Biology subjects

Li, Q.

Publications and source records attributed to Li, Q..

At least 451 records · Page 25Linked to original sources

bioRxiv2023

Doxorubicin inhibits phosphatidylserine decarboxylase and confers broad-spectrum antifungal activity

O_LIAs phospholipids of cell membranes, phosphatidylethanolamine (PE) and phosphatidylserine (PS) play crucial roles in glycerophospholipid metabolism. Broadly, some phospholipid biosynthesis enzymes serve as potential fungicide targets. Therefore, revealing the functions and mechanism of PE biosynthesis in plant pathogens would provide potential targets for crop disease control. C_LIO_LIWe performed analyses including phenotypic characterizations, lipidomics, enzyme activity, site-directed mutagenesis, and chemical inhibition assays to study the function of PS decarboxylase-encoding gene MoPSD2 in rice blast fungus Magnaporthe oryzae. C_LIO_LIThe Mopsd2 mutant was defective in development, lipid metabolism and plant infection. The PS level increased while PE decreased in Mopsd2, consistent with the enzyme activity. Furthermore, chemical doxorubicin inhibited the enzyme activity of MoPsd2 and showed antifungal activity against ten phytopathogenic fungi including M. oryzae and reduced disease severity of two crop diseases in the field. Three predicted doxorubicin-interacting residues are important for MoPsd2 functions. C_LIO_LIOur study demonstrates that MoPsd2 is involved in de novo PE biosynthesis and contributes to the development and plant infection of M. oryzae and that doxorubicin shows broad-spectrum antifungal activity as a fungicide candidate. The study also implicates that bacterium Streptomyces peucetius, which biosynthesizes doxorubicin, could be potentially used as an eco-friendly biocontrol agent. C_LI

pathology↗

bioRxiv2023

Cross-species regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes

Knowledge of locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our Validated Systematic Integration (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state Regulatory Potential (esRP) scores for each cCRE in each cell type, which were used to categorize dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbored distinctive transcription factor binding motifs that were similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we showed that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.

genomics↗

bioRxiv2023

Early microbial intervention reduces diarrhea while improves later milk production in newborn calves

The rumen of neonatal calves is not well-developed and exhibits limited functionality. Therefore, the establishment of intestinal microbiota may play an instrumental role in their health and performance, but it has been rarely explored. Thus, we aim to explore the temporal colonization of the gut microbiome and the potential benefits of early microbial intervention in newborn calves. We followed up on the temporal dynamics of the gut microbiome and plasma metabolome in 36 newborn calves during the first two months of life and established their relationships with their health status and performance. We also evaluated whether microbiota transplantation (MT) could influence their phenotypes by modulating metabolism and its impact on later milk production performance.We showed that the composition and ecological interactions of the gut microbiome are likely to reach maturity one month after birth. Temporal changes in the gut microbiome of newborn calves are widely associated with changes in their physiological statuses, such as growth and fiber digestion. Importantly, we observed that MT reshapes the gut microbiome of newborns by altering the abundance and interaction of Bacteroides species, as well as amino acid pathways, such as arginine biosynthesis. Two-year follow-up of those calves further showed that MT improves their later milk production. Notably, MT improves fiber digestion, antioxidant capacity of newborns while reducing diarrhea. MT also contributes to significant changes in the metabolomic landscape, and with putative causal mediation analysis, we suggest that altered gut microbial composition in newborns may influence physiological status through microbial-derived metabolites. The data from the study may help develop strategies to manipulate the gut microbiota during early life, which may be significantly relevant to the health and production of newborn calves. HIGHLIGHTSO_LIThe gut microbial composition and ecological interaction in newborn calves reach maturity one month after birth C_LIO_LITemporal shifts in the gut microbiome of newborn calves are associated with phenotypic changes, including growth, digestion, and antioxidative capacity C_LIO_LIEarly microbial intervention in newborn calves reduces diarrhea while improving later milk production C_LIO_LIThe gut microbial impact on newborn calves is mediated by plasma metabolites C_LI

