Biology subjects

Xu, Z.

Publications and source records attributed to Xu, Z..

At least 343 records · Page 19Linked to original sources

bioRxiv2022

Landscape of infection enhancing antibodies in COVID-19 and healthy donors

To assess the frequency of SARS-CoV-2 infection enhancing antibodies in the general population, we searched over 64 million heavy chain antibody sequences from healthy and COVID-19 patient repertoires for sequences similar to 11 previously reported enhancing antibodies. Although the distribution of sequence identities was similar in COVID-19 and healthy repertoires, the COVID-19 hits were significantly more clonally expanded than healthy hits. Furthermore, among the tested hits, 17 out of 94 from COVID-19, compared with 2 out of 96 from healthy, bound to the enhancing epitope. A total of 6 of the 19 epitope-binding antibodies enhanced ACE2 receptor binding to the spike protein. Together, this study revealed that enhancing antibodies are far more frequent in COVID-19 patients than in healthy donors, but a reservoir of potential enhancing antibodies exists in healthy donors that could potentially mature to actual enhancing antibodies upon infection.

immunology↗

bioRxiv2022

A deep learning approach for improved detection of homologous recombination deficiency from shallow genomic profiles

Homologous Recombination Deficiency (HRD) is a predictive biomarker of poly-ADP ribose polymerase 1 inhibitors (PARPi) response. Most HRD detection methods are based on genome wide enumeration of scarring events and require deep genome sequence profiles (> 30x). The cost and workflow-specific biases introduced by these genome profiling methods currently limits clinical adoption of HRD testing. We introduce the Genomic Integrity Index (GII), a Convolutional Neuronal Network, that leverages features from low pass (1x) Whole Genome Sequencing data to distinguish HRD positive and negative samples. In a cohort of 230 ovarian and breast cancer, we found GII supports accurate stratification of samples yielding results that are highly concordant with state-of-the-art HRD detection methods (0.865<AUC<0.996) which require 50x deeper coverage. We conclude that the deep learning framework supporting GII allows accurate detection of HRD from shallow genome profiles, reducing biases and data generation costs making it uniquely suited for clinical applications.

cancer biology↗

bioRxiv2022

CARD8 negatively regulates NLRP1 inflammasome activation level by interaction with NLRP1

NLRP1 inflammasome functions as canonical cytosolic sensor in response to intracellular infections and is implicated in auto-inflammatory diseases. But the regulation and signal transduction mechanisms of NLRP1 are incompletely understood. Here, we show that the T60 variant of CARD8, but not the canonical T48 isoform, negatively regulates NLRP1 inflammasome activation by directly interacting with the receptor molecule NLRP1 and inhibiting inflammasome assembly. Furthermore, our results suggest that the different ASC preference in three types of inflammasomes, namely ASC-indispensable NLRP1 inflammasome, ASC-dispensable mNLRP1b inflammasome and ASC-independent CARD8 inflammasome, is mainly caused by the CARD domain, not the UPA subdomain. Based on the systematic site-directed mutagenesis and structural analysis, we find that the signal transduction of NLRP1 inflammasome relies on multiple interaction surfaces on its death domain superfamily member CARD domain. Finally, our results partly explain the mechanism of the NLRP1 mutation-derived auto-inflammatory diseases caused by the overactivation of the NLRP1 inflammasome. In conclusion, our study not only reveals how CARD8 downregulates NLRP1 inflammasome activation, but also provides insights into the mechanisms of CARD-containing inflammasome assembly.

immunology↗

bioRxiv2022

Pan-cancer analysis reveals the value of FDX1 as a novel biomarker in the prognosis and immunotherapy in human tumors

