Biology subjects

Xu, L.

Publications and source records attributed to Xu, L..

At least 199 records · Page 11Linked to original sources

bioRxiv2024

BIT: Bayesian Identification of Transcriptional Regulators

Transcriptional regulators (TRs) are master controllers of gene expression and play a critical role in both normal tissue development and disease progression. However, existing computational methods for identification of TRs regulating specific biological processes have significant limitations, such as relying on distance on a linear chromosome or binding motifs that have low specificity. Many also use statistical tests in ways that lack interpretability and rigorous confidence measures. We introduce BIT, a novel Bayesian hierarchical model for in-silico TR identification. Leveraging a comprehensive library of TR ChIP-seq data, BIT offers a fully integrated Bayesian approach to assess genome-wide consistency between user-provided epigenomic profiling data and the TR binding library, enabling the identification of critical TRs while quantifying uncertainty. It avoids estimation and inference in a sequential manner or numerous isolated statistical tests, thereby enhancing accuracy and interpretability. BIT successfully identified critical TRs in perturbation experiments, functionally essential TRs in various cancer types, and cell-type-specific TRs within heterogeneous cell populations, offering deeper biological insights into transcriptional regulation.

bioinformatics↗

bioRxiv2024

Bright New Resources for Syphilis Research: Genetically Encoded Fluorescent Tags for Treponema pallidum and Sf1Ep Cells

The recently discovered methodologies to cultivate and genetically manipulate Treponema pallidum subsp. pallidum (T. pallidum) have significantly helped syphilis research, allowing the in vitro evaluation of antibiotic efficacy, performance of controlled studies to assess differential treponemal gene expression, and generation of loss-of-function mutants to evaluate the contribution of specific genetic loci to T. pallidum virulence. Building on this progress, we engineered the T. pallidum SS14 strain to express a red-shifted Green Fluorescent Protein (GFP) and Sf1Ep cells to express mCherry and blue fluorescent protein (BFP) for enhanced visualization. These new resources improve microscopy- and cell sorting-based applications for T. pallidum, better capturing the physical interaction between the host and pathogen, among other possibilities. Continued efforts to develop and share new tools and resources are required to help our overall knowledge of T. pallidum biology and syphilis pathogenesis reach that of other bacterial pathogens, including spirochetes. Graphical abstractBy employing genetic engineering, T. pallidum was modified to express GFP, and Sf1Ep cells to express mCherry on the cytoplasmic membrane and BFP in the nucleus. These new resources for syphilis research will facilitate experimental designs to better define the complex interplay between T. pallidum and the host during infection. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/596454v1_ufig1.gif" ALT="Figure 1"> View larger version (114K): org.highwire.dtl.DTLVardef@1cc5bcborg.highwire.dtl.DTLVardef@19e8a12org.highwire.dtl.DTLVardef@17aafdborg.highwire.dtl.DTLVardef@1af6823_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2024

Oral Exposure to Benzalkonium Chlorides in Male and Female Mice Reveals Sex-Dependent Alteration of the Gut Microbiome and Bile Acid Profile

Benzalkonium chlorides (BACs) are commonly used disinfectants in a variety of consumer and food-processing settings, and the COVID-19 pandemic has led to increased usage of BACs. The prevalence of BACs raises the concern that BAC exposure could disrupt the gastrointestinal microbiota, thus interfering with the beneficial functions of the microbes. We hypothesize that BAC exposure can alter the gut microbiome diversity and composition, which will disrupt bile acid homeostasis along the gut-liver axis. In this study, male and female mice were exposed orally to d7-C12- and d7-C16-BACs at 120 {micro}g/g/day for one week. UPLC-MS/MS analysis of liver, blood, and fecal samples of BAC-treated mice demonstrated the absorption and metabolism of BACs. Both parent BACs and their metabolites were detected in all exposed samples. Additionally, 16S rRNA sequencing was carried out on the bacterial DNA isolated from the cecum intestinal content. For female mice, and to a lesser extent in males, we found that treatment with either d7-C12- or d7-C16-BAC led to decreased alpha diversity and differential composition of gut bacteria with notably decreased actinobacteria phylum. Lastly, through a targeted bile acid quantitation analysis, we observed decreases in secondary bile acids in BAC-treated mice, which was more pronounced in the female mice. This finding is supported by decreases in bacteria known to metabolize primary bile acids into secondary bile acids, such as the families of Ruminococcaceae and Lachnospiraceae. Together, these data signify the potential impact of BACs on human health through disturbance of the gut microbiome and gut-liver interactions.

