Biology subjects

Meng, L.

Publications and source records attributed to Meng, L..

At least 73 records · Page 4Linked to original sources

bioRxiv2022

Statistical Methods for Detecting Circadian Rhythmicity and Differential Circadian Patterns with Repeated Measurement in Transcriptomic Applications

Circadian analysis via transcriptomic data has been successful in revealing the clock output changes underlying many diseases and physiological processes. Repeated measurement design in a circadian study is prevalent, in which the same subject is repeatedly measured over time. Several methods are currently available to perform circadian analysis, however, none of them take advantage of the repeated measurement design. And ignoring the within-subject correlation from the repeated measurement could result in lower statistical power. To address this issue, we developed linear mixed model based methods to detect (i) circadian rhythmicity (i.e., Rpt_rhythmicity) and (ii) differential circadian patterns comparing two experimental conditions (i.e., Rpt_diff). Our model includes a subject-specific random effect, which will account for the within-subject correlation. Via simulations, we showed our method not only could control the type I error rate around the nominal level, but also achieve higher statistical power compared to other methods that cannot model repeated measurement. The superior performance of Rpt_rhythmicity and Rpt_diff were also demonstrated in two real data applications, including a human restricted feeding data and a human sleep restriction data. An R package for our methods is publicly available on GitHub to promote the application of our methods.

bioinformatics↗

bioRxiv2022

Chromatin-modifying enzymes as modulators of nuclear size during lineage differentiation

The mechanism of nuclear size determination and alteration during normal lineage development and cancer pathologies which is not fully understood. As recently reported, chromatin modification can change nuclear morphology. Therefore, we screened a range of pharmacological chemical compounds that impact the activity of chromatin-modifying enzymes, in order to get a clue of the specific types of chromatin-modifying enzymes that remarkably effect nuclear size and shape. We found that interrupted activity of chromatin-modifying enzymes is associated with nuclear shape abnormalities. Furthermore, the activity of chromatin-modifying enzymes perturbs cell fate determination in cellular maintenance and lineage commitment. Our results indicated that chromatin-modifying enzyme regulates cell fate decision during lineage differentiation and is associate with nuclear size alteration. SignificanceHere we described for the first time the modulation of chromatin-modifying enzymes remarkably effects nuclear shape, and perturbs cell fate determination in cellular maintenance and lineage fate commitment in normal stem cells and leukemia cancer cells. We found that the irregularities of nuclear contour were highly related to pharmacological inhibition of chromatin-modifying enzyme activity. After manipulating a histone demethylase named GASC1, we found that upregulation of GASC1 impairs the differentiation of hESCs to terminally differentiated neural cells. Moreover, upregulation of GASC1 impairs the proliferation of leukemia cells due to cell cycle arrest in the G0/G1 phase and indicates misshapen nuclei. This study suggested that chromatin-modifying enzyme regulates the nuclear contour related cell fate decision also including cancer cell fate determination.

cancer biology↗

bioRxiv2022

Defining the age-dependent and tissue-specific circadian transcriptome in male mice

Cellular circadian clocks direct a daily transcriptional program that supports homeostasis and resilience. Emerging evidence supports age-associated changes in circadian functions. To define age-dependent changes at the systems level, we profiled the circadian transcriptome in the hypothalamus, lung, heart, kidney, skeletal muscle, and adrenal gland in 3 age groups. We found age-dependent and tissue-specific clock output changes. Aging reduced the number of rhythmically expressed genes (REGs), indicative of weakened circadian control. Many genes gained rhythmicity in old tissues, reflecting an adaptive response. REGs were enriched for the hallmarks of aging, adding a new dimension to our understanding of aging. Differential gene expression analysis found that there were temporally distinct clusters of genes in tissue-specific manner. Increased daily gene expression variability is a common feature of aged tissues. This novel analysis extends the landscape of the understanding of aging and highlights the impact of aging on circadian clock function and temporal changes in gene expression. HIGHLIGHTS- Rhythmically expressed genes (REGs) in Young, but not Old mice, are enriched for the aging hallmarks across all tissues. - The numbers of REGs decline across all tissues with age implicating the circadian clock in altered homeostasis. - Age- and tissue-specific differentially expressed genes (DEGs) cluster at specific times of the day. - Increase in gene expression variability over a day is a common feature of aging tissues.

