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The equiatomic face-centred cubic (FCC) CoNiCrFeMn alloy, known as the Cantor alloy, is renowned for its high ductility under extreme conditions, such as cryogenic temperatures. Despite this, it suffers from low hardness and yield strength (YS) and includes elements with significant supply concerns. This study introduces novel non-equiatomic CoNiCrFeMn alloys, designed using machine learning (ML)-assisted-high-throughput atomistic simulations to enhance sustainability and mechanical properties such as hardness and YS while maintaining the alloy's single-phase FCC structure. We incorporated two critical sustainability indicators, end-of-life recycling rate (EOL−RR) and lifetime (τ), to guide the alloy design process. Mean-flow stress (MFS), measured from the yield point to 15% strain during tensile tests, was used to assess and predict the mechanical properties. Two alloys, with cobalt contents of 12.5% and 21.5%, were developed and analysed. The Co12.5 alloy showed better sustainability (44% improvement in τ with almost the same mechanical properties), while the Co21.5 alloy exhibited better mechanical properties (20% improvement in MFS with almost the same sustainability) as the equiatomic system. Their stable FCC microstructures were confirmed through CALPHAD modelling and X-ray diffraction (XRD) analysis of vacuum arc melted, as-cast samples. The results highlight the potential of integrating sustainability metrics into high-performance alloy design.

Summary: Background: The HVTN 705 Imbokodo trial of 2636 people without HIV and assigned female sex at birth, conducted in southern Africa, evaluated a heterologous HIV-1 vaccine regimen: mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) at Months 0, 3, 6, 12 and alum-adjuvanted clade C gp140 at Months 6, 12. Per-protocol vaccine efficacy (VE) against HIV-1 diagnosis from seven to 24 months was 14.1% (95% CI: −22.0% to 39.5%). Immune correlates analysis was performed for markers selected based on prior evidence in efficacy trials and/or nonhuman primate models. Methods: Humoral and cellular immune response markers at Month 7 were evaluated as immune correlates of risk and of protection in a breakthrough case–control cohort (n = 52 cases, 246 non-cases). Primary markers were IgG binding to vaccine-strain gp140, IgG3 binding to diverse Env antigens (IgG3 Env breadth), IgG3 binding to diverse V1V2 antigens (IgG3 V1V2 breadth), antibody-dependent phagocytosis against the vaccine-strain gp140, Env-specific CD4+ and CD8+ T-cell responses, and multi-epitope functions. Findings: No immune markers were statistically significant correlates of risk. IgG3 V1V2 breadth trended toward an inverse association: hazard ratio 0.70 (95% CI: 0.36 to 1.35; p = 0.29) per 10-fold increase and 0.51 (95% CI: 0.21 to 1.24; p = 0.14) in a Cox model with all primary markers. The VE estimate was 11.8% (95% CI: −17.9% to 34.0%) at all IgG3 V1V2 breadth values below 667 weighted geometric mean net MFI; just above this value, the VE estimate sharply increased to 62.6% (95% CI: −17.9% to 89.6%), and further increased to 80.9% (95% CI: −17.9% to 99.5%) at 1471 MFI, the 95th percentile of the marker distribution. Mediation analysis yielded a VE of 35.7% (95% CI: 15.0% to 51.3%) attributable to the vaccine's impact on this marker. Interpretation: The trend in association of greater IgG3 V1V2 antibody breadth with lower likelihood of HIV acquisition is consistent with the identification of antibodies against V1V2 as immune correlates in three other HIV vaccine efficacy trials and suggests that a greater emphasis should be placed on studying this region in the HIV-1 envelope as a vaccine immunogen. Funding: National Institute of Allergy and Infectious Diseases and Janssen Vaccines & Prevention BV.

IL-23 is a cytokine produced by myeloid cells that drives the T helper 17 pathway and plays an essential role in the pathophysiology of plaque psoriasis. IL-23 activation initiates a cascade of cytokines subsequently inducing the expression of many psoriasis-related proteins. This study aimed to better understand the underlying mechanisms driving the differences between IL-23 and IL-17A blockade in patients with psoriasis and their implications for durability of clinical responses. Serum and/or skin biopsies were isolated from patients treated with guselkumab or secukinumab for evaluation of potential biomarkers of pharmacodynamic response to treatment. Guselkumab treatment led to significantly greater reductions of IL-17F and IL-22 serum levels than treatment with secukinumab at weeks 24 and 48, demonstrating sustained regulation of the IL-23/T helper 17 pathway. Analyses of proteomic and transcriptomic profiles of patient sera and skin biopsies demonstrated differential regulation of proteins involved in chemokine, TNF, and relevant immune signaling pathways to a greater degree with guselkumab than with secukinumab treatment. These data provide insights into the differences between the mechanisms and impact of IL-23 and IL-17A blockade in psoriasis, with implications for efficacy observations and treatment paradigms. Trial Registration: The original study was registered at ClinicalTrials.gov (NCT03090100).

Mitochondria facilitate thousands of biochemical reactions, covering a broad spectrum of anabolic and catabolic processes. Here we demonstrate that the adipocyte mitochondrial proteome is markedly altered across multiple models of insulin resistance and reveal a consistent decrease in the level of the mitochondrial processing peptidase miPEP. Objective: To determine the role of miPEP in insulin resistance. Methods: To experimentally test this observation, we generated adipocyte-specific miPEP knockout mice to interrogate its role in the aetiology of insulin resistance. Results: We observed a strong phenotype characterised by enhanced insulin sensitivity and reduced adiposity, despite normal food intake and physical activity. Strikingly, these phenotypes vanished when mice were housed at thermoneutrality, suggesting that metabolic protection conferred by miPEP deletion hinges upon a thermoregulatory process. Tissue specific analysis of miPEP deficient mice revealed an increment in muscle metabolism, and upregulation of the protein FBP2 that is involved in ATP hydrolysis in the gluconeogenic pathway. Conclusion: These findings suggest that miPEP deletion initiates a compensatory increase in skeletal muscle metabolism acting as a protective mechanism against diet-induced obesity and insulin resistance.