microbiology↗

bioRxiv2023

Artificial selection footprints in domestic chicken genomes

Accurate and low-cost next generation sequencing technologies make re-sequencing of large populations of a species possible. Although many studies related to artificial selection signatures of commercial and indigenous chickens have been carried out, quite a small number of genes have been found to be under selection. In this study, we re-sequenced 85 individuals of five indigenous chicken breeds with distinct traits from Yunnan, a southwest province of China. By analyzing these indigenous chickens together with 116 individuals of commercial chickens (broilers and layers) and 35 individuals of red jungle fowl, we find a substantially large number of selective sweeps and affected genes for each chicken breed using a rigorous statistic model than previously reported. We confirm most of previously identified selective sweeps and affected genes. Meanwhile the vast majority ([~]98.3%) of our identified selective sweeps overlap known chicken quantitative trait loci. Thus, our predictions are highly reliable. For each breed, we also identify candidate genes and selective sweeps that might be related to the unique traits of the chickens.

bioinformatics↗

bioRxiv2023

Hepatic conversion of acetyl-CoA to acetate plays crucial roles in energy stresses

Accumulating evidences indicate that acetate is increased in energy stresses such as diabetes mellitus and prolonged starvation. However, it is largely unknown how and where acetate is produced and what is its biological significance. We observed overproduction of acetate in an amount comparable to ketone bodies in patients and mice with diabetes or starvation. Mechanistically, ACOT 12&8 are dramatically upregulated in liver to convert FFA-derived acetyl-CoA to acetate and CoA. This conversion not only provides large amount of acetate which fuels brain preferentially rather than muscle, but also recycles CoA which is required for sustained fatty acid oxidation and ketogenesis. Taken together, we suggest that acetate is an emerging novel "ketone body" and may be used as a parameter to evaluate the progression of energy stress in the future.

biochemistry↗

bioRxiv2023

Genomic adaptation underlies nutrient-driven reprogramming in the malaria-causing parasite

Parasites often depend on metabolic adaptation to the host environment. An adaptive feature of malaria-causing parasites is digestion of hemoglobin (HB) to acquire amino acids (AAs). Here we describe a link between nutrient availability and translation elongation-dependent regulation of gene expression as an adaptive strategy. We show that, unexpectedly, tRNA expression in P. falciparum does not match the decoding need as tRNAs decoding AAs that are rare in HB are lowly expressed. This discrepancy renders codons of HB-rare AAs inefficiently decoded and transcripts levels negatively correlated with the requirement of HB-rare AAs for protein synthesis, which are consistent with poor codon optimality causing co-translational mRNA decay. Intriguingly, proliferation-related genes have evolved to require a high level of HB-rare AAs in their encoded proteins, thereby allowing the parasite to control its proliferation by repressing protein synthesis of these genes during nutrient stress. We conclude that the parasite modulates translation elongation by maintaining a discordant tRNA profile as a mechanism to exploit variations in AA-composition among genes as an adaptation strategy.

microbiology↗

bioRxiv2023

Endogenous Staphylococcus aureus CRISPR-cas system limits phage proliferation and efficiently excises from the genome as part of the SCCmec cassette

