Structure guided mutagenesis of Henipavirus Receptor Binding Proteins reveals molecular determinants of receptor usage and antibody binding epitopes.

Nipah virus (NiV) is a highly lethal, zoonotic henipavirus (HNV) that causes respiratory and neurological signs and symptoms in humans. Similar to other paramyxoviruses, HNVs mediate entry into host cells through the concerted actions of two surface glycoproteins: a receptor binding protein (RBP) that mediates attachment and a fusion glycoprotein (F) that triggers fusion in an RBP-dependent manner. NiV uses ephrin-B2 (EFNB2) and ephrin-B3 (EFNB3) as entry receptors. Ghana virus (GhV), a novel HNV identified in a Ghanaian bat, use EFNB2 but not EFNB3. In this study, we employ a structure-informed approach to identify receptor interfacing residues and systematically introduce GhV-RBP residues into a NiV-RBP backbone to uncover the molecular determinants of EFNB3 usage. We reveal two regions that severely impair EFNB3 binding by NiV-RBP and EFNB3-mediated entry by NiV pseudotyped viral particles. Further analyses uncovered two point mutations (NiVN557SGhV and NiVY581TGhV) pivotal for this phenotype. Moreover, we identify NiV interaction with Y120 of EFNB3 as important for usage of this receptor. Beyond these EFNB3-related findings, we reveal two domains that restrict GhV binding of EFNB2, identify the HNV-head as an immunodominant target for polyclonal and monoclonal antibodies, and describe putative epitopes for GhV and NiV-specific monoclonal antibodies. Cumulatively, the work presented here generates useful reagents and tools that shed insight to residues important for NiV usage of EFNB3, reveals regions critical for GhV binding of EFNB2, and describes putative HNV antibody binding epitopes.

Molecular biomarkers for assessing the heat-adapted phenotype: a narrative scoping review.

Heat acclimation/acclimatisation (HA) mitigates heat-related decrements in physical capacity and heat-illness risk and is a widely advocated countermeasure for individuals operating in hot environments. The efficacy of HA is typically quantified by assessing the thermo-physiological responses to a standard heat acclimation state test (i.e. physiological biomarkers), but this can be logistically challenging, time consuming, and expensive. A valid molecular biomarker of HA would enable evaluation of the heat-adapted state through the sampling and assessment of a biological medium. This narrative review examines candidate molecular biomarkers of HA, highlighting the poor sensitivity and specificity of these candidates and identifying the current lack of a single 'standout' biomarker. It concludes by considering the potential of multivariable approaches that provide information about a range of physiological systems, identifying a number of challenges that must be overcome to develop a valid molecular biomarker of the heat-adapted state, and highlighting future research opportunities.

Crevasse refreezing and signatures of retreat observed at Kamb Ice Stream grounding zone.

Ice streams flowing into Ross Ice Shelf are presently responsible for around 10% of the mass flux from West Antarctica, with the noteworthy exception of Kamb Ice Stream, which stagnated in the late 1800s. The subsequent reduction in ice supply led to grounding-line retreat at the coastal margin where Kamb transitions into the floating Ross Ice Shelf. Grounding-line migration is linked to broader changes in ice-sheet mass balance and sea level, but our understanding of related ice, ocean and seafloor interactions is limited by the difficulty in accessing these remote regions. Here we report in situ observations from an underwater vehicle deployed at Kamb that show how fine-scale variability in ice and ocean structure combine to influence a diversity of ice-ocean interactions. We found a stratified water column within a tenth of a degree of freezing at the ice base and mapped basal crevasses with supercooled water and active marine ice formation. At the seafloor, we interpret parallel ridges as crevasse impressions left as the ice lifted off during grounding-line retreat. These observations from a recently ungrounded sub-shelf environment illuminate both the geomorphological signatures of past grounding-line retreat and the fine-scale sensitivity of ongoing ice-ocean interactions to ice topography.

Effects of ileocolonic delivered vitamin B2, B3 and C (ColoVit) or the Groningen anti-inflammatory diet on disease course and microbiome of patients with Crohn's disease (VITA-GrAID study): a protocol for a randomised and partially blinded trial.

