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Zhao, W.

Publications and source records attributed to Zhao, W..

At least 235 records · Page 13Linked to original sources
bioRxiv2022

An expanded deep-branching thermophilic bacterial clade sheds light on the early evolution of bacteria

The origin of thermophilic bacteria is essential to our understanding of the early evolution of life. However, due to the lack of deep-branching culturable lineages, many controversies remain. Here, we report a novel deep-branching, sulfur-reducing, thermophilic bacterium that was isolated from a deep-sea hydrothermal vent using a newly developed cultivation strategy ("Subtraction-Suboptimal", StS). This bacterial lineage clusters together with other major thermophilic bacterial groups on phylogenomic trees and forms a robust superphylum-level clade that represents a major, early-diverging bacterial lineage. Ancestral analyses and metabolic modeling reveal the ancestor of this lineage might be a thermophilic and mixotrophic bacteria with a preference for amino acids utilization. These findings provide evolutionary insights into the early divergence of thermophilic bacteria and their adaptive strategies on early Earth.

microbiology↗
bioRxiv2022

The central autonomic system revisited - convergent evidence for a regulatory role of the insular and midcingulate cortex from neuroimaging meta-analyses

The autonomic nervous system regulates dynamic body adaptations to internal and external environment changes. Capitalizing on two different algorithms (Analysis of Brain Coordinates and GingerALE) that differ in empirical assumptions, we scrutinized the meta-analytic convergence of human neuroimaging studies investigating the neural basis of peripheral autonomic signal processing. Among the selected studies, we identified 42 records reporting 44 different experiments and testing 792 healthy individuals. The results of the two different algorithms converge in identifying the bilateral dorsal anterior insula and midcingulate cortex as the critical areas of the central autonomic system (CAN). However, whereas the bilateral dorsal anterior insula appears to be involved in processing autonomic nervous system signals regardless of task type, activity in the midcingulate cortex appears to be primarily engaged in processing autonomic signals during cognitive tasks and task-free conditions. Applying an unbiased approach, we were able to identify a single functionally condition-independent circuit that supports CAN activity. Although partially overlapping with the salience network, this functional circuit includes, in addition to the bilateral insular cortex and midcingulate cortex, the bilateral inferior parietal lobules and small clusters in the bilateral middle frontal gyrus. Our results do not support the hypothesis of divergent pathways for the sympathetic and parasympathetic systems or a robust involvement of the default mode network, particularly during parasympathetic activity. However, these results may be due to the relatively low number of studies investigating the parasympathetic system (12%), making our results more consistent with the central processing network of sympathetic activity. Remarkably, the critical regions of the CAN observed in this meta-analysis are among the most reported co-activated areas in neuroimaging studies and have been repeatedly shown as being dysregulated across different mental and neurological disorders. This suggests that the central dynamic interaction maintaining bodily homeostasis reported in several brain imaging studies may be associated with increased autonomic nervous system engagement and that disruptions in this interplay may underpin unspecific pathological symptoms across mental and neurological disorders.

neuroscience↗
bioRxiv2022

MADET: A Manually Curated Knowledgebase for Microbiomic Effects on Efficacy and Toxicity of Anticancer Treatments

A plethora of studies have reported the associations between microbiota and multiple diseases, leading to at least four databases to demonstrate microbiota-disease associations, i.e., gutMDisorder, mBodyMap, GMrepo and Amadis. Moreover, gut microbiota also mediates drug efficacy and toxicity, whereas a comprehensive database to elucidate the microbiota-drug associations is lacking. Here we report an open-access knowledgebase, MADET (Microbiomics of Anticancer Drug Efficacy and Toxicity), which harbors 453 manually annotated microbiota-drug associations from 24 papers. MADET provides user-friendly functions allowing users to freely browse, search, and download the data conveniently from the database. Users can customize their search filters in MADET using different types of keywords, including bacterial name (e.g., Akkermansia muciniphila), anticancer treatment (e.g., anti-PD-1 therapy) or cancer type (e.g., lung cancer) with different types of experimental evidence of microbiota-drug association and causation. We have also enabled user submission to further enrich the data document in MADET. The MADET database is freely available at https://www.madet.info. We anticipate that MADET will serve as a useful resource for a better understanding of the microbiota-drug associations and facilitate the future development of novel biomarkers and live biotherapeutic products for anticancer therapies.

