Biology subjects

Zhang, L.

Publications and source records attributed to Zhang, L..

At least 1,009 records · Page 56Linked to original sources

bioRxiv2022

A single-cell atlas of bobtail squid visual and nervous system highlights molecular principles of convergent evolution

Although the camera-type eyes of cephalopods and vertebrates are a canonical example of convergent morphological evolution, the cellular and molecular mechanisms underlying this convergence remain obscure. We used genomics and single cell transcriptomics to study these mechanisms in the visual system of the bobtail squid Euprymna berryi, an emerging cephalopod model. Analysis of 98,537 cellular transcriptomes from the squid visual and nervous system identified dozens of cell types that cannot be placed in simple correspondence with those of vertebrate or fly visual systems, as proposed by Ramon y Cajal and J.Z. Young. Instead, we find an unexpected diversity of neural types, dominated by dopamine, and previously uncharacterized glial cells. Surprisingly, we observe changes in cell populations and neurotransmitter usage during maturation and growth of the visual systems from hatchling to adult. Together these genomic and cellular findings shed new light on the parallel evolution of visual system complexity in cephalopods and vertebrates.

evolutionary biology↗

bioRxiv2022

Structural basis of a two-antibody cocktail exhibiting highly potent and broadly neutralizing activities against SARS-CoV-2 variants including diverse Omicron sublineages

SARS-CoV-2 variants of concern (VOCs), especially the latest Omicron, have exhibited severe antibody evasion. Broadly neutralizing antibodies with high potency against Omicron are urgently needed for understanding working mechanisms and developing therapeutic agents. In this study, we characterized previously reported F61, which was isolated from convalescent patients infected with prototype SARS-CoV-2, as a broadly neutralizing antibody against all VOCs including Omicron BA.1, BA.1.1, BA.2, BA.3 and BA.4 sublineages by utilizing antigen binding and cell infection assays. We also identified and characterized another broadly neutralizing antibody D2 with epitope distinct from that of F61. More importantly, we showed that a combination of F61 with D2 exhibited synergy in neutralization and protecting mice from SARS-CoV-2 Delta and Omicron BA.1 variants. Cryo-EM structures of the spike-F61 and spike-D2 binary complexes revealed the distinct epitopes of F61 and D2 at atomic level and the structural basis for neutralization. Cryo-EM structure of the Omicron-spike-F61-D2 ternary complex provides further structural insights into the synergy between F61 and D2. These results collectively indicated F61 and F61-D2 cocktail as promising therapeutic antibodies for combating SARS-CoV-2 variants including diverse Omicron sublineages.

biochemistry↗

bioRxiv2022

Microenvironmental Ammonia Enhances T cell Exhaustion in Colorectal Cancer

Effective therapies are lacking for patients with advanced colorectal cancer (CRC). The CRC tumor microenvironment has elevated metabolic waste products due to altered metabolism and proximity to the microbiota. The role of metabolite waste in tumor development, progression, and treatment resistance is unclear. We generated an autochthonous metastatic mouse model of CRC and unbiased multi-omic analyses in this model reveals a robust accumulation of tumoral ammonia. The high ammonia levels induce T cell metabolic reprogramming, increase exhaustion and decrease proliferation. CRC patients have increased serum ammonia, and our ammonia-related gene signature correlates with altered T cell response, adverse patient outcomes, and lack of response to immune checkpoint blockade. We demonstrate that enhancing ammonia clearance reactivates T cells, decreases tumor growth, and extends survival. Moreover, decreasing tumor-associated ammonia enhances anti-PD-L1 efficacy. Our findings indicate that ammonia detoxification can reactivate T cells, highlighting a new approach to enhance the efficacy of immunotherapies. Statement of SignificanceWe demonstrate that ammonia accumulates in the microenvironment of colorectal cancer. Ammonia alters T-cells redox singling leading to a decrease in T cell proliferation and an increase in T cell exhaustion. Enhancing ammonia clearance reduces tumor size, increases survival, and increases the efficacy to immunotherapies.

