Determining the signalling pathways that direct tissue expansion is a principal goal of regenerative biology. Vigorous pancreatic β-cell replication in juvenile mice and humans declines with age, and ...elucidating the basis for this decay may reveal strategies for inducing β-cell expansion, a long-sought goal for diabetes therapy. Here we show that platelet-derived growth factor receptor (Pdgfr) signalling controls age-dependent β-cell proliferation in mouse and human pancreatic islets. With age, declining β-cell Pdgfr levels were accompanied by reductions in β-cell enhancer of zeste homologue 2 (Ezh2) levels and β-cell replication. Conditional inactivation of the Pdgfra gene in β-cells accelerated these changes, preventing mouse neonatal β-cell expansion and adult β-cell regeneration. Targeted human PDGFR-α activation in mouse β-cells stimulated Erk1/2 phosphorylation, leading to Ezh2-dependent expansion of adult β-cells. Adult human islets lack PDGF signalling competence, but exposure of juvenile human islets to PDGF-AA stimulated β-cell proliferation. The discovery of a conserved pathway controlling age-dependent β-cell proliferation indicates new strategies for β-cell expansion.
To assist Chinese high school students in improving their career readiness and tackling career decision-making difficulties, we designed a synchronous online career intervention based on the ...Cognitive Information Processing (CIP) theory during the Covid-19 pandemic. The online career intervention consisted of a series of career courses to develop high school students' knowledge and skills in career planning, career assessments for exploring their vocational interests and academic self-concept, and a database providing basic information about university majors. To evaluate the intervention's effectiveness, 957 10th grade students were recruited in the study, 601 participants (girls = 227, boys = 324) were randomly assigned to the experimental group (online career intervention), and 356 (girls = 159, boys = 197) participants were randomly assigned to the control group (no any career interventions). All participants completed a pre- and post-intervention assessment of their career maturity, vocational identity and career decision-making difficulties. Results indicated that the online intervention significantly increased high school students' career readiness and reduced their career decision-making difficulties. The practical implications of this research for online career interventions directed at Chinese high school students are also discussed.
Pancreatic islet β-cell insufficiency underlies pathogenesis of diabetes mellitus; thus, functional β-cell replacement from renewable sources is the focus of intensive worldwide effort. However, in ...vitro production of progeny that secrete insulin in response to physiological cues from primary human cells has proven elusive. Here we describe fractionation, expansion and conversion of primary adult human pancreatic ductal cells into progeny resembling native β-cells. FACS-sorted adult human ductal cells clonally expanded as spheres in culture, while retaining ductal characteristics. Expression of the cardinal islet developmental regulators Neurog3, MafA, Pdx1 and Pax6 converted exocrine duct cells into endocrine progeny with hallmark β-cell properties, including the ability to synthesize, process and store insulin, and secrete it in response to glucose or other depolarizing stimuli. These studies provide evidence that genetic reprogramming of expandable human pancreatic cells with defined factors may serve as a general strategy for islet replacement in diabetes. DOI: http://dx.doi.org/10.7554/eLife.00940.001.
Gene targeting studies in primary human islets could advance our understanding of mechanisms driving diabetes pathogenesis. Here, we demonstrate successful genome editing in primary human islets ...using clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9). CRISPR-based targeting efficiently mutated protein-coding exons, resulting in acute loss of islet β-cell regulators, like the transcription factor PDX1 and the K
channel subunit KIR6.2, accompanied by impaired β-cell regulation and function. CRISPR targeting of non-coding DNA harboring type 2 diabetes (T2D) risk variants revealed changes in ABCC8, SIX2 and SIX3 expression, and impaired β-cell function, thereby linking regulatory elements in these target genes to T2D genetic susceptibility. Advances here establish a paradigm for genetic studies in human islet cells, and reveal regulatory and genetic mechanisms linking non-coding variants to human diabetes risk.
In recent years, employment has become a growing problem for Chinese college students, who often face issues of slow employment and lazy employment. Guided by the framework of career construction ...theory, we explored how proactive personality strengthens career adaptability. A total of 423 Chinese college students effectively completed the online survey. The results showed a positive correlation between proactive personality, future work self salience, future time perspective, and career adaptability. Additionally, proactive personality can directly affect career adaptability through three indirect paths: the separate intermediary effect of future work self salience, future time perspective, and the continuous mediating role of future work self salience and future time perspective. The results indicate that proactive personality increases career adaptability through the mediating role of future work self salience and future time perspective. This study contributes to our understanding of the mechanisms underlying the relationship between proactive personality and career adaptability. Additionally, the findings have implications for the career development of college students.
