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Sun, Q.

Publications and source records attributed to Sun, Q..

At least 55 records · Page 3Linked to original sources

Instruction-tuned extraction of virus-host interactions from integrated scientific evidence

MotivationViral infectious diseases continue to pose a major threat to global health. Understanding protein-protein interactions (PPIs) and RNA-protein interactions (RPIs) between viruses and hosts is essential for elucidating infection mechanisms. However, manual curation of these interactions from biomedical literature is inefficient, creating a pressing need for automated and scalable extraction methods. Large language models (LLMs), such as the generative pre-trained transformer (GPT) and bidirectional encoder representations from transformers (BERT), offer promising solutions. Yet, most existing datasets focus on abstracts, overlooking other information-rich sections. We aim to develop a data-efficient approach to extract virus-host interaction (VHI) entities from full-text biomedical articles, including Results, Methods and tables. To our knowledge, this is the first study to apply instruction tuning to full-text VHI extraction ResultsWe curated a dataset containing 3, 395 PPI and 674 RPI entities from the Results, Materials and Methods sections, along with 566 PPIs and 793 RPIs from tables. Under low-resource conditions (<500 training examples), our instruction-tuned ChatMed-VHI model achieves the best overall performance (F1: 89.7%, Precision: 95.3%), outperforming PubMedBERT (F1: 74.6%, Precision: 75.1%). When scaled to the full dataset (>4, 000 training examples), ChatMed-VHI maintained the highest overall performance, while PubMedBERT achieved slightly higher precision (92.3% vs. 91.3%). Notably, ChatMed-VHI improved F1 and recall by 2.79% but precision dropped by 4.20% with more training data, whereas PubMedBERT improved consistently across all metrics. These results demonstrate the effectiveness of instruction-tuned LLMs for full-text biomedical extraction tasks, and position ChatMed-VHI as a scalable, domain-adaptable solution for VHI mining.

bioinformatics↗

Diagnosing linearity along the carbon cascade in terrestrial biosphere models

Elevated carbon dioxide (eCO2) fertilises photosynthesis, driving an increase in terrestrial gross primary production (GPP). However, it is unclear how effectively increased GPP propagates along the "carbon (C) cascade" to increase net primary production (NPP) and vegetation C stocks (Cveg) in different plant compartments. Vegetation models simulate divergent C cycle projections and have been criticised for being overly photosynthesis-driven (source-driven), neglecting processes that lead to non-linear behaviour in response to the GPP increase, which may attenuate (or amplify) changes in NPP and vegetation C stocks. Here, we introduce an analytical framework to diagnose linearity (L) of the land C cycle as the ratio of relative changes in linked fluxes and pools and apply it to outputs from 16 models of the TRENDY v11 ensemble. We found widely varying patterns in L across models and for the different links. Six models showed a clear dominance of larger relative changes in NPP than in GPP in global simulations (LNPP:GPP >1 for >60% of gridcells), indicating increased carbon use efficiency under eCO2. Only three models had LNPP:GPP < 1 for >60% of gridcells. Four models showed a clear dominance of larger relative changes in steady-state Cveg than in NPP, while five models showed an opposite pattern - in both cases with a large spread of LCveg*:NPP across gridcells within models. Three models showed a larger relative increase in root C than in Cveg, while two models showed a clear dominance of the opposite pattern. Widely differing distributions of L across models and links reveal a strong influence of alternative process representations (nonlinear behaviour) in individual models. However, for all links, L deviations from 1 were roughly balanced across the model ensemble, leading to an overall linear behaviour of terrestrial C cycle representations.