BACKGROUND: Diet plays a pivotal role in the onset and progression of Crohn's disease (CD). Nutritional interventions revealed effects on intestinal inflammation and gut microbial composition. However, data from well-designed and controlled dietary trials are lacking. Therefore, evidence-based dietary recommendations are still unavailable to patients and physicians. Here, we aim to investigate the effects of an evidence-based anti-inflammatory diet, and an ileocolonic-targeted capsule containing vitamin B2, B3 and C (ColoVit) on patients with CD and their healthy household members. METHODS AND ANALYSIS: In this multicentre, randomised, placebo-controlled, partially blinded nutritional intervention trial, we aim to recruit 255 CD patients with Harvey-Bradshaw Index <8 and a faecal calprotectin (FCal) cut-off of ≥100 µg/g at baseline. Participants will be randomised into two experimental intervention groups and one placebo group. In the experimental groups, participants will either adhere to the Groningen anti-inflammatory diet (GrAID) or ingest an ileocolonic-delivered oral vitamin B2/B3/C capsule (ColoVit). The study consists of a 12-week controlled interventional phase, which proceeds to a 9-month observational follow-up phase in which patients allocated to the GrAID group will be requested to continue the intervention on their own accord. Household members of participating patients will be asked to participate in the trial as healthy subjects and are allocated to the same group as their peer. The primary study outcome for patients is the change in FCal level from baseline. The primary outcome for household members is the change in gut microbial composition, which is set as secondary outcome for patients. ETHICS AND DISSEMINATION: The protocol has been approved by the Institutional Review Board of the Stichting Beoordeling Ethiek Biomedisch Onderzoek in Assen, the Netherlands. Written informed consent will be obtained from all participants. Results will be disseminated through peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: NCT04913467.

A multiple linear regression approach to the estimation of carboxylic acid ester and lactone alkaline hydrolysis rate constants.

Pesticides, pharmaceuticals, and other organic contaminants often undergo hydrolysis when released into the environment; therefore, measured or estimated hydrolysis rates are needed to assess their environmental persistence. An intuitive multiple linear regression (MLR) approach was used to develop robust QSARs for predicting base-catalyzed rate constants of carboxylic acid esters (CAEs) and lactones. We explored various combinations of independent descriptors, resulting in four primary models (two for lactones and two for CAEs), with a total of 15 and 11 parameters included in the CAE and lactone QSAR models, respectively. The most significant descriptors include pKa, electronegativity, charge density, and steric parameters. Model performance is assessed using Drug Theoretics and Cheminformatics Laboratory's DTC-QSAR tool, demonstrating high accuracy for both internal validation (r2 = 0.93 and RMSE = 0.41-0.43 for CAEs; r2 = 0.90-0.93 and RMSE = 0.38-0.46 for lactones) and external validation (r2 = 0.93 and RMSE = 0.43-0.45 for CAEs; r2 = 0.94-0.98 and RMSE = 0.33-0.41 for lactones). The developed models require only low-cost computational resources and have substantially improved performance compared to existing hydrolysis rate prediction models (HYDROWIN and SPARC).

Seasonal temperatures in West Antarctica during the Holocene.

The recovery of long-term climate proxy records with seasonal resolution is rare because of natural smoothing processes, discontinuities and limitations in measurement resolution. Yet insolation forcing, a primary driver of multimillennial-scale climate change, acts through seasonal variations with direct impacts on seasonal climate1. Whether the sensitivity of seasonal climate to insolation matches theoretical predictions has not been assessed over long timescales. Here, we analyse a continuous record of water-isotope ratios from the West Antarctic Ice Sheet Divide ice core to reveal summer and winter temperature changes through the last 11,000 years. Summer temperatures in West Antarctica increased through the early-to-mid-Holocene, reached a peak 4,100 years ago and then decreased to the present. Climate model simulations show that these variations primarily reflect changes in maximum summer insolation, confirming the general connection between seasonal insolation and warming and demonstrating the importance of insolation intensity rather than seasonally integrated insolation or season duration2,3. Winter temperatures varied less overall, consistent with predictions from insolation forcing, but also fluctuated in the early Holocene, probably owing to changes in meridional heat transport. The magnitudes of summer and winter temperature changes constrain the lowering of the West Antarctic Ice Sheet surface since the early Holocene to less than 162 m and probably less than 58 m, consistent with geological constraints elsewhere in West Antarctica4-7.

Multidimensional spectroscopy of magneto-excitons at high magnetic fields.

