Biology subjects

Xia, W.

Publications and source records attributed to Xia, W..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

ChemXTree: A Tree-enhanced Classification Approach to Small-molecule Drug Discovery

The rapid advancement of machine learning, particularly deep learning, has propelled significant strides in drug discovery, offering novel methodologies for molecular property prediction. However, despite these advancements, existing approaches often face challenges in effectively extracting and selecting relevant features from molecular data, which is crucial for accurate predictions. Our work introduces ChemXTree, a novel graph-based model that integrates tree-based algorithms to address these challenges. By incorporating a Gate Modulation Feature Unit (GMFU) for refined feature selection and a differentiable decision tree in the output layer. Extensive evaluations on benchmark datasets, including MoleculeNet and eight additional drug databases, have demonstrated ChemXTrees superior performance, particularly in feature optimization. Permutation experiments and ablation studies further validate the effectiveness of GMFU, positioning ChemXTree as a significant advancement in molecular informatics, capable of rivaling state-of-the-art models.

bioinformatics↗

bioRxiv2023

Human and chimpanzee-similar primates have distinct language gene polymorphism patterns

The difference in language gene polymorphism pattern (LGPP) between human and other primates may help to provide novel useful knowledge for language learning. One of important findings from many years worldwide research is that the primates like chimpanzee cannot easily recognize language grammars (even words). In this study, 189 SNPs (Single Nucleotide Polymorphism) in 13 language genes were scanned in 29 whole genomes from different human and primates populations. The 19 distinct SNPs in primates genomes were pointed out in several language genes including TPK1 that correlates with humans syntactic and lexical ability. PCA analysis found that LGPPs for primates were highly aggregated together but they are distant from humans LGPPs; representative human samples displayed high dispersion levels from each other in the context of LGPP. The above results may highlight a possibility that the LGPP should have more intermediate forms between human and chimpanzee-like primates.

molecular biology↗

bioRxiv2023

Enterocloster clostridioformis induces host intestinal epithelial responses that protect against Salmonella infection

Promoting resistance to enteric pathogen infection is a core function of the gut microbiota. However, many of the host-commensal interactions that likely mediate this protection remain uncharacterised. By screening gnotobiotic mice monocolonised with a range of mouse-derived commensal bacteria we have identified Enterocloster clostridioformis as a protective species against Salmonella Typhimurium infection. Unlike the colonisation resistance induced by some commensal bacteria, E. clostridioformis selectively induces a previously uncharacterised microbe adaptation response at the level of the caecal intestinal epithelium and the underlying mucosal immune system to mediate host-dependent resistance to infection. Triggering this pathway may therefore constitute a novel strategy to enhance protective responses against enteric infections.

microbiology↗

bioRxiv2023

Phosphorylation and O-GlcNAcylation at the same alpha-synuclein site generate distinct fibril structures

-Synuclein (-syn) forms amyloid fibrils that are critical in the progression of Parkinsons disease (PD) and serves as the pathological hallmark of PD. Different posttranslational modifications (PTMs) have been identified at multiple sites of -syn, influencing its conformation, aggregation and function. Here, we investigate how disease-related phosphorylation and O-GlcNAcylation at the same -syn site (S87) affect fibril structure and neuropathology. Using semi-synthesis, we obtained homogenous -syn monomer with site-specific phosphorylation (pS87) and O-GlcNAcylation (gS87) at S87, respectively. Cryo-EM analysis revealed that pS87 and gS87 -syn form two novel but distinct fibril structures. The GlcNAc situated at S87 establishes interactions with K80 and E61, inducing a unique iron-like fold with the GlcNAc molecule on the iron handle. While, phosphorylation at the same site prevents a lengthy C-terminal region including residues 73-140 from incorporating into the fibril core due to electrostatic repulsion. Instead, the N-terminal half (1-72) shapes a novel arch-like fibril structure. We further show that both pS87 and gS87 -syn fibrils display reduced neurotoxicity and propagation activity compared with unmodified -syn fibril. Our findings demonstrate that different PTMs at the same site can produce distinct fibril structures, which emphasizes the precise regulation of PTMs to amyloid fibril formation and pathology.

