Causal relationship between circulating immune cells and the risk of type 2 diabetes: a Mendelian randomization study.

Objectives: Though type 2 diabetes (T2D) has been known as a metabolic disease caused by multiple factors, the etiology remains insufficiently understood. Here, we aimed to figure out whether circulating immune cell profiles causally impact T2D liability. Methods: We applied one genome-wide association study (GWAS) summary statistics of blood traits in 563,085 participants from the Blood Cell Consortium and another GWAS of flow cytometric profile of lymphocyte subsets comprising 3,757 Sardinians to identify genetically predicted blood immune cells. We also obtained GWAS summary statistics in 898,130 individuals from the DIAGRAM Consortium to evaluate genetically predicted T2D. We primarily used inverse variance weighted (IVW) and weighted median methods to perform Mendelian randomization analyses and sensitivity analyses to evaluate heterogeneity and pleiotropy. Results: For circulating blood leukocyte and its subpopulations, the increase of genetically predicted circulating monocyte count was causally correlated with a higher risk of T2D [odds ratio (OR) = 1.06, 95% confidence interval (CI) = 1.02-1.10, p = 0.0048]. For lymphocyte subsets, CD8+ T cell and CD4+ CD8dim T cell count were identified with causal effect on T2D susceptibility (CD8+ T cell: OR = 1.09, 95% CI = 1.03-1.17, p = 0.0053; CD4+ CD8dim T cell: OR = 1.04, 95% CI = 1.01-1.08, p = 0.0070). No pleiotropy was determined. Conclusions: These findings demonstrated that higher circulating monocyte and T-lymphocyte subpopulation predicted increased T2D susceptibility, which confirmed the immunity predisposition for T2D. Our results may have the potential to provide new therapeutic targets for the diagnosis and treatment of T2D.

Comprehensive Analysis of APA Events and Their Association With Tumor Microenvironment in Lung Adenocarcinoma.

BACKGROUND: Alternative polyadenylation (APA) is a pervasive posttranscriptional mechanism regulating gene expression. However, the specific dysregulation of APA events and its potential biological or clinical significance in lung adenocarcinoma (LUAD) remain unclear. METHODS: Here, we collected RNA-Seq data from two independent datasets: GSE40419 (n = 146) and The Cancer Genome Atlas (TCGA) LUAD (n = 542). The DaPars algorithm was employed to characterize the APA profiles in tumor and normal samples. Spearman correlation was used to assess the effects of APA regulators on 3' UTR changes in tumors. The Cox proportional hazard model was used to identify clinically relevant APA events and regulators. We stratified 512 patients with LUAD in the TCGA cohort through consensus clustering based on the expression of APA factors. FINDINGS: We identified remarkably consistent alternative 3' UTR isoforms between the two cohorts, most of which were shortened in LUAD. Our analyses further suggested that aberrant usage of proximal polyA sites resulted in escape from miRNA binding, thus increasing gene expression. Notably, we found that the 3' UTR lengths of the mRNA transcriptome were correlated with the expression levels of APA factors. We further identified that CPSF2 and CPEB3 may serve as key regulators in both datasets. Finally, four LUAD subtypes according to different APA factor expression patterns displayed distinct clinical results and oncogenic features related to tumor microenvironment including immune, metabolic, and hypoxic status. INTERPRETATION: Our analyses characterize the APA profiles among patients with LUAD and identify two key regulators for APA events in LUAD, CPSF2 and CPEB3, which could serve as the potential prognostic genes in LUAD.

Identification of genes regulating ovary differentiation after pollination in hazel by comparative transcriptome analysis.

BACKGROUND: Hazel (Corylus spp.) exhibits ovary differentiation and development that is initiated from the ovary primordium after pollination, conferring the plant with a unique delayed fertilization. Failure of development of the ovary and ovule after pollination can lead to ovary abortion and blank fruit formation, respectively, with consequent yield loss. However, the genes involved in ovary and ovule differentiation and development are largely unknown. RESULTS: In unpollinated pistillate inflorescences (stage F), the stigma shows an extension growth pattern. After pollination, a rudimentary ovary begins to form (stage S), followed by ovule differentiation (stage T) and growth (stage FO). Total RNA was obtained from pistillate inflorescences or young ovaries at stage F, S, T and FO, and sequencing was carried out on a HiSeq 4000 system. De novo assembly of sequencing data yielded 62.58 Gb of nucleotides and 90,726 unigenes; 5524, 3468, and 8714 differentially expressed transcripts were identified in F-vs-S, S-vs-T, and T-vs-FO paired comparisons, respectively. An analysis of F-vs-S, S-vs-T, and T-vs-FO paired comparisons based on annotations in the Kyoto Encyclopedia of Genes and Genomes revealed six pathways that were significantly enriched during ovary differentiation, including ko04075 (Plant hormone signal transduction). Auxin level increased after pollination, and an immunohistochemical analysis indicated that auxin was enriched at the growth center of pistillate inflorescences and young ovaries. These results indicate that genes related to auxin biosynthesis, transport, signaling, the floral quartet model, and flower development may regulate ovary and ovule differentiation and development in hazel. CONCLUSIONS: Our findings provide insight into the molecular mechanisms of ovary differentiation and development after pollination in this economically valuable plant.