We perform two-dimensional Fourier transform spectroscopy on magneto-excitons in GaAs at magnetic fields and observe Zeeman splitting of the excitons. The Zeeman components are clearly resolved as separate peaks due to the two-dimensional nature of the spectra, leading to a more accurate measurement of the Zeeman splitting and the Landé g factors. Quantum coherent coupling between Zeeman components is observed using polarization dependent one-quantum two-dimensional spectroscopy. We use two-quantum two-dimensional spectroscopy to investigate higher four-particle correlations at high magnetic fields and reveal the role of the Zeeman splitting on the two-quantum transitions. The experimental two-dimensional spectra are simulated using the optical Bloch equations, where many-body effects are included phenomenologically.

Predictors of Poor Functional Status in Adult Fontan Patients Living at Moderate Altitude.

Patients who have undergone Fontan palliation have reduced exercise tolerance measured by maximal oxygen consumption (VO2 max). Declining exercise capacity is associated with increased morbidity and mortality. The impact of hemodynamics and other variables on this population's functional status is not well understood. This study sought to identify variables that predict low VO2 max in Fontan patients living at moderate altitude (5,000-8,000 feet). We performed a retrospective cohort study of 44 adult Fontan patients living at moderate altitude who had undergone cardiopulmonary exercise testing (CPET) and cardiac catheterization. We evaluated hemodynamic parameters measured during catheterization, imaging results, and laboratory studies for correlation with VO2 max measured during CPET. Our study cohort (median age 30 years, 52% female) had exercise impairment with mean VO2 max of 21.6 mL/kg/min. Higher trans-pulmonary gradient (TPG) (p < 0.001) and mean pulmonary artery (PA) pressure (p = 0.013) were predictors of lower maximal and submaximal VO2. Higher BNP values correlated with lower VO2 max (p = 0.01). Platelet count, GGT, albumin, and pulmonary vasodilator therapy did not correlate with VO2 max. None of the studied variables were associated with higher minute ventilation to peak carbon dioxide production (VE/VCO2 slope) or change in VO2 max over time. In conclusion, higher TPG and mean PA pressure predicted lower exercise tolerance amongst our cohort of adult Fontan patients living at moderate altitude. Future studies are needed to determine if these clinical variables represent viable therapeutic targets that could result in improved exercise tolerance and outcomes in patients with Fontan circulation.

Virtual reality for acute and chronic pain management in adult patients: a narrative review.

Virtual reality is a computer-generated environment that immerses the user in an interactive artificial world. This ability to distract from reality has been utilised for the purposes of providing pain relief from noxious stimuli. As technology rapidly matures, there is potential for anaesthetists and pain physicians to incorporate virtual reality devices as non-pharmacological therapy in a multimodal pain management strategy. This systematic narrative review evaluates clinical studies that used virtual reality in adult patients for management of acute and chronic pain. A literature search found 690 citations, out of which 18 studies satisfied the inclusion criteria. Studies were assessed for quality using the Jadad and Nottingham-Ottawa Scales. Agreement on scores between independent assessors was 0.87 (95%CI 0.73-0.94). Studies investigated virtual reality use: intra-operatively; for labour analgesia; for wound dressing changes; and in multiple chronic pain conditions. Twelve studies showed reduced pain scores in acute or chronic pain with virtual reality therapy, five studies showed no superiority to control treatment arms and in one study, the virtual reality exposure group had a worsening of acute pain scores. Studies were heterogeneous in: methods; patient population; and type of virtual reality used. These limitations suggest the evidence-base in adult patients is currently immature and more rigorous studies are required to validate the use of virtual reality as a non-pharmacological adjunct in multimodal pain management.

Nutrients cause grassland biomass to outpace herbivory.

Human activities are transforming grassland biomass via changing climate, elemental nutrients, and herbivory. Theory predicts that food-limited herbivores will consume any additional biomass stimulated by nutrient inputs ('consumer-controlled'). Alternatively, nutrient supply is predicted to increase biomass where herbivores alter community composition or are limited by factors other than food ('resource-controlled'). Using an experiment replicated in 58 grasslands spanning six continents, we show that nutrient addition and vertebrate herbivore exclusion each caused sustained increases in aboveground live biomass over a decade, but consumer control was weak. However, at sites with high vertebrate grazing intensity or domestic livestock, herbivores consumed the additional fertilization-induced biomass, supporting the consumer-controlled prediction. Herbivores most effectively reduced the additional live biomass at sites with low precipitation or high ambient soil nitrogen. Overall, these experimental results suggest that grassland biomass will outstrip wild herbivore control as human activities increase elemental nutrient supply, with widespread consequences for grazing and fire risk.

The impact of air pollution on terrestrial managed and natural vegetation.