microbiology↗
bioRxiv2022

Intrinsic RNA targeting constrains the utility of CRISPR-Cas13 systems

CRISPR-Cas13 systems have been adapted as versatile toolkits for RNA-related applications. Here we systematically evaluate the performance of several popular Cas13 family effectors (Cas13a, Cas13b and Cas13d) under lentiviral vectors and reveal surprisingly differential defects and characteristics of these systems. Using RNA immunoprecipitation sequencing, transcriptome profiling, biochemistry analysis, high-throughput CRISPR-Cas13 screening and machine learning approaches, we determine that each Cas13 system has its intrinsic RNA targets in mammalian cells. Viral process-related host genes can be targeted by Cas13 and affect production of fertile lentiviral particles, thereby restricting the utility of lentiviral Cas13 systems. Multiple RNase activities of Cas13 are involved in endogenous RNA targeting. Unlike target-induced nonspecific collateral effect, intrinsic RNA cleavage can be specific, target-independent and dynamically tuned by varied states of Cas13 nucleases. Our work provides guidance on appropriate use of lentiviral Cas13 systems and further raises cautions about intrinsic RNA targeting during Cas13-based basic and therapeutic applications.

molecular biology↗
bioRxiv2022

Angiotensin II regulates the neural expression of subjective fear in humans

BackgroundRodent models and pharmacological neuroimaging studies in humans have been employed to test novel pharmacological agents to reduce fear. However, these strategies are limited with respect to determining process-specific effects on the actual subjective experience of fear which represents the key symptom why patients seek treatment. We here employed a novel precision pharmacological fMRI approach that is based on process-specific neuroaffective signatures to determine effects of the selective angiotensin II type 1 receptor (ATR1) antagonist losartan on the subjective experience of fear. MethodsIn a double-blind, placebo-controlled randomized pharmacological fMRI design n = 87 healthy participants were administered 50mg losartan or placebo before they underwent an oddball paradigm which included neutral, novel and fear oddballs. Losartan effects on brain activity and connectivity as well as on process-specific multivariate neural signatures were examined. ResultsAT1R blockade selectively reduces the neurofunctional reactivity to fear-inducing visual oddballs in terms of attenuating dorsolateral prefrontal activity and amygdala-ventral anterior cingulate (vACC) communication. Neurofunctional decoding further demonstrates fear-specific effects given that ATR1 blockade (1) reduces the neural expression of subjective fear, but not threat or non-specific negative expressions, and (2) does not affect reactivity to novel oddballs. ConclusionsThese results show a specific role of the AT1R in regulating subjective fear experience and demonstrate the feasibility of a precision pharmacological fMRI approach to the affective characterization of novel receptor targets for fear in humans.

neuroscience↗
bioRxiv2022

Sequence characterization of the complete chloroplast genome of Eupatorium fortunei

Eupatorium fortunei has been utilized as herbal medicine to cure various diseases in various regions of the world especially China, Korea, and other Asian countries. The available literature shows Eupatorium fortunei contain anti-metastatic, anti-angiogenic, anti-bacterial, and anti-oxidant, along with compounds to cure human cancer. In present study, Eupatorium fortunei was used as an experimental material, and its genome was sequenced based on high-throughput sequencing technology. We assembled the complete chloroplast genome of Eupatorium fortunei and obtained NCBI accession number (OK545755). We analyzed chloroplast genome structure of Eupatorium fortunei and systematic analysis was conducted, including the size of the entire genome sequence, genome volume, large single-copy (LSC), small single-copy (SSC), inverted repeat region (IR)-LSC/SSC boundaries, etc. The obtained results showed that chloroplast genome of Eupatorium fortunei is a typical tetrad structure with a total length of 152,401 bp and a sum of 133 annotated genes, including eight ribosomal RNA (rRNA)-encoding genes, 37 transfer RNA (tRNA)-encoding genes, 87 protein-encoding genes, and one pseudo-gene. A sum of 29 Single Sequence Repeats (SSR)s were identified for mono-nucleotide, di-nucleotide and tri-nucleotide microsatellites with mono-nucleotides in majority. The phylogenetic analysis revealed that Eupatorium fortunei is more closely related to Litothamnus nitidus and belongs to the same branch. The genome assembly and analysis of the chloroplast genome of Eupatorium fortunei provides more accurate evidence for further taxonomic identification and localization of Asteraceae/Compositae plant.

