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Ubc13-catalyzed K63 ubiquitination is a major control point for immune signaling. Recent evidence has shown that the control of multiple immune functions, including chronic inflammation, pathogen responses, lymphocyte activation, and regulatory signaling, is altered by K63 ubiquitination. In this review, we detail the novel cellular sensors that are dependent on K63 ubiquitination for their function in the immune signaling network. Many pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can target K63 ubiquitination to inhibit pathogen immune responses; we describe novel details of the pathways involved and summarize recent clinically relevant SARS-CoV-2-specific responses. We also discuss recent evidence that regulatory T cell (Treg) versus T helper (TH) 1 and TH17 cell subset regulation might involve K63 ubiquitination. Knowledge gaps that merit future investigation and clinically relevant pathways are also addressed.

Understanding which eosinophilic esophagitis (EoE) patients will respond to treatment with topical corticosteroids (tCS) remains challenging, and it is unknown whether obesity impacts treatment response. This study aimed to determine whether treatment outcomes to tCS in EoE patients vary by body mass index (BMI).This retrospective cohort study of the University of North Carolina EoE Clinicopathologic database assessed subjects age 14 years or older with a new diagnosis of EoE. Their BMI was calculated and histologic, symptom, and endoscopic responses were recorded after tCS treatment. The treatment response of obese (BMI, ≥30 kg/mWe identified 296 EoE patients treated with tCS. Baseline characteristics were similar, although obese EoE patients had more heartburn and hiatal hernias. Histologic response was higher for those who were nonobese compared with obese at fewer than 15 (61% vs 47%; P = .049) and 6 or fewer (54% vs 38%; P = .02) eosinophils per high-power field, respectively. In addition, nonobese patients had significantly greater endoscopic and symptomatic responses. On multivariate analysis, increasing BMI was associated independently with decreased histologic response after accounting for age, heartburn, dilation, and hiatal hernia whether BMI was assessed as a continuous variable (adjusted odds ratio [aOR], 0.93; 95% CI, 0.89-0.98), as nonobese vs obese (aOR, 0.38; 95% CI, 0.21-0.68), or in 4 categories (overweight vs normal [aOR, 0.46; 95% CI, 0.26-0.84] or obese vs normal [aOR, 0.26; 95% CI, 0.13-0.51]).As BMI increases in EoE patients, the odds of histologic, symptomatic, and endoscopic responses to tCS decreases, with obese patients having an approximately 40% odds of response.

The increasing use of orthopedic total hip arthroplasty implants has led to a consequent rise in the incidence of associated periprosthetic fractures (PPFs). Analysis of the National Joint Registry data showed the choice of cemented hip stem influenced the risk of a PPF occurring. However, the effect of implant design in relation to the risk of PPFs has not been investigated.The main objective is to compare the biomechanics of PPFs as a failure of the Exeter V40, CPT, and DePuy C-Stem stems in a composite Sawbone model to identify whether a difference in the risk of fracture exists between them. Twenty-six Sawbones were divided into 3 groups, cemented with the Stryker Exeter, Zimmer CPT, or DePuy C-Stem and then torqued to fracture.When compared with the Exeter, the CPT- and C-Stem-implanted Sawbone models would sustain PPFs at a statistically significantly lower rotation to failure (20.1° and 26.7° vs 33.6°, P .01) and torque to failure (124 Nm and 143 Nm vs 174 Nm, P .01) values. The energy release rate at failure for the Exeter was significantly higher than that for the CPT and C-Stem (61.2 Nm vs 21.8 Nm and 38.6 Nm, P .01), which led to more comminution.The CPT- and C-Stem-implanted femurs, although fracturing earlier, fractured in a simple pattern with less comminution. The differences in stem design mean higher stress at the critical point of failure in the CPT implanted femur compared with the Exeter and DePuy, which is likely the reason behind the observed increased risk of PPFs with the CPT implant.

New grades of γ/γ′ nickel-based superalloy for the additive manufacturing process are designed using computational approaches. Account is taken of the need to avoid defect formation via solidification and solid-state cracking. Processing trials are carried out using powder-based selective laser melting, comparing with the heritage alloys IN939 and CM247LC. Microstructural characterisation, calorimetry and hot tensile testing are used to assess the approach employed. The superior processability and mechanical behaviour of the new alloys are demonstrated. Suggestions are made for refinements to the modelling approach.