Introduction: Nodular lymphoid hyperplasia is usually encountered by gastroenterologists during a workup for chronic abdominal pain accompanied by food intolerance, hematochezia, or diarrhea. When an intestinal endoscopy is performed, the usual finding is multiple small submucosal nodules that are identified as lymphoid tissue by biopsy. Case presentation: A previously healthy 8-year-old boy presented with a several-day history of intermittent abdominal pain and vomiting. He had no history of diarrhea or bloody stools. He was afebrile, and all of the other vital signs were normal. His abdomen was distended and tender, particularly in the right upper quadrant. Blood work was normal, except for an elevated C-reactive protein. His imaging work-up consisted of an abdominal ultrasound that ruled out acute appendicitis and a computerized tomography (CT) scan that showed images suggestive of ileo-colic intussusception, with a soft tissue mass in the right upper quadrant. Due to his age, reduction of the intussusception by insufflation was not attempted. An exploratory laparotomy was done through an incision in the right lower quadrant. We found no intussusception; rather, the wall of the cecum and the base of the appendix were markedly thickened, causing a partial obstruction of the cecal lumen and the ileo-cecal valve. We proceeded with an ileo-cecectomy and ileocolic anastomosis. He was discharged home on the 4th postoperative day. The pathologic and molecular analysis confirmed the diagnosis of follicular lymphoid hyperplasia. Conclusion: Nodular lymphoid hyperplasia of the ileo-cecal region can mimic an ileo-colic intussusception. It should be included in the differential diagnosis, particularly in patients outside the age range of idiopathic intussusception.

Summary: Genetic correlation refers to the correlation between genetic determinants of a pair of traits. When using individual-level data, it is typically estimated based on a bivariate model specification where the correlation between the two variables is identifiable and can be estimated from a covariance model that incorporates the genetic relationship between individuals, e.g., using a pre-specified kinship matrix. Inference relying on asymptotic normality of the genetic correlation parameter estimates may be inaccurate when the sample size is low, when the genetic correlation is close to the boundary of the parameter space, and when the heritability of at least one of the traits is low. We address this problem by developing a parametric bootstrap procedure to construct confidence intervals for genetic correlation estimates. The procedure simulates paired traits under a range of heritability and genetic correlation parameters, and it uses the population structure encapsulated by the kinship matrix. Heritabilities and genetic correlations are estimated using the close-form, method of moment, Haseman-Elston regression estimators. The proposed parametric bootstrap procedure is especially useful when genetic correlations are computed on pairs of thousands of traits measured on the same exact set of individuals. We demonstrate the parametric bootstrap approach on a proteomics dataset from the Jackson Heart Study.

Attachment styles influence mental health and relationships through life. Few studies examine the adolescent factors associated with adult attachment styles. This paper examines the association between adolescent emotional and behavioral problems and maternal-adolescent communication with attachment style in early adulthood. Data from 3423 participants in a birth cohort study were examined. At 14-years, participants' mothers completed the Parent-Adolescent Communication Scale. Participants completed the Youth Self-Report at 14-years which measures internalizing and externalizing symptoms, and the Attachment Style Questionnaire (ASQ) at 21-years. The ASQ comprises five domains of internal working models of interpersonal relationships and attachment style: confidence (security), discomfort with closeness and relationships as secondary (avoidance), need for approval and preoccupation with relationships (anxiety). Associations were examined using general linear models. After adjustments, internalizing symptoms score was associated with all domains of attachment and externalizing symptoms score was associated with four domains of attachment insecurity, but not attachment security. Low openness in maternal-adolescent communication was most strongly associated with decreased confidence and high problem maternal-adolescent communication was associated with viewing relationships as secondary. Adolescents with emotional and behavioral problems and maternal-adolescent communication may benefit from attachment-based interventions to support the development of healthy relationships and attachments in young adulthood.

The pyruvate transporter MPC1 (mitochondrial pyruvate carrier 1) acts as a tumour-suppressor, loss of which correlates with a pro-tumorigenic phenotype and poor survival in several tumour types. In high-grade serous ovarian cancers (HGSOC), patients display copy number loss of MPC1 in around 78% of cases and reduced MPC1 mRNA expression. To explore the metabolic effect of reduced expression, we demonstrate that depleting MPC1 in HGSOC cell lines drives expression of key proline biosynthetic genes; PYCR1, PYCR2 and PYCR3, and biosynthesis of proline. We show that altered proline metabolism underpins cancer cell proliferation, reactive oxygen species (ROS) production, and type I and type VI collagen formation in ovarian cancer cells. Furthermore, exploring The Cancer Genome Atlas, we discovered the PYCR3 isozyme to be highly expressed in a third of HGSOC patients, which was associated with more aggressive disease and diagnosis at a younger age. Taken together, our study highlights that targeting proline metabolism is a potential therapeutic avenue for the treatment of HGSOC.