cancer biology↗

bioRxiv2022

Coiling of cellular protrusions around extracellular fibers

Protrusions at the leading-edge of a cell play an important role in sensing the extracellular cues, during cellular spreading and motility. Recent studies provided indications that these protrusions wrap (coil) around the extra-cellular fibers. The details of this coiling process, and the mechanisms that drive it, are not well understood. We present a combined theoretical and experimental study of the coiling of cellular protrusions on fibers of different geometry. Our theoretical model describes membrane protrusions that are produced by curved membrane proteins that recruit the protrusive forces of actin polymerization, and identifies the role of bending and adhesion energies in orienting the leading-edges of the protrusions along the azimuthal (coiling) direction. Our model predicts that the cells leading-edge coils on round fibers, but the coiling ceases for a fiber of elliptical (flat) cross-section. These predictions are verified by 3D visualization and quantitation of coiling on suspended fibers using Dual-View light-sheet microscopy (diSPIM). Overall, we provide a theoretical framework supported by high spatiotemporal resolution experiments capable of resolving coiling of cellular protrusions around extracellular fibers of varying diameters. Significance StatementCells adhere and migrate in environments that are composed of fibrous structures, such as the thin filaments of the extracellular matrix, or the wider axons and dendrites of neurons. In recent experiments, cells have been observed to form leading edge protrusions on such surfaces, that seem to coil around the extracellular fibers. However, the mechanism responsible for the formation of such coiling protrusions is not understood. Here, we provide a combined experimental and theoretical approach to explain the emergence of coiling protrusions. Our model is based on the self-organization of curved proteins that recruit actin polymerization at the leading edge of the cell, when spreading over an adhesive fiber.

biophysics↗

bioRxiv2022

Machine learning enables accurate prediction of breast cancer five-year survival using somatic genomic variants

Breast cancer is one of the most common cancers, accounting for about 30% of female cancers and a mortality rate of 15%. The 5-year survival rate is most commonly used to assess cancer progression and guide clinical practice. We used the CatBoost model to systematically construct a five-year mortality risk prediction model based on two independent data sets (BRCA_METABRIC, BRCA_TCGA). The model input data are the somatic genomic variants (copy number variation, SNP locus, cumulative mutation number of genes) and phenotype data of cancer samples. The optimal model combined all the above characteristics, and the AUC reached 0.70 in an independent external data set. At the same time, we also conducted a biological analysis of the characteristics of the model and found some potential biomarkers (TP53, DNAH11, MAP3K1, PHF20L1, etc.). The results of model risk stratification can be used as a guide for the prognosis of breast cancer.

bioinformatics↗

bioRxiv2022

Benchmarking de novo assembly methods on metagenomic sequencing data

Metagenome assembly is an efficient approach to deciphering the "microbial dark matter" in the microbiota based on metagenomic sequencing, due to the technical challenges involved in isolating and culturing all microbes in vitro. Although short-read sequencing has been widely used for metagenome assembly, linked- and long-read sequencing have shown their advancements by providing long-range DNA connectedness in assembly. Many metagenome assembly tools use dedicated algorithms to simplify the assembly graphs and resolve the repetitive sequences in microbial genomes. However, there remains no comprehensive evaluation of the pros and cons of various metagenomic sequencing technologies in metagenome assembly, and there is a lack of practical guidance on selecting the appropriate metagenome assembly tools. Therefore, this paper presents a comprehensive benchmark of 15 de novo assembly tools applied to 32 metagenomic sequencing datasets obtained from simulation, mock communities, or human stool samples. These datasets were generated using mainstream sequencing platforms, such as Illumina and BGISEQ short-read sequencing, 10x Genomics linked-read sequencing, and PacBio and Oxford Nanopore long-read sequencing. The assembly tools were extensively evaluated against many criteria, which revealed that compared with the other sequencing technologies, long-read assemblers generated the highest contig continuity but failed to reveal some medium- and high-quality metagenome-assembled genomes (MAGs). In addition, hybrid assemblers using both short- and long-read sequencing were promising tools to both improve contig continuity and increase the number of near-complete MAGs. This paper also discussed the running time and peak memory consumption of these tools and provided practical guidance on selecting them.