biochemistry↗

bioRxiv2023

ALS-causing SOD1 mutations H46R and G85R form similar novel amyloid fibril structures and promote ferroptosis in cells

More than two hundred genetic mutations of Cu, Zn-superoxide dismutase (SOD1) have been identified in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by the selective death of motor neurons through ferroptosis. Two ALS-causing SOD1 mutations, H46R and G85R, are metal-binding region mutants with reduced affinity for metal ions. Here, we generated amyloid fibrils from the apo forms of H46R and G85R under reducing conditions and determined their structures using cryo-EM. We built models for the fibril cores, comprising residues 85-153 for H46R and 82-153 for G85R. These mutations disrupt crucial interactions in the wild-type SOD1 fibril, resulting in amyloid fibrils with distinct structures compared to the wild-type fibril. Remarkably, H46R and G85R form similar novel amyloid fibril structures. The fibril cores display a serpentine fold containing seven or eight {beta}-strands, which are stabilized by a hydrophobic cavity. In the G85R fibril core, Arg85 and Asp101 form a salt bridge for stabilization. We demonstrate that fibril seeds from H46R and G85R cause more severe mitochondrial impairment and significantly promote ferroptosis in neuronal cells, compared with those from wild-type SOD1. Our findings reveal how different SOD1 mutations can result in similar amyloid fibril structures and contribute to ALS pathology.

biochemistry↗

bioRxiv2023

AnnoPRO: an innovative strategy for protein function annotation based on image-like protein representation and multimodal deep learning

Protein function annotation has been one of the longstanding issues, which is key for discovering drug targets and understanding physiological or pathological process. A variety of computational methods have therefore been constructed to facilitate the research developments in this particular direction. However, the annotation of protein function based on computational methods has been suffering from the serious "long-tail problem", and it remains extremely challenging for existing methods to improve the prediction accuracies for protein families in tail label levels. In this study, an innovative strategy, entitled AnnoPRO, for protein function annotation was thus constructed. First, a novel method enabling image-like protein representations was proposed. This method is unique in capturing the intrinsic correlations among protein features, which can greatly favor the application of the state-of-the-art deep learning methods popular in image classification. Second, a multimodal framework integrating multichannel convolutional neural network and long short-term memory neural network was constructed to realize a deep learning-based protein functional annotation. Since this framework was inspired by a reputable method used in image classification for dealing with its long-tail problem, our AnnoPRO was expected to significantly improve the annotation performance of the protein families in tail label level. Multiple case studies based on benchmark were also conducted, which confirmed the superior performance of AnnoPRO among the existing methods. All source codes and models of AnnoPRO were freely available to all users at https://github.com/idrblab/AnnoPRO, and would be essential complement to existing methods.

bioinformatics↗

bioRxiv2023

Accumulation of m6A exhibits stronger correlation with MAPT than beta-amyloid pathology in an APP NL-G-F /MAPT P301S mouse model of Alzheimer's disease

The study for the pathophysiology study of Alzheimers disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular {beta}-amyloid (A{beta}) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration. We now report on a double transgenic APPNL-G-F MAPTP301S mouse that at 6 months of age exhibits robust A{beta} plaque accumulation, intense MAPT pathology, strong inflammation and extensive neurodegeneration. The presence of A{beta} pathology potentiated the other major pathologies, including MAPT pathology, inflammation and neurodegeneration. However, MAPT pathology neither changed levels of amyloid precursor protein nor potentiated A{beta} accumulation. The APPNL-G-F/MAPTP301S mouse model also showed strong accumulation of N6-methyladenosine (m6A), which was recently shown to be elevated in the AD brain. M6A primarily accumulated in neuronal soma, but also co-localized with a subset of astrocytes and microglia. The accumulation of m6A corresponded with increases in METTL3 and decreases in ALKBH5, which are enzymes that add or remove m6A from mRNA, respectively. Thus, the APPNL- G-F/MAPTP301S mouse recapitulates many features of AD pathology beginning at 6 months of aging.

neuroscience↗

bioRxiv2022

Language gene polymorphism pattern survey provided important information for education context in human evolution

