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Frontiers in Genetics 2023In eukaryotic cells, the synthesis, processing, and degradation of mRNA are important processes required for the accurate execution of gene expression programmes. Fully... (Review)
Review
In eukaryotic cells, the synthesis, processing, and degradation of mRNA are important processes required for the accurate execution of gene expression programmes. Fully processed cytoplasmic mRNA is characterised by the presence of a 5'cap structure and 3'poly(A) tail. These elements promote translation and prevent non-specific degradation. Degradation via the deadenylation-dependent 5'-3' degradation pathway can be induced by trans-acting factors binding the mRNA, such as RNA-binding proteins recognising sequence elements and the miRNA-induced repression complex. These factors recruit the core mRNA degradation machinery that carries out the following steps: i) shortening of the poly(A) tail by the Ccr4-Not and Pan2-Pan3 poly (A)-specific nucleases (deadenylases); ii) removal of the 5'cap structure by the Dcp1-Dcp2 decapping complex that is recruited by the Lsm1-7-Pat1 complex; and iii) degradation of the mRNA body by the 5'-3' exoribonuclease Xrn1. In this review, the biochemical function of the nucleases and accessory proteins involved in deadenylation-dependent mRNA degradation will be reviewed with a particular focus on structural aspects of the proteins and enzymes involved.
PubMed: 37876592
DOI: 10.3389/fgene.2023.1233842 -
Peptides Dec 2023The aim of this personal reminiscence is to acquaint the reader with seminal workwork carried out in 1960 s and 1970 s that made possible the subsequent development of...
The aim of this personal reminiscence is to acquaint the reader with seminal workwork carried out in 1960 s and 1970 s that made possible the subsequent development of highly effective long-acting GLP-1R agonists and GLP-1R/GIPR co-agonists that are now in clinical practice for the treatment of Type 2 diabetes and obesity. The article highlights the particular contributions of the author's collaborators Ellis Samols and Desmond Turner in elucidating the nature and significance of gut glucagon-like immunoreactivity (enteroglucagon) and GIP. The potent incretin GLP-1(7-36)amide identified in the 1980 s met the criteria for a glucagon-like-substance with incretin like properties postulated to exist by Samols and others in 1966.
Topics: Humans; Incretins; Diabetes Mellitus, Type 2; Peptides; Glucagon-Like Peptide 1; Obesity; Glucagon-Like Peptide-1 Receptor; Gastric Inhibitory Polypeptide
PubMed: 37924847
DOI: 10.1016/j.peptides.2023.171115 -
Semergen Jun 2024The basis of COPD maintenance treatment is the long-acting bronchodilators and the inhaled corticosteroids. Faced with the recent modifications in the clinical practice... (Review)
Review
The basis of COPD maintenance treatment is the long-acting bronchodilators and the inhaled corticosteroids. Faced with the recent modifications in the clinical practice guidelines, we have carried out a review of studies that contrast the various therapeutic alternatives and pharmacological agents within each category, with the fundamental purpose of shedding light on which of these options prove to be more effective. Triple therapy stands out as essential in poorly controlled patients or with an eosinophilic phenotype, surpassing dual therapy. However, among the combinations of LAMA/LABA or LAMA/LABA/IC, no drug is observed to be superior in the reviewed evidence. Although triple therapies include corticosteroids, there does not appear to be a significant increase in side effects or pneumonia. Regarding monotherapy with LAMA, no significant differences are seen between the drugs, but in dual therapy with LABA/IC, the budesonide/formoterol combination seems to offer better control than fluticasone/salmeterol.
PubMed: 38925076
DOI: 10.1016/j.semerg.2024.102284 -
The Lancet Regional Health. Europe Nov 2023The current prevention efforts for STIs, HIV and viral hepatitis in the WHO European Region, especially in the Central and Eastern subregions, are hindered by healthcare... (Review)
Review
The current prevention efforts for STIs, HIV and viral hepatitis in the WHO European Region, especially in the Central and Eastern subregions, are hindered by healthcare disparities, data gaps, and limited resources. In this comprehensive narrative review, we aim to highlight both achievements and persisting challenges while also exploring new developments that could significantly impact the prevention of these infections in the near future. While pre-exposure prophylaxis (PrEP) for HIV has been broadly approved and implemented in 38 out of 53 countries in the region, challenges remain, including cost, limited licensing, and incomplete adherence. We explore innovative approaches like on-demand PrEP, long-acting injectable cabotegravir, and intravaginal rings that have shown promising results, alongside the use of six-monthly lenacapavir, the outcomes of which are pending. Additionally, the potential of doxycycline post-exposure prophylaxis has been discussed, revealing efficacy in reducing chlamydia and syphilis risk, but effectiveness against gonorrhoea being contingent on tetracycline resistance rates, and the need of further data to determine potential resistance development in other bacteria and its impact on the gut microbiome. We examine successful vaccination campaigns against HBV and HPV, the ongoing development of vaccines for chlamydia, syphilis, herpesvirus, and gonorrhoea, and challenges in HIV vaccine research, including lines of research with significant potential like sequential immunization, T-cell responses, and mRNA technology. This review underscores the research endeavors that pave the way for a more resilient and robust approach to combating STIs, HIV, and viral hepatitis in the region.