CRISPR-Cas is an adaptive immune system that allows bacteria to inactivate mobile genetic elements. Approximately 50% of bacteria harbor CRISPR-cas, however in the human pathogen Staphylococcus aureus, CRISPR-cas loci are less common and often studied in heterologous systems. We analyzed the prevalence of CRISPR-cas in genomes of methicillin resistant Staphylococcus aureus (MRSA) isolated in Denmark. Only 2.9 % of the strains carried CRISPR-cas systems, but for strains of sequence type ST630 over half were positive. All CRISPR-cas loci were type III-A and located within the staphylococcal chromosomal cassette (SCCmec) type V(5C2&5) conferring {beta}-lactam resistance. Curiously, only 23 different CRISPR spacers were identified in 69 CRISPR-positive strains and almost identical SCCmec cassettes, CRISPR arrays and cas genes, are present in staphylococcal species other than aureus, suggesting that these were transferred horizontally. For the ST630 strain 110900, we demonstrate that the SCCmec cassette containing CRISPR-cas excises from the chromosome at high frequency. However, the cassette was not transferable under the conditions investigated. One of the CRISPR spacers targets a late gene in the lytic bacteriophage (phage) virus philPLA-RODI, and we show that the system protects against phage infection by reducing phage burst size. However, CRISPR-Cas can be overloaded or bypassed by CRISPR escape mutants. Our results imply that the endogenous type III-A CRISPR-Cas system in S. aureus is active against targeted phages, albeit with low efficacy. This suggests native S. aureus CRISPR-Cas offers only partial immunity, and in nature may work in tandem with other defense systems. ImportanceCRISPR-Cas is an adaptive immune system enabling bacteria and archaea to protect themselves against mobile genetic elements such as phages. In strains of Staphylococcus aureus, CRISPR-cas is rare, but when present, it is located within the SCCmec element encoding resistance to methicillin and other {beta}-lactam antibiotics. We show that the entire module is excisable, with almost identical versions found in different species of non-aureus staphylococci suggesting that the system only rarely acquires new spacers in S. aureus. Additionally, we show that in its endogenous form, the S. aureus CRISPR-Cas is active but inefficient against lytic phages, with phages being able to form escape mutants or overload the system. This leads us to propose that CRISPR-Cas in S. aureus offers only partial immunity in native systems, and so may work together with other defense systems to prevent phage-mediated killing.

microbiology↗

bioRxiv2023

Spatial Transcriptomics Arena (STAr): an Integrated Platform for Spatial Transcriptomics Methodology Research

The emerging field of spatially resolved transcriptomics (SRT) has revolutionized biomedical research. SRT quantifies expression levels at different spatial locations, providing a new and powerful tool to interrogate novel biological insights. An essential question in the analysis of SRT data is to identify spatially variable (SV) genes; the expression levels of such genes have spatial variation across different tissues. SV genes usually play an important role in underlying biological mechanisms and tissue heterogeneity. Currently, several computational methods have been developed to detect such genes; however, there is a lack of unbiased assessment of these approaches to guide researchers in selecting the appropriate methods for their specific biomedical applications. In addition, it is difficult for researchers to implement different existing methods for either biological study or methodology development. Furthermore, currently available public SRT datasets are scattered across different websites and preprocessed in different ways, posing additional obstacles for quantitative researchers developing computational methods for SRT data analysis. To address these challenges, we designed Spatial Transcriptomics Arena (STAr), an open platform comprising 193 curated datasets from seven technologies, seven statistical methods, and analysis results. This resource allows users to retrieve high-quality datasets, apply or develop spatial gene detection methods, as well as browse and compare spatial gene analysis results. It also enables researchers to comprehensively evaluate SRT methodology research in both simulated and real datasets. Altogether, STAr is an integrated research resource intended to promote reproducible research and accelerate rigorous methodology development, which can eventually lead to an improved understanding of biological processes and diseases. STAr can be accessed at https://lce.biohpc.swmed.edu/star/.

genomics↗

bioRxiv2023

Quantitative Time-Course Analysis of Osmotic and Salt Stress in Arabidopsis thaliana using Short Gradient Multi-CV FAIMSpro BoxCar DIA

A major limitation when undertaking quantitative proteomic time-course experimentation is the tradeoff between depth-of-analysis and speed-of-analysis. In high complexity and high dynamic range sample types, such as plant extracts, balance between resolution and time is especially apparent. To address this, we evaluate multiple composition voltage (CV) High Field Asymetric Waveform Ion Mobility Spectrometry (FAIMSpro) settings using the latest label-free single-shot Orbitrap-based DIA acquisition workflows for their ability to deeply-quantify the Arabidopsis thaliana seedling proteome. Using a BoxCarDIA acquisition workflow with a -30 -50 -70 CV FAIMSpro setting we are able to consistently quantify >5000 Arabidopsis seedling proteins over a 21-minute gradient, facilitating the analysis of ~42 samples per day. Utilizing this acquisition approach, we then quantified proteome-level changes occurring in Arabidopsis seedling shoots and roots over 24 h of salt and osmotic stress, to identify early and late stress response proteins and reveal stress response overlaps. Here, we successfully quantify >6400 shoot and >8500 root protein groups, respectively, quantifying nearly ~9700 unique protein groups in total across the study. Collectively, we pioneer a short gradient, multi-CV FAIMSpro BoxCarDIA acquisition workflow that represents an exciting new analysis approach for undertaking quantitative proteomic time-course experimentation in plants.

