With the reform of the higher education system in China in recent years, the teaching management model of the higher education attracts more and more attention.Implementing the reform con-cerning credit unit system in Universities, developing a multi-skill, all-round development of talents, which has become an inevitable tendency in the development of Chinese higher education.In the paper, according to the present situation of teaching management models under the credit unit system, the existing problems of teaching management models are studied, and some solutions are analyzed.In the end, the author provides some suggestions for the further development and reform of teaching management models under the credit unit system in China.
Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found that donor islets contained β cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings for T1D, we sequenced the donor DNA and found a pathogenic heterozygous variant in the gene encoding hepatocyte nuclear factor-1α (HNF1A). In one of the first studies of human pancreatic islets with a disease-causing HNF1A variant associated with the most common form of monogenic diabetes, we found that HNF1A dysfunction leads to insulin-insufficient diabetes reminiscent of T1D by impacting the regulatory processes critical for glucose-stimulated insulin secretion and suggest a rationale for a therapeutic alternative to current treatment.
A hallmark of type 2 diabetes (T2D) is endocrine islet β-cell failure, which can occur via cell dysfunction, loss of identity, and/or death. How each is induced remains largely unknown. We used mouse β-cells deficient for myelin transcription factors (Myt TFs; including Myt1, -2, and -3) to address this question. We previously reported that inactivating all three Myt genes in pancreatic progenitor cells (MytPancΔ) caused β-cell failure and late-onset diabetes in mice. Their lower expression in human β-cells is correlated with β-cell dysfunction, and single nucleotide polymorphisms in MYT2 and MYT3 are associated with a higher risk of T2D. We now show that these Myt TF-deficient postnatal β-cells also dedifferentiate by reactivating several progenitor markers. Intriguingly, mosaic Myt TF inactivation in only a portion of islet β-cells did not result in overt diabetes, but this created a condition where Myt TF-deficient β-cells remained alive while activating several markers of Ppy-expressing islet cells. By transplanting MytPancΔ islets into the anterior eye chambers of immune-compromised mice, we directly show that glycemic and obesity-related conditions influence cell fate, with euglycemia inducing several Ppy+ cell markers and hyperglycemia and insulin resistance inducing additional cell death. These findings suggest that the observed β-cell defects in T2D depend not only on their inherent genetic/epigenetic defects but also on the metabolic load.
Background: Lung adenocarcinoma (LUAD) is the most common type of lung cancer with a complex tumor microenvironment. Neddylation, as a type of post-translational modification, plays a vital role in the development of LUAD. To date, no study has explored the potential of neddylation-associated genes for LUAD classification, prognosis prediction, and treatment response evaluation. Methods: Seventy-six neddylation-associated prognostic genes were identified by Univariate Cox analysis. Patients with LUAD were classified into two patterns based on unsupervised consensus clustering analysis. In addition, a 10-gene prognostic signature was constructed using LASSO-Cox and a multivariate stepwise regression approach. Results: Substantial differences were observed between the two patterns of LUAD in terms of prognosis. Compared with neddylation cluster2, neddylation cluster1 exhibited low levels of immune infiltration that promote tumor progression. Additionally, the neddylation-related risk score correlated with clinical parameters and it can be a good predictor of patient outcomes, gene mutation levels, and chemotherapeutic responses. Conclusion: Neddylation patterns can distinguish tumor microenvironment and prognosis in patients with LUAD. Prognostic signatures based on neddylation-associated genes can predict patient outcomes and guide personalized treatment.
Store-operated Ca2+ entry (SOCE) is a dynamic process that leads to refilling of endoplasmic reticulum (ER) Ca2+ stores through reversible gating of plasma membrane Ca2+ channels by the ER Ca2+ sensor Stromal Interaction Molecule 1 (STIM1). Pathogenic reductions in β-cell ER Ca2+ have been observed in diabetes. However, a role for impaired SOCE in this phenotype has not been tested. We measured the expression of SOCE molecular components in human and rodent models of diabetes and found a specific reduction in STIM1 mRNA and protein levels in human islets from donors with type 2 diabetes (T2D), islets from hyperglycemic streptozotocin-treated mice, and INS-1 cells (rat insulinoma cells) treated with proinflammatory cytokines and palmitate. Pharmacologic SOCE inhibitors led to impaired islet Ca2+ oscillations and insulin secretion, and these effects were phenocopied by β-cell STIM1 deletion. STIM1 deletion also led to reduced ER Ca2+ storage and increased ER stress, whereas STIM1 gain of function rescued β-cell survival under proinflammatory conditions and improved insulin secretion in human islets from donors with T2D. Taken together, these data suggest that the loss of STIM1 and impaired SOCE contribute to ER Ca2+ dyshomeostasis under diabetic conditions, whereas efforts to restore SOCE-mediated Ca2+ transients may have the potential to improve β-cell health and function.
