Project description:Experiments on model systems have revealed that cytokinesis in cells with contractile rings (amoebas, fungi, and animals) depends on shared molecular mechanisms in spite of some differences that emerged during a billion years of divergent evolution. Understanding these fundamental mechanisms depends on identifying the participating proteins and characterizing the mechanisms that position the furrow, assemble the contractile ring, anchor the ring to the plasma membrane, trigger ring constriction, produce force to form a furrow, disassemble the ring, expand the plasma membrane in the furrow, and separate the daughter cell membranes. This review reveals that fascinating questions remain about each step.
Project description:OBJECTIVE:The epidemiology of heart failure (HF) is changing. This study aimed to describe questions that arise during the routine care of HF patients that are unanswered by the current literature and describe how the type and focus of these questions has changed over time. METHODS:Investigators from the National Heart, Lung, and Blood Institute-sponsored Heart Failure Apprentice Network collected and categorized questions from 5 academic hospitals over 12 months. A total of 174 unanswered questions were collected and analyzed. RESULTS:Compared with 2004, there were more unanswered questions about "whether" to use therapies and fewer about "how" to use therapies. There were fewer questions about what therapeutic targets, therapy adjustment, and combination therapies. There were more questions about whether or how to stop therapies and how to add therapies back. Newly prominent topics, not observed in 2004, including novel therapeutics, refractory ventricular tachycardia, right heart failure, and nutrition/frailty, accounted for 24% of questions. CONCLUSIONS:Compared with 2004, there are fewer unanswered questions about how to use, adjust, and combine therapies. There were more unanswered questions about whether and how to stop therapies. Almost 25% of unanswered questions dealt with topics indicative of more advanced disease which were not observed in 2004.
Project description:More than 15% of the US population is currently >65 y old. As populations age there is a concomitant increase in age-related chronic diseases. One such disease is chronic kidney disease (CKD), which becomes more prevalent with age, especially over age 70 y. Individuals with CKD are at increased risk of cardiovascular disease, in part because arterial calcification increases as kidney function declines. Vitamin K is a shortfall nutrient among older adults that has been implicated in arterial calcification. Evidence suggests CKD patients have low vitamin K status, but data are equivocal because the biomarkers of vitamin K status can be influenced by CKD. Animal studies provide more compelling data on the underlying role of vitamin K in arterial calcification associated with CKD. The purpose of this review is to evaluate the strengths and limitations of the available evidence regarding the role of vitamin K in CKD.
Project description:Coronary atherosclerotic heart disease is a serious threat to human health. The results of the Canakinumab Anti-Inflammatory Thrombosis Outcome Study published in 2017 put an end to the perennial debate about the anti-inflammatory treatment of coronary atherosclerotic heart disease. In addition to interleukin 1? monoclonal antibody, interleukin 6 receptor antagonists and colchicine have also shown exciting results in clinical trials within the last 3 years. However, behind these successes, questions remain that need to be addressed. In this review, we summarize the successes and existing doubts of interleukin 1? antibodies, interleukin 6 receptor antagonists, and colchicine in the anti-inflammatory treatment of coronary atherosclerotic heart disease.
Project description:Several new therapies for hemophilia have emerged in recent years. These strategies range from extended half-life factor replacement products and non-factor options with improved pharmacokinetic profiles to gene therapy aiming for phenotypic cure. While these products have the potential to change hemophilia care dramatically, several challenges and questions remain regarding broader applicability, long-term safety, and which option to pursue for each patient. Here, we review these emerging therapies with a focus on controversies and unanswered questions in each category.
Project description:Upper respiratory tract infections ("common cold") are the most common acute illnesses in elite athletes. Numerous studies on exercise immunology have proposed that intense exercise may increase susceptibility to respiratory infections. Virological data to support that view are sparse, and several fundamental questions remain. Immunity to respiratory viral infections is highly complex, and there is a lack of evidence that minor short- or long-term alterations in immunity in elite athletes have clinical implications. The degree to which athletes are infected by respiratory viruses is unclear. During major sport events, athletes are at an increased risk of symptomatic infections caused by the same viruses as those in the general population. The symptoms are usually mild and self-limiting. It is anecdotally known that athletes commonly exercise and compete while having a respiratory viral infection; there are no virological studies to suggest that such activity would affect either the illness or the performance. The risk of myocarditis exists. Which simple mitigation procedures are crucial for effective control of seasonal respiratory viral infections is not known.
