Macromolecular structure phasing by neutron anomalous diffraction.

In this report we show for the first time that neutron anomalous dispersion can be used in a practical manner to determine experimental phases of a protein crystal structure, providing a new tool for structural biologists. The approach is demonstrated through the use of a state-of-the-art monochromatic neutron diffractometer at the Institut Laue-Langevin (ILL) in combination with crystals of perdeuterated protein that minimise the level of hydrogen incoherent scattering and enhance the visibility of the anomalous signal. The protein used was rubredoxin in which cadmium replaced the iron at the iron-sulphur site. While this study was carried out using a steady-state neutron beam source, the results will be of major interest for capabilities at existing and emerging spallation neutron sources where time-of-flight instruments provide inherent energy discrimination. In particular this capability may be expected to offer unique opportunities to a rapidly developing structural biology community where there is increasing interest in the identification of protonation states, protein/water interactions and protein-ligand interactions - all of which are of central importance to a wide range of fundamental and applied areas in the biosciences

Reframing landscape fragmentation's effects on ecosystem services.

REVIEWLandscape structure and fragmentation have important effects on ecosystem services, with a common assumption being that fragmentation reduces service provision. This is based on fragmentation's expected effects on ecosystem service supply, but ignores how fragmentation influences the flow of services to people. Here we develop a new conceptual framework that explicitly considers the links between landscape fragmentation, the supply of services, and the flow of services to people. We argue that fragmentation's effects on ecosystem service flow can be positive or negative, and use our framework to construct testable hypotheses about the effects of fragmentation on final ecosystem service provision. Empirical efforts to apply and test this framework are critical to improving landscape management for multiple ecosystem services.Australian Research Council Discovery ProjectAustralian Research Council's Centre of Excellence for Environmental DecisionsNERCChile Ministry of EducationCSIRO Integrative Natural Resource Management postgraduate fellowshipsCOLCIENCIA

A New Three-Dimensional Subsulfide Ir₂In₈S with Dirac Semimetal Behavior

Dirac and Weyl semimetals host exotic quasiparticles with unconventional transport properties, such as high magnetoresistance and carrier mobility. Recent years have witnessed a huge number of newly predicted topological semimetals from existing databases; however, experimental verification often lags behind such predictions. Common reasons are synthetic difficulties or the stability of predicted phases. Here, we report the synthesis of the Type-II Dirac semimetal Ir2In8S, an air-stable compound with a new structure type. This material has two Dirac crossings in its electronic structure along the Γ-Z direction of the Brillouin zone. We further show that Ir2In8S has a high electron carrier mobility of ~10,000 cm2/Vs at 1.8 K, and a large, non-saturating transverse magnetoresistance of ~6000% at 3.34 K in a 14 T applied field. Shubnikov de-Haas oscillations reveal several small Fermi pockets and the possibility of a nontrivial Berry phase. With its facile crystal growth, novel structure type, and striking electronic structure, Ir2In8S introduces a new material system to study topological semimetals and enable advances in the field of topological materials

On the relative roles of dynamics and chemistry governing the abundance and diurnal variation of low latitude thermospheric nitric oxide

We use data from two NASA satellites, the Thermosphere Ionosphere Energetics and Dynamics (TIMED) and the Aeronomy of Ice in the Mesosphere (AIM) satellites in conjunction with model simulations from the Thermosphere-Ionosphere-Mesosphere-Electrodynamics General Circulation Model (TIME-GCM) to elucidate the key dynamical and chemical factors governing the abundance and diurnal variation of nitric oxide (NO) at near solar minimum conditions and low latitudes. This analysis was enabled by the recent orbital precession of the AIM satellite which caused the solar occultation pattern measured by the Solar Occultation for Ice Experiment (SOFIE) to migrate down to low and mid latitudes for specific periods of time. We use a month of NO data collected in January 2017 to compare with two versions of the TIME-GCM, one driven solely by climatological tides and analysis-derived planetary waves at the lower boundary and free running at all other altitudes, while the other is constrained by a high-altitude analysis from the Navy Global Environmental Model (NAVGEM)up to the mesopause. We also compare SOFIE data with a NO climatology from the Nitric Oxide Empirical Model (NOEM). Both SOFIE and NOEM yield peak NO abundances of around 4×107cm−3; however, the SOFIE profile peaks about 6-8 km lower than NOEM. We show that this difference is likely a local time effect; SOFIE being a dawn measurement and NOEM representing late morning/near noon. The constrained version of TIME-GCM exhibits a low altitude dawn peak while the model that is forced solely at the lower boundary and free running above does not. We attribute this difference due to a phase change in the semi-diurnal tide in the NAVGEM-constrained model causing descent of high NO mixing ratio air near dawn. This phase difference between the two models arises due to differences in the mesospheric zonal mean zonal winds. Regarding the absolute NO abundance, all versions of the TIME-GCM overestimate this. Tuning the model to yield calculated atomic oxygen in agreement with TIMED data helps, but is insufficient. Further, the TIME-GCM underestimates the electron density [e-] as compared with the International Reference Ionosphere empirical model. This suggests a potential conflict with the requirements of NO modeling and [e-] modeling since one solution typically used to increase model [e-] is to increase the solar soft X ray flux which would, in this case, worsen the NO model/data discrepancy

Are people who participate in cultural activities more satisfied with life?

