Biology subjects

Wang, M.

Publications and source records attributed to Wang, M..

At least 559 records · Page 31Linked to original sources

bioRxiv2022

Endogenous Plasmids and Reductive Genome Evolution in Host-Associated Bacteria

Reductive genome evolution is commonly observed among host-associated bacteria including many important pathogens, such as Mycobacterium leprae but its molecular mechanism is not well understood 1-5. One of the most widely accepted hypotheses to explain bacterial genome reduction is Mullers ratchet, in which the associated bacteria tend to accumulate deleterious mutations for reduction in the absence of chromosomal recombination inside the eukaryotic host organism 1,2. Cardinium species belong to the family Amoebophilaceae of the CFB group bacteria, which are a group of endosymbiont bacteria widely distributed among arthropods, that along with Wolbachia can cause cytoplasmic incompatibility 6,7. In this study, we explored bacterial reductive evolution within the de novo assembled genomes of Cardinium endosymbionts in two astigmatic mites 8,9. Our results shed light on the reduction mechanism driven by endogenous plasmids and their encoded enzymes.

microbiology↗

bioRxiv2022

Resistance of SARS-CoV-2 Omicron Subvariant BA.4.6 to Antibody Neutralization

SARS-CoV-2 Omicron subvariants BA.4.6, BA.4.7, and BA.5.9 have recently emerged, and BA.4.6 appears to be expanding even in the presence of BA.5 that is globally dominant. Compared to BA.5, these new subvariants harbor a mutation at R346 residue in the spike glycoprotein, raising concerns for further antibody evasion. We compared the viral receptor binding affinity of the new Omicron subvariants with BA.5 by surface plasmon resonance. We also performed VSV-based pseudovirus neutralization assays to evaluate their antigenic properties using sera from individuals who received three doses of a COVID-19 mRNA vaccine (boosted) and patients with BA.1 or BA.2 breakthrough infection, as well as using a panel of 23 monoclonal antibodies (mAbs). Compared to the BA.5 subvariant, BA.4.6, BA.4.7, and BA.5.9 showed similar binding affinities to hACE2 and exhibited similar resistance profiles to boosted and BA.1 breakthrough sera, but BA.4.6 was slightly but significantly more resistant than BA.5 to BA.2 breakthrough sera. Moreover, BA.4.6, BA.4.7, and BA.5.9 showed heightened resistance over to a class of mAbs due to R346T/S/I mutation. Notably, the authorized combination of tixagevimab and cilgavimab completely lost neutralizing activity against these three subvariants. The loss of activity of tixagevimab and cilgavimab against BA.4.6 leaves us with bebtelovimab as the only therapeutic mAb that has retained potent activity against all circulating forms of SARS-CoV-2. As the virus continues to evolve, our arsenal of authorized mAbs may soon be depleted, thereby jeopardizing the wellbeing of millions of immunocompromised persons who cannot robustly respond to COVID-19 vaccines.

microbiology↗

bioRxiv2022

openNAU: An open-source platform for normalizing, analyzing, and visualizing untargeted metabolomics data

MotivationAs an important part of metabolomics analysis, untargeted metabolomics has become a powerful tool in the study of tumor mechanisms and the discovery of metabolic markers with high-throughput spectrometric data which also brings great challenges to data analysis from the extraction of raw data to the identification of differential metabolites. To date, a large number of analytical tools and processes have been developed and constructed to serve untargeted metabolomics research. The different selection of analytical tools and parameter settings lead to varied results of untargeted metabolomics data. Our goal is to establish an easily operated platform and obtain a repeatable analysis result. ResultsWe used the R language basic environment to construct the preprocessing system of the original data and the LAMP (Linux + Apache + MySQL + PHP) architecture to build a cloud mass spectrum data analysis system. An open-source analysis software for untargeted metabolomics data (openNAU) was constructed. It includes the extraction of raw mass data and quality control for the identification of differential metabolic ion peaks. A reference metabolomics database based on public databases was also constructed. Finally, a complete analysis system platform for untargeted metabolomics was established. This platform provides a complete template interface for the addition and updating of the analysis process, so we can finish complex analyses of untargeted metabolomics with simple human-computer interactions. Availability and ImplementationThe source code can be downloaded from https://github.com/zjuRong/openNAU. Contactsunqingrong@zju.edu.cn

bioinformatics↗

bioRxiv2022

Whether the ADP-ribosyltransferase activity of Ta-sro1, a noncanonical PARP protein, contributes to its function in salinity-stress tolerance?

