Crystallographic comparison of the estrogen and progesterone receptor's ligand binding domains

The 2.8-A crystal structure of the complex formed by estradiol and the human estrogen receptor-alpha ligand binding domain (hERalphaLBD) is described and compared with the recently reported structure of the progesterone complex of the human progesterone receptor ligand binding domain, as well as with similar structures of steroid/nuclear receptor LBDs solved elsewhere

Professional male rugby union players’ perceived psychological recovery and physical regeneration during the off-season

Objectives: We explored male professional rugby union players’ experiences and perceptions of their mental and physical health and well-being across the northern hemisphere off-season.Methods: 34 professional male rugby union players participated in individual semi-structured interviews (mean (SD) age=27.5 (4.3) years). Interviews were recorded, transcribed verbatim, and analysed using reflexive thematic analysis.Results: The off-season was characterised by three phases players undergo to preserve their mental and physical health and well-being to recover from the previous season and regenerate in preparation for the upcoming season. These included decompression from previous season, cognitive detachment from the rugby environment, and preparation for pre-season. Successful progression through all three phases was influenced by several variables (work and life demands, contextual factors, experience level). Recovery and regeneration strategies focused on physical distancing/getting away from the rugby environment to cognitively detach. Injured players appear an at-risk sub-group for threats to mental well-being (isolation, anxiety, reduced sense of achievement) as a result of reduced or minimal time away from the workplace due to treatment obligations. Younger professionals are a sub-group at risk of overtraining/injury due to inadequate rest, especially as this group are least likely to seek support/guidance.Conclusions: This study is the first investigation into male professional rugby union players’ experiences and perceptions of their mental and physical health and well-being across the off-season period. It highlights the distinct phases players undertake to mentally recover and regenerate and the need to consider education and support for potential at risk sub-groups

Chronic intermittent hypoxia increases rat sternohyoid muscle NADPH oxidase expression with attendant modest oxidative stress

Chronic intermittent hypoxia (CIH) causes upper airway muscle dysfunction. We hypothesized that the superoxide generating NADPH oxidase (NOX) is upregulated in CIH-exposed muscle causing oxidative stress. Adult male Wistar rats were exposed to intermittent hypoxia (5% O2 at the nadir for 90 s followed by 210 s of normoxia), for 8 h per day for 14 days. The effect of CIH exposure on the expression of NOX subunits, total myosin and 4-hydroxynonenal (4-HNE) protein adducts in sternohyoid muscle was determined by western blotting and densitometry. Sternohyoid protein free thiol and carbonyl group contents were determined by 1D electrophoresis using specific fluorophore probes. Aconitase and glutathione reductase activities were measured as indices of oxidative stress. HIF-1α content and key oxidative and glycolytic enzyme activities were determined. Contractile properties of sternohyoid muscle were determined ex vivo in the absence and presence of apocynin (putative NOX inhibitor). We observed an increase in NOX 2 and p47 phox expression in CIH-exposed sternohyoid muscle with decreased aconitase and glutathione reductase activities. There was no evidence, however, of increased lipid peroxidation or protein oxidation in CIH-exposed muscle. CIH exposure did not affect sternohyoid HIF-1α content or aldolase, lactate dehydrogenase, or glyceraldehyde-3-phosphate dehydrogenase activities. Citrate synthase activity was also unaffected by CIH exposure. Apocynin significantly increased sternohyoid force and power. We conclude that CIH exposure upregulates NOX expression in rat sternohyoid muscle with concomitant modest oxidative stress but it does not result in a HIF-1α-dependent increase in glycolytic enzyme activity. Constitutive NOX activity decreases sternohyoid force and power. Our results implicate NOX-dependent reactive oxygen species in CIH-induced upper airway muscle dysfunction which likely relates to redox modulation of key regulatory proteins in excitation-contraction coupling

