PLAGL1 overexpression induces cytoplasmic DNA accumulation that triggers cGAS/STING activation.

Pancreatic ß-cell damage mediated by apoptosis is believed to be a main trigger of type 1 diabetes mellitus (T1DM), which is proposed as an organ-specific autoimmune disease mediated by T cells. Nonetheless, the fundamental origins of T1DM remain uncertain. Here, we illustrate that an increase in PLAGL1 expression induces ß-cell apoptosis, as evidenced by mitochondrial membrane impairment and nucleolar degradation. The gene expression levels from cDNA samples were determined using qRT-PCR method. Western blot and Co-immunoprecipitation were applied for protein expression and interactions, respectively. Flow cytometry and TUNEL assay were used to detect pancreatic ß cell apoptosis. Female NOD/LtJ mice with recent-onset T1DM has been used in in vivo studies. Glucose-stimulated insulin secretion (GSIS) and glucose tolerance test (GTT) method is used for islet function assessment. Haematoxylin and Eosin (H&E) and Immunohistochemistry (IHC) were performed to evalute histological improvement of islet beta. Subsequent cytoplasmic DNA accumulation triggers DNA senser, the cyclic guanosine monophosphate-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. STING activation further stimulates downstream IRF3 and NF-kB pathways, thus boost type-I interferon signalling and NF-kB mediated inflammation. These findings elucidate a molecular mechanism linking PLAGL1 induced cell apoptosis to type-I interferon signalling and suggest a potential benefit for targeting cGAS/STING in T1DM treatment.

Functional and metabolic alterations of gut microbiota in children with new-onset type 1 diabetes.

Gut dysbiosis has been linked to type 1 diabetes (T1D); however, microbial capacity in T1D remains unclear. Here, we integratively profiled gut microbial functional and metabolic alterations in children with new-onset T1D in independent cohorts and investigated the underlying mechanisms. In T1D, the microbiota was characterized by decreased butyrate production and bile acid metabolism and increased lipopolysaccharide biosynthesis at the species, gene, and metabolite levels. The combination of 18 bacterial species and fecal metabolites provided excellently discriminatory power for T1D. Gut microbiota from children with T1D induced elevated fasting glucose levels and declined insulin sensitivity in antibiotic-treated mice. In streptozotocin-induced T1D mice, butyrate and lipopolysaccharide exerted protective and destructive effects on islet structure and function, respectively. Lipopolysaccharide aggravated the pancreatic inflammatory response, while butyrate activated Insulin1 and Insulin2 gene expression. Our study revealed perturbed microbial functional and metabolic traits in T1D, providing potential avenues for microbiome-based prevention and intervention for T1D.

Investigations of Micro-Deformation in Monocrystalline Copper at Low Temperatures via Indentation.

Indentation experiments on differently oriented faces of monocrystalline copper were conducted to investigate the micro-deformation process at temperatures ranging from room temperature to 150 K. The morphologies and textures of the residual imprints were observed using electron microscopy. Distinct slip bands were observed inside the imprints at 150 K compared to smooth surfaces at room temperature. Molecular dynamics simulations were performed to identify the deformation process beneath the indentation region. The results showed that plastic deformation was inhibited with decreasing temperature, but elastic recovery during the unloading process was enhanced, resulting in inner slip bands (ISBs) being observable in the residual imprints. The performances of these ISBs were strongly associated with the angles between the indentation direction and major slip surfaces and could be considered microscopic forms on the surfaces of aggregated geometrically necessary dislocations (GNDs). This work helped reveal the micro-deformation mechanism of indentations inside imprints.

Cost-effectiveness analysis of continuous subcutaneous insulin infusion versus multiple daily insulin for treatment of children with type 1 diabetes.

OBJECTIVE: To evaluate the health economics of using continuous subcutaneous insulin infusion (CSII) therapy versus multiple daily injections (MDI) therapy in children and adolescent patients with type 1 diabetes (T1D) in Qingdao, China. METHODS: A long-term cost-effectiveness analysis was conducted using the IQVIA Core Diabetes Model (CDM). The baseline characteristics of the simulated cohorts were obtained from 213 pediatric T1D patients who received care with CSII(104 cases) or MDI(109 cases) in Qingdao from 1 January 2015 to 31 March 2019. In the essential case, the expenditure of the complications and treatment of the disease with both therapies were evaluated in Chinese currency from the perspective of healthcare system. In a secondary analysis, the model used a 70-year time horizon, and a discount rate of 5% was applied to all future health outcomes and costs. A one-way sensitivity analysis was conducted on delta HbA1c, different prices of insulin pump, price of each upgrade cycle rates and different discount rates. Uncertainty was also evaluated by the probability sensitivity analysis and scenario analysis. RESULTS: In the base-case analysis, the lifetime total costs were lower for CSII group at ¥630,871 per patient compared with ¥672,672 for MDI group. The quality-adjusted life years (QALYs) gained were 11.612 and 11.197 for patients treated with CSII group and MDI group, respectively. The CSII group was cost-saving compared to MDI group. The feasibility of CSII group being cost-effective was 100% under the threshold of 3 times per capita GDP of China in 2019 (¥212,676) which was indicated from the probabilistic sensitivity analysis. Regarding scenario analysis, the ICER of the CSII group compared to MDI was between -151,583 and 153,366 RMB/QALYs, which is cost-effective. CONCLUSIONS: This economic evaluation compared CSII therapy versus MDI therapy for T1D children and adolescent patients in China and findings indicate that CSII should be considered a preferred treatment modality to MDI.

