Suppression of GATA3 promotes epithelial-mesenchymal transition and simultaneous cellular senescence in human extravillous trophoblasts.

The regulatory mechanism of the transcription factor GATA3 in the differentiation and maturation process of extravillous trophoblasts (EVT) in early pregnancy placenta, as well as its relevance to the occurrence of pregnancy disorders, remains poorly understood. This study leveraged single-cell RNA sequencing data from placental organoid models and placental tissue to explore the dynamic changes in GATA3 expression during EVT maturation. The expression pattern exhibited an initial upregulation followed by subsequent downregulation, with aberrant GATA3 localization observed in cases of recurrent miscarriage (RM). By identifying global targets regulated by GATA3 in primary placental EVT cells, JEG3, and HTR8/SVneo cell lines, this study offered insights into its regulatory mechanisms across different EVT cell models. Shared regulatory targets among these cell types and activation of trophoblast cell marker genes emphasized the importance of GATA3 in EVT differentiation and maturation. Knockdown of GATA3 in JEG3 cells led to repression of GATA3-induced epithelial-mesenchymal transition (EMT), as evidenced by changes in marker gene expression levels and enhanced migration ability. Additionally, interference with GATA3 accelerated cellular senescence, as indicated by reduced proliferation rates and increased activity levels for senescence-associated ß-galactosidase enzyme, along with elevated expression levels for senescence-associated genes. This study provides comprehensive insights into the dual role of GATA3 in regulating EMT and cellular senescence during EVT differentiation, shedding light on the dynamic changes in GATA3 expression in normal and pathological placental conditions.

Whole-exome sequencing reveals mutational profiles of anorectal and gynecological melanoma.

Mucosal melanoma is a rare and highly malignant type of melanoma. Among the sites that mucosal melanoma arises, anorectal and gynecological melanoma has more aggressive behavior and worse prognosis. There was no effective therapy for mucosal melanoma at present. Only a small number of mucosal melanoma patients which harbor mutations in BRAF or KIT benefit from targeted therapy. So it's an urgent need to identify more actionable mutations in mucosal melanoma. To identify more potential therapeutic targets in mucosal melanoma, 48 samples were collected from 44 patients with anorectal or gynecological melanoma and subjected to whole-exome sequencing. The tumor mutation burden was low with a median of 1.75 mutations per Mb. In chromosomal level, 1q, 6p and 8q of mucosal melanoma were significantly amplified while 9p, 10p, 10q, 16p and 16q were significantly deleted. Muc16 was the most frequently mutated oncogene in our samples(25%). The mutation frequency of KIT(20%) was comparable to the "triple-wild" genes-NRAS(20%), NF1(20%), and BRAF(11%). KMT2D mutation was found in 18.18% patients, which is previously unidentified. MAPK signaling pathway and lysine degradation were the most frequently mutated pathways. Moreover, patients with TP53 mutations tend to have worse clinical outcome (median survival time 19 vs. 50 months, log-rank P = 0.006). 2000 ore mutated genes involved in MAPK signaling pathway were identified, which expand the patients potentially benefit from ample MAPK inhibitors. KMT2D could be a potential therapeutic target. Moreover, TP53 could be a potential prognosis marker for mucosal melanoma.

Correlation between inflammatory marker and lipid metabolism in patients with uterine leiomyomas.

Introduction: Obesity is a risk factor for the development of uterine leiomyoma (UL), and the inflammatory response plays a key role in the pathogenesis of UL. Our objective was to assess whether there was an independent relationship between inflammatory markers and triglycerides (TG) in patients with UL. Methods: 1,477 UL participants who were hospitalized at the Jining Medical University between January 2016 and December 2022 were included in this cross-sectional study. The independent and dependent variables measured at baseline were inflammatory markers and TG levels, respectively. The covariates were age, body mass index (BMI), UL and menstrual status. Based on the number of fibroids, the study population was divided into Single-group and Multiple-group. Results: Univariate and multiple regression analyses and stratified analyses revealed significant positive correlations between neutrophil-lymphocyte ratio and systemic immune inflammation index and TG, and significant negative correlations between monocyte-lymphocyte ratio and TG. Conclusion: The findings show a significant correlation between the inflammatory response and lipid metabolism levels in UL patients. This provides direction for further research into the pathophysiology of UL and also helps to formulate hypotheses for predictive models of UL.