ecology↗

An Efficient Lasso Framework for Admixture-Aware Polygenic Scores

Polygenic scores (PGS) have promising clinical applications for risk stratification, disease screening, and personalized medicine. However, most PGS are trained on predominantly European ancestry cohorts and have limited portability to external populations. While cross-population PGS methods have demonstrated greater generalizability than single-ancestry PGS, they fail to properly account for individuals with recent admixture between continental ancestry groups. GAUDI is a recently proposed PGS method which overcomes this gap by leveraging local ancestry to estimate ancestry-specific effects, penalizing but allowing ancestry-differential effects. However, the modified fused LASSO approach used by GAUDI is computationally expensive and does not readily accommodate more than two-way admixture. To address these limitations, we introduce HAUDI, an efficient LASSO framework for admixed PGS construction. HAUDI re-parameterizes the GAUDI model as a standard LASSO problem, allowing for extension to multi-way admixture settings and far superior computational speed than GAUDI. In extensive simulations, HAUDI compares favorably to GAUDI while dramatically reducing computation time. In real data applications, HAUDI uniformly out-performs GAUDI across 18 clinical phenotypes, including total triglycerides (TG), C-reactive protein (CRP), and mean corpuscular hemoglobin concentration (MCHC), and shows substantial benefits over an ancestry-agnostic PGS for white blood cell count (WBC) and chronic kidney disease (CKD).

genomics↗

Construction of an engineered Escherichia coli with enhanced intestinal colonization and anti-inflammatory efficacy in colitis

Engineered probiotics are considered as effective and safe therapeutic strategies for the treatment of various diseases. Escherichia coli Nissle 1917 (EcN) has been widely used as a chassis strain for its safety and well-established genetic manipulation system. The limited intestinal colonization ability of EcN hampers its potential as a chassis for constructing synthetic probiotics in therapeutic applications. Here, an engineered EcN strain with high gastric acid and bile salts tolerance as well as enhanced intestinal adhesion ability was constructed by improving the expression of gastric acid and bile salts tolerance-associated genes and strengthening the expression of curli fiber formation genes, respectively. Meanwhile, oral administration of this engineered strain to colitis mice alleviated the disease severity and restored the disordered gut microbiome by decreasing the abundance of Escherichia-Shigella, whereas increasing norank_f_Muribaculaceae. We engineered EcN to improve its probiotic properties and anti-colitis efficacy, thereby establishing a platform for precision-designed synthetic probiotics.

microbiology↗

A complete and near-perfect rhesus macaque reference genome: lessons from subtelomeric repeats and sequencing bias

A truly complete, telomere-to-telomere (T2T), and error-free reference genome remains a foundational resource--and long-standing goal--for unbiased comparative and functional genomics. While recent T2T assemblies of humans and other primates have made substantial progress, most still contain thousands of base-level errors, particularly within highly repetitive regions. Here, we present T2T-MMU8v2.0, a near-perfect T2T assembly of the rhesus macaque (Macaca mulatta), representing the highest base-level accuracy reported in a primate genome to date. By employing an optimized ONT-only assembly strategy, we identify subtelomeric satellite-rich regions as the principal bottleneck to improving assembly quality, owing to technological biases in long-read platforms and limitations in current hybrid assembly frameworks. We discover 268 previously unannotated repeat families and resolve [~]8 Mbp of SATR satellite arrays, with over 99-fold enrichment in historically misassembled subtelomeric regions. These satellites form four distinct genomic architectures, each with unique SATR satellite composition, segmental duplication organization, and epigenetic signatures, distinct from the subtelomeric architectures observed in hominid genomes. Notably, in contrast to the largely gene-poor subtelomeric regions in African hominids, the SATR architectures in macaques harbor 58 actively transcribed genes, supported by open chromatin and expression data, suggesting gene innovation within these repetitive regions. Functionally, T2T-MMU8v2.0 improves read mappability and accuracy across sequencing platforms, and results in a 19% improvement of transcription start site enrichment scores and 5,821 additional chromatin accessibility peaks on average, thereby enhancing variant detection, regulatory annotation, and transcriptomic resolution in population genetics or single-nucleus studies. Together, this work establishes a new benchmark for genomics, offers a roadmap for resolving complex repetitive regions, and reveals previously unrecognized features of subtelomeric genome structure and evolution.

genomics↗

Early-life Exposure to Arsenic Primes the Offspring to Increased Asthma Risk: Transcriptome and Epigenome Analysis

