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Wan, T.

Publications and source records attributed to Wan, T..

18 recordsLinked to original sources

Platelets promote acute liver injury via extracellular vesicles-mediated Aldolase A

Platelets have emerged as active regulators of acute liver injury (ALI), yet the molecular mechanisms underlying their pathogenic functions remain poorly defined. Here, we demonstrate that platelets contribute to liver injury, in part, by metabolically reprogramming Kupffer cells (KCs). We show that platelets are actively recruited to the injured liver and communicate with KCs through extracellular vesicles (EVs), which deliver the glycolytic enzyme aldolase A (ALDOA) into recipient cells. This EV mediated transfer promotes glycolytic reprogramming in KCs, contributing to their proinflammatory activation and amplification of hepatic injury. Genetic ablation of Aldoa in platelets attenuated liver injury, demonstrating a pathogenic role for platelet derived ALDOA in vivo. Pharmacological inhibition of ALDOA with Aldometanib markedly attenuated liver injury. Circulating ALDOA levels were elevated in patients with ALI and correlated with disease severity. These findings uncover a platelet macrophage metabolic axis that drives ALI and nominate ALDOA as a therapeutic target and biomarker.

pathology↗

A New Paradigm of Transcriptional Regulation by the SufR-Like Iron-Sulfur Transcription Factors

SufR is an iron-sulfur ([4Fe-4S]) cluster-containing transcription factor belonging to an uncharacterized domain family (COG2345). It has been shown to negatively regulate the sulfur utilization factor (SUF) Fe-S biogenesis system in several Gram-negative and Gram-positive bacteria including Cyanobacteria, Mycobacteria and Streptomyces. The structural basis for its DNA recognition and transcriptional regulation by the SufR-like proteins remains enigmatic. In this study, we present the cryo-EM structure of Mycobacterium tuberculosis SufR bound to its promoter, revealing a new domain architecture. Our structural, biochemical and molecular analyses show that SufR possesses an unusual [4Fe-4S] cluster coordination environment in the sensory domain and recognizes its promoter via a dual-module mechanism using both the AT-hook and the helix-turn-helix (HTH) DNA-binding motif in the DNA-binding domain. This DNA recognition strategy differs from a canonical winged HTH transcription factor. Moreover, our bioinformatic analysis and structural modeling suggest that SufR and SufR-like proteins in the COG2345 family represent a large, previously uncharacterized family of transcription factors widely distributed across bacteria and archaea. Together, these findings establish SufR-like proteins as a new model for transcriptional regulation by Fe-S transcription factors in prokaryotes and uncover the underappreciated evolutionary versatility of AT-hooks.

biochemistry↗

Decreased endothelial cell retinoic acid signaling accelerates progression of single ventricle pulmonary arteriovenous malformations

BackgroundPulmonary arteriovenous malformations (PAVMs) are vascular complications that universally develop in patients with single ventricle congenital heart disease after Glenn surgery. However, the pathophysiological mechanisms underlying single ventricle PAVMs are poorly understood. To comprehensively evaluate molecular changes post-Glenn, we performed single-cell RNA sequencing (scRNAseq) on rat lung samples after Glenn surgery. MethodsUsing adult Sprague Dawley rats, we performed scRNAseq on unfiltered lung samples 3 weeks after left-sided Glenn or sham surgery. We compared endothelial cell (EC) differentially expressed genes (DEGs) in our model to two mouse models of hereditary hemorrhagic telangiectasia (HHT), a hereditary condition characterized by visceral AVMs. Finally, we modified the vitamin A (Vit A) content of Glenn and sham rat diets and re-assessed PAVM shunting and EC transcriptional differences. ResultsUsing scRNAseq (n=4 Glenn, n=4 sham), we identified 13 transcriptionally distinct lung cell clusters, including 3 EC clusters (general, capillary, lymphatic), with pronounced differences between Glenn and sham in the general EC cluster ([~]17% of genes). Comparison to HHT mouse models confirmed overlap of [~]18% of DEGs, including identification of significantly downregulated genes involved in and regulated by all-trans retinoic acid (ATRA) signaling in all 3 models. Dietary deficiency of Vit A intake, a precursor of ATRA, caused increased PAVM shunting (p<0.01) that was mitigated with excess dietary Vit A intake. Lastly, EC-specific RNAseq identified Vit A diet-induced gene expression differences, including regulation of PI3K signaling. ConclusionsIn this study, we report the novel application of scRNAseq to study mechanisms underlying single ventricle PAVMs in a surgical rat model. We identified multiple dysregulated biological processes in rat lung ECs post-Glenn, including decreased ATRA signaling and conserved gene expression patterns with HHT. Dietary modification of Vit A intake altered post-Glenn shunting and represents a novel potential therapeutic strategy for single ventricle PAVMs and HHT AVMs.