Although awareness that air pollution can damage vegetation dates back at least to the 1600s, the processes and mechanisms of damage were not rigorously studied until the late twentieth century. In the UK following the Industrial Revolution, urban air quality became very poor, with highly phytotoxic SO2 and NO2 concentrations, and remained that way until the mid-twentieth century. Since then both air quality, and our understanding of pollutants and their impacts, have greatly improved. Air pollutants remain a threat to natural and managed ecosystems. Air pollution imparts impacts through four major threats to vegetation are discussed through in a series of case studies. Gas-phase effects by the primary emissions of SO2 and NO2 are discussed in the context of impacts on lichens in urban areas. The effects of wet and dry deposited acidity from sulfur and nitrogen compounds are considered with a particular focus on forest decline. Ecosystem eutrophication by nitrogen deposition focuses on heathland decline in the Netherlands, and ground-level ozone at phytotoxic concentrations is discussed by considering impacts on semi-natural vegetation. We find that, although air is getting cleaner, there is much room for additional improvement, especially for the effects of eutrophication on managed and natural ecosystems. This article is part of a discussion meeting issue 'Air quality, past present and future'.

Evaluation of the Laguerre-Gaussian mode purity produced by three-dimensional-printed microwave spiral phase plates.

Computer-aided design software and additive manufacturing provide flexibility for the direct fabrication of multi-material devices. This design and fabrication versatility has been investigated for the manufacture of dielectric spiral phase plates (SPP) that generate electromagnetic waves with helical wavefronts. Three types of SPPs designed to produce an orbital angular momentum (OAM) mode number l = |1| were additively manufactured using material extrusion and polyjet fabrication methods. The OAM mode characteristics of the transformed helical microwaves as a function of the SPP geometrical features were investigated experimentally in the 12-18 GHz frequency range. The SPPs were further combined with an additively manufactured dielectric lens that provided a marked improvement in OAM mode purity. Finally, multiplexing and de-multiplexing of two OAM modes were demonstrated successfully using an optimum SPP geometry and arrangement.

Evidence for elevated psychiatric distress, poor sleep, and quality of life concerns during the COVID-19 pandemic among U.S. young adults with suspected and reported psychiatric diagnoses.

We report distress levels and functional outcomes based on self-reported pre-existing mental health conditions among U.S. young adults (N=898) during the COVID-19 pandemic (April 13-May 19, 2020). Depression, anxiety, and PTSD symptoms, as well as COVID-19-related concerns, sleep problems, and quality of life were compared across the following pre-existing mental health groups: 1) no diagnosis, 2) suspected diagnosis, 3) diagnosed and untreated, and 4) diagnosed and treated. Compared to those without a diagnosis, the likelihood of scoring above the clinical threshold for those with a diagnosis - whether treated or not - was more than six-fold for depression, and four-to six-fold for anxiety and PTSD. Individuals with a suspected diagnosis were 3 times more likely to score above the clinical threshold for depression and anxiety and 2 times more as likely to score above this threshold for PTSD compared to those with no diagnosis. We also present higher levels of COVID-19-related worry and grief, poorer sleep, and poorer reported health-related quality of life among those with either a suspected or reported mental health diagnosis. Findings provide evidence of vulnerability among individuals with a mental health diagnosis or suspected mental health concerns during the initial weeks of the COVID-19 pandemic.

Menthol as an Ergogenic Aid for the Tokyo 2021 Olympic Games: An Expert-Led Consensus Statement Using the Modified Delphi Method.

INTRODUCTION: Menthol topical application and mouth rinsing are ergogenic in hot environments, improving performance and perception, with differing effects on body temperature regulation. Consequently, athletes and federations are beginning to explore the possible benefits to elite sport performance for the Tokyo 2021 Olympics, which will take place in hot (~ 31 °C), humid (70% RH) conditions. There is no clear consensus on safe and effective menthol use for athletes, practitioners, or researchers. The present study addressed this shortfall by producing expert-led consensus recommendations. METHOD: Fourteen contributors were recruited following ethical approval. A three-step modified Delphi method was used for voting on 96 statements generated following literature consultation; 192 statements total (96/96 topical application/mouth rinsing). Round 1 contributors voted to "agree" or "disagree" with statements; 80% agreement was required to accept statements. In round 2, contributors voted to "support" or "change" their round 1 unaccepted statements, with knowledge of the extant voting from round 1. Round 3 contributors met to discuss voting against key remaining statements. RESULTS: Forty-seven statements reached consensus in round 1 (30/17 topical application/rinsing); 14 proved redundant. Six statements reached consensus in round 2 (2/4 topical application/rinsing); 116 statements proved redundant. Nine further statements were agreed in round 3 (6/3 topical application/rinsing) with caveats. DISCUSSION: Consensus was reached on 62 statements in total (38/24 topical application/rinsing), enabling the development of guidance on safe menthol administration, with a view to enhancing performance and perception in the heat without impairing body temperature regulation.