Emerging evidence supports FDX1s important role in the development and progression of cancer, but no extensive cancer analysis is available to date. This study was the first to comprehensively explore the expression of FDX1 in 33 types of cancer and the significance of FDX1 in clinical prognosis by using bioinformatics techniques. Meanwhile, we analyzed the relationship between FDX1 and pathological stage, as well as immune cell infiltration. Based on this, the important role of FDX1 in tumor immunotherapy was proposed. The expression of FDX1 was significantly different between normal and tumor samples in 17 of 33 types of cancer. Besides, Cox regression analysis showed that FDX1 is a protective gene in Kidney renal clear cell carcinoma (KIRC), Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), Liver hepatocellular carcinoma (LIHC), Kidney renal papillary cell carcinoma (KIRP), Mesothelioma (MESO), and Thyroid carcinoma (THCA). Porphyrin and oxidative metabolism pathway regulating integrator complex was involved in the process. Furthermore, high expression of FDX1 promoted infiltration of Eosinophils and monocyte in Adrenocortical carcinoma (ACC) and Kidney Chromophobe (KICH) by affecting the tumor microenvironment (TME) and was significantly correlated with immune checkpoint genes. Our first pan-cancer analysis elucidates the expression characteristics of FDX1 across different cancers and highlights its potential value as a prognostic biomarker, laying a foundation for further study of its immunotherapy mechanism in various cancers.

bioinformatics↗

bioRxiv2022

AIM1-dependent high basal SA accumulation modulates stomatal aperture in rice

The basal levels of salicylic acid (SA), an important plant hormone, vary dramatically among plant species. In the shoot, for example, the monocot plant rice contains almost 100 times higher SA levels than the dicot model plant Arabidopsis. Despite its high basal levels, neither the biosynthetic pathway nor the biological functions of SA is well understood in rice. Here, we report that the synthesis of basal SA in rice shoot is not altered in the mutant for the ISOCHORISMATE SYNTHASE (ICS) gene, but drastically reduced in the mutant for OsAIM1, which encodes a beta-oxidation enzyme in the phenylalanine ammonia-lyase (PAL) pathway. Analogous to its role in thermogenesis, compromised SA accumulation in the Osaim1 mutant led to a lower shoot temperature than wild-type plants. However, this shoot temperature defect was resulted from increased transpiration due to elevated steady-state stomatal aperture in the mutant. Furthermore, the high basal shoot SA level is required for sustained expression of WRKY45 to modulate the steady-state stomatal aperture and shoot temperature in rice. Taken together, these results provide the direct genetic evidence for the critical role of the PAL pathway in the biosynthesis of high levels of basal SA, which play an important role in the regulation of steady-state stomatal aperture to promote fitness under both normal and stress conditions.

plant biology↗

bioRxiv2022

De novo design of site-specific protein interactions with learned surface fingerprints

Physical interactions between proteins are essential for most biological processes governing life. However, the molecular determinants of such interactions have been challenging to understand, even as genomic, proteomic, and structural data grows. This knowledge gap has been a major obstacle for the comprehensive understanding of cellular protein-protein interaction (PPI) networks and for the de novo design of protein binders that are crucial for synthetic biology and translational applications. We exploit a geometric deep learning framework operating on protein surfaces that generates fingerprints to describe geometric and chemical features critical to drive PPIs. We hypothesized these fingerprints capture the key aspects of molecular recognition that represent a new paradigm in the computational design of novel protein interactions. As a proof-of-principle, we computationally designed several de novo protein binders to engage four protein targets: SARS-CoV-2 spike, PD-1, PD-L1, and CTLA-4. Several designs were experimentally optimized while others were purely generated in silico, reaching nanomolar affinity with structural and mutational characterization showing highly accurate predictions. Overall, our surface-centric approach captures the physical and chemical determinants of molecular recognition, enabling a novel approach for the de novo design of protein interactions and, more broadly, of artificial proteins with function.

bioengineering↗

bioRxiv2022

NcPath: A novel tool for visualization and enrichment analysis of human non-coding RNA and KEGG signaling pathways