Inorganic arsenic (iAs) in drinking water is a global health concern. This study tests whether maternal exposure to iAs in drinking water at the WHO provisional level (10{micro}g/L) increases offspring asthma risk via epigenetic reprogramming. F1 mice prenatally exposed to iAs were analyzed at 5 months for blood transcriptome and methylome changes and challenged with house allergens before lung function testing. Prenatal iAs exposure led to increased airway hyperresponsiveness (AHR) and altered inflammation gene expression and DNA methylation changes. Notably, miR-101c was epigenetically reprogrammed early in development, with persistent downregulation in both target (fetal and adult lungs) and surrogate (amniotic fluid and blood) tissues. These changes correlated with increased allergic AHR and TGF{beta} pathway dysregulation. Findings suggest that maternal iAs exposure primes offspring for asthma risk through epigenetic alterations and may inform risk assessment and biomarker development in affected communities. KEY FINDINGSO_LIIn utero exposure to 10 part per billion (or 10 {micro}g/L, the current WHO and EPA provisional level in drinking water) inorganic arsenic (iAs) increases offspring asthma risk. These results raise concerns about the current safety thresholds for iAs in drinking water (Fig. 1). C_LIO_LITranscriptomic and methylome analyses of blood leukocytes from 5-month-old F1 mice revealed that maternal iAs exposure induces transcriptional changes in genes related to allergic airway responses. Pathway analysis highlighted the involvement of miR-101c and its connection with TGF{beta} downstream targets in regulating extracellular matrix signaling, embryonic development, and inflammatory (Figs. 2 and 3). C_LIO_LITranscriptional changes in col3a1 and miR-101c in blood were strongly correlated with allergen-induced airway hyperresponsiveness (AHR), with similar alterations detected in plasma samples. These findings provide new insights into respiratory health in affected communities and support the development of biomarkers for iAs risk assessment (Figs. 4 and 5). C_LIO_LISeveral gene-specific epigenetic alterations induced by early-life iAs exposure were consistently observed in both surrogate (blood) and target (lung) tissues across developmental stages, offering new panels of easily accessible markers for early detection and monitoring of lung disease risk in offspring. The persistence of these markers over time makes them valuable for predictive modeling and life course studies. (Fig. 6). C_LIO_LIDownregulation of miR-101c was validated in fetal lung and amniotic fluid of the iAs-exposed group, suggesting that epigenetic reprogramming of miR-101c is initiated early in gestation (Fig. 7). These findings help uncover causal pathways linking environmental exposures to asthma pathogenesis. C_LIO_LIDistinct sex-specific patterns in blood transcriptome and methylome alterations in respond to early-life iAs exposure underscore the importance of considering sex as a biological variable in omics research. C_LI O_FIG O_LINKSMALLFIG WIDTH=149 HEIGHT=200 SRC="FIGDIR/small/668223v1_fig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1f5394eorg.highwire.dtl.DTLVardef@855bf8org.highwire.dtl.DTLVardef@1592328org.highwire.dtl.DTLVardef@1133ec4_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig. 1.C_FLOATNO Maternal iAs exposure and study design to assess offspring asthma risk. A) Schematic shows the exposure window in which F0 dams received iAs in drinking water from preconception through lactation, followed by collection of F1 progeny for transcriptomic and methylomic analysis. A subset of 5-month-old F1 progenies were assessed for the HDM allergen-induced airway reactivity and airway inflammation. B) Lung resistance was assessed following methacholine (30mg/mL) challenge. C) BAL cells were stained with Diff-Quick, and eosinophil counts are shown. Each datapoint represents a pup from an individual dam; error bars indicate SEM. Five to six dams were used. C_FIG O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/668223v1_fig2.gif" ALT="Figure 2"> View larger version (23K): org.highwire.dtl.DTLVardef@7dc1b1org.highwire.dtl.DTLVardef@378529org.highwire.dtl.DTLVardef@1076fe3org.highwire.dtl.DTLVardef@142d801_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig. 2.C_FLOATNO Blood transcriptome profiles and predicted canonical pathways and regulatory networks. A) Numbers of differentially expressed genes (DEGs) identified in male and female progeny are illustrated with a Venn diagram. Enriched canonical pathways ranked by the p value are shown. B) Using the set of DEGs