Direct rosiglitazone action on steroidogenesis and proinflammatory factor production in human granulosa-lutein cells

<p>Abstract</p> <p>Background</p> <p>Ovarian granulosa cells are the predominant source of estradiol and progesterone biosynthesis in vivo. Rosiglitazone, a synthetic agonist of the peroxisome proliferator-activated receptor gamma (PPAR gamma), is applied as the treatment of insulin resistance including women with PCOS. The aim of the study was to investigate the direct effects of rosiglitazone on steroidogenesis and proinflammatory factor production in human granulosa-lutein cells (GLCs).</p> <p>Methods</p> <p>Primary human GLCs were separated during in vitro fertilization and cultured in the presence of rosiglitazone, GW9662 (an antagonist of PPAR gamma) and hCG. The mRNA expression of key steroidogenic factors including 3beta- hydroxysteriod dehydrogenase (3beta-HSD), cytochrome P-450 scc (CYP11A1), cytochrome P-450 aromatase (CYP19A1), and steroidogenic acute regulatory protein (StAR) were detected by quantitative real-time PCR. Estradiol and progesterone levels in GLCs cultures were measured by chemiluminescence immunoassay, and the proinflammtory factors (TNFalpha and IL-6) in conditioned culture media were measured by ELISA.</p> <p>Results</p> <p>PPAR gamma mRNA levels increased up to 3.24 fold by rosiglitazone at the concentration of 30 microM compared to control (P < 0.05). hCG alone or hCG with rosiglitazone had no significant effects on PPAR gamma mRNA levels. The CYP19A1 mRNA level at exposure to rosiglitazone alone showed a drop, but was not significantly reduced comparing to control. The expression levels of enzymes 3beta-HSD and CYP11A1 in all treatments did not alter significantly. The StAR mRNA expression at exposure to rosiglitazone was significantly increased comparing to control (P < 0.05). The media concentrations of E2 and progesterone by rosiglitazone treatment showed a declining trend comparing to control or cotreatment with hCG, which did not reach significance. Most importantly, treatment with rosiglitazone decreased TNFalpha secretion in a statistically significant manner compared with control (P < 0.05). The concentration of IL-6 following rosiglitazone exposure did not significantly decrease comparing to control.</p> <p>Conclusion</p> <p>In cultured GLCs, rosiglitazone stimulated StAR expression, but did not significantly affect steroidogenic enzymes, as well as E2 and progesterone production. Moreover, rosiglitazone significantly decreased the production of TNFalpha in human GLCs, suggesting that PPAR gamma may play a role in the regulation of GLCs functions through inhibiting proinflammatory factors.</p

CodeFuse-13B: A Pretrained Multi-lingual Code Large Language Model

Code Large Language Models (Code LLMs) have gained significant attention in the industry due to their wide applications in the full lifecycle of software engineering. However, the effectiveness of existing models in understanding non-English inputs for multi-lingual code-related tasks is still far from well studied. This paper introduces CodeFuse-13B, an open-sourced pre-trained code LLM. It is specifically designed for code-related tasks with both English and Chinese prompts and supports over 40 programming languages. CodeFuse achieves its effectiveness by utilizing a high quality pre-training dataset that is carefully filtered by program analyzers and optimized during the training process. Extensive experiments are conducted using real-world usage scenarios, the industry-standard benchmark HumanEval-x, and the specially designed CodeFuseEval for Chinese prompts. To assess the effectiveness of CodeFuse, we actively collected valuable human feedback from the AntGroup's software development process where CodeFuse has been successfully deployed. The results demonstrate that CodeFuse-13B achieves a HumanEval pass@1 score of 37.10%, positioning it as one of the top multi-lingual code LLMs with similar parameter sizes. In practical scenarios, such as code generation, code translation, code comments, and testcase generation, CodeFuse performs better than other models when confronted with Chinese prompts.Comment: 10 pages with 2 pages for reference

Mutations in TUBB8 and Human Oocyte Meiotic Arrest

BACKGROUND Human reproduction depends on the fusion of a mature oocyte with a sperm cell to form a fertilized egg. The genetic events that lead to the arrest of human oocyte maturation are unknown. METHODS We sequenced the exomes of five members of a four-generation family, three of whom had infertility due to oocyte meiosis I arrest. We performed Sanger sequencing of a candidate gene, TUBB8, in DNA samples from these members, additional family members, and members of 23 other affected families. The expression of TUBB8 and all other β-tubulin isotypes was assessed in human oocytes, early embryos, sperm cells, and several somatic tissues by means of a quantitative reverse- transcriptase–polymerase-chain-reaction assay. We evaluated the effect of the TUBB8 mutations on the assembly of the heterodimer consisting of one α-tubulin polypeptide and one β-tubulin polypeptide (α/β-tubulin heterodimer) in vitro, on microtubule architecture in HeLa cells, on microtubule dynamics in yeast cells, and on spindle assembly in mouse and human oocytes. RESULTS We identified seven mutations in the primate-specific gene TUBB8 that were responsible for oocyte meiosis I arrest in 7 of the 24 families. TUBB8 expression is unique to oocytes and the early embryo, in which this gene accounts for almost all the expressed β-tubulin. The mutations affect chaperone-dependent folding and assembly of the α/β-tubulin heterodimer, disrupt microtubule behavior on expression in cultured cells, alter microtubule dynamics in vivo, and cause catastrophic spindle-assembly defects and maturation arrest on expression in mouse and human oocytes. CONCLUSIONS TUBB8 mutations have dominant-negative effects that disrupt microtubule behavior and oocyte meiotic spindle assembly and maturation, causing female infertility. (Funded by the National Basic Research Program of China and others.

