Temperature dependent elastic constants for crystals with arbitrary symmetry: combined first principles and continuum elasticity theory

To study temperature dependent elastic constants, a new computational method is proposed by combining continuum elasticity theory and first principles calculations. A Gibbs free energy function with one variable with respect to strain at given temperature and pressure was derived, hence the full minimization of the Gibbs free energy with respect to temperature and lattice parameters can be put into effective operation by using first principles. Therefore, with this new theory, anisotropic thermal expansion and temperature dependent elastic constants can be obtained for crystals with arbitrary symmetry. In addition, we apply our method to hexagonal beryllium, hexagonal diamond and cubic diamond to illustrate its general applicability.Comment: 22 pages, 3 figures, 2 table

Temperature dependent elastic constants and ultimate strength of graphene and graphyne

Based on the first principles calculation combined with quasi-harmonic approximation, in this work we focus on the analysis of temperature dependent lattice geometries, thermal expansion coefficients, elastic constants and ultimate strength of graphene and graphyne. For the linear thermal expansion coefficient, both graphene and graphyne show a negative region in the low temperature regime. This coefficient increases up to be positive at high temperatures. Graphene has superior mechanical properties, with Young modulus E11=371.0 N/m, E22=378.2 N/m and ultimate tensile strength of 119.2 GPa at room temperature. Based on our analysis, it is found that graphene's mechanical properties have strong resistance against temperature increase up to 1200 K. Graphyne also shows good mechanical properties, with Young modulus E11=224.7 N/m, E22=223.9 N/m and ultimate tensile strength of 81.2 GPa at room temperature, but graphyne's mechanical properties have a weaker resistance with respect to the increase of temperature than that of graphene

Middle Jurassic collision of an exotic microcontinental fragment: implications for magmatism across the southeast China continental margin

Thrusting, folding and metamorphism of late Paleozoic to middle Mesozoic sedimentary rocks, together with high precision U–Pb zircon ages from Middle to Late Jurassic volcanic and granitic rocks, reveals evidence for a major deformation event in northwestern Hong Kong between 164 and 161 Ma. This episode can be linked with collision of an exotic microcontinental fragment along the southeast China continental margin determined from contrasting detrital zircon provenance histories of late Paleozoic to middle Mesozoic sedimentary rocks either side of a NE-trending suture zone through central Hong Kong. The suture zone is also reflected by isotopic heterogeneities and geophysical anomalies in the crustal basement. Detrital zircon provenance of Early to Middle Jurassic rocks from the accreted terrane have little in common with the pre-Middle Jurassic rocks from southeast China. Instead, the zircon age spectra of the accreted terrane show close affinities to sources along the northern margin of east Gondwana. These data provide indisputable evidence for Mesozoic terrane accretion along the southeast China continental margin. In addition, collision of the exotic terrane, accompanied by subduction roll-back, is considered to have hastened foundering of the postulated flat-slab beneath southeast China leading to a widespread igneous flare-up event at 160 Ma

Machine Learning Identifies Clinical and Genetic Factors Associated With Anthracycline Cardiotoxicity in Pediatric Cancer Survivors

BACKGROUND Despite known clinical risk factors, predicting anthracycline cardiotoxicity remains challenging. OBJECTIVES This study sought to develop a clinical and genetic risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors. METHODS We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure. In a nested case-control design, 183 case patients with reduced left ventricular ejection fraction despite low-dose doxorubicin (\u3c= 250 mg/m(2)), and 106 control patients with preserved left ventricular ejection fraction despite doxorubicin \u3e250 mg/m(2) were selected as extreme phenotypes. Rare/low-frequency variants were collapsed to identify genes differentially enriched for variants between case patients and control patients. The expression levels of 5 top-ranked genes were evaluated in human induced pluripotent stem cell-derived cardiomyocytes, and variant enrichment was confirmed in a replication cohort. Using random forest, a risk prediction model that included genetic and clinical predictors was developed. RESULTS Thirty-one genes were differentially enriched for variants between case patients and control patients (p \u3c 0.001). Only 42.6% case patients harbored a variant in these genes compared to 89.6% control patients (odds ratio: 0.09; 95% confidence interval: 0.04 to 0.17; p = 3.98 x 10(-15)). A risk prediction model for cardiotoxicity that included clinical and genetic factors had a higher prediction accuracy and lower misclassification rate compared to the clinical-only model. In vitro inhibition of gene-associated pathways (PI3KR2, ZNF827) provided protection from cardiotoxicity in cardiomyocytes. CONCLUSIONS Our study identified variants in cardiac injury pathway genes that protect against cardiotoxicity and informed the development of a prediction model for delayed anthracycline cardiotoxicity, and it also provided new targets in autophagy genes for the development of cardio-protective drugs