genomics↗

bioRxiv2022

A comprehensive investigation of statistical and machine learning approaches for predicting complex human diseases on genomic variants

BackgroundQuantifying an individuals risk for common diseases is an important goal of precision health. The polygenic risk score (PRS), which aggregates multiple risk alleles of candidate diseases, has emerged as a standard approach for identifying high-risk individuals. A variety of tools have been developed to implement PRS. However, benchmarks for comparatively evaluating the performance of these different methods and for assessing their potential to guide future clinical applications are lacking. ResultsWe systematically validated and compared thirteen statistical methods, five machine learning models and two ensemble models using simulated data, twenty-two common diseases with internal training sets and four diseases with external summary statistics from the UK Biobank resource. The effects of disease heritability, single nucleotide polymorphism (SNP) effect size and sample size are evaluated using simulated data. We also investigated the correlations between methods and their standard deviations of different diseases. ConclusionsIn general, statistical methods outperform machine learning models, and ensemble models, such as Super Learner, generally perform the best for most situations. We observed the correlations were relatively high if the methods were from the same category and the external summary statistics from large cohort GWAS could decrease the standard deviation of method correlations. By varying three factors in the simulated data, we also identified that disease heritability had a strong effect on the predictive performance of individual methods. Both the number and effect sizes of risk SNPs are important; and while sample size strongly influences the performance of machine learning models, but not statistical methods.

bioinformatics↗

bioRxiv2022

Botrytis cinerea infection accelerates ripening and cell wall disassembly to promote disease in tomato fruit

Postharvest fungal pathogens benefit from the increased host susceptibility that occurs during fruit ripening. In unripe fruit, pathogens often remain quiescent and unable to cause disease until ripening begins, emerging at this point into destructive necrotrophic lifestyles that quickly result in fruit decay. Here, we demonstrate that one such pathogen, Botrytis cinerea, actively induces ripening processes to facilitate infections and promote disease. Assessments of ripening progression revealed that B. cinerea accelerated external coloration, ethylene production, and softening in unripe fruit, while mRNA sequencing of inoculated unripe fruit confirmed the corresponding upregulation of host genes involved in ripening processes, such as ethylene biosynthesis and cell wall degradation. Furthermore, an ELISA-based glycomics technique to assess fruit cell wall polysaccharides revealed remarkable similarities in the cell wall polysaccharide changes caused by both infections of unripe fruit and ripening of healthy fruit, particularly in the increased accessibility of pectic polysaccharides. Virulence and additional ripening assessment experiments with B. cinerea knockout mutants showed that induction of ripening is dependent on the ability to infect the host and break down pectin. The B. cinerea double knockout{Delta} bcpg1{Delta}bcpg2 lacking two critical pectin degrading enzymes was found to be incapable of emerging from quiescence even long after the fruit had ripened at its own pace, suggesting that the failure to accelerate ripening severely inhibits fungal survival on unripe fruit. These findings demonstrate that active induction of ripening in unripe tomato fruit is an important infection strategy for B. cinerea. One-Sentence SummaryPhysiological, transcriptional, and glycomic evidence indicates Botrytis cinerea hastens tomato fruit ripening to facilitate infection by a mechanism dependent on the fungal enzymes Bcpg1 and Bcpg2.

plant biology↗

bioRxiv2022

Long divergent haplotypes introgressed from wild sheep are associated with distinct morphological and adaptive characteristics in domestic sheep

The worldwide sheep population comprises more than 1000 breeds. Together, these exhibit a considerable morphological diversity, which has not been extensively investigated at the molecular level. Here, we analyze whole-genome sequencing individuals of 1,098 domestic sheep from 154 breeds, and 69 wild sheep from seven Ovis species. On average, we detected 6.8%, 1.0% and 0.2% introgressed sequence in domestic sheep originating from Iranian mouflon, urial and argali, respectively, with rare introgressions from other wild species. Interestingly, several introgressed haplotypes contributed to the morphological differentiations across sheep breeds, such as a RXFP2 haplotype from Iranian mouflon conferring the spiral horn trait, a MSRB3 haplotype from argali strongly associated with ear morphology, and a VPS13B haplotype probably originating from urial and mouflon possibly associated with facial traits. Our results reveal that introgression events from wild Ovis species contributed to the high rate of morphological differentiation in sheep breeds, but also to individual variation within breeds. We propose that long divergent haplotypes are a ubiquitous source of phenotypic variation that allows adaptation to a variable environment, and that these remain intact in the receiving population due to reduced recombination.

