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Abstract The Parkinson’s Families Project is a UK-wide study aimed at identifying genetic variation associated with familial and early-onset Parkinson’s disease (PD). We recruited individuals with a clinical diagnosis of PD and age at motor symptom onset ≤45 years and/or a family history of PD in up to third-degree relatives. Where possible, we also recruited affected and unaffected relatives. We analysed DNA samples with a combination of single nucleotide polymorphism (SNP) array genotyping, multiplex ligation-dependent probe amplification (MLPA), and whole-genome sequencing (WGS). We investigated the association between identified pathogenic mutations and demographic and clinical factors such as age at motor symptom onset, family history, motor symptoms (MDS-UPDRS) and cognitive performance (MoCA). We performed baseline genetic analysis in 718 families, of which 205 had sporadic early-onset PD (sEOPD), 113 had familial early-onset PD (fEOPD), and 400 had late-onset familial PD (fLOPD). 69 (9.6%) of these families carried pathogenic variants in known monogenic PD-related genes. The rate of a molecular diagnosis increased to 28.1% in PD with motor onset ≤35 years. We identified pathogenic variants in LRRK2 in 4.2% of families, and biallelic pathogenic variants in PRKN in 3.6% of families. We also identified two families with SNCA duplications and three families with a pathogenic repeat expansion in ATXN2, as well as single families with pathogenic variants in VCP, PINK1, PNPLA6, PLA2G6, SPG7, GCH1, and RAB32. An additional 73 (10.2%) families were carriers of at least one pathogenic or risk GBA1 variant. Most early-onset and familial PD cases do not have a known genetic cause, indicating that there are likely to be further monogenic causes for PD.

Abstract Inherited and acquired muscle diseases are an important cause of morbidity and mortality in human medical and veterinary patients. Researchers use models to study skeletal muscle development and pathology, improve our understanding of disease pathogenesis and explore new treatment options. Experiments on laboratory animals, including murine and canine models, have led to huge advances in congenital myopathy and muscular dystrophy research that have translated into clinical treatment trials in human patients with these debilitating and often fatal conditions. Whilst animal experimentation has enabled many significant and impactful discoveries that otherwise may not have been possible, we have an ethical and moral, and in many countries also a legal, obligation to consider alternatives. This review discusses the models available as alternatives to mammals for muscle development, biology and disease research with a focus on inherited myopathies. Cell culture models can be used to replace animals for some applications: traditional monolayer cultures (for example, using the immortalised C2C12 cell line) are accessible, tractable and inexpensive but developmentally limited to immature myotube stages; more recently, developments in tissue engineering have led to three-dimensional cultures with improved differentiation capabilities. Advances in computer modelling and an improved understanding of pathogenetic mechanisms are likely to herald new models and opportunities for replacement. Where this is not possible, a 3Rs approach advocates partial replacement with the use of less sentient animals (including invertebrates (such as worms Caenorhabditis elegans and fruit flies Drosophila melanogaster) and embryonic stages of small vertebrates such as the zebrafish Danio rerio) alongside refinement of experimental design and improved research practices to reduce the numbers of animals used and the severity of their experience. An understanding of the advantages and disadvantages of potential models is essential for researchers to determine which can best facilitate answering a specific scientific question. Applying 3Rs principles to research not only improves animal welfare but generates high-quality, reproducible and reliable data with translational relevance to human and animal patients.

Abstract Varicella-zoster virus (VZV) is the etiological agent of chickenpox and shingles, diseases characterised by epidermal virus replication in skin and mucosa and the formation of blisters. We have previously shown that VZV infection has a profound effect on keratinocyte differentiation, altering the normal pattern of epidermal gene expression. In particular, VZV infection reduces expression of suprabasal keratins 1 and 10 and desmosomal proteins, disrupting epidermal structure to promote expression of a blistering phenotype. Here, we extend these findings to show that VZV infection upregulates the expression of keratin 15 (KRT15), a marker expressed by basal epidermal keratinocytes and hair follicles stem cells. We demonstrate that KRT15 is essential for VZV replication in the skin, since downregulation of KRT15 inhibits VZV replication in keratinocytes, while KRT15 exogenous overexpression supports viral replication. Importantly, our data show that VZV upregulation of KRT15 depends on the expression of the VZV immediate early gene ORF62. ORF62 is the only regulatory gene that is mutated in the live attenuated VZV vaccine and contains four of the five fixed mutations present in the VZV Oka vaccine. Our data indicate that the mutated vaccine ORF62 is not capable of upregulating KRT15, suggesting that this may contribute to the vaccine attenuation in skin. Taken together our data present a novel association between VZV and KRT15, which may open a new therapeutic window for a topical targeting of VZV replication in the skin via modulation of KRT15.

Background: Primary biliary cholangitis (PBC) is a condition affecting the liver and immune system. In this study, the impact of autologous bone marrow-derived mononuclear cell (BM-MNC) transplantation on PBC patients was investigated. Methods: Sixteen eligible PBC patients participated at the National Scientific Medical Center in Astana, Kazakhstan, between 2017 and 2022, and BM-MNCs were harvested from their anterior iliac crest. After isolating and cultivating the BM-MNCs, they were infused back into the patient’s peripheral veins. Changes in BM-MNC and peripheral blood mononuclear cell (PB-MNC) phenotypes were assessed before and after a 24-hour cultivation period and 72 hours post-transplantation. We monitored liver function parameters over 6-month intervals and conducted flow cytometry analysis to assess CD markers on BM-MNCs before and after cultivation and PB-MNCs before and after transplantation. Statistical analysis included the Friedman test for liver parameters and the Wilcoxon signed-rank test for BM-MNC and PB-MNC comparisons.Results: Our findings revealed significant reductions in liver function tests after multiple transplantations. Flow cytometry analysis before and after a 24-hour culture and autologous BM-MNC infusion revealed the expansion of specific cell populations, with significant increases in CD3+, CD4+, CD16+, CD20+, CD25+, CD34+, CD105+, CD73+, СD117+, and CD34+populations, while CD4+25+, CD34+105+, and CD4+FOXP3+ populations decreased. Interestingly, a contradictory finding was observed with a decrease in bone marrow CD34+105+ cell lines (P=0.03) alongside an increase in peripheral CD34+105+ population (P=0.03).Conclusion: In summary, our study shows that BM-MNC transplantation in PBC patients leads to changes in immune cell populations and liver function. These findings suggest potential therapeutic applications of BM-MNC transplantation in managing PBC and offer insights into the dynamics of immune cells associated with this treatment approach.