The ACCESS Study is a prospective, multicenter registry to evaluate the efficacy and safety of trans-subclavian and axillary transcatheter aortic valve replacement (TAx-TAVR) with the latest-genera...

First, a short history is given of the use of the EEG as a biomarker of efficacy in anti-seizure medication (ASM) development. The generalized epileptiform EEG response to Intermittent Photic Stimulation (IPS), the photoparoxysmal EEG response or PPR, in particular, is a reliable reproducible measure since the 1950s. Over time, a "Photosensitivity Model", testing within the same patients the impact of potential new oral ASMs, along with dose-ranging data, on PPRs, has been developed successfully. The classical Photosensitivity Model consists of IPS and blood sampling for ASM measurement performed hourly between 8 AM and 5 PM over three consecutive days. This single-blind, placebo-controlled, pharmacokinetic-pharmacodynamic (PK/PD) Model is now commonly utilized as a Proof-of-Concept Phase 2a trial. For Generalized Tonic-Clonic Status Epilepticus (GTCSE), it is especially relevant to know the time for CNS entry and effect minutes after i.v. ASM treatment, since "time is brain". We, therefore, adapted successfully the Model to a time-efficient Model with the determination of photosensitivity ranges in minutes after equivalent doses of iv brivaracetam (BRV) and levetiracetam (LEV). This modified design allows one to monitor the time to CNS effect (i.e., PPR elimination) of a quickly-acting FDA-approved ASM given i.v., a crucial element in status epilepticus treatment. This paper was presented at the 8th London-Innsbruck Colloqium on Status Epilepticus and Acute Seizures held in September 2022.

The evolution of dislocation density with creep strain in single-crystal superalloys is studied quantitatively using high-resolution electron backscatter diffraction (HR-EBSD) and electron channelling contrast imaging under controlled diffraction conditions (cECCI). Data regarding dislocation density/structure is measured for deformation at 900 °C and 450 MPa up to ≈ 1% plastic strain. Effects of chemical composition are elucidated via three purpose-designed superalloys of differing rhenium and ruthenium contents. The evidence indicates that dislocation avalanching is already prevalent at plastic strains of ≈ 0.1%; thereafter, an exponential decay in the dislocation multiplication rate is indicative of self-hardening due to dislocation constriction within the matrix channels, as confirmed by the imaging. The results are rationalised using discrete dislocation dynamics modelling: a universal dislocation evolution law emerges, which will be useful for alloy design efforts.

An alloy design approach for titanium alloys is presented. New alloys are isolated, manufactured and tested with an emphasis on the superplastic response. The superplastic effect is found to be optimal between 650 to 750 ∘ C at strain rates between 8.3×10−2 and 8.3 × 10−3/s – this is a substantial improvement in terms of temperature and deformation rates over traditional titanium alloys such as Ti–6Al–4V. Elongations approaching ∼ 2000% are demonstrated. Electron backscatter diffraction studies confirm a randomisation of texture and absence of significant intragranular dislocation density, confirming superplasticity and thus grain-boundary sliding as the overarching deformation mechanism. At strain rates faster than 0.01/s, the alloys exhibit large elongations ( ∼ 200–500%) but softening is evident and lower ductility results. Our results reveal that the physical factors controlling the alloy composition/property/manufacturing interrelationship are understood and quantified. Physically-based constitutive equations are presented and used to demonstrate the practical advantages of the designed alloys.

Sustainable dryland management depends on understanding environmental factors driving the composition of current and future ecological communities. While there has been extensive research on aboveground plant communities, less is known about belowground soil seed bank communities. In the Colorado Plateau of the western United States, we simultaneously explored aboveground and belowground plant communities and how they varied across sites with similar climate but contrasting soil textures. We found that aboveground vegetation and belowground seed bank community composition each varied significantly among sites. We also observed marked aboveground-belowground compositional dissimilarity across sites, suggesting that the two spatially-associated communities may respond differently to the same environmental gradient. Lastly, we found that abundances of cheatgrass (Bromus tectorum) – one of the region's major exotic invasive plants – varied strongly with soil texture, a finding with implications for invasive species management. From our results, we highlight two general patterns for dryland managers. First, we show that aboveground and belowground plant communities can respond to the same environmental variation in a strongly divergent manner. Second, the data underscore a large potential role for soil texture and its associated factors in mediating plant community responses to a range of environmental conditions.

