by requiring pre-existing information such as drug-ADR associations or by inadequately integrating diverse data sources. Here, we introduce DeepADR, a multi-modal deep learning framework for predicting both the occurrence and frequency of ADRs using early-stage, readily available data. DeepADR integrates chemical structures and biological target profiles with semantic representations of ADR terms derived from a large language model. These heterogeneous parameters are fused using a Kolmogorov-Arnold Network (KAN), which effectively models complex, non-linear cross-modal interactions to capture underlying toxicological mechanisms. Our model outperforms existing methods in predicting both ADR occurrence and frequency, demonstrating robust generalization to new chemical entities. By effectively integrating chemical, biological, and semantic datasets, DeepADR provides a powerful, scalable tool for the early-stage safety assessment and candidate prioritization. This framework not only facilitates the prioritization of safer drug candidates but also offers a methodology for predicting the toxicity of other hazardous materials, holding significant promise for advancing public health.

bioinformatics↗

bioRxiv2025

Entamoeba histolytica Gal/GalNAc lectin intermediate subunit promotes inflammation and epithelial damage in intestinal amebiasis through its C3 region.

Entamoeba histolytica is a common enteric protozoan that sometimes transitions from a symbiont to a pathogen, causing intestinal amebiasis and extraintestinal abscesses in the host. The early-to-intermediate stages of intestinal amebiasis are characterized by an intense inflammatory response, during which host innate immune defenses play an important role. Here, using the cecal infection model of C3H/HeNCrl mice, we performed single-cell RNA sequencing of cecal tissues and identified the prominent pro-inflammatory function of host macrophages in intestinal amebiasis. On the amoebic cell surface, Igl is an intermediate subunit of galactose- and N-acetyl-D-galactosamine-inhibitable lectins, which contributes to parasite adherence. We proposed that E. histolytica Igl diffuses along with amoebic extracellular vesicles and contacts host macrophages, binding to the TLR4 co-receptor MD2 through its C3 region and initiating the TLR4/MyD88/NF-{kappa}B inflammatory signaling pathway in host cells. Moreover, by inducing macrophage inflammation and cytokine production, E. histolytica indirectly impairs intestinal epithelium integrity through the Igl protein. To our knowledge, this is the first report showing a host single-cell atlas in the field of amebiasis research. In response to the parasite invasion during intestinal amebiasis, our study provides new insights elucidating the inflammatory formation and epithelial damage of gut mucosal immune system, and also conduces to the identification of potential drug targets for these amoebas.

microbiology↗

bioRxiv2025

Membrane curvature regulates Ups1 dependent phosphatidic acid transfer across lipid bilayers

Mitochondria are essential organelles in eukaryotic cells, enclosed by two membranes with distinct compositions and functions. In addition to the endoplasmic reticulum, mitochondria are major sites of cellular lipid production. Cardiolipin, for example, is exclusively synthesized in the mitochondrial inner membrane. This requires the precursor lipid phosphatidic acid to be imported from the endoplasmic reticulum to the mitochondrial outer membrane. Subsequently phosphatidic acid is transferred to the inner membrane by the lipid transfer protein Ups1/PRELID1. The regulation of this process, the role of membrane physico-chemical properties, and the mechanisms by which energy barriers are overcome during lipid extraction and insertion remain poorly understood. Here, we demonstrate that Ups1 exhibits a strong preference for binding to positively curved membrane regions. Our findings reveal that phosphatidic acid extraction is energetically favored at these membrane domains, leading to enhanced lipid transfer between membranes with high positive curvature and we show that events at the donor membrane are rate limiting for the transfer cycle. Our data suggest that Ups1 membrane binding is modulated by pH, lipid composition, and membrane morphology, pointing to a complex, multipartite regulatory network underlying intra-mitochondrial lipid transfer.

biochemistry↗