physiology↗

Umbilical cord structure shapes feto-maternal heat exchange across mammals

The umbilical cord exhibits striking structural diversity across placental mammals; however, the consequences of such variation on physiological function are poorly understood. Combining comparative anatomy across 130 mammal species with ancestral-trait reconstruction, multimodal imaging, and physics-based transport modelling, we show that the human umbilical cord structure is uncommon in other mammals and that the ancestral umbilical cord was unspiralled, with three vessels and an allantoic duct. Across species, vessel number and cord length correlate with birth weight: four-vessel cords and the persistence of an allantoic duct occur in species with heavier neonates, while two-vessel cords are confined to small muroid rodents. Mathematical modelling predicts that oxygen delivery remains near maximal across all cord architectures, but placental heat removal depends strongly on umbilical flow, and moderately on cord length and coiling. Scaling of umbilical flow with birth weight implies that larger species approach near-maximal heat-removal capacity, while smaller species are less efficient. Finally, three-dimensional imaging of the human cord reveals a triple-helix configuration of umbilical vessels, rather than arteries simply twisting around a central vein. This, and other observed cross-sectional vessel configurations in mammals and atypical human cords, aligns with theoretically predicted arrangements that minimize inter-vessel shunting, supporting an adaptive role for cord geometry in thermal regulation function. Together, these findings reframe the umbilical cord as a heat-exchange system and link its structural diversity to evolutionary history, neonatal mass, and maternal investment, with implications for fetal resilience to environmental stress.

physiology↗

Type 1 Regulatory T cells induced by intestinal epithelial cells respond to food antigen

As the first-line barrier against food antigens, the intestinal epitheliums role in establishing peripheral immune tolerance to food remains completely unknown. Additionally, the specific types of regulatory T cells induced to maintain food tolerance--along with their antigen specificity--are still unclear. Here we found small intestinal FOXP3-IL-10+ Tr1 cells, but not Treg cells, can respond to food antigens presented by intestinal epithelial cells (IECs) in an antigen-specific manner. Through immunopeptidome analysis of MHCII-presented peptides, we demonstrate that IECs can present food-derived antigens. Importantly, these IEC-presented food antigens are exclusively recognized by the TCR repertoire of small intestinal Tr1 cells, not Treg cells. Furthermore, we show that T cells recognizing IEC-presented food antigens specifically differentiate into Tr1 cells in the siLP. These findings establish two key insights: first, that maintaining food tolerance represents a physiological function of Tr1 cells, and second, that IECs play a central role in maintaining food tolerance. Our work thus provides mechanistic understanding of how the intestinal epithelium contributes to immune tolerance through its antigen presentation capacity and subsequent Tr1 cell induction.

immunology↗

Pulsatile flow dynamics determine pulmonary arterial architecture

Single ventricle congenital heart disease (SV-CHD) is a uniformly lethal condition requiring the Glenn surgery, which as a side effect eliminates arterial pulsatility and contributes to pulmonary vascular complications. In Glenn patients, we quantified pulsatility loss in each dimension of force (flow, pressure, and stretch) using cardiac catheterization and MRI. To model and investigate the individual impact of each dimension of pulsatility loss on the pulmonary vasculature, we applied isolated pulsatile and non-pulsatile mechanical stimuli to pulmonary arterial endothelial cells (ECs) in vitro. We found that each dimension of force triggered distinct transcriptional responses, revealing force-specific regulation of structural and signaling pathways. Pulsatile stretch uniquely stimulated EC secretion of PDGFB, a key driver of vascular smooth muscle cell (vSMC) recruitment. In a rat Glenn model, loss of pulsatility led to vascular wall thinning, confirming in vivo relevance. Our findings uncover a mechanistic link between endothelial stretch sensing and PDGFB-mediated EC-vSMC crosstalk, essential for maintaining pulmonary artery architecture. Clinically, these insights suggest that restoring or mimicking pulsatile forces may help preserve vascular integrity and prevent remodeling in SV-CHD patients.