Modelling the Health and Economic Impacts of Population-Wide Testing, Contact Tracing and Isolation (PTTI) Strategies for COVID-19 in the UK

Background: The COVID-19 epidemic in the UK has resulted in over 280,000 reported cases and over 40,000 deaths as of 5th June 2020. In the context of a slower increase in reported cases and deaths associated with COVID-19 over the last few weeks compared to earlier in the epidemic, the UK is starting to relax the physical restrictions (‘lockdown’) that have been imposed since 23 March 2020. This has been accompanied by the announcement of a strategy to test people for infection, trace contacts of those tested positive, and isolate positive diagnoses. While such policies are expected to be impactful, there is no conclusive evidence of which approach to this is likely to achieve the most appropriate balance between benefits and costs. This study combines mathematical and economic modelling to estimate the impact, costs, feasibility, and health and economic effects of different strategies. / Methods: We provide detailed description, impact, costing, and feasibility assessment of population-scale testing, tracing, and isolation strategies (PTTI). We estimate the impact of different PTTI strategies with a deterministic mathematical model for SARS-CoV-2 transmission that accurately captures tracing and isolation of contacts of individuals exposed, infectious, and diagnosed with the virus. We combine this with an economic model to project the mortality, intensive care, hospital, and non-hospital case outcomes, costs to the UK National Health Service, reduction in GDP, and intervention costs of each strategy. Model parameters are derived from publicly available data, and the model is calibrated to reported deaths associated with COVID-19. We modelled 31 scenarios in total (Panel 2). The first 18 comprised nine with ‘triggers’ (labelled with the -Trig suffix) for subsequent lockdown periods (>40,000 new infections per day) and lockdown releases (<10,000 new infections per day), and nine corresponding scenarios without triggers, namely: no large-scale PTTI (scenario 1); scale-up of PTTI to testing the whole population every week, with May–July 2020 lockdown release (scenario 2b), or delayed lockdown release until scale-up complete on 31 August 2020 (scenario 2a); these two scenarios with mandatory use of face coverings (scenarios 3a and 3b); and scenarios 2a, 2b, 3a, 3b replacing untargeted PTTI with testing of symptomatic people only (scenarios 4a, 4b, 4c, 4d). The final 13 scenarios looked at: whole population weekly testing to suppress the epidemic with lower tracing success (scenarios 3b-Trig00, 3b-Trig10, 3b-Trig20, 3b-Trig30) and switched to targeted testing after two months when it may suppress the epidemic (scenarios 3b-Trig00-2mo and 3b-Trig30-2mo), and targeted testing with lower tracing success (scenarios 4d-Trig10, 4dTrig20, 4d-Trig30, 4d-Trig40, 4d-Trig50, 4d-Trig60, 4d-Trig70). / Findings: Given that physical distancing measures have already been relaxed in the UK, scenario 4d-Trig (targeted testing of symptomatic people only, with a mandatory face coverings policy and subsequent lockdown triggered to enable PTTI to suppress the epidemic), is a strategy that will result in the fewest deaths (~52,000) and has the lowest intervention costs (~£8bn). The additional lockdown results in total reduction in GDP of ~£503bn, less than half the cost to the economy of subsequent lockdowns triggered in a scenario without PTTI (scenario 1-Trig, ~£1180bn reduction in GDP, ~105,000 deaths). In summer months, with lower cold and flu prevalence, approximately 75,000 symptomatic people per day need to be tested for this strategy to work, assuming 64% of their contacts are effectively traced (~80% traced with 80% success) within the infectious period (most within the first two days and nearly all by seven days) and all are isolated – including those without any symptoms – for 14 days. Untargeted testing of everyone every week, if it were feasible, may work without tracing, but at a higher cost (scenario 3b-Trig00). This cost could be reduced by switching to targeted testing after the epidemic is suppressed (scenario 3b-Trig30-2mo), though we note the epidemic could be suppressed with targeted testing itself providing tracing and isolation has at least a 32% success rate (scenario 4dTrig40). / Interpretation: PTTI strategies to suppress the COVID-19 epidemic within the context of a relaxation of lockdown will necessitate subsequent lockdowns to keep the epidemic suppressed during PTTI scale-up. Targeted testing of symptomatic people only can suppress the epidemic if accompanied by mandated use of face coverings. The feasibility of PTTI depends on sufficient capacity, capabilities, infrastructure and integrated systems to deliver it. The political and public acceptability of alternative scenarios for subsequent lockdowns needs to take account of crucial implications for employment, personal and national debt, education, population mental health and non-COVID-19 disease. Our model is able to incorporate additional scenarios as the situation evolves

