Mitochondrial dysfunction and accumulation of damaged mitochondria are considered major contributors to aging. However, the molecular mechanisms responsible for these mitochondrial alterations remain ...unknown. Here, we demonstrate that mitofusin 2 (Mfn2) plays a key role in the control of muscle mitochondrial damage. We show that aging is characterized by a progressive reduction in Mfn2 in mouse skeletal muscle and that skeletal muscle Mfn2 ablation in mice generates a gene signature linked to aging. Furthermore, analysis of muscle Mfn2‐deficient mice revealed that aging‐induced Mfn2 decrease underlies the age‐related alterations in metabolic homeostasis and sarcopenia. Mfn2 deficiency reduced autophagy and impaired mitochondrial quality, which contributed to an exacerbated age‐related mitochondrial dysfunction. Interestingly, aging‐induced Mfn2 deficiency triggers a ROS‐dependent adaptive signaling pathway through induction of HIF1α transcription factor and BNIP3. This pathway compensates for the loss of mitochondrial autophagy and minimizes mitochondrial damage. Our findings reveal that Mfn2 repression in muscle during aging is a determinant for the inhibition of mitophagy and accumulation of damaged mitochondria and triggers the induction of a mitochondrial quality control pathway.
Synopsis
Reduced muscle mitochondrial fusion protein Mfn2 is a determinant for age‐induced decay of mitochondrial function and quality, contributing to age‐associated metabolic alterations and sarcopenia.
Aging is characterized by a reduction of Mfn2 protein expression in skeletal muscle.
Reduction in Mfn2 impairs mitochondrial quality control and mitochondrial function in skeletal muscle.
Mfn2‐deficient mice show unhealthy aging characterized by impaired metabolic homeostasis and sarcopenia.
Reduction in Mfn2 triggers a mitochondrial retrograde signalling pathway in order to minimize mitochondrial damage.
Reduced muscle mitochondrial fusion protein Mfn2 is a determinant for age‐induced decay of mitochondrial function and quality, contributing to age‐associated metabolic alterations and sarcopenia.
Abstract
An overarching challenge of the electrochemical carbon dioxide reduction reaction (eCO
2
RR) is finding an earth-abundant, highly active catalyst that selectively produces hydrocarbons at ...relatively low overpotentials. Here, we report the eCO
2
RR performance of two-dimensional transition metal carbide class of materials. Our results indicate a maximum methane (CH
4
) current density of −421.63 mA/cm
2
and a CH
4
faradic efficiency of 82.7% ± 2% for di-tungsten carbide (W
2
C) nanoflakes in a hybrid electrolyte of 3 M potassium hydroxide and 2 M choline-chloride. Powered by a triple junction photovoltaic cell, we demonstrate a flow electrolyzer that uses humidified CO
2
to produce CH
4
in a 700-h process under one sun illumination with a CO
2
RR energy efficiency of about 62.3% and a solar-to-fuel efficiency of 20.7%. Density functional theory calculations reveal that dissociation of water, chemisorption of CO
2
and cleavage of the C-O bond—the most energy consuming elementary steps in other catalysts such as copper—become nearly spontaneous at the W
2
C surface. This results in instantaneous formation of adsorbed CO—an important reaction intermediate—and an unlimited source of protons near the tungsten surface sites that are the main reasons for the observed superior activity, selectivity, and small potential.