An Assemblage of Lava Flow Features on Mercury

In contrast to other terrestrial planets, Mercury does not possess a great variety of volcanic features, its history of volcanism instead largely manifest by expansive smooth plains. However, a set of landforms at high northern latitudes on Mercury resembles surface flow features documented on Earth, the Moon, Mars, and Venus. The most striking of such landforms are broad channels that host streamlined islands and that cut through the surrounding intercrater plains. Together with narrower, more sinuous channels, coalesced depressions, evidence for local flooding of intercrater plains by lavas, and a first-order analysis of lava flow rates, the broad channels define an assemblage of flow features formed by the overland flow of, and erosion by, voluminous, high-temperature, low-viscosity lavas. This interpretation is consistent with compositional data suggesting that substantial portions of Mercury's crust are composed of magnesian, iron-poor lithologies. Moreover, the proximity of this partially flooded assemblage to extensive volcanic plains raises the possibility that the formation of these flow features may preface total inundation of an area by lavas emplaced in a flood mode and that they escaped complete burial only due to a waning magmatic supply. Finally, that these broad channels on Mercury are volcanic in nature yet resemble outflow channels on Mars, which are commonly attributed to catastrophic water floods, implies that aqueous activity is not a prerequisite for the formation of such distinctive landforms on any planetary body

Abnormal mitochondrial L-arginine transport contributes to the pathogenesis of heart failure and rexoygenation injury

Impaired mitochondrial function is fundamental feature of heart failure (HF) and myocardial ischemia. In addition to the effects of heightened oxidative stress, altered nitric oxide (NO) metabolism, generated by a mitochondrial NO synthase, has also been proposed to impact upon mitochondrial function. However, the mechanism responsible for arginine transport into mitochondria and the effect of HF on such a process is unknown. We therefore aimed to characterize mitochondrial L-arginine transport and to investigate the hypothesis that impaired mitochondrial L-arginine transport plays a key role in the pathogenesis of heart failure and myocardial injury

Loss of VGLUT3 Produces Circadian-Dependent Hyperdopaminergia and Ameliorates Motor Dysfunction and l-Dopa-Mediated Dyskinesias in a Model of Parkinson\u27s Disease.

UNLABELLED: The striatum is essential for many aspects of mammalian behavior, including motivation and movement, and is dysfunctional in motor disorders such as Parkinson\u27s disease. The vesicular glutamate transporter 3 (VGLUT3) is expressed by striatal cholinergic interneurons (CINs) and is thus well positioned to regulate dopamine (DA) signaling and locomotor activity, a canonical measure of basal ganglia output. We now report that VGLUT3 knock-out (KO) mice show circadian-dependent hyperlocomotor activity that is restricted to the waking cycle and is due to an increase in striatal DA synthesis, packaging, and release. Using a conditional VGLUT3 KO mouse, we show that deletion of the transporter from CINs, surprisingly, does not alter evoked DA release in the dorsal striatum or baseline locomotor activity. The mice do, however, display changes in rearing behavior and sensorimotor gating. Elevation of DA release in the global KO raised the possibility that motor deficits in a Parkinson\u27s disease model would be reduced. Remarkably, after a partial 6-hydroxydopamine (6-OHDA)-mediated DA depletion (∼70% in dorsal striatum), KO mice, in contrast to WT mice, showed normal motor behavior across the entire circadian cycle. l-3,4-dihydroxyphenylalanine-mediated dyskinesias were also significantly attenuated. These findings thus point to new mechanisms to regulate basal ganglia function and potentially treat Parkinson\u27s disease and related disorders. SIGNIFICANCE STATEMENT: Dopaminergic signaling is critical for both motor and cognitive functions in the mammalian nervous system. Impairments, such as those found in Parkinson\u27s disease patients, can lead to severe motor deficits. Vesicular glutamate transporter 3 (VGLUT3) loads glutamate into secretory vesicles for neurotransmission and is expressed by discrete neuron populations throughout the nervous system. Here, we report that the absence of VGLUT3 in mice leads to an upregulation of the midbrain dopamine system. Remarkably, in a Parkinson\u27s disease model, the mice show normal motor behavior. They also show fewer abnormal motor behaviors (dyskinesias) in response to l-3,4-dihydroxyphenylalanine, the principal treatment for Parkinson\u27s disease. The work thus suggests new avenues for the development of novel treatment strategies for Parkinson\u27s disease and potentially other basal-ganglia-related disorders

OCTOPUS database (v.2)