The usefulness of additively manufactured (AM) nitinol and Ti6Al4V parts for the aerospace, automotive, machine and tooling, and biomedical industries depends on how well they withstand corrosion. AM is a manufacturing process that makes it possible to create intricate geometries at a reasonable price. Although significant progress has been made in decreasing metal corrosion, not much research has been done on optimizing input processing parameters to lower corrosion rates. Unique phase structures and preferential evaporation of alloying components might arise because of the melting and quick re-solidification that take place during additive manufacturing. This study looks at how processing parameter changes impact the metal parts made by laser-powder bed fusion (L-PBF) in terms of their ability to resist corrosion in a bodily environment. Electrochemical testing was used to conduct the research at a body temperature of 37 °C in both Hanks and Ringers solutions. The findings suggest that an increase in laser power during AM improves the passivation layer of the metal. Furthermore, compared to nitinol, Ti6AL4V exhibits a greater corrosion resistance. When a smaller hatch distance and lower laser beam strength were used, the nitinol sample's susceptibility to corrosion was reduced. This study demonstrates how the corrosion resistance of metal parts made by additive manufacturing can be increased by adjusting the laser powder bed fusion processing parameters in a bodily environment.

Summary: Background: Incarceration is associated with drug-related harms among people who inject drugs (PWID). We trained >1800 police officers in Tijuana, Mexico on occupational safety and HIV/HCV, harm reduction, and decriminalization reforms (Proyecto Escudo). We evaluated its effect on incarceration, population impact and cost-effectiveness on HIV and fatal overdose among PWID. Methods: We assessed self-reported recent incarceration in a longitudinal cohort of PWID before and after Escudo. Segmented regression was used to compare linear trends in log risk of incarceration among PWID pre-Escudo (2012–2015) and post-Escudo (2016–2018). We estimated population impact using a dynamic model of HIV transmission and fatal overdose among PWID, with incarceration associated with syringe sharing and fatal overdose. The model was calibrated to HIV and incarceration patterns in Tijuana. We compared a scenario with Escudo (observed incarceration declines for 2 years post-Escudo among PWID from the segmented regression) compared to a counterfactual of no Escudo (continuation of stable pre-Escudo trends), assessing cost-effectiveness from a societal perspective. Using a 2-year intervention effect and 50-year time horizon, we determined the incremental cost-effectiveness ratio (ICER, in 2022 USD per disability-adjusted life years [DALYs] averted). Findings: Compared to stable incarceration pre-Escudo, for every three-month interval in the post-Escudo period, recent incarceration among PWID declined by 21% (adjusted relative risk = 0.79, 95% CI: 0.68–0.91). Based on these declines, we estimated 1.7% [95% interval: 0.7%–3.5%] of new HIV cases and 12.2% [4.5%–26.6%] of fatal overdoses among PWID were averted in the 2 years post-Escudo, compared to a counterfactual without Escudo. Escudo was cost-effective (ICER USD 3746/DALY averted compared to a willingness-to-pay threshold of $4842–$13,557). Interpretation: Escudo is a cost-effective structural intervention that aligned policing practices and human-rights-based public health practices, which could serve as a model for other settings where policing constitutes structural HIV and overdose risk among PWID. Funding: National Institute on Drug Abuse, UC MEXUS CONACyT, and the San Diego Center for AIDS Research (SD CFAR).

Summary: Background: Elicitation of broad immune responses is understood to be required for an efficacious preventative HIV vaccine. This Phase 1 randomized controlled trial evaluated whether administration of vaccine antigens separated at multiple injection sites vs combined, fractional delivery at multiple sites affected T-cell breadth compared to standard, single site vaccination. Methods: We randomized 90 participants to receive recombinant adenovirus 5 (rAd5) vector with HIV inserts gag, pol and env via three different strategies. The Standard group received vaccine at a single anatomic site (n = 30) compared to two polytopic (multisite) vaccination groups: Separated (n = 30), where antigens were separately administered to four anatomical sites, and Fractioned (n = 30), where fractions of each vaccine component were combined and administered at four sites. All groups received the same total dose of vaccine. Findings: CD8 T-cell response rates and magnitudes were significantly higher in the Fractioned group than Standard for several antigen pools tested. CD4 T-cell response magnitudes to Pol were higher in the Separated than Standard group. T-cell epitope mapping demonstrated greatest breadth in the Fractioned group (median 8.0 vs 2.5 for Standard, Wilcoxon p = 0.03; not significant after multiplicity adjustment for co-primary endpoints). IgG binding antibody response rates to Env were higher in the Standard and Fractioned groups vs Separated group. Interpretation: This study shows that the number of anatomic sites for which a vaccine is delivered and distribution of its antigenic components influences immune responses in humans. Funding: National Institute of Allergy and Infectious Diseases, NIH.

Summary: Sickle cell disease (SCD) is characterized by hemolysis, vaso-occlusion, and ischemia. HIV-1 infection was previously shown to be suppressed in SCD PBMCs. Here, we report that HIV-1 suppression is attributed to the increased expression of iron, hypoxia, and interferon-induced innate antiviral factors. Inhibition of upregulated antiviral genes, HMOX-1, CDKN1A, and CH25H, increased HIV-1 replication in SCD PBMCs, suggesting their critical role in HIV-1 suppression. Levels of IFN-β were elevated in SCD patients. Sickle cell hemoglobin (HbS) treatment of THP-1-derived and primary monocyte-derived macrophages induced production of IFN-β, upregulated antiviral gene expression, and suppressed HIV-1 infection. Infection with mouse-adapted EcoHIV was suppressed in the SCD mice that also exhibited elevated levels of antiviral restriction factors. Our findings suggest that hemolysis and release of HbS leads to the induction of IFN-β production, induction of cellular antiviral state by the expression of iron and IFN-driven factors, and suppression of HIV-1 infection.

