Biology subjects

Jing, X.

Publications and source records attributed to Jing, X..

At least 19 recordsLinked to original sources

bioRxiv2026

Mosaic foreleg convergence disentangles phylogeny from ecology in Cretaceous amber crickets

Mosaic evolution assembles organisms from ancestral and derived parts, and traits shaped by convergent selection can mislead phylogenetic reconstruction while recording ecology. Disentangling these two signals within the same anatomy is a challenge for placing fossils and reconstructing evolution in deep time. We present a character-partitioning framework that fixes a molecular backbone of living species, projects fossils onto it with partitioned morphological matrices, and quantifies each anatomical module's contribution to phylogenetic placement and ecological prediction. In mid-Cretaceous Myanmar amber crickets, which combine a cricket-like body with mole-cricket-like digging forelegs, the foreleg module drove most phylogenetic distortion and carried most ecological information: removing it restored a convergent living control species to its family and collapsed habitat-prediction accuracy from 77.8% to below the 44.4% baseline. Partitioning convergent modules thus separates phylogenetic signal from ecological information, turning mosaicism from a confound of fossil interpretation into a quantitative record of history and niche.

evolutionary biology↗

bioRxiv2026

A missense mutation in FBXL3 links circadian regulation to out-of-season estrus in sheep

Seasonal breeding is a remarkable adaptive trait, but it constrains efficient production in the sheep industry. Recent studies have shown that seasonal breeding is associated with endogenous circannual rhythms, which are regulated in part by the circadian clock system. FBXL3, a pivotal component of the SCF (SKP1 - CUL1 - F-box) E3 ubiquitin ligase complex, is a known determinant of the mammalian circadian period. In this study, we identified a missense mutation, T183M, in FBXL3 through selective sweep analysis. The allele frequency of this mutation differed significantly between sheep breeds exhibiting year-round estrus and those showing seasonal breeding patterns. The association between the T183M mutation and seasonal breeding was further validated using an ovariectomized, estradiol-implanted sheep model. We then generated mice carrying the homologous T183M mutation and found that they exhibited significantly lengthened circadian periods, accompanied by reduced CRY1 expression and increased CLOCK expression. Co-immunoprecipitation assays confirmed that the mutation reduced the interaction between FBXL3 and CRY1. These findings demonstrate an evolutionarily conserved role of FBXL3 in the circadian clock system. We propose that the T183M mutation disrupts day-length recognition, thereby influencing seasonal estrus in sheep. Author summarySeasonal breeding limits sheep productivity and is regulated by circadian rhythms, yet the key genetic determinants remain poorly understood. Here, we identified an FBXL3 T183M missense mutation whose allele frequency differed markedly between year-round-estrous and seasonally breeding sheep, and validated its association with seasonal reproduction in a sheep population. Functional analyses in mutant mice showed that this variant lengthened the circadian period, disrupted the expression of core clock genes, and weakened the interaction between FBXL3 and CRY1. These findings suggest that the FBXL3 T183M variant impairs day-length perception, thereby modulating seasonal estrus in sheep. Our study reveals a conserved circadian mechanism underlying seasonal breeding and highlights FBXL3 T183M as a promising genetic target for improving reproductive performance in sheep.

genetics↗

bioRxiv2026

M6A-modified circEZH2 Protects Endothelial Cells from Senescence and Suppresses Atherosclerosis by Stabilizing ZNF326