Abstract Background Patients with advanced cancer and family caregivers often use avoidant coping strategies, such as delaying advance care planning discussions, which contribute to deterioration in their quality of life. Mindfulness-based interventions have shown promise in improving quality of life in this population but have rarely been applied to advance care planning. This pilot trial examined the preliminary efficacy of a group-based Mindfulness to Enhance Quality of Life and Support Advance Care Planning (MEANING) intervention for patient-caregiver dyads coping with advanced cancer. Primary outcomes were patient and caregiver quality of life or well-being, and secondary outcomes included patient advanced care planning engagement (self-efficacy and readiness) and other psychological and symptom outcomes. Methods In this pilot trial, dyads coping with advanced cancer were recruited from five oncology clinics in the midwestern U.S. and randomized to six weekly group sessions of a mindfulness intervention (n = 33 dyads) or usual care (n = 22 dyads). Outcomes were assessed via surveys at baseline, post-intervention, and 1 month post-intervention. All available data were included in the multilevel models assessing intervention efficacy. Results Patients in the MEANING condition experienced significant increases in existential well-being and self-efficacy for advance care planning across follow-ups, whereas usual care patients did not. Other group differences in outcomes were not statistically significant. These outcomes included other facets of patient well-being, caregiver quality of life, patient readiness for advance care planning, caregiver burden, and patient and caregiver depressive symptoms, anxiety, sleep disturbance, cognitive avoidance, and peaceful acceptance of cancer. However, only MEANING patients showed moderate increases in psychological well-being across follow-ups, and MEANING caregivers showed moderate increases in quality of life at 1-month follow-up. Certain psychological outcomes, such as caregiver burden at 1-month follow-up, also showed moderate improvement in the MEANING condition. Patients in both conditions reported small to moderate increases in readiness to engage in advance care planning. Conclusions A mindfulness-based intervention showed promise in improving quality-of-life and advance care planning outcomes in patients and caregivers coping with advanced cancer and warrants further testing. Trial Registration ClinicalTrials.gov NCT03257007. Registered 22 August 2017, https://clinicaltrials.gov/ct2/show/NCT03257007 .

Abstract Aspects of the acute experience induced by the serotonergic psychedelic psilocybin predict symptomatic relief in multiple psychiatric disorders and improved well-being in healthy participants, but whether these therapeutic effects are immediate or are based on memories of the experience is unclear. To examine this, we co-administered psilocybin (25 mg) with the amnestic benzodiazepine midazolam in 8 healthy participants and assayed the subjective quality of, and memory for, the dosing-day experience. We identified a midazolam dose that allowed a conscious psychedelic experience to occur while partially impairing memory for the experience. Furthermore, midazolam dose and memory impairment tended to associate inversely with salience, insight, and well-being induced by psilocybin. These data suggest a role for memory in therapeutically relevant behavioral effects occasioned by psilocybin. Because midazolam blocks memory by blocking cortical neural plasticity, it may also be useful for evaluating the contribution of the pro-neuroplastic properties of psychedelics to their therapeutic activity.

Abstract Despite the increasing demand for efficient and sustainable chemical processes, the development of scalable systems using biocatalysis for fine chemical production remains a significant challenge. We have developed a scalable flow system using immobilized enzymes to facilitate flavin-dependent biocatalysis, targeting as a proof-of-concept asymmetric alkene reduction. The system integrates a flavin-dependent Old Yellow Enzyme (OYE) and a soluble hydrogenase to enable H2-driven regeneration of the OYE cofactor FMNH2. Molecular hydrogen was produced by water electrolysis using a proton exchange membrane (PEM) electrolyzer and introduced into the flow system via a designed gas membrane addition module at a high diffusion rate. The flow system shows remarkable stability and reusability, consistently achieving >99% conversion of ketoisophorone to levodione. It also demonstrates versatility and selectivity in reducing various cyclic enones and can be extended to further flavin-based biocatalytic approaches and gas-dependent reactions. This electro-driven continuous flow system, therefore, has significant potential for advancing sustainable processes in fine chemical synthesis.

ABSTRACT: An economic simulation was carried out over 183 milk-producing countries to estimate the global economic impacts of 12 dairy cattle diseases and health conditions: mastitis (subclinical and clinical), lameness, paratuberculosis (Johne's disease), displaced abomasum, dystocia, metritis, milk fever, ovarian cysts, retained placenta, and ketosis (subclinical and clinical). Estimates of disease impacts on milk yield, fertility, and culling were collected from the literature, standardized, meta-analyzed using a variety of methods ranging from simple averaging to random-effects models, and adjusted for comorbidities to prevent overestimation. These comorbidity-adjusted disease impacts were then combined with a set of country-level estimates for lactational incidence or prevalence or both, herd characteristics, and price estimates within a series of Monte Carlo simulations that estimated and valued the economic losses due to these diseases. It was estimated that total annual global losses are US$65 billion (B). Subclinical ketosis, clinical mastitis, and subclinical mastitis were the costliest diseases modeled, resulting in mean annual global losses of approximately US$18B, US$13B, and US$9B, respectively. Estimated global annual losses due to clinical ketosis, displaced abomasum, dystocia, lameness, metritis, milk fever, ovarian cysts, paratuberculosis, and retained placenta were estimated to be US$0.2B, US$0.6B, US$0.6B, US$6B, US$5B, US$0.6B, US$4B, US$4B, and US$3B, respectively. Without adjustment for comorbidities, when statistical associations between diseases were disregarded, mean aggregate global losses would have been overestimated by 45%. Although annual losses were greatest in India (US$12B), the United States (US$8B), and China (US$5B), depending on the measure of losses used (losses as a percentage of gross domestic product, losses per capita, losses as a percentage of gross milk revenue), the relative economic burden of these dairy cattle diseases across countries varied markedly.

In this study, the tensile behaviors of laser powder bed fused (L-PBF) and laser powder directed energy deposited (LP-DED) HAYNES® 214 were investigated at a wide range of test temperatures (−195, 25, 425, 650, 870 and 980 °C). Specimens fabricated in the vertical orientation were subjected to a three-step heat treatment including stress relief, hot isostatic pressing, and solution treatment. The non-heat treated microstructures of L-PBF and LP-DED specimens were dendritic and columnar, oriented in the build direction. Recrystallization occurred after solution annealing, with the nucleation and growth of equiaxed grains. Tensile results revealed higher strength for the L-PBF specimens compared to LP-DED up to 650 °C, attributed to their finer grain size. The highest strengths were recorded at cryogenic temperatures, where diminished dislocation mobility and deformation twinning provided increased resistance to plastic deformation. From room temperature to 425 °C, a gradual decrease in strength was ascribed to the increase in dislocation motion with temperature. Ductility was measured to be similar for both processes up to 650 °C, and fracture surface analysis showed transgranular failure at these temperatures. A ductility dip was observed between temperatures of 650–870 °C due to the activation of grain boundary sliding resulting in intergranular cracking. The heterogeneous grain size distribution in both L-PBF and LP-DED specimens led to the ductility being comparable for both processes. The highest test temperature of 980 °C introduced sufficient thermal energy to promote significant grain boundary sliding which resulted in intergranular fracture in the L-PBF and LP-DED specimens.

Abstract Background In 2021, an EULAR task force published a definition of difficult-to-treat rheumatoid arthritis (D2T RA). Our current knowledge of D2T RA with the EULAR definition is based on European and Asian cohorts, and no North American cohort has yet to be published. The aim of this study was to compare D2T RA patients to non-D2T RA who are good responders to advanced therapy, and to describe their evolution in an university health center patient cohort. Methods This is a retrospective single centre study of the medical records of all adults with RA on at least one biologic or target synthetic DMARD (b/tsDMARD). D2T RA group was defined according to the EULAR definition of D2T RA. The non-D2T RA group was defined as a b/tsDMARD good responder who had low-disease activity or remission for at least one year on 1 or 2 b/tsDMARD mechanism of action. We compared the patients’ comorbidities, and history of b/tsDMARD use. Descriptive statistics and proportions were calculated. Kaplan-Meier analysis with log-rank test was used to estimate and compare median survival. Results Among the 417 patients, 101 (24%) were D2T RA and 316 (76%) were non-D2T RA. D2T RA group was slightly younger (63 ± 9 years versus 65 ± 12 years, p = 0.045), more likely to have concomitant non-inflammatory pain (28% versus 8%, p

Abstract Aims To explore the potential interaction between use of SGLT2 inhibitors and the increase in haemoglobin in patients randomized to intravenous iron or the control group in the IRONMAN (Effectiveness of Intravenous Iron Treatment versus Standard Care in Patients with Heart Failure and Iron Deficiency) trial. Methods and results This was a post hoc exploratory analysis of the IRONMAN trial which randomized patients with heart failure, a left ventricular ejection fraction (LVEF) ≤ 45% and iron deficiency (transferrin saturation 16.5 g/dL [men] or >16 g/dL [women]). Conclusions In the IRONMAN trial, there was a trend to a greater increase in haemoglobin with ferric derisomaltose in iron‐deficient patients taking an SGLT2 inhibitor at baseline, as compared with those not taking one.