Summary: The major histocompatibility complex (MHC), Class-I-related (MR1) molecule presents microbiome-synthesized metabolites to Mucosal-associated invariant T (MAIT) cells, present at sites of herpes simplex virus (HSV) infection. During HSV type 1 (HSV-1) infection there is a profound and rapid loss of MR1, in part due to expression of unique short 3 protein. Here we show that virion host shutoff RNase protein downregulates MR1 protein, through loss of MR1 transcripts. Furthermore, a third viral protein, infected cell protein 22, also downregulates MR1, but not classical MHC-I molecules. This occurs early in the MR1 trafficking pathway through proteasomal degradation. Finally, HSV-2 infection results in the loss of MR1 transcripts, and intracellular and surface MR1 protein, comparable to that seen during HSV-1 infection. Thus HSV coordinates a multifaceted attack on the MR1 antigen presentation pathway, potentially protecting infected cells from MAIT cell T cell receptor-mediated detection at sites of primary infection and reactivation.

ABSTRACT: Estimating daily enteric hydrogen (H2) and methane (CH4) emitted from dairy cattle using spot sampling techniques requires accurate sampling schemes. These sampling schemes determine the number of daily samplings and their intervals. This simulation study assessed the accuracy of daily H2 and CH4 emissions from dairy cattle using various sampling schemes for gas collection. Gas emission data were available from a crossover experiment with 28 cows fed twice daily at 80% to 95% of the ad libitum intake, and an experiment that used a repeated randomized block design with 16 cows twice daily fed ad libitum. Gases were sampled every 12 to 15 min for 3 consecutive days in climate respiration chambers. Feed was fed in 2 equal portions per day in both experiments. Per individual cow-period combination, generalized additive models were fitted to all diurnal H2 and CH4 emission profiles. Per profile, the models were fitted using the generalized cross-validation, REML, REML while assuming correlated residuals, and REML while assuming heteroscedastic residuals. The areas under the curve (AUC) of these 4 fits were numerically integrated over 24 h to compute the daily production and compared with the mean of all data points, which was considered the reference. Next, the best of the 4 fits was used to evaluate 9 different sampling schemes. This evaluation determined the average predicted values sampled at 0.5, 1, and 2 h intervals starting at 0 h from morning feeding, at 1 and 2 h intervals starting at 0.5 h from morning feeding, at 6 and 8 h intervals starting at 2 h from morning feeding, and at 2 unequally spaced intervals with 2 or 3 samples per day. Sampling every 0.5 h was needed to obtain daily H2 productions not different from the selected AUC for the restricted feeding experiment, whereas less frequent sampling had predictions varying from 47% to 233% of the AUC. For the ad libitum feeding experiment, sampling schemes had H2 productions from 85% to 155% of the corresponding AUC. For the restricted feeding experiment, daily CH4 production needed samplings every 2 h or shorter, or 1 h or shorter, depending on sampling time after feeding, whereas sampling scheme did not affect CH4 production for the twice daily ad libitum feeding experiment. In conclusion, sampling scheme had a major impact on predicted daily H2 production, particularly with restricted feeding, whereas daily CH4 production was less severely affected by sampling scheme.

Objectives: We investigated the reinfection rate of vaccinated or convalescent immunized SARS-CoV-2 in 952 expatriate workers with SARS-CoV-2 serological antibody (Ab) patterns and surrogate T cell memory at recruitment and follow-up. Methods: Trimeric spike, nucleocapsid, and neutralizing Abs were measured, along with a T cell stimulation assay, targeting SARS-CoV-2 memory in clusters of differentiation (CD) 4+ and CD8+ T cells. The subjects were then followed up for reinfection for up to 6 months. Results: The seroprevalence positivity at enrollment was greater than 99%. The T cell reactivity in this population was 38.2%. Of the 149 (15.9%) participants that were reinfected during the follow-up period (74.3%) had nonreactive T cells at enrollment. Those who had greater than 100 binding Ab units/ml increase from the median concentration of antispike immunoglobulin G Abs had a 6% reduction in the risk of infection. Those who were below the median concentration had a 78% greater risk of infection. Conclusion: Significant immune protection from reinfection was observed in those who retained T cell activation memory. Additional protection was observed when the antispike was greater than the median value.

Summary: Many promising vaccine candidates and licensed vaccines lead to variable immune responses within humans. Studies suggest that environmental exposures in the gastrointestinal tract could contribute to a reduction in vaccine efficacy via immune tolerance at this site; this is partly achieved by a high abundance of regulatory T cells (Tregs). It is unclear if Treg subsets regulate systemic vaccine responses following oral antigen pre-exposure. Here, we implemented a conditional knock-out mouse model of RORγt+ Tregs to examine the role of these cells in mediating this process. Following oral exposure to the model antigen ovalbumin (OVA) prior to immunization, we found similar induction of vaccine-induced antibody responses in mice lacking RORγt expression in Tregs compared to sufficient controls. Use of various adjuvants led to distinct findings. Our data suggest that expression of RORγt+ within Tregs is not required to regulate tolerance to systemic vaccination following oral antigen exposure.