BACKGROUNDEndothelial cell senescence induces endothelial dysfunction, thereby contributing to atherosclerosis progression. Circular RNAs (circRNAs) play diverse roles in multiple physiological and pathological processes. N6-methyladenosine (m6A) is the most abundant internal RNA modification in eukaryotic RNAs and dynamically regulates RNA fate and function. However, the functions and therapeutic potential of m6A-modified circRNAs in endothelial cell senescence remain unknown. METHODSm6A-modified circRNAs associated with endothelial cell senescence were screened by circRNA expression and m6A-circRNA microarray profiling of endothelial cells and mouse aortic intima. circEZH2 expression was validated in endothelial cells, vascular tissues, and human atherosclerotic plaques by RT-qPCR, and RNA fluorescence in situ hybridization. The role of circEZH2 in endothelial senescence and atherosclerosis was assessed in vitro and in vivo. RNA pull-down, mass spectrometry, RNA immunoprecipitation, co-immunoprecipitation, ubiquitination assays, and rescue experiments were used to define the underlying mechanism. RESULTSWe identified A novel m6A-modified circRNA, circEZH2, that was downregulated in the aged aortic intima and advanced plaques. CircEZH2 was stabilized by m6A reader IGF2BP2. Endothelial cell-specific overexpression of circEZH2 delayed senescence and suppressed atherosclerosis progression. At the cellular level, circEZH2 overexpression delayed senescence, decreased p53/p21 levels and increased angiogenic activity of endothelial cells, while circEZH2 knockdown exhibited the opposite effect. Mechanistically, circEZH2 functions as a scaffold to promote USP37-mediated deubiquitination, thereby stabilizing ZNF326. Moreover, endothelial cell-specific knockdown of ZNF326 counteracts the anti-senescent and anti-atherosclerotic effects mediated by circEZH2 overexpression. CONCLUSIONSIn summary, the present study identifies circEZH2 as a novel suppressor of endothelial cell senescence, highlighting its potential as a therapeutic target for age-related atherosclerosis. GRAPHIC ABSTRACTA graphic abstract is available for this article. O_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC="FIGDIR/small/730538v1_ufig1.gif" ALT="Figure 1"> View larger version (78K): org.highwire.dtl.DTLVardef@d3a586org.highwire.dtl.DTLVardef@1180c1forg.highwire.dtl.DTLVardef@1c3d832org.highwire.dtl.DTLVardef@a6d424_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic abstract.C_FLOATNO Schematic model of m6A-modified circEZH2 regulation in endothelial cell senescence and atherosclerosis. In young endothelial cells, IGF2BP2 is highly expressed and recognizes m6A-modified circEZH2, thereby maintaining its RNA stability. CircEZH2 stabilizes ZNF326 protein through USP37-mediated deubiquitination, which leads to suppression of p21 and p53, delays endothelial cell senescence, ameliorates endothelial dysfunction, and ultimately suppresses the progression of atherosclerosis. C_FIG What Are the Clinical Implications?This study identifies circEZH2 as a novel m6A-modified circular RNA that is reduced in the aged aortic intima and in endothelial cells within advanced atherosclerotic plaques. Endothelial circEZH2 overexpression delays endothelial cell senescence, preserves endothelial function, and suppresses atherosclerotic lesion formation, supporting an important role for circEZH2 in vascular aging-associated atherosclerosis. Mechanistically, circEZH2 acts as a scaffold to enhance USP37-mediated deubiquitination and stabilization of ZNF326, while endothelial ZNF326 knockdown counteracts the anti-senescent and anti-atherosclerotic effects of circEZH2. These findings reveal the circEZH2-ZNF326 axis as a previously unrecognized mechanism regulating endothelial senescence and atherosclerosis progression. Our work supports the potential of circEZH2-based gene therapy as a novel therapeutic approach for atherosclerosis.

cell biology↗

bioRxiv2026

Genome-wide maps of transcription factor footprints identify noncoding variants rewiring gene regulatory networks with varTFBridge

Genome-wide association studies have identified millions of noncoding loci linked to human traits, yet how these variants alter gene regulation remains a major challenge, particularly for rare variants where whole-genome sequencing cohorts and high-resolution functional annotations remain limited. Here we show that single-molecule deaminase footprinting (FOODIE) in K562 cells captures up to 103-fold heritability enrichment for erythroid traits despite covering 0.12% of the genome. We introduce varTFBridge, integrating FOODIE footprinting with AlphaGenome variant effect prediction to identify causal noncoding variants altering transcription factor (TF)-mediated regulation. Applied to 490,640 UK Biobank genomes across 13 erythrocyte traits, varTFBridge prioritises 113 high-confidence regulatory variants (104 common, 9 rare), encompassing 2,173 linkages along the variant-TF binding- gene-trait cascade across 64 TFs and 108 genes. varTFBridge recapitulates rs112233623 and resolves its mechanism: GATA1/TAL1 co-binding disruption at a CCND3 enhancer altering red blood cell count and volume.