Additive manufacturing is used to produce open-cell scaffolds with tailored design to match bone performance. We used triply periodic minimal surfaces within a range of sizes and volume fractions designed to suit the needs of the different existing bone tissues – this meant manufacturing sub-millimetre unit cells with pore sizes between 200 and 500 μm. Ti–6Al–4 V is employed. Compression experiments reveal the stiffness and the collapse load of the scaffold as a function of geometry and density. This work confirms the suitability of the designed lattices to match the stiffness and the yield strength over a wide range of bone types.

Many species use stored energy to hibernate through periods of resource limitation. Hibernation, a physiological state characterized by depressed metabolism and body temperature, is critical to winter survival and reproduction, and therefore has been extensively quantified and modeled. Hibernation consists of alternating phases of extended periods of torpor (low body temperature, low metabolic rate), and energetically costly periodic arousals to normal body temperature. Arousals consist of multiple phases: warming, euthermia, and cooling. Warming and euthermic costs are regularly included in energetic models, but although cooling to torpid body temperature is an important phase of the torpor-arousal cycle, it is often overlooked in energetic models. When included, cooling cost is assumed to be 67% of warming cost, an assumption originally derived from a single study that measured cooling cost in ground squirrels. Since this study, the same proportional value has been assumed across a variety of hibernating species. However, no additional values have been derived. We derived a model of cooling cost from first principles and validated the model with empirical energetic measurements. We compared the assumed 67% proportional cooling cost with our model-predicted cooling cost for 53 hibernating mammals. Our results indicate that using 67% of warming cost only adequately represents cooling cost in ground squirrel-sized mammals. In smaller species, this value overestimates cooling cost and in larger species, the value underestimates cooling cost. Our model allows for the generalization of energetic costs for multiple species using species-specific physiological and morphometric parameters, and for predictions over variable environmental conditions.

A novel approach to accelerate greatly and simplify the determination of creep properties in metals is presented. The method combines advanced digital image correlation, thermal imaging, and conductive graded heating to produce and analyse viscoplastic deformation in a continuous range of temperatures at constant stresses. By differentiating the strain across small sections of the sample at different temperatures, one may extract the creep behaviour at many different temperatures and thus derive the activation energy. Just a single test and specimen is needed to make a first reasonable estimate. The method is suitable for all metals and alloys but is validated here for a prototype Ni-based single superalloy.

© 2021 Acta Materialia Inc. This investigation concerns superalloy samples produced by an additive manufacturing procedure. Microstructural examination confirmed that they exhibited a columnar grain structure, with the grains elongated in the growth (“build”) direction and exhibiting a strong texture involving alignment of 〈100〉 parallel to this axis. Samples were tensile tested along both build and transverse directions, being found to be both stiffer and harder in the latter. This material thus exhibits well-characterized anisotropy, making it well-suited to study of how this affects outcomes from an indentation-based procedure for obtaining stress-strain curves. This is termed Profilometry-based Inverse FEM for Plasticity Parameters from Indentation (PIP). True stress-strain curves obtained using this methodology were found to be entirely consistent with the directly-measured curves. Furthermore, it is shown that full 3-D characterization of the indent profiles can be used to obtain at least a semi-quantitative indication of the nature and strength of the plastic anisotropy. This constitutes a significant advance in the context of a technique that could have a transformative effect on mechanical testing procedures.

Distinct CD4+T cell epitopes have been associated with spontaneous control of HIV-1 replication, but analysis of antigen-dependent factors that influence epitope selection is lacking. To examine these factors, we used a cell-free antigen processing system that incorporates soluble HLA-DR (DR1), HLA-DM (DM), and cathepsins along with full-length protein antigens for epitope identification by LC-MS/MS. HIV-1 Gag, Pol, Env, Vif, Nef, Tat, and Rev were examined using this system. We identified 35 novel epitopes, including glycopeptides. Epitopes from smaller HIV-1 proteins with crystal structures mapped to regions of low protein stability and higher solvent accessibility. HIV-1 antigens associated with limited CD4+T cell responses were processed efficiently, while some protective epitopes were inefficiently processed. 66% of epitopes obtained from cell-free processing induced memory CD4+T cell responses in HIV-1+ donors, including 10 of 19 novel epitopes. Thus, an in vitro processing system can identify novel HIV-1 epitopes and reveal factors influencing epitope dominance.