Calcium Signals Driven by Single Channel Noise

Usually, the occurrence of random cell behavior is appointed to small copy numbers of molecules involved in the stochastic process. Recently, we demonstrated for a variety of cell types that intracellular Ca2+ oscillations are sequences of random spikes despite the involvement of many molecules in spike generation. This randomness arises from the stochastic state transitions of individual Ca2+ release channels and does not average out due to the existence of steep concentration gradients. The system is hierarchical due to the structural levels channel - channel cluster - cell and a corresponding strength of coupling. Concentration gradients introduce microdomains which couple channels of a cluster strongly. But they couple clusters only weakly; too weak to establish deterministic behavior on cell level. Here, we present a multi-scale modelling concept for stochastic hierarchical systems. It simulates active molecules individually as Markov chains and their coupling by deterministic diffusion. Thus, we are able to follow the consequences of random single molecule state changes up to the signal on cell level. To demonstrate the potential of the method, we simulate a variety of experiments. Comparisons of simulated and experimental data of spontaneous oscillations in astrocytes emphasize the role of spatial concentration gradients in Ca2+ signalling. Analysis of extensive simulations indicates that frequency encoding described by the relation between average and standard deviation of interspike intervals is surprisingly robust. This robustness is a property of the random spiking mechanism and not a result of control

Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in children aged 6-17 years: a preliminary report of COV006, a phase 2 single-blind, randomised, controlled trial.

BACKGROUND: Vaccination of children and young people against SARS-CoV-2 is recommended in some countries. Scarce data have been published on immune responses induced by COVID-19 vaccines in people younger than 18 years compared with the same data that are available in adults. METHODS: COV006 is a phase 2, single-blind, randomised, controlled trial of ChAdOx1 nCoV-19 (AZD1222) in children and adolescents at four trial sites in the UK. Healthy participants aged 6-17 years, who did not have a history of chronic respiratory conditions, laboratory-confirmed COVID-19, or previously received capsular group B meningococcal vaccine (the control), were randomly assigned to four groups (4:1:4:1) to receive two intramuscular doses of 5 × 1010 viral particles of ChAdOx1 nCoV-19 or control, 28 days or 84 days apart. Participants, clinical investigators, and the laboratory team were masked to treatment allocation. Study groups were stratified by age, and participants aged 12-17 years were enrolled before those aged 6-11 years. Due to the restrictions in the use of ChAdOx1 nCoV-19 in people younger than 30 years that were introduced during the study, only participants aged 12-17 years who were randomly assigned to the 28-day interval group had received their vaccinations at the intended interval (day 28). The remaining participants received their second dose at day 112. The primary outcome was assessment of safety and tolerability in the safety population, which included all participants who received at least one dose of the study drug. The secondary outcome was immunogenicity, which was assessed in participants who were seronegative to the nucleocapsid protein at baseline and received both prime and boost vaccine. This study is registered with ISRCTN (15638344). FINDINGS: Between Feb 15 and April 2, 2021, 262 participants (150 [57%] participants aged 12-17 years and 112 [43%] aged 6-11 years; due to the change in the UK vaccination policy, the study terminated recruitment of the younger age group before the planned number of participants had been enrolled) were randomly assigned to receive vaccination with two doses of either ChAdOx1 nCoV-19 (n=211 [n=105 at day 28 and n=106 at day 84]) or control (n=51 [n=26 at day 28 and n=25 at day 84]). One participant in the ChAdOx1 nCoV-19 day 28 group in the younger age bracket withdrew their consent before receiving a first dose. Of the participants who received ChAdOx1 nCoV-19, 169 (80%) of 210 participants reported at least one solicited local or systemic adverse event up to 7 days following the first dose, and 146 (76%) of 193 participants following the second dose. No serious adverse events related to ChAdOx1 nCoV-19 administration were recorded by the data cutoff date on Oct 28, 2021. Of the participants who received at least one dose of ChAdOx1 nCoV-19, there were 128 unsolicited adverse events up to 28 days after vaccination reported by 83 (40%) of 210 participants. One participant aged 6-11 years receiving ChAdOx1 nCoV-19 reported a grade 4 fever of 40·2°C on day 1 following first vaccination, which resolved within 24 h. Pain and tenderness were the most common local solicited adverse events for all the ChAdOx1 nCoV-19 and capsular group B meningococcal groups following both doses. Of the 242 participants with available serostatus data, 14 (6%) were seropositive at baseline. Serostatus data were not available for 20 (8%) of 262 participants. Among seronegative participants who received ChAdOx1 nCoV-19, anti-SARS-CoV-2 IgG and pseudoneutralising antibody titres at day 28 after the second dose were higher in participants aged 12-17 years with a longer interval between doses (geometric means of 73 371 arbitrary units [AU]/mL [95% CI 58 685-91 733] and 299 half-maximal inhibitory concentration [IC50; 95% CI 230-390]) compared with those aged 12-17 years who received their vaccines 28 days apart (43 280 AU/mL [95% CI 35 852-52 246] and 150 IC50 [95% CI 116-194]). Humoral responses were higher in those aged 6-11 years than in those aged 12-17 years receiving their second dose at the same 112-day interval (geometric mean ratios 1·48 [95% CI 1·07-2·07] for anti-SARS-CoV-2 IgG and 2·96 [1·89-4·62] for pseudoneutralising antibody titres). Cellular responses peaked after a first dose of ChAdOx1 nCoV-19 across all age and interval groups and remained above baseline after a second vaccination. INTERPRETATION: ChAdOx1 nCoV-19 is well tolerated and immunogenic in children aged 6-17 years, inducing concentrations of antibody that are similar to those associated with high efficacy in phase 3 studies in adults. No safety concerns were raised in this trial. FUNDING: AstraZeneca and the UK Department of Health and Social Care through the UK National Institute for Health and Care Research