ADP-ribosylation mediated by ADP-ribosyltransferases (ARTs) is an intricate modification that regulates diverse cellular processes including DNA repair, chromatin remodeling and gene transcription responding to stresses. In addition to the canonical poly(ADP-ribose) polymerases (PARPs), plant specific SRO (Similar to RCD One) family also contain the catalytic core of the PARP domain. However, whether the PARP domains in SROs execute the ART function is still under debate. In 2014, we reported a wheat SRO, Ta-sro1, had the ADP-ribosyltransferase activity and enhanced wheat seedling growth and abiotic stress resistance, however, a recent work by Vogt et al. showed that Ta-sro1 without ADP-ribosyltransferase activity. Based on the recent progress on PARPs and SROs in relation to ADP-ribosyltransferase activity, along with our former and recent evolving results, we argued that Ta-sro1 is a non-canonical ADP-ribosyltransferase with the enzymatic activity. Although we have revealed the novel mechanism of Ta-sro1 regulate redox homeostasis and enhance salinity stress tolerance through interacting with TaSIP1, it is of interest to further clarify whether and how the enzymatic activity of Ta-sro1 responsible for the salinity tolerance of wheat. Our study raises some interesting points and caveats that helpful for understanding the research progresses and debates about the enzymatic activity of SROs.

molecular biology↗

bioRxiv2022

The genome of a vestimentiferan tubeworm (Ridgeia piscesae) provides insights into its adaptation to a deep-sea environment

Vestimentifera (Polychaeta, Siboglinidae) is a taxon of deep-sea worm-like animals living in the deep-sea hydrothermal vent and cold seep areas. The morphology and lifespan of Ridgeia piscesae, which is the only vestimentiferan tubeworm species found in the hydrothermal vents on the Juan de Fuca Ridge, vary greatly according to the endemic environments. Recent analyses have revealed the genomic basis of adaptation in three vent- and seep-dwelling vestimentiferan tubeworms. However, the evolutionary history and mechanism of adaptation in R. piscesae, a unique species in the family Siboglinidae, is remained to be investigated. Here we report a high-quality genome of R. piscesae collected at Cathedral vent of the Juan de Fuca Ridge. Comparative genomic analysis revealed that that the high growth rates of vent-dwelling tubeworms might derive from small genome size. The small genome sizes of these tubeworms are attributed to the repeat content but not the number of genes and intron sizes. Additionally, four genes involved in cell proliferation were subject to positive selection in the genome of R. piscesae, suggesting that, besides apoptosis, cell proliferation is important for regulating growth rate in this species.

genomics↗

bioRxiv2022

Robust phenotypic plasticity of symbiotic organs facilitates the adaptation and evolution of deep-sea mussels

The rapid progress of deep-sea methane hydrate exploration and exploitation calls for a thorough evaluation of its potential impact on local chemosynthetic ecosystems, particularly on endemic species. As one dominant megafauna in cold seeps, the deep-sea mussels mainly rely on methanotrophic endosymbionts for nutrition and therefore could serve as a promising model in monitoring the exploitation of methane hydrate. However, knowledge on the long-term responses of deep-sea mussels to environmental stresses induced by methane hydrate exploitation, especially to methane reduction and deprivation, is still lacking. Here, we set up a laboratory system and cultivated methanotrophic deep-sea mussel Gigantidas platifrons without methane supply to survey the phenotypic changes after methane deprivation. While the mussels managed to survive for more than 10 months after the methane deprivation, drastic changes in the metabolism, function, and development of gill tissue, and in the association with methanotrophic symbionts were observed. In detail, the mussel digested all methanotrophic endosymbionts shortly after methane deprivation for nutrition and remodeled the global metabolism of gill to conserve energy. As the methane deprivation continued, the mussel replaced its bacteriocytes with ciliated cells to support filter-feeding, which is an atavistic trait in non-symbiotic mussels. During the long-term methane deprivation assay, the mussel also retained the generation of new cells to support the phenotypic changes of gill and even promoted the activity after being transplanted back to deep-sea, showing the potential resilience after long-term methane deprivation. Evidences further highlighted the participation of symbiont sterol metabolism in regulating these processes, which might be one direct cue for the mussels to respond to methane deprivation. These results collectively show the phenotypic plasticity of deep-sea mussels and their dynamic responses to methane deprivation, providing essential information in assessing the long-term influence of methane hydrate exploitation.