Continuum models and miniaturised experiments are used to elucidate the high-temperature forgeability of the Ni-based superalloy Inconel 903. Uniaxial compression high temperature tests allow the derivation of an apparent activation energy and the strain rate sensitivity of the deformation process, and to propose a unified constitutive model that captures the underlying physics of deformation. Metallographic analysis is then used to elucidate changes in microstructure which arise during the deformation process; microstructure evolution models which define the changes in grain size and recrystallisation during high temperature compression are proposed. Miniaturised forging experiments in double-cone specimens validate the modelling approach under relevant forging conditions at different temperatures and deformation rates. Finally, the deformation behaviour of this material in an industrially relevant manufacturing scenario – the forging process of a turbine disc – is studied numerically. Keywords: Superalloys, Forging, Process modelling, Continuum plasticity, Turbine discs

Vaccines are considered one of the greatest advances in modern medicine. The global burden of numerous infectious diseases has been significantly reduced, and in some cases, effectively eradicated through the deployment of specific vaccines. However, efforts to develop effective new vaccines against infectious pathogens such as influenza, Human immunodeficiency virus (HIV), dengue virus (DENV), chikungunya virus (CHIKV), Ebola virus, and Zika virus (ZIKV) have proven challenging. Zika virus is a mosquito-vectored flavivirus responsible for periodic outbreaks of disease in Africa, Southeast Asia, and the Pacific Islands dating back over 50 years. Over this period, ZIKV infections were subclinical in most infected individuals and resulted in mild cases of fever, arthralgia, and rash in others. Concerns about ZIKV changed over the past two years, however, as outbreaks in Brazil, Central American countries, and Caribbean islands revealed novel aspects of infection including vertical and sexual transmission modes. Cases have been reported showing dramatic neurological pathologies including microcephaly and other neurodevelopmental problems in babies born to ZIKV infected mothers, as well as an increased risk of Guillain-Barre syndrome in adults. These findings prompted the World Health Organization to declare ZIKV a public health emergency in 2016, which resulted in expanded efforts to develop ZIKV vaccines and immunotherapeutics. Several ZIKV vaccine candidates that are immunogenic and effective at blocking ZIKV infection in animal models have since been developed, with some of these now being evaluated in the clinic. Additional therapeutics under investigation include anti-ZIKV monoclonal antibodies (mAbs) that have been shown to neutralize infection in vitro as well as protect against morbidity in mouse models of ZIKV infection. In this review, we summarize the current understanding of ZIKV biology and describe our efforts to rapidly develop a vaccine against ZIKV.

Global change has impacted forests through altered disturbance regimes. In the western US, climate change has resulted in extensive and severe mountain pine beetle outbreaks. These outbreaks have the potential to impact forest function through the selection of certain phenotypes. We investigated the potential for bark beetle-induced selection by way of measuring growth and climate response in mountain pine beetle-killed and surviving lodgepole pine in the Northern Rockies. We had three objectives: (1) investigate differences in growth between beetle-killed and surviving lodgepole pine prior to a recent outbreak, (2) compare the climate-growth relationships for beetle-killed and surviving lodgepole pine and how those relationships explain observed growth differences and predict mortality risk, and (3) investigate growth differences and growth-climate relationships across north- and south-facing aspects and over an elevation range representing local climate gradients. Significantly higher growth rates were observed in beetle-killed trees at low-elevation sites, but not at mid or high elevations. While aspect influenced overall growth, it did not have a significant influence on the difference in growth between beetle-killed and surviving trees. Growth showed significant relationships with several climate variables (i.e., previous-year August temperatures, October temperatures, annual precipitation, and summertime climatic water deficit), with slight differences in those relationships between beetle-killed and surviving trees. Mixed effects models demonstrated that higher growth rates and age increased the probability of mortality during the outbreak at all elevations, and also that climatic water deficit and previous-year August maximum temperatures were related to the magnitude of growth differences between beetle-killed and surviving trees. Overall, mountain pine beetles tended to attack large, fast-growing, lodgepole trees, especially at lower elevations where trees may be more susceptible to seasonal water stress.