pharmacology and toxicology↗

bioRxiv2024

Structural insights into transcription regulation of the global virulence factor PhoP from Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb), remaining as the leading cause of the worldwide threat Tuberculosis, relies heavily on its transcriptional reprogramming of diverse stress genes to swiftly adapt to adverse environments and ensure infections. The global virulence factor PhoP plays a pivotal role in coordinating transcription activation or repression of the essential phosphate-nitrogen metabolic remodeling genes. However, what defines PhoP to deferentially act as an activator or a repressor remains largely unexplored. Here, we determine one cryo-EM structure of Mtb RNAP-promoter open complex, three cryo-EM structures of PhoP-dependent transcription activation complexes (PhoP-TACs) consisting of Mtb RNA polymerase (RNAP), different number of PhoP molecules binding to different types of well-characterized consensus promoters, and one cryo-EM structure of Mtb PhoP-dependent transcription repression complex (PhoP-TRC) comprising of Mtb RNAP, PhoP, the nitrogen metabolism regulator GlnR and their co-regulated promoter. Structural comparisons reveal phosphorylation of PhoP is required for stabilization of PhoP-TACs, PhoP specifically recognizes promoters as novel tandem dimers and recruits RNAP through extensively interacting with its conserved {beta} flap and {sigma}AR4 domains. Strikingly, the distinct promoter spacer length and PhoP-GlnR interactions in PhoP-TRC constrain the upstream DNA into a distinct topology and retain PhoP in a novel dragging repression mode. Collectively, these data highlight the dual regulatory mechanisms of PhoP-dependent transcription regulation in governing stress adaptation. These findings provide structural basis for developing potential anti-tuberculosis drugs and/or interventions.

microbiology↗

bioRxiv2024

Growth of Staphylococcus aureus in the presence of oleic acid shifts the glycolipid fatty acid profile and increases resistance to antimicrobial peptides

Staphylococcus aureus readily adapts to various environments and quickly develops antibiotic resistance, which has led to an increase in multidrug-resistant infections. Hence, S. aureus presents a significant global health issue and its adaptations to the host environment are crucial for understanding pathogenesis and antibiotic susceptibility. When S. aureus is grown conventionally, its membrane lipids contain a mix of branched-chain and straight-chain saturated fatty acids. However, when unsaturated fatty acids are present in the growth medium, they become a major part of the total fatty acid composition. This study explores the biophysical effects of incorporating straight-chain unsaturated fatty acids into S. aureus membrane lipids. Membrane preparations from cultures supplemented with oleic acid showed more complex differential scanning calorimetry scans than those grown in tryptic soy broth alone. When grown in the presence of oleic acid, the cultures exhibited a transition significantly above the growth temperature, attributed to the presence of glycolipids with long-chain fatty acids causing acyl chain packing frustration within the bilayer. Functional aspects of the membrane were assessed by studying the kinetics of dye release from unilamellar vesicles induced by the antimicrobial peptide mastoparan X. Dye release was slower from liposomes prepared from cells grown in oleic acid-supplemented cultures, suggesting that changes in membrane lipid composition and biophysics protect the cell membrane against peptide-induced lysis. These findings underscore the intricate relationship between the growth environment, membrane lipid composition, and the physical properties of the bacterial membrane, which should be considered when developing new strategies against S. aureus infections.

