Epigenetic regulation of Dlg1, via Kaiso, alters mitotic spindle polarity and promotes intestinal tumourigenesis

Both alterations to the epigenome and loss of polarity have been linked to cancer initiation, progression and metastasis. It has previously been demonstrated that loss of the epigenetic reader protein Kaiso suppresses intestinal tumourigenesis in the Apc+/min mouse model, in which altered polarity plays a key role. Thus, we investigated the link between Kaiso deficiency, polarity and suppression of intestinal tumourigenesis. We used Kaiso deficient mice to conditionally delete Apc within the intestinal epithelia and demonstrated up-regulation of the spindle polarity genes Dlg1 and Dlgap1. To understand the role of Dlg1 we generated Villin-creApc+/minDlg1flx/flx Kaiso-/y mice to analyse gene expression, survival, tumour burden and spindle orientation. In vivo analysis of the Dlg1 deficient intestine revealed improper orientation of mitotic spindles and a decreased rate of cellular migration. Loss of Dlg1 decreased survival in Apc+/min mice, validating its role as a tumour suppressor in the intestine. Significantly the increased survival of Apc+/minKaisoy/- mice was shown to be dependent on Dlg1 expression. Taken together this data indicates that maintenance of spindle polarity in the intestinal crypt requires appropriate regulation of Dlg1 expression. As Dlg1 loss leads to incorrect spindle orientation and a delay in cells transiting the intestinal crypt. We propose that the delayed exit from the crypt increases the window in which spontaneous mutations can become fixed, producing a 'tumour-permissive' environment, without an increase in mutation rate. Implications: Loss of mitotic spindle polarity delays the exit of cells from the intestinal crypt and promotes a tumourigenic environment

Solid oxide fuel cell hybrid system: a detailed review of an environmentally clean and efficient source of energy

This paper reports a review of an environmentally clean and efficient source of energy such as solid oxide fuel cell hybrid systems. Due to climate concerns, most nations are seeking alternative means of generating energy from a clean, efficient and environmental-friendly method. However, this has proven a big hurdle for both academic and industry researchers over many years. Currently, practical and technically feasible solution can be obtained via an integration of a microturbine and a fuel cell (hybrid systems). Combining the two distinct systems in a hybrid arrangement the efficiency of the microturbine increases from 25-30% to the 60-65% range. Hence, this paper outlines an engineering power generation solution towards the acute global population growth, the growing need, environmental concerns, intelligent use of energy with attendant environmental and hybrid system layouts concerning arising problems and tentative proposed solutions. Furthermore, advantages of a solid oxide fuel cell hybrid systems with respect to the other technologies are identified and discussed rationally. Special attention is devoted to modelling with software and emulator rigs and system prototypes. The paper also reviews the limitations and the benefits of these hybrid systems in relationship with energy, environment and sustainable development. Few potential applications, as long-term potential actions for sustainable development, and the future of such devices are further discussed

The graduate school guide: How to prepare for the qualifying exam and assemble a thesis/graduate committee

Qualifying exams and thesis committees are crucial components of a PhD candidate's journey. However, many candidates have trouble navigating these milestones and knowing what to expect. This article provides advice on meeting the requirements of the qualifying exam, understanding its format and components, choosing effective preparation strategies, retaking the qualifying exam, if necessary, and selecting a thesis committee, all while maintaining one's mental health. This comprehensive guide addresses components of the graduate school process that are often neglected

S100A12 in Digestive Diseases and Health: A Scoping Review

Calgranulin proteins are an important class of molecules involved in innate immunity. These members of the S100 class of the EF-hand family of calcium-binding proteins have numerous cellular and antimicrobial functions. One protein in particular, S100A12 (also called EN-RAGE or calgranulin C), is highly abundant in neutrophils during acute inflammation and has been implicated in immune regulation. Structure-function analyses reveal that S100A12 has the capacity to bind calcium, zinc, and copper, processes that contribute to nutritional immunity against invading microbial pathogens. S100A12 is a ligand for the receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), and CD36, which promote cellular and immunological pathways to alter inflammation. We conducted a scoping review of the existing literature to define what is known about the association of S100A12 with digestive disease and health. Results suggest that S100A12 is implicated in gastroenteritis, necrotizing enterocolitis, gastritis, gastric cancer, Crohn’s disease, irritable bowel syndrome, inflammatory bowel disease, and digestive tract cancers. Together, these results reveal S100A12 is an important molecule broadly associated with the pathogenesis of digestive diseases

Ablation of Sam50 is associated with fragmentation and alterations in metabolism in murine and human myotubes