Noncoding RNAs play important roles in transcriptional processes and participate in the regulation of various biological functions, in particular miRNAs and lncRNAs. Despite their importance for several biological functions, the existing signaling pathway databases do not include information on miRNA and lncRNA. Here, we redesigned a novel pathway database named NcPath by integrating and visualizing a total of 178,308 human experimentally-validated miRNA-target interactions (MTIs), 36,537 experimentally-verified lncRNA target interactions (LTIs), and 4,879 experimentally-validated human ceRNA networks across 222 KEGG pathways (including 27 sub-categories). To expand the application potential of the redesigned NcPath database, we identified 553,523 reliable lncRNA-PCG interaction pairs by integrating co-expression relations, ceRNA relations, co-TF-binding interactions, co-Histone-modification interactions, cis-regulation relations and lncPro Tool predictions between lncRNAs and protein-coding genes. In addition, to determine the pathways in which miRNA/lncRNA targets are involved, we performed a KEGG enrichment analysis using an hypergeometric test. The NcPath database also provides information on MTIs/LTIs/ceRNA networks, PubMed IDs, gene annotations and the experimental verification method used. In summary, the NcPath database will serve as an important and continually updated platform that provides annotation and visualization of the pathways on which noncoding RNAs (miRNA and lncRNA) are involved, and provide support to multimodal noncoding RNAs enrichment analysis. The NcPath database is freely accessible at http://ncpath.pianlab.cn/.

bioinformatics↗

bioRxiv2022

Persistent Inflammatory Lipotoxicity Impedes Pancreatic β-cell Function in Diet-Induced Obese Mice Despite Correction of Glucotoxicity

Insulin resistance is a hallmark feature of Type 2 Diabetes (T2D), but the progression of the disease is closely linked to a deterioration in {beta}-cell mass and function. While the precise mechanisms of {beta}-cell failure are unclear, chronic hyperglycemia (glucotoxicity) and dyslipidemia (lipotoxicity) are considered contributing factors; however, the relative importance of these insults on {beta}-cell function remains controversial. To examine this, we dissociated glucotoxicity from lipotoxicity using a high-fat diet (HFD)-fed mouse model of T2D and the glucose-lowering SGLT2 inhibitor, canagliflozin (CANA). As expected, HFD-feeding impaired glucose tolerance and isolated islet function. However, despite improvements in glucose tolerance and indices of {beta}-cell insulin secretory function in vivo, CANA failed to restore isolated {beta}-cell function. Shotgun lipidomics analysis of isolated islets revealed that HFD-feeding induced glycerophospholipid remodeling with a persistent increase in arachidonic acid (20:4)-enriched molecular species. Further analysis revealed that lysophosphatidylcholine (LPC) was the predominant lipid class elevated in HFD islets following correction of glucotoxicity with CANA. In follow-up experiments, LPC stimulations acutely and dose-dependently impaired glucose-stimulated insulin secretion (GSIS) in isolated wild-type islets, mechanistically linking this lipid class to {beta}-cell dysfunction. Our findings indicate that persistent inflammatory lipotoxicity impedes {beta}-cell function in diet-induced obese (DIO) rodents even after normalization of hyperglycemia. If replicated in humans, these data suggest that interventions targeting lipotoxicity may be beneficial for the long-term protection of pancreatic {beta}-cell function in T2D.

physiology↗

bioRxiv2022

Improved antibody-specific epitope prediction using AlphaFold and AbAdapt

Antibodies recognize their cognate antigens with high affinity and specificity, but the prediction of binding sites on the antigen (epitope) corresponding to a specific antibody remains a challenging problem. To address this problem, we developed AbAdapt, a pipeline that integrates antibody and antigen structural modeling with rigid docking in order to derive antibody-antigen specific features for epitope prediction. In this study, we assess the impact of integrating the state-of-the-art protein modeling method AlphaFold with the AbAdapt pipeline and demonstrate significant improvement in the prediction of antibody-specific epitope residues.

bioinformatics↗

bioRxiv2022

Nucleoli and the nucleoli-centromere association are dynamic during normal development and in cancer

