α1-Antitrypsin deficiency and the risk of COVID-19: an urgent call to action.
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ABSTRACT:
SUBMITTER: Yang C
PROVIDER: S-EPMC7826115 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The Z mutation (E342K) of α1-antitrypsin (α1-AT), carried by 4% of Northern Europeans, predisposes to early onset of emphysema due to decreased functional α1-AT in the lung and to liver cirrhosis due to accumulation of polymers in hepatocytes. However, it remains unclear why the Z mutation causes intracellular polymerization of nascent Z α1-AT and why 15% of the expressed Z α1-AT is secreted into circulation as functional, but polymerogenic, monomers. Here, we solve the crystal structure of the Z-monomer and have engineered replacements to assess the conformational role of residue Glu-342 in α1-AT. The results reveal that Z α1-AT has a labile strand 5 of the central β-sheet A (s5A) with a consequent equilibrium between a native inhibitory conformation, as in its crystal structure here, and an aberrant conformation with s5A only partially incorporated into the central β-sheet. This aberrant conformation, induced by the loss of interactions from the Glu-342 side chain, explains why Z α1-AT is prone to polymerization and readily binds to a 6-mer peptide, and it supports that annealing of s5A into the central β-sheet is a crucial step in the serpins' metastable conformational formation. The demonstration that the aberrant conformation can be rectified through stabilization of the labile s5A by binding of a small molecule opens a potential therapeutic approach for Z α1-AT deficiency.
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Project description:A model on the role of character strengths in individual, collective, and species success is proffered. It is derived from viewing character strengths from a species perspective as opposed to one of individual differences/personality psychology. The history of the VIA initiative on character science is overviewed, and results to date are summarized in terms of promoting well-being, helping to accomplish aspirational intentions, and allowing the greater good of the collective to grow. "The character strengths response" is described as the response capacities that character strengths may enable for helping us fulfill the human promise of surviving, thriving, and successfully creating a next-generation so that individuals and the collective flourish while also living in harmonious balance with other species. An argument is presented that there is an urgent need for advancing population-wide psychological maturity to be better prepared to navigate the difficult decisions that accompany growing technological powers, and that the character strengths response warrants special attention of research funding to accomplish this imperative.
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Project description:α1-Antitrypsin deficiency (AATD) has been historically under-recognised and under-diagnosed; recently it has begun to receive greater interest in terms of attempts at deeper elucidation of pathology and treatment options. However, the concept of disease phenotypes within AATD (emphysema, chronic bronchitis, bronchiectasis or a combination of phenotypes) has not been proposed or studied. Of the three neutrophil serine proteases, neutrophil elastase was historically believed to be the sole contributor to disease pathology in AATD. Recently, Proteinase-3 has been increasingly studied as an equal, if not greater, contributor to the disease process. Cathepsin G, however, has not been extensively evaluated in this area. Matrix metalloproteinases have also been mentioned in the pathogenesis of AATD but have not been widely explored. This article considers the available evidence for differential protease activity in patients with AATD, including the contribution to distinct phenotypes of the disease. Owing to limited literature in this area, extrapolations from studies of other chronic lung diseases with similar phenotypes, including COPD and bronchiectasis, have been made. We consider a new framework of understanding defined by protease-driven endotypes of disease which may lead to new opportunities for precision medicine. α1-antitrypsin deficiency is a heterogeneous disease driven by aberrant protease activity in the presence of low α1-AT levels. Understanding mechanisms driving pathological processes in α1-ATD phenotypes could identify novel therapeutic targets.https://bit.ly/2XeILCp
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Project description:The social burden of Bangladesh's already prevalent child marriage problem has further flared up amid the ongoing COVID-19 pandemic. We aim to briefly report on the current scenario of underage marriage in Bangladesh from available sources and highlight concerns. The prevalence of child marriage has increased by at least 13% due to pandemic-enforced long-term school closure throughout the country, while many cases remain unreported. Exacerbated financial crisis, the prolonged shutdown of educational institutions and social insecurities are the principal triggering factors for such a high pace of child marriages. We urge the government and local administrations to address the current situation through concerted and integrated efforts to combat the early marriage crisis in Bangladesh.
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Project description:α1-Antitrypsin (α1AT) deficiency (α1ATD) is a consequence of defective folding, trafficking, and secretion of α1AT in response to a defect in its interaction with the endoplasmic reticulum proteostasis machineries. The most common and severe form of α1ATD is caused by the Z-variant and is characterized by the accumulation of α1AT polymers in the endoplasmic reticulum of the liver leading to a severe reduction (>85%) of α1AT in the serum and its anti-protease activity in the lung. In this organ α1AT is critical for ensuring tissue integrity by inhibiting neutrophil elastase, a protease that degrades elastin. Given the limited therapeutic options in α1ATD, a more detailed understanding of the folding and trafficking biology governing α1AT biogenesis and its response to small molecule regulators is required. Herein we report the correction of Z-α1AT secretion in response to treatment with the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA), acting in part through HDAC7 silencing and involving a calnexin-sensitive mechanism. SAHA-mediated correction restores Z-α1AT secretion and serpin activity to a level 50% that observed for wild-type α1AT. These data suggest that HDAC activity can influence Z-α1AT protein traffic and that SAHA may represent a potential therapeutic approach for α1ATD and other protein misfolding diseases.