common in both sexes, Ingenuity Pathway Analysis (IPA) highlights TGF as a central upstream regulator linking overlapping DEGs related to extracellular matrix signaling (orange), inflammation (yellow), and embryonic development/cell metabolism (blue). C_FIG O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/668223v1_fig3.gif" ALT="Figure 3"> View larger version (23K): org.highwire.dtl.DTLVardef@1732b53org.highwire.dtl.DTLVardef@216332org.highwire.dtl.DTLVardef@1f794d1org.highwire.dtl.DTLVardef@14b62df_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig. 3.C_FLOATNO Blood methylome analysis and associations between miR-101c and TGF-related differentially expressed genes. A) Number of differentially methylated CpGs (DMCs) identified in male and female progeny are illustrated with a Venn diagram. There are four DMCs overlapping DMCs annotated to miR-101c. B) Expression levels of miR-101c are shown. C) IPA-derived network linking this miRNA to TGF-related DEGs. Each datapoint represents a pup from an individual dam; error bars indicate SEM. Four to five dams were used. C_FIG O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/668223v1_fig4.gif" ALT="Figure 4"> View larger version (38K): org.highwire.dtl.DTLVardef@482e86org.highwire.dtl.DTLVardef@e666bdorg.highwire.dtl.DTLVardef@631538org.highwire.dtl.DTLVardef@10618f6_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig. 4.C_FLOATNO Relationship between iAs-induced blood transcriptional changes and allergen-induced AHR. This figure presents correlation patterns between baseline blood DEGs expression changes prior to HDM challenge and subsequent changes in AHR. Pearson correlation coefficients are depicted using a color gradient to distinguish positive (blue) and negative (peach) associations. * Positive correlation: r>0.8, p<0.05; ^ negative correlation: r<-0.8, p<0.05 C_FIG O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/668223v1_fig5.gif" ALT="Figure 5"> View larger version (20K): org.highwire.dtl.DTLVardef@150d27eorg.highwire.dtl.DTLVardef@12b4edeorg.highwire.dtl.DTLVardef@4702a8org.highwire.dtl.DTLVardef@1ff9600_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig. 5.C_FLOATNO Circulating miR-101c levels in progeny exposed to maternal iAs. Plasma levels of miR-101c and COL3A1 protein are shown at different developmental stages. A) Relative expression of miR-101c across F1 progeny at juvenile (3 weeks of age) and adult (5 months of age) prenatally exposed to iAs. B) Levels of COL3A1 protein are shown at juvenile and adult F1 progeny. Each datapoint represents a pup from an individual dam, error bars indicate SEM. C_FIG O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/668223v1_fig6.gif" ALT="Figure 6"> View larger version (46K): org.highwire.dtl.DTLVardef@d0ec76org.highwire.dtl.DTLVardef@5468a2org.highwire.dtl.DTLVardef@1a17e85org.highwire.dtl.DTLVardef@17956ce_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig. 6.C_FLOATNO Comparison of transcriptional patterns across tissues and developmental stages. Expression changes (FC: fold changes vs. unexposed) of DEGs and miR-101c are compared between blood and lung tissues in both A) juvenile (3 weeks of age) and B) adult (5 months of age) progeny. Blue and orange bars represent FC in blood from male and female progeny, respectively. Black bars represent FC in lung tissues. Solid bars indicate statistically significant changes. C_FIG O_FIG O_LINKSMALLFIG WIDTH=154 HEIGHT=200 SRC="FIGDIR/small/668223v1_fig7.gif" ALT="Figure 7"> View larger version (22K): org.highwire.dtl.DTLVardef@131ef23org.highwire.dtl.DTLVardef@14b0652org.highwire.dtl.DTLVardef@8c1b30org.highwire.dtl.DTLVardef@4cf6d9_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig. 7.C_FLOATNO Fetal lung and amniotic fluid levels of miR-101c. Relative levels of miR-101c are shown in fetal lung tissues and matched amniotic fluid at embryonic day 16. Data illustrate expression patterns in the context of maternal iAs exposure. Each datapoint represents a pup from an individual dam, error bars indicate SEM. C_FIG GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/668223v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@e25f49org.highwire.dtl.DTLVardef@1dddc22org.highwire.dtl.DTLVardef@9f4244org.highwire.dtl.DTLVardef@1b787e9_HPS_FORMAT_FIGEXP M_FIG C_FIG Description: F1 progeny prenatally exposed to iAs were assessed for blood transcriptomic and DNA methylome analysis at 5 months of age. Correlation analysis between transcriptional changes and allergen-induced airway hyperresponsiveness (AHR) was conducted to examine the epigenetic impact of maternal iAs exposure on offspring asthma risk.

