Otopetrins (Otop1-Otop3) comprise one of two known eukaryotic proton-selective channel families. Otop1 is required for otoconia formation and a candidate mammalian sour taste receptor. Here we report ...cryo-EM structures of zebrafish Otop1 and chicken Otop3 in lipid nanodiscs. The structures reveal a dimeric architecture, with each subunit forming 12 transmembrane helices divided into structurally similar amino (N) and carboxy (C) domains. Cholesterol-like molecules occupy various sites in Otop1 and Otop3 and occlude a central tunnel. In molecular dynamics simulations, hydrophilic vestibules formed by the N and C domains and in the intrasubunit interface between N and C domains form conduits for water entry into the membrane core, suggesting three potential proton conduction pathways. By mutagenesis, we tested the roles of charged residues in each putative permeation pathway. Our results provide a structural basis for understanding selective proton permeation and gating of this conserved family of proton channels.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Cancer cells that transit from primary tumours into the circulatory system are known as circulating tumour cells (CTCs). These cancer cells have unique phenotypic and genotypic characteristics which ...allow them to survive within the circulation, subsequently extravasate and metastasise. CTCs have emerged as a useful diagnostic tool using "liquid biopsies" to report on the metastatic potential of cancers. However, CTCs by their nature interact with components of the blood circulatory system on a constant basis, influencing both their physical and morphological characteristics as well as metastatic capabilities. These properties and the associated molecular profile may provide critical diagnostic and prognostic capabilities in the clinic. Platelets interact with CTCs within minutes of their dissemination and are crucial in the formation of the initial metastatic niche. Platelets and coagulation proteins also alter the fate of a CTC by influencing EMT, promoting pro-survival signalling and aiding in evading immune cell destruction. CTCs have the capacity to directly hijack immune cells and utilise them to aid in CTC metastatic seeding processes. The disruption of CTC clusters may also offer a strategy for the treatment of advance staged cancers. Therapeutic disruption of these heterotypical interactions as well as direct CTC targeting hold great promise, especially with the advent of new immunotherapies and personalised medicines. Understanding the molecular role that platelets, immune cells and the coagulation cascade play in CTC biology will allow us to identify and characterise the most clinically relevant CTCs from patients. This will subsequently advance the clinical utility of CTCs in cancer diagnosis/prognosis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
To provide evidence‐based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA).
Methods
A core group led the ...development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946–2014), PubMed (1966–2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework.
Results
In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS.
Conclusion
These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Cockayne syndrome (CS) is an accelerated aging disorder characterized by progressive neurodegeneration caused by mutations in genes encoding the DNA repair proteins CS group A or B (CSA or CSB). ...Since dietary interventions can alter neurodegenerative processes, Csbm/m mice were given a high-fat, caloric-restricted, or resveratrol-supplemented diet. High-fat feeding rescued the metabolic, transcriptomic, and behavioral phenotypes of Csbm/m mice. Furthermore, premature aging in CS mice, nematodes, and human cells results from aberrant PARP activation due to deficient DNA repair leading to decreased SIRT1 activity and mitochondrial dysfunction. Notably, β-hydroxybutyrate levels are increased by the high-fat diet, and β-hydroxybutyrate, PARP inhibition, or NAD+ supplementation can activate SIRT1 and rescue CS-associated phenotypes. Mechanistically, CSB can displace activated PARP1 from damaged DNA to limit its activity. This study connects two emerging longevity metabolites, β-hydroxybutyrate and NAD+, through the deacetylase SIRT1 and suggests possible interventions for CS.
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•Hyperactivation of PARP1 drives SIRT1 depression in Cockayne syndrome (CS)•A high-fat diet, β-hydroxybutyrate, or NAD+ replenishment rescue phenotypes in CS•PARP inhibition and β-hydroxybutyrate increase SIRT1 activity in CS-cells•CSB displaces PARylated PARP1 from damaged DNA and suppresses its activity
Cockayne syndrome group B (CSB) is associated with hyperactivation of the DNA damage response enzyme PARP1 leading to NAD+ depletion, SIRT1 attenuation, and decreased acetyl-CoA formation. Increasing NAD+ or enhancing acetyl-CoA via ketogenesis rescues the accelerated aging. CSB protein interacts with PARP1 to prevent increasing signaling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
OBJECTIVES:This study evaluated theoretically derived mechanisms and common therapeutic factors to test their role in accounting for pain-related outcome change during group-delivered cognitive ...therapy, mindfulness meditation, and mindfulness-based cognitive therapy for chronic low back pain.
METHODS:A secondary analysis of a pilot randomized controlled trial was used to explore the primary mechanisms of pretreatment to posttreatment changes in pain control beliefs, mindful observing, and pain catastrophizing, and the secondary common factor mechanisms of therapeutic alliance, group cohesion, and amount of at-home skill practice during treatment. The primary outcome was pain interference; pain intensity was a secondary outcome.
RESULTS:Large effect size changes in the 3 primary mechanisms and the outcome variables were found across the conditions. Across all 3 treatment conditions, change in pain control beliefs and pain catastrophizing were significantly associated with improved pain interference, but not pain intensity. Therapeutic alliance was significantly associated with pain intensity improvement and change in the therapy-specific mechanisms across the 3 conditions. Mindful observing, group cohesion, and amount of at-home practice were not significantly associated with changes in the outcomes.