Study on language gene polymorphism patterns (LGPP) across different populations could provide important information on human evolution. In this study, as a preliminary observation, we adopted 148 single nucleic polymorphism (SNP) sites from 13 language genes, each with 4-13 SNPs. These SNPs were screened across 112 whole genome sequences (including 59 ancient genomes ranging from 2000 BP to 120000 BP) from five continents (Africa, Asia, Europe, North America, and South America). We found that four distinct LGPPs featured across human evolution history, though it is still to decipher whether they correspond to the three batches of out-of-Africa ancient humans and modern human; Surprisingly, ten ancient samples from the small country, Nepal, contain all 4 basic LGPPs, suggesting that the southern foothills and nearby of the Qinghai-Tibet Plateau were likely an agglomeration place for ancient humans; Chinese samples also have 3-4 basic LGPPs. Of note, some types of Neanderthals and Denisovans possessed a LGPP almost the same as modern humans.

evolutionary biology↗

bioRxiv2022

Establishment of porcine ovarian follicles treated with t-BHP for an in vitro aging model

Ovarian aging is closely associated with low female fertility. Excessive oxidative stress can induce ovarian senescence and follicular atresia, thereby reducing reproductive performance. In this study, intact antral follicles of pigs were treated with tert-butyl hydroperoxide (t-BHP) to simulate aging stimulation conditions. The results showed that 200 M t-BHP induced the senescence-related phenotype of antral follicles, which was time-dependent and changed significantly after 6 h of treatment. t-BHP can induce an increase in reactive oxygen species (ROS) and senescence mediated by Caspase-3, P53, Foxo1, and SOD. Senescence-associated {beta}-galactosidase (SA-{beta}-Gal) staining revealed an increase in the number of positive cells. Enzyme-linked immunosorbent assays (ELISA) showed that the level of reactive oxygen species increased, and that the ratio of progesterone (P4) to estradiol (E2) increased. Finally, the findings of this study showed that the relative expression levels of Caspase-3, P53, Foxo1 mRNA, and protein increased, while the relative expression levels of SOD decreased. In conclusion, treatment with 200 M of t-BHP effectively induced follicular senescence at 6 h. Therefore, the in vitro treatment of follicles with 200 M t-BHP for 6 h may be a feasible in vitro culture model to simulate ovarian senescence in gilts.

genetics↗

bioRxiv2022

Adipocyte-secreted IL-6 sensitizes macrophages to IL-4 signaling

Complex bidirectional crosstalk between adipocytes and adipose tissue immune cells plays an important role in regulating adipose function, inflammation, and insulin responsiveness. Adipocytes secrete the pleiotropic cytokine IL-6 in response to both inflammatory and catabolic stimuli. Previous studies suggest that IL-6 secretion from adipocytes in obesity may promote adipose tissue inflammation. Here we investigated catabolic stimulation of adipocyte IL-6 secretion and its impact on adipose tissue immune cells. In obesity, catecholamine resistance reduces cAMP-driven adipocyte IL-6 secretion in response to catabolic signals. By restoring adipocyte catecholamine sensitivity in obese adipocytes, amlexanox stimulates adipocyte-specific IL-6 secretion. Here we report that in this context, adipocyte secreted IL-6 activates local macrophage STAT3 to promote Il4ra expression, thereby sensitizing them to IL-4 signaling, and promoting an anti-inflammatory gene expression pattern. Supporting a paracrine adipocyte to macrophage mechanism, these effects could be recapitulated using adipocyte conditioned media to pretreat bone marrow derived macrophages prior to polarization with IL-4. The effects of IL-6 signaling in the adipose tissue are complex and context specific. These results suggest that cAMP driven IL-6 secretion from adipocytes sensitizes adipose tissue macrophages to IL-4 signaling.

immunology↗

bioRxiv2022

Trophoblast and blood vessel organoid cultures recapitulate the role of WNT2B in promoting intravillous vascularization in human intrauterine and ectopic pregnancy