bioinformatics↗

bioRxiv2025

Peptide molecular glues select between BET paralogues by exploiting allosteric sites and conformational dynamics

Achieving selective target inhibition is critical for minimising drug side effects. This can be especially challenging when targeting individual members of protein families with high sequence similarity. A well-recognised example is the Bromodomain and Extraterminal domain (BET) family of proteins. Chemical inhibition of the acetyllysine (AcK)-binding bromodomains (BDs) of BET proteins has shown considerable promise in a range of disease models. However, despite over a decade of medicinal chemistry efforts, it has proven challenging to develop BET BD inhibitors that exhibit high selectivity between BET family paralogues. Cyclic peptides are versatile scaffolds for therapeutic development and often exhibit high selectivity and affinity for their targets. To explore their potential as selective BET BD inhibitors, we have used mRNA display to identify cyclic peptide ligands for the N-terminal BD of BRD2 and BRD4. The structurally diverse cyclic peptides enriched from the selections boast superior selectivity and affinity to previously developed inhibitors. Most strikingly, we isolated cyclic peptides with [~]1000-fold higher affinity for their target BD over the paralogous BDs, far surpassing selectivities reported to date. Our biochemical and structural data suggest that paralogue-selective cyclic peptides act as molecular glues, exploiting both subtle sequence differences at locations far from the AcK-binding pocket and differences in conformational dynamics between BET BD paralogues to achieve this unprecedented level of specificity. This work provides a blueprint for the development of new classes of selective BET inhibitors and, more generally, underscores the potential of exploiting protein dynamics in the design of selective ligands.

biochemistry↗

bioRxiv2025

Aird-MSI: a high compression rate and decompression speed format for mass spectrometry imaging data

Mass spectrometry imaging has emerged as a pivotal tool in spatial metabolomics, yet its reliance on the imzML format poses critical challenges in data storage, transmission, and computational efficiency. While imzML ensures cross-platform compatibility, its lower compressed binary architecture results in large file sizes and high parsing overhead, hindering cloud-based analysis and real-time visualization. This study introduces an enhanced Aird compression format optimized for spatial metabolomics through two innovations: (1) a dynamic combinatorial compression algorithm for integer-based encoding of m/z and intensity data; (2) a coordinate-separation storage strategy for rapid spatial indexing. Experimental validation on 47 public datasets demonstrated significant performance gains. Compared to imzML, Aird achieved a 70% reduction in storage footprint (mean compression ratio: 30.03%) while maintaining near-lossless data precision (F1-score = 99.26% at 0.1 ppm m/z tolerance). For high-precision-controlled datasets, Aird accelerated loading speeds by 15-fold in MZmine. The Aird format overcomes crucial bottlenecks in spatial metabolomics by harmonizing storage efficiency, computational speed, and analytical precision, reducing I/O latency for large cohorts. By achieving near-native feature detection accuracy, Aird establishes a robust infrastructure for translational applications, including disease biomarker discovery and pharmacokinetic imaging.

bioinformatics↗

bioRxiv2025

Clonal Heterogeneity in Human Pancreatic Ductal Adenocarcinoma and Its Impact on Tumor Progression