evolutionary biology↗

bioRxiv2022

Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission

Schizophrenia affects approximately 1% of the world population. Genetics, epigenetics, and environmental factors are known to play a role in this psychiatric disorder. While there is a high concordance in monozygotic twins, about half of twin pairs are discordant for schizophrenia. We characterized human-induced pluripotent stem cell (iPSC)-derived hippocampal neurons from two pairs of monozygotic twins that are discordant for a schizophrenia diagnosis. We compared the affected and the non-affected siblings and compared all of them to twin sets where none of the siblings suffered from schizophrenia. We found that the neurons derived from the schizophrenia patients were less arborized, were hypoexcitable with immature spike features, and exhibited a significant reduction in synaptic activity with dysregulation in synapse-related genes. Interestingly, the neurons derived from the co-twin siblings who did not have schizophrenia formed another distinct group that was different from the neurons in the group of the affected twin siblings but also different from the neurons in the group of the control twins. The neurons in the unaffected co-twin group were also less arborized than the neurons from controls but more arborized than those from affected siblings. Some of their spike features were immature (but less immature than neurons derived from the affected siblings). Importantly, their synaptic activity was not affected. Since schizophrenia is a genetically complex disorder, our twin study allows the measurement of neuronal phenotypes with a similar genetic background. The differences between the siblings may arise due to changes that occurred after the split of the egg into twins. Therefore, our study confirms that dysregulation of synaptic pathways, as well as changes in the rate of synaptic events, distinguishes between individuals affected with schizophrenia and unaffected individuals, even in those having a very similar genetic background.

neuroscience↗

bioRxiv2022

Identifying disease-associated circRNAs based on edge-weighted graph attention and heterogeneous graph neural network

MotivationCircular RNAs (circRNAs) with varied biological activities are implicated in pathogenic processes, according to new findings. They are regarded as promising biomarkers for the diagnosis and prognosis due to their structural features. Computational approaches, as opposed to traditional experiments, can identify the circRNA-disease connections at a lower cost. Multi-source pathogenesis data can help to reduce data sparsity and infer probable connections at the system level. The majority of available approaches create a homologous network using multi-source data, but they lose the datas heterogeneity. Effective solutions that make use of the peculiarities of multi-source data are urgently needed. ResultsIn this paper, we propose a model (CDHGNN) based on edge-weighted graph attention and heterogeneous graph neural networks for discovering probable circRNA-disease correlations prediction. The circRNA network, miRNA network, disease network and heterogeneous network are constructed based on the introduced multi-source data on circRNAs, miRNAs, and diseases. The features for each type of node in the network are then extracted using a designed edge-weighted graph attention network model. Using the revised node features, we learn meta-path contextual information and use heterogeneous neural networks to assign attention weights to different types of edges. CDHGNN outperforms state-of-the-art algorithms with comparable accuracy, according to the findings of the trial. Edge-weighted graph attention networks and heterogeneous graph networks have both improved performance significantly. Furthermore, case studies suggest that CDHGNN is capable of identifying particular molecular connections and can be used to investigate pathogenic pathways. Contactjxwang@mail.csu.edu.cn