Centromeres are known to cluster around nucleoli in drosophila and mammalian cells. However, the functional significance of nucleoli-centromere interaction remains underexplored. We hypothesize that if this conserved interaction is functionally important, it should be dynamic under different physiological and pathological conditions. We examined the nucleolar structure and centromeres at various differentiation stages using cell culture models. The results show dynamic changes of nucleolar number, area, and nucleoli-centromere interactions at differentiation stages and in cancer cells. Embryonic stem cells usually have a single large nucleolus, which associates with a high percentage of centromeres. As cells differentiate into intermediate states, the nucleolar number increases and the association with centromeres decreases. In terminally differentiated cells, including myotubes, neurons and keratinocytes, the number of nucleoli and their association with centromeres are at the lowest. Cancer cells demonstrate the pattern of nucleoli number and nucleoli-centromere association that is akin to proliferative less differentiated cell types, suggesting that nucleolar reorganization and changes in nucleoli-centromere interactions may help facilitate malignant transformation. This idea is supported in a case of pediatric rhabdomyosarcoma, in which induced differentiation inhibits cell proliferation and reduces nucleolar number and centromere association. These findings suggest active roles of nucleolar structure in centromere function and genome organization critical for cellular function in both normal development and cancer.

cell biology↗

bioRxiv2022

Inferring Neural Activity Before Plasticity: A Foundation for Learning Beyond Backpropagation

For both humans and machines, the essence of learning is to pinpoint which components in its information processing pipeline are responsible for an error in its output -- a challenge that is known as credit assignment. How the brain solves credit assignment is a key question in neuroscience, and also of significant importance for artificial intelligence. It has long been assumed that credit assignment is best solved by backpropagation, which is also the foundation of modern machine learning. However, it has been questioned whether it is possible for the brain to implement backpropagation and learning in the brain may actually be more efficient and effective than backpropagation. Here, we set out a fundamentally different principle on credit assignment, called prospective configuration. In prospective configuration, the network first infers the pattern of neural activity that should result from learning, and then the synaptic weights are modified to consolidate the change in neural activity. We demonstrate that this distinct mechanism, in contrast to backpropagation, (1) underlies learning in a well-established family of models of cortical circuits, (2) enables learning that is more efficient and effective in many contexts faced by biological organisms, and (3) reproduces surprising patterns of neural activity and behaviour observed in diverse human and animal learning experiments. Our findings establish a new foundation for learning beyond backpropagation, for both understanding biological learning and building artificial intelligence.

neuroscience↗

bioRxiv2022

Peripheral sensory neuron CB2 cannabinoid receptors are necessary for both CB2-mediated antinociceptive efficacy and sparing of morphine tolerance in a mouse model of neuropathic pain

Painful peripheral neuropathy is the most common neurological complication associated with human immune deficiency virus (HIV) infection. Currently available treatments fail to provide adequate symptom relief, indicating the need for novel treatment strategies. To address this gap in knowledge, we characterized the impact of cannabinoid CB2 agonists, which lack psychoactivity associated with central CB1 activation, on antiretroviral-induced neuropathic nociception and identified cell types expressing CB2 that mediate the antinociceptive efficacy of CB2 agonists. Two structurally distinct CB2 agonists (AM1710 and LY2828360) alleviated antiretroviral-induced neuropathic pain, benefits which were absent in CB2 knockout mice. Conditional deletion of CB2 from peripheral sensory neurons eliminated the antinociceptive efficacy of CB2 agonists. We also asked whether LY2828360 treatment could reverse established morphine tolerance in the ddC-induced neuropathy model and whether CB2 expression on peripheral sensory neurons is necessary for sparing of morphine tolerance by LY2828360. The present studies suggest that CB2 activation may alleviate HIV-associated antiretroviral neuropathy and identify a previously unreported mechanism through which CB2 activation produces antinociceptive efficacy. Our results also provide the first evidence that a CB2 agonist can reverse established morphine tolerance and demonstrate that CB2 localized to peripheral sensory neurons mediates the opioid tolerance sparing efficacy of CB2 agonists.

neuroscience↗

bioRxiv2022

A toxin-mediated policing system in Bacillus improves population fitness via penalizing non-cooperating phenotypic cheaters