Project description:DNA topoisomerases are enzymes that catalyze changes in the torsional and flexural strain of DNA molecules. Earlier studies implicated these enzymes in a variety of processes in both prokaryotes and eukaryotes, including DNA replication, transcription, recombination, and chromosome segregation. Studies performed over the past 3 years have provided new insight into the roles of various topoisomerases in maintaining eukaryotic chromosome structure and facilitating the decatenation of daughter chromosomes at cell division. In addition, recent studies have demonstrated that the incorporation of ribonucleotides into DNA results in trapping of topoisomerase I (TOP1)-DNA covalent complexes during aborted ribonucleotide removal. Importantly, such trapped TOP1-DNA covalent complexes, formed either during ribonucleotide removal or as a consequence of drug action, activate several repair processes, including processes involving the recently described nuclear proteases SPARTAN and GCNA-1. A variety of new TOP1 inhibitors and formulations, including antibody-drug conjugates and PEGylated complexes, exert their anticancer effects by also trapping these TOP1-DNA covalent complexes. Here we review recent developments and identify further questions raised by these new findings.
Project description:Crosstalk between the BMP and TGF-β signaling pathways regulates many complex developmental processes from the earliest stages of embryogenesis throughout adult life. In many situations, the two signaling pathways act reciprocally. For example, TGF-β signaling is generally pro-fibrotic, whereas BMP signaling is anti-fibrotic and pro-calcific. Sex-specific differences occur in many diseases including cardiovascular pathologies. Differing ratios of fibrosis and calcification in stenotic valves suggests that BMP/TGF-β signaling may vary in men and women. In this review, we focus on the current understanding of the interplay between sex and BMP/TGF-β signaling and pose several unanswered questions.
Project description:Pulmonary embolism (PE) continues to represent a significant health care burden and its incidence is steadily increasing worldwide. Constantly evolving therapeutic options and the rarity of randomized controlled trial data to drive clinical guidelines impose challenges on physicians caring for patients with PE. Recently, PE response teams have been developed and recommended to help address these issues by facilitating a consensus among local experts while advocating the management of acute PE according to each individual patient profile. In this review, we focus on the clinical challenges supporting the need for a PE response team, report the current evidence for their implementation, assess their impact on PE management and outcomes, and address unanswered questions and future directions.
Project description:Policies and measures to control pandemics are often failing. While biological factors controlling transmission are usually well explored, little is known about the environmental drivers of transmission and infection. For instance, respiratory droplets and aerosol particles are crucial vectors for the airborne transmission of the severe acute respiratory syndrome coronavirus 2, the causation agent of the coronavirus 2019 pandemic (COVID-19). Once expectorated, respiratory droplets interact with atmospheric particulates that influence the viability and transmission of the novel coronavirus, yet there is little knowledge on this process or its consequences on virus transmission and infection. Here we review the effects of atmospheric particulate properties, vortex zones, and air pollution on virus survivability and transmission. We found that particle size, chemical constituents, electrostatic charges, and the moisture content of airborne particles can have notable effects on virus transmission, with higher survival generally associated with larger particles, yet some viruses are better preserved on small particles. Some chemical constituents and surface-adsorbed chemical species may damage peptide bonds in viral proteins and impair virus stability. Electrostatic charges and water content of atmospheric particulates may affect the adherence of virion particles and possibly their viability. In addition, vortex zones and human thermal plumes are major environmental factors altering the aerodynamics of buoyant particles in air, which can strongly influence the transport of airborne particles and the transmission of associated viruses. Insights into these factors may provide explanations for the widely observed positive correlations between COVID-19 infection and mortality with air pollution, of which particulate matter is a common constituent that may have a central role in the airborne transmission of the novel coronavirus.Supplementary informationThe online version contains supplementary material available at 10.1007/s10311-022-01557-z.