cell biology↗

HSF4: A Prognostic Predictor and Potential Therapeutic Target in Colorectal Cancer with Implications for Patient Immune Status

Colorectal cancer (CRC) is among the most prevalent malignancies globally, characterized by high morbidity and mortality rates. The Heat Shock Factor (HSF) family of genes plays a critical role in the cellular response to environmental stress, particularly heat stress. These genes encode transcription factors that regulate the expression of heat shock proteins, which are essential for maintaining cellular homeostasis under stressful conditions. Recently, there has been a growing interest in the role of HSF family genes in the development and progression of CRC. In this study, we conducted a comprehensive analysis of CRC samples from The Cancer Genome Atlas (TCGA) database to identify potential therapeutic targets. A total of 533 gene expression matrices, were downloaded and processed, including 42 normal and 491 tumor samples. Differential expression analysis of the HSF family genes, revealed HSF4 as the most significantly differentially expressed gene between normal and tumor samples. Consequently an HSF4-related signature was constructed, stratifying all CRC patients in the TCGA dataset into low-risk or high-risk groups based on HSF4 expression. Survival analysis demonstrated a significant association between HSF4 expression and clinical outcomes indicating that the signature possesses substantial. Correlation analysis further revealed significant relationships between HSF4 expression and clinical features including Stage, T stage, M stage, and N stage. Univariate and multivariate Cox regression analyses confirmed the prognostic significance of HSF4. Functional analysis of differentially expressed genes based on HSF4 expression levels demonstrated enrichment in critical biological processes and pathways. Furthermore, HSF4 exhibited unique properties within the tumor microenvironment (TME). Additional analysis indicated that different risk groups exhibit varying levels of immune cell infiltration and cell proliferation capacity. Notably, the low-risk group showed increased sensitivity to multiple chemotherapeutic agents due to its lower IC50 values. In conclusion, this study presents the first signature for predicting the prognosis and immunological status of CRC patients based on HSF family genes. Our findings suggest that HSF4 may serve as a potential therapeutic target in CRC.

cancer biology↗

Aromatic Patch in WhiB-Like Transcription Factors Facilitates Primary Sigma Factor Interaction in Mycobacterium tuberculosis

WhiB-like (Wbl) family proteins are a unique family of iron-sulfur ([4Fe-4S]) cluster-bound transcription factors found exclusively in Actinobacteria and actinobacteriophages, including the notoriously persistent pathogen Mycobacterium tuberculosis (Mtb). Despite their critical roles in cell development, stress response and antibiotic resistance, the mechanisms of gene regulation by the Wbl family proteins are not fully understood due to the lack of a canonical DNA-binding motif in most Wbl proteins. Here, we present structural and biochemical evidence demonstrating that all Mtb Wbl proteins bind to the same site in the conserved region 4 of the primary sigma 70 factor facilitated by a previously unrecognized structural motif, the aromatic patch, in the Wbl family. Our phylogenetic findings provide compelling evidence for a complex evolutionary relationship of Wbls between actinobacteria and the associated phages. Together, this work fills a critical gap in our understanding of the function, mechanism and evolutionary origin of Wbls.

biochemistry↗

Genetic code expansion reveals site-specific lactylation in living cells reshapes protein function

Still in its infancy, the functions of lactylation remain elusive. To address this, we established a comprehensive workflow for lactylation studies that integrates the discovery of lactylation sites with proteomics, the expression of site-specifically lactylated proteins in living cells via genetic code expansion (GCE), and the evaluation of the resulting biological consequences. Specifically, we developed a wet-and-dry-lab combined proteomics strategy, and identified highly conserved lactylation at ALDOA-K147. Driven by its potential biological significance, we site-specifically expressed this lactylated ALDOA in mammalian cells and interrogated the biological changes. We discovered that it not only inhibited enzyme activity but also elicited gain-of-function effects----it dramatically reshaped the functionality of ALDOA by improving stability, enhancing nuclear translocation and affecting gene expression. Further, we demonstrated broad applicability of this workflow to study distinct histone lactylation sites. Together, we anticipate its wide uses in elucidating causative links between site-specific lactylation and target-centric or cell-wide changes.

