Permanent neonatal diabetes mellitus (PNDM) can be caused by insulin mutations. We generated induced pluripotent stem cells from fibroblasts of a patient with PNDM and undetectable insulin at birth ...due to a homozygous mutation in the translation start site of the insulin gene. Differentiation of mutant cells resulted in insulin-negative endocrine stem cells expressing MAFA, NKX6.1, and chromogranin A. Correction of the mutation in stem cells and differentiation to pancreatic endocrine cells restored insulin production and insulin secretion to levels comparable to those of wild-type cells. Grafting of corrected cells into mice, followed by ablating mouse β cells using streptozotocin, resulted in normal glucose homeostasis, including at night, and the stem cell-derived grafts adapted insulin secretion to metabolic changes. Our study provides proof of principle for the generation of genetically corrected cells autologous to a patient with non-autoimmune insulin-dependent diabetes. These cases should be readily amenable to autologous cell therapy.
•Neonatal diabetes due to homozygous mutation in the start codon of the insulin gene•iPSCs with INSATG>ATA mutation give rise to hormone-negative endocrine cells•Gene correction restores insulin production•Insulin-producing cells protect mice from diabetes
Stem cells from a subject with diabetes due to a mutation in the insulin locus can be corrected and insulin secretion restored. Grafted cells protect a mouse model from diabetes. This is a proof of principle for cell replacement for an insulin-dependent form of diabetes. Due to absence of autoimmunity such cases may be suitable for autologous cell therapy.
Sulfonylureas (SUs) are effective and affordable antidiabetic drugs. However, chronic use leads to secondary failure, limiting their utilization. Here, we identify cytochrome b5 reductase 3 (Cyb5r3) ...down-regulation as a mechanism of secondary SU failure and successfully reverse it. Chronic exposure to SU lowered Cyb5r3 abundance and reduced islet glucose utilization in mice in vivo and in ex vivo murine islets. Cyb5r3 β cell-specific knockout mice phenocopied SU failure. Cyb5r3 engaged in a glucose-dependent interaction that stabilizes glucokinase (Gck) to maintain glucose utilization. Hence, Gck activators can circumvent Cyb5r3-dependent SU failure. A Cyb5r3 activator rescued secondary SU failure in mice in vivo and restored insulin secretion in ex vivo human islets. We conclude that Cyb5r3 is a key factor in the secondary failure to SU and a potential target for its prevention, which might rehabilitate SU use in diabetes.
Fusarium crown rot and wheat sharp eyespot are major soil-borne diseases of wheat, causing serious losses to wheat yield in China. We applied high-throughput sequencing combined with qPCR to ...determine the effect of winter wheat seed dressing, with either Trichoderma atroviride HB20111 spore suspension or a chemical fungicide consisting of 6% tebuconazole, on the fungal community composition and absolute content of pathogens Fusarium pseudograminearum and Rhizoctonia cerealis in the rhizosphere at 180 days after planting. The results showed that the Trichoderma and chemical fungicide significantly reduced the amount of F. pseudograminearum in the rhizosphere soil (p < 0.05), and also changed the composition and structure of the fungal community. In addition, field disease investigation and yield measurement showed that T. atroviride HB20111 treatment reduced the whiteheads with an average control effect of 60.1%, 14.9% higher than the chemical treatment; T. atroviride HB20111 increased yield by 7.7%, which was slightly more than the chemical treatment. Therefore, T. atroviride HB20111 was found to have the potential to replace chemical fungicides to control an extended range of soil-borne diseases of wheat and to improve wheat yield.
Recent studies with human embryonic stem (hES) cells have established new protocols for substantial generation of pancreatic progenitors from definitive endoderm. These findings add to the efficient ...derivation of definitive endoderm, which is controlled by Wnt and Nodal pathways, and delineate a step forward in the quest for alternative beta-cell sources. It also indicates that critical refining of the available strategies might help define a universal protocol for pancreatic differentiation applicable to several cell lines, therefore offering the possibility for transplantation of immune-matched or patient-specific hES-derived beta-cells. We appraise here the fundamental role that bone morphogenetic protein, fibroblast growth factor, and retinoid signaling play during pancreas development, and describe a fundamental emergence of their combination in recent studies that generated pancreatic cells from hES cells. We finally enumerate some prospects that might improve further differentiation of the progenitor cells into functional beta-cells needed in diabetes cell therapy.