genomics↗

bioRxiv2022

Nrf2 prevents diabetic cardiomyopathy via antioxidation and normalization of glucose and lipid metabolism in the heart

ObjectiveMetabolic disorders and oxidative stress are the main causes of diabetic cardiomyopathy. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) exerts a powerful antioxidant effect and prevents the progression of diabetic cardiomyopathy. However, the mechanism of its cardiac protection and direct action on cardiomyocytes are not well understood. MethodsIn this study, cardiomyocyte-restricted Nrf2 transgenic mice (Nrf2-TG) were used to directly observe whether cardiomyocyte-specific overexpression of Nrf2 can prevent diabetic cardiomyopathy and correct glucose and lipid metabolism disorders in the heart. ResultsCompared to wild-type (WT) mice, Nrf2-TG mice showed resistance to diabetic cardiomyopathy in a streptozotocin (STZ)-induced type 1 diabetes mouse model. This was primarily manifested as improved echocardiography results as well as reduced myocardial fibrosis, cardiac inflammation, and oxidative stress. ConclusionThese results showed that Nrf2 can directly act on cardiomyocytes to play a cardioprotective role. Mechanistically, the cardioprotective effects of Nrf2 depend on its antioxidation activity, partially through improving glucose and lipid metabolism by targeting the metabolic pathways of Akt/GSK-3 {beta}/HK-II and AMPK/Sirt1/PGC-1.

molecular biology↗

bioRxiv2022

Activation of the chemokine receptor CCR1 and preferential recruitment of Gαi suppress RSV replication: implications for developing novel RSV treatment strategies

Respiratory syncytial virus (RSV) is a major pathogen that can cause acute respiratory infectious diseases of the upper and lower respiratory tract, especially in children, elderly individuals and immunocompromised people. Generally, following viral infection, respiratory epithelial cells secrete cytokines and chemokines to recruit immune cells and initiate innate and/or adaptive immune responses. However, whether chemokines affect viral replication in non-immune cells is rarely clear. In this study, we detect that chemokine CCL5 was highly expressed, while expression of its receptor, CCR1, was downregulated in respiratory epithelial cells after RSV infection. When we overexpressed CCR1 on respiratory epithelial cells in vivo/in vitro, viral load was significantly suppressed, which can be restored by the neutralizing antibody for CCR1. Interestingly, the antiviral effect of CCR1 was not related to type I interferon (IFN-I), apoptosis induction or viral adhesion or entry inhibition; in contrast, it was related to the preferential recruitment and activation of adaptor Gi, which promoted inositol 1,4,5-triphosphate receptor type 3 (ITPR3) expression, leading to inhibited STAT3 phosphorylation, explicitly, phosphorylated (p)-STAT3 was verified to be among the important factors regulating the activity of HSP90, which has been previously reported to be a chaperone of RSV RNA polymerase. In summary, we are the first to reveal that CCR1 on the surface of non-immune cells regulates RSV replication through a previously unknown mechanism that does not involve IFN-I induction.

microbiology↗

bioRxiv2022

Elasticity generates indissoluble biomolecular condensates

While biomolecular condensates are often liquid-like, many experiments found that condensates also exhibit solid-like behaviors, making them indissoluble in conditions liquid condensates dissolve. Despite the biological significance of indissoluble condensates to cellular fitness, the mechanisms underlying the indissolubility of solid-like condensates are still unclear. In this work, we study the effects of elasticity on the dissolution of biomolecular condensates. We demonstrate that the bulk stress inside condensates may prevent the condensates from dissolution and obtain a new mechanical equilibrium condition of elastic condensates. Moreover, we theoretically predict a phase diagram of indissolubility for biomolecular condensates and identify a minimum bulk modulus for the condensates to be indissoluble. To verify our theories, we simulate the two-fluid model in which the slow component corresponding to biomolecules generates elastic stress. Our theoretical predictions are nicely confirmed and independent of microscopic details. Our works show that elasticity makes biomolecular condensates less prone to dissolution.

biophysics↗

bioRxiv2021

Discovery of a class of giant virus relatives displaying unusual functional traits and prevalent within plankton: the Mirusviricetes

