The dynamic network of mitochondria fragments under stress allowing the segregation of damaged mitochondria and, in case of persistent damage, their selective removal by mitophagy. Mitochondrial ...fragmentation upon depolarisation of mitochondria is brought about by the degradation of central components of the mitochondrial fusion machinery. The OMA1 peptidase mediates the degradation of long isoforms of the dynamin‐like GTPase OPA1 in the inner membrane. Here, we demonstrate that OMA1‐mediated degradation of OPA1 is a general cellular stress response. OMA1 is constitutively active but displays strongly enhanced activity in response to various stress insults. We identify an amino terminal stress‐sensor domain of OMA1, which is only present in homologues of higher eukaryotes and which modulates OMA1 proteolysis and activation. OMA1 activation is associated with its autocatalyic degradation, which initiates from both termini of OMA1 and results in complete OMA1 turnover. Autocatalytic proteolysis of OMA1 ensures the reversibility of the response and allows OPA1‐mediated mitochondrial fusion to resume upon alleviation of stress. This differentiated stress response maintains the functional integrity of mitochondria and contributes to cell survival.
Synopsis
A sensor domain for mitochondrial stress and a novel self‐degradation mechanism enables the mitochondrial protease OMA1 to reversibly control mitochondrial fragmentation in response to various cellular stresses.
Various cellular stress conditions activate OMA1 and induce OPA1 processing and mitochondrial fragmentation.
A stress‐sensor domain is present outside the conserved metallopeptidase domain in the amino terminal region of mammalian OMA1.
OMA1 activation is accompanied by its autocatalytic turnover ensuring the reversibility of the response.
A sensor domain for mitochondrial stress and a novel self‐degradation mechanism enables the mitochondrial protease OMA1 to reversibly control mitochondrial fragmentation in response to various cellular stresses.
Is it time for airway management education to be mandatory? Baker, P.A.; Feinleib, J.; O’Sullivan, E.P.
British journal of anaesthesia : BJA,
September 2016, 20160901, 2016-Sep, 2016-09-00, Letnik:
117, Številka:
suppl_1
Journal Article
Genomic bins belonging to multiple archaeal lineages were recovered from distinct redox regimes in sediments of the White Oak River estuary. The reconstructed archaeal genomes were identified as ...belonging to the rice cluster subgroups III and V (RC-III, RC-V), the Marine Benthic Group D (MBG-D), and a newly described archaeal class, the Theionarchaea. The metabolic capabilities of these uncultured archaea were inferred and indicated a common capability for extracellular protein degradation, supplemented by other pathways. The multiple genomic bins within the MBG-D archaea shared a nearly complete reductive acetyl-CoA pathway suggesting acetogenic capabilities. In contrast, the RC-III metabolism appeared centered on the degradation of detrital proteins and production of H
, whereas the RC-V archaea lacked capabilities for protein degradation and uptake, and appeared to be specialized on carbohydrate fermentation. The Theionarchaea appeared as complex metabolic hybrids; encoding a complete tricarboxylic acid cycle permitting carbon (acetyl-CoA) oxidation, together with a complete reductive acetyl-CoA pathway and sulfur reduction by a sulfhydrogenase. The differentiated inferred capabilities of these uncultured archaeal lineages indicated lineage-specific linkages with the nitrogen, carbon and sulfur cycles. The predicted metabolisms of these archaea suggest preferences for distinct geochemical niches within the estuarine sedimentary environment.
A general scheme for trust-region methods on Riemannian manifolds is proposed and analyzed. Among the various approaches available to (approximately) solve the trust-region subproblems, particular ...attention is paid to the truncated conjugate-gradient technique. The method is illustrated on problems from numerical linear algebra. PUBLICATION ABSTRACT
Type-1 and type-3 interferons (IFNs) are important for control of viral replication; however, less is known about the role of Type-2 IFN (IFNγ) in anti-viral immunity. We previously observed that ...lung infection with Mycobacterium bovis BCG achieved though intravenous (iv) administration provides strong protection against SARS-CoV-2 in mice yet drives low levels of type-1 IFNs but robust IFNγ. Here we examine the role of ongoing IFNγ responses to pre-established bacterial infection on SARS-CoV-2 disease outcomes in two murine models. We report that IFNγ is required for iv BCG induced reduction in pulmonary viral loads, an outcome dependent on IFNγ receptor expression by non-hematopoietic cells. Importantly, we show that BCG infection prompts pulmonary epithelial cells to upregulate IFN-stimulated genes with reported anti-viral activity in an IFNγ-dependent manner, suggesting a possible mechanism for the observed protection. Finally, we confirm the anti-viral properties of IFNγ by demonstrating that the recombinant cytokine itself provides strong protection against SARS-CoV-2 challenge when administered intranasally. Together, our data show that a pre-established IFNγ response within the lung is protective against SARS-CoV-2 infection, suggesting that concurrent or recent infections that drive IFNγ may limit the pathogenesis of SARS-CoV-2 and supporting possible prophylactic uses of IFNγ in COVID-19 management.