Microbial cooperation is vulnerable to exploitation by social cheaters. Although the strategies for controlling genotypic cheaters have been well investigated, the mechanism and significance of preventing phenotypic cheating remain largely unknown. Here, we revealed the molecular mechanism and ecological significance of a policing system for punishing phenotypic cheaters in the community of a plant beneficial strain Bacillus velezensis SQR9. Coordinated activation of extracellular matrix (ECM) production and autotoxin bacillunoic acids (BAs) biosynthesis/self-immunity, punished public goods-nonproducing cheaters in strain SQR9s community. Spo0A was identified to be the co-regulator for triggering both ECM production and BAs synthesis/immunity, which activates acetyl-CoA carboxylase (ACC) to produce malonyl-CoA, an essential precursor for BAs biosynthesis, thereby stimulating BAs production and self-immunity. Elimination of phenotypic cheaters by this policing system, significantly enhanced population fitness under different stress conditions and in plant rhizosphere. This study provides insights into our understanding of maintenance and evolution of microbial cooperation.

microbiology↗

bioRxiv2022

Structure and mechanism of LARGE1 matriglycan polymerase

Matriglycan is a linear polysaccharide of alternating xylose and glucuronate that binds extracellular matrix proteins and acts as a receptor for Lassa fever virus. LARGE1 synthesizes matriglycan on dystroglycan and mutations in LARGE1 cause muscular dystrophy with abnormal brain development. However, the mechanism of matriglycan polymerization by LARGE1 is unknown. Here, we report the cryo-EM structure of LARGE1. We show that LARGE1 functions as a dimer to polymerize matriglycan by alternating activities between the xylose transferase domain on one protomer and the glucuronate transferase domain on the other protomer. Biochemical analyses using a recombinant Golgi form of dystroglycan reveal that LARGE1 polymerizes matriglycan processively. Our results provide mechanistic insights into LARGE1 function and may facilitate novel therapeutic strategies for treating neuromuscular disorders or arenaviral infections. One-Sentence SummaryDimeric LARGE1 processively polymerizes matriglycan on dystroglycan using orthogonal active sites on alternate protomers.

biochemistry↗

bioRxiv2022

Housekeeping gene gyrA, a potential molecular marker for Bacillus ecology study

Bacillus is a ubiquitous microorganism and is one of the most commercially important species widely used in industry, agriculture and healthcare. Bacillus is relatively well understood at the single-cell level; however, molecular tools that determine diversity and ecology of Bacillus community are limited, which limits our understanding of how the Bacillus community works. In the present study, we investigated the potential of the housekeeping gene gyrA as a molecular marker for determining the diversity of Bacillus species. The amplification efficiency for Bacillus species diversity could be greatly improved by primer design. Therefore, we designed a novel primer pair gyrA3 that can detect at least 92 Bacillus species and related species. For Bacillus amyloliquefaciens, Bacillus pumilus, and Bacillus megaterium, we observed that the high variability of the gyrA gene allows for more detailed clustering at the subspecies level that cannot be achieved by the 16S rRNA gene. Since gyrA provides better phylogenetic resolution than 16S rRNA and informs on the diversity of the Bacillus community, we propose that gyrA gene may have broad application prospects in the study of Bacillus ecology.