genomics↗

DAXX governs the silencing of LINE1 during spermatogenesis in mice

The suppression of transposable elements in germline is critical for safeguarding fertility. Here we identify that the DAXX, a potent transcription repressor and an H3.3 chaperone, is indispensable for transposable elements silencing during spermatogenesis. Male mice with conditional knockout of Daxx in germ cells mediated by Ddx4-cre display delayed meiotic progression, deformed and reduced production of sperms, and an age-dependent decline in fertility. The ablation of DAXX results in activation of evolutionarily young LINE1 and ERVs subfamilies. Mechanistically, DAXX interacts with DMAP1 to maintain DNA methylation of LINE1 in meiotic cells. In summary, this study identifies DAXX as a previously unknown regulator of spermatogenesis and demonstrates that it functions as an epigenetic regulator to maintain the silencing the young LINE1 by DNA methylation.

developmental biology↗

MuSHIN: A multi-way SMILES-based hypergraph inference network for metabolic model reconstruction

Genome-scale metabolic models (GEMs) are indispensable tools for probing cellular metabolism, enabling predictions of metabolic fluxes, guiding strain optimization, and advancing biomedical research. However, their predictive capacity is often compromised by incomplete reaction networks, stemming from gaps in biochemical knowledge, annotation inaccuracies, and insufficient experimental validations. Here we present MuSHIN (Multi-way SMILES-based Hypergraph Interface Network), a novel deep hypergraph learning method that integrates network topology with biochemical domain knowledge to predict missing reactions in GEMs. Evaluated on 926 high- and intermediate-quality GEMs with artificially removed reactions, MuSHIN significantly outperforms state-of-the-art methods, achieving up to a 17% improvement across multiple metrics and maintaining robust recovery even under severe network sparsity. Furthermore, MuSHIN substantially enhances phenotypic predictions in 24 draft GEMs associated with fermentation by resolving critical metabolic gaps, as validated against experimental measurements. Together, these findings highlight MuSHINs potential to advance GEM reconstruction and accelerate discoveries in systems biology, metabolic engineering, and precision medicine.

bioinformatics↗

DREAM-GNN: Dual-route embedding-aware graph neural networks for drug repositioning

Drug repositioning presents a compelling strategy to accelerate therapeutic development by uncovering new indications for existing compounds. However, current computational methods are often limited in their ability to integrate heterogeneous biomedical data and model the intricate, multi-scale relationships underlying drug-disease associations, while large-scale experimental validation remains prohibitively resource-intensive. Here we present DREAM-GNN (Dual-Route Embedding-Aware Model for Graph Neural Networks), a multi-view deep graph learning framework that incorporates biomedical domain knowledge with two complementary graphs capturing both topological structure and feature similarity to enable accurate and biologically meaningful prediction of drug-disease associations. Extensive experiments on benchmark datasets demonstrate that DREAM-GNN significantly outperforms current state-of-the-art methods in recovering artificially removed repositioning candidates. These results establish DREAM-GNN as a robust and generalizable computational framework with broad potential to streamline drug discovery and advance precision medicine.

bioinformatics↗

Intestinal Epithelial C/EBPβ Deficiency Impairs Colitis-Associated Tumorigenesis by Disrupting CXCL1 /CXCL2/CXCL5-CXCR2-Mediated Neutrophil Infiltration

