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"Davis, Gavin M."
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Dichloroacetate Stabilizes Mitochondrial Fusion Dynamics in Models of Neurodegeneration
Mitochondrial dysfunction is a recognized hallmark of neurodegenerative diseases and abnormal mitochondrial fusion-fission dynamics have been implicated in the pathogenesis of neurodegenerative disorders. This study characterizes the effects of metabolic flux inhibitors and activators on mitochondrial fusion dynamics in the neuronal cell culture model of differentiated PC12 cells. Using a real time confocal microscopy assay, it was found that the carnitine palmitoyltransferase I (CPTI) inhibitor, etomoxir, reduced mitochondrial fusion dynamics in a time-dependent manner. Etomoxir also decreased JO
, ΔΨ
and reactive oxygen species (ROS) production rates. The mitochondrial pyruvate carrier (MPC) inhibitor, UK5099, reduced fusion dynamics and in combination with etomoxir these inhibitory effects were amplified. Use of the pyruvate dehydrogenase (PDH) kinase inhibitor dichloroacetate, which is known to increase metabolic flux through PDH, reversed the etomoxir-induced effects on fusion dynamics, JO
, ΔΨ
but not ROS production rates. Dichloroacetate also partially reversed inhibition of mitochondrial fusion dynamics caused by the parkinsonian-inducing neurotoxin, MPP
. These results suggest that dichloroacetate-induced activation of metabolic flux in the mitochondrion may be a mechanism to restore normal mitochondrial fusion-fission dynamics in metabolically challenged cells.
Journal Article
Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages
Mitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1β in vitro. Accordingly, HIF-1α and IL-1β are highly expressed in an LPS-induced in vivo model of acute inflammation using
Arg2
−/−
mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell.
IL-10 can limit inflammation in part by inhibiting miR-155. Here the authors show how this axis induces mitochondrial arginase-2 to alter the mitochondrial dynamics and bioenergetics of macrophages and make these cells less pro-inflammatory.
Journal Article
Mitochondrial complex I controls blood brain barrier permeability
Mitochondrial electron transport chain (ETC) complexes are key mediators of energy metabolism in astrocytes and neurons, with subsequent effects on memory, behaviour and neurodegeneration. Mitochondrial dysfunction and increased blood brain barrier (BBB) permeability are known pathologies in Parkinsons and Alzheimers diseases. However, knowledge of how ETC activities regulate metabolic flux and influence permeability in the BBB is lacking. Using metabolic flux control analysis we show that complex I is a critical control point for oxidative flux and permeability in brain microvascular endothelial cells derived from human induced pluripotent stem cells. Inhibition of complex I activity immediately reduced the transendothelial electrical resistance (TEER) by 60%, leading to an increase in protein transport across the BBB. These events were accompanied by a transient reduction in ATP that was recovered, along with TEER values, over an extended time period. Furthermore, while inhibition of downstream complexes III or IV decreased oxygen respiration rates, no effects on BBB permeability were identified, due to compensatory glycolytic flux and maintenance of ATP synthesis. These data show that mitochondrial complex I is critical for maintaining energy production in endothelial cells and transiently controls BBB permeability, which may contribute to brain disorders where complex I dysfunction is a hallmark. Competing Interest Statement The authors have declared no competing interest.
Paper
Consensus statement on concussion in sport: the 6th International Conference on Concussion in Sport–Amsterdam, October 2022
For over two decades, the Concussion in Sport Group has held meetings and developed five international statements on concussion in sport. This 6th statement summarises the processes and outcomes of the 6th International Conference on Concussion in Sport held in Amsterdam on 27–30 October 2022 and should be read in conjunction with the (1) methodology paper that outlines the consensus process in detail and (2) 10 systematic reviews that informed the conference outcomes. Over 3½ years, author groups conducted systematic reviews of predetermined priority topics relevant to concussion in sport. The format of the conference, expert panel meetings and workshops to revise or develop new clinical assessment tools, as described in the methodology paper, evolved from previous consensus meetings with several new components. Apart from this consensus statement, the conference process yielded revised tools including the Concussion Recognition Tool-6 (CRT6) and Sport Concussion Assessment Tool-6 (SCAT6, Child SCAT6), as well as a new tool, the Sport Concussion Office Assessment Tool-6 (SCOAT6, Child SCOAT6). This consensus process also integrated new features including a focus on the para athlete, the athlete’s perspective, concussion-specific medical ethics and matters related to both athlete retirement and the potential long-term effects of SRC, including neurodegenerative disease. This statement summarises evidence-informed principles of concussion prevention, assessment and management, and emphasises those areas requiring more research.
Journal Article
Consensus statement on concussion in sport—the 5th international conference on concussion in sport held in Berlin, October 2016
Correspondence to Dr Paul McCrory, The Florey Institute of Neuroscience and Mental Health, Heidelberg 3084, Victoria, Australia; paulmccrory@icloud.com Preamble The 2017 Concussion in Sport Group (CISG) consensus statement is designed to build on the principles outlined in the previous statements1–4 and to develop further conceptual understanding of sport-related concussion (SRC) using an expert consensus-based approach. First and foremost, this document is intended to guide clinical practice; however, the authors feel that it can also help form the agenda for future research relevant to SRC by identifying knowledge gaps. At present, there is no perfect diagnostic test or marker that clinicians can rely on for an immediate diagnosis of SRC in the sporting environment. Because of this evolving process, it is not possible to rule out SRC when an injury event occurs associated with a transient neurological symptom. [...]tests include the SCAT5, which incorporates the Maddocks' questions6 7 and the Standardised Assessment of Concussion (SAC).8–10 It is worth noting that standard orientation questions (eg, time, place, person) are unreliable in the sporting situation when compared with memory assessment.7 11 It is recognised, however, that abbreviated testing paradigms are designed for rapid SRC screening on the sidelines and are not meant to replace a comprehensive neurological evaluation; nor should they be used as a standalone tool for the ongoing management of SRC.