Introduction: The risk of complications associated with transvenous ICDs make the subcutaneous implantable cardiac defibrillator (S-ICD) a valuable alternative in patients with adult congenital heart disease (ACHD). However, higher S-ICD ineligibility and higher inappropriate shock rates-mostly caused by T wave oversensing (TWO)- are observed in this population. We report a novel application of deep learning methods to screen patients for S-ICD eligibility over a longer period than conventional screening. Methods: Adult patients with ACHD and a control group of normal subjects were fitted with a 24-h Holters to record their S-ICD vectors. Their T:R ratio was analysed utilising phase space reconstruction matrices and a deep learning-based model to provide an in-depth description of the T: R variation plot for each vector. T: R variation was compared statistically using t-test. Results: 13 patients (age 37.4 ± 7.89 years, 61.5 % male, 6 ACHD and 7 control subjects) were enrolled. A significant difference was observed in the mean and median T: R values between the two groups (p

Abstract Transition metal carbides have been adopted in energy storage, conversion, and extreme environment applications. Advancements in their 2D counterparts, known as MXenes, enable the design of unique structures at the ~1 nm thickness scale. Alkali cations have been essential in MXenes manufacturing processing, storage, and applications, however, exact interactions of these cations with MXenes are not fully understood. In this study, using Ti3C2T x , Mo2TiC2T x , and Mo2Ti2C3T x MXenes, we present how transition metal vacancy sites are occupied by alkali cations, and their effect on MXene structure stabilization to control MXene’s phase transition. We examine this behavior using in situ high-temperature x-ray diffraction and scanning transmission electron microscopy, ex situ techniques such as atomic-layer resolution secondary ion mass spectrometry, and density functional theory simulations. In MXenes, this represents an advance in fundamentals of cation interactions on their 2D basal planes for MXenes stabilization and applications. Broadly, this study demonstrates a potential new tool for ideal phase-property relationships of ceramics at the atomic scale.

Abstract Government policy in England aims for the elimination of bovine tuberculosis (bTB). This policy includes culling of European badger (Meles meles) to reduce cattle TB incidence. The rationale is based on a field trial, the Randomised Badger Culling Trial (RBCT) 1998–2005, which reported a substantial decrease in bTB herd incidence where badger culling had been implemented, in comparison to untreated control areas. The RBCT was undertaken because previous studies of reductions in badgers by culling, reported a possible association between bTB in badger and cattle, but none could directly show causation. The effect of intensive widespread (proactive) culling in the RBCT was reported in 2006 in the journal Nature. Analysis of an extensive badger removal programme in England since 2013 has raised concerns that culling has not reduced bTB herd incidence. The present study re-examined RBCT data using a range of statistical models. Most analytical options showed no evidence to support an effect of badger culling on bTB herd incidence ‘confirmed’ by visible lesions and/or bacterial culture post mortem following a comparative intradermal skin test (SICCT). However, the statistical model chosen by the RBCT study was one of the few models that showed an effect. Various criteria suggest that this was not an optimal model, compared to other analytical options available. The most likely explanation is that the RBCT proactive cull analysis over-fitted the data with a non-standard method to control for exposure giving it a poor predictive value. Fresh appraisal shows that there was insufficient evidence to conclude RBCT proactive badger culling affected bTB breakdown incidence. The RBCT found no evidence of an effect of culling on ‘total’ herd incidence rates. Total herd incidences include those confirmed as bTB at necropsy and those herds where there was at least one animal animal positive to the comparative intradermal skin test, the standard diagnostic test used for routine surveillance, but not confirmed at necropsy. This was also the case using the more suitable statistical models. Use only of ‘confirmed’ herd incidence data, together with a more recent (2013) published perception that RBCT data presented ‘a strong evidence base….with appropriate detailed statistical or other quantitative analysis’ should be reconsidered. The results of the present report are consistent with other analyses that were unable to detect any disease control benefits from badger culling in England (2013–2019). This study demonstrates one form of potential driver to the reproducibility crisis, in this case with disease control management in an increasingly intensified livestock industry.

RAGE (receptor for advanced glycation end-products) represents a class of multi-ligand pattern recognition receptors highly expressed in the vertebrate lung. Our previous work demonstrated unique patterns of RAGE expression in the developing murine lung and regulation by key transcription factors including NKX2.1 and FoxA2. The current investigation employed conditional lung-specific upregulation via a TetOn transgenic mouse model (RAGE TG) and nontransgenic controls. RAGE expression was induced in RAGE TG mice throughout gestation (embryonic day, E0-E18.5) or from E15.5-E18.5 and compared to age-matched controls. High-resolution respirometry was used to assess mitochondrial respiration and context was provided by quantifying ATP and reactive oxygen species (ROS) generation. Lung lysates were also screened by immunoblotting for MAPK/PI3K signaling intermediates. RAGE upregulation increased mitochondrial oxygen consumption in the E0-E18.5 and E15.5-E18.5 groups compared to controls. RAGE TG mice also had increased ATP concentrations, which persisted even after controlling for oxygen consumption. In contrast, ROS generation was diminished in RAGE TG animals compared to controls. Lastly, in both RAGE TG groups, pERK and pp38 were significantly decreased, whereas pAKT was significantly elevated, suggesting that RAGE signaling is likely perpetuated via pAKT pathways. Together, these data demonstrate that despite lung hypoplasia in RAGE TG mice, the remaining tissue experiences a favorable shift in mitochondrial bioenergetics without excessive redox assault and a preference for AKT signaling over ERK or p38.

Abstract With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTART1 binding to the analogues is validated using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assays. Imaging of invading merozoites shows the inhibitors prevent the development of ring-stage parasites potentially by inhibiting the expansion of the encasing parasitophorous vacuole membrane. The PfSTART1-targeting compounds also block transmission to mosquitoes and with multiple stages of the parasite’s lifecycle being affected, PfSTART1 represents a drug target with a new mechanism of action.

Abstract Culture-based microbial natural product discovery strategies fail to realize the extraordinary biosynthetic potential detected across earth’s microbiomes. Here we introduce Small Molecule In situ Resin Capture (SMIRC), a culture-independent method to obtain natural products directly from the environments in which they are produced. We use SMIRC to capture numerous compounds including two new carbon skeletons that were characterized using NMR and contain structural features that are, to the best of our knowledge, unprecedented among natural products. Applications across diverse marine habitats reveal biome-specific metabolomic signatures and levels of chemical diversity in concordance with sequence-based predictions. Expanded deployments, in situ cultivation, and metagenomics facilitate compound discovery, enhance yields, and link compounds to candidate producing organisms, although microbial community complexity creates challenges for the later. This compound-first approach to natural product discovery provides access to poorly explored chemical space and has implications for drug discovery and the detection of chemically mediated biotic interactions.