bioinformatics↗
bioRxiv2022

A Causal Role of Human Laryngeal Motor Cortex in Speech Lexical Tone and Voicing Perception

Speech perception is believed to recruit the left motor cortex. However, the exact role of the laryngeal subregion and its right counterpart in speech perception, as well as their temporal patterns of involvement remain unclear. To address these questions, we conducted a hypothesis-driven study, utilizing transcranial magnetic stimulation on the left or right dorsal laryngeal motor cortex (dLMC) when participants performed perceptual decision on Mandarin lexical tone or consonant (voicing contrast) presented with or without noise. We used psychometric function and hierarchical drift-diffusion model to disentangle perceptual sensitivity and dynamic decision-making parameters. Results showed that bilateral dLMCs were engaged with effector specificity, and this engagement was left-lateralized with right upregulation in noise. Furthermore, the dLMC contributed to various decision stages depending on the hemisphere and task difficulty. These findings substantially advance our understanding of the hemispherical lateralization and temporal dynamics of bilateral dLMC in sensorimotor integration during speech perceptual decision-making.

neuroscience↗
bioRxiv2022

Identification of C270 as a novel site for allosteric modulators of SARS-CoV-2 papain-like protease

The papain-like protease (PLpro) in coronavirus is one of key cysteine proteases responsible for the proteolytic processing of viral polyproteins, and plays an important role in dysregulation of host immune response. PLpro is a promising therapeutic target with a major challenge in inhibitor design due to the restricted S1/S2 sites for two consecutive glycine of substrates. Here we reported the discovery of two activators of the SARS-CoV-2 PLpro from a biochemical screening, and the identification of the unique residue, C270, as an allosteric and covalent regulation site for the activators. This site was also specifically modified by glutathione oxidized, resulting in the S-glutathionylation and activation of the protease. Furthermore, one compound was found to allosterically inhibit the protease by covalent binding to this crucial site. Together, these results elucidated an unrevealed molecular mechanism for allosteric modulation of the proteases activity, and provided a new strategy for discovery of allosteric inhibitors of the SARS-CoV-2 PLpro.

molecular biology↗
bioRxiv2022

Mechanical activation of mitochondrial energy metabolism during cell differentiation

In multicellular lives, differentiation of many types of stem and progenitor cells is often accompanied by a metabolic transition from glycolysis to mitochondrial oxidative phosphorylation. The mechanisms driving this metabolic transition in vivo are largely unknown. Here, we show that, during differentiation of the Drosophila female germline cyst, the surrounding somatic cells compress the cyst and increase the tension of cyst cells membranes. Transmembrane channel-like, an evolutionarily conserved ion channel involved in mechanosensation, maintains cytosolic Ca2+ levels in compressed differentiating cysts. Cytosolic Ca2+ induces transcriptional activation of oxidative phosphorylation through a CaMKI-Fray-JNK signaling relay. Our findings demonstrate a molecular link between cell mechanics and mitochondrial energy metabolism, with implications in other developmentally orchestrated metabolic transitions in mammals. One-Sentence SummaryMechanical forces from the surrounding tissue activate mitochondrial energy metabolism in differentiating cells in vivo.

cell biology↗
bioRxiv2022

BNIP3 upregulation characterizes cancer cell subpopulation with increased fitness and proliferation

BNIP3 is a BH3 only protein with both pro-apoptotic and pro-survival roles depending on the cellular context. It remains unclear how BNIP3 RNA level dictates cell fate decisions of cancer cells. Here we undertook a quantitative analysis of BNIP3 expression and functions in single cell datasets of various epithelial malignancies. Our results demonstrated that BNIP3 upregulation characterizes cancer cell subpopulations with increased fitness and proliferation. We further validated the upregulation of BNIP3 in liver cancer organoids compared with 2D culture. Taken together, the combination of in silico perturbations using public single cell datasets and experimental cancer modeling using organoids ushered in a new approach to address cancer heterogeneity.

