Autophagy in major human diseases Klionsky, Daniel J; Petroni, Giulia; Amaravadi, Ravi K ...
The EMBO journal,
01 October 2021, Letnik:
40, Številka:
19
Journal Article
Recenzirano
Odprti dostop
Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease ...in a plethora of experimental models. Consistently, mutations in autophagy‐related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.
This review provides an exhaustive overview of the contribution of autophagy to multiple pathological phenotypes in vivo, and discusses the therapeutic potential of autophagy modulation in disease prevention and treatment.
Autophagy is the process by which organelles and portions of the cytoplasm are degraded in lysosomes. Several different forms of autophagy are known that are distinguishable chiefly by the mode in ...which cargo is delivered to the lysosome for degradation. Ubiquilin was recently reported to regulate macroautophagy, the form of autophagy in which cytosolic cargo is packaged in a double-membrane structure or autophagosome that fuses with lysosomes for degradation. We confirm here using different morphological and biochemical procedures that ubiquilin is present in autophagosomes in HeLa cells and in brain and liver tissue of mouse. Coimmunoprecipitation studies indicated that ubiquilin binds the autophagosome marker LC3 in a complex and that reduction of ubiquilin expression reduces autophagosome formation, which correlates with a reduction in maturation of LC3-I to the LC3-II form of the protein. We found that ubiquilin is degraded during both macroautophagy and during chaperone-mediated autophagy (CMA), the latter of which involves the active transport of proteins into lysosomes. We discuss the implication of this degradation in mediating cross-talk between macroautophagy and CMA. Finally, we demonstrate that ubiquilin protects cells against starvation-induced cell death propagated by overexpression of mutant Alzheimer's disease PS2N141I protein and green fluorescent protein (GFP)-huntingtin exon-1 fusion protein containing 74 polyglutamines.
Advances in cryo-electron microscopy (cryo-EM) have made it possible to obtain structures of large biological macromolecules at near-atomic resolution. This “resolution revolution” has encouraged the ...use and development of modeling tools able to produce high-quality atomic models from cryo-EM density maps. Unfortunately, many practical problems appear when combining different packages in the same processing workflow, which make difficult the use of these tools by non-experts and, therefore, reduce their utility. We present here a major extension of the image processing framework Scipion that provides inter-package integration in the model building area and full tracking of the complete workflow, from image processing to structure validation.
Short-term peripheral venous catheters are a significant source of healthcare-acquired bloodstream infections and a preventable cause of death.
To assess the effectiveness of interventions applied to ...reduce the incidence and mortality associated with short-term peripheral venous catheter-related bloodstream infections (PVCR-BSIs).
The intervention included continuous PVCR-BSI surveillance, implementation of preventive measures related to catheter insertion and maintenance in accordance with evidence-based recommendations and the hospital's own data, front-line staff educational campaigns, and assessment of adherence to hospital guidelines by ward rounds. A Poisson regression model was used to estimate the trend of rate per year.
From January 2003 to December 2016, 227 episodes of PVCR-BSI were identified among hospitalized patients at a university hospital. The mean age of patients was 67 years (standard deviation 14 years), 69% were male and the median Charlson score was 3 (interquartile range 2–5). Staphylococcus aureus caused 115 (50.7%) episodes. Thirty-day mortality was 13.2%. After implementation of the intervention, the incidence of PVCR-BSIs decreased significantly from 30 episodes in 2003 (1.17 episodes/10,000 patient-days) to eight episodes in 2016 (0.36/10,000 patient-days). The number of episodes caused by S. aureus decreased from 18 episodes in 2003 (0.70/10,000 patient-days) to three episodes in 2016 (0.14/10,000 patient-day), and mortality decreased from seven cases in 2003 (0.27/10,000 patient-days) to zero cases in 2016 (0.00/10,000 patient-days).
Surveillance, implementation of a multi-modal strategy and periodical assessment of healthcare workers' adherence to hospital guidelines led to a sustained reduction in PVCR-BSIs. This reduction had a major impact on S. aureus BSI rates and associated mortality.
Animals aften announce their unprofitability to predators through conspicuous coloured signals. Here we tested whether the apparently conspicuous colour designs of the four European Coraciiformes and ...Upupiformes species may have evolved as aposematic signals, or whether instead they imply a cost in terms of predation risk. Because previous studies suggested that these species are unpalatable, we hypothesized that predators could avoid targeting them based on their colours. An experiment was performed where two artificial models of each bird species were exposed simultaneously to raptor predators, one painted so as to resemble the real colour design of these birds, and the other one painted using cryptic colours. Additionally, we used field data on the black kite's diet to compare the selection of these four species to that of other avian prey. Conspicuous models were attacked in equal or higher proportions than their cryptic counterparts, and the attack rate on the four species increased with their respective degree of contrast against natural backgrounds. The analysis of the predator's diet revealed that the two least attacked species were negatively selected in nature despite their abundance. Both conspicuous and cryptic models of one of the studied species (the hoopoe) received fewer attacks than cryptic models of the other three species, suggesting that predators may avoid this species for characteristics other than colour. Globally, our results suggest that the colour of coraciiforms and upupiforms does not function as an aposematic signal that advises predators of their unprofitability, but also that conspicuous colours may increase predation risk in some species, supporting thus the handicap hypothesis.