DNA viruses have a major influence on the ecology and evolution of cellular organisms, but their overall diversity and evolutionary trajectories remain elusive. Here, we performed a phylogeny-guided genome-resolved metagenomic survey of the sunlit oceans and discovered plankton-infecting relatives of herpesviruses that form a putative new phylum dubbed Mirusviricota. The virion morphogenesis module of this large monophyletic clade is typical of viruses from the realm Duplodnaviria, with the major capsid protein fold being a likely structural intermediate between the capsid proteins of Caudoviricetes (tailed phages) and Herpesvirales (animal-infecting viruses). Yet, a substantial fraction of Mirusviricota genes, including hallmark transcription machinery genes missing in herpesviruses, are closely related homologs of large and giant eukaryotic DNA viruses from another viral realm. The remarkable chimeric attributes of Mirusviricota provide missing links in the evolution of both herpesviruses and giant viruses. Furthermore, mirusviruses are widespread and transcriptionally active from pole to pole, encoding complex functional traits used during the infection of microbial eukaryotes. The Mirusviricota prevalence, functional activity, diversification, and atypical evolutionary traits point to a lasting role of mirusviruses in the ecology of marine ecosystems that might have not only predated but also contributed to the emergence of herpesviruses and giant viruses.

evolutionary biology↗

bioRxiv2021

Diversity, function and evolution of marine invertebrate genomes

Invertebrates, animals (metazoans) without backbones, encompass [~]97% of all animal yet remains understudied. They have provided insights into molecular mechanisms underlying fundamentally identical mechanisms in phylogenetically diverse animals, including vertebrates. Marine invertebrates have long fascinated researchers due to their abundance, diversity, adaptations, and impact on ecosystems and human economies. Here, we report a compendium and appraisal of 190 marine invertebrate genomes spanning 21 phyla, 43 classes, 92 orders, and 134 families. We identify a high proportion and long unit size of tandem repeats, likely contributing to reported difficulties in invertebrate genome assembly. A well-supported phylogenetic tree of marine invertebrates from 974 single-copy orthologous genes resolved topological controversies. We show that Ctenophora is at the basal phylum and Porifera is the sister group of Parahoxozoa; that Xenacoelomorpha is within Bilateria and is the sister group to Protostomia, rejecting three out of four hypotheses in the field; and that Bryozoa is at the basal position of Lophotrochozoa, not grouped into Lophophorata. We also present insights into the genetic underpinnings of metazoans from Hox genes, innate immune gene families, and nervous system gene families. Our marine invertebrate genome compendium provides a unified foundation for studies on their evolution and effects on ecological systems and human life.

genomics↗

bioRxiv2021

Identification of age-associated proteins and functional alterations in human primary retinal pigment epithelium cells

BackgroundRetinal pigmented epithelium (RPE) has essential functions to nourish and support the neural retina, and is of vital importance in the pathogenesis of age-related retinal degeneration. However, the exact molecular changes of RPE in aging remain poorly defined. MethodsWe isolated human primary RPE (hRPE) cells from 18 eye donors distributed over a wide age range (10 - 67 years). A quantitative proteomic analysis was performed to analyze their intracellular and secreted protein changes, and potential age-associtated mechanisms were validated by ARPE-19 and hRPE cells. ResultsAge-stage related subtypes and age-associtated proteins and functional alterations were revealed. Proteomic data and verifications showed that RNF123 and RNF149 related ubiquitin-mediated proteolysis might be an important clearance mechanism in elimination of oxidative damaged proteins in aged hRPE. In older hRPE cells, apoptotic signaling related pathways were up-regulated and endoplasmic reticulum organization was down-regulated both in intracellular and secreted proteome. ConclusionsThis work paints a detailed molecular picture of human RPE in aging process and provides new insights for molecular characteristics of RPE in aging and related clinical retinal conditions.