systems biology↗
bioRxiv2022

Angiotensin blockade enhances motivational reward learning via enhancing ventral striatal prediction error and frontostriatal communication

Adaptive human learning utilizes reward prediction errors (RPEs) that scale the differences between expected and actual outcomes to optimize future choices. Depression has been linked with biased RPE signaling and an exaggerated impact of negative outcomes on learning which may promote amotivation and anhedonia. The present proof-of-concept study combined computational modelling and multivariate decoding with neuroimaging to determine the influence of the selective competitive angiotensin II type 1 receptor antagonist losartan on learning from positive or negative outcomes and the underlying neural mechanisms in healthy humans. In a double-blind, between-subjects, placebo-controlled pharmaco-fMRI experiment, 61 healthy male participants (losartan, n=30; placebo, n=31) underwent a probabilistic selection reinforcement learning task incorporating a learning and transfer phase. Losartan improved choice accuracy for the hardest stimulus pair via increasing expected value sensitivity towards the rewarding stimulus relative to the placebo group during learning. Computational modelling revealed that losartan reduced the learning rate for negative outcomes and increased exploitatory choice behaviors while preserving learning for positive outcomes. These behavioral patterns were paralleled on the neural level by increased RPE signaling in orbitofrontal-striatal regions and enhanced positive outcome representations in the ventral striatum (VS) following losartan. In the transfer phase, losartan accelerated response times and enhanced VS functional connectivity with left dorsolateral prefrontal cortex when approaching maximum rewards. These findings elucidate the potential of losartan to reduce the impact of negative outcomes during learning and subsequently facilitate motivational approach towards maximum rewards in the transfer of learning. This may indicate a promising therapeutic mechanism to normalize distorted reward learning and fronto-striatal functioning in depression.

neuroscience↗
bioRxiv2022

Tracking SARS-CoV-2 Omicron diverse spike gene mutations identifies multiple inter-variant recombination events

The current pandemic of COVID-19 is fueled by more infectious emergent Omicron variants. Ongoing concerns of emergent variants include possible recombinants, as genome recombination is an important evolutionary mechanism for the emergence and re-emergence of human viral pathogens. Although recombination events among SARS-CoV-1 and MERS-CoV were well-documented, it has been difficult to detect the recombination signatures in SARS-CoV-2 variants due to their high degree of sequence similarity. In this study, we identified diverse recombination events between two Omicron major subvariants (BA.1 and BA.2) and other variants of concern (VOCs) and variants of interest (VOIs), suggesting that co-infection and subsequent genome recombination play important roles in the ongoing evolution of SARS-CoV-2. Through scanning high-quality completed Omicron spike gene sequences, eighteen core mutations of BA.1 variants (frequency >99%) were identified (eight in NTD, five near the S1/S2 cleavage site, and five in S2). BA.2 variants share three additional amino acid deletions with the Alpha variants. BA.1 subvariants share nine common amino acid mutations (three more than BA.2) in the spike protein with most VOCs, suggesting a possible recombination origin of Omicron from these VOCs. There are three more Alpha-related mutations (del69-70, del144) in BA.1 than BA.2, and therefore BA.1 may be phylogenetically closer to the Alpha variant. Revertant mutations are found in some dominant mutations (frequency >95%) in the BA.1 subvariant. Most notably, multiple additional amino acid mutations in the Delta spike protein were also identified in the recently emerged Omicron isolates, which implied possible recombination events occurred between the Omicron and Delta variants during the on-going pandemic. Monitoring the evolving SARS-CoV-2 genomes especially for recombination is critically important for recognition of abrupt changes to viral attributes including its epitopes which may call for vaccine modifications.

microbiology↗
bioRxiv2022

In situ architecture of human kinetochore-microtubule interface visualized by cryo-electron tomography