Correlation Between Platelet-Lymphocyte Ratio and Neutrophil-Lymphocyte Ratio in Patients with Uterine Leiomyoma: A Cross-Sectional Study.

The inflammatory reaction has been proven to be a key factor in the pathogenesis of uterine leiomyoma. The platelet-lymphocyte ratio (PLR) and the neutrophil-lymphocyte ratio (NLR) are inexpensive and reliable inflammatory biomarkers. However, evidence of the relationship between PLR and NLR in patients with uterine leiomyoma is limited. This study aimed to explore the relationship between PLR and NLR in patients with incident uterine leiomyoma. This cross-sectional study included 763 patients with uterine leiomyoma who were first diagnosed in our hospital between January 2016 and December 2016. Patient characteristics were collected for univariate analysis, smooth curve fitting, and multivariate piecewise linear regression. Overall, 722 patients with an average age of 40.16 ± 5.99 years were included. The average PLR was 161.22 ± 65.33. Univariate analysis revealed a significant positive correlation between PLR and NLR (P < 0.0001). In addition, the non-linear relationship between the PLR and NLR was tested using smooth curve fitting after adjusting for potential confounding factors. The multivariate piecewise linear regression model showed that there was a significant positive correlation between PLR and NLR in both PLR <226.45 (ß 0.01, 95% CI: 0.01, 0.01;P < 0.0001) and >226.45 (ß 0.00, 95% CI: 0.00, 0.00; P=0.0026). In conclusion, PLR and NLR are positively correlated in patients with uterine leiomyoma. This result clarifies the promoting role of inflammation in the occurrence of uterine leiomyoma.

Spatiotemporal Trends of Legacy and Alternative Flame Retardants in Harbor Seals from the Coasts of California, the Gulf of Maine, and Sweden.

Temporal trends of polybrominated diphenyl ethers (PBDEs) have been extensively studied in various environmental compartments globally. However, despite the increasing use of alternative flame retardants following PBDE bans, the spatiotemporal trends of these replacements have rarely been studied, and the available results are often inconsistent. In the present study, we retrospectively investigated the spatiotemporal trends of PBDEs and a suite of alternative brominated FRs (aBFRs) and chlorinated FRs (i.e., dechloranes or DECs) in three harbor seal (Phoca vitulina) populations from the coasts of California, the Gulf of Maine, and southern Sweden during 1999-2016. We observed significantly decreasing trends of ΣPBDEs in all the three populations at an annual rate of 9-11%, which were predominantly driven by the declining concentrations of tetra- and penta-BDEs. The levels of ΣaBFRs decreased significantly in seals from California (mainly 1,3,5-tribromobenzene) and Sweden (mainly hexabromobenzene), while no trend was observed for those from Maine. By contrast, DECs (dominated by DEC 602) did not decrease significantly in any population. Compared with the consistent PBDE congener profiles across regions, aBFRs and DECs exhibited varying compositional profiles between regions, likely indicating region-specific sources of these alternative FR mixtures. Spatial analysis also revealed regional differences in the concentrations of PBDEs, aBFRs, and DECs in harbor seals. Our reconstructed spatiotemporal trends suggest the effective regulation of commercial penta-BDE mix in these regions and warrant further monitoring of the higher brominated BDEs and alternative FRs.

Spatial Distribution and Congener Profiles of Polybrominated Diphenyl Ethers in Surface Sediment from Sanmen Bay and Xiamen Bay, Southeast China.