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

Purpose: Ultrahigh resolution spectral domain-OCT (UHR SD-OCT) enables in vivo visualization of micrometric structural markers which differentially associate with normal aging versus age-related macular degeneration (AMD). This study explores the hypothesis that UHR SD-OCT can detect and quantify sub-retinal pigment epithelium (RPE) deposits in early AMD, separating AMD pathology from normal aging. Design: Prospective cross-sectional study. Participants: A total of 53 nonexudative (dry) AMD eyes from 39 patients, and 63 normal eyes from 39 subjects. Methods: Clinical UHR SD-OCT scans were performed using a high-density protocol. Exemplary high-resolution histology and transmission electron microscopy images were obtained from archive donor eyes. Three trained readers evaluated and labeled outer retina morphological features, including the appearance of a hyporeflective split within the RPE–RPE basal lamina (RPE-BL)–Bruch’s membrane (BrM) complex on UHR brightness (B)-scans. A semi-automatic segmentation algorithm measured the thickness of the RPE-BL-BrM split/hyporeflective band. Main Outcome Measures: Qualitative description of outer retinal morphological changes on UHR SD-OCT B-scans; the proportion of the RPE-BL-BrM complex with visible split (%) and the thickness of the resulting hyporeflective band (μm). Results: In young normal eyes, UHR SD-OCT consistently revealed an RPE-BL-BrM split/hyporeflective band. Its visibility and thickness were less in eyes of advanced age. However, the split/hyporeflective band was again visible in early AMD eyes. Both qualitative reading and quantitative thickness measurements showed significantly elevated visibility and thickness of the RPE-BL-BrM split/hyporeflective in early AMD eyes compared to age-matched controls. Conclusions: Our imaging results strongly support the hypothesis that appearance of the RPE-BL-BrM split/hyporeflective band in older subjects is dominated by the BL deposit, an indicator of early AMD well known from histology. Ultrahigh resolution SD-OCT can be used to investigate physiological aging as well as early AMD pathology in clinical imaging studies. Developing quantifiable markers associated with disease pathogenesis and progression can facilitate drug discovery, as well as reduce clinical trial times. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Soil tests and Multichannel Analysis of Surface Waves (MASW) data were conducted in Hatsalatladi village, Botswana, to investigate the occurrence of ground fissures within the village and to identify the likely causes of the fissures and their depth extent. The MASW data were collected to gain insights into the variation of shear wave velocity with depth. The dataset shows that the shear wave velocity ranged from 150 m/s – 500 m/s, with Poisson's ratios ranging from 0.02 to 0.25. A low-velocity zone (LVZ) was observed in the upper 5 m of the subsurface with velocities ranging from 200 m/s to 350 m/s.The soil plasticity was measured through the plastic and liquid Atterberg tests. Atterberg limits measurements obtained from the three survey sites show that the plastic index of the soil samples collected from depths of 1 m fall within the 10–20% range. Specifically, the Filled Crack survey site had a plastic index of 16%, while the Abandoned House and Bridge sites had 18.7% and 13.5%, respectively. Soil samples from Filled Crack and Abandoned House site revealed a linear shrinkage of 6.4%, while the Bridge site soil sample had a linear shrinkage of 2.9%. The sieve analysis test results are also presented.

Voice technology and fully virtual digital assistants are becoming increasingly prevalent in many industries, including the scientific laboratory. This environment can greatly benefit from the use of hands-free digital assistants due to the fact that scientists regularly need access to tools and information while performing bench work. The use of a digital assistant in this environment has the potential to streamline laboratory work and reduce the chances of human error due to contamination and the context switching involved in moving between experiments and information storage media. Because the particular protocols and reagents used by each laboratory are often different, there is a need to create custom digital assistants for individual laboratories. In this technical brief we describe a custom software and web application, referred to as the HelixAI platform, that can be used to create digital assistants for individual scientific laboratories. Digital assistants created with this platform can be accessed through any Alexa-enabled smart speaker device. Here we describe the process by which labs can use this platform to create their own digital assistants, along with a description of the underlying technology. An assistant containing information from the scientific company New England Biolabs (NEB) has been created using this software and will serve as an example throughout this paper.

This article aims to translate and carry out the cross-cultural adaptation of the WAST - Woman Abuse Screening Tool, designed in English and used to track violence by an intimate partner. For adaptation, the conceptual equivalence of terms and semantics between the original version in English and the version translated into Portuguese was evaluated, the result of two translations and back-translation, discussion by a panel of experts, establishment of the preliminary version and finally testing in 88 participants of both sexes, selected in two health units at the level of primary health care. The cross-cultural adaptation resulted in an equivalence of concepts and semantics between the initial translation and the final back-translation. From the testing it was concluded that the version of WAST translated and adapted to the Mozambican context, has good internal consistency, the scales of WAST-Short (α = 0.813) such as those of IPV or WAST-Long (α = 0.834) are highly related. The two scales do not discriminate between men and women (WAST-Short p = 0.204, WAST-Long p = 0.271). Implications are discussed for more effective HIV prevention and treatment counseling.

Drought is one of the climatic events that threaten water availability, food security, and local livelihoods in semi-arid areas. Whilst studies have evolved on the impacts of climate change on humanity, especially in Sub-Saharan Africa, limited scholarly insight exists on the impacts of specific climatic stressors and shocks and how residents respond to such. This study contributes to climate change policy planning debates by analysing the trends, impacts and local responses to drought drawing on household questionnaires, participatory field observations, key informant interviews, and focus group discussions. The CUSUM and Mann-Kendall tests were used to analyse weather data (rainfall and temperature) to establish their trends. The Standardized Precipitation Index (SPI) was used to determine drought occurrences and intensities. The results showed significant variation: rise and decline in temperature and rainfall over the years. The SPI (range from -0.01 to -2.8) indicated extreme, severe, moderate, and mild drought (mild (73%) being the notorious) event that instigated crop failure, drying of water sources, loss of pasture, food shortages, high prices of foodstuffs, malnutrition, water scarcity, and health problems and loss of livestock. Households responded by utilizing crop residues and tree branches as fodder for livestock, reducing the number of times households eat, and changing crop varieties and planting dates. This study argues that considering the geographical variation of climatic shocks and stressors, a focus on the specific climatic event may offer the possibility for an in-depth understanding of its impacts on local residents, and useful for engendering climate planning policy intervention in Sub-Saharan Africa.

