Hayesfranck0183
Biallelic mutations in the PTF1A enhancer are the commonest cause of isolated pancreatic agenesis. These patients do not have severe neurological features associated with loss-of-function PTF1A mutations. Their clinical phenotype and disease progression have not been well characterized.
To evaluate phenotype and genotype characteristics and long-term follow-up of patients with PTF1A enhancer mutations.
Twelve tertiary pediatric endocrine referral centers.
Thirty patients with diabetes caused by PTF1A enhancer mutations. Median follow-up duration was 4 years.
Presenting and follow-up clinical (birthweight, gestational age, symptoms, auxology) and biochemical (pancreatic endocrine and exocrine functions, liver function, glycated hemoglobin) characteristics, pancreas imaging, and genetic analysis.
Five different homozygous mutations affecting conserved nucleotides in the PTF1A distal enhancer were identified. The commonest was the Chr10g.23508437A>G mutation (n = 18). Two patients were homozygous urrent extrapancreatic features which likely reflect long-term intestinal malabsorption.
Numerous studies have shown that cardiovascular disease (CVD) represents the most important cause of mortality among people with diabetes mellitus (DM). However, no studies have evaluated the risk of CVD-related mortality among different DM subgroups.
We aimed to examine all-cause, CVD-related, and cancer-related mortality for different DM subgroups.
We included participants (age ≥ 20 years) from the National Health and Nutrition Examination Survey III (NHANES III) data set. We evaluated the risks of all-cause and cause-specific (CVD and cancer) mortality among 5 previously defined diabetes subgroups severe autoimmune diabetes (SAID), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD).
The hazard ratios (HRs) for all-cause and cause-specific (CVD and cancer) mortality were measured for each of the 5 DM subgroups. We also evaluated the odds ratios (ORs) for retinopathy and nephropathy in each subgo have a higher CVD-related mortality than the MOD subgroup. The all-cause and cancer-related mortality rates were similar across the different diabetes subgroups. In addition, compared to the MARD subgroup, the SAID and SIDD subgroups had a higher retinopathy risk, but there was no difference in nephropathy among the subgroups.
Our study of patients from the NHANES III data set indicated that among the different DM subgroups, the MARD subgroup tended to have a higher CVD-related mortality than the MOD subgroup. The all-cause and cancer-related mortality rates were similar across the different diabetes subgroups. In addition, compared to the MARD subgroup, the SAID and SIDD subgroups had a higher retinopathy risk, but there was no difference in nephropathy among the subgroups.Plasmodium falciparum, the human malaria parasite harbors a metastable proteome which is vulnerable to proteotoxic stress conditions encountered during its lifecycle. How parasite's chaperone machinery is able to maintain its aggregation-prone proteome in functional state, is poorly understood. As HSP70-40 system forms the central hub in cellular proteostasis, we investigated the protein folding capacity of PfHSP70-1 and PfHSP40 chaperone pair and compared it with human orthologs (HSPA1A and DNAJA1). Despite the structural similarity, we observed that parasite chaperones and their human orthologs exhibit striking differences in conformational dynamics. Comprehensive biochemical investigations revealed that PfHSP70-1 and PfHSP40 chaperone pair has better protein folding, aggregation inhibition, oligomer remodeling and disaggregase activities than their human orthologs. Chaperone-swapping experiments suggest that PfHSP40 can also efficiently cooperate with human HSP70 to facilitate the folding of client-substrate. SPR-derived kinetic parameters reveal that PfHSP40 has higher binding affinity towards unfolded substrate than DNAJA1. Interestingly, the observed slow dissociation rate of PfHSP40-substrate interaction allows PfHSP40 to maintain the substrate in folding-competent state to minimize its misfolding. Structural investigation through small angle x-ray scattering gave insights into the conformational architecture of PfHSP70-1 (monomer), PfHSP40 (dimer) and their complex. Overall, our data suggest that the parasite has evolved functionally diverged and efficient chaperone machinery which allows the human malaria parasite to survive in hostile conditions. The distinct allosteric landscapes and interaction kinetics of plasmodial chaperones open avenues for the exploration of small-molecule based antimalarial interventions.Several studies have investigated a potential association between the endothelial lipase gene (LIPG) 584C/T polymorphism and susceptibility to coronary artery disease (CAD), but a uniform conclusion is yet to be reached. To better evaluate the true relationship between the LIPG 584C/T polymorphism and the risk of CAD, a meta-analysis of 14 case-control studies with 9731 subjects was performed. Relevant articles published through August 2020 were searched in the CNKI, PubMed, Embase and Web of Science databases. Thirteen articles, including 14 eligible case-control studies with 4025 cases and 5706 controls, were enrolled in the present meta-analysis. The Newcastle-Ottawa Scale (NOS) scores of the case-control studies ranged from 6 to 8. The pooled results indicated that there is a significant association between the LIPG 584C/T polymorphism and CAD in the homozygote comparison model and the allelic comparison model. Subgroup analyses revealed that the LIPG 584C/T mutation significantly decreased the risk of CAD in the subgroups of African, CAD, hospital-based (HB), and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) populations in some genetic models. selleck kinase inhibitor No publication bias was found in our meta-analysis, which certifies the robustness of the current meta-analysis. Trial sequential analysis (TSA) also confirmed the stability of our results. The results of our meta-analysis indicate that the LIPG 584C/T polymorphism plays a protective role in the incidence of CAD. More high-quality case-control studies on various ethnicities are needed to confirm our results.