Coastal areas are influenced by anthropogenic input of a variety of organic pollutants, among which polybrominated diphenyl ethers (PBDEs) represent an important group. In the present study, we investigated the contamination status of PBDEs in surface sediment from two economically important Bays in Southeast China, Sanmen Bay (SMB; n = 29) and Xiamen Bay (XMB; n = 10). Concentrations of ∑PBDEs ranged from 2.2 to 78.5 ng/g dw (median 5.7 ng/g dw) in SMB and 7.9-276.0 ng/g dw (median 43.5 ng/g dw) in XMB, respectively. A nearshore-offshore decreasing trend was observed for both ∑PBDEs and BDE-209 concentrations, indicating strong urban influences. Although the current levels would not produce any significant impact on benthos and aquatic ecosystems of the studied regions, continuous monitoring is needed to understand the temporal trends of contamination in the important coastal waters and whether sediment-associated PBDEs constitute a potential source to aquatic ecosystems.

Polyhalogenated Carbazoles in Surface Sediment from Sanmen Bay, East China Sea: Spatial Distribution and Congener Profile.

Polyhalogenated carbazoles (PHCZs) have recently emerged as a group of halogenated pollutants with broad occurrences and bioaccumulation potential in aquatic systems. However, investigations on their occurrences in coastal waters remain very limited. In the present study we investigated PHCZs in surface sediment collected from 29 sites in Sanmen Bay, East China Sea. The results demonstrated a universal presence of PHCZs in sediment, with concentrations of ∑PHCZs (including all congeners) ranging from 7.7 to 17.5 ng/g dry weight (median: 11.3 ng/g dw). The PHCZ congener composition profile revealed a dominance of 3,6-dichlorocarbazole (36-CCZ) with comparable concentration with that of carbazole. Given that PHCZs are widely distributed in Sanmen Bay sediment and their concentrations rivaled other well-known persistent organic pollutants in the same area, this group of halogenated pollutants merits additional investigations of their potential risks to the studied aquatic system, as well as other important watersheds.

In vivo acquired sorafenib-resistant patient-derived tumor model displays alternative angiogenic pathways, multi-drug resistance and chromosome instability.

Acquired resistance to targeted therapies is an important clinical challenge. Research focusing on acquired resistance is hindered by the lack of relevant model systems. In the present study, the generation and characterization of an in vivo acquired sorafenib-resistant hepatocellular carcinoma (HCC) xenograft model derived from a patient tumor is reported. A cancer cell line (LIXC-004SR) was generated from a tumor that had developed following ~100 days of sorafenib treatment of a HCC patient-derived xenograft (PDX) model (LIX004). The xenograft tumors derived from this cell line demonstrated sorafenib-resistance in vivo. By contrast, a cell line (LIXC-004NA) generated from a vehicle-treated LIX004 PDX model remained sensitive to sorafenib in vivo. Following treatment with sorafenib in vivo, angiogenesis was significantly elevated in the LIXC-004SR tumors when compared with that in the LIXC-004NA tumors. The LIXC-004SR cell culture supernatant stimulated human umbilical vein endothelial cell proliferation and extracellular-signal-regulated kinase and protein kinase B phosphorylation, which can only be inhibited by the combination of sorafenib and a fibroblast growth factor receptor 1 (FGFR1) inhibitor, AZD4547. The tumor growth of the sorafenib-resistant LIXC-004SR xenograft was inhibited by the FGFR1 inhibitor in vivo, suggesting that one of the underlying mechanisms of the acquired resistance is likely due to activation of alternative angiogenic pathways. The LIXC-004SR cell line also exhibited signs of multi-drug resistance and genetic instability. Taken together, these data suggest that this in vivo model of acquired resistance from a PDX model may reflect sorafenib-resistance in certain patients and may facilitate drug resistance research, as well as contributing to the clinical prevention and management of drug resistance.

OsSPL13 controls grain size in cultivated rice.