Abstract During primary varicella zoster virus (VZV) infection, infected lymphocytes drive primary viremia, causing systemic dissemination throughout the host, including the skin. This results in cytokine expression, including interferons (IFNs), which partly limit infection. VZV also spreads from skin keratinocytes to lymphocytes prior to secondary viremia. It is not clear how VZV achieves this while evading the cytokine response. Here, we show that VZV glycoprotein C (gC) binds IFN-γ and modifies its activity, increasing the expression of a subset of IFN-stimulated genes (ISGs), including intercellular adhesion molecule 1 (ICAM1), chemokines and immunomodulatory genes. The higher ICAM1 protein level at the plasma membrane of keratinocytes facilitates lymphocyte function-associated antigen 1-dependent T cell adhesion and expression of gC during infection increases VZV spread to peripheral blood mononuclear cells. This constitutes the discovery of a strategy to modulate IFN-γ activity, upregulating a subset of ISGs, promoting enhanced lymphocyte adhesion and virus spread.

Abstract In recent years, pharmaceutical counterfeiting has become an increasingly dangerous situation. A patient who unknowingly consumes a counterfeit drug is at a serious health risk. To address this problem, a low-cost and robust approach for authentication that can be administered at the point-of-care is required. Our proposed solution uses Optical Physical Unclonable Functions (PUFs); patterns formed by a stochastic process that can be used for authentication. We create edible PUFs (ePUFs) using electrospray deposition, which utilizes strong electric fields to atomize a liquid suspension into a plume of micro-scale droplets that are delivered to the target. The ePUFs are electrospray-deposited from an edible ink directly onto the surface of the drug tablets. The process parameters (flow rate, translation speed, and suspension concentration) govern the characteristics of the ePUF to provide highly stochastic patterns. To evaluate our approach, 200 ePUFs were deposited onto tablets at various conditions, followed by imaging and storage of the patterns in a database. For ePUF authentication, a machine vision approach was created using the open source SIFT pattern matching algorithm. Using optimized pattern-matching constraints, our algorithm was shown to be 100% successful in authenticating the cellphone images of the ePUFs to the database. Additionally, the algorithm was found to be robust against changes in illumination and orientation of the cellphone images.

Abstract Living systems rely on molecular building blocks with low structural symmetry. Therefore, constituent amino acids and nucleotides yield short-lived nuclear magnetic responses to electromagnetic radiation. Magnetic signals are at the basis of molecular imaging, structure determination and interaction studies. In solution state, as the molecular weight of analytes increases, coherences with long lifetimes are needed to yield advantageous through-space magnetisation transfers. Interactions between magnetic nuclei can only be detected provided the lifetimes of spin order are sufficient. In J-coupled pairs of nuclei, long-lived coherences (LLC’s) connect states with different spin-permutation symmetry. Here in, we show sustained LLC’s in protein Lysozyme, weighing 14.3 kDa, with lifetimes twice as long as those of classical magnetisation for the aliphatic protons of glycine residues. We found for the first time that, in a protein of significant molecular weight, LLC’s yield substantial through-space magnetisation transfers: spin-order transfer stemming from LLC’s overcame transfers from classical coherences by factors > 2. Furthermore, in agreement with theory, the permutation symmetry of LLC-based transfers allows mapping interacting atoms in the protein structure with respect to the molecular plane of glycine residues in a stereospecific manner. These findings can extend the scope of liquid-state high-resolution biomolecular spectroscopy.

Abstract Context The COVID-19 pandemic has reignited a commitment from the health policy and health services research communities to rebuilding trust in healthcare and created a renewed appetite for measures of trust for system monitoring and evaluation. The aim of the present paper was to develop a multidimensional measure of trust in healthcare that: (1) Is responsive to the conceptual and methodological limitations of existing measures; (2) Can be used to identify systemic explanations for lower levels of trust in equity-deserving populations; (3) Can be used to design and evaluate interventions aiming to (re)build trust. Methods We conducted a 2021 review of existing measures of trust in healthcare, 72 qualitative interviews (Aug-Dec 2021; oversampling for equity-deserving populations), an expert review consensus process (Oct 2021), and factor analyses and validation testing based on two waves of survey data (Nov 2021, n = 694; Jan-Feb 2022, n = 740 respectively). Findings We present the Trust in Multidimensional Healthcare Systems Scale (TIMHSS); a 38-item correlated three-factor measure of trust in doctors, policies, and the system. Measurement of invariance tests suggest that the TIMHSS can also be reliably administered to diverse populations. Conclusions This global measure of trust in healthcare can be used to measure trust over time at a population level, or used within specific subpopulations, to inform interventions to (re)build trust. It can also be used within a clinical setting to provide a stronger evidence base for associations between trust and therapeutic outcomes.

Abstract Lack of rigorous reproducibility and validation are significant hurdles for scientific development across many fields. Materials science, in particular, encompasses a variety of experimental and theoretical approaches that require careful benchmarking. Leaderboard efforts have been developed previously to mitigate these issues. However, a comprehensive comparison and benchmarking on an integrated platform with multiple data modalities with perfect and defect materials data is still lacking. This work introduces JARVIS-Leaderboard, an open-source and community-driven platform that facilitates benchmarking and enhances reproducibility. The platform allows users to set up benchmarks with custom tasks and enables contributions in the form of dataset, code, and meta-data submissions. We cover the following materials design categories: Artificial Intelligence (AI), Electronic Structure (ES), Force-fields (FF), Quantum Computation (QC), and Experiments (EXP). For AI, we cover several types of input data, including atomic structures, atomistic images, spectra, and text. For ES, we consider multiple ES approaches, software packages, pseudopotentials, materials, and properties, comparing results to experiment. For FF, we compare multiple approaches for material property predictions. For QC, we benchmark Hamiltonian simulations using various quantum algorithms and circuits. Finally, for experiments, we use the inter-laboratory approach to establish benchmarks. There are 1281 contributions to 274 benchmarks using 152 methods with more than 8 million data points, and the leaderboard is continuously expanding. The JARVIS-Leaderboard is available at the website: https://pages.nist.gov/jarvis_leaderboard/

Freshwater crayfish are amongst the largest macroinvertebrates and play a keystone role in the ecosystems they occupy. Understanding the global distribution of these animals is often hindered due to a paucity of distributional data. Additionally, non-native crayfish introductions are becoming more frequent, which can cause severe environmental and economic impacts. Management decisions related to crayfish and their habitats require accurate, up-to-date distribution data and mapping tools. Such data are currently patchily distributed with limited accessibility and are rarely up-to-date. To address these challenges, we developed a versatile e-portal to host distributional data of freshwater crayfish and their pathogens (using Aphanomyces astaci, the causative agent of the crayfish plague, as the most prominent example). Populated with expert data and operating in near real-time, World of Crayfish™ is a living, publicly available database providing worldwide distributional data sourced by experts in the field. The database offers open access to the data through specialized standard geospatial services (Web Map Service, Web Feature Service) enabling users to view, embed, and download customizable outputs for various applications. The platform is designed to support technical enhancements in the future, with the potential to eventually incorporate various additional features. This tool serves as a step forward towards a modern era of conservation planning and management of freshwater biodiversity.