Introduction: In-vivo techniques using near-infrared spectroscopy (NIRS) have been developed to assess skeletal muscle mitochondrial oxidative capacity. However, the test-retest and day-to-day reliability of NIRS-derived mitochondrial oxidative capacity has yet to be established in older individuals. Therefore, the primary aim of this study was to determine the day-to-day and test-retest reliability of NIRS-derived mitochondrial oxidative capacity in older adults. The secondary aim was to examine the relationship between NIRS-derived mitochondrial capacity and whole-body aerobic fitness. Material and methods: Twenty-four healthy individuals (19 M, 5F; aged 60 ± 4 years; maximal oxygen uptake (V̇O2peak) = 41.2 ± 6.8 ml.kg−1.min−1) completed three visits to the laboratory. Visit one assessed isometric maximal voluntary contractions of the knee extensors and aerobic capacity through an incremental exercise test. In visits two and three participants completed two measurements of NIRS-derived mitochondrial oxidative capacity in the vastus lateralis (VL). Results: NIRS-derived mitochondrial oxidative capacity was found to have good to excellent day-to-day reliability (Day 1 vs Day 2; coefficient of variation (CV) = 7.0 %; standard error of measurement (SEM) = 5.2; intra-class correlation coefficient (ICC) = 0.94) and test re-test reliability (Day 1 [Test 1 vs Test 2]; CV = 5.0 %; SEM = 3.7; ICC 0.97 and Day 2 [Test 1 vs Test 2]; CV = 6.3 %; SEM = 4.9; ICC = 0.93). NIRS-derived mitochondrial oxidative capacity was found to be significantly correlated with V̇O2peak (r = −0.61; R2 = 0.37; P = 0.002), oxygen uptake at the gas exchange threshold (r = −0.49; R2 = 0.24; P = 0.02), and oxygen uptake at the respiratory compensation point (r = −0.57; R2 = 0.32; P = 0.004). Conclusion: NIRS provides a reliable method for deriving a measure of VL mitochondrial oxidative capacity in highly active older adults and demonstrates a significant relationship with measures of whole-body aerobic fitness.

Hypothesis: The aim of this study was to investigate the reproducibility, reliability, and accuracy of Mirels’ score in upper limb bony metastatic disease and validate its use in predicting pathologic fractures. Methods: Forty-five patients with upper limb bony metastases met the inclusion criteria (62% male 28/45). The mean age was 69 years (SD 9.5), and the most common primaries were lung (29%, 13/45), followed by prostate and hematological (each 20%, 9/45). The most commonly affected bone was the humerus (76%, 35/45), followed by the ulna (6.5%, 3/45). Mirels’ score was calculated in 32 patients; with plain radiographs at index presentation scored using Mirels’ system by 6 raters. The radiological aspects (lesion size and appearance) were scored twice by each rater (2 weeks apart). Intraobserver and interobserver reliability were calculated using Fleiss’ kappa test. Bland-Altman plots compared the variances of both individual components and the total Mirels’ score. Results: The overall fracture rate of upper limb metastatic lesions was 76% (35/46) with a mean follow-up of 3.6 years (range 11 months-6.8 years). Where time from diagnosis to fracture was known (n = 20), fractures occurred at a median 19 days (interquartile range 60-10), and 80% (16/20) occurred within 3 months of diagnosis.Mirels’ score of ≥9 did not accurately predict lesions that fractured (fracture rate 11%, 5/46, for Mirels’ ≥ 9 vs. 65%, 30/46, for Mirels’ ≤ 8, P

Variation in methylcytosine is perhaps the most well-studied epigenetic mechanism of gene regulation. Methods that have been developed and implemented for assessing DNA methylation require sample DNA to be extracted, purified and chemically-processed through bisulfite conversion before downstream analysis. While some automated solutions exist for each of these individual process steps, a fully integrated solution for accomplishing the entire process in a high-throughput manner has yet to be demonstrated. Thus, sample processing methods still require numerous manual steps that may reduce sample throughput and precision, while increasing the risk of contamination and human error. In this work, we present an integrated, automated solution for performing the entire sample preparation process, including DNA extraction, purification, bisulfite conversion and PCR plate preparation within in an enclosed environment. The method employs silica-coated magnetic particles that eliminate the need for a centrifuge or vacuum manifold, thereby reducing the complexity and cost of the required automation platform. Toward this end, we also compare commercial DNA extraction and bisulfite conversion kits to identify a protocol suitable for automation to significantly improve genomic and bisulfite-treated DNA yields over manufacturer protocols. Overall, this research demonstrated development of an automated protocol that offers the ability to generate high-quality, bisulfite-treated DNA samples in a high-throughput and clean environment with minimal user intervention and comparable yields to manual processing.

Summary: Thalamoreticular circuitry plays a key role in arousal, attention, cognition, and sleep spindles, and is linked to several brain disorders. A detailed computational model of mouse somatosensory thalamus and thalamic reticular nucleus has been developed to capture the properties of over 14,000 neurons connected by 6 million synapses. The model recreates the biological connectivity of these neurons, and simulations of the model reproduce multiple experimental findings in different brain states. The model shows that inhibitory rebound produces frequency-selective enhancement of thalamic responses during wakefulness. We find that thalamic interactions are responsible for the characteristic waxing and waning of spindle oscillations. In addition, we find that changes in thalamic excitability control spindle frequency and their incidence. The model is made openly available to provide a new tool for studying the function and dysfunction of the thalamoreticular circuitry in various brain states.

