A Bacterial Effector Reveals the V-ATPase-ATG16L1 Axis that Initiates Xenophagy.

Antibacterial autophagy (xenophagy) is an important host defense, but how it is initiated is unclear. Here, we performed a bacterial transposon screen and identified a T3SS effector SopF that potently blocked Salmonella autophagy. SopF was a general xenophagy inhibitor without affecting canonical autophagy. S. Typhimurium ΔsopF resembled S. flexneri ΔvirAΔicsB with the majority of intracellular bacteria targeted by autophagy, permitting a CRISPR screen that identified host V-ATPase as an essential factor. Upon bacteria-caused vacuolar damage, the V-ATPase recruited ATG16L1 onto bacteria-containing vacuole, which was blocked by SopF. Mammalian ATG16L1 bears a WD40 domain required for interacting with the V-ATPase. Inhibiting autophagy by SopF promoted S. Typhimurium proliferation in vivo. SopF targeted Gln124 of ATP6V0C in the V-ATPase for ADP-ribosylation. Mutation of Gln124 also blocked xenophagy, but not canonical autophagy. Thus, the discovery of SopF reveals the V-ATPase-ATG16L1 axis that critically mediates autophagic recognition of intracellular pathogen.

Regulation of Cell Cycle to Stimulate Adult Cardiomyocyte Proliferation and Cardiac Regeneration.

Human diseases are often caused by loss of somatic cells that are incapable of re-entering the cell cycle for regenerative repair. Here, we report a combination of cell-cycle regulators that induce stable cytokinesis in adult post-mitotic cells. We screened cell-cycle regulators expressed in proliferating fetal cardiomyocytes and found that overexpression of cyclin-dependent kinase 1 (CDK1), CDK4, cyclin B1, and cyclin D1 efficiently induced cell division in post-mitotic mouse, rat, and human cardiomyocytes. Overexpression of the cell-cycle regulators was self-limiting through proteasome-mediated degradation of the protein products. In vivo lineage tracing revealed that 15%-20% of adult cardiomyocytes expressing the four factors underwent stable cell division, with significant improvement in cardiac function after acute or subacute myocardial infarction. Chemical inhibition of Tgf-ß and Wee1 made CDK1 and cyclin B dispensable. These findings reveal a discrete combination of genes that can efficiently unlock the proliferative potential in cells that have terminally exited the cell cycle.

AnimalMetaOmics: a multi-omics data resources for exploring animal microbial genomes and microbiomes.

The Animal Meta-omics landscape database (AnimalMetaOmics, https://yanglab.hzau.edu.cn/animalmetaomics#/) is a comprehensive and freely available resource that includes metagenomic, metatranscriptomic, and metaproteomic data from various non-human animal species and provides abundant information on animal microbiomes, including cluster analysis of microbial cognate genes, functional gene annotations, active microbiota composition, gene expression abundance, and microbial protein identification. In this work, 55 898 microbial genomes were annotated from 581 animal species, including 42 924 bacterial genomes, 12 336 virus genomes, 496 archaea genomes and 142 fungi genomes. Moreover, 321 metatranscriptomic datasets were analyzed from 31 animal species and 326 metaproteomic datasets from four animal species, as well as the pan-genomic dynamics and compositional characteristics of 679 bacterial species and 13 archaea species from animal hosts. Researchers can efficiently access and acquire the information of cross-host microbiota through a user-friendly interface, such as species, genomes, activity levels, expressed protein sequences and functions, and pan-genome composition. These valuable resources provide an important reference for better exploring the classification, functional diversity, biological process diversity and functional genes of animal microbiota.

CsPAT1, a GRAS transcription factor, promotes lignin accumulation by antagonistic interacting with CsWRKY13 in tea plants.