Clinical Outcome and Cost-Effectiveness Analysis of CSII Versus MDI in Children and Adolescent With Type 1 Diabetes Mellitus in a Public Health Care System of China.

Objectives: To evaluate the clinical and economic consequences of continuous subcutaneous insulin infusion (CSII) vs. multiple daily injections (MDI) in children and adolescents with type 1 diabetes mellitus (T1DM) from a public health care system in developed areas of developing country, considering changes in glycemic Control, daily insulin requirements, lipid profile, body mass index (BMI), frequency of severe hypoglycemia and Diabetic Ketoacidosis (DKA) and diabetic complications. Methods: This was a retrospective cohort study of children and adolescents with T1DM. Data were collected at baseline and the end of every year including glycated hemoglobin (HbA1c), insulin dose, lipid profile, blood pressure, and adverse events (severe hypoglycemia and DKA). The Cost-effectiveness analysis was performed using the IQVIA CORE Diabetes Model (CDM) to simulate diabetes progression by utilizing the clinical data obtained from the two groups. The main outcome measures were Life Expectancy, Quality adjusted life years (QALYs), Total Costs and Incremental Costs and Effectiveness Ratio (ICER) of CSII compared with MDI in Chinese pediatric patients with T1DM in Qingdao City (60 years). Results: Mean HbA1c values and daily insulin doses were significantly lower in those receiving CSII therapy throughout follow-up. Mean direct lifetime costs were ¥ 67,137 higher with CSII treatment than with MDI for pediatric patients. Treatment with CSII was associated with an improvement in life expectancy of 0.41 years for pediatric patients compared with MDI based on CORE diabetes model simulation. The corresponding gains in QALYs were 0.42. These data produced corresponding ICER is ¥ 161,815 per QALY for pediatric T1DM patients in Qingdao. Sensitivity analyses suggested that our base-case assumptions were mostly robust. Conclusions: CSII is associated with improved long-term clinical outcomes compared with MDI. Based on this model analysis, CSII appears to be more cost-effective for the Qingdao TIDM pediatric population and health care system.

[Long-term follow-up of efficacy of insulin pump in the treatment of children with type 1 diabetes mellitus].

OBJECTIVE: To study the clinical effect of continuous subcutaneous insulin infusion (CSⅡ) versus multiple daily injection (MDI) on blood glucose control in children with type 1 diabetes mellitus (T1DM). METHODS: A retrospective analysis was performed on the medical data of 91 children with T1DM who were treated with CSⅡ for more than 1 year and 75 children with T1DM who were treated with MDI. The two groups were compared in terms of glycosylated hemoglobin (HbA1C) and the recurrence of diabetic ketoacidosis (DKA) to evaluate the difference in the efficacy during the 3-year follow-up. A survey was conducted for the children in the CSⅡ group and their family members to investigate the degree of satisfaction with insulin pump. RESULTS: There was no significant difference in age, sex, and course of diabetes between the CSⅡ and MDI groups at disease onset and in the first year, the second year, and the third year of follow-up (P > 0.05). There was no significant difference in the HbA1C level between the two groups at disease onset (P > 0.05), but in the first year of follow-up, the CSⅡ group had a significantly lower HbA1C level than the MDI group (P=0.04). There was no significant difference in the HbA1C level between the two groups in the second year and the third year of follow-up (P > 0.05). The CSⅡ group had a higher proportion of children with HbA1C < 7.5% than the MDI group in the first year, the second year, and the third year of follow-up (P > 0.05). Within the 3 years of follow-up, 2 children in the CSⅡ group and 8 in the MDI group experienced the recurrence of DKA. In the third year of follow-up, there was no significant difference in blood pressure and blood lipids between the CSⅡ and MDI groups (P > 0.05). Most children and their family members (87%) were satisfied with CSⅡ treatment. CONCLUSIONS: Children with T1DM treated with CSⅡ have a better control of blood glucose than those treated with MDI, and children and their family members are satisfied with CSⅡ treatment. Therefore, it holds promise for clinical application.

A non-toxic enzyme-linked immunosorbent assay for aflatoxin B1 using anti-idiotypic antibodies as substitutes.

BACKGROUND: Immunoassays are widely employed techniques to detect aflatoxins since they are rapid, selective and sensitive. One common disadvantage of them is using aflatoxins as standard substances, which may trigger exposure risks to operators and environmental contamination without proper handling. Anti-idiotypic antibodies (anti-Ids or Ab2s), also named as internal-image anti-Ids, are able to mimic and function as antigens, so a non-toxic enzyme-linked immunosorbent assay (ELISA) for aflatoxin B1 (AFB1 ) is developed and validated using anti-Ids as substitutes. RESULTS: Mouse monoclonal anti-idiotypic antibody (McAb2) to AFB1 was generated by the hybridoma technique using Fab fragments of rabbit anti-AFB1 idiotype antibody (Ab1) as immunogen. As indicated by indirect competitive ELISA, McAb2, represented an internal-image of antigen AFB1 , was able to bind Fab with competition to AFB1 . Then, analysis of AFB1 in spiked samples by non-toxic ELISA using anti-Ids as substitutes was developed, and it showed no significant differences with comparison to AFB1 as competitive antigens. CONCLUSION: Our work demonstrated that anti-Ids could be used as internal-image mimicry of AFB1 , and it had potential applications in immunoassays for antigen substitution to reduce operational risk for operators and environmental contamination. © 2016 Society of Chemical Industry.