With the outbreak of COVID-19, many offline academic activities have been turned online, and virtual academic communities have been further emphasized. Based on this situation, this study took the ...Eagly and Chaiken’s Heuristic-System Model of Persuasion and the general rules of behavioral decision as a theoretical basis, established a theoretical model of sustainable knowledge sharing willingness in virtual academic communities. Firstly, this study developed the scale of willingness to share sustainable knowledge based on the heuristic system model of persuasion. After analyzing the data of 62 participants, the scale was revised. Secondly, 256 valid data were collected from China, the United States, Singapore, and Indonesia. Finally, the conceptual model and theoretical hypothesis were tested based on the data. The results show that knowledge sharing satisfaction is affected by heuristic factors (knowledge sharing quantity, knowledge source credibility) and system factors (knowledge sharing quality, knowledge sharing usefulness), and has a significant positive correlation with sustainable knowledge sharing willingness.
Substantial economic losses, building damage, and loss of life have been caused by secondary disasters that result from strong earthquakes. Earthquake disaster chains occur when secondary disasters ...take place in sequence. In this paper, we summarize 23 common earthquake disaster chains, whose structures include the serial, parallel, and parallel–serial (dendroid disaster chain) types. Evaluating the probability of powerful earthquake disaster chains is urgently needed for effective disaster prediction and emergency management. To this end, we introduce Bayesian networks (BNs) to assess powerful earthquake disaster chains. The structural graph of a powerful earthquake disaster chain is presented, and the proposed BN modeling method is provided and discussed. BN model of the earthquake–landslides–barrier lakes–floods disaster chain is established. The use of BN shows that such a model enables the effective analysis of earthquake disaster chains. Probability inference reveals that population density, loose debris volume, flooded areas, and landslide dam stability are the most critical links that lead to loss of life in earthquake disaster chains.
Developing systems to identify the cell type-specific functions regulated by genes linked to type 2 diabetes (T2D) risk could transform our understanding of the genetic basis of this disease. ...However, in vivo systems for efficiently discovering T2D risk gene functions relevant to human cells are currently lacking. Here we describe powerful interdisciplinary approaches combining Drosophila genetics and physiology with human islet biology to address this fundamental gap in diabetes research. We identify Drosophila orthologs of T2D-risk genes that regulate insulin output. With human islets, we perform genetic studies and identify cognate human T2D-risk genes that regulate human beta cell function. Loss of BCL11A, a transcriptional regulator, in primary human islet cells leads to enhanced insulin secretion. Gene expression profiling reveals BCL11A-dependent regulation of multiple genes involved in insulin exocytosis. Thus, genetic and physiological systems described here advance the capacity to identify cell-specific T2D risk gene functions.
Little is known about the mechanisms governing neonatal growth and maturation of organs. Here we demonstrate that calcineurin/Nuclear Factor of Activated T cells (Cn/NFAT) signaling regulates ...neonatal pancreatic development in mouse and human islets. Inactivation of calcineurin b1 (Cnb1) in mouse islets impaired dense core granule biogenesis, decreased insulin secretion, and reduced cell proliferation and mass, culminating in lethal diabetes. Pancreatic β cells lacking Cnb1 failed to express genes revealed to be direct NFAT targets required for replication, insulin storage, and secretion. In contrast, glucokinase activation stimulated Cn-dependent expression of these genes. Calcineurin inhibitors, such as tacrolimus, used for human immunosuppression, induce diabetes. Tacrolimus exposure reduced Cn/NFAT-dependent expression of factors essential for insulin dense core granule formation and secretion and neonatal β cell proliferation, consistent with our genetic studies. Discovery of conserved pathways regulating β cell maturation and proliferation suggests new strategies for controlling β cell growth or replacement in human islet diseases.
► Cn/NFAT regulates mouse and human postnatal β cell maturation and proliferation ► Cn/NFAT signaling is essential for β cell dense core granule biogenesis ► Molecular mechanisms underlying tacrolimus-induced iatrogenic diabetes mellitus ► Glucose metabolism linked by Ca2+ and Cn/NFAT signaling to β cell transcription
Therapeutic modulation of human pancreatic islet β cell proliferation and function is a long-sought goal in diabetes research. Goodyer et al. report that calcineurin/NFAT signaling coordinates postnatal islet development by controlling the expression of genes governing β cell proliferation, maturation, and dense core granule formation in mice and humans.
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