Lignin is an important component of plant cell walls and plays crucial roles in the essential agronomic traits of tea quality and tenderness. However, the molecular mechanisms underlying the regulation of lignin biosynthesis in tea plants remain unclear. CsWRKY13 acts as a negative regulator of lignin biosynthesis in tea plants. In this study, we identified a GRAS transcription factor, phytochrome A signal transduction 1 (CsPAT1), that interacts with CsWRKY13. Silencing CsPAT1 expression in tea plants and heterologous overexpression in Arabidopsis demonstrated that CsPAT1 positively regulates lignin accumulation. Further investigation revealed that CsWRKY13 directly binds to the promoters of CsPAL and CsC4H and suppresses transcription of CsPAL and CsC4H. CsPAT1 indirectly affects the promoter activities of CsPAL and CsC4H by interacting with CsWRKY13, thereby facilitating lignin biosynthesis in tea plants. Compared with the expression of CsWRKY13 alone, the co-expression of CsPAT1 and CsWRKY13 in Oryza sativa significantly increased lignin biosynthesis. Conversely, compared with the expression of CsPAT1 alone, the co-expression of CsPAT1 and CsWRKY13 in O. sativa significantly reduced lignin accumulation. These results demonstrated the antagonistic regulation of the lignin biosynthesis pathway by CsPAT1 and CsWRKY13. These findings improve our understanding of lignin biosynthesis mechanisms in tea plants and provide insights into the role of the GRAS transcription factor family in lignin accumulation.

Bi-allelic human TEKT3 mutations cause male infertility with oligoasthenoteratozoospermia owing to acrosomal hypoplasia and reduced progressive motility.

Oligoasthenoteratozoospermia (OAT) can result in male infertility owing to reduced sperm motility and abnormal spermatozoan morphology. The Tektins are a family of highly conserved filamentous proteins expressed in the axoneme and associated structures in many different metazoan species. Earlier studies on mice identified Tektin3 (Tekt3) as a testis-enriched gene, and knockout of Tekt3 resulted in asthenozoospermia in the mice. Here, whole-exome sequencing of 100 males with asthenozoospermia from unrelated families was performed, followed by Sanger sequencing, leading to the identification of TEKT3 as a candidate gene in two of these patients and their associated family members. In total, three mutations in the TEKT3 gene were identified in both these patients, including one homozygous deletion-insertion mutation (c.543_547delinsTTGAT: p.Glu182*) and one compound heterozygous mutation (c.[548G > A]; [752A > C], p.[Arg183Gln]; [Gln251Pro]). Both of these mutations resulted in the complete loss of TEKT3 expression. The patients were both found to produce sperm that, although those showed no apparent defects in the flagellar structure, had reduced progressive motility. In contrast to mice, most sperm from these two patients exhibited acrosomal hypoplasia, although this did not prevent the use of the sperm for in vitro fertilization through an ICSI approach. TEKT3 was found to bind to other TEKT proteins, suggesting that these proteins form a complex within human spermatozoa. Overall, these results suggest that a loss of TEKT3 function can contribute to OAT incidence in humans. TEKT3 deficiencies can reduce sperm motility and contribute to severe acrosomal hypoplasia in spermatozoa, compromising their normal function.

Genomic analyses of wild argali, domestic sheep, and their hybrids provide insights into chromosome evolution, phenotypic variation, and germplasm innovation.

Understanding the genetic mechanisms of phenotypic variation in hybrids between domestic animals and their wild relatives may aid germplasm innovation. Here, we report the high-quality genome assemblies of a male Pamir argali (O ammon polii, 2n = 56), a female Tibetan sheep (O aries, 2n = 54), and a male hybrid of Pamir argali and domestic sheep, and the high-throughput sequencing of 425 ovine animals, including the hybrids of argali and domestic sheep. We detected genomic synteny between Chromosome 2 of sheep and two acrocentric chromosomes of argali. We revealed consistent satellite repeats around the chromosome breakpoints, which could have resulted in chromosome fusion. We observed many more hybrids with karyotype 2n = 54 than with 2n = 55, which could be explained by the selfish centromeres, the possible decreased rate of normal/balanced sperm, and the increased incidence of early pregnancy loss in the aneuploid ewes or rams. We identified genes and variants associated with important morphological and production traits (e.g., body weight, cannon circumference, hip height, and tail length) that show significant variations. We revealed a strong selective signature at the mutation (c.334C > A, p.G112W) in TBXT and confirmed its association with tail length among sheep populations of wide geographic and genetic origins. We produced an intercross population of 110 F2 offspring with varied number of vertebrae and validated the causal mutation by whole-genome association analysis. We verified its function using CRISPR-Cas9 genome editing. Our results provide insights into chromosomal speciation and phenotypic evolution and a foundation of genetic variants for the breeding of sheep and other animals.