bioinformatics↗

bioRxiv2021

Delayed implantation induced by letrozole in mice

Implantation timing is key for a successful pregnancy. Short delay in embryo implantation caused by targeted gene ablation produced a cascading problem in the later stages of the pregnancy. Although several delayed implantation models have been established in wild mice, almost none of them is suitable for investigating the delay on the late events of pregnancy. Here, we report a new delayed implantation model established by the intraperitoneally administration of letrozole at 5 mg/kg body weight on the day 3 of pregnancy. In these mice, initiation of implantation was induced at will by the injection of estradiol (E2). When the estradiol (3 ng) was injected on day 4 of pregnancy (i.e., without delay), the embryo implantation restarted, and the pregnancy continued normally. However, high dose of estrogen (25 ng) caused compromised implantation. We also found that only 67% of the female mice could be pregnant normally and finally gave birth when the injection of estradiol (3 ng) was on day 5 of pregnancy (i.e., one day delay). Most of the failed pregnancies had impaired decidualization, decreased plasma progesterone levels and compromised angiogenesis. Progesterone supplementation could rescue decidualization failure in the mice. Collectively, we established a new model of delayed implantation by letrozole, which can be easily used to study the effect and mechanisms of delay of embryo implantation on the progression of late pregnancy events.

developmental biology↗

bioRxiv2021

Augmenting Neutralization breadth against Diverse HIV-1 by increasing the Ab-Ag interface on V2

Understanding maturation pathways of broadly neutralizing antibodies (bnAbs) against HIV-1 in non-human primates can be highly informative for HIV-1 vaccine development. We now obtained a lineage of J038 from Chinese rhesus macaques after 7-years of SHIV infection. J038 has short complementary determining loops and neutralizes 54% of global circulating HIV-1 strains. Its binding induces a unique "up" conformation for one of the V2 loops in the trimeric envelope glycoprotein (Env) and is heavily dependent on glycan, which provides nearly half of the binding surface. The unmutated common ancestor of the J038 lineage antibodies binds monomeric gp120 and neutralizes the autologous virus. Continuous maturation enhances neutralization potency and breadth of J038 lineage antibodies via expanding antibody-Env contact areas surrounding the core region contacted by germline-encoded residues. Developmental details and recognition features of J038 lineage antibodies revealed here provide a new pathway for maturation elicitation of V2-targeting bnAbs. Highlights* Long-term infected NHPs develop antibodies neutralizing up to 54% of HIV-1 strains * Antibody J038 binds one V2 loop on HIV-1 Env trimer in a unique "up" position * UCA of the J038 lineage effectively neutralizes the autologous virus * J038 lineage antibodies mature through gradually increased contact to glycans

immunology↗

bioRxiv2021

Teaching Python for Data Science: Collaborative development of a modular & interactive curriculum

We are bioinformatics trainees at the University of Michigan who started a local chapter of Girls Who Code to provide a fun and supportive environment for high school women to learn the power of coding. Our goal was to cover basic coding topics and data science concepts through live coding and hands-on practice. However, we could not find a resource that exactly met our needs. Therefore, over the past three years, we have developed a curriculum and instructional format using Jupyter notebooks to effectively teach introductory Python for data science. This method, inspired by The Carpentries organization, uses bite-sized lessons followed by independent practice time to reinforce coding concepts, and culminates in a data science capstone project using real-world data. We believe our open curriculum is a valuable resource to the wider education community and hope that educators will use and improve our lessons, practice problems, and teaching best practices. Anyone can contribute to our educational materials on GitHub.

scientific communication and education↗

bioRxiv2021

Likelihood-based Tests for Detecting CircadianRhythmicity and Differential Circadian Patterns in Transcriptomic Applications

Circadian rhythmicity in transcriptomic profiles has been shown in many physiological processes, and the disruption of circadian patterns has been founded to associate with several diseases. In this paper, we developed a series of likelihood-based methods to detect (i) circadian rhythmicity (denoted as LR rhythmicity) and (ii) differential circadian patterns comparing two experimental conditions (denoted as LR diff). In terms of circadian rhythmicity detection, we demonstrated that our proposed LR rhythmicity could better control the type I error rate compared to existing methods under a wide variety of simulation settings. In terms of differential circadian patterns, we developed methods in detecting differential amplitude, differential phase, differential basal level, and differential fit, which also successfully controlled the type I error rate. In addition, we demonstrated that the proposed LR diff could achieve higher statistical power in detecting differential fit, compared to existing methods. The superior performance of LR rhythmicity and LR diff was demonstrated in two real data applications, including a brain aging data (gene expression microarray data of human postmortem brain) and a time-restricted feeding data (RNA sequencing data of human skeletal muscles). An R package for our methods is publicly available on GitHub https://github.com/diffCircadian/diffCircadian.