This article contains measurements of raw radial growth, distance to pith, and calculated basal area increments (BAI) from 444 5-mm increment cores (237 trees) collected in July 2016 from the Beaverhead-Deerlodge National Forest, MT. These data were used for the study presented in “Mountain pine beetle attack faster growing lodgepole pine at low elevations in western Montana, USA” [1] . Plot locations where increment cores were taken as well as code to calculate BAI are also included. Cores were collected from lodgepole pine ( Pinus contorta ) trees that were killed during a recent bark beetle outbreak (220 cores; 117 trees) as well as trees that survived the outbreak (210 cores; 113 trees) in twelve stands spanning north and south aspects and three elevational bands along a 600-m gradient. 14 additional cores were collected from 7 strip-attacked trees. Increment cores were prepared and measured using standard dendrochronological techniques, “An Introduction to Tree-Ring Dating” [2] . Master chronologies for each aspect-elevation combination were created using approximately ten cores from surviving trees at each location. Cores were cross-dated, then scanned at 2400 dpi. Annual ring widths were measured using CooRecorder 7.7, “Cybis Electronic, CDendro and CooRecorder V.7.7” [3] , and final chronologies were quantitatively validated in COFECHA, “Computer-assisted quality control in tree-ring dating and measurement, Tree-Ring Society” [4] .

Background Gestational diabetes affects almost 1 in 10 pregnancies and is associated with adverse outcomes including fetal demise. Pregnancy complications related to diabetes are attributed to placental vascular dysfunction. With diabetes, maternal hyperglycemia is thought to promote placental vasoconstriction. However, it remains poorly understood if and how hyperglycemia leads to placental vascular dysfunction or if humoral factors related to maternal diabetes are responsible. Methods and Results Utilizing a human placenta dual cotyledon, dual perfusion assay we examined the arterial pressure response to the thromboxane mimetic U44619, in cotyledons exposed to normal vs. a hyperglycemic infusion into the intervillous space. Tissues were then analyzed for the activity of key signaling molecules related to vascular tone; eNOS, Akt, PKA and VEGFR2. Results indicate a significant increase in fetal vascular resistance with maternal exposure to hyperglycemia. This response corresponded with a reduction in the phosphorylation of eNOS at Ser1177 and Akt at Thr308. In contrast, VEGFR2 at Tyr1175 and PKA at Thr197 were not different with hyperglycemia. Conclusion Reductions of eNOS and Akt phosphorylation at key residues implicated in nitric oxide production suggest that hyperglycemia alters the vasodilatory signaling of placental vessels. In contrast, acute hyperglycemic exposure may not alter vasoconstriction via VEGF and PKA signaling. Altogether our results link hyperglycemic exposure in human placentas to nitric oxide signaling; a mechanisms that may account for the elevations in vascular resistance commonly observed in diabetic pregnancies.

© 2018 The US and Mexico share a common history in many areas, including language and culture. They face ecological changes due to the increased frequency and severity of droughts and rising energy demands; trends that entail economic costs for both nations and major implications for human wellbeing. We describe an ongoing effort by the Environment Working Group (EWG), created by The University of California's UC-Mexico initiative in 2015, to promote binational research, teaching, and outreach collaborations on the implications of climate change for Mexico and California. We synthesize current knowledge about the most pressing issues related to climate change in the US-Mexico border region and provide examples of cross-border discoveries and research initiatives, highlighting the need to move forward in six broad rubrics. This and similar binational cooperation efforts can lead to improved living standards, generate a collaborative mindset among participating universities, and create an international network to address urgent sustainability challenges affecting both countries.

Despite the routine development and distribution of seasonal influenza vaccines, influenza remains an important pathogen contributing to significant human morbidity as well as mortality each year. The seasonal variability of influenza creates a significant issue for vaccine development of seasonal strains that can afford protection from infection or disease based on serotype matching. It is appreciated that the globular head of the HA antigen contained in the vaccines generates antibodies that result in HAI activity that are a major correlates of the protection against a particular strain. Due to seasonal genetic changes in the HA protein, however, new vaccine strains are needed to be developed continually to match the new HA antigen of that seasons virus. A distinct advantage in seasonal vaccine development would be if a small group of antigens could be developed that could span many seasons without needed to be replaced due to this genetic drift. Here we report on a synthetic microconsensus approach that relies on a small collection of 4 synthetic H1HA DNA antigens which together induce broad protective HAI immunity spanning decades of H1 influenza viruses in mice, guinea pigs and non-human primates. The protective HAI titers induced by microconsensus immunogens are fully functional in vivo as immunized ferrets were completely protected from A/Mexico/InDRE4487/2009 virus infection and morbidity associated with lethal challenge. These results are encouraging that a limited easy-to-formulate collection of invariant antigens can be developed which can span seasonal vaccine changes allowing for continued immune protection.