Tubal ectopic pregnancy (TEP), a pregnancy complication caused by aberrant implantation in fallopian tubes, accounts for 9-13% pregnancy-related deaths. The lack of models for human TEP hampers the understanding of its pathological mechanisms. Here, we employed multiple models to investigate the crosstalk between human trophoblast development and intravillous vascularization. We found that the severity of TEP, the size of placental villi, and the depth of trophoblast invasion are correlated with the extent of intravillous vascularization. We identified a key pro-angiogenic factor secreted by trophoblasts, WNT2B, that promotes villous vasculogenesis, angiogenesis, and vascular network expansion. In an organoid coculture model consisting of trophoblast organoids and blood vessel organoids, knockdown of WNT2B in trophoblast organoids compromises their pro-angiogenic effect on the development of blood vessel organoids. These organoid-based models reveal an important role for WNT-mediated angiogenesis in pregnancies and could be employed to investigate the commutations between trophoblasts and endothelial/endothelial progenitor cells.

cell biology↗

bioRxiv2022

An immune-lncRNA risk model to predict prognosis for patients with head and neck squamous cell carcinoma

Backgroundlong noncoding RNA (lncRNA) are closely correlated with the occurrence and development of tumors. The purpose of this research is to construct a risk model of immune-related lncRNAs that can be used for predicting the survival and prognosis of head and neck squamous cell carcinoma (HNSCC) patients and further exploring the immune function of immune-lncRNAs. Methodsobtained detailed transcriptional data and clinical information for 545 cases of HNSCC from The Cancer Genome Atlas (TCGA). Combined lncRNAs and the immune gene sets from the Molecular Signatures Database (MSigDB) were employed to construct co{square}expression networks, the significant correlation of immune-lncRNAs obtained from the results of Cox regression analysis were used to build the model. Survival analysis and QRT-PCR were used to confirm the expression of immune-lncRNAs and optimize the risk model. Then single-cell RNA Sequencing (scRNA-seq) dataset analysis of laryngeal squamous cell carcinoma (LSCC), co-expression analysis, correlation analysis and immunohistochemistry were used to explore the immune function of immune-lncRNAs. ResultsA total of 13 immune-lncRNAs including AC104083.1AC004148.2AL357033.4AC116914.2AC024075.1AC008115.3PCED1B-AS1RAB11B-AS1AC004687.1 AL450992.2EP300-AS1AC024075.2AC136475.2 were identified to construct the risk model. In this model, low-risk patients had higher overall survival (OS, P=1.923e-12, hazard ratio=2.104, 95% CI: 1.622-2.730). AC004687.1 and PCED1B-AS1 were overexpressed in T cells and were closely related to the genes encoding major histocompatibility complex II (MHC II) molecules. And the results of QRT-PCR and immunohistochemistry showed the expression significant positively correlated with HLA-DR which is one of the MHC II classical molecules. Conclusionthe immune-associated risk model constructed by 13 lncRNAs has good prognostic value for HNSCC. AC004687.1 and PCED1B-AS1 are significant correlating to clinical characteristics and MHC II, we provide a new insight into the immune function of lncRNAs.

bioinformatics↗

bioRxiv2021

Different structures and pathologies of alpha-synuclein fibrils derived from preclinical and postmortem patients of Parkinson's disease

-Synuclein (-syn) fibrillar aggregates are the major component of Lewy bodies and Lewy neurites presenting as the pathology hallmark of Parkinsons disease (PD). Studies have shown that -syn is potential to form different conformational fibrils associated with different synucleinopathies, but whether the conformation of -syn fibrils changes in different phases of related diseases is to be explored. Here, we amplified -syn aggregates from the cerebrospinal fluid (CSF) of preclinical (pre-PD) and late-stage postmortem PD (post-PD) patients. Our results show that compared to the CSF of pre-PD, that of post-PD is markedly stronger in seeding in vitro -syn aggregation, and the amplified fibrils are more potent in inducing endogenous -syn aggregation in neurons. Cryo-electron microscopic structures further reveal that the difference between the pre-PD- and post-PD-derived fibrils lies on a minor polymorph which in the pre-PD fibrils is morphologically straight, while in the post-PD fibrils represents a single protofilament assembled by a distinctive conformation of -syn. Our work demonstrates structural and pathological differences between pre-PD and post-PD -syn aggregation and suggests potential alteration of -syn fibrils during the progression of PD clinical phases. Significance StatementIncreasing evidence support different conformational -syn fibrils in patients with different -synucleinopathies, but whether the conformation of -syn fibrils changes in different phases of related diseases is unknown. Here, we show that -syn fibrils amplified from the cerebrospinal fluid (CSF) of the late-stage postmortem PD (post-PD) patient are more potent in inducing endogenous -syn aggregation in neurons than that amplified from the preclinical (pre-PD) patient. Cryo-EM structures further reveal that the post-PD fibrils contain a novel conformation that is distinct from either the pre-PD fibrils or those previously reported. Our work suggests conformational evolution of -syn fibrils along with PD progression.