Climate simulations for 1880-2003 with GISS modelE

We carry out climate simulations for 1880-2003 with GISS modelE driven by ten measured or estimated climate forcings. An ensemble of climate model runs is carried out for each forcing acting individually and for all forcing mechanisms acting together. We compare side-by-side simulated climate change for each forcing, all forcings, observations, unforced variability among model ensemble members, and, if available, observed variability. Discrepancies between observations and simulations with all forcings are due to model deficiencies, inaccurate or incomplete forcings, and imperfect observations. Although there are notable discrepancies between model and observations, the fidelity is sufficient to encourage use of the model for simulations of future climate change. By using a fixed well-documented model and accurately defining the 1880-2003 forcings, we aim to provide a benchmark against which the effect of improvements in the model, climate forcings, and observations can be tested. Principal model deficiencies include unrealistically weak tropical El Nino-like variability and a poor distribution of sea ice, with too much sea ice in the Northern Hemisphere and too little in the Southern Hemisphere. The greatest uncertainties in the forcings are the temporal and spatial variations of anthropogenic aerosols and their indirect effects on clouds.Comment: 44 pages; 19 figures; Final text accepted by Climate Dynamic

Evenness mediates the global relationship between forest productivity and richness

1. Biodiversity is an important component of natural ecosystems, with higher species richness often correlating with an increase in ecosystem productivity. Yet, this relationship varies substantially across environments, typically becoming less pronounced at high levels of species richness. However, species richness alone cannot reflect all important properties of a community, including community evenness, which may mediate the relationship between biodiversity and productivity. If the evenness of a community correlates negatively with richness across forests globally, then a greater number of species may not always increase overall diversity and productivity of the system. Theoretical work and local empirical studies have shown that the effect of evenness on ecosystem functioning may be especially strong at high richness levels, yet the consistency of this remains untested at a global scale. 2. Here, we used a dataset of forests from across the globe, which includes composition, biomass accumulation and net primary productivity, to explore whether productivity correlates with community evenness and richness in a way that evenness appears to buffer the effect of richness. Specifically, we evaluated whether low levels of evenness in speciose communities correlate with the attenuation of the richness–productivity relationship. 3. We found that tree species richness and evenness are negatively correlated across forests globally, with highly speciose forests typically comprising a few dominant and many rare species. Furthermore, we found that the correlation between diversity and productivity changes with evenness: at low richness, uneven communities are more productive, while at high richness, even communities are more productive. 4. Synthesis. Collectively, these results demonstrate that evenness is an integral component of the relationship between biodiversity and productivity, and that the attenuating effect of richness on forest productivity might be partly explained by low evenness in speciose communities. Productivity generally increases with species richness, until reduced evenness limits the overall increases in community diversity. Our research suggests that evenness is a fundamental component of biodiversity–ecosystem function relationships, and is of critical importance for guiding conservation and sustainable ecosystem management decisions