biophysics↗

bioRxiv2024

The genetic architecture and evolutionary consequences of the human pelvic form

Human pelvic shape has undergone significant evolutionary change since the divergence from the chimpanzee lineage. This transformation, involving the reduction of the pelvic canal size to support bipedal locomotion, is thought to give rise to the obstetrical dilemma, a hypothesis highlighting the mismatch between the large brain size of infants and the narrowed birth canal in females. Empirical evidence for this classic hypothesis has been equivocal, largely due to a lack of sample size and appropriate types of data. To elucidate the genetic underpinnings of pelvic morphology, we applied a deep learning model to 31,115 dual-energy X-ray absorptiometry (DXA) from the UK Biobank, extracting a set of seven pelvic proportion (PP) phenotypes, including measures of the birth canal. All PPs were found to be highly heritable ([~]25-40%) and a genome-wide association study of these traits identified 179 independent loci. Unlike other skeletal proportions including long bone lengths, the subpubic angle associated with the birth canal exhibits a genetic correlation between sexes significantly less than 1, in line with sex-specific reproductive function. PPs were also left-right asymmetric but not heritable and instead associated with handedness. We conducted phenotypic and genetic association analyses to link PPs to 3 facets of the dilemma: locomotion, pelvic floor function and childbirth. Larger birth canal phenotypes were associated with reduced walking pace, decreased risk of back pain, and increased risk of hip osteoarthritis - phenotypes linked to locomotor efficiency. We also observed that a narrower birth canal width was associated with a reduced risk of pelvic floor disorders. When examining childbirth-related outcomes, narrower birth canal phenotypes were associated with increased risk of emergency cesarean sections and obstructed labor due to insufficient dilation, but not obstructed labor due to positioning of the fetus. Finally, we examined whether the dilemma might have been alleviated through evolution. We found no association between any PPs and gestational duration, contrary to the initial prediction by Washburn in 1960. However, we found that the birth weight of the child, a proxy for skull and brain size, was genetically correlated with birth canal width but not with other PPs. Collectively, our study offers fresh insight on a 60-year-old debate in human evolutionary studies. Our results support the idea that the obstetrical dilemma has played a central role in the co-evolution of the human brain and pelvis, while also highlighting the potential role of associated factors such as pelvic floor health.

genetics↗

bioRxiv2024

A delta-tubulin/epsilon-tubulin/Ted protein complex is required for centriole architecture

Centrioles have a unique, conserved architecture formed by three linked "triplet" microtubules arranged in nine-fold symmetry. The mechanisms by which these triplet microtubules are formed are not understood and likely involve the noncanonical tubulins delta-tubulin and epsilon-tubulin. Previously, we found that human cells deficient in delta-tubulin or epsilon-tubulin form abnormal centrioles, characterized by an absence of triplet microtubules, lack of central core protein POC5, and a futile cycle of centriole formation and disintegration (Wang et al., 2017). Here, we show that human cells lacking either of the associated proteins TEDC1 and TEDC2 have these same phenotypes. Using ultrastructure expansion microscopy, we find that mutant centrioles elongate to the same length as control centrioles in G2-phase. These mutants fail to recruit inner scaffold proteins of the central core and have an expanded proximal region. During mitosis, the mutant centrioles elongate further before fragmenting and disintegrating. All four proteins physically interact and TEDC1 and TEDC2 are capable forming a subcomplex in the absence of the tubulins. These results support an AlphaFold Multimer model of the tetramer in which delta-tubulin and epsilon-tubulin are predicted to form a heterodimer. TEDC1 and TEDC2 localize to centrosomes and are mutually dependent on each other and on delta-tubulin and epsilon-tubulin for localization. Our results demonstrate that delta-tubulin, epsilon-tubulin, TEDC1, and TEDC2 function together to promote robust centriole architecture. This work also lays the groundwork for future molecular studies of this complex, providing a basis for determining the mechanisms that underlie the assembly and interplay between the triplet microtubules and inner centriole structure.