Dryland ecosystems can be constrained by low soil fertility. Within drylands, the soil nutrient and organic carbon (C) cycling that does occur is often mediated by soil surface communities known as biological soil crusts (biocrusts), which cycle C and nutrients in the top ca. 0–2 cm of soil. However, the degree to which biocrusts are influencing soil fertility and biogeochemical cycling in deeper, subsurface mineral soils is unclear. The movement of dissolved resources from biocrusts to deeper soil layers in leachate may be one of the main mechanisms through which biocrust fertility is transferred downward towards deeper microbial communities and plant roots occurring within mineral soil. Here we examined the role of biocrust leachate in contributing to subsurface nutrient and soluble C pools and subsurface microbial cycling. We collected biocrusts from three biocrust successional stages and explored resource pools in situ at multiple soil depths, while collecting leachate and measuring nutrient and organic C concentrations and metabolite composition from each successional stage in the laboratory. After four leachate collections, we conducted an incubation of mineral soil collected from below each biocrust successional stage to measure heterotrophic microbial CO2 flux and biomass. Overall, our findings observed that the degree of nutrient and C connectivity between biocrusts and the sub-crust mineral soil depended on the biocrust successional stage and the element being considered, and the influence of biocrust successional stage on mineral soil CO2 flux is likely related to long-term resource build up. Together, our results suggest that the influence of biocrust leachate on subsurface mineral soil is complex and context dependent, but, over longer time periods and at later successional stages, can have measurable effects on dryland soil biogeochemical cycling with feedbacks to resource availability and CO2 flux.

Valproic acid (VPA) is an older first-line antiepileptic drug with a complex pharmacokinetic (PK) profile, currently under investigation for several novel neurologic and non-neurologic indications. Our study objective was to design and validate a mechanistic model of VPA disposition in adults and children; and evaluate its predictive performance of drug-drug interactions (DDIs). This study expands upon existing physiologically based pharmacokinetic (PBPK) models for VPA by incorporating UGT enzyme kinetics and an advanced dissolution, absorption, and metabolism (ADAM) model for extended-release (ER) formulation. PBPK models for VPA IR and ER formulations were constructed using Simcyp Simulator (Version 15). First-order absorption was used for the immediate-release (IR) formulation and the ADAM model, including a controlled-release profile, for ER. Data from twenty-one published clinical studies were used to assess model performance. The model accurately predicted the concentration-time profiles of IR formulation for single-dose and steady-state doses ranging from 200 mg to 1000 mg. Similarly profiles were also simulated for ER formulation after a single-dose and steady-state doses of 500 mg and 1000 mg, respectively. In addition, simulated PK profiles agreed well with the observed data from studies in which VPA ER formulation was given to pediatric patients and VPA IR formulation to adult patients with cirrhosis. The model was further validated with individual adult data from a Phase I clinical trial consisting of eight cohorts after IV infusion of VPA with doses ranging from 15 to 150 mg/kg. Co-administrations of VPA as an enzyme-inhibitor with victim drug phenytoin or lorazepam, as well as a substrate with enzyme inducer carbamazepine or phenobarbital, were simulated with the model to evaluate drug-drug interaction. The simulated serum concentration-time profiles were within the 5th and 95th percentiles, and the majority of the predicted area-under-the-curve (AUC) and peak plasma concentration (C(max)) values were within 25% of the reported average values. The comprehensive VPA PBPK model defined by this study may be used to support dosage regimen optimization to improve the safety and efficacy profile of this agent under different scenarios.

Digital technology such as metal additive manufacturing (AM) provides flexible process design freedom to fabricate intricate three-dimensional structures layer-by-layer. However, its manufacturability relies on the fundamental understanding of melt pool physics and fluid (metal) dynamics. The effect of metal vapour and porosity induced during the laser-materials interaction can influence the additive manufacturability. In this work, composition-process relationship of laser-based powder-bed fusion ( L -PBF) AM is studied via computational fluid dynamics modelling to rationalise solid-liquid-vapour transformation where empirical-based approach is used to generate thermo-physical property of about 100 nickel-based superalloys at the liquid state. It is found that with larger vapor mass loss, the porosity tends to be higher. However, the higher vapour mass loss means faster cooling rate. This is indicated that the thermal-fluid flow process, which is also governed by the thermo-physical property, strongly affects the additive manufacturability. Additive manufacturability map based upon porosity, cooling rate from liquid to solid, volatile mass loss criteria has been established to link the composition in nickel-based superalloys with their thermo-physical property. This offers a thermal-fluid science based tool in designing compositions of novel superalloys for AM applications.