bioinformatics↗

bioRxiv2021

Neuromodulation of Behavioral Specialization: Tachykinin Signaling Inhibits Task-Specific Behavioral Responsiveness in Honeybee Workers

Behavioral specialization is key to the success of social insects and often compartmentalized among colony members leading to division of labor. Response thresholds to task-specific stimuli proximally regulate behavioral specialization but their neurobiological regulation is not understood. Here, we show that response thresholds to task-relevant stimuli correspond to the specialization of three behavioral phenotypes of honeybee workers. Quantitative neuropeptidome comparisons suggest two tachykinin-related peptides (TRP2 and TRP3) as candidates for the modification of these response thresholds. Based on our characterization of their receptor binding and downstream signaling, we then confirm the functional role of tachykinins: TRP2 injection and RNAi cause consistent, opposite effects on responsiveness to task-specific stimuli of each behaviorally specialized phenotype but not to stimuli that are unrelated to their tasks. Thus, our study demonstrates that TRP-signaling regulates the degree of task-specific responsiveness of specialized honeybee workers and may control the context-specificity of behavior in animals more generally.

evolutionary biology↗

bioRxiv2020

Enteric glial cells respond to a dietary change in the lamina propria in a MyD88-dependent manner

Immune and nervous system sensing are two important ways of detecting inner and outer environmental changes. Immune cell activation in the gut can promote metabolic disorders. However, whether enteric nervous system sensing and activities are also important in metabolic syndromes is not clear. Enteric glial cells (EGCs) are thought to have sensing ability, but little is known about the potential connections between EGC and metabolic disorders. Consuming a modern Western-type high-fat low-fiber diet increases the risk of obesity. Here, we reported that dietary shift from a normal chow diet to a high-fat diet in wild-type (WT) C57BL/6 mice induced a transient emergence of glial fibrillary acidic protein (GFAP)-positive EGC network in the ileal lamina propria, accompanied by an increase of glial-derived neurotrophic factors production. Inhibition of EGC metabolic activity via gliotoxin fluorocitrate or glial-intrinsic deletion of myeloid differentiation factor 88 (Myd88) in mice blocked this dietary change-induced activity. Furthermore, we found a different role of MYD88 in glial cells versus adipocyte in diet-induced obesity. The glial Myd88 knockout mice gained less body weight after HFD feeding compared to the littermate controls. In contrast, adipocyte deletion of Myd88 in mice had no impact on the weight gain but had exacerbated glucose metabolic disorders. Pharmacological interventions of glial activities by fluorocitrate prevented body weight gain in a dietary type- and glial MYD88-independent manner. Collectively, our data reveal a previously unappreciated function of EGC in sensing a dietary shift-induced perturbation and glial activities as a whole may play roles in diet-induced obesity. New & NoteworthyIt is known that obesity and its related metabolic syndrome can damage the neuronal system. However, whether the neuronal system also participates in the development of obesity is unclear. Diet is an important contributing factor to obesity. Our study reveals that consuming a high-fat diet can induce a transient enteric glial cell response via its intrinsic sensing molecule(s). Inhibiting overall glial cell activities may have an impact on the development of the metabolic syndrome.

neuroscience↗

bioRxiv2020

Quantitative assessment of NCLDV-host interactions predicted by co-occurrence analyses

