Structures of human γδ T cell receptor-CD3 complex.

Gamma delta (γδ) T cells, a unique T cell subgroup, are crucial in various immune responses and immunopathology1-3. The γδ T cell receptor (TCR), which is generated by γδ T cells, recognizes a diverse range of antigens independently of the major histocompatibility complex2. The γδ TCR associates with CD3 subunits, initiating T cell activation and holding great potential in immunotherapy4. Here we report the structures of two prototypical human Vγ9Vδ2 and Vγ5Vδ1 TCR-CD3 complexes5,6, revealing two distinct assembly mechanisms that depend on Vγ usage. The Vγ9Vδ2 TCR-CD3 complex is monomeric, with considerable conformational flexibility in the TCRγ-TCRδ extracellular domain and connecting peptides. The length of the connecting peptides regulates the ligand association and T cell activation. A cholesterol-like molecule wedges into the transmembrane region, exerting an inhibitory role in TCR signalling. The Vγ5Vδ1 TCR-CD3 complex displays a dimeric architecture, whereby two protomers nestle back to back through the Vγ5 domains of the TCR extracellular domains. Our biochemical and biophysical assays further corroborate the dimeric structure. Importantly, the dimeric form of the Vγ5Vδ1 TCR is essential for T cell activation. These findings reveal organizing principles of the γδ TCR-CD3 complex, providing insights into the unique properties of γδ TCR and facilitating immunotherapeutic interventions.

Molecular and structural basis of the dual regulation of the polycystin-2 ion channel by small-molecule ligands.

Mutations in the PKD2 gene, which encodes the polycystin-2 (PC2, also called TRPP2) protein, lead to autosomal dominant polycystic kidney disease (ADPKD). As a member of the transient receptor potential (TRP) channel superfamily, PC2 functions as a non-selective cation channel. The activation and regulation of the PC2 channel are largely unknown, and direct binding of small-molecule ligands to this channel has not been reported. In this work, we found that most known small-molecule agonists of the mucolipin TRP (TRPML) channels inhibit the activity of the PC2_F604P, a gain-of-function mutant of the PC2 channel. However, two of them, ML-SA1 and SF-51, have dual regulatory effects, with low concentration further activating PC2_F604P, and high concentration leading to inactivation of the channel. With two cryo-electron microscopy (cryo-EM) structures, a molecular docking model, and mutagenesis results, we identified two distinct binding sites of ML-SA1 in PC2_F604P that are responsible for activation and inactivation, respectively. These results provide structural and functional insights into how ligands regulate PC2 channel function through unusual mechanisms and may help design compounds that are more efficient and specific in regulating the PC2 channel and potentially also for ADPKD treatment.

CLT-seq as a universal homopolymer-sequencing concept reveals poly(A)-tail-tuned ncRNA regulation.

Dynamic tuning of the poly(A) tail is a crucial mechanism for controlling translation and stability of eukaryotic mRNA. Achieving a comprehensive understanding of how this regulation occurs requires unbiased abundance quantification of poly(A)-tail transcripts and simple poly(A)-length measurement using high-throughput sequencing platforms. Current methods have limitations due to complicated setups and elaborate library preparation plans. To address this, we introduce central limit theorem (CLT)-managed RNA-seq (CLT-seq), a simple and straightforward homopolymer-sequencing method. In CLT-seq, an anchor-free oligo(dT) primer rapidly binds to and unbinds from anywhere along the poly(A) tail string, leading to position-directed reverse transcription with equal probability. The CLT mechanism enables the synthesized poly(T) lengths, which correspond to the templated segment of the poly(A) tail, to distribute normally. Based on a well-fitted pseudogaussian-derived poly(A)-poly(T) conversion model, the actual poly(A)-tail profile is reconstructed from the acquired poly(T)-length profile through matrix operations. CLT-seq follows a simple procedure without requiring RNA-related pre-treatment, enrichment or selection, and the CLT-shortened poly(T) stretches are more compatible with existing sequencing platforms. This proof-of-concept approach facilitates direct homopolymer base-calling and features unbiased RNA-seq. Therefore, CLT-seq provides unbiased, robust and cost-efficient transcriptome-wide poly(A)-tail profiling. We demonstrate that CLT-seq on the most common Illumina platform delivers reliable poly(A)-tail profiling at a transcriptome-wide scale in human cellular contexts. We find that the poly(A)-tail-tuned ncRNA regulation undergoes a dynamic, complex process similar to mRNA regulation. Overall, CLT-seq offers a simplified, effective and economical approach to investigate poly(A)-tail regulation, with potential implications for understanding gene expression and identifying therapeutic targets.