biophysics↗

bioRxiv2021

A Potential Novel COVID-19 Vaccine With RBD-HR1/HR2 Hexamer Structure

The COVID-19 pandemic and the continued spreading of the SARS-CoV-2 variants have brought a grave public health consequence and severely devastated the global economy with recessions. Vaccination is considered as one of the most promising and efficient methods to end the COVID-19 pandemic and mitigate the disease conditions if infected. Although a few vaccines have been developed with an unprecedented speed, scientists around the world are continuing pursuing the best possible vaccines with innovations. Comparing to the expensive mRNA vaccines and attenuated/inactivated SARS-CoV-2 vaccines, recombinant protein vaccines have certain advantages, including their safety (non-virus components), potential stronger immunogenicity, broader protection, ease of scaling-up production, reduced cost, etc. In this study, we reported a novel COVID-19 vaccine generated with RBD-HR1/HR2 hexamer that was creatively fused with the RBD domain and heptad repeat 1 (HR1) or heptad repeat 2 (HR2) to form a dumbbell-shaped hexamer to target the spike S1 subunit. The novel hexamer COVID-19 vaccine induced high titers of neutralizing antibody in mouse studies (>100,000), and further experiments also showed that the vaccine also induced an alternative antibody to the HR1 region, which probably alleviated the drop of immunogenicity from the frequent mutations of SARS-CoV-2.

biochemistry↗

bioRxiv2021

Methylome inheritance and enhancer dememorization reset an epigenetic gate safeguarding embryonic programs

Drastic epigenetic reprogramming is essential to convert terminally-differentiated gametes to totipotent embryos. However, it remains puzzling why post-fertilization global DNA reprogramming occurs only in mammals but not in non-mammalian vertebrates. In zebrafish, global methylome inheritance is however accompanied by sweeping enhancer "dememorization" as they become fully methylated. By depleting maternal dnmt1 using oocyte microinjection in situ, we eliminated DNA methylation in zebrafish early embryos, which died around gastrulation with severe differentiation defects. Strikingly, methylation deficiency leads to extensive derepression of adult tissue-specific genes and CG-rich enhancers, which acquire ectopic TF binding and, unexpectedly, H3K4me3. By contrast, embryonic enhancers are generally CG-poor and evade DNA methylation repression. Hence, global DNA hypermethylation inheritance coupled with enhancer dememorization installs an epigenetic gate that safeguards embryonic programs and ensures temporally ordered gene expression. We propose that "enhancer dememorization" underlies and unifies distinct epigenetic reprogramming modes in early development between mammals and non-mammals.

developmental biology↗

bioRxiv2021

CRISPRi screens in human astrocytes elucidate regulators of distinct inflammatory reactive states

In response to central nervous system injury or disease, astrocytes become reactive, adopting context-dependent states and functional outputs. Certain inflammatory insults induce reactive astrocytes that lose homeostatic functions and gain harmful outputs through cellular pathways that are not fully understood. Here, we combined single-cell transcriptomics with CRISPRi screening in human iPSC-derived astrocytes to systematically interrogate inflammatory astrocyte reactivity. We found that autocrine-paracrine IL-6 and interferon signaling downstream of canonical NF-{kappa}B activation drove two distinct inflammatory reactive signatures - one promoted by and the other inhibited by STAT3. These signatures overlapped with those observed in other experimental contexts, including mouse models, and their markers were upregulated in the human brain in Alzheimers disease and hypoxic ischemic encephalopathy. Furthermore, we validated that these signatures were regulated by Stat3 in vivo. These results and the platform we established have the potential to guide the development of therapeutics to selectively modulate different aspects of inflammatory astrocyte reactivity.

