The pleckstrin homology domain-interacting protein (PHIP) was originally identified as a 902-amino-acid (aa) protein that regulates insulin receptor-stimulated GLUT4 translocation in skeletal-muscle cells. Immunoblotting and immunohistological analyses of pancreatic ␤-cells reveal prominent expression of a 206-kDa PHIP isoform restricted to the nucleus. Herein, we report the cloning of this larger, 1,821-aa isoform of PHIP (PHIP1), which represents a novel WD40 repeat-containing protein. We demonstrate that PHIP1 overexpression stimulates insulin-like growth factor 1-dependent and -independent proliferation of ␤-cells, an event which correlates with transcriptional upregulation of the cyclin D2 promoter and the accumulation of cyclin D2 protein. RNA interference knockdown of PHIP1 in INS-1 cells abrogates insulin receptor substrate 2 (IRS2)-mediated DNA synthesis, providing for a specific role for PHIP1 in the enhancement of IRS2-dependent signaling responses leading to ␤-cell growth. Finally, we provide evidence that PHIP1 overexpression blocks free fatty acid-induced apoptosis in INS-1 cells, which is accompanied by marked activation of phosphoprotein kinase B (PKB)/AKT and the concomitant inhibition of caspase-9 and caspase-3 cleavage. Our finding that the restorative effect of PHIP1 on ␤-cell lipotoxicity can be attenuated by the overexpression of dominant-negative PKB suggests a key role for PKB in PHIP1-mediated cytoprotection. Taken together, these findings provide strong support for PHIP1 as a novel positive regulator of ␤-cell function. We suggest that PHIP1 may be involved in the induction of long-term gene expression programs to promote ␤-cell mitogenesis and survival.Type 1 and type 2 are the two principal forms of diabetes and account for more than 99% of all known forms of this metabolic disorder (29). Type 1 diabetes results from autoimmune destruction of the pancreatic ␤ cells and manifests itself when less than 10 to 20% of functional ␤ cells remain in the islets (13). Type 2 diabetes is characterized by the development of ␤-cell dysfunction and the progressive reduction of ␤-cell mass via reduced proliferation and increased apoptosis, although, unlike type 1 diabetes, it is the result of peripheral insulin resistance and chronic exposure to high levels of glucose and long-chain free fatty acids (FFA), known as glucotoxicity and lipotoxicity, respectively (28, 31).Biochemical and genetic evidence strongly implicate insulin and insulin-like growth factor 1 (IGF-1) as critical factors in ␤-cell function (21). The activated receptors engage and phosphorylate various cellular proteins, including insulin receptor substrate (IRS) protein family members. Recent studies, both in vitro and in transgenic animals, have revealed an important role for IRS2 in the control of ␤-cell growth and survival (15,17,25). There are two signaling cascades downstream of IRS2 in ␤ cells that have been characterized extensively: the phosphatidylinositol 3Ј-kinase (PI3-kinase)/protein kinase B (PKB) pathway and the Ras/Raf...

Cell adhesion is regulated by a variety of Ca2+-regulated pathways that depend on Ca2+-binding proteins. One such protein is calreticulin, an ER-resident protein. Calreticulin signalling from within the ER can affect processes outside the ER, such as expression of several adhesion-related genes, most notably vinculin and fibronectin. In addition, changes in the expression level of calreticulin strongly affect tyrosine phosphorylation of cellular proteins, which is known to affect many adhesion-related functions. While calreticulin has been localized to cellular compartments other than the ER, it appears that only the ER-resident calreticulin affects focal-contact-dependent adhesion. In contrast, calreticulin residing outside the ER may be involved in contact disassembly and other adhesion phenomena. Here, we review the role of calreticulin in focal contact initiation, stabilization, and turnover. We propose that calreticulin may regulate cell-substratum adhesion by participating in an "ER-to-nucleus" signalling and in parallel "ER-to-cell surface" signalling based on posttranslational events.

Background: The effect of the COVID-19 pandemic has transformed medical education and is likely to have long-lasting effects on student learning, mental well-being, and eating behaviour. This study aimed to examine the learning behaviors of medical students at the American University of Integrative Sciences (AUIS), Barbados, during the COVID-19 pandemic. Methods: A cross-sectional web-based online survey was administered to medical students at AUIS from July until November 2021. The data collecting instrument recorded students’ demographic and learning behaviour information (Meo et al. 2020), and eating disorders (SCOFF questionnaire). Results: The overall response rate was 55% (n=120). In relation to learning behaviour, students agreed with the following statements: ‘deterioration in work performance and studying’ (48.4%), ‘remember subject’s contents appropriately’ (40.4%), ‘concentration on the studies’ (40.3%), ‘difficulty in performing two tasks simultaneously’ (38.7%), ‘difficulty in performing mental calculations’ (33.9%), ‘difficulty in recalling recent information’ (32.3%), and ‘difficulty in recalling old information’ (38.7%). Among the 8 dimensions of learning behaviors, deterioration in work performance or studying, and difficulties in recalling recent information were found to be significantly associated with the gender of the students. For SCOFF questionnaire, approximately 24.2% screened positive for eating disorders. Screening with the SCOFF test demonstrated that female, older (>25 years), overweight + obese, Clinical Sciences + PreMed, and non-USA-based students were at more risk of eating disorders. Conclusions: The results indicate that during the COVID-19 pandemic AUIS students have developed learning difficulties, and are likely to have eating disorders. University policymakers should take appropriate measures to support a healthy learning environment and improve students' mental well-being and eating behaviours.

Background: The effect of the COVID-19 pandemic has transformed medical education and is likely to have long-lasting effects on student learning, mental well-being, and eating behaviour. This study aimed to examine the learning behaviours of medical students at the American University of Integrative Sciences (AUIS), Barbados, during the COVID-19 pandemic. Methods: A cross-sectional web-based on-line survey was administered to medical students at AUIS from July to November 2021. The data collecting instrument recorded students’ demographic and learning behaviour information and eating disorders (SCOFF questionnaire). Results: The overall response rate was 55% (n = 120). In relation to learning behaviour, students agreed with the following statements: ‘deterioration in work performance and studying’ (48.4%), ‘remember subject’s contents appropriately’ (40.4%), ‘concentration on the studies’ (40.3%), ‘difficulty in performing two tasks simultaneously’ (38.7%), ‘difficulty in performing mental calculations’ (33.9%), ‘difficulty in recalling recent information’ (32.3%), and ‘difficulty in recalling old information’ (38.7%). Among the eight dimensions of learning behaviours, deterioration in work performance or studying and difficulties in recalling recent information were found to be significantly associated with the gender of the students. For the SCOFF questionnaire, approximately 24.2% screened positive for eating disorders. Screening with the SCOFF test demonstrated that females, older (>25 years), overweight + obese, Clinical Sciences + PreMed, and non-USA-based students were at more risk of eating disorders. Conclusions: The results indicate that during the COVID-19 pandemic, AUIS students have developed learning difficulties and are likely to have eating disorders. University policymakers should take appropriate measures to support a healthy learning environment and improve students’ mental well-being and eating behaviours.

Abstract"naplastic thyroid cancer "TC is highly aggressive and has a poor therapeutic response and leads to high mortality. It has been shown that activation of intracellular c-Jun N-terminal kinase JNK and c-""L signaling pathways is one of the manifestations of the highly resistant response to radiotherapy in "TC. Pharmacological inhibition of these pathways in combination with radiotherapy is a potential treatment modality of "TC.