The FLOWERING LOCUS T 5b positively regulates photoperiodic flowering and improves the geographical adaptation of soybean.

Plants can sense the photoperiod to flower at the right time. As a sensitive short-day crop, soybean (Glycine max) flowering varies greatly depending on photoperiods, affecting yields. Adaptive changes in soybeans rely on variable genetic loci such as E1 and FLOWERING LOCUS T orthologs. However, the precise coordination and control of these molecular components remain largely unknown. In this study, we demonstrate that GmFT5b functions as a crucial factor for soybean flowering. Overexpressed or mutated GmFT5b resulted in significantly early or later flowering, altering expression profiles for several downstream flowering-related genes under a long-day photoperiod. GmFT5b interacts with the transcription factor GmFDL15, suggesting transcriptional tuning of flowering time regulatory genes via the GmFT5b/GmFDL15 complex. Notably, GmFT5a partially compensated for GmFT5b function, as ft5a ft5b double mutants exhibited an enhanced late-flowering phenotype. Association mapping revealed that GmFT5b was associated with flowering time, maturity, and geographical distribution of soybean accessions, all associated with the E1 locus. Therefore, GmFT5b is a valuable target for enhancing regional adaptability. Natural variants or multiple mutants in this region can be utilized to generate optimized soybean varieties with precise flowering times.

Single-cell insights: pioneering an integrated atlas of chromatin accessibility and transcriptomic landscapes in diabetic cardiomyopathy.

BACKGROUND: Diabetic cardiomyopathy (DCM) poses a growing health threat, elevating heart failure risk in diabetic individuals. Understanding DCM is crucial, with fibroblasts and endothelial cells playing pivotal roles in driving myocardial fibrosis and contributing to cardiac dysfunction. Advances in Multimodal single-cell profiling, such as scRNA-seq and scATAC-seq, provide deeper insights into DCM's unique cell states and molecular landscape for targeted therapeutic interventions. METHODS: Single-cell RNA and ATAC data from 10x Multiome libraries were processed using Cell Ranger ARC v2.0.1. Gene expression and ATAC data underwent Seurat and Signac filtration. Differential gene expression and accessible chromatin regions were identified. Transcription factor activity was estimated with chromVAR, and Cis-coaccessibility networks were calculated using Cicero. Coaccessibility connections were compared to the GeneHancer database. Gene Ontology analysis, biological process scoring, cell-cell communication analysis, and gene-motif correlation was performed to reveal intricate molecular changes. Immunofluorescent staining utilized various antibodies on paraffin-embedded tissues to verify the findings. RESULTS: This study integrated scRNA-seq and scATAC-seq data obtained from hearts of WT and DCM mice, elucidating molecular changes at the single-cell level throughout the diabetic cardiomyopathy progression. Robust and accurate clustering analysis of the integrated data revealed altered cell proportions, showcasing decreased endothelial cells and macrophages, coupled with increased fibroblasts and myocardial cells in the DCM group, indicating enhanced fibrosis and endothelial damage. Chromatin accessibility analysis unveiled unique patterns in cell types, with heightened transcriptional activity in myocardial cells. Subpopulation analysis highlighted distinct changes in cardiomyocytes and fibroblasts, emphasizing pathways related to fatty acid metabolism and cardiac contraction. Fibroblast-centered communication analysis identified interactions with endothelial cells, implicating VEGF receptors. Endothelial cell subpopulations exhibited altered gene expressions, emphasizing contraction and growth-related pathways. Candidate regulators, including Tcf21, Arnt, Stat5a, and Stat5b, were identified, suggesting their pivotal roles in DCM development. Immunofluorescence staining validated marker genes of cell subpopulations, confirming PDK4, PPARγ and Tpm1 as markers for metabolic pattern-altered cardiomyocytes, activated fibroblasts and endothelial cells with compromised proliferation. CONCLUSION: Our integrated scRNA-seq and scATAC-seq analysis unveils intricate cell states and molecular alterations in diabetic cardiomyopathy. Identified cell type-specific changes, transcription factors, and marker genes offer valuable insights. The study sheds light on potential therapeutic targets for DCM.