molecular biology↗

bioRxiv2022

Analysis of Inbred Mouse strains' High-Impact Genotype-phenotype Hypotheses (AIMHIGH) reveals novel disease-causing candidate genes

Inbred mouse strains reveal the molecular basis of mammalian traits and diseases, particularly recessive ones. We utilized mouse community curated resources to set up an automated screen to discover novel testable gene function hypotheses. Using 11,832 community contributed strain-differentiating experiments and trait presence/absence scoring, we searched for all experiments where strains can be split by their phenotypic values (e.g., high vs. low responders). Then, using 48 sequenced strains, we found one or more candidate gene for each experiment where homozygous high-impact variants (such as stopgain, frameshifts) segregate strains into these same binary grouping. Our approach rediscovered 212 known gene-phenotype relationships, almost always highlighting potentially novel causal variants, as well as thousands of gene function hypotheses. To help find the most exciting hypotheses, we improved the state of the art in machine learning driven literature-based discovery (LBD). Reading on our top 3 ranked candidate genes per experiment reveals 80% of rediscovered relationships, compared to 5% reading at random. We proposed 1,842 novel gene-phenotype testable hypotheses using our approach. We built a web portal at aimhigh.stanford.edu to allow researchers to view all our testable hypotheses in detail. Our open-source code can be rerun as more sequenced strains and phenotyping experiments become available.

genomics↗

bioRxiv2022

Predicting regional somatic mutation rates using DNA motifs

How the locus-specificity of epigenetic modifications is regulated remains an unanswered question. A contributing mechanism is that epigenetic enzymes are recruited to specific loci by DNA binding factors recognizing particular sequence motifs (referred to as epi-motifs). Using these motifs to predict biological outputs depending on local epigenetic state such as somatic mutation rates would confirm their functionality. Here, we used DNA motifs including known TF motifs and epi-motifs as a surrogate of epigenetic signals to predict somatic mutation rates in 13 cancers at an average 23kbp resolution. We implemented an interpretable neural network model, called contextual regression, to successfully learn the universal relationship between mutations and DNA motifs, and uncovered motifs that are most impactful on the regional mutation rates such as TP53 and epi-motifs associated with H3K9me3. Furthermore, we identified genomic regions with significantly higher mutation rates than the expected values in each individual tumor and demonstrated that such cancer-specific regions can accurately predict cancer types. (The code is available from https://github.com/Wang-lab-UCSD/SomaticMutation) Significance StatementThe relationship between DNA motifs and somatic mutation rates in cancers is not fully understood, especially at high resolution. Here we developed an interpretable neural network model to successfully predict somatic mutation rates using DNA motifs in 13 diverse cancers and identified the most informative motifs. Furthermore, we showed that the genomic regions with significant higher mutation rates than the predicted values can be used for cancer classification.

bioinformatics↗

bioRxiv2022

Strain dropouts reveal interactions that govern the metabolic output of the gut microbiome