Biological soil crusts (biocrusts) are communities predominately comprised of lichens, bryophytes, fungi, algae, and cyanobacteria that form at the soil surface in dryland ecosystems worldwide. Biocrusts can influence the vascular plant community by altering surface hydrology, nutrient cycling, and the availability of microsites suitable for germination. Fire frequency has increased in many dryland systems, but the potential impacts of fire on biocrust-plant interactions remains unclear. Our study explores how biocrusts and the heating associated with fire affect plant growth across five North American desert sites: the Chihuahuan, Colorado Plateau, Great Basin, Mojave, and Sonoran. Using field-collected biocrusts and mineral soil samples from each of these five deserts, we investigated soil biogeochemical differences and the implications of soil heating and biocrust cover on greenhouse grown Elymus elymoides plants. Results showed plant biomass and leaf production were largely determined by the desert where soils originated, and that the soils collected from the Great Basin site, whether heated or not, were generally higher in nutrients and distinct from the other North American desert sites. In contrast, the Chihuahuan site was lower in nutrients and plant biomass growth compared with the other desert sites. In the short term, biocrusts and heating did not significantly affect the biogeochemical profile of individual desert site soils. However, biocrusts and soil heating positively influenced plant growth, and the combination of these factors influenced plants more strongly than either factor considered separately. These findings highlight the importance of biocrusts in mediating resources and suggest additional mechanisms through which fire may alter or accentuate dynamics between biocrusts and vascular plants.

Extreme drought can strongly impact belowground communities and biogeochemical processes, including soil microbial community composition and extracellular enzyme activities (EEAs), which are considered key agents in ecosystem carbon (C) and nutrient cycling. However, our understanding of how seasonal timing of drought during the growing season affects soil microbial communities and their activity remains notably poor. In this study, we investigated the responses of soil physicochemical properties, EEAs, and bacterial community composition to extreme-duration drought imposed in the early-, mid-, or late-stages of the growing season in a semiarid grassland ecosystem in Inner Mongolia, China. Compared with the ambient control, the activities of C-, nitrogen (N)-, and phosphorus (P)-acquisition enzymes were significantly decreased in the mid- and/or late-stages of drought. Bacterial community diversity also significantly decreased in the mid- and late-stage drought treatments. Soil water content was the most important factor explaining changes in soil EEAs and bacterial community composition. At the end of the growing season, the activities of C-, N-, and P-acquisition enzymes had mostly recovered, while the bacterial community diversity in the mid- and late-stage drought treatments was still lower than the ambient control. Overall, our study demonstrates that the effects of extreme drought on soil EEAs and bacterial community composition depend on the timing of drought. Our results highlight that understanding the effects of extreme-duration drought at different stages of the growing season may play a vital role in predicting the responses of belowground function to global changes in grassland ecosystems.

Current guidelines support active surveillance (AS) for select patients with favorable intermediate risk (FIR) prostate cancer (CaP). A significant proportion of FIR CaP patients undergoing surgical treatment are found to have evidence of adverse pathology. Our objective was to determine the incidence and predictors of pathologic upgrading in FIR AS patients undergoing radical prostatectomy.The Surveillance, Epidemiology, and End Results Prostate with Watchful Waiting (WW) database was used to identify men younger than 80 years with National Comprehensive Cancer Network FIR CaP initially opting for AS and/or WW between 2010 and 2015 and subsequently underwent radical prostatectomy at least one year following diagnosis. Patients were assigned into one of three subgroups based on their intermediate risk factor: Gleason Score 7(3 + 4) (Group 1), prostate specific antigen level of 10-20 ng/ml (Group 2), and cT2b-c (Group 3). Pathologic upgrading was present in Group 1 if pathologic GS was 7 (4 + 3) or worse. For patients in Groups 2 and 3, upgrading occurred if pathologic GS was 7 (3 + 4) or worse. Oncologic and sociodemographic predictors of pathologic upgrading were evaluated univariable and multivariable logistic regression analysis.18,760 patients were identified. Pathologic upgrading occurred in 138 (13.3%), 59 (25.0%), and 8,011 (45.8%) patients in groups 1, 2, and 3 respectively. Pathologic downgrading occurred in 226 (21.7%) patients in group 1. Significant predictors of pathologic upgrading on multivariable analysis included older age at diagnosis: 70 to 79 vs. 40 to 49 years (Groups 1 and 3, P0.05), a more recent diagnosis: 2014 to2015 vs. 2010-2011 (Groups 2 and 3, P0.005), higher volume disease: 37.5% to 49.9% vs. 0% to 12.4% (Groups 2 and 3, P0.005), and clinically palpable disease (Groups 1 and 2, P0.05). Additional risk factors for upgrading included uninsured or Medicaid status, diagnosis in a Western region (Group 2), African American ethnicity and higher socioeconomic status (Group 3) CONCLUSIONS: FIR CaP is a clinically heterogeneous risk group with incidence of pathologic upgrading ranging from 13.3% in those with GS 7 (3 + 4) to 45.8% in those with cT2b-c disease. Risk of pathologic upgrading in FIR CaP patients initially managed with AS and/or WW is significantly associated with multiple patient-level oncologic and sociodemographic variables.