Modeling disrupted synapse formation in wolfram syndrome using hESCs-derived neural cells and cerebral organoids identifies Riluzole as a therapeutic molecule.

Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders, which are also manifested by wolfram syndrome (WS). Whether and how the causative gene WFS1 deficiency affects synapse formation remain elusive. By mirroring human brain development with cerebral organoids, WFS1-deficient cerebral organoids not only recapitulate the neuronal loss in WS patients, but also exhibit significantly impaired synapse formation and function associated with reduced astrocytes. WFS1 deficiency in neurons autonomously delays neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impairs neurite outgrowth and synapse formation with elevated cytosolic calcium. Intriguingly, WFS1 deficiency in astrocytes decreases the expression of glutamate transporter EAAT2 by NF-κB activation and induces excessive glutamate. When co-cultured with wildtype neurons, WFS1-deficient astrocytes lead to impaired neurite outgrowth and increased cytosolic calcium in neurons. Importantly, disrupted synapse formation and function in WFS1-deficient cerebral organoids and impaired neurite outgrowth affected by WFS1-deficient astrocytes are efficiently reversed with Riluzole treatment, by restoring EAAT2 expression in astrocytes. Furthermore, Riluzole rescues the depressive-like behavior in the forced swimming test and the impaired recognition and spatial memory in the novel object test and water maze test in Wfs1 conditional knockout mice. Altogether, our study provides novel insights into how WFS1 deficiency affects synapse formation and function, and offers a strategy to treat this disease.

Causal association between serum 25-hydroxyvitamin D levels and right ventricular structure and function: A Mendelian randomization study.

BACKGROUND AND AIM: Deficient concentrations of vitamin D have been linked to several cardiovascular conditions, but the causal relationship between serum 25-hydroxyvitamin D (25(OH)D) levels and right ventricular structure and function remains unclear. Mendelian randomization (MR) was employed to inspect this association. METHODS AND RESULTS: Genetic instrumental variables associated with 25(OH)D levels were acquired from genome-wide association studies (GWAS) analyses. Summary statistics for right ventricular structure and function, including right ventricular end diastolic volume, right ventricular end systolic volume, right ventricular stroke volume, and right ventricular ejection fraction, were acquired from publicly available GWAS datasets. For the primary analysis, the inverse variance weighted (IVW) method was utilized in performing the MR analysis. Additionally, secondly analyses were conducted to estimate the robustness and consistency of the attained conclusions. The MR analysis did not reveal a considerable causal association between serum 25(OH)D levels and right ventricular end diastolic volume (ß: 0.112, 95% confident interval [CI]: -0.006 to 0.230, p = 0.063), right ventricular end systolic volume (ß: 0.102, 95% CI: -0.021 to 0.226, p = 0.105), right ventricular stroke volume (ß: 0.095, 95% CI: -0.018 to 0.207, p = 0.099), or right ventricular ejection fraction (ß: -0.005, 95% CI: -0.123 to 0.112, p = 0.928). CONCLUSIONS: Our findings did not reveal any substantial evidence supporting a causal relationship between serum 25(OH)D levels and the structure and function of the right ventricle. These findings suggest that serum 25(OH)D levels may not directly influence right ventricular parameters assessed.