molecular biology↗

Glenn circulation causes early and progressive shunting in a surgical model of pulmonary arteriovenous malformations

BackgroundPulmonary arteriovenous malformations (PAVMs) universally develop in patients with single ventricle congenital heart disease (CHD). Single ventricle PAVMs have been recognized for over 50 years, yet they are poorly understood, and we lack any medical therapies. To improve our understanding of single ventricle PAVM initiation and progression, we developed a surgical rat model of Glenn circulation and characterized PAVM physiology over multiple time points. MethodsUsing adult rats, we performed a left thoracotomy and end-to-end anastomosis of the left superior vena cava to the left pulmonary artery (unilateral Glenn), or sham surgical control. To assess for PAVM physiology in the left lung, we quantified intrapulmonary shunting using two independent methods (bubble echocardiography and fluorescent microsphere injection) at 2 weeks, 2 months, and 6 months. Additionally, we performed arterial blood gas measurements to assess oxygenation and plethysmography to assess ventilation. ResultsWe identified pathologic intrapulmonary shunting by bubble echocardiography as early as 2 weeks post-Glenn surgery, and shunting continued chronically at 2- and 6-months post-Glenn. Shunting also progressed over time, demonstrated by increased shunting of 10{micro}m microspheres at 6 months. Shunting was accompanied by mildly decreased arterial oxygenation, but there were no differences in ventilation as quantified by plethysmography. ConclusionsOur surgical animal model of unilateral Glenn circulation re-creates the clinical condition of single ventricle PAVMs with early and progressive intrapulmonary shunting. This model is poised to characterize single ventricle PAVM pathophysiology and lead to mechanistic and therapeutic discovery. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/588015v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@b1c722org.highwire.dtl.DTLVardef@1889af9org.highwire.dtl.DTLVardef@1767519org.highwire.dtl.DTLVardef@1c230_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

Integrative phylogenetic analysis of the genus Episoriculus (Mammalia: Eulipotyphla: Soricidae)

Shrews in the genus Episoriculus are among the least-known mammals in China, where representatives occur mainly in the Himalayan and Hengduan mountains. We sequence one mitochondrial and three nuclear genes from 77 individuals referable to this genus, collect morphometric data for five shape and 11 skull measurements from 56 specimens, and use museum collections and GenBank sequences to analyze phylogenetic relationships between this and related genera in an integrated molecular and morphometric approach. Whereas historically anywhere from two to eight species have been recognized in this genus, we conclude that six (E. baileyi, E. caudatus, E. leucops, E. macrurus, E. sacratus, E. soluensis) are valid. We dissent from recent systematic reviews of this genus and regard E. sacratus to be a valid taxon, E. umbrinus to be a subspecies of E. caudatus, and transfer E. fumidus to Pseudosoriculus. Our record of E. soluensis is the first for China, and expands the previously recognized distribution of this taxon from Nepal and NE India into the adjacent Yadong and Nyalam counties. One further undescribed Episoriculus taxon may exist in Tibet.

zoology↗

Molecular and morphological analyses of the genus Episoriculus with the description of a new subgenus

Shrews in the genus Episoriculus are among the least known mammals in China. It occurs mainly in the Himalayas and the Hengduan Mountains. We report the sequencing and analyses of one mitochondrial gene (Cyt b) and three nuclear genes (Apob, Brca1, and Rag2) for 77 specimens, and analyses of morphological measurements for 56 specimens. Phylogenetic and morphological studies answer three longstanding questions. First, Episoriculus sacratus and E. umbrinus are valid species, and not subspecies of E. caudatus. Second, Pseudosoriculus fumidus is a valid taxon that does not belong to the genus Episoriculus. Third, the genus Episoriculus has eight valid species: E. baileyi, E. caudatus, E. leucops, E. macrurus, E. sacratus, E. soluensis, Episoriculus sp., and E. umbrinus. Ultimately, we erected subgenus Longacauda subgen. nov. for morphologically distinct E. macrurus, which leaves the nominate subgenus Episoriculus with the remaining seven congeners.