microbiology↗

bioRxiv2022

Manipulating the 3D organization of the largest synthetic yeast chromosome

Whether synthetic genomes can power life has attracted broad interest in the synthetic biology field, especially when the synthetic genomes are extensively modified with thousands of designer features. Here we report de novo synthesis of the largest eukaryotic chromosome thus far, synIV, a 1,454,621-bp Saccharomyces cerevisiae chromosome resulting from extensive genome streamlining and modification. During the construction of synIV, we developed megachunk assembly combined with a hierarchical integration strategy, which significantly increased the accuracy and flexibility of synthetic chromosome construction and facilitated chromosome debugging. In addition to the drastic sequence changes made to synIV by rewriting it, we further manipulated the three-dimensional structure of synIV in the yeast nucleus to explore spatial gene regulation within the nuclear space. Surprisingly, we found few gene expression changes, suggesting that positioning inside the yeast nucleoplasm plays a minor role in gene regulation. Lastly, we tethered synIV to the inner nuclear membrane via its hundreds of loxPsym sites and observed transcriptional repression of the entire chromosome, demonstrating chromosome-wide transcription manipulation without changing the DNA sequences. Our manipulation of the spatial structure of the largest synthetic yeast chromosome shed light on higher-order architectural design of the synthetic genomes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/487066v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@18bf586org.highwire.dtl.DTLVardef@1a471d5org.highwire.dtl.DTLVardef@12d7690org.highwire.dtl.DTLVardef@1c32510_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDe novo synthesis of the largest eukaryotic chromosome, synIV C_LIO_LISynIV shows similar 3D structure to wild-type IV, despite thousands of changes made to it C_LIO_LI"Inside-out" repositioning of synIV in nucleus shows minor transcriptional changes C_LIO_LIMultipoint tethering synIV to inner nuclear membrane represses transcription of whole chromosome C_LI

synthetic biology↗

bioRxiv2022

HTL/KAI2 signalling substitutes for light to control plant germination

Deciphering signalling pathways is essential to understanding how organisms respond to environmental cues but elucidating how these signalling pathways evolve in new environments is less clear.1,2 Most plants, for example, monitor multiple environmental cues to optimize the time and place to germinate. Some root parasitic plants, however, germinate in response to small molecules like strigolactones (SLs) emanating from host roots3,4 whilst a number of ephemeral weeds germinate in response to chemicals called karrikins (KARs) released after a forest fire.5,6 Although these species represent distinct clades, they use the same HYPOSENSITIVE TO LIGHT/KARRIKIN INSENSITIVE 2 (HTL/KAI2) signalling pathway to perceive strigolactones or karrikins, which suggests convergent evolution.3,5 Because specialist lifestyles are derived traits, it is not clear if HTL/KAI2 signalling in these species evolved from a specific germination-signalling pathway or whether this pathway had other functions that were co-opted for specialist germination circumstances. Here, we show HTL/KAI2 signalling in Arabidopsis bypasses the light requirement for germination. In part, this is because the HTL/KAI2 downstream component, SMAX1 impinges on PHYTOCHROME INTERACTING FACTOR 1/PHYTOCHROME INTERACTING FACTOR 3-LIKE 5 (PIF1/PIL5)-regulated hormone response pathways conducive to germination. We identified Arabidopsis accessions that can germinate in the dark, which had altered expression of HTL/KAI2 signalling components, suggesting that divergence in this signalling pathway occurs in nature. Moreover, Arabidopsis HTL/KAI2-regulated gene signatures were observed in germinating Striga seed. The ability of HTL/KAI2 signalling to substitute for light advances an explanation for how some specialist plants evolved their underground germination behaviour in response to specific environments.

plant biology↗

bioRxiv2022

Evidence for the role of music on the growth and signal response in duckweed

Sound vibration, an external mechanical force, has been proved to modulate plant growth and development like rain, wind, and vibration. However, the role of music on plants, especially on signal response, has been usually neglected in research. Herein, we investigated the growth state, gene expression, and signal response in duckweed treated with soft music. The protein content in duckweed after music treatment for 7 days was about 1.6 times that in duckweed without music treatment. Additionally, Fv/Fm in duckweed treated with music was 0.78, which was significantly higher in comparison with the control group (P < 0.01). Interestingly, music promoted the Glu and Ca signaling response. To further explore the global molecular mechanism, we performed transcriptome analysis. A total of 1296 DEGs were found for all these investigated genes in duckweed treated with music compared to the control group. Among these, up-regulation of the expression of metabolism-related genes related to glycolysis, cell wall biosynthesis, oxidative phosphorylation, and pentose phosphate pathways were found. Overall, these results provided a molecular basis to music-triggered signal response, transcriptomic, and growth changes in duckweed, which also highlighted the potential of music as an environmentally friendly stimulus to promote improved protein production in duckweed.

plant biology↗