Hypoxia-inducible factor prolyl hydroxylase inhibitor alleviates heatstroke-induced acute kidney injury by activating BNIP3-mediated mitophagy.

Hypoxia-induced inflammation and apoptosis are important pathophysiological features of heat stroke-induced acute kidney injury (HS-AKI). Hypoxia-inducible factor (HIF) is a key protein that regulates cell adaptation to hypoxia. HIF-prolyl hydroxylase inhibitor (HIF-PHI) stabilizes HIF to increase cell adaptation to hypoxia. Herein, we reported that HIF-PHI pretreatment significantly improved renal function, enhanced thermotolerance, and increased the survival rate of mice in the context of HS. Moreover, HIF-PHI could alleviate HS-induced mitochondrial damage, inflammation, and apoptosis in renal tubular epithelial cells (RTECs) by enhancing mitophagy in vitro and in vivo. By contrast, mitophagy inhibitors Mdivi-1, 3-MA, and Baf-A1 reversed the renoprotective effects of HIF-PHI. Mechanistically, HIF-PHI protects RTECs from inflammation and apoptosis by enhancing Bcl-2 adenovirus E18 19-kDa-interacting protein 3 (BNIP3)-mediated mitophagy, while genetic ablation of BNIP3 attenuated HIF-PHI-induced mitophagy and abolished HIF-PHI-mediated renal protection. Thus, our results indicated that HIF-PHI protects renal function by upregulating BNIP3-mediated mitophagy to improve HS-induced inflammation and apoptosis of RTECs, suggesting HIF-PHI as a promising therapeutic agent to treat HS-AKI.

CRAMdb: a comprehensive database for composition and roles of microbiome in animals.

CRAMdb (a database for composition and roles of animal microbiome) is a comprehensive resource of curated and consistently annotated metagenomes for non-human animals. It focuses on the composition and roles of the microbiome in various animal species. The main goal of the CRAMdb is to facilitate the reuse of animal metagenomic data, and enable cross-host and cross-phenotype comparisons. To this end, we consistently annotated microbiomes (including 16S, 18S, ITS and metagenomics sequencing data) of 516 animals from 475 projects spanning 43 phenotype pairs to construct the database that is equipped with 9430 bacteria, 278 archaea, 2216 fungi and 458 viruses. CRAMdb provides two main contents: microbiome composition data, illustrating the landscape of the microbiota (bacteria, archaea, fungi, and viruses) in various animal species, and microbiome association data, revealing the relationships between the microbiota and various phenotypes across different animal species. More importantly, users can quickly compare the composition of the microbiota of interest cross-host or body site and the associated taxa that differ between phenotype pairs cross-host or cross-phenotype. CRAMdb is freely available at (http://www.ehbio.com/CRAMdb).

Both intrinsic and microenvironmental factors contribute to the regulation of stem cell quiescence.

Precise regulation of stem cell quiescence is essential for tissue development and homeostasis. Therefore, its aberrant regulation is intimately correlated with various human diseases. However, the detailed mechanisms of stem cell quiescence and its specific role in the pathogenesis of various diseases remain to be determined. Recent studies have revealed that the intrinsic and microenvironmental factors are the potential candidates responsible for the orderly switch between the dormant and activated states of stem cells. In addition, defects in signaling pathways related to internal and external factors of stem cells might contribute to the initiation and development of diseases by altering the dormancy of stem cells. In this review, we focus on the mechanisms underlying stem cell quiescence, especially the involvement of intrinsic and microenvironmental factors. In addition, we discuss the relationship between the anomalies of stem cell quiescence and related diseases, hopefully providing therapeutic insights for developing novel treatments.

tRNA-derived fragments: Unveiling new roles and molecular mechanisms in cancer progression.