Effect of levosimendan on clinical outcomes in adult patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials.

It is currently unknown whether levosimendan can improve clinical outcomes in patients undergoing cardiac surgery. This meta-analysis aimed to assess the effect of levosimendan on mortality and the duration of intensive care unit (ICU) and hospital stay in adult patients undergoing cardiac surgery. A comprehensive search for eligible articles was conducted in PubMed, OVID and Cochrane databases of clinical trials and the Web of Science from database inception to August 2017. Stata/SE 11.0 was used to calculate the pooled odds ratio for postoperative mortality and the pooled standardized mean difference (SMD) for the duration of ICU stay and hospital stay. A total of 30 randomized controlled trials were included in the final analysis; the pooled results indicated that perioperative administration of levosimendan was associated with a reduction in postoperative mortality [5.8% vs 8.5%; odds ratio 0.66, 95% confidence interval 0.50-0.86, P = 0.002; I2 = 17.1%; 25 trials; 3239 patients] and length of ICU stay (SMD -0.32, 95% CI -0.58 to 0.06, P = 0.017; I2 = 88.0%; 23 trials; 2536 patients) compared with the control group but not in length of hospital stay (SMD -0.41, 95% CI -0.89 to 0.07, P = 0.094; I2 = 95.9%; 18 trials; 2047 patients). A subanalysis was conducted for trials published after 2015, and it suggested that levosimendan could not reduce the postoperative mortality (odds ratio = 0.91, 95% CI 0.63-1.31, P = 0.626; I2 = 0.9%), length of ICU stay (SMD -0.03, 95% CI -0.32 to 0.27, P = 0.850; I2 = 81.2%) or length of hospital stay (SMD 0.06, 95%CI -0.43 to 0.54, P = 0.821; I2 = 91.3%). To summarize, the evidence from studies published in the last 3 years indicated that perioperative administration of levosimendan was not associated with better clinical outcomes in adult patients undergoing cardiac surgery.

Comparative Transcriptome Analysis Reveal Candidate Genes Potentially Involved in Regulation of Primocane Apex Rooting in Raspberry (Rubus spp.).

Raspberries (Rubus spp.) exhibit a unique rooting process that is initiated from the stem apex of primocane, conferring an unusual asexual mode of reproduction to this plant. However, the full complement of genes involved in this process has not been identified. To this end, the present study analyzed the transcriptomes of the Rubus primocane and floricane stem apex at three developmental stages by Digital Gene Expression profiling to identify genes that regulate rooting. Sequencing and de novo assembly yielded 26.82 Gb of nucleotides and 59,173 unigenes; 498, 7,346, 4,110, 7,900, 9,397, and 4,776 differently expressed genes were identified in paired comparisons of SAF1 (floricane at developmental stage 1) vs. SAP1 (primocane at developmental stage 1), SAF2 vs. SAP2, SAF3 vs. SAP3, SAP1 vs. SAP2, SAP1 vs. SAP3, and SAP2 vs. SAP3, respectively. SAP1 maintains an extension growth pattern; SAP2 then exhibits growth arrest and vertical (downward) gravitropic deflection; and finally, short roots begin to form on the apex of SAP3. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis of SAP1 vs. SAP2 revealed 12 pathways that were activated in response to shoot growth arrest and root differentiation, including circadian rhythm-plant (ko04712) and plant hormone signal transduction (ko04075). Our results indicate that genes related to circadian rhythm, ethylene and auxin signaling, shoot growth, and root development are potentially involved in the regulation of primocane apex rooting in Rubus. These findings provide a basis for elucidating the molecular mechanisms of primocane apex rooting in this economically valuable crop.