Dysregulated transcription factors critically link chronic inflammation to oncogenesis in colitis-associated colorectal cancer (CAC), but their mechanistic roles remain incompletely understood. By integrating microarray and transcriptome sequencing data from ulcerative colitis (UC), colitis-associated cancer (CAC), and colorectal cancer (CRC) patients, we identify C/EBP{beta} as a key transcriptional regulator whose elevated expression inversely correlates with survival. In azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CAC models, intestinal epithelial C/EBP{beta} is upregulated during tumor progression, correlating with exacerbated tumor burden and neutrophil infiltration. Mice with intestinal epithelial-specific Cebpb deletion (Cebpb{Delta}IEC) show resistance to carcinogenesis, accompanied by reduced neutrophil infiltration and tumor growth. Mechanistically, C/EBP{beta} transcriptionally activates CXCR2 ligands (CXCL1, CXCL2, and CXCL5) to drive neutrophil recruitment. Pharmacological inhibition of CXCR2 phenocopies the anti-tumor effects of Cebpb{Delta}IEC deletion, further validating this axis as a therapeutic target. Correlation analysis in patient tissues confirms positive relationships between C/EBP{beta}, CXCR2 ligands, and neutrophil infiltration, suggesting that targeting the C/EBP{beta}-CXCL1/2/5-CXCR2 axis may offer a novel strategy for CAC treatment.

cancer biology↗

Fos labels a distinct excitatory neuron ensemble for memory retrieval

Experience-triggered expression of Fos has been extensively used as a marker representing memory engram. It is generally assumed that Fos-positive neurons are preferentially excited by the experience, yet this has not been directly examined. In this study, we tracked neuron activity and Fos expression in somatosensory cortex and dentate gyrus of hippocampus in mice, during electric shock-induced fear memory formation and retrieval. Contrary to the prevailing view, we found that calcium features fail to predict Fos for individual cells. Fos-positive neurons show no specific activation to stimuli during memory encoding, but their activities become stimuli-selective during retrieval. Surprisingly, inhibiting neurons that will express Fos during encoding does not affect the induction of memory-guided behavior upon their activation. Network simulation and voltage imaging further showed that connectivity to interneurons, not stimulus responsiveness, is a major factor determining Fos expression. Our results indicate that Fos labels excitatory neurons specific for memory retrieval.

neuroscience↗

A pan-generic marker panel for apples to enable genetic research and breeding across Malus species

AbstractWild Malus species harbor untapped genetic diversity to advance apple breeding, particularly for disease resistance and stress tolerance. However, existing marker panels, developed mainly using Malus domestica accessions, introduce ascertainment bias and limit detecting rare variants in wild species. We developed and validated a medium-density and cost-effective pan-generic 3K apple DArTag panel optimized to capture genome-wide variation across the Malus genus. The panel was constructed using conserved, syntenic, and collinear genomic blocks identified within the core genome of 13 Malus accessions for cross-species transferability. The panel was validated across three bi-parental mapping populations totaling 593 progeny. Across these populations, 2,461-3,234 SNP markers were polymorphic and 1,482-2,620 were informative. Each population contained over 900 multiallelic micro-haplotype loci, with several hundred loci exhibiting three or four distinct haplotypes. Markers were uniformly distributed across all 17 chromosomes, each containing between 60- 230 informative SNPs. The panel was further evaluated on 174 diverse germplasm accessions from 20 Malus species. It exhibited strong cross-species transferability, exceptionally low rates of missing data (<0.5%), and clear genetic differentiation between wild and domesticated accessions. Genome-wide association studies (GWAS) identified a major locus on chromosome 4 significantly linked to fruit length, weight, and width in addition to trait-specific associations on chromosomes 1, 6, 9, and 11. The cost-effectiveness of genotyping per sample (<$15), combined with these results, underscore the panels broad utility for quantitative trait locus (QTL) mapping in bi- parental and diverse populations, marker-assisted selection in the breeding programs, and genetic diversity analysis across the Malus genus.

genetics↗

The XPF-like domain in SHOC1 required for homologous recombination and safeguarding autosome from meiotic silencing of unsynapsed chromatin