The reality of human-induced climate change is unequivocal and exerts an ever-increasing global impact. Access to the latest scientific information on current climate change and projection of future trends is important for planning adaptation measures and for informing international efforts to reduce emissions of greenhouse gases (GHGs). Identification of hazards and risks may be used to assess vulnerability, determine limits to adaptation, and enhance resilience to climate change. This article highlights how recent research programs are continuing to elucidate current processes and advance projections across major climate systems and identifies remaining knowledge gaps. Key findings include projected future increases in monsoon rainfall, resulting from a changing balance between the rainfall-reducing effect of aerosols and rainfall-increasing GHGs; a strengthening of the storm track in the North Atlantic; an increase in the fraction of precipitation that falls as rain at both poles; an increase in the frequency and severity of El Niño Southern Oscillation (ENSO) events, along with changes in ENSO teleconnections to North America and Europe; and an increase in the frequency of hazardous hot-humid extremes. These changes have the potential to increase risks to both human and natural systems. Nevertheless, these risks may be reduced via urgent, science-led adaptation and resilience measures and by reductions in GHGs.

Rationale & Objective: Older adults in the United States often receive kidney therapies that do not align with their goals. Palliative care (PC) specialists are experts in assisting patients with the goals of care discussions and decision support, yet views and experiences of older patients who have received PC while contemplating kidney therapy decisions and their nephrologists remain unexplored. We evaluated the acceptability of CKD-EDU, a PC-based kidney therapy decision support intervention for adults ≥75 years of age. Study Design: Qualitative study. Setting & Participants: Two trained research coordinators interviewed patients and nephrologists participating in the CKD-EDU study. Analytical Approach: Three coders analyzed the qualitative data using a thematic analysis approach to identify salient themes pertaining to intervention acceptability. Results: Patients (n = 19; mean age: 80 years) viewed the PC intervention favorably, noting PC physicians' excellent communication skills, whole-person care, and decision-making support, including comprehension of prognostic information. Nephrologists (n = 24; mean age) welcomed PC assistance in decision making, support for conservative kidney management, and symptom management; a minority voiced concerns about third-party involvement in their practice. Limitations: Single-center study. Conclusions: Overall, patients and nephrologists generally found the PC intervention to be acceptable. Future testing of the current PC-based decision support intervention in a larger randomized controlled trial for older people navigating kidney therapy decisions is needed. Plain-Language Summary: Literature on the acceptability of palliative care for kidney therapy decision making for older adults is scarce. This qualitative study establishes the acceptability of a palliative care (PC)-based kidney therapy decision support pilot intervention among older adults with advanced chronic kidney disease (CKD). Both patients and nephrologists found the intervention acceptable. Future testing of this PC-based intervention in an adequately powered randomized controlled trial for older individuals navigating kidney therapy decisions is needed.

Polariton condensates occur away from thermal equilibrium, in an open system where heat and particles are continually exchanged with reservoirs. These phenomena have been extensively analyzed in terms of kinetic equations. Based on the collection of knowledge about polariton kinetics provided by these simulations and by experimental studies, we constructed a few-level model that captures the main processes involved in the buildup of a ground-state population of polaritons. This allows condensation to be understood as the output of a thermal machine and exposes the thermodynamic constraints on its occurrence. The model consists of a three-level system interacting with a field and connected to a hot and a cold thermal reservoir that represent a non-resonant pump and the lattice phonons. This subsystem can drive a condensate, through polariton–polariton scattering, which produces work in the form of coherent light emission from the microcavity. We obtain a phase diagram as a function of the temperatures of the two baths and investigate the possible types of phase transition that lead to the condensate phase.

Abstract. ➤ The COVID-19 pandemic created a persistent surgical backlog in elective orthopedic surgeries. ➤ Artificial intelligence (AI) uses computer algorithms to solve problems and has potential as a powerful tool in health care. ➤ AI can help improve current and future orthopedic backlogs through enhancing surgical schedules, optimizing preoperative planning, and predicting postsurgical outcomes. ➤ AI may help manage existing waitlists and increase efficiency in orthopedic workflows.

This study was designed to determine whether exposure to low-dose endotoxin (lipopolysaccharide; LPS) during gestation can enhance immunity to a subsequent LPS challenge in piglets after weaning. Pregnant sows (parity: 2.6 ± 1.4) were assigned to prenatal immune stimulation (PIS; n = 7; administered 2.5 µg/kg BW LPS, i.m.) or saline treatment groups (CON; n = 7) administered at day 78 ± 1.8 of gestation. From the two prenatal treatment groups, barrows (n = 17 PIS, 17 CON) were identified at weaning (21 ± 1.3 day of age) to subsequently receive a post-weaning LPS challenge. On day −1, the pigs were fitted with indwelling jugular catheters and subcutaneous temperature loggers. On day 0, the pigs were challenged i.v. with LPS (10 µg/kg BW), and blood samples were collected at −2, 0, 1, 2, 4, 6, 8, 12, and 24 h relative to LPS challenge. There was a treatment × time interaction for subcutaneous temperature (P < 0.01), where the temperature increased more quickly at 1 and 2 h post-challenge in PIS compared to CON pigs. There was a tendency (P = 0.08) for less change in white blood cells, relative to baseline values, in PIS compared to CON pigs. There was a treatment × time interaction (P = 0.01) for lymphocyte concentrations where the concentrations were reduced in PIS compared to CON pigs at 8 h post-challenge. There was also a treatment × time interaction (P = 0.01) for the change in eosinophil concentrations, where there was less change in eosinophil concentrations from 1 to 12 h in PIS compared to CON pigs. There was a tendency (P ≤ 0.06) for a treatment × time interaction for serum interleukin-6 (IL-6) and IL-8. Granulocyte-macrophage colony-stimulating factor tended to be greater, and tumor necrosis factor-α tended to be reduced in PIS compared to CON pigs (P ≤ 0.08). These data suggest that exposure to endotoxin in utero may influence the postnatal innate immune response to endotoxin. More research is necessary to further understand the mechanism behind the differences observed and the potential long-term influence of prenatal immune stimulation on pig offspring.

Abstract Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6‐guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT‐PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6‐impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6‐guided trial recommendations. The primary study outcome is the 3‐month absolute change in the composite pain intensity score assessed using Patient‐Reported Outcomes Measurement Information System (PROMIS) measures. Follow‐up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment.

Abstract A crucial factor influencing the mass balance of the West Antarctic Ice Sheet is the Amundsen Sea Low (ASL), a climatological low‐pressure region situated off the West Antarctic coast. However, albeit the deepening of the ASL since the 1950s has been attributed to anthropogenic forcing, the multi‐decadal variability of the ASL remains poorly understood, because of a lack of long observations. Here, we apply a newly developed data assimilation method to reconstruct the ASL over 1870–2000. We study the forced and internal variability of the ASL using our new reconstruction in concert with existing large ensembles of climate model simulations. Our findings robustly demonstrate that an atmospheric teleconnection originating from the tropical Indo‐Pacific is the main driver of ASL variability at the multi‐decadal time scale, with resemblance to the Interdecadal Pacific Oscillation. Since the mid‐20th century, anthropogenic forcing has emerged as a dominant contributor to the strengthening of the ASL.