cell biology↗

bioRxiv2024

Proteolytic processing of both RXLR and EER motifs in oomycete effectors

Arg-any amino acid-Leu-Arg (RXLR) effectors are central oomycete virulence factors that target diverse host proteins and processes to suppress plant immunity. Relatively little is known about how they are processed post-translationally before delivery into host cells. Proteolytic cleavage at the RXLR motif was observed to occur prior to secretion in all Phytophthora infestans effectors tested, suggesting it is a general rule, and was observed to occur between the leucine and the second arginine. There was no cleavage of a naturally occurring second RXLR motif in a structured region of Pi21388/AvrBlb1, or one introduced at a similar position in effector Pi04314, in keeping with the motif being positionally constrained, potentially to disordered regions closely following the signal peptide. Remarkably, independent proteolytic cleavage of the Glu-Glu-Arg (EER) motif, often found immediately downstream of the RXLR, was also observed in diverse effectors, occurring immediately after the arginine. Expression of full-length effectors in host plant Nicotiana benthamiana revealed that, although secreted, they were poorly processed, suggesting that RXLR and EER cleavage does not occur in all eukaryotic cells. Our observations indicate that, whether possessing both RXLR and EER, or either motif alone, these effectors are likely proteolytically processed prior to secretion in all cases.

plant biology↗

bioRxiv2024

Temporally controlled nervous system-to-gut signaling bidirectionally regulates longevity in Caenorhabditis elegans

The nervous system modulates aging by secreting signaling molecules to cell-nonautonomously regulate the physiological state of distal tissues such as the gut. However, the underlying mechanisms are not well understood. Here, using C. elegans as a model, we identified two distinct neuroendocrine signaling circuits through which motor neurons signal the gut in early life to shorten lifespan but in mid-late life to extend lifespan. Both circuits employ the same neurotransmitter acetylcholine (ACh), while recruiting two different gut ACh receptors ACR-6 and GAR-3 to regulate the transcription factor DAF-16 and HSF-1 in early and mid-late life, respectively. Strikingly, the gut expression of ACR-6 is restricted to early life, whereas that of GAR-3 is confined to mid-late life, providing a potential mechanism for the temporal control of the two circuits. These results identify a novel mechanism that empowers the nervous system to bidirectionally regulate longevity by differentially signaling the gut at different life stages.

cell biology↗

bioRxiv2024

Glia-derived secretory fatty acid binding protein Obp44a regulates lipid storage and efflux in the developing Drosophila brain

Glia derived secretory factors play diverse roles in supporting the development, physiology, and stress responses of the central nervous system (CNS). Through transcriptomics and imaging analyses, we have identified Obp44a as one of the most abundantly produced secretory proteins from Drosophila CNS glia. Protein structure homology modeling and Nuclear Magnetic Resonance (NMR) experiments reveal Obp44a as a fatty acid binding protein (FABP) with a high affinity towards long-chain fatty acids in both native and oxidized forms. Further analyses demonstrate that Obp44a effectively infiltrates the neuropil, traffics between neuron and glia, and is secreted into hemolymph, acting as a lipid chaperone and scavenger to regulate lipid and redox homeostasis in the developing brain. In agreement with this essential role, deficiency of Obp44a leads to anatomical and behavioral deficits in adult animals and elevated oxidized lipid levels. Collectively, our findings unveil the crucial involvement of a noncanonical lipid chaperone to shuttle fatty acids within and outside the brain, as needed to maintain a healthy brain lipid environment. These findings could inspire the design of novel approaches to restore lipid homeostasis that is dysregulated in CNS diseases.

developmental biology↗

bioRxiv2024

Modulation of pedunculopontine input to the basal ganglia relieves motor symptoms in Parkinsonian mice