DISCUSSION:Cognitive therapy, mindfulness meditation, and mindfulness-based cognitive therapy for chronic low back pain were all associated with significant changes in the primary mechanisms to a similar degree. Change in perceived pain control and pain catastrophizing emerged as potential “meta-mechanisms” that might be a shared pathway that contributes to improved pain-related outcomes across treatments. Further, strong working alliance may represent a critical therapeutic process that both promotes and interacts with therapeutic techniques to influence outcome.
Flycatcher1 (FLYC1), a MscS homolog, has recently been identified as a candidate mechanosensitive (MS) ion channel involved in Venus flytrap prey recognition. FLYC1 is a larger protein and its ...sequence diverges from previously studied MscS homologs, suggesting it has unique structural features that contribute to its function. Here, we characterize FLYC1 by cryo-electron microscopy, molecular dynamics simulations, and electrophysiology. Akin to bacterial MscS and plant MSL1 channels, we find that FLYC1 central core includes side portals in the cytoplasmic cage that regulate ion preference and conduction, by identifying critical residues that modulate channel conductance. Topologically unique cytoplasmic flanking regions can adopt 'up' or 'down' conformations, making the channel asymmetric. Disruption of an up conformation-specific interaction severely delays channel deactivation by 40-fold likely due to stabilization of the channel open state. Our results illustrate novel structural features and likely conformational transitions that regulate mechano-gating of FLYC1.
International evidence suggests that green space has beneficial effects on general and mental health but little is known about how lifetime exposure to green space influences cognitive ageing. ...Employing a novel longitudinal life course approach, we examined the association between lifetime availability of public parks and cognitive ageing. Lifetime residential information was gathered from the participants of the Lothian Birth Cohort 1936 using a “life-grid” questionnaire at age 78 years. Parks information from 1949, 1969 and 2009 was used to determine a percentage of parks within a 1500 m buffer zone surrounding residence for childhood, adulthood, and later adulthood periods. Linear regressions were undertaken to test for association with age-standardised, residualised change in cognitive function (Moray House Test score) from age 11 to 70 years, and from age 70 to 76 (n = 281). The most appropriate model was selected using the results of a partial F-test, and then stratified by demographic, genetic and socioeconomic factors. The local provision of park space in childhood and adulthood were both important in explaining the change in cognitive function in later life. The association between childhood and adulthood park availability and change in the Moray House Test Score from age 70 to 76 was strongest for women, those without an APOE e4 allele (a genetic risk factor), and those in the lowest socioeconomic groups.
Greater neighbourhood provision of public parks from childhood through to adulthood may help to slow down the rate of cognitive decline in later life, recognising that such environmental associations are always sensitive to individual characteristics.
•Lifecourse approaches are necessary to investigate green space and cognitive ageing.•Better cognitive ageing depended on more park provision in childhood and adulthood.•Childhood park provision was modified by adulthood park provision.•Association was strongest in females, without an APOE e4 alelle and in a lower SES.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract
Cryo-electron microscopy (cryo-EM) enables the determination of membrane protein structures in native-like environments. Characterising how membrane proteins interact with the surrounding ...membrane lipid environment is assisted by resolution of lipid-like densities visible in cryo-EM maps. Nevertheless, establishing the molecular identity of putative lipid and/or detergent densities remains challenging. Here we present LipIDens, a pipeline for molecular dynamics (MD) simulation-assisted interpretation of lipid and lipid-like densities in cryo-EM structures. The pipeline integrates the implementation and analysis of multi-scale MD simulations for identification, ranking and refinement of lipid binding poses which superpose onto cryo-EM map densities. Thus, LipIDens enables direct integration of experimental and computational structural approaches to facilitate the interpretation of lipid-like cryo-EM densities and to reveal the molecular identities of protein-lipid interactions within a bilayer environment. We demonstrate this by application of our open-source LipIDens code to ten diverse membrane protein structures which exhibit lipid-like densities.
Purpose
This paper aims to examine the role strategic problem identification and resolution played in identifying and capturing new sources of competitive advantage as CSL Limited (CSL) transformed ...itself into the world’s fifth-largest biotechnology company. Historical accounts of superior business growth are usually explained by looking back to identify a firm’s sources of competitive advantage. However, what managers really want to know is how to identify opportunities to create and capture competitive advantage ahead of competitors.
Design/methodology/approach
The authors examined CSL’s journey between 1994 and 2019 through a case study approach and the lens of the problem-identification and problem-solving perspective (PSP). The PSP assumes strategic problems act as antecedents to discovering and capturing new sources of competitive advantage. The problems a firm identifies and resolves influences whether or not, in what direction and for whom an organization creates value.
Findings
The authors provide examples of the strategic problems CSL identified and how they acted as the catalyst to proactively identify new sources of competitive advantage. The formulated problems helped manager to see in advance what resources, capabilities and governance mechanisms would be required to create and capture value.
Originality/value
Generalizing the lessons learned, the authors propose a business-problem classification framework and portfolio approach to encourage managers to identify, formulate and resolve different types of strategic problems. These problems could motivate firms to tackle problems beyond which they have successfully tackled before and discover new sources of competitive advantage ahead of competitors.
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