The gut microbiome is complex, raising questions about the role of individual strains in the community. Here, we address this question by focusing on a functional unit within the community, the metabolic niche that controls bile acid 7-dehydroxylation. By constructing variants of a complex defined community in which we drop out strains that occupy this niche, we explore how interactions within and between niches shape community-level metabolism. Omitting both members of the niche, Clostridium scindens (Cs) and Clostridium hylemonae (Ch), eliminates secondary bile acid production and reshapes the community in a highly specific manner: eight strains go up or down in relative abundance by >100-fold, while the remaining strains are largely unaffected. In single-strain dropout communities (i.e., a strain swap within the niche), Cs and Ch reach the same relative abundance and dehydroxylate bile acids to a similar extent. However, the effect on strains in other niches differs markedly: Clostridium sporogenes increases >1000-fold in the {Delta}Cs but not {Delta}Ch dropout, reshaping the pool of microbiome-derived phenylalanine metabolites. Thus, strains that are functionally redundant within a niche can have widely varying impacts outside the niche, and a strain swap can ripple through the community in an unpredictable manner, resulting in a large impact on an unrelated community-level phenotype. Mice colonized by the {Delta}Cs{Delta}Ch community show decreased liver steatosis relative to those colonized by the {Delta}Ch community, demonstrating that a single strain from the microbiome can have a substantive impact on host physiology. Our work opens the door to the mechanistic studies of the role of an individual strain on community ecology and host physiology.

microbiology↗

bioRxiv2022

Insight into the evolutionary assemblage of cranial kinesis from a Cretaceous bird

The independent movements and flexibility of various parts of the skull, called cranial kinesis, is an evolutionary innovation that is found in living vertebrates only in some squamates and crown birds, and considered to be a major factor underpinning much of the enormous phenotypic and ecological diversity of living birds, the most diverse group of extant amniotes. Compared to the postcranium, our understanding of the evolutionary assemblage of the characteristic modern bird skull has been hampered by sparse fossil records of early cranial materials, with competing hypotheses regarding the evolutionary development of cranial kinesis among early members of the avialans. Here, a detailed three-dimensional reconstruction of the skull of the Early Cretaceous enantiornithine Yuanchuavis kompsosoura allows for its in depth description, including elements that are poorly known among early diverging avialans but are central to deciphering the mosaic assembly of features required for modern avian cranial kinesis. Our reconstruction of the skull shows evolutionary and functional conservation of the temporal and palatal regions by retaining the ancestral theropod dinosaurian configuration within the skull of this otherwise derived and volant bird. Geometric morphometric analysis of the palatine suggests that loss of the jugal process represents the first step in the structural modifications of this element leading to the kinetic crown bird condition. The mixture of plesiomorphic temporal and palatal structures together with a derived avialan rostrum and postcranial skeleton encapsulated in Yuanchuavis manifests the key role of evolutionary mosaicism and experimentation in early bird diversification.

paleontology↗

bioRxiv2022

Machine learning reveals conserved chromatin patterns determining meiotic recombination sites in plants

Distribution of meiotic recombination events in plants has been associated with local chromatin and DNA characteristics, chromosome landmark proximity, and other features1-7. However, relative importance of these characteristics is unclear and it is unknown if they are sufficient to unambiguously determine recombination landscape8. Here, we analyzed over 40 DNA sequence, chromatin, and chromosome location features of maize and Arabidopsis recombination sites using machine learning9,10. We discovered that a combination of just three features, CG methylation, CHG methylation, and nucleosome occupancy, enabled identification of exact crossover site with 90% accuracy. These results imply redundancy of most recombination site characteristics. Recombination takes place in a small fraction of the genome with chromatin features distinct from those of genome at large. Surprisingly, crossover sites show elevated heterochromatin histone marks despite low DNA methylation. Crossover site features show broad evolutionary conservation, which will enable creating genetic maps in species where conventional mapping is unfeasible.

plant biology↗

bioRxiv2022

Brassinosteroids signaling component SlBZR1 promotes fruit ripening in tomato

Fruit ripening evolved to be attractive to frugivores that derive energy and nutrition from the fruits in exchange for assisting seed dispersal, which is accompanied by the dramatically change of fruit characteristics, including color, aroma, and texture. The plant hormone ethylene plays a key role in climacteric fruit ripening, while the role of other phytohormones as well as their cross talk with ethylene in modulating fruit ripening remains elusive. Here, we report growth-promoting phytohormone brassinosteroids promote fruit ripening in tomato through regulation of ethylene biosynthesis. Exogenous BR treatment and the increase of endogenous BR content in SlCYP90B3-OE promoted ethylene production and fruit ripening. SlBZR1, a central component and positive regulator of BR signaling pathway, promotes ethylene production and carotenoid accumulation through direct transcriptional regulation of SlACO1, SlACO3 and SlPSY1. Furthermore, SlBIN2, a negative regulator of BR signaling upstream of SlBZR1, decreases ethylene production and carotenoid accumulation. Together, our results demonstrate that BR signaling integrates ethylene and carotenoid biosynthetic pathway to regulate fruit ripening.