N6-methyladenosine modification of KLF2 may contribute to endothelial-to-mesenchymal transition in pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a progressive disease characterized by pulmonary vascular remodeling. Increasing evidence indicates that endothelial-to-mesenchymal transition (EndMT) in pulmonary artery endothelial cells (PAECs) is a pivotal trigger initiating this remodeling. However, the regulatory mechanisms underlying EndMT in PH are still not fully understood. METHODS: Cytokine-induced hPAECs were assessed using RNA methylation quantification, qRT-PCR, and western blotting to determine the involvement of N6-methyladenosine (m6A) methylation in EndMT. Lentivirus-mediated silencing, overexpression, tube formation, and wound healing assays were utilized to investigate the function of METTL3 in EndMT. Endothelial-specific gene knockout, hemodynamic measurement, and immunostaining were performed to explore the roles of METTL3 in pulmonary vascular remodeling and PH. RNA-seq, RNA Immunoprecipitation-based qPCR, mRNA stability assay, m6A mutation, and dual-luciferase assays were employed to elucidate the mechanisms of RNA methylation in EndMT. RESULTS: The global levels of m6A and METTL3 expression were found to decrease in TNF-α- and TGF-ß1-induced EndMT in human PAECs (hPAECs). METTL3 inhibition led to reduced endothelial markers (CD31 and VE-cadherin) and increased mesenchymal markers (SM22 and N-cadherin) as well as EndMT-related transcription factors (Snail, Zeb1, Zeb2, and Slug). The endothelial-specific knockout of Mettl3 promoted EndMT and exacerbated pulmonary vascular remodeling and hypoxia-induced PH (HPH) in mice. Mechanistically, METTL3-mediated m6A modification of kruppel-like factor 2 (KLF2) plays a crucial role in the EndMT process. KLF2 overexpression increased CD31 and VE-cadherin levels while decreasing SM22, N-cadherin, and EndMT-related transcription factors, thereby mitigating EndMT in PH. Mutations in the m6A site of KLF2 mRNA compromise KLF2 expression, subsequently diminishing its protective effect against EndMT. Furthermore, KLF2 modulates SM22 expression through direct binding to its promoter. CONCLUSIONS: Our findings unveil a novel METTL3/KLF2 pathway critical for protecting hPAECs against EndMT, highlighting a promising avenue for therapeutic investigation in PH.

MicroRNA-30e-3p reduces coronary microembolism-induced cardiomyocyte pyroptosis and inflammation by sequestering HDAC2 from the SMAD7 promoter.

This study investigates the mechanism by which microRNA (miR)-30e-3p reduces coronary microembolism (CME)-induced cardiomyocyte pyroptosis and inflammation. Cardiac function tests, histological staining, and transmission electron microscopy were performed on CME-model rats injected with adeno-associated viral vectors. Cardiomyocytes were transfected 24 h before a cellular model of pyroptosis was established via treatment with 1 µg/mL lipopolysaccharide (LPS) for 4 h and 5 mM ATP for 30 min. Pyroptosis, inflammation, and Wnt/ß-catenin signaling in cardiomyocytes were detected. Dual-luciferase reporter assays and/or RNA pull-down assays were performed to verify the binding of miR-30e-3p to HDAC2 mRNA or HDAC2 to the SMAD7 promoter. Chromatin immunoprecipitation was used to assess the level of H3K27 acetylation at the SMAD7 promoter. miR-30e-3p and SMAD7 expression levels were downregulated and HDAC2 expression was upregulated with CME. The overexpression of miR-30e-3p restored cardiac functions in CME-model rats and reduced serum cTnI, IL-18, and IL-1ß levels, microinfarcts, inflammatory cell infiltration, apoptosis, collagen content, and GSDMD-N, cleaved caspase-1, and NLRP3 expression in the myocardium, but these effects were reversed by SMAD7 knockdown. The overexpression of miR-30e-3p or knockdown of HDAC2 reduced LDH, IL-18, and IL-1ß secretion, propidium iodide intake, and GSDMD-N, NLRP3, cleaved caspase-1, Wnt3a, Wnt5a, and ß-catenin expression in the cardiomyocyte model. miR-30e-3p inhibited the expression of HDAC2 by binding HDAC2 mRNA. HDAC2 repressed the expression of SMAD7 by catalyzing H3K27 deacetylation at the SMAD7 promoter. miR-30e-3p, by binding HDAC2 to promote SMAD7 expression, reduces CME-induced cardiomyocyte pyroptosis and inflammation.

