The low-complexity domain of the FUS RNA binding protein self-assembles via the mutually exclusive use of two distinct cross-β cores

The low-complexity (LC) domain of the fused in sarcoma (FUS) RNA binding protein self-associates in a manner causing phase separation from an aqueous environment. Incubation of the FUS LC domain under physiologically normal conditions of salt and pH leads to rapid formation of liquid-like droplets that mature into a gel-like state. Both examples of phase separation have enabled reductionist biochemical assays allowing discovery of an N-terminal region of 57 residues that assembles into a labile, cross-β structure. Here we provide evidence of a nonoverlapping, C-terminal region of the FUS LC domain that also forms specific cross-β interactions. We propose that biologic function of the FUS LC domain may operate via the mutually exclusive use of these N- and C-terminal cross-β cores. Neurodegenerative disease–causing mutations in the FUS LC domain are shown to imbalance the two cross-β cores, offering an unanticipated concept of LC domain function and dysfunction.

Review of Modern Insulin Pumps and the Perioperative Management of the Type 1 Diabetic Patient for Ambulatory Dental Surgery

The use of continuous insulin pump systems for effective management of glycemic control in the patient with type 1 diabetes mellitus (T1DM) is steadily increasing. Although the types of devices and their respective manufacturers vary, insulin pumps all utilize similar underlying concepts based on the delivery of exogenous insulin to patients with T1DM in manners that more closely approximate the normal biologic function and performance of the pancreas. As insulin pumps becomes more commonplace and their use more widespread, the sedation or anesthesia provider must ensure familiarity with the basic knowledge of pump function and the various perioperative management considerations. This review provides a concise overview of the pathophysiology of T1DM, introduces foundational aspects of common insulin pump systems, and discusses several general recommendations regarding the perioperative management of insulin pumps during dental surgeries.

The Role of Interleukin-27 in Atherosclerosis: A Contemporary Review

Atherosclerosis is a chronic inflammation characterized by an imbalance between inhibitors and stimulators of the inflammatory system that leads to the formation of atherosclerotic plaques in the vessel walls. Interleukin (IL)-27 is one of the recently discovered cytokines that have an immunomodulatory role in autoimmune and inflammatory diseases. However, the definite role of IL-27 in the pathogenesis of atherosclerosis remains unclear. Recent studies on cardiomyocytes and vascular endothelium have demonstrated mechanisms through which IL-27 could potentially modulate atherosclerosis. Upregulation of the IL-27 receptor was also observed in the atherosclerotic plaques. In addition, circulatory IL-27 levels were increased in patients with acute coronary syndrome and myocardial infarction. A regenerative, neovascularization, and cardioprotective role of IL-27 has also been implicated. Future studies are warranted to elucidate the biologic function and clinical significance of IL-27 in atherosclerosis.

The Molecular Functions of MeCP2 in Rett Syndrome Pathology

MeCP2 protein, encoded by the MECP2 gene, binds to DNA and affects transcription. Outside of this activity the true range of MeCP2 function is still not entirely clear. As MECP2 gene mutations cause the neurodevelopmental disorder Rett syndrome in 1 in 10,000 female births, much of what is known about the biologic function of MeCP2 comes from studying human cell culture models and rodent models with Mecp2 gene mutations. In this review, the full scope of MeCP2 research available in the NIH Pubmed (https://pubmed.ncbi.nlm.nih.gov/) data base to date is considered. While not all original research can be mentioned due to space limitations, the main aspects of MeCP2 and Rett syndrome research are discussed while highlighting the work of individual researchers and research groups. First, the primary functions of MeCP2 relevant to Rett syndrome are summarized and explored. Second, the conflicting evidence and controversies surrounding emerging aspects of MeCP2 biology are examined. Next, the most obvious gaps in MeCP2 research studies are noted. Finally, the most recent discoveries in MeCP2 and Rett syndrome research are explored with a focus on the potential and pitfalls of novel treatments and therapies.

Overview of Inositol and Inositol Phosphates on Chemoprevention of Colitis-Induced Carcinogenesis

Chronic inflammation is one of the most common and well-recognized risk factors for human cancer, including colon cancer. Inflammatory bowel disease (IBD) is defined as a longstanding idiopathic chronic active inflammatory process in the colon, including ulcerative colitis and Crohn’s disease. Importantly, patients with IBD have a significantly increased risk for the development of colorectal carcinoma. Dietary inositol and its phosphates, as well as phospholipid derivatives, are well known to benefit human health in diverse pathologies including cancer prevention. Inositol phosphates including InsP3, InsP6, and other pyrophosphates, play important roles in cellular metabolic and signal transduction pathways involved in the control of cell proliferation, differentiation, RNA export, DNA repair, energy transduction, ATP regeneration, and numerous others. In the review, we highlight the biologic function and health effects of inositol and its phosphates including the nature and sources of these molecules, potential nutritional deficiencies, their biologic metabolism and function, and finally, their role in the prevention of colitis-induced carcinogenesis.