Global urban environmental change drives adaptation in white clover

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale

Construction and evaluation of immune-related diagnostic model in patients with heart failure caused by idiopathic dilated cardiomyopathy

Abstract Objective The purpose of the study was to construct the potential diagnostic model of immune-related genes during the development of heart failure caused by idiopathic dilated cardiomyopathy. Method GSE5406 and GSE57338 were downloaded from the GEO website ( https://www.ncbi.nlm.nih.gov/geo/ ). CIBERSORT was used for the evaluation of immune infiltration in idiopathic dilated cardiomyopathy (DCM) of GSE5406. Differently expressed genes were calculated by the limma R package and visualized by the volcano plot. The immune-related genes were downloaded from Immport, TISIDB, and InnateDB. Then the immune-related differential genes (IRDGs) were acquired from the intersection. Protein–protein interaction network (PPI) and Cytoscape were used to visualize the hub genes. Three machine learning methods such as random forest, logical regression, and elastic network regression model were adopted to construct the prediction model. The diagnostic value was also validated in GSE57338. Results Our study demonstrated the obvious different ratio of T cell CD4 memory activated, T cell regulatory Tregs, and neutrophils between DCM and control donors. As many as 2139 differential genes and 274 immune-related different genes were identified. These genes were mainly enriched in lipid and atherosclerosis, human cytomegalovirus infection, and cytokine-cytokine receptor interaction. At the same time, as many as fifteen hub genes were identified as the IRDGs (IFITM3, IFITM2, IFITM1, IFIT3, IFIT1, HLA-A, HLA-B, HLA-C, ADAR, STAT1, SAMHD1, RSAD2, MX1, ISG20, IRF2). Moreover, we also discovered that the elastic network and logistic regression models had a higher diagnostic value than that of random forest models based on these hub genes. Conclusion Our study demonstrated the pivotal role of immune function during the development of heart failure caused by DCM. This study may offer new opportunities for the detection and intervention of immune-related DCM

Identification of the Potential Genes Regulating Seed Germination Speed in Maize

Seed germination is the crucial stage in plant life cycle. Rapid and uniform germination plays an essential role in plant development and grain yield improvement. However, the molecular mechanism underlying seed germination speed is largely unknown due to the complexity of the dynamic process and the difficulty in phenotyping. Here, we conducted a time-series comparative transcriptome study of two elite maize inbred lines, 72-3 and F9721, with striking difference in seed germination speed, and identified a major locus underlying maize germination speed through genome-wide association analysis (GWAS) of an F2 segregation population. Comparative transcriptome study identified 12 h after imbibition (HAI) as the critical stage responsible for the variation in germination speed. The differentially expressed genes (DEGs) between 72-3 and F9721 were mainly enriched in metabolic pathways, biosynthesis of secondary metabolites, oxidoreductase activity pathways, hormone signal transduction, and amino acid transporter activity pathways. GWAS revealed that germination speed was controlled by a major locus on chromosome 1 with the leading SNP as AX-91332814, explaining 10.63% of phenotypic variation. A total of 87 proposed protein-coding genes surrounding the locus were integrated with DEGs. Combined with evidence from the gene expression database and gene synteny with other model species, we finally anchored three genes as the likely candidates regulating germination speed in maize. This study provides clues for the further exploration of genes controlling the maize seed germination speed, thus facilitating breeding of rapid germinated elite lines through marker assistant selection

Evaluation of follicular synchronization caused by estrogen administration and its reproductive outcome.

To evaluate multiple follicular development synchronization after estrogen stimulation in prepubertal mice, follicular responsiveness to gonadotropin superovulation, the prospective reproductive potential and ovarian polycystic ovary syndrome (PCOS)-like symptoms at adulthood, prepubertal mice were intraperitoneally injected with estrogen to establish an animal model with solvent as control. When synchronized tertiary follicles in ovaries, in vitro oocyte maturation and fertilization rates, blastocyst formation rate, developmental potential into offspring by embryo transfer, adult fertility and PCOS-like symptoms, and involved molecular mechanisms were focused, it was found that estrogen stimulation (10 μg/gBW) leads to follicular development synchronization at the early tertiary stage in prepubertal mice; reproduction from oocytes to offspring could be realized by means of the artificial reproductive technology though the model mice lost their natural fertility when they were reared to adulthood; and typical symptoms of PCOS, except changes in inflammatory pathways, were not remained up to adulthood. So in conclusion, estrogen can lead to synchronization in follicular development in prepubertal mice, but does not affect reproductive outcome of oocytes, and no typical symptoms of PCOS remained at adulthood despite changes related to inflammation