Due to slow kinetics of oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) during discharging and charging processes, it is essential to rationally design and synthesize non-precious ...metal bifunctional electrocatalysts with good performance for metal-air batteries. Herein, Ag-MnFe2O4 heterojunction nanoparticles supported on N, S, P-codoped graphene (NSPG) are developed with enhanced ORR and OER bifunctional electrocatalytic activities and stability. In contrast, S, P-doped graphene (SPG) and N, P-doped graphene (NPG) show less stabilization for the heterojunction particles. For example, under alkaline conditions, the ORR half-wave potential of Ag-MnFe2O4/NSPG can reach 0.831 V, and the over potential for OER is 0.56 V at the current density 10 mA·cm−2. Furthermore, Ag-MnFe2O4/NSPG shows better methanol resistance and durability than Pt/C catalysts.
Heterozygous coding sequence mutations of the INS gene are a cause of permanent neonatal diabetes (PNDM), requiring insulin therapy similar to T1D. While the negative effects on insulin processing ...and secretion are known, how dominant insulin mutations result in a continued decline of beta cell function after birth is not well understood.
We explored the causes of beta cell failure in two PNDM patients with two distinct INS mutations using patient-derived iPSCs and mutated hESCs.
we detected accumulation of misfolded proinsulin and impaired proinsulin processing in vitro, and a dominant-negative effect of these mutations on beta-cell mass and function after transplantation into mice. In addition to anticipated ER stress, we found evidence of beta-cell dedifferentiation, characterized by an increase of cells expressing both Nkx6.1 and ALDH1A3, but negative for insulin and glucagon.
These results highlight a novel mechanism, the loss of beta cell identity, contributing to the loss and functional failure of human beta cells with specific insulin gene mutations.
•A stem cell model of permanent neonatal diabetes (PNDM) due to insulin mutations.•Insulin mutations cause accumulation of misfolded proinsulin, insulin multimers, and impaired secretion.•Insulin misfolding mutations promote de-differentiation to insulin negative, ALDH1A3 and NKX6.1 positivecells.•Insulin processing defects and de-differentiation affect beta cell function within different time frames.•Gene correction demonstrates promise for autologous cell therapy for insulin-dependent diabetes.
We have established a real-time fluorescent quantitative PCR system that can detect wheat crown rot rapidly and accurately quantify fungi, Fusarium species and
Fusarium pseudograminearum
in the ...rhizosphere soil of infected wheat through the standard curve produced, with a view to the early stage of wheat Provide help in predicting the occurrence of wheat crown rot.
The introduction of impure atoms or crystal defects is a promising strategy for enhancing the photocatalytic activity of semiconductors. However, the synergy of these two effects in 2D atomic layers ...remains unexplored. In this case, the preparation of molybdenum-doped thin ZnIn2S4-containing S vacancies (Mo-doped Sv-ZnIn2S4) is conducted using a one-pot solvothermal method. The coordination of Mo doping and S vacancies not only enhances visible light absorption and facilitates the separation of photogenerated carriers but also provides many active sites for photocatalytic reactions. Meanwhile, the Mo-S bonds play function as high-speed channels to rapidly transfer carriers to the active sites, which can directly promote hydrogen evolution. Consequently, Sv-ZnIn2S4 with an optimized amount of Mo doping exhibits a high hydrogen evolution rate of 5739 μmol g−1 h−1 with a corresponding apparent quantum yield (AQY) of 21.24% at 420 nm, which is approximately 5.4 times higher than the original ZnIn2S4. This work provides a new strategy for the development of highly efficient and sustainable 2D atomic photocatalysts for hydrogen evolution.
Five types of KNO
3
-NH
4
VO
3
-rare earth metal nitrate (K-V-rare earth metal) catalysts supported on
a
-porous alumina ceramic substrates were prepared by a coating method. All the catalysts were ...characterized by X-ray diffraction and thermogravimetry/differential scanning calorimetry. Catalytic activities were evaluated by a soot oxidation reaction using a temperature-programmed reaction system. The experimental results show that the addition of rare earth metal compound could obviously improve the catalytic activities of the K-V-based catalysts. The proper ratio of K-V-rare earth metal catalysts can not only lower the soot onset ignition temperature, but also quicken the soot oxidation rate. The crystalline phases formed by K, V, and rare earth metal are stable.
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