Locomotion, the ability to move, is driven by central pattern generators in the spinal cord. However, its initiation, selection of gait and arrest are controlled by command centers in the brain stem of which the best understood is the mesencephalic locomotor region (MLR). Stimulation of the MLR can initiate or arrest movement, but its neural projections and the neural circuits that mediate these actions are poorly understood. Here we show that glutamatergic neurons in the pedunculopontine nucleus (PPN), a major part of the MLR, project to the substantial nigra pars reticulata (SNr) where they innervate neurons that send afferents to the ventro medial motor thalamus (VM). Stimulation of this input to the SNr in mice slows voluntary and driven movement by modifying gait, with higher frequencies arresting gait. In Parkinsons disease (PD), a neurodegenerative disorder, the cardinal symptoms are bradykinesia, tremor and rigidity. Using an mouse model of PD, we show that inhibition of PPN input to the SNr rescues bradykinesia. This is the first description of a circuit in the mammalian brain that regulates movement and gait selection. Targeting of this circuit may be a more effective modality for treating the motor symptoms of PD.

neuroscience↗

bioRxiv2024

The Spx stress regulator confers high-level β-lactam resistance and decreases susceptibility to last-line antibiotics in methicillin resistant Staphylococcus aureus

Infections caused by methicillin resistant Staphylococcus aureus (MRSA) are a leading cause of mortality worldwide. MRSA have acquired resistance to next generation {beta}-lactam antibiotics through the horizontal acquisition of the mecA resistance gene. Development of high resistance is, however, often associated with additional mutations in a set of chromosomal core genes, known as potentiators which through poorly described mechanisms enhance resistance. The yjbH gene was recently identified as a hot spot for adaptive mutations during severe infections. Here, we show that inactivation of yjbH increased {beta}-lactam MICs up to 16-folds and transformed MRSA cells with low level of resistance to being homogenously highly resistant to {beta}-lactams. The yjbH gene encodes an adaptor protein that targets the transcriptional stress regulator Spx for degradation by the ClpXP protease. Using CRISPRi to knock down spx transcription, we unambiguously linked hyper-resistance to accumulation of Spx. Spx was previously proposed to be essential, however, our data indicate that Spx is dispensable for growth at 37{degrees}C but becomes essential in the presence of antibiotics with various targets. On the other hand, high Spx levels bypassed the role of PBP4 in {beta}-lactam resistance and broadly decreased MRSA susceptibility to compounds targeting the cell wall or the cell membrane including vancomycin, daptomycin, and nisin. Strikingly, Spx potentiated resistance independently of its redox sensing switch. Collectively, our study identifies a general stress pathway that, in addition to promoting the development of high-level, broad-spectrum {beta}-lactam resistance, also decreases MRSA susceptibility to critical antibiotics of last resort.

microbiology↗

bioRxiv2024

The impact of Bacillus coagulans X3 on available nitrogen content, bacterial community composition, and nitrogen functional gene levels when composting cattle manure

This study was designed to probe available nitrogen levels, bacterial community composition, and the levels of nitrogen functional genes present when composting cattle manure with or without the addition of Bacillus coagulans X3. Bacterial supplementation was associated with the prolongation of the thermophilic stage and improved maturity of the resultant compost. At the maturity stage, samples to which B. coagulans X3 had been added exhibited significant increases in ammonium nitrogen, nitrate nitrogen, and total nitrogen levels. The dominant bacterial phyla observed in these composting samples were Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteriota, and Chloroflexi.B. coagulans X3 addition resulted in significant increases in relative Firmicutes abundance during the thermophilic and cooling stages, while also increasing amoA and nosZ gene abundance and reducing nirS gene levels over the course of composting. Together, these data suggest that B. coagulans X3 supplementation provides an effective means of enhancing nitrogen content in the context of cattle manure composting through the regulation of nitrification and denitrification activity.

microbiology↗

bioRxiv2024

Common methods of making giant vesicles (except emulsion techniques) capture intended lipid ratios

