Primary biliary cholangitis (PBC) is an autoimmune liver disease with a strong hereditary component. Here, we report a genome-wide association study that included 1,122 PBC cases and 4,036 controls of Han Chinese descent, with subsequent replication in a separate cohort of 907 PBC cases and 2,127 controls. Our results show genome-wide association of 14 PBC risk loci including previously identified 6p21 (HLA-DRA and DPB1), 17q12 (ORMDL3), 3q13.33 (CD80), 2q32.3 (STAT1/STAT4), 3q25.33 (IL12A), 4q24 (NF-κB) and 22q13.1 (RPL3/SYNGR1). We also identified variants in IL21, IL21R, CD28/CTLA4/ICOS, CD58, ARID3A and IL16 as novel PBC risk loci. These new findings and histochemical studies showing enhanced expression of IL21 and IL21R in PBC livers (particularly in the hepatic portal tracks) support a disease mechanism in which the deregulation of the IL21 signalling pathway, in addition to CD4 T-cell activation and T-cell co-stimulation are critical components in the development of PBC.
Working memory training has been widely used to investigate working memory processes. We have shown previously that visual working memory benefits only from intra-modal visual but not from across-modal auditory working memory training. In the present functional magnetic resonance imaging study we examined whether auditory working memory processes can also be trained specifically and which training-induced activation changes accompany theses effects. It was investigated whether working memory training with strongly distinct auditory materials transfers exclusively to an auditory (intra-modal) working memory task or whether it generalizes to a (across-modal) visual working memory task. We used adaptive n-back training with tonal sequences and a passive control condition. The memory training led to a reliable training gain. Transfer effects were found for the (intra-modal) auditory but not for the (across-modal) visual transfer task. Training-induced activation decreases in the auditory transfer task were found in two regions in the right inferior frontal gyrus. These effects confirm our previous findings in the visual modality and extents intra-modal effects in the prefrontal cortex to the auditory modality. As the right inferior frontal gyrus is frequently found in maintaining modality-specific auditory information, these results might reflect increased neural efficiency in auditory working memory processes. Furthermore, task-unspecific (amodal) activation decreases in the visual and auditory transfer task were found in the right inferior parietal lobule and the superior portion of the right middle frontal gyrus reflecting less demand on general attentional control processes. These data are in good agreement with amodal activation decreases within the same brain regions on a visual transfer task reported previously.
Background: Cesarean section (CS) rate has risen dramatically and stayed at a very high level in China over the past two to three decades. Given the short-and long-term adverse effects of CS, effective strategies are needed to reduce unnecessary CS. We aimed to evaluate whether a multifaceted intervention would decrease the CS rate in China. Methods:We carried out a cluster-randomized field trial with a multifaceted intervention in Shanghai, China, from 2015 to 2017. A total of 20 hospitals were randomly allocated into an intervention or a control group. The intervention consisted of more targeted health education to pregnant women, improved hospital CS policy, and training of midwives/doulas for 8 months. The study included a baseline survey, the intervention, and an evaluation survey. The primary outcome was the changes of overall CS rate from the pre-intervention to the post-intervention period. A subgroup analysis stratified by the Robson classification was also conducted to examine the CS change among women with various obstetric characteristics.Results: A total of 10,752 deliveries were randomly selected from the pre-intervention period and 10,521 from the post-intervention period. The baseline CS rates were 42.5% and 41.5% in the intervention and control groups, respectively, while the post-intervention CS rates were 43.4% and 42.4%, respectively. Compared with the control group, the intervention did not significantly reduce the CS rate (adjusted OR = 0.92; 95% CI 0.73, 1.15). Similar results were obtained in subgroup analyses stratified by the risk level of pregnancy, maternal age, number of previous CS, or parity. Scarred uterus and maternal request remained the primary reasons for CS after the interventions in both groups. The intervention did not alter the perinatal outcomes (adjusted change of risk score = − 0.06; 95%CI − 0.43, 0.31). Conclusions: A multifaceted intervention including more targeted prenatal health education, improved hospital CS policy, and training of midwives/doulas, did not significantly reduce the CS rate in Shanghai, China. However, our experience in implementing a multifaceted intervention may provide useful information to other similar areas with high CS use. Trial registration: This trial was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn) (ChiCTR-IOR-16009041) on 17 August 2016.
The human insulin-like growth factor-II (IGF-II) gene transcribes four mRNAs (P1 mRNA-P4 mRNA), and P3 mRNA overexpression contributes to hepatocarcinogenesis. IGF-II-derived miR-483-5p is implicated in the development of cancers. Here, we investigated the involvement of miR-483-5p in P3 mRNA overexpression regulation and its role in hepatocellular carcinoma. Our results showed that miR-483-5p up-regulated P3 mRNA transcription by targeting the 5′-untranslated region (5′UTR) of P3 mRNA in hepatocellular carcinoma. The mechanism was involved in recruiting of an argonaute 1(Ago1)-argonaute 2 (Ago2) complex to the P3 mRNA 5′UTR and the P3 promoter of IGF-II gene by miR-483-5p, accompanied by increased enrichment of RNA polymerase II and activating histone marks histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 27 acetylation (H3K27ac), and histone 4 lysine 5/8/12/16 acetylation (H4Kac) at the P3 promoter. High miR-483-5p expression was an independent predictor for shorter survival of HCC patients. The findings suggest that miR-483-5p promotes P3 mRNA transcription by recruiting the Ago1-Ago2 complex to the P3 mRNA 5′UTR and is associated with poor prognosis of HCC. Our results display a potential new model for miRNAs to up-regulate gene expression.
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