Broadband analog signal processors utilizing silicon photonics have demonstrated a significant impact in numerous application spaces, offering unprecedented bandwidths, dynamic range, and tunability. In the past decade, microwave photonic techniques have been applied to neuromorphic processing, resulting in the development of novel photonic neural network architectures. Neuromorphic photonic systems can enable machine learning capabilities at extreme bandwidths and speeds. Herein, low‐quality factor microring resonators are implemented to demonstrate broadband optical weighting. In addition, silicon photonic neural network architectures are critically evaluated, simulated, and optimized from a radio‐frequency performance perspective. This analysis highlights the linear front‐end of the photonic neural network, the effects of linear and nonlinear loss within silicon waveguides, and the impact of electrical preamplification.

Background: Predicting post-transplant (PT) survival in lung allocation remains an elusive goal. We analyzed the impact of donor factors on PT survival and how these relationships vary among transplant recipients. Methods: We studied primary bilateral lung transplant recipients (n = 7,609) from the US Scientific Registry of Transplant Recipients (19 February 2015-1 February 2020). Main and interaction effects were evaluated and adjusted across candidate age, sex, and diagnosis. Models predicting PT survival were compared to the PT Composite Allocation Score model (PT-CAS): (1) Cox regression donor multivariable model (COX), (2) COX + PT-CAS, (3) random forest model (RF), and (4) RF + PT-CAS. Model discrimination and calibration measures were compared. Results: Interactions between donor and recipient factors emerged by age: lower survival for donation after circulatory death organs for recipients aged 55 to 69 years, donor smoking for recipients aged 30 to 54 and 70+, Hispanic donor for recipients

Abstract Background Sedentary behavior (SB) is a recognized risk factor for many chronic diseases. ActiGraph and activPAL are two commonly used wearable accelerometers in SB research. The former measures body movement and the latter measures body posture. The goal of the current study is to quantify the pattern and variation of movement (by ActiGraph activity counts) during activPAL-identified sitting events, and examine associations between patterns and health-related outcomes, such as systolic and diastolic blood pressure (SBP and DBP). Methods The current study included 314 overweight postmenopausal women, who were instructed to wear an activPAL (at thigh) and ActiGraph (at waist) simultaneously for 24 hours a day for a week under free-living conditions. ActiGraph and activPAL data were processed to obtain minute-level time-series outputs. Multilevel functional principal component analysis (MFPCA) was applied to minute-level ActiGraph activity counts within activPAL-identified sitting bouts to investigate variation in movement while sitting across subjects and days. The multilevel approach accounted for the nesting of days within subjects. Results At least 90% of the overall variation of activity counts was explained by two subject-level principal components (PC) and six day-level PCs, hence dramatically reducing the dimensions from the original minute-level scale. The first subject-level PC captured patterns of fluctuation in movement during sitting, whereas the second subject-level PC delineated variation in movement during different lengths of sitting bouts: shorter (< 30 minutes), medium (30 -39 minutes) or longer (> 39 minute). The first subject-level PC scores showed positive association with DBP (standardized $$\hat{\beta }$$ β ^ : 2.041, standard error: 0.607, adjusted p = 0.007), which implied that lower activity counts (during sitting) were associated with higher DBP. Conclusion In this work we implemented MFPCA to identify variation in movement patterns during sitting bouts, and showed that these patterns were associated with cardiovascular health. Unlike existing methods, MFPCA does not require pre-specified cut-points to define activity intensity, and thus offers a novel powerful statistical tool to elucidate variation in SB patterns and health. Trial registration ClinicalTrials.gov NCT03473145; Registered 22 March 2018; https://clinicaltrials.gov/ct2/show/NCT03473145 ; International Registered Report Identifier (IRRID): DERR1-10.2196/28684

Abstract Growing evidence has confirmed the critical role played by basal channels beneath Antarctic ice shelves in both ice shelf stability and freshwater input to the surrounding ocean. Here we show, using a 3D ice shelf-ocean boundary current model, that deeper basal channels can lead to a significant amplification in channelized basal melting, meltwater channeling, and warming and salinization of the channel flow. All of these channelized quantities are also modulated by channel width, with the level of modulation determined by channel height. The explicit quantification of channelized basal melting and the meltwater transport in terms of channel cross-sectional shape is potentially beneficial for the evaluation of ice shelf mass balance and meltwater contribution to the nearshore oceanography. Complicated topographically controlled circulations are revealed to be responsible for the unique thermohaline structure inside deep channels. Our study emphasizes the need for improvement in observations of evolving basal channels and the hydrography inside them, as well as adjacent to the ice front where channelized meltwater emerges.

Abstract Background While dyadic faculty–mentored relationship research currently saturates the mentoring literature, recent developments suggest the need for a broader consideration of a student's mentor network. Research taking a network approach may provide deeper insights into the formation and benefits of mentorship for undergraduate students in science, technology, engineering, and mathematics (STEM) disciplines. Utilizing Developmental Mentor Network Theory and ego-centric social network analysis, this pre-registered study evaluates how the characteristics of mentees and mentors relate to both the content of support and structure of mentor networks in a large sample of White and Hispanic/Latino(a) STEM undergraduates across 12 universities. Results Results were nuanced but showed that perceived psychological similarity with their mentor(s) predicted both dyadic and network average levels of mentor support (i.e., psychosocial, career, role modeling) and relational satisfaction. Furthermore, results point to homophily and engagement in undergraduate research effects on mentor network structures. Conclusions These findings highlight the importance of using a network approach to deepen our understanding of the factors (e.g., psychological similarity) that may influence the formation and maintenance of robust and diverse supportive mentoring networks.

As we enter the age of electrochemical propulsion, there is an increasing tendency to discuss the viability or otherwise of different electrochemical propulsion systems in zero-sum terms. These discussions are often grounded in a specific use case; however, given the need to electrify the wider transport sector it is evident that we must consider systems in a holistic fashion. When designed adequately, the hybridisation of power sources within automotive applications has been demonstrated to positively impact fuel cell efficiency, durability, and cost, while having potential benefits for the safety of vehicles. In this paper, the impact of the fuel cell to battery hybridisation degree is explored through the key design parameter of system mass. Different fuel cell electric hybrid vehicle (FCHEV) scenarios of various hydridisation degrees, including light-duty vehicles (LDVs), Class 8 heavy goods vehicles (HGVs), and buses are modelled to enable the appropriate sizing of the proton exchange membrane (PEMFC) stack and lithium-ion battery (LiB) pack and additional balance of plant. The operating conditions of the modelled PEMFC stack and battery pack are then varied under a range of relevant drive cycles to identify the relative performance of the systems. By extending the model further and incorporating a feedback loop, we are able to remove the need to include estimated vehicle masses a priori enabling improving the speed and accuracy of the model as an analysis tool for vehicle mass and performance estimation.