Label-Free, Reusable, Equipment-Free, and Visual Detection of Hydrogen Sulfide Using a Colorimetric and Fluorescent Dual-Mode Sensing Platform.

In this work, we have found for the first time that the fluorescence of rhodamine B (RhB) would be dramatically reduced after it bound to hemin/G-quadruplex and reacted with •OH. Based on this finding, we have designed a colorimetric and fluorescent dual-mode sensing platform for visual detection of hydrogen sulfide (H2S). The constructed sensor is based on the formation of dsDNA and the G-quadruplex structure by the cytosine-Ag+-cytosine mismatch, causing H2O2-mediated catalysis to oxidize ABTS or RhB to induce a colorimetric or fluorescent change. In the presence of H2S, the solution color for colorimetric and fluorescent assays would change from dark green to pink and from green (fluorescence off) to bright yellow (fluorescence on), respectively. This dual-mode assay showed high selectivity toward H2S over other interference materials with a low measurable detection limit value (below than 2.5 µM), and it has been successfully applied to H2S visual detection in real samples. Moreover, the dual-mode sensing strategy presented an excellent reutilization character both in colorimetric and fluorescent assays. This method was employed as a label-free, simple, fast, and equipment-free platform for H2S detection with high selectivity and reusability. This work realized naked-eye detection both in colorimetric and fluorescent analysis at a lower concentration of H2S, demonstrating a promising strategy for on-site visual detection of H2S.

Wfs1 loss-of-function disrupts the composition of mouse pancreatic endocrine cells from birth and impairs Glut2 localization to cytomembrane in pancreatic ß cells.

Wfs1 is an endoplasmic reticulum (ER) membrane located protein highly expressed in pancreatic ß cells and brain. Wfs1 deficiency causes adult pancreatic ß cells dysfunction following ß cells apoptosis. Previous studies mainly focus on the Wfs1 function in adult mouse pancreatic ß cells. However, whether Wfs1 loss-of-function impairs mouse pancreatic ß cell from its early development is unknown. In our study, Wfs1 deficiency disrupts the composition of mouse pancreatic endocrine cells from early postnatal day 0 (P0) to 8 weeks old, with decreased percentage of ß cells and increased percentage of α and δ cells. Meanwhile, Wfs1 loss-of-function leads to reduced intracellular insulin content. Notably, Wfs1 deficiency impairs Glut2 localization and causes the accumulation of Glut2 in mouse pancreatic ß cell cytoplasm. In Wfs1-deficient mice, glucose homeostasis is disturbed from early 3 weeks old to 8 weeks old. This work reveals that Wfs1 is significantly required for the composition of pancreatic endocrine cells and is essential for Glut2 localization in mouse pancreatic ß cells.

Tex10 interacts with STAT3 to regulate hepatocellular carcinoma growth and metastasis.

Testis expression 10 (Tex10) is reported to be associated with tumorigenesis in several types of cancer types, but its role in hepatocellular carcinoma (HCC) metastasis has not been investigated. In this study, the expression of Tex10 in the HCC cell line and tissue microarray was determined by Western blot and immunohistochemistry (IHC), respectively. RNA sequencing-based transcriptome analysis was performed to identify the Tex10-mediated biological process. Cell Counting Kit-8, colony formation, transwell assays, xenograft tumor growth, and lung metastasis experiments in nude mice were applied to assess the effects of Tex10 on cell proliferation, migration, invasion, and metastasis. The underlying mechanisms were further investigated using dual-luciferase reporter, co-immunoprecipitation, immunofluorescence, and chromatin immunoprecipitation assays. We found that Tex10 was upregulated in HCC tumor tissues compared to adjacent normal tissues, with its expression correlated with a poor prognosis. Gene ontology function enrichment analysis revealed alterations in several biological processes in response to Tex10 knockdown, especially cell motility and cell migration. Functional studies demonstrated that Tex10 promotes HCC cell proliferation, migration, invasion, and metastasis in vitro and in vivo. Moreover, Tex10 was shown to regulate invasion and epithelial-mesenchymal transition via signal transducer and activator of transcription 3 (STAT3) signaling. Mechanistically, Tex10 was found to interact with STAT3 and promote its transcriptional activity. In addition, we found that Tex10 promotes p300-mediated STAT3 acetylation, while p300 silencing abolishes Tex10-enhanced STAT3 transcriptional activity. Together, these findings indicate that Tex10 functions as an oncogene by upregulating STAT3 activity, thus suggesting that Tex10 may serve as a prognostic biomarker and/or therapeutic target for HCC patients.