bioinformatics↗

bioRxiv2022

A hippocampal-anterior thalamic circuit associated with learning rate in ageing

Memory normally declines with ageing and these age-related cognitive changes are associated with changes in brain structure. Episodic memory retrieval has been widely studied during ageing, whereas learning has received less attention. Here we examined the neural correlates of episodic learning rate in ageing. Our study sample consisted of 982 cognitively healthy female and male older participants from the Vallecas Project cohort, without a clinical diagnosis of mild cognitive impairment or dementia. The learning rate across the three consecutive recall trials of the verbal memory task (Free and Cued Selective Reminding Test) recall trials was used as a predictor of grey matter (GM) using voxel-based morphometry, and WM microstructure using tract-based spatial statistics on fractional anisotropy (FA) and mean diffusivity (MD) measures. Immediate Recall improved by 1.4 items per trial on average, and this episodic learning rate was faster in women and negatively associated with age. Structurally, hippocampal and anterior thalamic GM volume correlated positively with learning rate. Learning also correlated with the integrity of WM microstructure (high FA and low MD) in an extensive network of tracts including bilateral anterior thalamic radiation, fornix, and long-range tracts. These results suggest that episodic learning rate is associated with key anatomical structures for memory functioning, motivating further exploration of the differential diagnostic properties between episodic learning rate and retrieval in ageing.

neuroscience↗

bioRxiv2022

Single cell transcriptomic profiling of tauopathy in a novel 3D neuron-astrocyte coculture model

The use of iPSC derived brain organoid models to study neurodegenerative disease has been hampered by a lack of systems that accurately and expeditiously recapitulate pathogenesis in the context of neuron-glial interactions. Here we report development of a system, termed AstTau, which propagates toxic human tau oligomers in iPSC derived neuron-astrocyte spheroids. The AstTau system develops much of the neuronal and astrocytic pathology observed in tauopathies including misfolded, phosphorylated, oligomeric, and fibrillar tau, strong neurodegeneration, and reactive astrogliosis. Single cell transcriptomic profiling combined with immunochemistry characterizes a model system that can more closely recapitulate late-stage changes in adult neurodegeneration. The transcriptomic studies demonstrate striking changes in neuroinflammatory and heat shock protein (HSP) chaperone systems in the disease process. Treatment with the HSP90 inhibitor PU-H71 was used to address the putative dysfunctional HSP chaperone system and produced a strong reduction of pathology and neurodegeneration, highlighting the potential of AstTau as a rapid and reproducible tool for drug discovery.

neuroscience↗

bioRxiv2022

Increased glucose availability sensitizes pancreatic cancer to chemotherapy

Pancreatic cancer (Pancreatic Ductal Adenocarcinoma; PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, leaving chemotherapy as the best available systematic treatment. The discovery of safe and available adjuncts that improve chemotherapeutic efficacy would potentially improve survival outcomes. We show that a hyperglycemic state enhances the efficacy of conventional single- and multi-agent chemotherapies against PDAC. Molecular analyses of tumors exposed to relatively high glucose levels revealed that a key metabolic pathway, glutathione biosynthesis, is diminished and underlies chemo-sensitization by enhancing oxidative injury to cancer cells. Inhibition of this pathway under normal conditions phenocopied a hyperglycemic state by enhancing chemotherapeutic efficacy in mouse PDAC, while rescuing the pathway under high glucose abrogated the anti-tumor effects observed with chemotherapy.

cancer biology↗

bioRxiv2022

TME induced TRAIL secretion from engineered macrophages for anti-tumor therapy

Capacity of tumor niche chemotaxis and long-term persistency making macrophage as great vehicles for anti-tumor factor delivery. Macrophages-based delivery of chemokines or cytokines have been tested for tissue homeostasis and cancer repression. TRAIL as a promising anti-tumor cytokine, made little clinical progress due to limited stability and off-target toxicity. Here we engineered macrophages with tumor micro-environment (TME)-induced trimerized CP1-TRAIL secretion under the TME specific promoter Arg1 (Tri-TRAIL-iM). The Tri-TRAIL-iM cells displayed high specific inducible activity in both cell-based co-culture assay and in tumor baring mice models. Compared to normal TRAIL over-expressed macrophages under none-inducible promoter, Tri-TRAIL-iM infiltrated to tumor sites and showed superior apoptosis induction of cancer cells and tumor growth repression as well as less systemic side effect. This inducible delivery TRAIL strategy can be effectively further applied in clinical studies and can be coupled with other engineered methods to maximize the therapeutic outcomes for solid tumors.