Plant pathogens manipulate the cellular environment of the host to facilitate infection and colonization that often lead to plant diseases. To accomplish this, many specialized pathogens secrete virulence proteins called effectors into the host cell, which subvert processes such as immune signaling, gene transcription, and host metabolism. Phytophthora infestans, the causative agent of potato late blight, employs an expanded repertoire of RxLR effectors with WY domains to manipulate the host through direct interaction with protein targets. However, our understanding of the molecular mechanisms underlying the interactions between WY effectors and their host targets remains limited. In this study, we performed a structural and biophysical characterization of the P. infestans WY effector Pi04314 in complex with the potato Protein Phosphatase 1-c (PP1c). We elucidate how Pi04314 uses a WY domain and a specialized C-terminal loop carrying a KVxF motif that interact with conserved surfaces on PP1c, known to be used by host regulatory proteins for guiding function. Through biophysical and in planta analyses, we demonstrate that Pi04314 WY or KVxF mutants lose their ability to bind PP1c. The loss of PP1c binding correlates with changes in PP1c nucleolar localization and a decrease in lesion size in plant infection assays. This study provides insights into the manipulation of plant hosts by pathogens, revealing how effectors exploit key regulatory interfaces in host proteins to modify their function and facilitate disease. [Graphic: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

Actinobacillus pleuropneumoniae is the causative agent of pleuropneumonia, an economically important lung disease in pigs. In draft genomes of two Cypriot clinical A. pleuropneumoniae isolates (MIDG3457 and MIDG3459), we previously identified single genomic regions with homology to Mu-like bacteriophage and presented preliminary evidence of active phage. Here, updated Phastest genomic analysis identified two loci in both MIDG3457 and MIDG3459 that were predicted to encode proteins with high homology to, and whose organisation was characteristic of, Mu-like phages. Phylogenetically, the closest matches were with Mannheimia Vb and Glaesserella SuMu phages. Phastest scored the loci as “complete”, indicating they produced active phage. PCR amplification of the Mu-like phage c and tail genes from DNase-treated polyethylene glycol 8000 (PEG)-precipitated supernatants of MIDG3457 and MIDG3459 (grown in either Brain Heart Infusion-NAD or Grace’s Insect Medium-NAD broth) indicated the presence of intact virions. The phages from MIDG3457 and MIDG3459 were named PluMu 3457-1, 3457-2, and PluMu 3459-1 and PluMu 3459-2, respectively. Transmission electron microscopy (TEM) of the PEG-precipitated supernatants of broth-grown MIDG3459 identified virions with icosahedral heads and tails, consistent with other Mu-like phages. We conclude that MIDG3459 produces an active Mu-like phage.

Over the last few decades, several new materials and techniques have been developed for bone regeneration. Scaffolds based on demineralized dentin matrix (DDM) present an attractive option due to their availability and several animal and human studies have been conducted to ascertain their utility in regenerative dentistry. The aim of this review was to summarize the recent studies conducted on DDM and used for bone grafts. PubMed, Web of Science, and Scopus were used to search for studies published within the last 10 years. The keywords and terms used were: “demineralized dentine matrix”, “bone grafting”, “bone augmentation” and “guided tissue regeneration” in various combinations. Original studies (in vitro, animal and human) and systematic reviews were included in the literature search. The literature search initially identified 23 studies (16 animal studies and 7 clinical reports. Most studies included in this review indicate that DDM has demonstrated promising results in a variety of dental and regenerative medicine applications. Further studies are required to completely comprehend its characteristics and prospective applications. Future studies should also focus on optimizing the processing protocols for the production of DDM-based scaffolds.

Abstract The relative contributions of anthropogenic climate change and internal variability in sea level rise from the West Antarctic Ice Sheet are yet to be determined. Even the way to address this question is not yet clear, since these two are linked through ice-ocean feedbacks and probed using ice sheet models with substantial uncertainty. Here we demonstrate how their relative contributions can be assessed by simulating the retreat of a synthetic ice sheet setup using an ice sheet model. Using a Bayesian approach, we construct distributions of sea level rise associated with this retreat. We demonstrate that it is necessary to account for both uncertainties arising from both a poorly-constrained model parameter and stochastic variations in climatic forcing, and our distributions of sea level rise include these two. These sources of uncertainty have only previously been considered in isolation. We identify characteristic effects of climate change on sea level rise distributions in this setup, most notably that climate change increases both the median and the weight in tails of distributions. From these findings, we construct metrics quantifying the role of climate change on both past and future sea level rise, suggesting that its attribution is possible even for unstable marine ice sheets.

Abstract Background Solid tumors such as glioblastoma (GBM) exhibit hypoxic zones that are associated with poor prognosis and immunosuppression through multiple cell intrinsic mechanisms. However, release of extracellular vesicles (EVs) has the potential to transmit molecular cargos between cells. If hypoxic cancer cells use EVs to suppress functions of macrophages under adequate oxygenation, this could be an important underlying mechanism contributing to the immunosuppressive and immunologically cold tumor microenvironment of tumors such as GBM. Methods EVs were isolated by differential ultracentrifugation from GBM cell culture supernatant. EVs were thoroughly characterized by transmission and cryo-electron microscopy, nanoparticle tracking analysis (NTA), and EV marker expression by Western blot and fluorescent NTA. EV uptake by macrophage cells was observed using confocal microscopy. The transfer of miR-25/93 as an EV cargo to macrophages was confirmed by miRNA real-time qPCR. The impact of miR-25/93 on the polarization of recipient macrophages was shown by transcriptional analysis, cytokine secretion and functional assays using co-cultured T cells. Results We show that indirect effects of hypoxia can have immunosuppressive consequences through an EV and microRNA dependent mechanism active in both murine and human tumor and immune cells. Hypoxia enhanced EV release from GBM cells and upregulated expression of miR-25/93 both in cells and in EV cargos. Hypoxic GBM-derived EVs were taken up by macrophages and the miR-25/93 cargo was transferred, leading to impaired cGAS-STING pathway activation revealed by reduced type I IFN expression and secretion by macrophages. The EV-treated macrophages downregulated expression of M1 polarization-associated genes Cxcl9, Cxcl10 and Il12b, and had reduced capacity to attract activated T cells and to reactivate them to release IFN-γ, key components of an efficacious anti-tumor immune response. Conclusions Our findings suggest a mechanism by which immunosuppressive consequences of hypoxia mediated via miRNA-25/93 can be exported from hypoxic GBM cells to normoxic macrophages via EVs, thereby contributing to more widespread T-cell mediated immunosuppression in the tumor microenvironment.

Abstract To enhance risk stratification in patients suspected of coronary artery disease, the assessment of coronary artery calcium (CAC) could be incorporated, especially when CAC can be readily assessed on previously performed non-gated chest computed tomography (CT). Guidelines recommend reporting on patients’ extent of CAC on these non-cardiac directed exams and various studies have shown the diagnostic and prognostic value. However, this method is still little applied, and no current consensus exists in clinical practice. This review aims to point out the clinical utility of different kinds of CAC assessment on non-gated CTs. It demonstrates that these scans indeed represent a merely untapped and underestimated resource for risk stratification in patients with stable chest pain or an increased risk of cardiovascular events. To our knowledge, this is the first review to describe the clinical utility of different kinds of visual CAC evaluation on non-gated unenhanced chest CT. Various methods of CAC assessment on non-gated CT are discussed and compared in terms of diagnostic and prognostic value. Furthermore, the application of these non-gated CT scans in the general practice of cardiology is discussed. The clinical utility of coronary calcium assessed on non-gated chest CT, according to the current literature, is evident. This resource of information for cardiac risk stratification needs no specific requirements for scan protocol, and is radiation-free and cost-free. However, some gaps in research remain. In conclusion, the integration of CAC on non-gated chest CT in general cardiology should be promoted and research on this method should be encouraged.

Introduction: Rarely solitary sternum metastases are addressed by resection. Two additional cases are presented as they are interesting because of their long-term follow-up. Case Presentation: Case 1: A renal cell carcinoma was treated by transabdominal nephrectomy at age 64. Right iliac bone and sternum metastases were diagnosed 7 months later and treated by internal hemipelvectomy followed by sternum metastasectomy 6 weeks after the internal hemipelvectomy. At 12-year follow-up, the patient appears disease free. Case 2: Prostate cancer was treated by prostatectomy at age 67. A subsequent solitary sternum metastasis was resected 10 years later for persistent PSA-activity despite repeated radiotherapy. The patient remains asymptomatic for 3 years now. Conclusion: Resection of sternum metastases may have curative potential and should be considered in tumours known to be rather resistant to chemo- and/or radiotherapy.