tRNA-derived fragments (tRFs) are novel small noncoding RNAs (sncRNAs) that range from approximately 14 to 50 nt. They are generated by the cleavage of mature tRNAs or precursor tRNAs (pre-tRNAs) at specific sites. Based on their origin and length, tRFs can be classified into three categories: (1) tRF-1 s; (2) tRF-3 s, tRF-5 s, and internal tRFs (i-tRFs); and (3) tRNA halves. They play important roles in stress response, signal transduction, and gene expression processes. Recent studies have identified differential expression of tRFs in various tumors. Aberrantly expressed tRFs have critical clinical value and show promise as new biomarkers for tumor diagnosis and prognosis and as therapeutic targets. tRFs regulate the malignant progression of tumors via various mechanisms, primarily including modulation of noncoding RNA biogenesis, global chromatin organization, gene expression regulation, modulation of protein translation, regulation of epigenetic modification, and alternative splicing regulation. In conclusion, tRF-mediated regulatory pathways could present new avenues for tumor treatment, and tRFs could serve as promising therapeutic targets for cancer therapy.

GCN5 mediates DNA-PKcs crotonylation for DNA double-strand break repair and determining cancer radiosensitivity.

BACKGROUND: DNA double-strand break (DSB) induction and repair are important events for determining cell survival and the outcome of cancer radiotherapy. The DNA-dependent protein kinase (DNA-PK) complex functions at the apex of DSBs repair, and its assembly and activity are strictly regulated by post-translation modifications (PTMs)-associated interactions. However, the PTMs of the catalytic subunit DNA-PKcs and how they affect DNA-PKcs's functions are not fully understood. METHODS: Mass spectrometry analyses were performed to identify the crotonylation sites of DNA-PKcs in response to γ-ray irradiation. Co-immunoprecipitation (Co-IP), western blotting, in vitro crotonylation assays, laser microirradiation assays, in vitro DNA binding assays, in vitro DNA-PK assembly assays and IF assays were employed to confirm the crotonylation, identify the crotonylase and decrotonylase, and elucidate how crotonylation regulates the activity and function of DNA-PKcs. Subcutaneous xenografts of human HeLa GCN5 WT or HeLa GCN5 siRNA cells in BALB/c nude mice were generated and utilized to assess tumor proliferation in vivo after radiotherapy. RESULTS: Here, we reveal that K525 is an important site of DNA-PKcs for crotonylation, and whose level is sharply increased by irradiation. The histone acetyltransferase GCN5 functions as the crotonylase for K525-Kcr, while HDAC3 serves as its dedicated decrotonylase. K525 crotonylation enhances DNA binding activity of DNA-PKcs, and facilitates assembly of the DNA-PK complex. Furthermore, GCN5-mediated K525 crotonylation is indispensable for DNA-PKcs autophosphorylation and the repair of double-strand breaks in the NHEJ pathway. GCN5 suppression significantly sensitizes xenograft tumors of mice to radiotherapy. CONCLUSIONS: Our study defines K525 crotonylation of DNA-PKcs is important for the DNA-PK complex assembly and DSBs repair activity via NHEJ pathway. Targeting GCN5-mediated K525 Kcr of DNA-PKcs may be a promising therapeutic strategy for improving the outcome of cancer radiotherapy.

Thermophoretic Aggregation Imaging of Tumor-Derived Exosomes by CRISPR-Cas13a-Based Nanoprobes.

The inherent heterogeneity of tumor-derived exosomes holds great promise for enhancing the precision of cancer diagnostics. MicroRNAs (miRNAs) encapsulated in tumor-associated exosomes have emerged as valuable biomarkers for the early detection of cancers. Nevertheless, the flexible structure and inherent instability of RNA limit its application in biological diagnostics. The CRISPR-Cas13a system, distinguished by its target-responsive "collateral effect", represents a powerful tool for advancing cancer diagnostics. In this study, we harness the CRISPR-Cas13a system as an innovative signal amplification tool to image cancer-related exosomal miRNA in situ. Furthermore, we capitalize on the thermophoretic aggregation effect exhibited by gold nanoparticles (Au NPs) to consolidate the fluorescent signals generated by the CRISPR-Cas13a system. Subsequently, the developed nanoprobe is applied to detect lung cancer-related exosomal miRNA from human serum, enabling the aggregated visualization of low-abundance cancer exosomes in individuals with lung cancer compared with healthy individuals. This sensitive thermophoretic aggregation assay provides a diagnostic tool for lung cancer in the clinic.

Superior Energy Storage Capability and Fluorescence Negative Thermal Expansion of NaNbO3-Based Transparent Ceramics by Synergistic Optimization.