Vascular catheter-related bloodstream infections (CRBSIs) are highly preventable hospital-acquired infections and a major threat to patient safety. While there is significant information regarding ...CRBSI outcome among intensive care unit (ICU) patients, data regarding non-ICU patients are scarce.
To determine the risk factors associated with 30-day mortality among non-ICU patients with nosocomial CRBSIs.
Prospective cohort study of non-ICU patients with nosocomial CRBSIs in a tertiary care centre between January 2004 and December 2014. The primary outcome was 30-day mortality, defined as death from any cause within 30 days of CRBSI. Follow-up was performed 30 days after CRBSI onset. Time until death was the dependent variable in Cox regression analysis.
In total, 546 cases of CRBSI were identified. The mean age of patients was 64.5 years interquartile range (IQR) 55–75 years, 66% were male, and the mean Charlson score was 3.59 (IQR 2–5). Of the 546 cases, 58.4% resulted from central venous catheters and 41.6% from peripheral venous catheters. The causative agents were Gram-positive cocci (70.1% of cases), Gram-negative bacilli (31.1%) and Candida spp. (1%). Mortality within 30 days was 13.9%, with no significant changes over the study period. Independent risk factors for 30-day mortality were Charlson score ≥4 hazard ratio (HR) 1.80, 95% confidence interval (CI) 1.19–2.73, Staphylococcus aureus infection (HR 2.67, 95% CI 1.61–4.43) and Candida spp. infection (HR 6.1, 95% CI 2.08–18.04). Age; area of admission; type, use and site of vascular catheter; and administration of appropriate empirical antibiotic treatment were not independent risk factors for 30-day mortality.
Nosocomial CRBSIs outside ICUs are associated with high risk of mortality, particularly among patients with a higher Charlson score and bloodstream infections caused by Staphylococcus aureus and Candida spp.
This study aims to determine the level of culture of a new subsidiary of a company in Colombia and define strategies to increase the level of culture in a way that promotes the organization in this ...region. Following the organizational culture theories, the Organizational Culture Assessment Instrument was used to measure the aspects of organizational culture. The transfer and adoption of culture are achieved through knowledge sharing within and across the departments and units of large organizations. The comparison between the current and desired state of culture shows a gap in the clan culture, as the company wishes to establish a working environment that promotes teamwork and employee participation, creates confidence, and provides opportunities for professional development. Executives can measure the strength of organizational culture with the aim of updating, strengthening, or modifying the existing culture to improve performance and gain sustainability.
Cryo‐electron microscopy (cryoEM) has become a well established technique to elucidate the 3D structures of biological macromolecules. Projection images from thousands of macromolecules that are ...assumed to be structurally identical are combined into a single 3D map representing the Coulomb potential of the macromolecule under study. This article discusses possible caveats along the image‐processing path and how to avoid them to obtain a reliable 3D structure. Some of these problems are very well known in the community. These may be referred to as sample‐related (such as specimen denaturation at interfaces or non‐uniform projection geometry leading to underrepresented projection directions). The rest are related to the algorithms used. While some have been discussed in depth in the literature, such as the use of an incorrect initial volume, others have received much less attention. However, they are fundamental in any data‐analysis approach. Chiefly among them, instabilities in estimating many of the key parameters that are required for a correct 3D reconstruction that occur all along the processing workflow are referred to, which may significantly affect the reliability of the whole process. In the field, the term overfitting has been coined to refer to some particular kinds of artifacts. It is argued that overfitting is a statistical bias in key parameter‐estimation steps in the 3D reconstruction process, including intrinsic algorithmic bias. It is also shown that common tools (Fourier shell correlation) and strategies (gold standard) that are normally used to detect or prevent overfitting do not fully protect against it. Alternatively, it is proposed that detecting the bias that leads to overfitting is much easier when addressed at the level of parameter estimation, rather than detecting it once the particle images have been combined into a 3D map. Comparing the results from multiple algorithms (or at least, independent executions of the same algorithm) can detect parameter bias. These multiple executions could then be averaged to give a lower variance estimate of the underlying parameters.
Single‐particle analysis (SPA) by cryo‐electron microscopy comprises the estimation of many parameters along its image‐processing pipeline. Overfitting observed in SPA is normally due to misestimated parameters, and the only way to identify these is by comparing the estimates of multiple algorithms or, at least, multiple executions of the same algorithm.
Over the past two decades, the molecular machinery that underlies autophagic responses has been characterized with ever increasing precision in multiple model organisms. Moreover, it has become clear ...that autophagy and autophagy‐related processes have profound implications for human pathophysiology. However, considerable confusion persists about the use of appropriate terms to indicate specific types of autophagy and some components of the autophagy machinery, which may have detrimental effects on the expansion of the field. Driven by the overt recognition of such a potential obstacle, a panel of leading experts in the field attempts here to define several autophagy‐related terms based on specific biochemical features. The ultimate objective of this collaborative exchange is to formulate recommendations that facilitate the dissemination of knowledge within and outside the field of autophagy research.
Autophagy‐related responses are described in an increasing number of distinct biological contexts. This review discusses the use of appropriate terms for autophagic processes with the aim to provide recommendations and avoid confusion in the field of autophagy research.
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