PubMed: 37927439
DOI: 10.1016/j.lanepe.2023.100738 -
Pediatric Radiology Apr 2024A transseptal coronary artery course, also known as a transconal course, is an anomalous course of the left main coronary artery (LMCA) or the left anterior descending... (Review)
Review
A transseptal coronary artery course, also known as a transconal course, is an anomalous course of the left main coronary artery (LMCA) or the left anterior descending artery (LAD) through the conal septal myocardium. The conal septal myocardium is the posterior wall of the right ventricular outflow tract (RVOT), acting as a dividing myocardial wall between the subaortic and subpulmonary outflow tracts. The initial segment of a transseptal coronary artery has an extraconal course between the aorta and the RVOT cranial to the true intramyocardial segment. The transseptal coronary artery then emerges out of the conal septal myocardium at the epicardial surface on the lateral aspect of the RVOT. Many consider the transseptal coronary artery to be a benign entity. However, there are few case reports of severe cardiac symptoms such as myocardial ischemia, arrhythmia, and even sudden cardiac deaths due to potential coronary artery compression in the systolic phase. In this article, we seek to describe the imaging findings of transseptal coronary artery course on coronary computed tomography angiography (CTA), discuss their clinical analysis, and briefly discuss the management of these lesions.
PubMed: 38637337
DOI: 10.1007/s00247-024-05911-x -
Current Atherosclerosis Reports Sep 2023The goal of this article is to characterize the endothelium's role in the development of hypertension and dyslipidemia and to point out promising therapeutic directions. (Review)
Review
PURPOSE OF REVIEW
The goal of this article is to characterize the endothelium's role in the development of hypertension and dyslipidemia and to point out promising therapeutic directions.
RECENT FINDINGS
Dyslipidemia may facilitate the development of hypertension, whereas the collaboration of these two silent killers potentiates the risk of atherosclerosis. The common pathophysiological denominator for hypertension and dyslipidemia is endothelial cell dysfunction, which manifests as dysregulation of homeostasis, redox balance, vascular tone, inflammation, and thrombosis. Treatment focused on mediators acting in these processes might be groundbreaking. Metabolomic research on hypertension and dyslipidemia has revealed new therapeutic targets. State-of-the-art solutions integrating interview, clinical examination, innovative imaging, and omics profiles along with artificial intelligence have been already shown to improve patients' risk stratification and treatment. Pathomechanisms underlying hypertension and dyslipidemia take place in the endothelium. Novel approaches involving endothelial biomarkers and bioinformatics advances could open new perspectives in patient management.
Topics: Humans; Artificial Intelligence; Hypertension; Dyslipidemias; Crime; Endothelium
PubMed: 37594602
DOI: 10.1007/s11883-023-01132-z -
Cureus Aug 2023It is believed that 9-18% of patients with hypertension have resistant hypertension, a serious medical disease. The increased cardiovascular risk associated with this... (Review)
Review
It is believed that 9-18% of patients with hypertension have resistant hypertension, a serious medical disease. The increased cardiovascular risk associated with this illness demands appropriate diagnosis and treatment. It is necessary to conduct an in-depth investigation of the various etiologies, indicators of risk, and multiple disorders of resistant hypertension. This is crucial in order to establish the diagnosis and make the best decisions regarding therapy. Treatment should also take lifestyle changes into account in addition to medicinal and interventional therapy. When there is a suspicion of resistant hypertension, examining the medications used to treat the hypertensive patient after ruling out pseudo hypertension, improper blood pressure monitoring and control, and the white-coat effect are necessary. Resistant hypertension, according to a specific definition, is a condition that cannot be treated with more than two antihypertensive drugs, including a diuretic. An effective multidrug therapy for the treatment of resistant hypertension includes angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, diuretics, long-acting calcium channel blockers, and mineralocorticoid receptor antagonists. However, alternative, cutting-edge treatments, such as renal denervation or baroreflex activation, could develop a brand-new avenue for decreasing blood pressure. These new surgical interventions might prove out to be of immense importance in coming times. Secondary causes of resistant hypertension, such as obstructive sleep apnea, coronary artery diseases, nephropathy, or endocrinal diseases, must be checked out in order to make an accurate diagnosis of this illness. This review article briefly summarizes the epidemiology, risk factors, causes, pathogenesis, diagnosis, and treatment approaches that may help with the long-term management of resistant hypertension.