plant biology↗

bioRxiv2023

Retrieved Sequence Augmentation for Protein Representation Learning

The advancement of protein representation learning has been significantly influenced by the remarkable progress in language models. Accordingly, protein language models perform inference from individual sequences, thereby limiting their capacity to incorporate evolutionary knowledge present in sequence variations. Existing solutions, which rely on Multiple Sequence Alignments (MSA), suffer from substantial computational overhead and suboptimal generalization performance for de novo proteins. In light of these problems, we introduce a novel paradigm called Retrieved Sequence Augmentation (RSA) that enhances protein representation learning without necessitating additional alignment or preprocessing. RSA associates query protein sequences with a collection of structurally or functionally similar sequences in the database and integrates them for subsequent predictions. We demonstrate that protein language models benefit from retrieval enhancement in both structural and property prediction tasks, achieving a 5% improvement over MSA Transformer on average while being 373 times faster. Furthermore, our model exhibits superior transferability to new protein domains and outperforms MSA Transformer in de novo protein prediction. This study fills a much-encountered gap in protein prediction and brings us a step closer to demystifying the domain knowledge needed to understand protein sequences. Code is available at https://github.com/HKUNLP/RSA.

bioinformatics↗

bioRxiv2023

A cleaved METTL3 potentiates the METTL3-WTAP interaction and breast cancer progression

N6-methyladenosine (m6A) methylation of RNA by the methyltransferase complex (MTC), with core components including METTL3-METTL14 heterodimers and Wilms tumor 1-associated protein (WTAP), contributes to breast tumorigenesis, but the underlying regulatory mechanisms remain elusive. Here, we identify a novel cleaved form METTL3a (residues 239-580 of METTL3). We find that METTL3a is required for the METTL3-WTAP interaction, RNA m6A deposition, as well as cancer cell proliferation. Mechanistically, we find that METTL3a is essential for the METTL3-METTL3 interaction, which is a prerequisite step for recruitment of WTAP in MTC. Analysis of m6A sequencing data shows that depletion of METTL3a globally disrupts m6A deposition, and METTL3a mediates mTOR activation via m6A-mediated suppression of TMEM127 expression. Moreover, we find that METTL3 cleavage is mediated by proteasome in an mTOR-dependent manner, revealing positive regulatory feedback between METTL3a and mTOR signaling. Our findings reveal METTL3a as an important component of MTC, and suggest the METTL3a-mTOR axis as a potential therapeutic target for breast cancer.

cell biology↗

bioRxiv2023

Conflicts are represented in a cognitive space to reconcile domain-general and domain-specific cognitive control

Cognitive control resolves conflicts between task-relevant and -irrelevant information to enable goal-directed behavior. As conflicts can arise from different sources (e.g., sensory input, internal representations), how a limited set of cognitive control processes can effectively address diverse conflicts remains a major challenge. Based on the cognitive space theory, different conflicts can be parameterized and represented as distinct points in a (low-dimensional) cognitive space, which can then be resolved by a limited set of cognitive control processes working along the dimensions. It leads to a hypothesis that conflicts similar in their sources are also represented similarly in the cognitive space. We designed a task with five types of conflicts that could be conceptually parameterized. Both human performance and fMRI activity patterns in the right dorsolateral prefrontal (dlPFC) support that different types of conflicts are organized based on their similarity, thus suggesting cognitive space as a principle for representing conflicts.