Journal Article
Rest and exercise early after sport-related concussion: a systematic review and meta-analysis
ObjectiveTo synthesise the evidence regarding the risks and benefits of physical activity (PA), prescribed aerobic exercise treatment, rest, cognitive activity and sleep during the first 14 days after sport-related concussion (SRC).DesignMeta-analysis was performed for PA/prescribed exercise interventions and a narrative synthesis for rest, cognitive activity and sleep. Risk of bias (ROB) was determined using the Scottish Intercollegiate Guidelines Network and quality assessed using Grading of Recommendations, Assessment, Development and Evaluations.Data sourcesMEDLINE, Embase, APA PsycInfo, Cochrane Central Register of Controlled Trials, CINAHL Plus and SPORTDiscus. Searches were conducted in October 2019 and updated in March 2022.Eligibility criteriaOriginal research articles with sport-related mechanism of injury in >50% of study sample and that evaluated how PA, prescribed exercise, rest, cognitive activity and/or sleep impact recovery following SRC. Reviews, conference proceedings, commentaries, editorials, case series, animal studies and articles published before 1 January 2001 were excluded.Results46 studies were included and 34 had acceptable/low ROB. Prescribed exercise was assessed in 21 studies, PA in 15 studies (6 PA/exercise studies also assessed cognitive activity), 2 assessed cognitive activity only and 9 assessed sleep. In a meta-analysis of seven studies, PA and prescribed exercise improved recovery by a mean of −4.64 days (95% CI −6.69, –2.59). After SRC, early return to light PA (initial 2 days), prescribed aerobic exercise treatment (days 2–14) and reduced screen use (initial 2 days) safely facilitate recovery. Early prescribed aerobic exercise also reduces delayed recovery, and sleep disturbance is associated with slower recovery.ConclusionEarly PA, prescribed aerobic exercise and reduced screen time are beneficial following SRC. Strict physical rest until symptom resolution is not effective, and sleep disturbance impairs recovery after SRC.PROSPERO registration numberCRD42020158928.
Journal Article
Physiological blood–brain transport is impaired with age by a shift in transcytosis
The vascular interface of the brain, known as the blood–brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability
1
–
3
. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins
4
,
5
. Thus, it is unclear whether permeability to individually injected exogenous tracers—as is standard in BBB studies—fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery.
Tagging and tracking the blood plasma proteome as a discovery tool reveals widespread endogenous transport of proteins into the healthy brain and the pharmacologically modifiable mechanisms by which the brain endothelium regulates this process with age.
Journal Article
KBase: The United States Department of Energy Systems Biology Knowledgebase
To the Editor: Over the past two decades, the scale and complexity of genomics technologies and data have advanced from sequencing genomes of a few organisms to generating metagenomes, genome variation, gene expression, metabolites, and phenotype data for thousands of organisms and their communities. A major challenge in this data-rich age of biology is integrating heterogeneous and distributed data into predictive models of biological function, ranging from a single gene to entire organisms and their ecologies. Here we present the DOE Systems Biology Knowledgebase (KBase, http://kbase.us), an open-source software and data platform that enables data sharing, integration, and analysis of microbes, plants, and their communities. Once a Narrative has been shared or made public, other users can copy the Narrative and rerun it on their own data, or modify it to suit their scientific needs. [...]public Narratives serve as resources for the user community by capturing valuable data sets, associated computational analyses, and scientific context describing the rationale behind a scientific study in a form that is immediately reproducible and reusable.
Journal Article
Linking robust spatiotemporal datasets to assess and monitor habitat attributes of a threatened species
Accessibility of multispectral, multitemporal imagery combined with recent advances in cloud computing and machine learning approaches have enhanced our ability to model habitat characteristics across broad spatial and temporal scales. We integrated a large dataset of known nest and roost sites of a threatened species, the Mexican spotted owl ( Strix occidentalis lucida ), in the southwestern USA with Landsat imagery processed using the Continuous Change Detection and Classification (CCDC) time series algorithm on Google Earth Engine. We then used maximum entropy modeling (Maxent) to classify the landscape into four ‘spectral similarity’ classes that reflected the degree to which 30-m pixels contained a multispectral signature similar to that found at known owl nest/roost sites and mapped spectral similarity classes from 1986–2020. For map interpretation, we used nationally consistent forest inventory data to evaluate the structural and compositional characteristics of each spectral similarity class. We found a monotonic increase of structural characteristics typically associated with owl nesting and roosting over classes of increasing similarity, with the ‘very similar’ class meeting or exceeding published minimum desired management conditions for owl nesting and roosting. We also found an increased rate of loss of forest vegetation typical of owl nesting and roosting since the beginning of the 21 st century that can be partly attributed to increased frequency and extent of large (≥400 ha) wildfires. This loss resulted in a 38% reduction over the 35-year study period in forest vegetation most similar to that used for owl nesting and roosting. Our modelling approach using cloud computing with time series of Landsat imagery provided a cost-effective tool for landscape-scale, multidecadal monitoring of vegetative components of a threatened species’ habitat. Our approach could be used to monitor trends in the vegetation favored by any other species, provided that high-quality location data such as we presented here are available.
Journal Article