Researchers choose different methods of making giant unilamellar vesicles in order to satisfy different constraints of their experimental designs. A challenge of using a variety of methods is that each may produce vesicles of different lipid compositions, even if all vesicles are made from a common stock mixture. Here, we use mass spectrometry to investigate ratios of lipids in vesicles made by five common methods: electroformation on indium tin oxide slides, electroformation on platinum wires, gentle hydration, emulsion transfer, and extrusion. We made vesicles from either 5-component or binary mixtures of lipids chosen to span a wide range of physical properties: di(18:1)PC, di(16:0)PC, di(18:1)PG, di(12:0)PE, and cholesterol. For a mixture of all five of these lipids, ITO electroformation, Pt electroformation, gentle hydration, and extrusion methods result in only minor shifts ([≤] 5 mol%) in lipid ratios of vesicles relative to a common stock solution. In contrast, emulsion transfer results in [~]80% less cholesterol than expected from the stock solution, which is counterbalanced by a surprising overabundance of saturated PC-lipid relative to all other phospholipids. Experiments using binary mixtures of some of the lipids largely support results from the 5-component mixture. Exact values of lipid ratios variations likely depend on the details of each method, so a broader conclusion is that experiments that increment lipid ratios in small steps will be highly sensitive to the method of lipid formation and to sample-to-sample variations, which are low (roughly {+/-}2 mol% in the 5-component mixture and either scale proportionally with increasing mole fraction or remain low). Experiments that increment lipid ratios in larger steps or that seek to explain general trends or new phenomena will be less sensitive to the method used. SIGNIFICANCE STATEMENTSmall changes to the amounts and types of lipids in membranes can drastically affect the membranes behavior. Unfortunately, it is unknown whether (or to what extent) different methods of making vesicles alter the ratios of lipids in membranes, even when identical stock solutions are used. This presents challenges for researchers when comparing data with colleagues who use different methods. Here, we measure ratios of lipid types in vesicle membranes produced by five methods. We assess each methods reproducibility and compare resulting vesicle compositions across methods. In doing so, we provide a quantitative basis that the scientific community can use to estimate whether differences between their results can be simply attributed to differences between methods or to sample-to-sample variations.

biophysics↗

bioRxiv2024

Jianpi Jiedu Recipe inhibits proliferation through reactive oxygen species-induced incomplete autophagy and reduces PD-L1 expression in colon cancer

BackgroundJianpi Jiedu Recipe has been used to treat digestive tract tumors in China since ancient times, and its reliability has been proven by clinical research. Currently, the specific biological mechanism of JPJDR in treating tumors is unclear. MethodologyCCK-8 assay was used to detect cell viability. Clone formation assay and EdU assay were used to detect cell proliferation potential. DCFH-DA probe and JC-1 probe were used to detect total intracellular reactive oxygen species and mitochondrial membrane potential, respectively. Western blotting and immunofluorescence were used to detect protein expression level and subcellular localization of cells. RFP-GFP-LC3B reporter system was used to observe the type of autophagy in cells. Xenograft tumor model was used to study the therapeutic effect of JPJDR in vivo. ResultsJPJDR has a good inhibitory effect on various colorectal cancer cells and effectively reduces the proliferation ability of HT29 cells. After treatment with JPJDR, the amount of reactive oxygen species in HT29 cells increased significantly and the mitochondrial membrane potential decreased. JPJDR induced the accumulation of autophagosomes in HT29 cells and was shown to be incomplete autophagy. At the same time, JPJDR reduced the expression of PD-L1.Meanwhile, JPJDR can exert a good therapeutic effect in xenograft tumor mice. ConclusionJPJDR is a low-toxic and effective anti-tumor agent that can effectively treat colon cancer in vitro and in vivo. Its mechanism may be through inducing mitochondrial dysfunction and incomplete autophagy injury to inhibit the proliferation of colon cancer cells.