neuroscience↗

bioRxiv2023

Physiological reprogramming in vivo mediated by Sox4 pioneer factor activity

Tissue damage elicits cell fate switching through a process called metaplasia, but how the starting cell fate is silenced and the new cell fate is activated has not been investigated in animals. In cell culture, pioneer transcription factors mediate "reprogramming" by opening new chromatin sites for expression that can attract transcription factors from the starting cells enhancers. Here we report that Sox4 is sufficient to initiate hepatobiliary metaplasia in the adult liver. In lineage-traced cells, we assessed the timing of Sox4-mediated opening of enhancer chromatin versus enhancer decommissioning. Initially, Sox4 directly binds to and closes hepatocyte regulatory sequences via a motif it overlaps with Hnf4a, a hepatocyte master regulator. Subsequently, Sox4 exerts pioneer factor activity to open biliary regulatory sequences. The results delineate a hierarchy by which gene networks become reprogrammed under physiological conditions, providing deeper insight into the basis for cell fate transitions in animals.

cell biology↗

bioRxiv2023

Mucociliary Clearance Augmenting Drugs Block SARS-Cov-2 Replication in Human Airway Epithelial Cells

The coronavirus disease (COVID-19) pandemic, caused by SARS-CoV-2 coronavirus, is devastatingly impacting human health. A prominent component of COVID-19 is the infection and destruction of the ciliated respiratory cells, which perpetuates dissemination and disrupts protective mucociliary transport (MCT) function, an innate defense of the respiratory tract. Thus, drugs that augment MCT could improve barrier function of the airway epithelium, reduce viral replication and, ultimately, COVID-19 outcomes. We tested five agents known to increase MCT through distinct mechanisms for activity against SARS-CoV-2 infection using a model of human respiratory epithelial cells terminally differentiated in an air/liquid interphase. Three of the five mucoactive compounds tested showed significant inhibitory activity against SARS-CoV-2 replication. An archetype mucoactive agent, ARINA-1, blocked viral replication and therefore epithelial cell injury, thus, it was further studied using biochemical, genetic and biophysical methods to ascertain mechanism of action via improvement of MCT. ARINA-1 antiviral activity was dependent on enhancing the MCT cellular response, since terminal differentiation, intact ciliary expression and motion was required for ARINA-1-mediated anti-SARS-CoV2 protection. Ultimately, we showed that improvement of cilia movement was caused by ARINA-1-mediated regulation of the redox state of the intracellular environment, which benefited MCT. Our study indicates that Intact MCT reduces SARS-CoV-2 infection, and its pharmacologic activation may be effective as an anti-COVID-19 treatment.

microbiology↗

bioRxiv2023

The landscape of m1A modification and its posttranscriptional regulatory functions in primary neurons

Cerebral ischaemia-reperfusion injury, during which neurons undergo oxygen-glucose deprivation/reoxygenation (OGD/R), is a notable pathological process in many neurological diseases. N1-methyladenosine (m1A) is an RNA modification that can affect gene expression and RNA stability. The m1A landscape and potential functions of m1A modification in neurons remain poorly understood. We explored RNA (mRNA, lncRNA, and circRNA) m1A modification in normal and OGD/R-treated neurons and the effect of m1A on diverse RNAs. We investigated the m1A landscape in primary neurons, identified m1A-modified RNAs, and found that OGD/R increased the number of m1A RNAs. m1A modification might also affect the regulatory mechanisms of noncoding RNAs, e.g., lncRNA-RBP interactions and circRNA translation. We showed that m1A modification mediates the circRNA/lncRNA-miRNA-mRNA ceRNA mechanism and that 3UTR methylation of mRNAs can hinder miRNA-mRNA binding. Three methylation patterns were identified, and genes with different patterns had intrinsic mechanisms with potential m1A-regulatory specificity. Systematic analysis of the m1A landscape in normal and OGD/R neurons lays a critical foundation for understanding RNA methylation and provides new perspectives and a theoretical basis for treating and developing drugs for OGD/R pathology-related diseases.

neuroscience↗

bioRxiv2023

Quorum sensing inhibits Type III-A CRISPR-Cas system activity through repressing positive regulators SarA and ArcR in Staphylococcus aureus