Nucleocytoplasmic DNA viruses (NCLDVs) are highly diverse and abundant in marine environments. However, knowledge of their hosts is limited because only a few NCLDVs have been isolated so far. Taking advantage of the recent large-scale marine metagenomics census, in silico host prediction approaches are expected to fill the gap and further expand our knowledge of virus-host relationships for unknown NCLDVs. In this study, we built co-occurrence networks of NCLDVs and eukaryotic taxa to predict virus-host interactions using Tara Oceans sequencing data. Using the positive likelihood ratio to assess the performance of host prediction for NCLDVs, we benchmarked several co-occurrence approaches and demonstrated an increase in the odds ratio of predicting true positive relationships four-fold compared with random host predictions. To further refine host predictions from high-dimensional co-occurrence networks, we developed a phylogeny-informed filtering method, Taxon Interaction Mapper, and showed it further improved the prediction performance by twelve-fold. Finally, we inferred virophage - NCLDV networks to corroborate that co-occurrence approaches are effective for predicting interacting partners of NCLDVs in marine environments. ImportanceNCLDVs can infect a wide range of eukaryotes although their life cycle is less dependent on hosts compared with other viruses. However, our understanding of NCLDV- host systems is highly limited because few of these viruses have been isolated so far. Co-occurrence information has been assumed to be useful to predict virus-host interactions. In this study, we quantitatively show the effectiveness of co-occurrence inference for NCLDV host prediction. We also improve the prediction performance with a phylogeny-guided method, which leads to a concise list of candidate host lineages for three NCLDV families. Our results underpin the usage of co-occurrence approach for metagenomic exploration of the ecology of this diverse group of viruses.

microbiology↗

bioRxiv2020

Chloroquine and hydroxychloroquine as ACE2 blockers to inhibit viropexis of COVID-19 Spike psedotype virus

BackgroundThe novel coronavirus disease (2019-nCoV) has been affecting global health since the end of 2019 and there is no sign that the epidemic is abating. The major issue for controlling the infectious is lacking efficient prevention and therapeutic approaches. Chloroquine (CQ) and Hydroxychloroquine (HCQ) have been reported to treat the disease, but the underlying mechanism remains controversial. PurposeThe objective of this study is to investigate whether CQ and HCQ could be ACE2 blockers and used to inhibit 2019-nCoV virus infection. MethodsIn our study, we used CCK-8 staining, flow cytometry and immunofluorescent staining to evaluate the toxicity and autophagy of CQ and HCQ, respectively, on ACE2 high-expressing HEK293T cells (ACE2h cells). We further analyzed the binding character of CQ and HCQ to ACE2 by molecular docking and surface plasmon resonance (SPR) assays, 2019-nCoV spike pseudotyped virus was also used to observe the viropexis effect of CQ and HCQ in ACE2h cells. ResultsResults showed that HCQ is slightly more toxic to ACE2h cells than CQ. Both CQ and HCQ could bind to ACE2 with KD =(7.31{+/-}0.62)e-7 M and (4.82{+/-}0.87)e-7 M, respectively. They exhibit equivalent suppression effect for the entrance of 2019-nCoV spike pseudotyped virus into ACE2h cells. ConclusionsCQ and HCQ both inhibit the entrance 2019-nCoV into cells by blocking the binding of the virus with ACE2. Our findings provide novel insights into the molecular mechanism of CQ and HCQ treatment effect on virus infection.

biochemistry↗

bioRxiv2020

Three genomes of Osteoglossidae shed light on ancient teleost evolution

Osteoglossiformes is a basal clade of teleost, originated from late Jurassic and had seen the process of continental drift. The genomic differences amongst Osteoglossiformes species should reflect the unique evolve history of that time. Here, we presented the chromosome-level genome of Heterotis niloticus which is the only omnivore species of Osteoglossidae spreading in Africa. Together with other two Osteoglossidae species genomes of Arapaima gigas and Scleropages formosus which spread in South America and Australia respectively, we found great evolutionary differences in gene families and transposable elements. Phylogenetic analysis showed that the ancestor of H. niloticus and A. gigas diverged with S. formosus at [~]106.1Mya, consistent with the time of Afro-South American drift and A. gigas speciated from the ancestor of H. niloticus and A. gigas at [~]59.2 Mya, consistent with the separation of Eurasia and North American continents. And we proposed the evolutionary traces of Osteoglossidae species based on comparative genomics analysis and their living geographic habitats. We identified loss of LINEs and LTRs, fast evolutionary rate in parallel to fast pseudogenization rate in H. niloticus and A. gigas comparing to S. formosus during the evolutionary process. We also found notable OR genes contraction in H. niloticus, which might be related to the diet transition. Taken together, we reconstructed the evolutionary process of Osteoglossidae using three representative genomes, providing a possible clue for biogeographic and evolution study of ancient teleost clade.

genomics↗