Transparent dielectric ceramics are splendid candidates for transparent pulse capacitors (TPCs) due to splendid cycle stability and large power density. However, the performance and service life of TPCs at present are threatened by overheating damage caused by dielectric loss. Here, a cooperative optimization strategy of microstructure control and superparaelectric regional regulation is proposed to simultaneously achieve excellent energy storage performance and real-time temperature monitoring function in NaNbO3-based ceramics. By introducing aliovalent ions and oxides with large bandgap energy, the size of polar nanoregions is continuously reduced. Due to the combined effect of increased relaxor behavior and fine grains, excellent comprehensive performances are obtained through doping appropriate amounts of Bi, Yb, Tm, and Zr, Ta, Hf in A- and B-sites of the NaNbO3 matrix, including recoverable energy storage density (5.39 J cm-3), extremely high energy storage efficiency (91.97%), ultra-fast discharge time (29 ns), and superior optical transmittance (≈47.5% at 736 nm). Additionally, the phenomenon of abnormal fluorescent negative thermal expansion is realized due to activation mechanism of surface phonon at high temperatures that can promote the formation of [Yb···O]-Tm3+ pairs, showing great potential in real-time temperature monitoring of TPCs. This research provides ideas for developing electronic devices with multiple functionalities.

Recent Advances in Electrochemiluminescence Visual Biosensing and Bioimaging.

Electrochemiluminescence (ECL) is one of the most powerful techniques that meet the needs of analysis and detection in a variety of scenarios, because of its highly analytical sensitivity and excellent spatiotemporal controllability. ECL combined with microscopy (ECLM) offers a promising approach for quantifying and mapping a wide range of analytes. To date, ECLM has been widely used to image biological entities and processes, such as cells, subcellular structures, proteins and membrane transport properties. In this review, we first introduced the mechanisms of several classic ECL systems, then highlighted the progress of visual biosensing and bioimaging by ECLM in the last decade. Finally, the characteristics of ECLM were summarized, as well as some of the current challenges. The future research interests and potential directions for the application of ECLM were also outlooked.

Shedding light on the hidden human proteome expands immunopeptidome in cancer.

Unrestrained cellular growth and immune escape of a tumor are associated with the incidental errors of the genome and transcriptome. Advances in next-generation sequencing have identified thousands of genomic and transcriptomic aberrations that generate variant peptides that assemble the hidden proteome, further expanding the immunopeptidome. Emerging next-generation sequencing technologies and a number of computational methods estimated the abundance of immune infiltration from bulk transcriptome have advanced our understanding of tumor microenvironments. Here, we will characterize several major types of tumor-specific antigens arising from single-nucleotide variants, insertions and deletions, gene fusion, alternative splicing, RNA editing and non-coding RNAs. Finally, we summarize the current state-of-the-art computational and experimental approaches or resources and provide an integrative pipeline for the identification of candidate tumor antigens. Together, the systematic investigation of the hidden proteome in cancer will help facilitate the development of effective and durable immunotherapy targets for cancer.

Single-molecule photoelectron tunnelling spectroscopy.

Experimental mapping of transmission is essential for understanding and controlling charge transport through molecular devices and materials. Here we developed a single-molecule photoelectron tunnelling spectroscopy approach for mapping transmission beyond the HOMO-LUMO gap of the single diketopyrrolopyrrole molecule junction using an ultrafast-laser combined scanning tunnelling microscope-based break junction set-up at room temperature. Two resonant transport channels of ultrafast photocurrent are found by our photoelectron tunnelling spectroscopy, ranging from 1.31 eV to 1.77 eV, consistent with the LUMO + 1 and LUMO + 2 in the transmission spectrum obtained by density functional theory calculations. Moreover, we observed the modulation of resonant peaks by varying bias voltages, which demonstrates the ability to quantitatively characterize the effect of the electric field on frontier molecular orbitals. Our single-molecule photoelectron tunnelling spectroscopy offers an avenue that allows us to explore the nature of energy-dependent charge transport through single-molecule junctions.

Cytoskeletal and inter-cellular junction remodelling in endometrial organoids under oxygen-glucose deprivation: a new potential pathological mechanism for thin endometria.