Although the pancreatic duodenal homeobox 1 (Pdx-1) transcription factor is known to play an indispensable role in β cell development and secretory function, recent data also implicate Pdx-1 in the maintenance of endoplasmic reticulum (ER) health. The sarco-endoplasmic reticulum Ca(2+) ATPase 2b (SERCA2b) pump maintains a steep Ca(2+) gradient between the cytosol and ER lumen. In models of diabetes, our data demonstrated loss of β cell Pdx-1 that occurs in parallel with altered SERCA2b expression, whereas in silico analysis of the SERCA2b promoter revealed multiple putative Pdx-1 binding sites. We hypothesized that Pdx-1 loss under inflammatory and diabetic conditions leads to decreased SERCA2b levels and activity with concomitant alterations in ER health. To test this, siRNA-mediated knockdown of Pdx-1 was performed in INS-1 cells. The results revealed reduced SERCA2b expression and decreased ER Ca(2+), which was measured using fluorescence lifetime imaging microscopy. Cotransfection of human Pdx-1 with a reporter fused to the human SERCA2 promoter increased luciferase activity 3- to 4-fold relative to an empty vector control, and direct binding of Pdx-1 to the proximal SERCA2 promoter was confirmed by chromatin immunoprecipitation. To determine whether restoration of SERCA2b could rescue ER stress induced by Pdx-1 loss, Pdx1(+/-) mice were fed a high-fat diet. Isolated islets demonstrated an increased spliced-to-total Xbp1 ratio, whereas SERCA2b overexpression reduced the Xbp1 ratio to that of wild-type controls. Together, these results identify SERCA2b as a novel transcriptional target of Pdx-1 and define a role for altered ER Ca(2+) regulation in Pdx-1-deficient states.
Type 2 diabetes (T2D) affects over 380 million individuals worldwide and is characterized by peripheral insulin resistance and inadequate insulin secretion from the pancreatic β cell. During the development of T2D and in the face of increasing peripheral insulin resistance, the β cell undergoes a compensatory response to both increase insulin production and secretion. Here, we tested the hypothesis that intact activity of the sarco‐endoplasmic reticulum calcium ATPase (SERCA) pump, which transports 2 calcium molecules into the ER lumen during each catalytic cycle and is responsible for maintaining a robust ER calcium pool, is a critical determinant of the β cell's adaptive response to diet‐induced obesity. To this end, mice with a total body heterozygous deletion of SERCA2 (S2HET) and wild‐type littermate controls (WT) were placed on high fat diet (HFD) containing 45% of kilocalories from fat for 16 weeks. Compared to WT controls, S2HET mice showed equivalent body weight gain and fat content. Interestingly, S2HET mice demonstrated fasting hyperglycemia, hypoinsulinemia, and significantly impaired glucose tolerance. Insulin sensitivity and insulin signaling in liver, skeletal muscle, and adipose tissue were not different between S2HETs and WT controls, suggesting a primary defect at the level of the β cell. Histologic analysis of pancreatic sections obtained after 16 weeks of HFD revealed significantly reduced β cell mass as well as reduced β cell proliferation in S2HET mice. To define mechanisms underlying these observations, a SERCA2 deficient rat insulinoma cell line (S2KO INS‐1) was created using CRISPR/Cas9 technology. At baseline, thymidine incorporation was reduced in S2KO INS‐1 cells. Cell cycle analysis revealed a dramatic shift towards decreased proliferation and a G1/S block, while SERCA2b restoration by adenoviral transduction was able to fully rescue these defects. In the meantime, we observed the expression of adaptive and terminal ER stress markers including Bip, Dnajc3, hsp90b1, Pdia4 and spliced Xbp‐1 were elevated in both S2KO INS‐1 cells and isolated S2HET islets. Consistent with this, further analysis by polyribosomal profiling analysis revealed a translational initiation block in both S2KO cells and islets isolated from S2HET mice. In aggregate, these data suggest that impaired SERCA2 activity and altered ER calcium homeostasis lead to increased β cell ER stress and impaired proliferation, thereby limiting the β cell compensatory response to diet‐induced obesity. Support or Funding Information NIH R01 DK 093954 and VA Merit Award 1I01BX001733
Background: Recent studies have revealed that SUMOylation modifications are involved in various biological processes, including cancer development and progression. However, the precise role of SUMOylation in lung adenocarcinoma (LUAD), especially in the tumor immune microenvironment, is not yet clear. Methods: We identified SUMOylation patterns by unsupervised consensus clustering based on the expression of SUMOylation regulatory genes. The tumor microenvironment in lung adenocarcinoma was analyzed using algorithms such as GSVA and ssGSEA. Key genes of SUMOylation patterns were screened for developing a SUMOylation scoring model to assess immunotherapy and chemotherapy responses in lung adenocarcinoma patients. Experiments were conducted to validate the differential expression of model genes in lung adenocarcinoma. Finally, we constructed a nomogram based on the SUMOylation score to assess the prognosis of individual lung adenocarcinoma patients. Results: Two patterns of SUMOylation were identified, namely, SUMO-C1, which showed anti-tumor immune phenotype, and SUMO-C2, which showed immunosuppressive phenotype. Different genomic subtypes were also identified; subtype gene-T1 exhibited a reciprocal restriction between the immune microenvironment and stromal microenvironment. High SUMOylation scores were indicative of poor lung adenocarcinoma prognosis. SUMOylation score was remarkably negatively correlated with the infiltration of anti-tumor immune cells, and significantly positively correlated with immune cells promoting immune escape and immune suppression. In addition, patients with low scores responded better to immunotherapy. Therefore, the developed nomogram has a high prognostic predictive value. Conclusion: The SUMOylation patterns can well discriminate the tumor microenvironment features of lung adenocarcinoma, especially the immune cell infiltration status. The SUMOylation score can further assess the relationship between SUMOylation and immune cell crosstalk and has significant prognostic value and can be used to predict immunotherapy and chemotherapy response in patients with lung adenocarcinoma.
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