OCTOPUS v.2 is an Open Geospatial Consortium (OGC) compliant web-enabled database that allows users to visualise, query, and download cosmogenic radionuclide, luminescence, and radiocarbon ages and denudation rates associated with erosional landscapes, Quaternary depositional landforms, and archaeological records, along with ancillary geospatial (vector and raster) data layers. The database follows the FAIR (Findability, Accessibility, Interoperability, and Reuse) data principles and is based on open-source software deployed on the Google Cloud Platform. Data stored in the database can be accessed via a custom-built web interface and via desktop geographic information system (GIS) applications that support OGC data access protocols. OCTOPUS v.2 hosts five major data collections. CRN Denudation and ExpAge consist of published cosmogenic 10Be and 26Al measurements in modern fluvial sediment and glacial samples respectively. Both collections have a global extent; however, in addition to geospatial vector layers, CRN Denudation also incorporates raster layers, including a digital elevation model, gradient raster, flow direction and flow accumulation rasters, atmospheric pressure raster, and CRN production scaling and topographic shielding factor rasters. SahulSed consists of published optically stimulated luminescence (OSL) and thermoluminescence (TL) ages for fluvial, aeolian, and lacustrine sedimentary records across the Australian mainland and Tasmania. SahulArch consists of published OSL, TL, and radiocarbon ages for archaeological records, and FosSahul consists of published late-Quaternary records of direct and indirect non-human vertebrate (mega)fauna fossil ages that have been systematically quality rated. Supporting data are comprehensive and include bibliographic, contextual, and sample-preparation- and measurement-related information. In the case of cosmogenic radionuclide data, OCTOPUS also includes all necessary information and input files for the recalculation of denudation rates using the open-source program CAIRN. OCTOPUS v.2 and its associated data curation framework allow for valuable legacy data to be harnessed that would otherwise be lost to the research community. The database can be accessed at https://octopusdata.org (last access: 1 July 2022). The individual data collections can also be accessed via their respective digital object identifiers (DOIs) (see Table 1)

Comprehensive Evaluation of the 5XFAD Mouse Model for Preclinical Testing Applications: A MODEL-AD Study.

The ability to investigate therapeutic interventions in animal models of neurodegenerative diseases depends on extensive characterization of the model(s) being used. There are numerous models that have been generated to study Alzheimer\u27s disease (AD) and the underlying pathogenesis of the disease. While transgenic models have been instrumental in understanding AD mechanisms and risk factors, they are limited in the degree of characteristics displayed in comparison with AD in humans, and the full spectrum of AD effects has yet to be recapitulated in a single mouse model. The Model Organism Development and Evaluation for Late-Onset Alzheimer\u27s Disease (MODEL-AD) consortium was assembled by the National Institute on Aging (NIA) to develop more robust animal models of AD with increased relevance to human disease, standardize the characterization of AD mouse models, improve preclinical testing in animals, and establish clinically relevant AD biomarkers, among other aims toward enhancing the translational value of AD models in clinical drug design and treatment development. Here we have conducted a detailed characterization of the 5XFAD mouse, including transcriptomics, electroencephalogram

'It's a film' : medium specificity as textual gesture in Red road and The unloved

British cinema has long been intertwined with television. The buzzwords of the transition to digital media, 'convergence' and 'multi-platform delivery', have particular histories in the British context which can be grasped only through an understanding of the cultural, historical and institutional peculiarities of the British film and television industries. Central to this understanding must be two comparisons: first, the relative stability of television in the duopoly period (at its core, the licence-funded BBC) in contrast to the repeated boom and bust of the many different financial/industrial combinations which have comprised the film industry; and second, the cultural and historical connotations of 'film' and 'television'. All readers of this journal will be familiar – possibly over-familiar – with the notion that 'British cinema is alive and well and living on television'. At the end of the first decade of the twenty-first century, when 'the end of medium specificity' is much trumpeted, it might be useful to return to the historical imbrication of British film and television, to explore both the possibility that medium specificity may be more nationally specific than much contemporary theorisation suggests, and to consider some of the relationships between film and television manifest at a textual level in two recent films, Red Road (2006) and The Unloved (2009)