Acute‐on‐chronic liver failure (ACLF) is characterized by acute decompensation (AD) of cirrhosis, organ failure(s), and high 28‐day mortality. We investigated whether assessments of patients at ...specific time points predicted their need for liver transplantation (LT) or the potential futility of their care. We assessed clinical courses of 388 patients who had ACLF at enrollment, from February through September 2011, or during early (28‐day) follow‐up of the prospective multicenter European Chronic Liver Failure (CLIF) ACLF in Cirrhosis study. We assessed ACLF grades at different time points to define disease resolution, improvement, worsening, or steady or fluctuating course. ACLF resolved or improved in 49.2%, had a steady or fluctuating course in 30.4%, and worsened in 20.4%. The 28‐day transplant‐free mortality was low‐to‐moderate (6%‐18%) in patients with nonsevere early course (final no ACLF or ACLF‐1) and high‐to‐very high (42%‐92%) in those with severe early course (final ACLF‐2 or ‐3) independently of initial grades. Independent predictors of course severity were CLIF Consortium ACLF score (CLIF‐C ACLFs) and presence of liver failure (total bilirubin ≥12 mg/dL) at ACLF diagnosis. Eighty‐one percent had their final ACLF grade at 1 week, resulting in accurate prediction of short‐ (28‐day) and mid‐term (90‐day) mortality by ACLF grade at 3‐7 days. Among patients that underwent early LT, 75% survived for at least 1 year. Among patients with ≥4 organ failures, or CLIF‐C ACLFs >64 at days 3‐7 days, and did not undergo LT, mortality was 100% by 28 days. Conclusions: Assessment of ACLF patients at 3‐7 days of the syndrome provides a tool to define the emergency of LT and a rational basis for intensive care discontinuation owing to futility. (Hepatology 2015;62:243‐252)
Increasing evidence indicates that endoplasmic reticulum (ER) stress activates the adaptive unfolded protein response (UPR), but that beyond a certain degree of ER damage, this response triggers ...apoptotic pathways. The general mechanisms of the UPR and its apoptotic pathways are well characterized. However, the metabolic events that occur during the adaptive phase of ER stress, before the cell death response, remain unknown. Here, we show that, during the onset of ER stress, the reticular and mitochondrial networks are redistributed towards the perinuclear area and their points of connection are increased in a microtubule-dependent fashion. A localized increase in mitochondrial transmembrane potential is observed only in redistributed mitochondria, whereas mitochondria that remain in other subcellular zones display no significant changes. Spatial re-organization of these organelles correlates with an increase in ATP levels, oxygen consumption, reductive power and increased mitochondrial Ca²⁺ uptake. Accordingly, uncoupling of the organelles or blocking Ca²⁺ transfer impaired the metabolic response, rendering cells more vulnerable to ER stress. Overall, these data indicate that ER stress induces an early increase in mitochondrial metabolism that depends crucially upon organelle coupling and Ca²⁺ transfer, which, by enhancing cellular bioenergetics, establishes the metabolic basis for the adaptation to this response.
Key components of learning ecologies: A Delphi assessment González‐Sanmamed, Mercedes; Muñoz‐Carril, Pablo‐César; Santos‐Caamaño, Francisco‐José
British journal of educational technology,
July 2019, 2019-07-00, 20190701, Volume:
50, Issue:
4
Journal Article
Peer reviewed
Open access
The educational landscape has changed in recent years, requiring reflection about new pedagogical methods and theories. There are three important perspectives as drivers of pedagogical reflection: ...lifelong and life‐wide learning, the idea of learning as a social construct in which internal elements and changing external factors converge, and the recognition of technology as a resource that can promote ubiquitous and expanded learning. Learning ecology has been proposed as a conceptual and empirical framework, but its still emergent nature along with its multidimensionality and complexity require further exploration. The Delphi study we present as part of a broader research project aims to identify the components of learning ecologies. Three panel rounds with international experts were carried out, after which two important dimensions emerged in the structure of learning ecologies. The first is related to intrinsic “learning dispositions,” which is made up of three categories: the subject's ideas about learning, their motivations and expectations. The second dimension, called “learning processes,” comprises four components: relationships, resources, actions and context. The identification of the components of learning ecologies and their influence on formal, non‐formal and informal training processes will provide guidance for educational policies and help to better organize training programmes.
Sharing economy businesses have emerged in recent years as a disruptive approach to the traditional way of planning, modeling and doing business. The phenomenon has gained significant traction within ...a wide range of domains including entrepreneurship, innovation, technology and management more broadly. Despite this surge and interest, there is a lack of empirical research regarding the increasing diversity of sharing economy business models and the implications for business growth, community impact, sustainability and public policy. With this research, we sought to leverage a rigorous comparative method, fs/QCA, to assess the business models of 36 firms in the sharing economy. Leveraging a rich set of qualitative data, our analysis leveraged seven dimensions of sharing economy business models drawn from extant research, revealing a typology comprising five ideal types that collectively account for the constellation of possible, empirically-relevant business models across the sharing economy. The emergent dilemmas and paradoxes as well as implications of these typologies of business models for startups, investors and policymakers are explored.