Diphencyprone (DPCP), a topical contact sensitizer, has shown efficacy in treating cutaneous melanoma metastases, including at times beyond the directly treated sites, but biomarkers indicative of treatment response have not been characterized. Thus, we performed a proteomic analysis of the skin and serum of five patients with cutaneous melanoma metastases treated with DPCP on days 0, 63, and 112 of the treatment course. In the serum, we found a significant upregulation (P < 0.05) in 13 of 96 assessed immuno-oncology proteins after DPCP treatment. Upregulated proteins included those of the T helper 1 axis (CXCL9, CXCL10), immune checkpoint proteins (PD-1), and various proteins with roles in promoting tumor immunity such as CD80 and TNFRSF4/9. Given the positive clinical response to topical treatment noted in the five patients studied, these proteins may represent prognostic biomarkers in the serum for evaluating the efficacy of DPCP treatment of cutaneous melanoma metastases. Because DPCP does not lead to nonspecific immune-related adverse events seen with immune checkpoint inhibitors, our study provides evidence for potential tumor-specific systemic immune activation and systemic antitumor effectors elicited by topical DPCP.

Summary: The most abundant cellular divalent cations, Mg2+ (mM) and Ca2+ (nM-μM), antagonistically regulate divergent metabolic pathways with several orders of magnitude affinity preference, but the physiological significance of this competition remains elusive. In mice consuming a Western diet, genetic ablation of the mitochondrial Mg2+ channel Mrs2 prevents weight gain, enhances mitochondrial activity, decreases fat accumulation in the liver, and causes prominent browning of white adipose. Mrs2 deficiency restrains citrate efflux from the mitochondria, making it unavailable to support de novo lipogenesis. As citrate is an endogenous Mg2+ chelator, this may represent an adaptive response to a perceived deficit of the cation. Transcriptional profiling of liver and white adipose reveals higher expression of genes involved in glycolysis, β-oxidation, thermogenesis, and HIF-1α-targets, in Mrs2−/− mice that are further enhanced under Western-diet-associated metabolic stress. Thus, lowering mMg2+ promotes metabolism and dampens diet-induced obesity and metabolic syndrome.

Summary: Intracellular long-chain acyl-coenzyme As (LC-acyl-CoAs) are thought to be under tight spatial and temporal controls, yet the ability to image LC-acyl-CoAs in live cells is lacking. Here, we developed a fluorescence resonance energy transfer (FRET) sensor for LC-acyl-CoAs based on the allosterically regulated interaction between α/β hydrolase domain-containing 5 (ABHD5) and Perilipin 5. The genetically encoded sensor rapidly detects intracellular LC-acyl-CoAs generated from exogenous and endogenous fatty acids (FAs), as well as synthetic ABHD5 ligands. Stimulation of lipolysis in brown adipocytes elevated intracellular LC-acyl-CoAs in a cyclic fashion, which was eliminated by inhibiting PNPLA2 (ATGL), the major triglyceride lipase. Interestingly, inhibition of LC-acyl-CoA transport into mitochondria elevated intracellular LC-acyl-CoAs and dampened their cycling. Together, these observations reveal an intimate feedback control between LC-acyl-CoA generation from lipolysis and utilization in mitochondria. We anticipate that this sensor will be an important tool to dissect intracellular LC-acyl-CoA dynamics as well to discover novel synthetic ABHD5 ligands. Motivation: Intracellular long-chain acyl-coenzyme As (LC-acyl-CoAs) are thought to be under tight spatial and temporal controls, yet the ability to image LC-acyl-CoAs in live cells is lacking. We sought to create a fluorescence resonance energy transfer (FRET) sensor of LC-acyl-CoAs and synthetic ABHD5 ligands based on the reversible interactions between ABHD5 and PLIN5. The sensor allows dynamic imaging of intracellular LC-acyl-CoA levels in targeted subcellular compartments. In addition, since ABHD5 has emerged as a therapeutic target for metabolic disease and cancer, a robust FRET-based sensor could aid in the identification of novel synthetic and natural ABHD5 ligands.

Recent work has focused on understanding the link between diet quality and environmental impact, however it is also important to consider the role food processing plays in this relationship. Using model meal plans, this paper examines the link between nutrient content, environmental impact, and processing. Four distinct meal plans were considered – ‘Healthy’, ‘Unhealthy’, ‘Healthy (plant-based)’, ‘Healthy (plant-based, processed)’. For each a variety of environmental impact, processing and nutritional composition metrics were compared. Alternative healthy eating index (AHEI) score for the Unhealthy diet was significantly lower than the other three diets. The ‘Healthy (plant-based)’ diet had the highest AHEI score but was not significantly different to the ‘Healthy (plant-based, processed)’ and ‘Healthy’ diet scores. The greenhouse gas emissions for the two plant based diets were not significantly different to each other or to the ‘Healthy’ diet but were significantly lower than the ‘Unhealthy’ diet. The ‘Healthy’, ‘Unhealthy’, and ‘Healthy (plant-based)’ diets had similar processing specific energy consumption values however, the ‘Healthy (plant-based, processed)’ diets had significantly greater specific energy consumption. There was no clear link between diet quality and food processing when considered using processing specific energy value. When the number of processes in each diet was estimated, the unhealthier diet had considerably more processes associated with it. Examining the interaction of nutritional quality, environmental impact and processing of diets in this way highlights the complexity of the inter-relationships. Understanding these interactions is necessary to support the transition to healthy diets from sustainable sources.

The data in this article are related to the research article “Stacking-Mediated Diffusion of Ruthenium Nanoclusters in Bilayer Graphene and Graphite” (J G McHugh, 2022). The data consists of Ru atom cluster intercalation calculations on graphene surfaces, within AA/AB bilayer graphene and graphite. We tabulate data for cluster sizes of 3, 4, 5 and 7 Ru atoms, which includes adsorption energies and diffusion energy barriers between all the highly symmetric sites in graphene/graphite. These data were obtained from density functional theory calculations. We provide tabulated data of relaxed structures that are useful for future classical interatomic potential fittings.