Faithful segregation of chromosomes during mitosis relies on a carefully coordinated and intricate interplay between the centromere, kinetochore, and spindle microtubules. Despite its importance, the architecture of this interface remains elusive. Here we used in situ cryo-electron tomography to visualize the native architecture of the kinetochore-microtubule interface in human U2OS cells at different stages of mitosis. We find that the centromere forms a pocket-like structure around kinetochore microtubules. Two morphologically distinct fibrillar densities form end-on and side-on connections to the plus-ends of microtubules within this centromeric pocket. Our data suggest a dynamic kinetochore-microtubule interface with multiple interactions between outer kinetochore components and spindle microtubules.

cell biology↗
bioRxiv2022

Cerebral organoids for modeling of HSV-1-induced-multiscale neuropathology associated with Alzheimers disease and phenotypic rescue

Herpes simplex virus type I (HSV-1) infection is a potential risk factor involved in the pathogenesis of Alzheimers disease (AD) and contributes to the AD viral hypothesis. However, further understanding of the neuropathological effects of the HSV-1 infection is hampered by the limitations of existing infection models due to the distinct differences between human brains and other mammalians brains. Here we generated cerebral organoid models derived from pluripotent stem cells to investigate the HSV-induced pathogenesis associated with AD and the role of antiviral drugs in the phenotypic rescue. Our results identified that the HSV-1-infected cerebral organoids recapitulated multiscale neuropathology pertaining to the onset and progression of AD across the genetic, cellular, and tissue levels, including the multicellular A{beta} deposition, dysregulated endogenous AD mediators, reactive gliosis, neuroinflammation, and neural loss. Furthermore, we identified that two antiviral drugs, namely Ribavirin (RBV) and Valacyclovir (VCV), inhibited HSV-1 replication and rescued the neuropathological phenotypes associated with AD in the HSV-1-infected cerebral organoids, implying their therapeutic potential to slow down the progression of AD. Our study provides a high-fidelity human-relevant in-vitro HSV-1 infection model to reconstitute the multiscale neuropathological features associated with AD and discover therapeutic drug candidates relevant to the AD viral hypothesis. IMPORTANCEAD is a progressive neurodegenerative disorder characterized by neuronal death, brain atrophy, and cognitive impairment. HSV-1 is a neurotropic double-stranded DNA virus resulting in long-term neurological sequelae in adults. There is accumulating evidence indicating that AD may be associated with HSV-1 infections. In this study, we generated human-physiologically related cerebral organoids derived from human embryonic stem cells (hESCs) to investigate the influence of HSV-1 infection on the neuropathology associated with AD. We found that the HSV-1-infected cerebral organoids could model typical neuropathological features associated with AD. Additionally, we discovered that both RBV and VCV significantly rescued the HSV-1-induced pathological phenotypes associated with AD. These findings may open new avenues of consideration related to HSV-1 infection and AD. Furthermore, the contribution of these antiviral drugs to AD linked to HSV-1 infection will provide new clues to potential new therapies.

neuroscience↗
bioRxiv2022

Metagenomic and Metabolomic Analyses Reveal Synergistic Effects of Fecal Microbiota Transplantation and Anti-PD-1 Therapy on Treating Colorectal Cancer

Anti-PD-1 immunotherapy has saved numerous lives of cancer patients; however, it only exerts efficacy in 10-15% of patients with colorectal cancer. Fecal microbiota transplantation (FMT) is a potential approach to improving the efficacy of anti-PD-1 therapy, whereas the detailed mechanisms and the applicability of this combination therapy remain unclear. In this study, we evaluated the synergistic effect of FMT with anti-PD-1 in curing colorectal tumor-bearing mice using a multi-omics approach. Mice treated with the combination therapy showed superior survival rate and tumor control, compared to the mice received anti-PD-1 therapy or FMT alone. Metagenomic analysis showed that composition of gut microbiota in tumor-bearing mice treated with anti-PD-1 therapy was remarkably altered through receiving FMT. Particularly, Bacteroides genus, including FMT-increased B. thetaiotaomicron, B. fragilis, and FMT-decreased B. ovatus might contribute to the enhanced efficacy of anti-PD-1 therapy. Furthermore, metabolomic analysis upon mouse plasma revealed several potential metabolites that upregulated after FMT, including punicic acid and aspirin, might promote the response to anti-PD-1 therapy via their immunomodulatory functions. This work broadens our understanding of the mechanism by which FMT improves the efficacy of anti-PD-1 therapy, which may contribute to the development of novel microbiota-based anti-cancer therapies.