STUDY QUESTION: What is the pathological mechanism involved in a thin endometrium, particularly under ischaemic conditions? SUMMARY ANSWER: Endometrial dysfunction in patients with thin endometrium primarily results from remodelling in cytoskeletons and cellular junctions of endometrial epithelial cells under ischemic conditions. WHAT IS KNOWN ALREADY: A healthy endometrium is essential for successful embryo implantation and subsequent pregnancy; ischemic conditions in a thin endometrium compromise fertility outcomes. STUDY DESIGN, SIZE, DURATION: We recruited 10 patients with thin endometrium and 15 patients with healthy endometrium. Doppler ultrasound and immunohistochemical results confirmed the presence of insufficient endometrial blood perfusion in patients with thin endometrium. Organoids were constructed using healthy endometrial tissue and cultured under oxygen-glucose deprivation (OGD) conditions for 24 h. The morphological, transcriptomic, protein expression, and signaling pathway changes in the OGD organoids were observed. These findings were validated in both thin endometrial tissue and healthy endometrial tissue samples. PARTICIPANTS/MATERIALS, SETTING, METHODS: Endometrial thickness and blood flow were measured during the late follicular phase using transvaginal Doppler ultrasound. Endometrial tissue was obtained via hysteroscopy. Fresh endometrial tissues were used for the generation and culture of human endometrial organoids. Organoids were cultured in an appropriate medium and subjected to OGD to simulate ischemic conditions. Apoptosis and cell death were assessed using Annexin-V/propidium iodide staining. Immunofluorescence analysis, RNA sequencing, western blotting, simple westerns, immunohistochemistry, and electron microscopy were conducted to evaluate cellular and molecular changes. MAIN RESULTS AND THE ROLE OF CHANCE: Patients with thin endometrium showed significantly reduced endometrial thickness and altered blood flow patterns compared to those with healthy endometrium. Immunohistochemical staining revealed fewer CD34-positive blood vessels and glands in the thin endometrium group. Organoids cultured under OGD conditions exhibited significant morphological changes, increased apoptosis, and cell death. RNA-seq identified differentially expressed genes related to cytoskeletal remodeling and stress responses. OGD induced a strong cytoskeletal reorganization, mediated by the RhoA/ROCK signaling pathway. Additionally, electron microscopy indicated compromised epithelial integrity and abnormal cell junctions in thin endometrial tissues. Upregulation of hypoxia markers (HIF-1α and HIF-2α) and activation of the RhoA/ROCK pathway were also observed in thin endometrial tissues, suggesting ischemia and hypoxia as underlying mechanisms. LARGE SCALE DATA: none. LIMITATIONS AND REASONS FOR CAUTION: The study was conducted in an in vitro model, which may not fully replicate the complexity of in vivo conditions. WIDER IMPLICATIONS OF THE FINDINGS: This research provides a new three-dimensional in vitro model of thin endometrium, as well as novel insights into the pathophysiological mechanisms of endometrial ischaemia in thin endometrium, offering potential avenues for identifying therapeutic targets for treating fertility issues related to thin endometrium. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Natural Science Foundation of China (81925013); National Key Research and Development Project of China (2022YFC2702500, 2021YFC2700303, 2021YFC2700601); the Capital Health Research and Development Project (SF2022-1-4092); the National Natural Science Foundation of China (82288102, 81925013, 82225019, 82192873); Special Project on Capital Clinical Diagnosis and Treatment Technology Research and Transformation Application (Z211100002921054); the Frontiers Medical Center, Tianfu Jincheng Laboratory Foundation(TFJC2023010001). The authors declare that no competing interests exist.

Staphylococcal enterotoxin B exposed to pregnant rats inhibits the hedgehog signaling pathway in thymic T lymphocytes of the offspring.

