Biology subjects

Shang, F.

Publications and source records attributed to Shang, F..

5 recordsLinked to original sources

bioRxiv2026

MiRNA let-7a-5p Ameliorates Pulmonary Fibrosis by Suppressing TGFBR1-Mediated Endothelial-to-Mesenchymal Transition

Background Idiopathic Pulmonary Fibrosis (IPF) is a fatal chronic lung disease with limited therapeutic options. While alveolar epithelial injury and fibroblast activation are well-studied, endothelial-mesenchymal transition (EndoMT) is emerging as a critical pathogenic mechanism. The regulatory role of exosomal miRNAs in pulmonary fibrosis remains unclear. This study investigates serum exosomal miRNAs, particularly let-7a-5p, in modulating EndoMT during the onset of pulmonary fibrosis. Methods Clinical cohorts of IPF patients and healthy controls were enrolled. Serum exosomal miRNAs were profiled, followed by differential expression and functional enrichment analyses. In vitro experiments involved human pulmonary artery endothelial cells (HPAECs) transfected with let-7a-5p mimic or inhibitor. Dual-luciferase reporter assays confirmed the binding between let-7a-5p and TGFBR1. HPAECs were co-cultured with lung epithelial cells to examine paracrine signaling. In vivo studies used a bleomycin-induced mouse model with let-7a-5p agomir administration. Assessments included histopathological staining, hydroxyproline content, Western blot, qPCR, micro-CT, and pulmonary function tests. Results Let-7a-5p was significantly downregulated in serum exosomes from IPF patients, correlating with clinical indicators. Mechanistically, let-7a-5p directly bound the TGFBR1 3'UTR to inhibit its expression. Inhibition of let-7a-5p upregulated -SMA, FN1, smad2/3 phosphorylation, and collagen I, while downregulating CD31 and VE-cadherin. Therapeutically, let-7a-5p mimic reversed bleomycin-induced EndoMT and suppressed epithelial-mesenchymal transition (EMT) via paracrine signaling. Mice administered agomir showed reduced fibrosis, improved lung function, and suppressed TGF-{beta}/Smad signaling. Conclusion Serum exosomal let-7a-5p suppresses pulmonary fibrosis by targeting TGFBR1 to inhibit EndoMT. Its downregulation in IPF patients correlates with disease progression, highlighting its biomarker potential.

molecular biology↗

bioRxiv2025

Mechanical Responses of the Giant Nesprin-2

The nesprin protein family serves as a critical physical bridge between the cytoskeleton-a fundamental structural scaffold and mechanotransduction hub of the cell, and the nucleus-an intriguing and emerging mechano-responsive element. Due to the external mechanical cues and the nucleo-cytoskeletal dynamics, the nesprins are physiologically under forces. However, the dynamics of nesprins within physiological forces and loading rates remain largely unexplored. In this study, we employ magnetic tweezers based single-molecule manipulation alongside molecular dynamic simulations and AlphaFold structural predictions to comprehensively investigate the dynamics of force-bearing spectrin repeat (SR) domains of the giant nesprin-2 protein. Through direct quantification, we unveil that the numerous SRs undergo mechanical unfolding and refolding dynamics with distinct transition rates within several pN scale. Furthermore, we show that the giant nesprin-2 could act as an effective molecular absorber adeptly maintaining forces on the nucleoskeleton and cytoskeleton linkage within a few pN across displacement spans exceeding {micro}m. Notably, our findings imply that subtle pN-level mechanical forces intricately modulate nesprin-protein interactions via the dynamics of domain folding and unfolding. Collectively, our study offers a comprehensive understanding of the mechanical characteristics of giant nesprin-2, shedding light on its pivotal role in nucleoskeleton-cytoskeleton mechanotransduction.

biophysics↗

bioRxiv2023

Memory B cells dominate the early antibody-secreting cell response to SARS-CoV-2 mRNA vaccination in naive individuals independently of their antibody affinity

Memory B cells (MBCs) formed over the individuals lifetime constitute nearly half of the adult peripheral blood B cell repertoire in humans. To assess their response to novel antigens, we tracked the origin and followed the differentiation paths of MBCs in the early anti-S response to mRNA vaccination in SARS-CoV-2-naive individuals on single-cell and monoclonal antibody level. Newly generated and pre-existing MBCs differed in their differentiation paths despite similar levels of SARS-CoV-2 and common corona virus S-reactivity. Pre-existing highly mutated MBCs showed no signs of germinal center re-entry and rapidly developed into mature antibody secreting cells (ASCs). In contrast, newly generated MBCs derived from naive precursors showed strong signs of antibody affinity maturation before differentiating into ASCs. Thus, although pre-existing human MBCs have an intrinsic propensity to differentiate into ASCs, the quality of the anti-S antibody and MBC response improved through the clonal selection and affinity maturation of naive precursors. HighlightsO_LImRNA vaccination of SARS-CoV-2 naive individuals recruits naive and pre-existing MBCs with similar levels of S-reactivity into the response C_LIO_LIS-reactive naive but not pre-existing MBCs undergo affinity maturation C_LIO_LIS-reactive pre-existing MBCs dominate the early ASC response independent of their antigen affinity C_LIO_LIHigh-affinity S-reactive MBCs and ASCs develop over time and originate from affinity matured naive precursors C_LI

immunology↗

bioRxiv2023

Direct serotonin release in humans shapes decision computations within aversive environments

The role of serotonin in human behaviour is critically informed by approaches which allow in vivo modification of synaptic serotonin. However, characterising the effects of increased serotonin signalling in human models of behaviour is challenging given the limitations of available experimental probes (e.g., SSRIs). Here we use a now accessible approach to directly increase synaptic serotonin in humans - a selective serotonin releasing agent - and examine its influence on domains of behaviour historically considered core functions of serotonin. Computational techniques including reinforcement learning and drift diffusion modelling were fit to observed behaviour. Reinforcement learning models revealed that increased synaptic serotonin reduced sensitivity specifically for outcomes in aversive but not appetitive contexts. Furthermore, increasing synaptic serotonin enhanced behavioural inhibition, and shifted bias towards impulse control during exposure to aversive emotional probes. These effects were seen in the context of overall improvements in memory for neutral verbal information. Our findings highlight the direct effects of increased synaptic serotonin on human behaviour, underlining its critical role in guiding decision-making within aversive and neutral contexts, and offering broad implications for longstanding theories of central serotonin function.

neuroscience↗

bioRxiv2020

Resolving fate and transcriptome of hematopoietic stem cell clones

Adult bone marrow harbors a mosaic of hematopoietic stem cell (HSC) clones of embryonic origin, and recent work suggests that such clones may have coherent lineage fates. To probe under physiological conditions whether HSC clones with different fates are transcriptionally distinct, we developed PolyloxExpress - a Cre recombinase-dependent DNA substrate for in situ barcoding that allows parallel readout of barcodes and transcriptomes in single cells. We describe differentiation-inactive, multilineage and lineage-restricted HSC clones, find that they reside in distinct regions of the transcriptional landscape of hematopoiesis, and identify corresponding gene signatures. All clone types contain proliferating HSCs, indicating that differentiation-inactive HSCs can undergo symmetric self-renewal. Our work establishes an approach for studying determinants of stem cell fate in vivo and provides molecular evidence for fate coherence of HSC clones.

immunology↗