During meiosis, a group of evolutionarily conserved ZMM proteins plays essential roles in stabilizing the recombination intermediates and promoting crossover (CO) formation. In mice, SHOC1 forms a trimeric complex with the other two ZMM proteins, SPO16 and TEX11, to bind recombination intermediates after strand invasion. Although genetic variants of SHOC1 are clinically associated with meiotic arrest and male infertility, their precise molecular mechanisms and evolutionarily conserved functions in human gametogenesis remain enigmatic. Here, we delineated species-specific divergences between human and mouse SHOC1 complex, and identified a missense variant within the XPF-like domain in SHOC1 (c.A1769G:p.Q590R) that was associated with meiotic arrest and non-obstructive azoospermia (NOA). The disorder of the XPF-like domain in SHOC1 impaired DNA double-strand breaks repair by compromising its ability to bind branched DNA structures and the recruitment of M1AP, REDIC1, and ZMM factors to recombination intermediates, ultimately abolishing CO formation. Furthermore, the variant disrupted dynamic 3D chromatin structure in pachytene spermatocytes and induced defects in homologous chromosome synapsis. More importantly, the XPF-like domain in SHOC1 was revealed to prevent autosome intrusion into the sex body compartment, thereby safeguarding critical autosomal loci from meiotic silencing of unsynapsed chromatin (MSUC). Overall, our study demonstrated that the XPF-like domain in SHOC1 is required for homologous recombination and safeguarding autosome from MSUC in meiosis.

developmental biology↗

PEARL: Integrative multi-omics classification and omics feature discovery via deep graph learning

Integrating multi-omics data provides valuable insights into biological processes by capturing information across multiple molecular layers, enabling a comprehensive understanding of complex diseases and driving advancements in precision medicine. However, existing computational methods for multi-omics integration face significant challenges, such as low reliability and poor generalizability, due to the high dimensionality and low sample size nature of omics data. To address these challenges, we present PEARL (Pearson-Enhanced spectrAl gRaph convoLutional networks), a novel deep graph learning method for biomedical classification and functional important omics features identification. PEARL leverages a simple yet effective learning architecture to achieve superior and robust performance in high-dimensional, low-sample-size multi-omics settings. Our results demonstrate that PEARL significantly outperforms existing state-of-the-art methods on both synthetic and real biomedical datasets. Furthermore, applied to Alzheimers disease (AD) brain multi-omics data, features prioritized by PEARL lead to functionally important genes that demonstrate significant enrichment in AD-related pathways. These findings highlight PEARLs practical utility in biomedical research and its potential to enhance biological interpretability in multi-omics studies.

bioinformatics↗

De Novo Hydration of Cryo-EM Reconstructions through Molecular Dynamics Simulations of the Excess Chemical Potential

Predicting the precise positions of water molecules at the protein interface remains a formidable challenge, fueling active research in this field. Here, we present a novel approach based on molecular dynamics simulations that utilizes statistical thermodynamic signatures of water at protein interfaces to improve the accuracy of water placement in cryo-EM maps, with apoferritin as a model benchmark system. The interaction energy of solvent with the protein is insufficient to distinguish between high- and lower-consensus water positions, consistent with reports of earlier work. Instead, we employ a detailed statistical thermodynamic analysis based on the excess chemical potential (WT) - a measure of the thermodynamic balance between the interaction energy of an interfacial water molecule with the protein and its free energy of interaction with all of the other solvent molecules. WT is proportional to the log ratio of the local density of water molecules at the protein interface to the bulk density. 85% of the top 100 water locations with the most favorable excess chemical potential values are observed in one or more high resolution Cryo-EM maps deposited in the PDB, and 70% of the top 200 water locations indexed by excess chemical potential are observed in the cryo-EM maps. This work paves the way for the development of a cryo-EM refinement tool that integrates molecular dynamics simulations with cryo-EM data for high-resolution modeling of water networks.

biochemistry↗

Evolutionary Sequence and Structural Basis for the Epistatic Origins of Drug Resistance in HIV

