Notes

Potent Lys Patch-Containing Stapled Proteins Focusing on PCSK9.
As a result, although there are various discussions, there appear to be differences in ovarian cancer risk by population and BRCA mutation location. If it becomes possible to estimate the risk of developing BRCA-related cancer for each BRCA mutation type, the age at risk-reducing salpingo-oophorectomy can be determined individually. see more The decision would bring great benefits to young women with germline BRCA mutations.
Thousands of genetic variants have been associated with hematological traits, though target genes remain unknown at most loci. Moreover, limited analyses have been conducted in African ancestry and Hispanic/Latino populations; hematological trait associated variants more common in these populations have likely been missed.

To derive gene expression prediction models, we used ancestry-stratified datasets from the Multi-Ethnic Study of Atherosclerosis (MESA, including
= 229 African American and
= 381 Hispanic/Latino participants, monocytes) and the Depression Genes and Networks study (DGN,
= 922 European ancestry participants, whole blood). We then performed a transcriptome-wide association study (TWAS) for platelet count, hemoglobin, hematocrit, and white blood cell count in African (
= 27,955) and Hispanic/Latino (
= 28,324) ancestry participants.

Our results revealed 24 suggestive signals (
< 1 × 10
) that were conditionally distinct from known GWAS identified variants and successfully replicated these signals in European ancestry subjects from UK Biobank. We found modestly improved correlation of predicted and measured gene expression in an independent African American cohort (the Genetic Epidemiology Network of Arteriopathy (GENOA) study (
= 802), lymphoblastoid cell lines) using the larger DGN reference panel; however, some genes were well predicted using MESA but not DGN.