We conducted a cross-sectional study to estimate the prevalence of metabolic syndrome, a clustering of risk factors associated with cardiovascular disease, among 86 adults who had allogeneic ...hematopoietic-cell transplant (HCT) as compared with 258 age- and gender-matched US population controls selected from the 2005-2006 National Health and Nutrition Examination Survey database. The median age at study enrollment was 50 years (range, 21-71), and patients were at a median of 3 years (range, 1-21) from HCT. The prevalence of metabolic syndrome was 49% (95% confidence intervals (CI), 38-60%) among HCT recipients, a 2.2-fold (95% CI, 1.3-3.6, P=0.002) increase compared with controls. The prevalence rates of elevated blood pressure and hypertriglyceridemia were significantly higher among HCT recipients than among controls, but the prevalence rates of abdominal obesity, elevated blood glucose and low high-density lipoprotein cholesterol were not. HCT survivors with metabolic syndrome were more likely to have microalbuminuria (43 vs 10%) and elevated creatinine (31 vs 11%). No patient, donor or transplant characteristics were associated with the diagnosis of metabolic syndrome. We conclude that metabolic syndrome occurs frequently among allogeneic HCT survivors who are seen by transplant physicians. Approaches to screening, prevention and management of metabolic syndrome should be developed for HCT recipients.
Summary
Across multiple disciplines undertaking airway management globally, preventable episodes of unrecognised oesophageal intubation result in profound hypoxaemia, brain injury and death. These ...events occur in the hands of both inexperienced and experienced practitioners. Current evidence shows that unrecognised oesophageal intubation occurs sufficiently frequently to be a major concern and to merit a co‐ordinated approach to address it. Harm from unrecognised oesophageal intubation is avoidable through reducing the rate of oesophageal intubation, combined with prompt detection and immediate action when it occurs. The detection of ‘sustained exhaled carbon dioxide’ using waveform capnography is the mainstay for excluding oesophageal placement of an intended tracheal tube. Tube removal should be the default response when sustained exhaled carbon dioxide cannot be detected. If default tube removal is considered dangerous, urgent exclusion of oesophageal intubation using valid alternative techniques is indicated, in parallel with evaluation of other causes of inability to detect carbon dioxide. The tube should be removed if timely restoration of sustained exhaled carbon dioxide cannot be achieved. In addition to technical interventions, strategies are required to address cognitive biases and the deterioration of individual and team performance in stressful situations, to which all practitioners are vulnerable. These guidelines provide recommendations for preventing unrecognised oesophageal intubation that are relevant to all airway practitioners independent of geography, clinical location, discipline or patient type.
Advanced hybrid joints, which incorporate a specially designed array of macro-scale pins that provide mechanical interlocking reinforcement, have been developed in order to address the challenges ...associated with joining fibre reinforced composites to metals. In the present work, important joint characteristics including strength, mechanical fatigue, damage tolerance and durability have been studied and discussed. The results indicate that with advanced hybrid joints it is possible to achieve the benefits of the respective bonded and bolted systems but with virtually zero net weight gain, or conceivably a weight reduction as the increased performance of the hybrid scheme could facilitate smaller joints. The authors also present initial results from a comprehensive manufacturing and scalability trial, and demonstrate that low-cost, large-scale manufacture of hybrid joints is now feasible.
Central thalamic deep brain stimulation (CT-DBS) is an investigational therapy to treat enduring cognitive dysfunctions in structurally brain injured (SBI) patients. However, the mechanisms of CT-DBS ...that promote restoration of cognitive functions are unknown, and the heterogeneous etiology and recovery profiles of SBI patients contribute to variable outcomes when using conventional DBS strategies,which may result in off-target effects due to activation of multiple pathways. To disambiguate the effects of stimulation of two adjacent thalamic pathways, we modeled and experimentally compared conventional and novel 'field-shaping' methods of CT-DBS within the central thalamus of healthy non-human primates (NHP) as they performed visuomotor tasks. We show that selective activation of the medial dorsal thalamic tegmental tract (DTTm), but not of the adjacent centromedian-parafascicularis (CM-Pf) pathway, results in robust behavioral facilitation. Our predictive modeling approach in healthy NHPs directly informs ongoing and future clinical investigations of conventional and novel methods of CT-DBS for treating cognitive dysfunctions in SBI patients, for whom no therapy currently exists.
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