microbiology↗
bioRxiv2022

Guiding Irregular Nuclear Morphology on Nanopillar Array for Malignancy Differentiation in Tumor cells

For more than a century, abnormal nuclei in tumor cells, presenting subnuclear invaginations and folds on the nuclear envelope, have been known to be associated with high malignancy and poor prognosis. However, current nuclear morphology analysis focuses on the features of the entire nucleus, overlooking the malignancy-related subnuclear features in nanometer scale. The main technical challenge is to probe such tiny and randomly distributed features inside cells. We here employ nanopillar arrays to guide subnuclear features into ordered patterns enabling their quantification as a strong indicator of cell malignancy. Both breast and liver cancer cells were validated, as well as the quantification of nuclear abnormality heterogeneity. The alterations of subnuclear patterns were also explored as effective readouts for drug treatment. We envision this nanopillar-enabled quantification of subnuclear abnormal features in tumor cells opens a new angle in characterizing malignant cells and studying the unique nuclear biology in cancer. TeaserA nanopillar-based assay quantifying the abnormal nuclear morphology in tumor cells at single-cell level.

bioengineering↗
bioRxiv2022

SERM: a self-consistent deep learning solution forrapid and accurate gene expression recovery

Single cell RNA sequencing (scRNA-seq) is a promising technique to determine the states of individual cells and classify novel cell subtypes. Computationally, the processing of scRNA-seq data presents a daunting challenge because of the noisy nature and humongous size and dimensionality of the data. Compromised solution by omitting the genes with low expression is commonly taken in current scRNA-seq analysis, which leads to inaccurate gene counts. In this paper, we introduce a broadly applicable data-driven gene expression recovery framework, referred to as the self-consistent expression recovery machine (SERM), to impute the missing gene expression. Using deep learning, SERM first learns from a subset of the noisy gene expression data to estimate the underlying data distribution. SERM then recovers the overall gene expression data by imposing a self-consistency on the gene expression matrix, thus ensuring that the expression levels are similarly distributed in different parts of the matrix. We show that SERM significantly improves the accuracy of gene imputation with at least 100-fold increase in computational efficiency in comparison to the state-of-the-art techniques. Thus SERM promises to provide an urgently needed computational solution for rapid and accurate recovery of big genomic expression data. SERM is available as a web-based computational tool (https://www.analyxus.com/compute/serm) and its source codes can be found in https://github.com/xinglab-ai/self-consistent-expression-recovery-machine.

bioinformatics↗
bioRxiv2021

Network design principle for robust oscillatory behaviors with respect to biological noise

Oscillatory behaviors, which are ubiquitous in transcriptional regulatory networks, are often subject to inevitable biological noise. Thus a natural question is how transcriptional regulatory networks can robustly achieve accurate oscillation in the presence of biological noise. Here, we search all two- and three-node transcriptional regulatory network topologies for those robustly capable of accurate oscillation against the parameter variability (extrinsic noise) or stochasticity of chemical reactions (intrinsic noise). We find that, no matter what source of the noise is applied, the topologies containing the repressilator with positive auto-regulation show higher robustness of accurate oscillation than those containing the activator-inhibitor oscillator, and additional positive auto-regulation enhances the robustness against noise. Nevertheless, the attenuation of different sources of noise is governed by distinct mechanisms: the parameter variability is buffered by the long period, while the stochasticity of chemical reactions is filtered by the high amplitude. Furthermore, we analyze the noise of a synthetic human nuclear factor {kappa}B (NF-{kappa}B) signaling network by varying three different topologies, and verify that the addition of a repressilator to the activator-inhibitor oscillator, which leads to the emergence of high-robustness motif--the repressilator with positive auto-regulation, improves the oscillation accuracy in comparison to the topology with only an activator-inhibitor oscillator. These design principles may be applicable to other oscillatory circuits.

systems biology↗