neuroscience↗

bioRxiv2021

Prodromal dysfunction of α5GABA-A receptor modulated hippocampal ripples in Alzheimer's disease

Decades of research attempting to slow the onset of Alzheimers disease (AD) indicates that a better understanding of memory will be key to the discovery of effective therapeutic approaches. Here, we ask whether prodromal neural network dysfunction might occur in the hippocampal trisynaptic circuit by using 5IA as a selective negative modulator of extrasynaptic 5GABA-A receptors in TgF344-AD transgenic rats, a model for early onset AD. The results demonstrate that orally bioavailable 5IA, an established memory enhancer, increases CA1 pyramidal cell mean firing rates and peak CA1 ripple amplitude during wakeful immobility in wild type F344 rats resting in a familiar environment. We show that TgF344-AD rats, which express human amyloid-beta precursor protein (with the Swedish mutation) and human presenilin-1 (with a {Delta} exon 9 mutation), exhibit high serum A{beta}42 and A{beta}40 levels by 3 months of age. By 9 months of age, CA1 ripples in young adult TgF344-AD rats are nonresponsive to 5IA indicating network dysfunction prior to the onset of AD pathology and memory dysfunction. These results demonstrate, to the best of our knowledge, the first evidence for prodromal 5GABA-A receptor dysfunction in the AD hippocampal trisynaptic circuit. Moreover, as 5GABA-A receptors are located extrasynaptically and subserve the function of tonic inhibition we posit that an early stage of memory dysfunction involves the disruption of tonic inhibition in the hippocampus.

neuroscience↗

bioRxiv2021

Exploring the natural origins of SARS-CoV-2

The lack of an identifiable intermediate host species for the proximal animal ancestor of SARS-CoV-2, and the large geographical distance between Wuhan and where the closest evolutionary related coronaviruses circulating in horseshoe bats (Sarbecoviruses) have been identified, is fuelling speculation on the natural origins of SARS-CoV-2. We have comprehensively analysed phylogenetic relations between SARS-CoV-2, and the related bat and pangolin Sarbecoviruses sampled so far. Determining the likely recombination events reveals a highly reticulate evolutionary history within this group of coronaviruses. Clustering of the inferred recombination events is non-random with evidence that Spike, the main target for humoral immunity, is beside a recombination hotspot likely driving antigenic shift in the ancestry of bat Sarbecoviruses. Coupled with the geographic ranges of their hosts and the sampling locations, across southern China, and into Southeast Asia, we confirm horseshoe bats, Rhinolophus, are the likely SARS-CoV-2 progenitor reservoir species. By tracing the recombinant sequence patterns, we conclude that there has been relatively recent geographic movement and co-circulation of these viruses ancestors, extending across their bat host ranges in China and Southeast Asia over the last 100 years or so. We confirm that a direct proximal ancestor to SARS-CoV-2 is yet to be sampled, since the closest relative shared a common ancestor with SARS-CoV-2 approximately 40 years ago. Our analysis highlights the need for more wildlife sampling to (i) pinpoint the exact origins of SARS-CoV-2s animal progenitor, and (ii) survey the extent of the diversity in the related Sarbecoviruses phylogeny that present high risk for future spillover. HighlightsO_LIThe origin of SARS-CoV-2 can be traced to horseshoe bats, genus Rhinolophus, with ranges in both China and Southeast Asia. C_LIO_LIThe closest known relatives of SARS-CoV-2 exhibit frequent transmission among their Rhinolophus host species. C_LIO_LISarbecoviruses have undergone extensive recombination throughout their evolutionary history. C_LIO_LIAccounting for the mosaic patterns of these recombinants is important when inferring relatedness to SARS-CoV-2. C_LIO_LIBreakpoint patterns are consistent with recombination hotspots in the coronavirus genome, particularly upstream of the pike open reading frame with a coldspot in S1. C_LI

evolutionary biology↗