Association Between Immunoglobulin G4-Related Ophthalmic Disease and Nonlymphoid Malignancy Case Series and Comprehensive Review of the Literature.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) and immunoglobulin G4-related ophthalmic disease (IgG4-ROD) complicated with nonlymphoid malignancy (NL-malignancy) are rare. No exact relationship between IgG4-RD and NL-malignancies has been established yet, and there have been few reports of different types of IgG4-ROD and related malignancies. METHODS: We retrospectively reviewed medical records of patients diagnosed with IgG4-RD and NL-malignancy, whichever occurred first, from January 2015 to March 2021. In addition, the literature on the relationship between IgG4-ROD and NL-malignancy was reviewed. RESULTS: There were 115 patients diagnosed with IgG4-RD, and 10 patients were enrolled in the study with NL-malignancy. Three patients were diagnosed with IgG4-ROD. One patient reported a previous history of cancer, and the other 2 patients developed cancer at or after the diagnosis of IgG4-RD. The 3 patients' cancers were located in the lung, gastrointestinal tract, and thyroid. CONCLUSIONS: There may be potential malignancy occurrence during follow-up of IgG4-RD patients, especially among elderly patients. In addition, IgG4-RD could be a paraneoplastic syndrome at or before the diagnosis of malignancy.

Preparing future general practitioners: the effects of individual, familial, and institutional characteristics.

BACKGROUND: There is a substantially increasing need for general practitioners (GPs) for future unpredictable pandemic crises, especially at the community-based health services (CBHS) level to protect the vast and varied grassroot-level population in China. Thus, it is crucial to understand the factors that affect Chinese medical students' GP career choices and commitments to CBHS. METHODS: Leveraging the self-administered data collected across the country, this study conducted logistic regressions with 3,438 medical students. First, descriptive statistics of outcome variables and independent variables were provided. Then, stepwise logistic regression models were built, starting from adding individual characteristics, and then familial and institutional characteristics. Last, post-estimation was conducted to further assess whether there were significant marginal effects. RESULTS: Results showed that women students were 24% less likely to choose GP careers but were 1.25 times more likely to commit to CBHS than their men peers, holding other individual, familial, and institutional characteristics constant. In addition, students who major in GP-orientated were more likely to choose GP careers and commit to CBHS, respectively, than those who major in clinical medicine. Furthermore, familial characteristics like annual income and mother's educational level only significantly predicted commitments to CBHS. Notably, sex-related differences in GP career choices and commitments to CBHS - by different regions - were observed. CONCLUSIONS: Understanding the factors that affect medical students' GP career choices sheds light on how medical education stakeholders can make informed decisions on attracting more medical students to GP-orientated majors, which in turn cultivates more GP professionals to meet the nation's demand for GPs. In addition, by understanding the factors that influence medical students' commitment to CBHS, policymakers could make beneficial policies to increase medical students' motivations to the grassroot-level health institutions, and devote to CBHS as gatekeepers for a large population of residents' health.

Rapid and Non-Destructive Estimation of Moisture Content in Caragana Korshinskii Pellet Feed Using Hyperspectral Imaging.