Although genetic diversity has a cardinal role in domestication, abundant natural allelic variations across the rice genome that cause agronomically important differences between diverse varieties have not been fully explored. Here we implement an approach integrating genome-wide association testing with functional analysis on grain size in a diverse rice population. We report that a major quantitative trait locus, GLW7, encoding the plant-specific transcription factor OsSPL13, positively regulates cell size in the grain hull, resulting in enhanced rice grain length and yield. We determine that a tandem-repeat sequence in the 5' UTR of OsSPL13 alters its expression by affecting transcription and translation and that high expression of OsSPL13 is associated with large grains in tropical japonica rice. Further analysis indicates that the large-grain allele of GLW7 in tropical japonica rice was introgressed from indica varieties under artificial selection. Our study demonstrates that new genes can be effectively identified on the basis of genome-wide association data.

Genetic discovery for oil production and quality in sesame.

Oilseed crops are used to produce vegetable oil. Sesame (Sesamum indicum), an oilseed crop grown worldwide, has high oil content and a small diploid genome, but the genetic basis of oil production and quality is unclear. Here we sequence 705 diverse sesame varieties to construct a haplotype map of the sesame genome and de novo assemble two representative varieties to identify sequence variations. We investigate 56 agronomic traits in four environments and identify 549 associated loci. Examination of the major loci identifies 46 candidate causative genes, including genes related to oil content, fatty acid biosynthesis and yield. Several of the candidate genes for oil content encode enzymes involved in oil metabolism. Two major genes associated with lignification and black pigmentation in the seed coat are also associated with large variation in oil content. These findings may inform breeding and improvement strategies for a broad range of oilseed crops.

The draft genome of the grass carp (Ctenopharyngodon idellus) provides insights into its evolution and vegetarian adaptation.

The grass carp is an important farmed fish, accounting for ∼16% of global freshwater aquaculture, and has a vegetarian diet. Here we report a 0.9-Gb draft genome of a gynogenetic female adult and a 1.07-Gb genome of a wild male adult. Genome annotation identified 27,263 protein-coding gene models in the female genome. A total of 114 scaffolds consisting of 573 Mb are anchored on 24 linkage groups. Divergence between grass carp and zebrafish is estimated to have occurred 49-54 million years ago. We identify a chromosome fusion in grass carp relative to zebrafish and report frequent crossovers between the grass carp X and Y chromosomes. We find that transcriptional activation of the mevalonate pathway and steroid biosynthesis in liver is associated with the grass carp's adaptation from a carnivorous to an herbivorous diet. We believe that the grass carp genome could serve as an initial platform for breeding better-quality fish using a genomic approach.

Genomic analysis of hybrid rice varieties reveals numerous superior alleles that contribute to heterosis.

Exploitation of heterosis is one of the most important applications of genetics in agriculture. However, the genetic mechanisms of heterosis are only partly understood, and a global view of heterosis from a representative number of hybrid combinations is lacking. Here we develop an integrated genomic approach to construct a genome map for 1,495 elite hybrid rice varieties and their inbred parental lines. We investigate 38 agronomic traits and identify 130 associated loci. In-depth analyses of the effects of heterozygous genotypes reveal that there are only a few loci with strong overdominance effects in hybrids, but a strong correlation is observed between the yield and the number of superior alleles. While most parental inbred lines have only a small number of superior alleles, high-yielding hybrid varieties have several. We conclude that the accumulation of numerous rare superior alleles with positive dominance is an important contributor to the heterotic phenomena.

A haplotype map of genomic variations and genome-wide association studies of agronomic traits in foxtail millet (Setaria italica).

Foxtail millet (Setaria italica) is an important grain crop that is grown in arid regions. Here we sequenced 916 diverse foxtail millet varieties, identified 2.58 million SNPs and used 0.8 million common SNPs to construct a haplotype map of the foxtail millet genome. We classified the foxtail millet varieties into two divergent groups that are strongly correlated with early and late flowering times. We phenotyped the 916 varieties under five different environments and identified 512 loci associated with 47 agronomic traits by genome-wide association studies. We performed a de novo assembly of deeply sequenced genomes of a Setaria viridis accession (the wild progenitor of S. italica) and an S. italica variety and identified complex interspecies and intraspecies variants. We also identified 36 selective sweeps that seem to have occurred during modern breeding. This study provides fundamental resources for genetics research and genetic improvement in foxtail millet.