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by profound desmoplasia and cellular heterogeneity, which cannot be fully resolved using traditional bulk sequencing approaches. To understand the contribution of this heterogeneity to PDAC biology, we analyzed a large cohort of primary human PDAC samples (n = 62), profiling 443,451 single cells and 53,236 spatial transcriptomic spots using a combined single-cell RNA sequencing and spatial transcriptomics approach. Our analysis revealed significant intratumoral heterogeneity, with multiple genetically distinct neoplastic clones co-existing within individual tumors. These clones exhibited diverse transcriptional states and subtype profiles, challenging the traditional binary classification of PDAC into basal and classical subtypes; instead, our findings support a transcriptional continuum influenced by clonal evolution and spatial organization. Additionally, these clones each interacted uniquely with surrounding cell types in the tumor microenvironment. Phylogenetic analysis uncovered a rare but consistent classical-to-basal clonal transition associated with MYC amplification and immune response depletion, which were validated experimentally, suggesting a mechanism driving the emergence of a more aggressive basal clonal phenotype. Spatial analyses further revealed dispersed clones enriched for epithelial-to-mesenchymal transition (EMT) activity and immune suppression, correlating with metastatic potential and colonization of lymph node niches. These dispersed clones tended to transition toward a basal phenotype, contributing to disease progression. Our findings highlight the critical role of clonal diversity, transcriptional plasticity, and TME interactions in shaping human PDAC biology. This work provides new insights into the molecular and spatial heterogeneity of PDAC and offers potential avenues for therapeutic intervention targeting clonal evolution and the mechanisms driving metastasis.

cancer biology↗

bioRxiv2024

Identification and analysis of DEGs of mouse tumor cells by integrated bioinformatics methods

Mutations and genome instability are hallmarks of cancer. The advanced Next Generation Sequencing(NGS) technology now enables rapid and cost-effective analysis for tumoral and normal genomic translational research. In this research, mRNA sequencing was applied to get the whole transcriptome data of mouse B16F10 melanoma and CT26 colon carcinoma cells. Up regulation genes and down regulation genes were identified in tumor cells with differentially expressed genes(DEGs) analysis. The DEGs were analyzed with GO, KEGG and Reactome pathway enrichment study. Results demonstrated the DEGs and enriched pathways were mainly associated with cell proliferation and biosynthetic processing. Further, gene fusion and alternative splicing analysis reveled fusion genes and skipped exons were extensive exist within the chromosomes of tumor cells. Together, the integrated DEGs and bioinformatics analysis in this article may shed light on further research of cancer treating targets and molecular mechanisms of carcinogenesis.

bioinformatics↗

bioRxiv2024

Development of a novel peripherally acting alpha2A-adrenergic receptor antagonist for anti-diabetic

Yohimbine, a potent alpha2A-adrenergic receptor (2AAR) antagonist, was found therapeutic potential for type 2 diabetes through improving insulin release. However, the adverse side effects mediated by its actions in the brain hampered its use. Here, based on molecular docking analysis and structural modification, we have developed a novel peripherally acting yohimbine derivative (CDS479-2). CryoEM data found that yohimbine and CDS479-2 have similar interactions with the structure of 2AAR. Importantly, CDS479-2 shows similar 2AAR antagonist activity as yohimbine, but with very limited access to the brain, and thus avoiding the unwanted central effects such as hypertension and anxiety. Acute administration of CDS479-2 by injection or gavage lowered blood glucose levels and improved glucose tolerance in the high-fat diet-induced obesity (DIO) mice, an animal model for human type 2 diabetes. Remarkably, DIO mice received 2 weeks of daily administration of CDS479-2, but not yohimbine, exhibited sustained normoglycaemia, and increased density of the insulin-producing beta cells, in which important proliferation genes were found upregulated. Moreover, the overall protein expression levels of their pancreas were more similar to that of the healthy chow-fed mice. Thus, CDS479-2 may indicate a new direction for type 2 diabetes treatment. Importantly, the strategy we employed in this study will inspire the optimization for drugs that with both peripheral and central targets. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/628818v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1d3d7corg.highwire.dtl.DTLVardef@1afbad3org.highwire.dtl.DTLVardef@12a1aborg.highwire.dtl.DTLVardef@1341a02_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