synthetic biology↗

Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice

Cancer survivors suffer from progressive frailty, multimorbidity and premature morbidity. We hypothesize that therapy-induced senescence and senescence progression via bystander effects is a significant cause of this premature ageing phenotype. Accordingly, the study addresses the question whether a short anti-senescence intervention is able to block progression of radiation-induced frailty and disability in a pre-clinical setting. Male mice were sub-lethally irradiated at 5 months of age and treated (or not) with either a senolytic drug (Navitoclax or dasatinib + quercetin) for 10 days or with the senostatic metformin for 10 weeks. Follow up was for one year. Treatments commencing within a month after irradiation effectively reduced frailty progression (p<0.05) and improved muscle (p<0.01) and liver (p<0.05) function as well as short-term memory (p<0.05) until advanced age with no need for repeated interventions. Senolytic interventions that started late, after radiation-induced premature frailty was manifest, still had beneficial effects on frailty (p<0.05) and short-term memory (p<0.05). Metformin was similarly effective as senolytics. At therapeutically achievable concentrations metformin acted as a senostatic neither via inhibition of mitochondrial complex I, nor via improvement of mitophagy or mitochondrial function, but by reducing non-mitochondrial ROS production via NOX4 inhibition in senescent cells. Our study suggests that the progression of adverse long-term health and quality-of-life effects of radiation exposure, as experienced by cancer survivors, might be rescued by short-term adjuvant anti-senescence interventions.

cancer biology↗

Comparative genomic and pan-genomic characteristion of Staphylococcus epidermidis from different sources unveils the molecular basis and potential biomarkers of pathogenic strains

Coagulase-negative Staphylococcus (CoNS) is the most common pathogen causing traumatic endophthalmitis, Staphylococcus epidermidis is the most common species which colonizes human skin, eye surfaces and nasal cavity and is the main cause of nosocomial infection, specially foreign body-related bloodstream infections (FBR-BSIs). Although some studies have reported the genome characteristics of S. epidermidis, a comprehensive understanding of its pathogenicity and the genome of ocular trauma-sourced strains is still lacking. In this study, we sequenced, analyzed and reported the whole genomes of 11 ocular trauma-sourced samples of S. epidermidis that caused traumatic endophthalmitis. By integrating publicly available genomes, we obtained a total of 187 S. epidermidis samples from healthy and diseased eyes, skin, respiratory tract and blood. Combined with pangenome, phylogenetic and comparative genomic analyses, our study supported that S. epidermidis, regardless of niche source, exhibits two founder lineages with different pathogenicities. Moreover, we identified potential biomarkers associated with the virulence of S. epidermidis, namely, essD, uhpt, sdrF, sdrG, fbe and icaABCDR. The essD and uhpt genes have high homology with esaD and hpt in Staphylococcus aureus, showing that the genomes of S. epidermidis and S. aureus may have communicated during evolution, while the sdrF, sdrG, fbe, and icaABCDR genes are related to biofilm formation. Compared to S. epidermidis from blood sources, ocular-sourced strains causing intraocular infection had no direct relationship with biofilm formation. In conclusion, this study not only provided additional data resources for studies on S. epidermidisis, but also improved understanding of the evolution and pathogenicity of different source strains. ImportantsIn this study, we comprehensively analysied and reported the whole genome sequence (WGS) of the strains that caused traumatic endophthalmitis. Through comparative genomic analyses among 187 S. epidermidis samples from healthy and diseased eyes, skin, respiratory tract and blood, we identified 10 potential biomarkers of pathogenic strains. Finally, we revealed S. epidermidis-induced traumatic endophthalmitis may be independent of biofilm formation. Overall, our data may facilitate comparative research of S. epidermidis and provide clinical value for identifying pathogenic or contaminating strains.