The draft genome of the fast-growing non-timber forest species moso bamboo (Phyllostachys heterocycla).

Bamboo represents the only major lineage of grasses that is native to forests and is one of the most important non-timber forest products in the world. However, no species in the Bambusoideae subfamily has been sequenced. Here, we report a high-quality draft genome sequence of moso bamboo (P. heterocycla var. pubescens). The 2.05-Gb assembly covers 95% of the genomic region. Gene prediction modeling identified 31,987 genes, most of which are supported by cDNA and deep RNA sequencing data. Analyses of clustered gene families and gene collinearity show that bamboo underwent whole-genome duplication 7-12 million years ago. Identification of gene families that are key in cell wall biosynthesis suggests that the whole-genome duplication event generated more gene duplicates involved in bamboo shoot development. RNA sequencing analysis of bamboo flowering tissues suggests a potential connection between drought-responsive and flowering genes.

A map of rice genome variation reveals the origin of cultivated rice.

Crop domestications are long-term selection experiments that have greatly advanced human civilization. The domestication of cultivated rice (Oryza sativa L.) ranks as one of the most important developments in history. However, its origins and domestication processes are controversial and have long been debated. Here we generate genome sequences from 446 geographically diverse accessions of the wild rice species Oryza rufipogon, the immediate ancestral progenitor of cultivated rice, and from 1,083 cultivated indica and japonica varieties to construct a comprehensive map of rice genome variation. In the search for signatures of selection, we identify 55 selective sweeps that have occurred during domestication. In-depth analyses of the domestication sweeps and genome-wide patterns reveal that Oryza sativa japonica rice was first domesticated from a specific population of O. rufipogon around the middle area of the Pearl River in southern China, and that Oryza sativa indica rice was subsequently developed from crosses between japonica rice and local wild rice as the initial cultivars spread into South East and South Asia. The domestication-associated traits are analysed through high-resolution genetic mapping. This study provides an important resource for rice breeding and an effective genomics approach for crop domestication research.

Genome-wide association study of flowering time and grain yield traits in a worldwide collection of rice germplasm.

A high-density haplotype map recently enabled a genome-wide association study (GWAS) in a population of indica subspecies of Chinese rice landraces. Here we extend this methodology to a larger and more diverse sample of 950 worldwide rice varieties, including the Oryza sativa indica and Oryza sativa japonica subspecies, to perform an additional GWAS. We identified a total of 32 new loci associated with flowering time and with ten grain-related traits, indicating that the larger sample increased the power to detect trait-associated variants using GWAS. To characterize various alleles and complex genetic variation, we developed an analytical framework for haplotype-based de novo assembly of the low-coverage sequencing data in rice. We identified candidate genes for 18 associated loci through detailed annotation. This study shows that the integrated approach of sequence-based GWAS and functional genome annotation has the potential to match complex traits to their causal polymorphisms in rice.

Genome-wide association studies of 14 agronomic traits in rice landraces.

Uncovering the genetic basis of agronomic traits in crop landraces that have adapted to various agro-climatic conditions is important to world food security. Here we have identified ∼ 3.6 million SNPs by sequencing 517 rice landraces and constructed a high-density haplotype map of the rice genome using a novel data-imputation method. We performed genome-wide association studies (GWAS) for 14 agronomic traits in the population of Oryza sativa indica subspecies. The loci identified through GWAS explained ∼ 36% of the phenotypic variance, on average. The peak signals at six loci were tied closely to previously identified genes. This study provides a fundamental resource for rice genetics research and breeding, and demonstrates that an approach integrating second-generation genome sequencing and GWAS can be used as a powerful complementary strategy to classical biparental cross-mapping for dissecting complex traits in rice.