plant biology↗

bioRxiv2022

NFATc1 negatively determines chondrocyte differentiation in articular cartilage progenitors

The origin and differentiation mechanism of articular chondrocytes remain poorly understood. Broadly, the difference in developmental mechanisms of articular and growth-plate cartilage is still less elucidated. Here, we identified that the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) is a crucial regulator of articular, but not growth-plate, chondrocyte differentiation during development. At the early stage of mouse knee development (embryonic day 13.5), NFATc1-expressing cells were mainly located in the flanking region of the joint interzone. With development, NFATc1-expressing cells generated almost all articular chondrocytes, but not chondrocytes in limb growth-plate primordium. NFATc1-expressing cells displayed prominent capacities for colony formation and multipotent differentiation. Transcriptome analyses revealed a set of characteristic genes in NFATc1-enriched articular cartilage progenitors. Strikingly, the expression of NFATc1 was diminished with articular chondrocyte differentiation, and suppressing NFATc1 expression in articular cartilage progenitors was sufficient to induce spontaneous chondrogenesis while overexpressing NFATc1 suppresses chondrogenesis. Mechanistically, NFATc1 negatively regulated the transcriptional activity of the Col2a1 gene. Thus, our results reveal that NFATc1 characterizes articular, but not growth-plate, cartilage progenitors and negatively determines articular chondrocyte differentiation at least partly through regulating COL2A1 gene transcription.

developmental biology↗

bioRxiv2022

Precision 1070 nm Ultrafast Laser-induced Photothrombosis (PLP) of Depth-targeted Vessels in vivo

The cerebrovasculature plays an essential role in neurovascular and homeostatic functions in health and disease conditions. Many efforts have been made for developing vascular thrombosis methods to study vascular dysfunction in vivo, while technical challenges remain, such as accuracy and depth-selectivity to target single vessel in the cerebral cortex. Herein, we first demonstrates the evaluation and quantification of the feasibility and effects of Rose Bengal (RB)-induced photothrombosis with 720-1070 nm ultrafast lasers in raster scan. A flexible and reproducible approach is then proposed to employ a 1070 nm ultrafast laser with spiral scan for producing RB-induced occlusion, which is described as precision ultrafast laser-induced photothrombosis (PLP). Combine with two-photon microscopy imaging, this PLP displays highly precise and fast occlusion induction of various vessel types, sizes, and depths, which enhances the precision and power of the photothrombosis protocol. Overall, the PLP method provides a real-time, practical, precise, and depth-selected single-vessel photothrombosis technology in cerebral cortex with commercially available optical equipment, which is crucial for exploring brain vascular function with high spatial temporal resolution in brain.

neuroscience↗

bioRxiv2022

Membrane curvature governs the distribution of Piezo1 in cellulo

Piezo1 is a bona fide mechanosensitive ion channel ubiquitously expressed in mammalian cells. The distribution of Piezo1 within a cell is essential for various biological processes including cytokinesis, cell migration, and wound healing. However, the underlying principles that guide the subcellular distribution of Piezo1 remain largely unexplored. Here, we demonstrate that membrane curvature serves as a key regulator of the spatial distribution of Piezo1 in the plasma membrane of living cells. Piezo1 depletes from highly curved membrane protrusions such as filopodia and enriches to nanoscale membrane invaginations. Quantification of the curvaturedependent sorting of Piezo1 directly reveals the in situ nano-geometry of the Piezo1-membrane complex. Piezo1 density on filopodia increases upon activation, independent of Ca2+, suggesting flattening of the channel upon opening. Consequently, the expression of Piezo1 inhibits filopodia formation, an effect that diminishes with channel activation.