| S-EPMC3488095 | biostudies-literature
Project description:BackgroundHypertension is a leading cause of cardiovascular disease (CVD) and affects nearly one in two adults in the United States when defined as a blood pressure of at least 130/80 mm Hg or on antihypertensive medication (Virani et al., 2021, Circulation, 143, e254). Long-standing disparities in hypertension awareness, treatment, and control among racial and ethnic populations exist in the United States. High-quality evidence exists for how to prevent and control hypertension and for the role nurses can play in this effort. In response to the 2020 Surgeon General's Call to Action to Control Hypertension, nursing leaders from 11 national organizations identified the critical roles and actions of nursing in improving hypertension control and cardiovascular health, focusing on evidence-based nursing interventions and available resources.AimsTo develop a unified "Call to Action for Nurses" to improve control of hypertension and cardiovascular health and provide information and resources to execute this call.MethodsThis paper outlines roles that registered nurses, advanced practice nurses, schools of nursing, professional nursing organizations, quality improvement nurses, and nursing researchers can play to control hypertension and prevent CVD in the United States. It describes evidence-based interventions to improve cardiovascular health and outlines actions to bring hypertension and CVD to the forefront as a national priority for nursing.Linking evidence to actionEvidence-based interventions exist for nurses to lead efforts to prevent and control hypertension, thus preventing much CVD. Nurses can take actions in their communities, their healthcare setting, and their organization to translate these interventions into real-world practice settings.
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Project description: Not available
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Project description:Diabetes, hypertension and cardiovascular disease have been listed as risk factors for severe coronavirus disease 2019 (COVID-19) since the first report of the disease in January 2020. However, this report did not mention chronic kidney disease (CKD) nor did it provide information on the relevance of estimated glomerular filtration rate (eGFR) or albuminuria. As the disease spread across the globe, information on larger populations with greater granularity on risk factors emerged. The recently published OpenSAFELY project analysed factors associated with COVID-19 death in 17 million patients. The picture that arose differs significantly from initial reports. For example, hypertension is not an independent risk factor for COVID-19 death [adjusted hazard ratio (aHR) 0.89], but renal disease very much is. Dialysis (aHR 3.69), organ transplantation (aHR 3.53) and CKD (aHR 2.52 for patients with eGFR <30 mL/min/1.73 m2) represent three of the four comorbidities associated with the highest mortality risk from COVID-19. The risk associated with CKD Stages 4 and 5 is higher than the risk associated with diabetes mellitus (aHR range 1.31-1.95, depending upon glycaemic control) or chronic heart disease (aHR 1.17). In another recent publication, the Global Burden of Disease collaboration identified that worldwide, CKD is the most prevalent risk factor for severe COVID-19. Moreover, the distribution of risk factors for COVID-19 mortality appears to be different in patients with CKD when compared with the general population. The high prevalence of CKD in combination with the elevated risk of mortality from COVID-19 in CKD necessitates urgent action for this group of patients. This article defines essential action points (summarized in Box 1), among which is advocating the inclusion of CKD patients in clinical trials testing the efficacy of drugs and vaccines to prevent severe COVID-19.
| S-EPMC7771976 | biostudies-literature
Project description:We argue that predictions of a 'tsunami' of mental health problems as a consequence of the pandemic of coronavirus disease 2019 (COVID-19) and the lockdown are overstated; feelings of anxiety and sadness are entirely normal reactions to difficult circumstances, not symptoms of poor mental health. Some people will need specialised mental health support, especially those already leading tough lives; we need immediate reversal of years of underfunding of community mental health services. However, the disproportionate effects of COVID-19 on the most disadvantaged, especially BAME people placed at risk by their social and economic conditions, were entirely predictable. Mental health is best ensured by urgently rebuilding the social and economic supports stripped away over the last decade. Governments must pump funds into local authorities to rebuild community services, peer support, mutual aid and local community and voluntary sector organisations. Health care organisations must tackle racism and discrimination to ensure genuine equal access to universal health care. Government must replace highly conditional benefit systems by something like a universal basic income. All economic and social policies must be subjected to a legally binding mental health audit. This may sound unfeasibly expensive, but the social and economic costs, not to mention the costs in personal and community suffering, though often invisible, are far greater.
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Project description:Corona Virus Disease 2019 (COVID-19) has emerged as a pandemic leading to unprecedented disruption of global health and economy. Transmembrane protease serine 2 (TMPRSS2) has been found to be critical in priming the viral spike protein and the host ACE2 receptor before the virus enters into the host cell. Recent studies have experimentally demonstrated that Alpha 1 antitrypsin (encoded by SERPINA1 gene) is an inhibitor of TMPRSS2 and provided support to the already approved therapy as a candidate for COVID-19. Interestingly Alpha 1 antitrypsin deficiency is common among Europeans. Here we have provided in silico evidence that Alpha 1 antitrypsin can interact with TMPRSS2 and both of them are co-expressed in the human liver and lung. We then analyzed the gnomAD dataset to show that Europeans and Latinos have a substantially higher carrier frequency of Alpha 1 Antitrypsin Deficiency (~12%) compared to other large ethnicities. Therefore, we hypothesize that Alpha 1 antitrypsin deficiency might be a risk factor for severe infection with SARS-CoV-2. We propose Alpha 1 antitrypsin status as a potential prognostic predictor of COVID-19 outcome.
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