These analyses demonstrate the importance of performing TWAS and other genetic analyses across diverse populations and of balancing sample size and ancestry background matching when selecting a TWAS reference panel.
These analyses demonstrate the importance of performing TWAS and other genetic analyses across diverse populations and of balancing sample size and ancestry background matching when selecting a TWAS reference panel.Copy number variations (CNVs) can modulate phenotypes by affecting protein-coding sequences directly or through interference of gene expression. Recent studies in cancer and limb defects pinpointed the relevance of non-coding gene regulatory elements such as long non-coding RNAs (lncRNAs) and topologically associated domain (TAD)-related gene-enhancer interactions. The contribution of such non-coding elements is largely unexplored in congenital heart defects (CHD). We performed a retrospective analysis of CNVs reported in a cohort of 270 CHD patients. We reviewed the diagnostic yield of pathogenic CNVs, and performed a comprehensive reassessment of 138 CNVs of unknown significance (CNV-US), evaluating protein-coding genes, lncRNA genes, and potential interferences with TAD-related gene-enhancer interactions. Fifty-two of the 138 CNV-US may relate to CHD, revealing three candidate CHD regions, 19 candidate CHD genes, 80 lncRNA genes of interest, and six potentially CHD-related TAD interferences. Our study thus indicates a potential relevance of non-coding gene regulatory elements in CNV-related CHD pathogenesis. Shortcomings in our current knowledge on genomic variation call for continuous reporting of CNV-US in international databases, careful patient counseling, and additional functional studies to confirm these preliminary findings.Recent advances in understanding the genetic causes and anatomic subtypes of cardiac defects have revealed new links between genetic etiology, pathogenetic mechanisms and cardiac phenotypes. Although the same genetic background can result in different cardiac phenotypes, and similar phenotypes can be caused by different genetic causes, researchers' effort to identify specific genotype-phenotype correlations remains crucial. In this review, we report on recent advances in the cardiac pathogenesis of three genetic diseases Down syndrome, del22q11.2 deletion syndrome and Ellis-Van Creveld syndrome. In these conditions, the frequent and specific association with congenital heart defects and the recent characterization of the underlying molecular events contributing to pathogenesis provide significant examples of genotype-phenotype correlations. Defining these correlations is expected to improve diagnosis and patient stratification, and it has relevant implications for patient management and potential therapeutic options.Genetically engineered (GE) pigs with various combinations of genetic profiles have been developed using heterologous promoters. This study aimed to identify autologous promoters for high and ubiquitous expression of xenotransplantation relevant genes in GE pigs. A 1.4 kb upstream regulatory sequence of porcine elongation factor 1α (pEF1α) gene was selected and isolated for use as a promoter. Activity of the pEF1α promoter was subsequently compared with that of the cytomegalovirus (CMV) promoter, CMV enhancer/chicken β-actin (CAG) promoter, and human EF1α (hEF1α) promoter in different types of pig-derived cells. Comparative analysis of luciferase and mutant human leukocyte antigen class E-F2A-β-2 microglobulin (HLA-E) expression driven by pEF1α, CMV, CAG, and hEF1α promoters revealed the pEF1α promoter mediated comparable expression levels with those of the CAG promoter in porcine ear skin fibroblasts (PEFs) and porcine kidney-15 (PK-15) cells, but lower than those of the CAG promoter in porcine aortic endothelial cells (PAECs). The pEF1α promoter provided long-term stable HLA-E expression in PEFs, but the CAG promoter failed to sustain those levels of expression. For xenogeneic serum-induced cytotoxicity assays, the cells were cultured for several hours in growth medium supplemented with primate serum. Notably, the pEF1α promoter induced significant increases in luciferase and HLA-E expression in response to primate serum in PAECs compared with those driven by the CAG promoter, suggesting the pEF1α promoter could regulate temporal expression of heterologous genes under xenogeneic-cytotoxic conditions. These results suggest the pEF1α promoter may be valuable for development of GE pigs spatiotemporally and stably expressing immunomodulatory genes for xenotransplantation.Cottonseed oil is rich in unsaturated fatty acids (UFAs) and serves as an edible oil in human nutrition. Reports suggest that acyl-coenzyme A diacylglycerol acyltransferases (DGAT) and wax ester synthase/DGAT (WSD1) genes encode a key group of enzymes that catalyze the final step for triacylglycerol biosynthesis and enable an important rate-limiting process. However, their roles in oil biosynthesis and the fatty acid profile of cotton seed are poorly understood. Therefore, the aim of this study was to identify and characterize DGAT and WSD1 genes in cotton plants and examine their roles in oil biosynthesis, the fatty acid profile of cotton seeds, and abiotic stress responses. In this study, 36 GhDGAT and GhWSD1 genes were identified in upland cotton (G. hirsutum) and found to be clustered into four groups GhDGAT1, GhDGAT2, GhDGAT3, and GhWSD1. Gene structure and domain analyses showed that the GhDGAT and GhWSD1 genes in each group are highly conserved. Gene synteny analysis indicated that segmental and tandem duplication events occurred frequently during cotton evolution. Expression analysis revealed that GhDGAT and GhWSD1 genes function widely in cotton development and stress responses; moreover, several environmental stress and hormone response-related cis-elements were detected in the GhDGAT and GhWSD1 promoter regions. The predicted target transcription factors and miRNAs imply an extensive role of GhDGAT and GhWSD1 genes in stress responses. Increases in GhDGAT3 gene expression with increases in cottonseed oil accumulation were observed. Transformation study results showed that there was an increase in C181 content and a decrease in C182 and C183 contents in seeds of Arabidopsis transgenic plants overexpressing GhDGAT3D compared with that of control plants. Overall, these findings contributed to the understanding of the functions of GhDGAT and GhWSD1 genes in upland cotton, providing basic information for further research.Circular RNAs (circRNAs) are transcripts generated by back-splicing. CircRNAs might regulate cellular processes by different mechanisms, including interaction with miRNAs and RNA-binding proteins. CircRNAs are pleiotropic molecules whose dysregulation has been linked to human diseases and can drive cancer by impacting gene expression and signaling pathways. The detection of circRNAs aberrantly expressed in disease conditions calls for the investigation of their functions. Here, we propose CircIMPACT, a bioinformatics tool for the integrative analysis of circRNA and gene expression data to facilitate the identification and visualization of the genes whose expression varies according to circRNA expression changes. This tool can highlight regulatory axes potentially governed by circRNAs, which can be prioritized for further experimental study. The usefulness of CircIMPACT is exemplified by a case study analysis of bladder cancer RNA-seq data. The link between circHIPK3 and heparanase (HPSE) expression, due to the circHIPK3-miR558-HPSE regulatory axis previously determined by experimental studies on cell lines, was successfully detected. CircIMPACT is freely available at GitHub.Hearing loss (HL) is the most frequent sensory disorder, affecting about 1-3 per 1000 live births, with more than half of the cases attributable to genetic causes. Despite the fact that many HL causative genes have already been identified, current genetic tests fail to provide a diagnosis for about 40% of the patients, suggesting that other causes still need to be discovered. Here, we describe a four-generation Italian family affected by autosomal dominant non-syndromic hearing loss (ADNSHL), in which exome sequencing revealed a likely pathogenic variant in NCOA3 (NM_181659.3, c.2909G>C, p.(Gly970Ala)), a gene recently described as a novel candidate for ADNSHL in a Brazilian family. A comparison between the two families highlighted a series of similarities both the identified variants are missense, localized in exon 15 of the NCOA3 gene and lead to a similar clinical phenotype, with non-syndromic, sensorineural, bilateral, moderate to profound hearing loss, with a variable age of onset. Our findings (i.e., the identification of the second family reported globally with HL caused by a variant in NCOA3) further support the involvement of NCOA3 in the etiopathogenesis of ADNSHL, which should, thus, be considered as a new gene for autosomal dominant non-syndromic hearing loss.Pedigree information is necessary for the maintenance of diversity for wild and captive populations. Accurate pedigree is determined by molecular marker-based parentage analysis, which may be influenced by the polymorphism and number of markers, integrity of samples, relatedness of parents, or different analysis programs. Here, we described the first development of 208 single nucleotide polymorphisms (SNPs) and 11 microsatellites for giant grouper (Epinephelus lanceolatus) taking advantage of Genotyping-by-sequencing (GBS), and compared the power of SNPs and microsatellites for parentage and relatedness analysis, based on a mixed family composed of 4 candidate females, 4 candidate males and 289 offspring. CERVUS, PAPA and COLONY were used for mutually verification. We found that SNPs had a better potential for relatedness estimation, exclusion of non-parentage and individual identification than microsatellites, and > 98% accuracy of parentage assignment could be achieved by 100 polymorphic SNPs (MAF cut-off less then 0.
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