The emergence of drug resistance in the human immunodeficiency virus (HIV) remains a formidable challenge to the long-term efficacy of antiretroviral therapy (ART). A growing body of evidence highlights the critical role of epistasis, the dependence of mutational effects on the sequence context, in shaping the fitness landscape of HIV under ART-induced selection pressure. However, the biophysical origins of the epistatic interactions involved in engendering drug-resistance mutations (DRMs) remain unclear. Are the mutational correlations "intrinsic" to the properties of the protein, or do they arise because of drug binding? We use a Potts sequence-covariation statistical energy model built on patient-derived HIV-1 protein sequences to construct computational double mutant cycles that probe pairwise epistasis for all observed mutations across the three major HIV drug-target enzymes. We find that the strongest epistatic effects occur between mutations at residue positions that frequently mutate during the course of ART, termed resistance-associated positions. To investigate the structural origins of the strongest epistatic interactions, we perform [~]100 free energy perturbation molecular dynamics simulations, revealing that the primary contribution to the pairwise epistasis between DRMs arises from cooperative effects on protein stability and folding as an intrinsic consequence of the protein mutational landscape. The results collectively reinforce a mechanism of resistance evolution whereby viruses escape drug pressure by selectively engendering mutations at "intrinsically" coupled sites, allowing them to cooperatively ameliorate fitness detriments incurred by individual DRMs. SignificanceEpistasis refers to the phenomenon where the effect of a mutation on protein structure and function is dependent on the genetic sequence background of the mutation, resulting in the combined effect of mutations being non-additive. Epistasis plays a significant role in the evolution of drug resistance in viruses such as HIV under therapeutic selection pressure. We combine a protein sequence coevolutionary model and molecular dynamics free energy simulations to identify and probe the mechanistic origins of the strongest epistatic interactions connecting HIV drug-resistance mutations. The work establishes a foundation to probe the molecular bases of epistasis and predict the evolution of resistance predicated on the knowledge of epistatic interaction networks.

biophysics↗

A pan-positive allosteric modulator that mediates sustainable GPCR activation

Approximately 1/3 of all clinical drugs exert their therapeutic effects by modulating the activity of G protein-coupled receptors (GPCRs). Thus, there is a constant interest in finding novel ways to modulate GPCR activity. In this work, through a newly established Survival Pressure Selection (SPS) method for high-throughput screening of GPCR agonists, we discover that atazanavir functions as an agonist for GPR119. Further studies suggest that atazanavir is capable of activating a number of Family A GPCRs, including the {beta}1 adrenergic receptor ({beta}1AR), the {beta}2 adrenergic receptor ({beta}2AR) and the opoioid receptor (OR). Cryo-EM structures reveal that atazanavir binds to an allosteric pocket near TM6/7 in both GPR119 and the {beta}1AR. Pharmacological studies suggest that atazanavir mediates non-canonical signaling of Family A GPCRs. During this process, G protein and {beta}-arrestin are spatially close, but {beta}-arrestin forms a complex with the receptor and G protein instead of desensitizing G protein signaling, thus resulting in sustained G protein signaling. The work expands the signal transduction modes and pharmacological properties of allosteric modulators for GPCRs and provides a general starting point for developing therapeutics targeting this allosteric site.

biochemistry↗

A GPCR-G protein-β-arrestin megacomplex induced by an allosteric modulator

GPCRs signal through both G protein pathways and {beta}-arrestin pathways. Previous work suggests that {beta}-arrestins bind to GPCRs through different modes, including core engagement and tail engagement. Core engagement competes with G proteins and terminates G protein signaling, while tail engagement can coexist with G proteins, mediating sustained intracellular activation of the receptor - a process dependent on the high affinity between {beta}-arrestin and the phosphorylated C-terminus of the receptor. In this study, we determined the structure of a GPCR - G protein - {beta}-arrestin-1 complex stabilized by an allosteric modulator. The compound, atazanavir, acts like molecular glue to anchor {beta}-arrestin-1 to the receptors TM6 and TM7 regions. This pendulum binding mode is structurally compatible with simultaneous G protein binding. We further demonstrate that the atazanavir-mediated {beta}-arrestin recruitment does not require the receptors C-terminal region. This work illustrates a novel paradigm of GPCR-G protein-{beta}-arrestin1 megacomplex assembly and opens up new avenues for modulating GPCR function.

biochemistry↗