pharmacology and toxicology↗

bioRxiv2024

Predictable functional biogeography of marine microbial heterotrophs

Heterotrophic bacteria and archaea ( heteroprokaryotes) drive global carbon cycling, but how to quantitatively organize their functional complexity remains unclear. We generated a global-scale understanding of marine heteroprokaryotic functional biogeography by synthesizing genetic sequencing data with a mechanistic marine ecosystem model. We incorporated heteroprokaryotic diversity into the trait-based model along two axes: substrate lability and growth strategy. Using genetic sequences along three ocean transects, we compiled 21 heteroprokaryotic guilds and estimated their degree of optimization for rapid growth (copiotrophy). Data and model consistency indicated that gradients in grazing and substrate lability predominantly set biogeographical patterns, and identified deep-ocean slow copiotrophs whose ecological interactions control the surface accumulation of dissolved organic carbon.

ecology↗

bioRxiv2024

Morroniside promotes skin wound re-epithelialization by facilitating epidermal stem cell proliferation through GLP-1R-mediated upregulation of β-catenin expression

Epidermal stem cells (EpSCs) play a vital role in skin wound healing through re-epithelialization. Identifying chemicals that can promote EpSC proliferation is helpful for treating skin wounds. This study investigates the effect of morroniside on cutaneous wound healing in mice and explores the underlying mechanisms. Application of 10-50 g/mL of morroniside to the skin wound promotes wound healing in mice. In vitro studies demonstrate that morroniside stimulates the proliferation of mouse and human EpSCs in a time- and dose-dependent manner. Mechanistic studies reveal that morroniside promotes the proliferation of EpSCs by facilitating the cell cycle transition from the G1 to S phase. Morroniside increases the expression of {beta}-catenin via the glucagon-like peptide-1 receptor (GLP-1R)-mediated PKA, PKA/PI3K/AKT and PKA/ERK signalling pathways, resulting in the increase of cyclin D1 and cyclin E1 expression, either directly or by upregulating c-Myc expression. This process ultimately leads to EpSC proliferation. Administration of morroniside to mouse skin wounds increases the phosphorylation of AKT and ERK, the expression of {beta}-catenin, c-Myc, cyclin D1, and cyclin E1, as well as the proliferation of EpSCs, in periwound skin tissue, and accelerates wound re-epithelialization. These effects of morroniside are mediated by the GLP-1R. Overall, these results indicate that morroniside promotes skin wound healing by stimulating the proliferation of EpSCs via increasing {beta}-catenin expression and subsequent upregulation of c-Myc, cyclin D1, and cyclin E1 expression through GLP-1R signalling pathways. Morroniside has clinical potential for treating skin wounds.

pharmacology and toxicology↗

bioRxiv2024

Assessing NGS-based computational methods for predicting transcriptional regulators with query gene sets

This article provides an in-depth review of computational methods for predicting transcriptional regulators with query gene sets. Identification of transcriptional regulators is of utmost importance in many biological applications, including but not limited to elucidating biological development mechanisms, identifying key disease genes, and predicting therapeutic targets. Various computational methods based on next-generation sequencing (NGS) data have been developed in the past decade, yet no systematic evaluation of NGS-based methods has been offered. We classified these methods into two categories based on shared characteristics, namely library-based and region-based methods. We further conducted benchmark studies to evaluate the accuracy, sensitivity, coverage, and usability of NGS-based methods with molecular experimental datasets. Results show that BART, ChIP-Atlas, and Lisa have relatively better performance. Besides, we point out the limitations of NGS-based methods and explore potential directions for further improvement. Key pointsO_LIAn introduction to available computational methods for predicting functional TRs from a query gene set. C_LIO_LIA detailed walk-through along with practical concerns and limitations. C_LIO_LIA systematic benchmark of NGS-based methods in terms of accuracy, sensitivity, coverage, and usability, using 570 TR perturbation-derived gene sets. C_LIO_LINGS-based methods outperform motif-based methods. Among NGS methods, those utilizing larger databases and adopting region-centric approaches demonstrate favorable performance. BART, ChIP-Atlas, and Lisa are recommended as these methods have overall better performance in evaluated scenarios. C_LI

bioinformatics↗