The influence of various aspects of life on wellbeing has been extensively researched. However, despite little empirical evidence, participation in leisure activities has been assumed to increase subjective wellbeing. Leisure is important because it is more under personal control than other sources of life satisfaction. This study asked whether people who participate in cultural leisure activities have higher life satisfaction than people who do not, if different types of leisure have the same influence on life satisfaction and if satisfaction is dependent on the frequency of participation or the number of activities undertaken. It used data from UKHLS Survey to establish associations between type, number and frequency of participation in leisure activities and life satisfaction. Results showed an independent and positive association of participation in sport, heritage and active-creative leisure activities and life satisfaction but not for participation in popular entertainment, theatre hobbies and museum/galleries. The association of reading hobbies and sedentary-creative activities and life satisfaction was negative. High life satisfaction was associated with engaging in a number of different activities rather than the frequency of participation in each of them. The results have implications for policy makers and leisure services providers, in particular those associated with heritage recreation. Subjective wellbeing measures, such as life satisfaction, and not economic measures alone should be considered in the evaluation of services. The promotion of leisure activities which are active and promote social interaction should be considered in programmes aimed at improving the quality of life

Intra-hepatic arterial pseudoaneurysm causing life-threatening upper gastrointestinal bleed after removal of biliary drainage catheter

Hepatic artery pseudoaneurysms are an uncommon complication of percutaneous biliary drainage catheter insertion. The authors report a case of a hepatic artery pseudoaneurysm following percutaneous internal-external biliary drain insertion. This led to massive haemobilia when the catheter was removed and presented clinically as life-threatening upper gastrointestinal bleed. The clinical and imaging manifestations are discussed along with the management of the patient

Enhanced flow-motion complexity of skin microvascular perfusion in Sherpas and lowlanders during ascent to high altitude

An increased and more effective microvascular perfusion is postulated to play a key role in the physiological adaptation of Sherpa highlanders to the hypobaric hypoxia encountered at high altitude. To investigate this, we used Lempel-Ziv complexity (LZC) analysis to explore the spatiotemporal dynamics of the variability of the skin microvascular blood flux (BF) signals measured at the forearm and finger, in 32 lowlanders (LL) and 46 Sherpa highlanders (SH) during the Xtreme Everest 2 expedition. Measurements were made at baseline (BL) (LL: London 35 m; SH: Kathmandu 1300 m) and at Everest base camp (LL and SH: EBC 5,300 m). We found that BF signal content increased with ascent to EBC in both SH and LL. At both altitudes, LZC of the BF signals was significantly higher in SH, and was related to local slow-wave flow-motion activity over multiple spatial and temporal scales. In SH, BF LZC was also positively associated with LZC of the simultaneously measured tissue oxygenation signals. These data provide robust mechanistic information of microvascular network functionality and flexibility during hypoxic exposure on ascent to high altitude. They demonstrate the importance of a sustained heterogeneity of network perfusion, associated with local vaso-control mechanisms, to effective tissue oxygenation during hypobaric hypoxia

Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders

Background Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families. Methods Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Results A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. Conclusions This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts

Does hypoxia play a role in the development of sarcopenia in humans? Mechanistic insights from the Caudwell Xtreme Everest Expedition

OBJECTIVES: Sarcopenia refers to the involuntary loss of skeletal muscle and is a predictor of physical disability/mortality. Its pathogenesis is poorly understood, although roles for altered hypoxic signaling, oxidative stress, adipokines and inflammatory mediators have been suggested. Sarcopenia also occurs upon exposure to the hypoxia of high altitude. Using data from the Caudwell Xtreme Everest expedition we therefore sought to analyze the extent of hypoxia-induced body composition changes and identify putative pathways associated with fat-free mass (FFM) and fat mass (FM) loss. METHODS: After baseline testing in London (75m), 24 investigators ascended from Kathmandu (1300m) to Everest base camp (EBC 5300m) over 13 days. Fourteen investigators climbed above EBC, eight of whom reached the summit (8848m). Assessments were conducted at baseline, during ascent and after one, six and eight week(s) of arrival at EBC. Changes in body composition (FM, FFM, total body water, intra- and extra-cellular water) were measured by bioelectrical impedance. Biomarkers of nitric oxide and oxidative stress were measured together with adipokines, inflammatory, metabolic and vascular markers. RESULTS: Participants lost a substantial, but variable, amount of body weight (7.3±4.9kg by expedition end; p<0.001). A progressive loss of both FM and FFM was observed, and after eight weeks, the proportion of FFM loss was 48% greater than FM loss (p<0.008). Changes in protein carbonyls (p<0.001) were associated with a decline in FM whereas 4-hydroxynonenal (p<0.001) and IL-6 (p<0.001) correlated with FFM loss. GLP-1 (r=-0.45, p<0.001) and nitrite (r=-0.29, p<0.001) concentration changes were associated with FFM loss. In a multivariate model, GLP-1, insulin and nitrite were significant predictors of FFM loss while protein carbonyls were predicted FM loss. CONCLUSIONS: The putative role of GLP-1 and nitrite as mediators of the effects of hypoxia on FFM is an intriguing finding. If confirmed, nutritional and pharmacological interventions targeting these pathways may offer new avenues for prevention and treatment of sarcopenia

Canine respiratory coronavirus employs caveolin-1-mediated pathway for internalization to HRT-18G cells

Canine respiratory coronavirus (CRCoV), identified in 2003, is a member of the Coronaviridae family. The virus is a betacoronavirus and a close relative of human coronavirus OC43 and bovine coronavirus. Here, we examined entry of CRCoV into human rectal tumor cells (HRT-18G cell line) by analyzing co-localization of single virus particles with cellular markers in the presence or absence of chemical inhibitors of pathways potentially involved in virus entry. We also targeted these pathways using siRNA. The results show that the virus hijacks caveolin-dependent endocytosis to enter cells via endocytic internalization