Moisture content is an important parameter for estimating the quality of pellet feed, which is vital in nutrition, storage, and taste. The ranges of moisture content serve as an index for factors such as safe storage and nutrition stability. A rapid and non-destructive model for the measurement of moisture content in pellet feed was developed. To achieve this, 144 samples of Caragana korshinskii pellet feed from various regions in Inner Mongolia Autonomous Region underwent separate moisture content control, measurement using standard methods, and captured their images using a hyperspectral imaging (HSI) system in the spectral range of 935.5-2539 nm. The Monte Carlo cross validation (MCCV) was used to eliminate abnormal sample data from the spectral data for better model accuracy, and a global model of moisture content was built by using partial least squares regression (PLSR) with seven preprocessing techniques and two spectral feature extraction techniques. The results showed that the regression model developed by PLSR based on second derivative (SD) and competitive adaptive reweighted sampling (CARS) resulted in better performance for moisture content. The model showed predictive abilities for moisture content with a coefficient of determination of 0.9075 and a root mean square error (RMSE) of 0.4828 for the training set; and a coefficient of determination of 0.907 and a root mean square error (RMSE) of 0.5267 for the test set; and a relative prediction error of 3.3 and the standard error of 0.307.

MicroRNA-136-5p protects cardiomyocytes from coronary microembolization through the inhibition of pyroptosis.

This study investigated how miR-136-5p partially affected cardiomyocyte pyroptosis in rats with coronary microembolization (CME). The cardiac function and structure of rats with CME were evaluated using echocardiography, hematoxylin and eosin staining, Masson staining, and troponin I level. Pyroptosis was induced by lipopolysaccharide (LPS) in isolated rat cardiomyocytes and evaluated by the expression of caspase-1, NOD-like receptor family pyrin domain-containing 3, interleukin-1ß, and gasdermin D-N. After cell transfection, the expression of Ataxin-1 like (ATXN1L), pyrin domain-containing 1 (PYDC1), and pyroptosis-related proteins was assessed. Dual-luciferase reporter and immunoprecipitation assays were used to verify the relationships among miR-136-5p, ATXN1L, and capicua (CIC). MiR-136-5p was under-expressed, whereas ATXN1L was overexpressed in rats with CME and in LPS-treated primary cardiomyocytes. MiR-136-5p targeted ATXN1L, and ATXN1L bound to CIC to suppress PYDC1 expression. MiR-136-5p overexpression suppressed pyroptosis by inhibiting the binding of ATXN1L with CIC and promoting PYDC1 expression, which was reversed by simultaneous elevation of ATXN1L. In conclusion, miR-136-5p suppressed pyroptosis by upregulating PYDC1 via ATXN1L/CIC axis, thereby attenuating cardiac damage caused by CME.

Interdigitated photoconductive antenna-based two-color femtosecond laser filamentation THz time-domain spectral detection.

Two-color femtosecond (fs) laser filamentation in the gas medium is an effective way to generate broadband and high intensity terahertz (THz) pulse. The interdigitated photoconductive antenna (iPCA) has the advantages of both broadband detection and high signal-to-noise ratio (SNR), which is a very effective way to detect the THz pulse produced by two-color fs laser filamentation. The THz signal from two-color fs laser filamentation is comprehensively characterized by the iPCA, which achieves high SNR, high sensitivity, and polarization detection. This work provides a new idea for high power broadband THz coherent detection.

LncRNA TUG1 competitively binds to miR-340 to accelerate myocardial ischemia-reperfusion injury.

The aberrant expression of long noncoding RNA (lncRNA) taurine-upregulated gene 1 (TUG1) has been previously associated with myocardial ischemia-reperfusion injury (MIRI), but the underlying molecular mechanisms remain elusive. The current study aimed to clarify the functional role of TUG1/microRNA (miR)-340/histone deacetylase 4 (HDAC4)/ß-catenin/glucose transporter type 1 (GLUT1) axes in MIRI. The database-based analyses performed predicted the downstream factors of lncRNA TUG1. In the MIRI mouse models and hypoxia/reoxygenation (H/R)-induced cardiomyocyte models, the expression of TUG1/miR-340/HDAC4/ß-catenin/GLUT1 was manipulated to examine their effects on the infarction area, cardiomyocyte viability and apoptosis employing the Evans blue/TTC double staining, CCK-8 and TUNEL assays. Furthermore, the dual luciferase reporter and RIP assays verified the binding affinity of miR-340 to TUG1 and HDAC4. Subsequently, a negative correlation between miR-340 and TUG1 or HDAC4 expression was identified in myocardial tissues of MIRI mice and H/R-induced cardiomyocyte models, along with a positive correlation between TUG1 and HDAC4. Additionally, it was established that TUG1 bound to miR-340, and miR-340 targeted HDAC4. TUG1 upregulated HDAC4 expression, thereby promoting MIRI in the mouse models. HDAC4 was proven to repress the expression of ß-catenin and its target gene GLUT1. Moreover, the in vivo experiments validated that the inhibition of TUG1/miR-340/HDAC4/ß-catenin/GLUT1 axes alleviated MIRI in mice. Collectively, the current study uncovered the role of TUG1/miR-340/HDAC4/ß-catenin/GLUT1 axes in MIRI mouse models and H/R-induced cardiomyocyte models which may be a potential therapeutic target for MIRI treatment.