D-glucuronyl C5-epimerase binds to EGFR to suppress kidney fibrosis

Renal tubular cells may actively participate in fibrosis processes leading to end-stage renal failure. However, which molecule play pivotal role in the fibrogenesis is still vague. Glucuronyl C5-epimerase (Hsepi, gene name, Glce) is a key enzyme that catalyzes biosynthesis of Heparan sulfate (HS) chains attached to HS proteoglycan which are ubiquitously located on cell membrane. Homozygous Glce-/- mice may cause embryonic lethality and multi-organ defects. However, whether Glce plays a key role in kidney fibrosis is unknown. Here, we show that Glce expression is significant attenuated in kidneys of patients with renal fibrosis and the animal models. Further study shows that renal tubular-specific Glce deletion in mice exacerbate kidney fibrosis while AAV-mediated overexpressing of Glce in UUO-treated mice may ameliorate kidney fibrosis associated with epithelial-mesenchymal transition (EMT) progress via the TGF-{beta}/Smad2/3 signaling pathway. Mechanism study demonstrates that Glce protein may bind to EGFR to inactivate EGFR/ERK signaling and further impede TGF-{beta}/Smad-driven EMT and renal fibrosis in Glce-/- and the wild type mice. Interestingly, the anti-fibrosis function is independent of Glce enzymatic activation. These data uncover a novel function for Glce which plays a key role in kidney tissues against fibrosis.

pathology↗

bioRxiv2024

Mechano-adaptation: Exercise-driven Piezo1 & Piezo2 augmentation and chondroprotection in articular cartilage

Chondrocytes in adult joints are mechanosensitive post-mitotic quiescent cells with robustly expressed both Piezo1 and Piezo2 ion channels. Here, we examined the mechano-adaptation and Piezo modulations in articular chondrocytes using a mouse exercise model. We first found differential expression patterns of PIEZO1 and PIEZO2 in articular chondrocytes of healthy knee joints; chondrocytes in tibial cartilage (T) exhibit significantly higher PIEZO1 and PIEZO2 than femoral chondrocytes (F). Interestingly, a few weeks of exercise caused both PIEZO1 and PIEZO2 augmentation in F and T compared to the sedentary control group. Despite the increased expression levels of these mechanosensors, chondrocytes in exercised cartilage exhibit significantly reduced mechanical susceptibility against 1mJ impact. PIEZO1 modulation was relatively more rapid than PIEZO2 channels post-exercise. We tested the exercise-induced effect using Piezo1-conditional knockout (Pz1-cKO; Agc1CreERT2;Piezo1fl/fl). Pz1-cKO mice exhibit diminished exercise-driven chondroprotection against 1mJ impact, suggesting essential roles of Piezo1-mediated mechanotransduction for physiologic-induced cartilage matrix homeostasis. In addition, using a mouse OA model, we further found the modulated PIEZO1 in chondrocytes, consistent with reports in Ren et al., but without PIEZO2 modulations over OA progression. In summary, our data reveal the distinctly tuned Piezo1 and Piezo2 channels in chondrocytes post-exercise and post-injury, in turn modulating the mechanical susceptibility of chondrocytes. We postulate that Piezo1 is a tightly-regulated biphasic biomarker; Piezo1 antagonism may increase cellular survival post-injury and Piezo1 (with Piezo2) agonism to promote cartilage ECM restoration.

bioengineering↗

bioRxiv2023

Comparison of chronic aerosol inhalation with combustible cigarette and e-cigarette on the psychiatric behaviors and neuroimmune profile in mice

With the worldwide use of electronic cigarettes (e-cigarettes) as a substitution for tobacco, the effects of e-cigarette vapor exposure on human health have been investigated. However, the comparison of long-term effects of aerosol inhalation with combustible cigarette and e-cigarette on the psychiatric behaviors has not been fully revealed. The present study examines the distinct effects of combustible cigarette and e-cigarette on anxiety, depression, cognition, and social behaviors. Here we found that the combustible cigarette induced the higher level of anxiety after long-term inhalation compared to the e-cigarettes with or without the tobacco flavor. Since the mechanism of action on the psychiatric behaviors entails the alterations on the neuroimmune-sensors and principal regulators such as glial cells, we further profiled the alterations of microglia and astrocytes by chronic inhalation of combustible tobacco cigarette, specifically the negative correlations between the IBA-1 level in the locus coeruleus (LC) and the latency to nest in VLT; as well as the GFAP level in LC and the open arm time in EPM were observed. Our current data provided an insight into the less impact of e-cigarettes on the anxiety-like behaviors and neuroimmune activation compared to combustible tobacco cigarettes which is not related to the flavor in e-cigarette, and the modulation on the neuroimmune signals in LC could be a therapeutic target for smoking-related anxiety.