Methamphetamine (METH) is an addictive illicit drug used worldwide that causes significant damage to blood vessels resulting in cardiovascular dysfunction. Recent studies highlight increased prevalence of cardiovascular disease (CVD) and associated complications including hypertension, vasospasm, left ventricular hypertrophy, and coronary artery disease in younger populations due to METH use. Here we report that METH administration in a mouse model of ‘binge and crash’ decreases cardiovascular function via cystathionine gamma lyase (CSE), hydrogen sulfide (H2S), nitric oxide (NO) (CSE/H2S/NO) dependent pathway. METH significantly reduced H2S and NO bioavailability in plasma and skeletal muscle tissues co-incident with a significant reduction in flow-mediated vasodilation (FMD) and blood flow velocity revealing endothelial dysfunction. METH administration also reduced cardiac ejection fraction (EF) and fractional shortening (FS) associated with increased tissue and perivascular fibrosis. Importantly, METH treatment selectively decreased CSE expression and sulfide bioavailability along with reduced eNOS phosphorylation and NO levels. Exogenous sulfide therapy or endothelial CSE transgenic overexpression corrected cardiovascular and associated pathological responses due to METH implicating a central molecular regulatory pathway for tissue pathology. These findings reveal that therapeutic intervention targeting CSE/H2S bioavailability may be useful in attenuating METH mediated cardiovascular disease.

Mangrove forests provide harvestable wood and non-wood resources to human society globally. The current study evaluated value chain of mangrove wood products from Lamu, Kenya, and how these impacts on resources’ sustainability. Results show that, exploitation of mangrove wood products in Kenya involves several actors, including national regulator, licensees, cutters, transporters, stockists and the consumers. Based on the differences between allowable and harvest data, Lamu mangroves can be said to be under-exploited. For the 1992–2018 period, an average of 223.5 scores ha−1yr−1 of mangrove poles were target for harvesting from Lamu. During the same period, the harvest data indicate an average of 6.2 scores ha−1yr−1 of mangrove poles were removed. However, based on stand level data generated as part of this study, mangroves in Lamu are over-exploited and stocked with non-merchantable poles. There are differentiated net income among various actors in mangrove trade in Kenya. Mangrove cutters are among the ‘losers’ in mangrove trade value chain earning a monthly net income of USD118.6 ± 17.9. Winners in mangrove trade is the Kenya Forest Service, Licensees, transporters, and mangrove dealers (or stockists) in urban centers. The findings of this study are critical in development of the harvesting plan for Lamu mangroves. The results will provide insights toward streamlining mangrove trade for community development, revenue generation and environmental sustainability.

Purpose: To compare the accuracies of the previously proposed square-root-transformed and perimeter-adjusted metrics for estimating length-type geographic atrophy (GA) growth rates. Design: Cross-sectional and simulation-based study. Participants: Thirty-eight eyes with GA from 27 patients. Methods: We used a previously developed atrophy-front growth model to provide analytical and numerical evaluations of the square-root-transformed and perimeter-adjusted growth rate metrics on simulated and semisimulated GA growth data. Main Outcome Measures: Comparison of the accuracies of the square-root-transformed and perimeter-adjusted metrics on simulated and semisimulated GA growth data. Results: Analytical and numerical evaluations showed that the accuracy of the perimeter-adjusted metric is affected minimally by baseline lesion area, focality, and circularity over a wide range of GA growth rates. Average absolute errors of the perimeter-adjusted metric were approximately 20 times lower than those of the square-root-transformed metrics, per evaluation on a semisimulated dataset with growth rate characteristics matching clinically observed data. Conclusions: Length-type growth rates have an intuitive, biophysical interpretation that is independent of lesion geometry, which supports their use in clinical trials of GA therapeutics. Taken in the context of prior studies, our analyses suggest that length-type GA growth rates should be measured using the perimeter-adjusted metric, rather than square-root-transformed metrics.

Biofouling of gasoline can occur during fuel storage caused by bacteria and fungi that form a biofilm at a fuel/water interface and that produce organic acids and sulfides. Fuel additives are applied to gasoline to prevent biofouling but are relatively expensive, are not always effective against biofilms, and do not contribute to the combustibility of gasoline. Bio-isobutanol is an approved, certified advanced biofuel and is added up to 16% (v/v) in gasoline blends “iBut16”; n-butanol blends are currently under review. Microorganisms are inhibited by n-butanol or isobutanol when the aqueous concentration reaches >2-3% (w/v). We determined that n-butanol partitions into the aqueous phase of a model gasoline/water system reaching concentrations of 42 g/L and up to 48 g/L from gasoline blends at 10% and 24% (v/v), respectively. Likewise, isobutanol blended in gasoline at 10% and 24% (v/v) partitioned into an aqueous phase at 45 g/L and 53 g/L, respectively. Several bacterial and fungal strains that originate from fuel storage tanks, or are known to be solvent tolerant, were evaluated for their potential growth in a range of n- and isobutanol concentrations. Growth rates for all strains tested were reduced by 40–100% relative to untreated controls in n- and isobutanol concentrations of 1.5 and 2.0% (v/v). No observable growth occurred for any of the microorganisms in solvent concentrations at 3.0% (v/v). T amphiphilic and chaotropic properties of n- or isobutanol help them inhibit microbial growth and could serve as effective biocides during fuel storage as well as being valuable fuel additives.