•Sharing business modeling is complex yet the one-size model fits all logic prevails.•It seeks to understand the inner complexity and diversity of sharing business models.•Using fsQCA, it analyses 36 firms deriving a typology of 5 business models.•It enables a more fine-grained understanding of the sharing business space.•It reveals a number of paradoxes, challenges and opportunities for a range of actors.
Calls for a transformation towards more sustainable consumption and production (SCP) have been intensifying. As urban populations swell across the planet, cities are faced with increasing pressure on ...infrastructure, economic and ecological systems. Yet, with their high population densities and ubiquity of information and communication technologies, cities are becoming breeding grounds for a new, circular economy driven by emerging and long-standing sharing activities. This research provides a comprehensive view of SCP systems in cities by integrating and examining sharing economy activities in the context of two continuums, i.e. SCP and private/public orientation. Based on these two analytical dimensions, the paper evaluates and plots five groups of 18 sharing activities to create a Sharing Cities-SCP Typology comprised by five ideal types. Each of these five types represents a unique form of SCP activity, with the potential to directly impact SCP systems in the context of urban environments. By enabling diversity and hybridity in the SCP analysis, we allow for a theoretical expansion of SCP models and a new way of understanding how they may play out in cities.
•The paper examines the relationship between sharing economy activities and SCP in cities.•It analyzes several classification alternatives in light of substantive data.•It examines sharing activities in light of two continuums, i.e. SCP and private/public orientation.•It evaluates 18 activities to develop a Sharing Cities-SCP Typology comprised of 5 ideal types, each representing a unique form of SCP activity.•In the context of sustainable business, we extend the notion of hybrid modeling by incorporating the consumption and production dimensions.
The analysis of the processes and elements articulating effective Computer Supported Collaborative Learning (CSCL) constitutes a focal research stream in education. Following these streams, ...satisfaction and perceived impact on learning have already been stablished as determining aspects of any type of learning and, particularly, of CSCL. The goal of this study was to identify factors affecting students' satisfaction and perception of impact on learning in CSCL. The Partial Least Squares technique was used, applying a questionnaire to 701 students in a virtual university. The proposed model exhibited high predictive performance, confirming the 13 hypotheses established. The variables confirmation, perceived usefulness, and perceived enjoyment positively and significantly influenced students’ satisfaction with CSCL. Perceived ease of use and perceived usefulness positively and significantly influenced attitude, and attitude, together with perceived enjoyment, were determining factors in perceived impact on learning. These are factors that should be considered when designing CSCL to be implemented both at the institutional and class level, and teachers and students should be aware of these interdependencies for CSCL to be successful.
•We identified factors influencing satisfaction and perceived learning in CSCL students.•Confirmation and perceived usefulness positively influence students' satisfaction with CSCL.•Satisfaction significantly influences the perception of the impact of learning in CSCL.•Perceived usefulness and ease of use influence attitudes towards CSCL.•Attitude and perceived enjoyment are variables that predict perceived impact on learning.
Mitochondrial dynamics is a complex process that impacts on mitochondrial biology.
Recent evidence indicates that proteins participating in mitochondrial dynamics have additional cellular roles. ...Mitofusin 2 (Mfn2) is a potent modulator of mitochondrial metabolism with an impact on energy metabolism in muscle, liver, and hypothalamic neurons. In addition, Mfn2 is subjected to tight regulation. Hence, factors such as proinflammatory cytokines, lipid availability, or glucocorticoids block its expression, whereas exercise and increased energy expenditure promote its upregulation.
Importantly, Mfn2 controls cell metabolism and insulin signaling by limiting reactive oxygen species production and by modulation of endoplasmic reticulum stress. In this connection, it is critical to understand precisely the molecular mechanisms involved in the global actions of Mfn2.
Future directions should concentrate into the analysis of those mechanisms, and to fully demonstrate that Mfn2 represents a cellular hub that senses the metabolic and hormonal milieu and drives the control of metabolic homeostasis.
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