Reported Weight Change in Older Adults and Presence of Frailty.

OBJECTIVE: A 5% change in weight is a significant predictor for frailty and obesity. We ascertained how self-reported weight change over the lifespan impacts rates of frailty in older adults. METHODS: We identified 4,984 subjects ≥60 years with body composition measures from the National Health and Nutrition Examination Survey. An adapted version of Fried's frailty criteria was used as the primary outcome. Self-reported weight was assessed at time current,1 and 10 years earlier and at age 25. Weight changes between each time point were categorized as ≥ 5%, ≤5% or neutral. Logistic regression assessed the impact of weight change on the outcome of frailty. RESULTS: Among 4,984 participants, 56.5% were female, mean age was 71.1 years, and mean BMI was 28.2kg/m2. A weight loss of ≥ 5% had a higher association with frailty compared to current weight, age 25 (OR 2.94 [1.72,5.02]), 10 years ago (OR 1.68 [1.05,2.69]), and 1 year ago (OR 1.55 [1.02,2.36]). Weight gain in the last year was associated with increased rate of frailty (1.59 [1.09,2.32]). CONCLUSION: There is an association between frailty and reported weight loss over time while only weight gain in the last year has an association with frailty.

Superdirective dimers of coupled self-resonant split ring resonators: Analytical modelling and numerical and experimental validation.

Superdirective antennas developed over the last century have received renewed interest in recent years from the development of metamaterials. These arrays of electromagnetic resonators (or meta-atoms) carrying short wavelength electro- and/or magneto-inductive waves support current distributions with very high spatial frequency as required by the classical conditions for superdirectivity. As meta-atoms can have both electric and magnetic dipole characteristics (and hence radiation properties), developing antennas exploiting these distributions can challenge conventional intuitions regarding the optimal configurations required. In this work we are reporting the development of a genuinely superdirective array using split ring resonators (SRRs). We provide a comprehensive analytical model characterizing the radiation from SRR dimers in which excitation of only one split ring leads to superdirective radiation via mutually coupled modes. Our model exploits simple circuit descriptions of coupled resonant circuits, combined with standard radiation formulae for curvilinear current distributions. Using this simple model we are able to map directivity against possible SRR locations and orientations in two dimensions and identify the unique optimal configuration which meets the requirements for superdirective emission. We validate the theoretical findings by comparison to both full wave simulations and experiments showing that our SRR dimer achieves endfire directivity very close to the maximum theoretical value.

Acceptability of intravenous propofol sedation for adolescent dental care.

PURPOSE: Propofol is an intravenous anaesthetic agent commonly utilised in general anaesthesia, however in sub-anaesthetic concentrations can be utilised to provide sedation through automated dosing of target-controlled infusion (TCI). TCI has been shown to provide accurate and stable predicted plasma and effect-site concentrations of propofol. A four-part mixed-method prospective study was undertaken to evaluate the safety and patient acceptability of intravenous propofol sedation in adolescent patients requiring dental care. There is a paucity in the literature on patient-reported outcomes and patient safety in the management of adolescent patients for dental treatment. METHODS: Demographics were recorded including age, gender, ASA Classification and Children's Fear Survey Schedule-Dental Subscale (CFSS-DS) completed pre-operatively. Behaviour ratings of the Frankl and Houpt scales were recorded followed by post-operative questionnaire and telephone consultation. Consultation was completed following the procedure to determine patient satisfaction, memory of the procedure and any reported side effects of treatment. Qualitative thematic analysis was utilised. RESULTS: 55 patients were recruited for the study, of which 49 (mean age 14.67 years) completed the sedation study and were treated safely with no post-operative complications. The mean lowest oxygen saturation was 98.12% SpO2 (SD 2.6). Thematic analysis demonstrated positive patient-reported outcomes to IV sedation. CONCLUSION: Propofol TCI sedation is an effective treatment modality for the management of dentally anxious adolescents as a safe alternative to general anaesthesia, allowing the opportunity for increased provision of treatment per visit on those patients with a high dental need. Further randomised controlled trials comparing propofol TCI to other pharmacological managements are required.