animal behavior and cognition↗

bioRxiv2023

Phylogeny-metabolism dual-directed single-cell genomics for dissecting and mining ecosystem function

Although microbiome-wide association studies (MWAS) have uncovered many marker organisms for an ecosystem trait, mechanisms of most microbiota-mediated processes remain elusive, due to challenges in validating the markers in situ metabolic activities and tracing such activities to individual genomes. Here we introduced a phylogeny-metabolism dual-directed single-cell genomics approach called Fluorescence-In-Situ-Hybridization-guided Single-Cell Raman-activated Sorting and Sequencing (FISH-scRACS-Seq). It directly localizes individual cells from target taxon via a FISH probe for marker organism, profiles their in situ metabolic functions via single-cell Raman spectra, sorts cells of target taxonomy and target metabolism, and produces indexed, high-coverage and precisely-one-cell genomes. From cyclohexane-contaminated seawater, cells representing the MWAS-derived marker taxon of {gamma}-Proteobacteria and that are actively degrading cyclohexane in situ were directly identified via FISH and Raman respectively, then sorted and sequenced for one-cell full genomes. In such a Pseudoalteromonas fuliginea cell, we discovered a three-component cytochrome P450 system that can convert cyclohexane to cyclohexanol in vitro, representing a previously unknown group of cyclohexane-degrading enzymes and organisms. By culture-independently unveiling enzymes, pathways, genomes and their in situ functions specifically for those single-cells with ecological relevance, FISH-scRACS-Seq is a rational and generally applicable approach for dissecting and mining microbiota functions. TeaserFISH-scRACS-Seq is a new strategy to dissect microbiota functional mechanism at single-cell resolution.

microbiology↗

bioRxiv2023

CircRNAs and their regulatory networks associated with the antioxidant enzymes and immune responses of Asian honey bee larvae to fungal infection

Non-coding RNA (ncRNA) plays an important role in the regulation of immune responses, growth, and development in plants and animals. Here, the identification, characteristic investigation, and molecular verification of circRNAs in Apis cerana cerana larval guts were conducted, and the expression pattern of larval circRNAs during Ascosphaera apis infection was analyzed. This was followed by exploration of the potential regulatory part of differentially expressed circRNAs (DEcircRNAs) in host immune responses. A total of 3178 circRNAs in the larval guts of A. c. cerana were identified, with a length distribution ranging from 15 nt to 96007 nt. Additionally, 45, 33, and 48 up-regulated circRNAs, as well as 110, 62, and 38 down-regulated circRNAs were identified in the A.-apis-inoculated 4-, 5-, and 6-day-old larval guts in comparison with the corresponding uninoculated larval guts. These DEcircRNAs were predicted to target 29, 25, and 18 parental genes, which were relative to 12, 20, and 17 GO terms as well as 144, 114, and 61 KEGG pathways, including five cellular and four humoral immune pathways containing melanization, phagosomes, lysosomes, endocytosis, apoptosis, MAPK, Ras, and Jak-STAT signaling pathways. Furthermore, complex competing endogenous RNA (ceRNA) regulatory networks were detected as being formed among DEcircRNAs, DEmiRNAs, and DEmRNAs. The target DEmRNAs were engaged in 36, 47, and 47 GO terms as well as 331, 332, and 331 pathways, including six cellular and six humoral immune-related pathways. In total, nineteen DEcircRNAs, five DEmiRNAs, and three mRNAs were included in the sub-networks relative to three antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione S-transferase (GST). Finally, back-splicing sites within 15 circRNAs and the difference in the 15 DEcircRNAs expression between uninoculated and A.-apis-inoculated larval guts were confirmed utilizing molecular methods. These findings not only enrich our understanding of bee host-fungal pathogen interactions, but also lay a foundation for illuminating the mechanism underlying the DEcircRNA-mediated immune defense of A. c. cerana larvae against A. apis invasion.

molecular biology↗

bioRxiv2023

Warming and altered precipitation independently and interactively suppress alpine soil microbial growth in a decadal-long experiment