microbiology↗

Neglected Quaternary legacy of biodiversity for the Mountains of Southwest China

Mountains of Southwest China (MSWC) is a biodiversity hotspot with a very unique and highly complex terrain. However, with the majority of studies focusing on the biogeographic consequences of massive mountain building, the Quaternary legacy of biodiversity for the MSWC has long been overlooked. Here, we took a comparative phylogeography approach to examine factors that shaped community-wide diversification. With data from 30 vertebrate species, the results reveal spatially concordant genetic structure, with temporally clustered divergence events during severe glacial cycles, indicating the importance of riverine barriers in the phylogeographic history of the vertebrate community. We conclude that the repeated glacial cycles are associated with temporal synchrony of divergence patterns that are themselves structured by the heterogeneity of the montane landscape has of the MSWC. This orderly process of diversifications has profound implications for conservation by highlighting the relative independence of different geographic areas in which communities have responded similarly to climate changes and calls for further comparative phylogeographic investigations to reveal the extent to which these findings might apply more broadly to other taxa in this biodiversity hotspot.

evolutionary biology↗

Structural variability and functional association in the epiphytic bacteria assemblies of freshwater macrophytes (Myriophyllum spicatum)

The underlying principles influencing bacteria community assembly have long been of interest in the field of microbial ecology. Environmental heterogeneity is believed to be important in controlling the uniqueness and variability of communities. However, little is known about the influence of the host macrophytes on epiphytic bacteria assembly processe. Here, we produced two contrasting artificial water environments (eutrophic and oligotrophic) for reciprocal transplant experiment of Myriophyllum spicatum, to recover the colonization of epiphytic bacteria accompanied with plants growth. Comparative analysis addressed a higher species diversity in epiphytic bacteria than in bacterioplankton, and the highest microbiome richness in sediment. Our data revealed that the organization of epiphytic bacterial community was interfered by both plant status (i.e. branch number, net photosynthesis rate etc.) and water bodies (i.e. total phosphate, total nitrogen, pH etc.) while plant status effected the assembly in priority to water. 16S rRNA sequencing further indicated that the epiphytic assemblies were motivated by functionalization and interplay with hosts as a whole. The results complemented new evidences for the lottery process in the epiphytic bacteria assembly traits and shed insights into the assembly patterns referring to functional adaptation across epiphytic bacteria and macrophytes.\n\nImportanceA robust understanding of inter-adaptation between microbiome and the host plants have been established basing on vast majority of researches. However, great efforts were made mostly on rhizosphere microbiome. By contrast, referring to another representative group, macrophytes who composed of the freshwater ecosystem were relatively less investigated on such issue. Our study pioneered the experimental operation to interrogate the triadic relationship among macrophytes, epiphytic bacteria and water body. The research present here showed significant exemplar on discussion of plant associate bacteria adaptation taking account of host colonization as well as the epiphytes. The results expand the hypotheses of bacteria assembly principle and provides potential leads on understanding of plant - microbe interactions.

microbiology↗

Cryptic phylogeographic history sheds light on the generation of species diversity in sky-island mountains

Biodiversity hotspots should be given high priority for conservation under the situation of global climate change. The sky islands in southwestern China are characterized by extraordinarily high species diversity and are among one of the worlds top biodiversity hotspots. However, neither the actual species diversity in this region or mechanisms generating this diversity are well explored. Here, we report on the phylogeographic analysis of the long-tailed mole (Scaptonyx fusicaudus), a semi-fossorial mammal that inhabits the montane cool forests across the Chinese sky islands and is considered to represent one species divided into two subspecies. Analyses using DNA sequence data from one mitochondrial and six nuclear genes revealed that populations inhabiting different mountains exhibited exceptionally strong geographic structure. The lowlands and large rivers act as \"soft\" and \"hard\" barriers to dispersal, respectively, isolating evolutionary lineages for up to 11 million years. Our results suggest that the mountain ranges act as interglacial refugia buffering populations from climate fluctuations, further facilitating allopatric diversification. Strikingly, species delimitation analyses suggests that the long-tailed mole may comprise 18 operational taxonomic units and 17 putative species. Our results suggest that for low-vagility species, the complex topography of the Chinese sky islands has shaped genetic diversity and structure and promoted exceptional diversification through a combination of eco-environmental stability as well as geographic fragmentation. The patterns observed in S. fusicaudus may be representative for other cold- adapted species, reflecting the generation of mammalian faunal diversity in the sky-island mountains of southwestern China.

zoology↗