Development pattern of ocular biometric parameters and refractive error in young Chinese adults: a longitudinal study of first-year university students.

BACKGROUND: The increase in the prevalence of myopia has become a matter of serious public health concern, and few studies to date have examined the ocular biometric parameters of myopia in young Chinese adults. This study aimed to investigate the longitudinal ocular biometric and refractive development of first-year university students and the influence of near work. METHODS: This study included 526 first-year university students from Tianjin Medical University (mean age, 18.34 years; 313 females and 213 males). From 2016 to 2018, participants underwent ocular biometry measurements and subjective refraction annually. Near-work activities such as the use of electronic devices, online games, reading, and writing as well as demographic data were recorded by questionnaires. RESULTS: The prevalence of myopia in this population from 2016 to 2018 was 92.40%, 92.59%, and 92.97%, respectively. Importantly, the prevalence of high myopia increased significantly from 20.91% to 28.33% (P < .001). The spherical equivalent refraction was significantly more myopic by approximately - 0.38 D (from - 4.18 ± 2.44 to - 4.56 ± 2.57 D; P < .001) during the period. The axial length, central corneal thickness, and lens thickness became significantly different (all P < .05), and the axial length significantly increased by 0.12 mm during 2 years (P < .001). Using binary logistic regression analysis, the data indicated that spending more time on online games (odds ratio, 2.09; 95% confidence interval, 1.33-3.29) could speed up the progression of myopia (P < .05). CONCLUSIONS: This study showed that the prevalence of high myopia continued to increase in undergraduate students over 2 years. Baseline myopia correlated with myopic shift, the time spent on online games, and parental myopia were significantly associated with an increase in myopia in these young adult populations.

The Pathogen-Induced MATE Gene TaPIMA1 Is Required for Defense Responses to Rhizoctonia cerealis in Wheat.

The sharp eyespot, mainly caused by the soil-borne fungus Rhizoctonia cerealis, is a devastating disease endangering production of wheat (Triticum aestivum). Multi-Antimicrobial Extrusion (MATE) family genes are widely distributed in plant species, but little is known about MATE functions in wheat disease resistance. In this study, we identified TaPIMA1, a pathogen-induced MATE gene in wheat, from RNA-seq data. TaPIMA1 expression was induced by Rhizoctonia cerealis and was higher in sharp eyespot-resistant wheat genotypes than in susceptible wheat genotypes. Molecular biology assays showed that TaPIMA1 belonged to the MATE family, and the expressed protein could distribute in the cytoplasm and plasma membrane. Virus-Induced Gene Silencing plus disease assessment indicated that knock-down of TaPIMA1 impaired resistance of wheat to sharp eyespot and down-regulated the expression of defense genes (Defensin, PR10, PR1.2, and Chitinase3). Furthermore, TaPIMA1 was rapidly induced by exogenous H2O2 and jasmonate (JA) treatments, which also promoted the expression of pathogenesis-related genes. These results suggested that TaPIMA1 might positively regulate the defense against R. cerealis by up-regulating the expression of defense-associated genes in H2O2 and JA signal pathways. This study sheds light on the role of MATE transporter in wheat defense to Rhizoctonia cerealis and provides a potential gene for improving wheat resistance against sharp eyespot.