biophysics↗

bioRxiv2022

Stochastic optimal control to guide adaptive cancer therapy

Although adaptive cancer therapy shows promise in integrating evolutionary dynamics into treatment scheduling, the stochastic nature of cancer evolution has seldom been taken into account. Various sources of random perturbations can impact the evolution of heterogeneous tumors, making performance metrics of any treatment policy random as well. In this paper, we propose an efficient method for selecting optimal adaptive treatment policies under randomly evolving tumor dynamics. The goal is to improve the cumulative "cost" of treatment, a combination of the total amount of drugs used and the total treatment time. As this cost also becomes random in any stochastic setting, we maximize the probability of reaching the treatment goals (tumor stabilization or eradication) without exceeding a pre-specified threshold (or a "budget"). We use a novel Stochastic Optimal Control formulation and Dynamic Programming to find such "threshold-aware" optimal treatment policies. Our approach enables an efficient algorithm to compute these policies for a range of threshold values simultaneously. Compared to treatment plans shown to be optimal in a deterministic setting, the new "threshold-aware" policies significantly improve the chances of the therapy succeeding under the budget, which is correlated with a lower general drug usage. We illustrate this method using two specific examples, but our approach is far more general and provides a new tool for optimizing adaptive therapies based on a broad range of stochastic cancer models. Author SummaryTumor heterogeneities provide an opportunity to improve therapies by leveraging complex (often competitive) interactions of different types of cancer cells. These interactions are usually stochastic due to both individual cell differences and random events affecting the patient as a whole. The new generation of cancer models strive to account for this inherent stochasticity, and adaptive treatment plans need to reflect it as well. In optimizing such treatment, the most common approach is to maximize the probability of eventually stabilizing or eradicating the tumor. In this paper, we consider a more nuanced version of success, maximizing the probability of reaching these therapy goals before the cumulative burden from the disease and treatment exceed a chosen threshold. Importantly, our method allows computing such optimal treatment plans efficiently and for a range of thresholds at once. If used on a high-fidelity personalized model, our general approach could potentially be used by clinicians to choose the most suitable threshold after a detailed discussion of a specific patients goals (e.g., to include the trade-offs between toxicity and quality of life).

cancer biology↗

bioRxiv2022

eccDNA purification, full-length sequencing, and genomic mapping

Extrachromosomal circular DNA (eccDNA) has been discovered for more than half a century1. However, its biogenesis and function have just begun to be elucidated. One hurdle that prevented our understanding of eccDNA is the difficulty in obtaining pure eccDNA from cells. The current eccDNA purification methods mainly rely on exonuclease digestion after alkaline lysis. Due to its low abundance and heterogeneity in size, the current eccDNA purification methods are not efficient in obtaining pure eccDNA. Here, we describe a new 3-step eccDNA purification (3SEP) procedure by adding a new step that allows circular, but not linear, DNA that escaped from exonuclease digestion, bound to silica beads in solution A. Our method allows eccDNA purification with high purity and reproducibility. Additionally, we developed a full-length sequencing and genomic mapping method by combining rolling cycle amplification (RCA) with Nanopore sequencing, through which the consensus sequence of multiple tandem copies of eccDNA contained within the debranched RCA product is derived and mapped to its genomic origin. Collectively, our protocol will facilitate eccDNA identification, characterization, and has the potential for diagnostic and clinic applications.

cell biology↗

bioRxiv2022

The adipose-neural axis is critically involved in cardiac arrhythmias

Dysfunction of the sympathetic nervous system and increase of epicardial adipose tissue (EAT) have been independently associated with the occurrence of cardiac arrhythmia. However, their exact roles in triggering arrhythmia remain elusive due to a lack of appropriate human disease models. Here, using the in vitro co-culture system with sympathetic neurons, cardiomyocytes, and adipocytes, we show that adipocyte-derived leptin could activate sympathetic neurons and increase the release of NPY, which in turn trigger arrhythmia of cardiomyocytes by interaction with NPY1R and subsequently enhancing the activity of NCX and CaMKII. The arrhythmic phenotype could be partially blocked by leptin neutralizing antibody, or an inhibitor of NPY1R, NCX or CaMKII. More importantly, increased EAT thickness accompanied with higher leptin/NPY blood levels was detected in atrial fibrillation patients compared to control group. Our study provides the first evidence that adipose-neural axis would contribute to arrhythmogenesis and represent a potential therapeutic target for arrhythmia.

cell biology↗