Objective：The triglyceride-glucose (TyG) index is an indicator for insulin resistance (IR). Several studies have validated the impact of the TyG index on cerebrovascular disease. However, the value of the TyG index in patients with subarachnoid hemorrhage (SAH), requiring admission to the intensive care unit (ICU), remains unclear. In this study, we aimed to investigate the relationship between the TyG index and clinical outcomes in SAH patients. Methods：: In this study, we identified patients with severe SAH requiring ICU admission from the Medical Information Marketplace for Intensive Care (MIMIC-IV) database. These patients were then categorized into tertiles based on their TyG index levels. After adjusting for confounders, multivariate Cox proportional hazards analysis and restricted cubic spline analysis were performed to assess the relationship between the TyG index and clinical outcomes in critically ill SAH patients. Results：: The study outcomes included in-hospital mortality and ICU mortality. The rate of in-hospital mortality and ICU mortality were 16.8 % and 13.1 %, respectively. After adjusting for confounders, multivariate Cox proportional hazards analysis showed that an elevated TyG index was significantly associated with all-cause mortality. Specifically, patients with a high TyG index had a significantly higher risk of in-hospital mortality (adjusted hazard ratio: 1.72; 95 % confidence interval: 0.81–3.66; P = 0.16) and ICU mortality (adjusted hazard ratio: 2.60; 95 % confidence interval: 1.04–6.43; P = 0.039). The TyG index was most strongly associated with ICU mortality. Moreover, restricted cubic spline curves demonstrated a progressive increase in the risk of all-cause mortality with an increase in the TyG index. Conclusion：: Overall, our findings suggest that the TyG index may be a useful tool in identifying SAH patients at a higher risk of all-cause mortality in both, the hospital and the ICU setting.

Analog photonic information processing can be implemented with low chip area using wavelength-division multiplexed systems, which typically manipulate light using micro-ring resonators. Micro-rings are uniquely susceptible to thermal crosstalk, with negative system performance consequences if not addressed. Existing thermal sensitivity mitigation methods face drawbacks including high complexity, high latency, high digital and analog hardware requirements, and CMOS incompatibility. Here, we demonstrate a passive thermal desensitization mechanism for silicon micro-ring resonators exploiting self-heating resulting from optical absorption. We achieve a 49% reduction in thermal crosstalk sensitivity and 1 µs adaptation latency using a system with no specialized micro-ring engineering, no additional control hardware, and no additional calibration. Our theoretical model indicates the potential for significant further desensitization gains with optimized micro-ring designs. Self-heating desensitization can be combined with active thermal stabilization to achieve both responsiveness and accuracy or applied independently to thermally desensitize large photonic systems for signal processing or neural network inference.

IntroductionPseudomonas aeruginosa is a leading cause of canine otitis externa. Enrofloxacin is often applied topically to treat this condition, although recalcitrant and recurring infections are common. There is evidence that exposure to blue light (400–470 nm) has a bactericidal effect on P. aeruginosa and other microorganisms.MethodsIn the present study, we tested the biocidal effect of blue light (375–450 nm), alone or in combination with enrofloxacin, against six isolates of P. aeruginosa from dogs with otitis externa (5 of which were resistant to enrofloxacin).ResultsTreatment of planktonic cell cultures with blue light resulted in significant (p < 0.5) reductions in Colony Forming Units (CFU) for all seven strains tested, in some cases below the limit of detection. The greatest bactericidal effect was observed following exposure to light at 405 nm wavelength (p < 0.05). Exposure to blue light for 20 min usually resulted in a greater reduction in Pseudomonas aeruginosa than enrofloxacin treatment, and combination treatment typically resulted in the largest reductions in CFU. Analysis of the genome sequences of these strains established that enrofloxacin resistance was likely the result of a S466F substitution in GyrB. However, there was no clear association between genotype and susceptibility to blue light treatment.DiscussionThese results suggest that blue light treatment, particularly at 405 nm wavelength, and especially in combination with enrofloxacin therapy, could be an effective treatment for otherwise recalcitrant canine otitis externa caused by Pseudomonas aeruginosa. It may also provide a way of extending the usefulness of enrofloxacin therapy which would otherwise be ineffective as a sole therapeutic agent.

Dynamic changes in the endoplasmic reticulum (ER) morphology are central to maintaining cellular homeostasis. Microtubules (MT) facilitate the continuous remodeling of the ER network into sheets and tubules by coordinating with many ER-shaping protein complexes, although how this process is controlled by extracellular signals remains unknown. Here we report that TAK1, a kinase responsive to various growth factors and cytokines including TGF-β and TNF-α, triggers ER tubulation by activating αTAT1, an MT-acetylating enzyme that enhances ER-sliding. We show that this TAK1/αTAT1-dependent ER remodeling promotes cell survival by actively downregulating BOK, an ER membrane-associated proapoptotic effector. While BOK is normally protected from degradation when complexed with IP3R, it is rapidly degraded upon their dissociation during the ER sheets-to-tubules conversion. These findings demonstrate a distinct mechanism of ligand-induced ER remodeling and suggest that the TAK1/αTAT1 pathway may be a key target in ER stress and dysfunction.

Central African rainforests are predicted to be disproportionately affected by future climate change. How species will cope with these changes is unclear, but rapid environmental changes will likely impose strong selection pressures. Here we examined environmental drivers of genomic variation in the central African puddle frog (Phrynobatrachus auritus) to identify areas of elevated environmentally-associated turnover. We also compared current and future climate models to pinpoint areas of high genomic vulnerability where allele frequencies will have to shift the most in order to keep pace with future climate change. Neither physical landscape barriers nor the effects of past Pleistocene refugia influenced genomic differentiation. Alternatively, geographic distance and seasonal aspects of precipitation are the most important drivers of SNP allele frequency variation. Patterns of genomic differentiation coincided with key ecological gradients across the forest-savanna ecotone, montane areas, and a coastal to interior rainfall gradient. Areas of greatest vulnerability were found in the lower Sanaga basin, the southeastern region of Cameroon, and southwest Gabon. In contrast with past conservation efforts that have focused on hotspots of species richness or endemism, our findings highlight the importance of maintaining environmentally heterogeneous landscapes to preserve genomic variation and ongoing evolutionary processes in the face of climate change.

Summary: Workplace violence (WPV) against healthcare workers (HCW) is a globally growing problem in healthcare systems. Despite decades of research and interventions violent incidents are rising in their severity and frequency.A structured review of PubMed and Scopus databases and supplementary internet searches, resulted in a synthesis of evidence covering multiple countries and healthcare worker populations. High rates of WPV are increasingly common due to unmet patient expectations, poor communication, long wait times and organizational factors such as resourcing and infrastructure.We highlight links between WPV and poor worker health outcomes, staff turnover, reduced patient safety and medical errors. Few prevention and mitigation activities have shown sustained effects, highlighting the challenges in understanding and addressing the complex interplay of factors that drive violence against HCWs.The rapidly rising incidence of WPV requires special consideration and action from multiple stakeholders including patients and visitors, healthcare providers, law enforcement, media and policy makers.