PubMed: 37719515
DOI: 10.7759/cureus.43617 -
Nature Biotechnology Nov 2023RNA base editing refers to the rewriting of genetic information within an intact RNA molecule and serves various functions, such as evasion of the endogenous immune... (Review)
Review
RNA base editing refers to the rewriting of genetic information within an intact RNA molecule and serves various functions, such as evasion of the endogenous immune system and regulation of protein function. To achieve this, certain enzymes have been discovered in human cells that catalyze the conversion of one nucleobase into another. This natural process could be exploited to manipulate and recode any base in a target transcript. In contrast to DNA base editing, analogous changes introduced in RNA are not permanent or inheritable but rather allow reversible and doseable effects that appeal to various therapeutic applications. The current practice of RNA base editing involves the deamination of adenosines and cytidines, which are converted to inosines and uridines, respectively. In this Review, we summarize current site-directed RNA base-editing strategies and highlight recent achievements to improve editing efficiency, precision, codon-targeting scope and in vivo delivery into disease-relevant tissues. Besides engineered editing effectors, we focus on strategies to harness endogenous adenosine deaminases acting on RNA (ADAR) enzymes and discuss limitations and future perspectives to apply the tools in basic research and as a therapeutic modality. We expect the field to realize the first RNA base-editing drug soon, likely on a well-defined genetic disease. However, the long-term challenge will be to carve out the sweet spot of the technology where its unique ability is exploited to modulate signaling cues, metabolism or other clinically relevant processes in a safe and doseable manner.
Topics: Humans; RNA; Gene Editing
PubMed: 37735261
DOI: 10.1038/s41587-023-01927-0 -
The American Journal of Medicine Jan 2024Apparent resistant hypertension, defined as uncontrolled office blood pressure despite ≥ 3 antihypertensive medications including a diuretic or use of ≥ 4... (Review)
Review
Apparent resistant hypertension, defined as uncontrolled office blood pressure despite ≥ 3 antihypertensive medications including a diuretic or use of ≥ 4 medications regardless of blood pressure, occurs in ≤ 15% of treated hypertensives. Apparent refractory hypertension, defined as uncontrolled office pressure despite use of 5 or more medications including a diuretic, occurs in ≤ 10% of resistant cases. Both are associated with increased comorbidity and enhanced cardiovascular risk. To rule out pseudo-resistant or pseudo-refractory hypertension, employ guideline-based methodology for obtaining pressure, maximize the regimen, rule out white-coat effect, and assess adherence. True resistant hypertension is characterized by volume overload and aldosterone excess, refractory by enhanced sympathetic tone. Spironolactone is the preferred agent for resistance, with lower doses. Spironolactone, potassium binders, or both, are preferred if the estimated glomerular filtration rate is below 45. If significant albuminuria, finerenone is indicated. The optimal treatment of refractory hypertension is unclear, but sympathetic inhibition (α-β blockade, centrally acting sympathoinhibitors, or both) seems reasonable. Renal denervation has shown minimal benefit for resistance, but its role in refractory hypertension remains to be defined.
Topics: Humans; Spironolactone; Hypertension; Antihypertensive Agents; Blood Pressure; Diuretics; Blood Pressure Monitoring, Ambulatory
PubMed: 37832756
DOI: 10.1016/j.amjmed.2023.09.015 -
Nature Structural & Molecular Biology Nov 2023A translating ribosome is typically thought to follow the reading frame defined by the selected start codon. Using super-resolution ribosome profiling, here we report...
A translating ribosome is typically thought to follow the reading frame defined by the selected start codon. Using super-resolution ribosome profiling, here we report pervasive out-of-frame translation immediately from the start codon. Start codon-associated ribosomal frameshifting (SCARF) stems from the slippage of ribosomes during the transition from initiation to elongation. Using a massively paralleled reporter assay, we uncovered sequence elements acting as SCARF enhancers or repressors, implying that start codon recognition is coupled with reading frame fidelity. This finding explains thousands of mass spectrometry spectra that are unannotated in the human proteome. Mechanistically, we find that the eukaryotic initiation factor 5B (eIF5B) maintains the reading frame fidelity by stabilizing initiating ribosomes. Intriguingly, amino acid starvation induces SCARF by proteasomal degradation of eIF5B. The stress-induced SCARF protects cells from starvation by enabling amino acid recycling and selective mRNA translation. Our findings illustrate a beneficial effect of translational 'noise' in nutrient stress adaptation.
Topics: Humans; Codon, Initiator; Frameshifting, Ribosomal; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Amino Acids; Protein Biosynthesis
PubMed: 37957305
DOI: 10.1038/s41594-023-01119-z