Warming and precipitation anomalies affect terrestrial carbon balance partly through altering microbial eco-physiological processes (e.g., growth and death) in soil. However, little is known about how such processes responds to simultaneous regime shifts in temperature and precipitation. We used the 18O-water quantitative stable isotope probing approach to estimate bacterial growth in alpine meadow soils of the Tibetan Plateau after a decade of warming and altered precipitation manipulation. Our results showed that the growth of major taxa was suppressed by the single and combined effects of temperature and precipitation, eliciting 40-90% of growth reduction of whole community. The antagonistic interactions of warming and altered precipitation on population growth were common (~70% taxa), represented by the weak antagonistic interactions of warming and drought, and the neutralizing effects of warming and wet. The members in Solirubrobacter and Pseudonocardia genera had high growth rates under changed climate regimes. These results are important to understand and predict the soil microbial dynamics in alpine meadow ecosystems suffering from multiple climate change factors.

microbiology↗

bioRxiv2023

RaptorX-Single: single-sequence protein structure prediction by integrating protein language models

Protein structure prediction has been greatly improved by deep learning in the past few years. However, the most successful methods rely on multiple sequence alignment (MSA) of the sequence homologs of the protein under prediction. In nature a protein folds in the absence of its sequence homologs and thus, a MSA-free structure prediction method is desired. Here we develop a single sequence-based protein structure prediction method RaptorX-Single by integrating several protein language models and a structure generation module and then study its advantage over MSA-based prediction methods. Our experimental results indicate that in addition to running much faster than MSA-based methods such as AlphaFold2, RaptorX-Single outperforms AlphaFold2 and other MSA-free methods in predicting the structure of antibodies, proteins of very few sequence homologs and single mutation effects. RaptorX-Single also compares favorably to MSA-based AlphaFold2 when the protein under prediction has a large number of sequence homologs.

bioinformatics↗

bioRxiv2023

Massive expansion of the pig gut virome based on global metagenomic mining

The pig gut virome plays a crucial role in the gut microbial ecosystem of pigs, yet a comprehensive reference database is still lacking. To address this gap, we established the Pig Virome Database (PVD) of the gut that comprises 5,566,804 viral contig sequences from 4,650 publicly available gut metagenomic samples using a pipeline named "metav" developed in this study. The majority of viral operational taxonomic units (vOTUs) were identified as Caudoviricetes (65.36%). By clustering sequences, we identified 48,299 vOTU genomes, of which 92.83% were not found in existing major databases. The PVD database contains a total of 18,161,503 protein-coding genes that can be used to explore the functional potential of the pig gut virome. Our study showed that the PVD can improve the detection of viruses that carry antibiotic/metal resistance genes, mobile genetic elements, virulence factor genes, and quorum sensing systems. These findings highlight the extensive diversity of viruses in the pig gut and provide detailed insight into host-virus interactions.

microbiology↗

bioRxiv2023

A cataract-causing Y204X mutation of CRYβB1 promotes C-terminal degradation and higher-order oligomerization

Crystallin (Cry) proteins are a class of main structural proteins of vertebrate eye lens, and their solubility and stability directly determine transparency and refractive power of the lens. Mutation in genes that encode for these Cry proteins is the common cause for congenital cataract. Despite extensive studies, the pathogenic and molecular mechanisms remain unclear. In this study, we identified a novel mutation in CRYBB1 from a congenital cataract family, and demonstrated that this mutation led to an earlier termination of protein translation, resulting in a 49-residue truncation at the CRY{beta}B1 C-terminus. This mutant is susceptible to proteolysis and allows us to determine a 1.2- [A] resolution crystal structure of CRY{beta}B1 without the entire C-terminal domain. In this crystal lattice, two N-terminal domain monomers form a dimer that structurally resembles a wild-type (WT) monomer, but with different surface characteristics. Biochemical analyses suggest that this mutant is significantly more liable to aggregate and degrade, when compared to WT CRY{beta}B1. All our results provide an insight into the mechanism regarding how a mutant Cry contributes to the development of congenital cataract possibly through alteration of inter-protein interactions that result in the opacity of eye lens.

biochemistry↗