The Hedgehog (Hh) signaling pathway is involved in T cell differentiation and development and plays a major regulatory part in different stages of T cell development. A previous study by us suggested that prenatal exposure to staphylococcal enterotoxin B (SEB) changed the percentages of T cell subpopulation in the offspring thymus. However, it is unclear whether prenatal SEB exposure impacts the Hh signaling pathway in thymic T cells. In the present study, pregnant rats at gestational day 16 were intravenously injected once with 15 µg SEB, and the thymi of both neonatal and adult offspring rats were aseptically acquired to scrutinize the effects of SEB on the Hh signaling pathway. It firstly found that prenatal SEB exposure clearly caused the increased expression of Shh and Dhh ligands of the Hh signaling pathway in thymus tissue of both neonatal and adult offspring rats, but significantly decreased the expression levels of membrane receptors of Ptch1 and Smo, transcription factor Gli1, as well as target genes of CyclinD1, C-myc, and N-myc in Hh signaling pathway of thymic T cells. These data suggest that prenatal SEB exposure inhibits the Hh signaling pathway in thymic T lymphocytes of the neonatal offspring, and this effect can be maintained in adult offspring via the imprinting effect.

Role of MEF2C in the Endothelial Cells Derived from Human Induced Pluripotent Stem Cells.

Human induced pluripotent stem cells (hiPSCs) not only provide an abundant source of vascular cells for potential therapeutic applications in vascular disease but also constitute an excellent model for understanding the mechanisms that regulate the differentiation and the functionality of vascular cells. Here, we reported that myocyte enhancer factor 2C (MEF2C) transcription factor, but not any other members of the MEF2 family, was robustly upregulated during the differentiation of vascular progenitors and endothelial cells (ECs) from hiPSCs. Vascular endothelial growth factors (VEGF) strongly induced MEF2C expression in endothelial lineage cells. The specific upregulation of MEF2C during the commitment of endothelial lineage was dependent on the extracellular signal regulated kinase (ERK). Moreover, knockdown of MEF2C with shRNA in hiPSCs did not affect the differentiation of ECs from these hiPSCs, but greatly reduced the migration and tube formation capacity of the hiPSC-derived ECs. Through a chromatin immunoprecipitation-sequencing, genome-wide RNA-sequencing, quantitative RT-PCR, and immunostaining analyses of the hiPSC-derived endothelial lineage cells with MEF2C inhibition or knockdown compared to control hiPSC-derived ECs, we identified TNF-related apoptosis inducing ligand (TRAIL) and transmembrane protein 100 (TMEM100) as novel targets of MEF2C. This study demonstrates an important role for MEF2C in regulating human EC functions and highlights MEF2C and its downstream effectors as potential targets to treat vascular malfunction-associated diseases.

LncRNA FOXD1-AS1 regulates pancreatic cancer stem cell properties and 5-FU resistance by regulating the miR-570-3p/SPP1 axis as a ceRNA.

Cancer stem cells (CSCs) play a pivotal role in the pathogenesis of human cancers. Previous studies have highlighted the role of long non-coding RNA (lncRNA) in modulating the stemness of CSCs. In our investigation, we identified an upregulation of lncRNA FOXD1-AS1 in CSCs. The enforced expression of lncRNA FOXD1-AS1 promotes tumorigenesis and self-renewal in pancreatic cancer CSCs. Conversely, the knockdown of lncRNA FOXD1-AS1 inhibits tumorigenesis and self-renewal in pancreatic cancer CSCs. Furthermore, our findings reveal that lncRNA FOXD1-AS1 enhances self-renewal and tumorigenesis in pancreatic cancer CSCs by up-regulating osteopontin/secreted phosphoprotein 1(SPP1) and acting as a ceRNA to sponge miR-570-3p in pancreatic cancer (PC) CSCs. Additionally, lncRNA FOXD1-AS1 depleted pancreatic cancer cells exhibit heightened sensitivity to 5-FU-indued cell growth inhibition and apoptosis. Analysis of patient-derived xenografts (PDX) indicates that a low level of lncRNA FOXD1-AS1 may serve as a predictor of 5-FU benefits in PC patients. Moreover, the introduction of SPP1 can reverse the sensitivity of lncRNA FOXD1-AS1-knockdown PC cells to 5-FU-induced cell apoptosis. Importantly, molecular studies have indicated that the elevated levels of lncRNAFOXD1-AS1 in PC are facilitated through METTL3 and YTHDF1-dependent m6A methylation. In summary, our results underscore the critical functions of lncRNA FOXD1-AS1 in the self-renewal and tumorigenesis of pancreatic cancer CSCs, positioning lncRNA FOXD1-AS1 as a promising therapeutic target for PC.