Overexpressed Pseudogene MT1L Associated with Tumor Immune Infiltrates and Indicates a Worse Prognosis in BLCA

Background BLCA is common cancer worldwide, aggressive, and fatal. Immunotherapy (ICT) has achieved an excellent curative effect in BLCA; however, only part of these patients can benefit from ICT treatment. MT1L belongs to pseudogene, and a previous study has suggested that MT1L can be used as an indicator of prognosis in colorectal cancer. However, the role of MT1L in BLCA has not yet been illuminated. Methods Data was collected from TCGA, and logistic regression, Kaplan-Meier Plotter, and multivariate Cox analysis have been performed to demonstrate the correlation between pseudogene MT1L and prognosis in BLCA. To identify the association of MT1L with tumor-infiltrating immune cells, TIMER and TISIDB were utilized. And GSEA was performed to illuminate the potential biologic function. Results The expression of MT1L was decreased in BLCA. And it is positively connected with immune cells, like Tregs(ρ=0.708) and MDSCs(ρ=0.664). We also confirmed that MT1L is related to typical markers of immune cells，like PD-1, CTLA-4. Besides, the high MT1L expression level is related to the high stage of T, N, and the high grade in BLCA and the increased expression of MT1L was significantly associated with the shorter OS of BLCA patients (P<0.05). Multivariate Cox analysis revealed that MT1L expression could be an independent prognostic factor of BLCA. Conclusion Collectively, our findings demonstrated that pseudogene MT1L regulates the immune microenvironment, correlates with poor survival, and serves as an independent prognostic biomarker in BLCA.

LINC00205 promotes malignancy in lung cancer by recruiting FUS and stabilizing CSDE1

Lung cancer (LC) is characterized by high morbidity and mortality. Numerous long noncoding RNAs (lncRNAs) have been reported to be involved in the initiation and progression of human cancers, including LC. Long intergenic non-protein coding RNA 205 (LINC00205) is identified as a novel lncRNA, which has only been unmasked to be a potential cancer promoter in hepatocellular carcinoma and pancreatic cancer. The biologic function and the molecular mechanism of LINC00205 in LC require to be investigated. In the present study, we observed the elevated expression of LINC00205 in LC tissues and cells through real-time quantitative PCR (RT-qPCR). Additionally, silencing LINC00205 inhibited LC cell growth and migration, but aggravated cell apoptosis. Moreover, we found that LINC00205 recruited FUS to maintain the mRNA stability of cold shock domain containing E1 (CSDE1) and therefore up-regulated CSDE1 expression in LC. Further, the effects of LINC00205 on LC cell proliferation, apoptosis and migration were all erased by CSDE1 overexpression. These findings demonstrated that LINC00205 facilitates malignant phenotypes in LC by recruiting FUS to stabilize CSDE1, suggesting LINC00205 as a potential target for LC therapy.

Biosimilars

Biologic therapy for treatment of rheumatoid arthritis (RA) has evolved considerably over the past 20 years. Biosimilar development continues to accelerate at a frenetic pace worldwide. Initial regulatory efforts were developed within the EU and subsequent guidelines have now evolved in over 20 countries. Biosimilars by definition are highly similar, with ‘comparable quality, safety, and efficacy’ (EMA) and ‘no clinically meaningful differences in safety, purity, and potency’ (FDA) to the reference product. Development and manufacturing are based on reverse engineering of the reference product as only the primary amino acid sequence is known. Testing of primary, secondary, tertiary, and quaternary structure, binding pharmacokinetics, and stability is required. Characterization of post-translational modifications and biologic function, pharmacokinetics, evaluation of immunogenicity, and at least one comparative efficacy clinical trial are major requirements for regulatory approval. Clinical trials to assess biosimilarity are required in only one clinical indication and may be extrapolated to other indications for which the reference product is approved. Both single and multiple switching trials (between biosimilar and reference product) have yielded consistent results across numerous patient populations and diseases, with no evidence of detrimental outcomes. Two prospective large observational series (Danbio and Nor-Switch) have similarly assessed non-medical switching. Several open-label switching studies have revealed equivalent efficacy, safety, and discontinuation rates but real-world studies have raised concerns about potential nocebo responses.