Fundamental insights are presented into the factors influencing the temperature-dependent strengthening of nickel by transition metal solutes. Strain rate jump tests are used using the alloying elements Ta, W and Re which lie beside one another in the d-block. At 800 °C, the hardening induced by Ta is significantly greater than that by W and Re. At T ≥ 1000 °C, Re becomes more potent than Ta at slow strain rates; at 1200 °C it is the most effective at all the strain rates employed. The results are interpreted using theory for temperature-dependent strengthening that emphasises solute–dislocation interaction. It is confirmed that at low temperatures the solute strengthening is controlled by paraelastic interaction – the solute with the largest size difference with the host Ni is the most potent. At higher temperatures, the evidence indicates that solutes collect on dislocations such that the slowest diffusing solutes confer maximal resistance to dislocation glide and climb; thus Re is particularly potent. The findings elucidate the role of transition metal solutes in strengthening. Moreover, they provide the necessary quantitative data for ongoing alloy design efforts.

The ‘Photosensitivity Model' uses a standardized stimulation protocol of repeated intermittent photic stimulation (IPS) over a three-day period, with administration of a single dose of an investigational antiepileptic drug (AED) after a baseline IPS day in photosensitive patients, followed by a third IPS day to determine duration of effect. This ‘Photosensitivity Model' has shown its value in the development of new AEDs. Levetiracetam (LEV), currently a first-line AED in new-onset focal epilepsies, was not effective in classical animal models, but showed dose-dependent efficacy in the human ‘Photosensitivity Model'. Nevertheless, concerns have been expressed that AEDs selectively suppressing focal seizures might not suppress generalized photoparoxysmal EEG responses (PPR), the pharmacodynamic outcome measure in the Model. Herein, the following questions have been addressed: I. Can patients with generalized epileptiform discharges, evoked by IPS, so-called PPR, have focal epilepsy (focal seizures)? II. Are the photosensitive patients with focal epilepsy, who have participated in the photosensitivity trials, non-responsive to a new AED under investigation, as compared to those with generalized epilepsies? III. Are "focal epilepsy" AEDs effective both in the ‘Photosensitivity Model' and in real life in photosensitive patients? We performed a systematic literature review of PPR in focal seizures and focal epilepsy and we analyzed data (published and unpublished) from 20 different potential AEDs studied prospectively in the ‘Photosensitivity Model'. Finally, the PPR effects of Na + channel-blocking AEDs (considered as the most typical AEDs for focal epilepsy) are discussed with unequivocal examples given of the focal nature of a patient's PPR. Based on the entire data evidence, we conclude that: 1. PPRs certainly exist in focal epilepsy (17% on average); 2. Clinical signs and symptoms of PPRs can be focal and 3. PPRs can definitely be used to identify or to prove efficacy of new AEDs for patients with focal epilepsy.

As the global population ages, there is an opportunity to benefit from the increased longevity of a healthy older adult population. Healthy older individuals often contribute financially to younger generations by offering financial assistance, paying more in taxes than benefits received, and providing unpaid childcare and voluntary work. Governments must address the challenges of income insecurity, access to health care, social isolation, and neglect that currently face elderly adults in many countries. A reduction in disparities in these areas can lead to better health outcomes and allow societies to benefit from longer, healthier lives of their citizens.