cancer biology↗

bioRxiv2022

Induction of neutralizing antibodies against SARS-CoV-2 variants by a multivalent mRNA-lipid nanoparticle vaccine encoding SARS-CoV-2/SARS-CoV Spike protein receptor-binding domains

To address the need for multivalent vaccines against Coronaviridae that can be rapidly developed and manufactured, we compared antibody responses against SARS-CoV, SARS-CoV-2, and several variants of concern in mice immunized with mRNA-lipid nanoparticle vaccines encoding homodimers or heterodimers of SARS-CoV/SARS-CoV-2 receptor-binding domains. All vaccine constructs induced robust anti-viral antibody responses, and the heterodimeric vaccine elicited an IgG response capable of cross-neutralizing SARS-CoV, SARS-CoV-2 Wuhan-Hu-1, B.1.351 (beta), and B.1.617.2 (delta) variants.

immunology↗

bioRxiv2022

The arthropod associates of 155 North American cynipid oak galls

The identities of most arthropod associates of cynipid-induced oak galls in the western Palearctic are generally known. However, a comprehensive accounting of associates has been performed for only a small number of the galls induced by the estimated 700 species of cynipid gall wasp in the Nearctic. This gap in knowledge stymies many potential studies of diversity, coevolution, and community ecology, for which oak gall systems are otherwise ideal models. We report rearing records of insects and other arthropods from more than 527,306 individual galls representing 201 different oak gall types collected from 32 oak tree species in North America. Of the 201 gall types collected, 155 produced one or more animals. A total of 151,075 animals were found in association with these 155 gall types, and of these 61,044 (40.4%) were gall wasps while 90,031 (59.6%) were other arthropods. We identified all animals to superfamily, family, or, where possible, to genus. We provide raw numbers and summaries of collections, alongside notes on natural history, ecology, and previously published associations for each taxon. For eight common gall-associated genera (Synergus, Ceroptres, Euceroptres, Ormyrus, Torymus, Eurytoma, Sycophila, and Euderus), we also connect rearing records to gall wasp phylogeny, geography, and ecology - including host tree and gall location (host organ), and their co-occurrence with other insect genera. Though the diversity of gall wasps and the large size of these communities is such that many Nearctic oak gall-associated insects still remain undescribed, this large collection and identification effort should facilitate the testing of new and varied ecological and evolutionary hypotheses in Nearctic oak galls.

zoology↗

bioRxiv2022

Extensive diversity of RNA viruses in ticks revealed by metagenomics in northeastern China

Recently, several emerging tick-borne viruses have been identified to be associated with human diseases in northeastern China. Here, we used metagenomics to investigate the virome diversity in Haemaphysalis japonica, H. conicinna, Dermacentor silvarum, and Ixodes persulcatus ticks in northeastern China. A total of 22 RNA viruses were identified and belonged to more eight viral families, including four each in Nairoviridae and Phenuiviridae, three each in Flaviviridae, Rhabdoviridae, and Solemoviridae, two in Chuviridae, and one each in Partitiviridae, Tombusviridae, and unclassified. Of them, eight viruses were novel species, belonging to Nairoviridae (Jian nairovirus and Yichun nairovirus), Phenuiviridae (Mudanjiang phlebovirus), Rhabdoviridae (Tahe rhabdovirus 1-3), Chuviridae (Yichun mivirus), and Tombusviridae (Yichun tombus-like virus), and five members were established human pathogens, including Alongshan virus, tick-borne encephalitis virus, Songling virus, Beiji nairovirus, and Nuomin virus. I. persulcatus ticks had significant higher viral species than those in H. japonica, H. concinna, and D. silvarum ticks. Significant differences in tick viromes were observed among Daxingan, Xiaoxingan and Changbai mountains. These findings showed an extensive diversity of RNA viruses in ticks in northeastern China, revealed potential public health threats from the emerging tick-borne viruses. Further studies are needed to explain the natural circulation and pathogenicity of these viruses.

microbiology↗