The sorting and assembly machinery (SAM) Complex is responsible for assembling β‐barrel proteins in the mitochondrial membrane. Comprising three subunits, Sam35, Sam37, and Sam50, the SAM complex connects the inner and outer mitochondrial membranes by interacting with the mitochondrial contact site and cristae organizing system complex. Sam50, in particular, stabilizes the mitochondrial intermembrane space bridging (MIB) complex, which is crucial for protein transport, respiratory chain complex assembly, and regulation of cristae integrity. While the role of Sam50 in mitochondrial structure and metabolism in skeletal muscle remains unclear, this study aims to investigate its impact. Serial block‐face‐scanning electron microscopy and computer‐assisted 3D renderings were employed to compare mitochondrial structure and networking in Sam50‐ deficient myotubes from mice and humans with wild‐type (WT) myotubes. Furthermore, autophagosome 3D structure was assessed in human myotubes. Mitochondrial metabolic phenotypes were assessed using Gas Chromatography‐Mass Spectrometry‐based metabolomics to explore differential changes in WT and Sam50‐deficient myotubes. The results revealed increased mitochondrial fragmentation and autophagosome formation in Sam50‐deficient myotubes compared to controls. Metabolomic analysis indicated elevated metabolism of propanoate and several amino acids, including ß‐ Alanine, phenylalanine, and tyrosine, along with increased amino acid and fatty acid metabolism in Sam50‐deficient myotubes. Furthermore, impairment of oxidative capacity was observed upon Sam50 ablation in both murine and human myotubes, as measured with the XF24 Seahorse Analyzer. Collectively, these findings support the critical role of Sam50 in establishing and maintaining mitochondrial integrity, cristae structure, and mitochondrial metabolism. By elucidating the impact of Sam50‐deficiency, this study enhances our understanding of mitochondrial function in skeletal muscle

IL28B Genetic Variation Is Associated with Spontaneous Clearance of Hepatitis C Virus, Treatment Response, Serum IL-28B Levels in Chinese Population

<p><b>Background:</b> The interleukin-28B gene (IL28B) locus has been associated with host resistance to hepatitis C virus (HCV) infection and response to PEG-IFN/RBV treatment in western populations. This study was to determine whether this gene variant is also associated with spontaneous clearance of HCV infection, treatment response and IL-28B protein production in Chinese patients.</p> <p><b>Methods:</b> We genotyped IL28B genetic variations (rs12980275, rs8103142, rs8099917 and rs12979860) by pyrosequencing DNA samples from cohorts consisting of 529 subjects with persistent HCV infection, 196 subjects who cleared the infection, 171 healthy individuals and 235 chronic HCV patients underwent IFN/RBV treatment. The expression of IL-28B were measured by ELISA and RT-PCR.</p> <p><b>Results:</b> We found that the four IL28B variants were in complete linkage disequilibrium (r2 = 0.97–0.98). The rs12979860 CC genotype was strongly associated with spontaneously HCV clearance and successful IFN/RBV treatment compared to the CT/TT. IL-28B levels in persistent HCV patients were significantly lower than subjects who spontaneously resolved HCV and healthy controls and were also associated with high levels of ALT (alanine aminotransferase) and AST (aspartate aminotransferase). IL-28B levels were also significantly lower in individuals carrying T alleles than CC homozygous.</p> <p><b>Conclusions:</b> Thus, the rs12979860-CC variant upstream of IL28B gene is associated with spontaneous clearance of HCV, susceptible to IFN/RBV treatment and increased IL-28B levels in this Chinese population.</p&gt

Pro-asthmatic cytokines regulate unliganded and ligand-dependent glucocorticoid receptor signaling in airway smooth muscle

To elucidate the regulation of glucocorticoid receptor (GR) signaling under pro-asthmatic conditions, cultured human airway smooth muscle (HASM) cells were treated with proinflammatory cytokines or GR ligands alone and in combination, and then examined for induced changes in ligand-dependent and -independent GR activation and downstream signaling events. Ligand stimulation with either cortisone or dexamethsone (DEX) acutely elicited GR translocation to the nucleus and, comparably, ligand-independent stimulation either with the Th2 cytokine, IL-13, or the pleiotropic cytokine combination, IL-1β/TNFα, also acutely evoked GR translocation. The latter response was potentiated by combined exposure of cells to GR ligand and cytokine. Similarly, treatment with either DEX or IL-13 alone induced GR phosphorylation at its serine-211 residue (GRSer211), denoting its activated state, and combined treatment with DEX+IL-13 elicited heightened and sustained GRSer211phosphorylation. Interestingly, the above ligand-independent GR responses to IL-13 alone were not associated with downstream GR binding to its consensus DNA sequence or GR transactivation, whereas both DEX-induced GR:DNA binding and transcriptional activity were significantly heightened in the presence of IL-13, coupled to increased recruitment of the transcriptional co-factor, MED14. The stimulated GR signaling responses to DEX were prevented in IL-13-exposed cells wherein GRSer211 phosphorylation was suppressed either by transfection with specific serine phosphorylation-deficient mutant GRs or treatment with inhibitors of the MAPKs, ERK1/2 and JNK. Collectively, these novel data highlight a heretofore-unidentified homeostatic mechanism in HASM cells that involves pro-asthmatic cytokine-driven, MAPK-mediated, non-ligand-dependent GR activation that confers heightened glucocorticoid ligand-stimulated GR signaling. These findings raise the consideration that perturbations in this homeostatic cytokine-driven GR signaling mechanism may be responsible, at least in part, for the insensirtivity to glucocorticoid therapy that is commonly seen in individuals with severe asthma

Juneteenth in STEMM and the barriers to equitable science

We are 52 Black scientists. Here, we establish the context of Juneteenth in STEMM and discuss the barriers Black scientists face, the struggles they endure, and the lack of recognition they receive. We review racism's history in science and provide institutional-level solutions to reduce the burdens on Black scientists