CRISPR-Cas is an adaptive immune system that protects prokaryotes from the invasion of foreign genetic elements. The components and immunity mechanisms of CRISPR-Cas have been extensively studied, but the regulation of this system in Staphylococci remains unclear. Here, we show that in the S. aureus Type III-A CRISPR-Cas system, the Pcas of 300 bp located in cas1 displays as a critical regulatory node that initiates the transcription of cas gene clusters. We discovered two transcriptional regulators, SarA and CRP-like ArcR, promote the expression and activity of the CRISPR-Cas system by directly binding to the novel promoter Pcas. Furthermore, we demonstrated that the cell-cell communication, known as quorum sensing (QS), inhibits the activity of CRISPR-Cas system by repressing the positive regulators SarA and ArcR. Bioinformatic analyses suggest that Pcas is conserved in many Type II and III CRISPR-Cas systems in Firmicutes. Our data reveal a new regulatory mechanism for QS-mediated repression of the Type III-A CRISPR-Cas system, which may allow S. aureus to acquire foreign genetic elements encoding antibiotic resistance or virulence factors specifically at high cell density.

microbiology↗

bioRxiv2023

Loss of PTPMT1 limits mitochondrial utilization of carbohydrates and leads to muscle atrophy and heart failure

While mitochondria in different tissues have distinct preferences for energy sources, they are flexible in utilizing competing substrates for metabolism according to physiological and nutritional circumstances. However, the regulatory mechanisms and significance of metabolic flexibility are not completely understood. Here we report that the deletion of PTPMT1, a mitochondria-based phosphatase, critically alters mitochondrial fuel selection - the utilization of pyruvate, a key mitochondrial substrate derived from glucose (the major simple carbohydrate), is inhibited, whereas the fatty acid utilization is enhanced. PTPMT1 knockout does not impact the development of the skeletal muscle or heart. However, the metabolic inflexibility ultimately leads to muscular atrophy, heart failure, and sudden death. Mechanistic analyses reveal that the prolonged substrate shift from carbohydrates to lipids causes oxidative stress and mitochondrial destruction, which in turn results in marked accumulation of lipids and profound damage in the knockout muscle cells and cardiomyocytes. Interestingly, PTPMT1 deletion from the liver or adipose tissue does not generate any local or systemic defects. These findings suggest that PTPMT1 plays an important role in maintaining mitochondrial flexibility and that their balanced utilization of carbohydrates and lipids is essential for both the skeletal muscle and the heart despite the two tissues having different preferred energy sources.

cell biology↗

bioRxiv2023

Generation of nanobodies acting as silent and positive allosteric modulators of the α7 nicotinic acetylcholine receptor

The 7 nicotinic acetylcholine receptor (nAChR), a potential drug target for treating cognitive disorders, mediates communication between neuronal and non-neuronal cells. Although many competitive antagonists, agonists, and partial-agonists have been found and synthesized, they have not led to effective therapeutic treatments. In this context, small molecules acting as positive allosteric modulators binding outside the orthosteric, acetylcholine, site have attracted considerable interest. Two single-domain antibody fragments, C4 and E3, against the extracellular domain of the human 7-nAChR were generated through alpaca immunization with cells expressing a human 7-nAChR/mouse 5-HT3A chimera, and are herein described. They bind to the 7-nAChR but not to the other major nAChR subtypes, 4{beta}2 and 3{beta}4. E3 acts as a slowly associating positive allosteric modulator, strongly potentiating the acetylcholine-elicited currents, while not precluding the desensitization of the receptor. An E3-E3 bivalent construct shows similar potentiating properties but displays very slow dissociation kinetics conferring quasi-irreversible properties. Whereas, C4 does not alter the receptor function, but fully inhibits the E3-evoked potentiation, showing it is a silent allosteric modulator competing with E3 binding. Both nanobodies do not compete with -bungarotoxin, localizing at an allosteric extracellular binding site away from the orthosteric site. The functional differences of each nanobody, as well as the alteration of functional properties through nanobody modifications indicate the importance of this extracellular site. The nanobodies will be useful for pharmacological and structural investigations; moreover, they, along with the extracellular site, have a direct potential for clinical applications.

neuroscience↗