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Abstract Background Nicotine use and nicotine use disorder (NUD) are the leading causes of preventable death in the United States. Persons with mental disorders (e.g., bipolar disorder) are differentially susceptible to nicotine use. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are indicated for type 2 diabetes mellitus (T2DM) and obesity and show preliminary evidence of efficacy in addiction-related behaviours. Herein, we synthesize extant preclinical and clinical evidence evaluating the effect of GLP-1RAs on neurobiological systems and behaviours salient to nicotine consumption and cessation. Methods Online databases (MedLine, Embase, AMED, PsychINFO, JBI EBP Database, PubMed, Web of Science, Google Scholar) were searched from inception to May 21, 2024. Relevant studies were also extracted from the reference lists of the obtained articles. All articles were screened against inclusion and exclusion criteria. Results Administration of GLP-1RAs reduced nicotine self-administration and nicotine-seeking behaviour in animal models that, in some cases, is sustained beyond exposure to the agent. GLP-1RAs also mitigated post-nicotine cessation weight gain, craving, withdrawal, and hyperphagia. The preceding effects are attributable to modulation of reward-related brain regions (e.g., mesolimbic dopamine system), resulting in nicotine aversion. GLP-1RAs were also efficacious as adjunctive therapies [e.g., in combination with nicotine replacement therapies (NRTs)]. Conclusion The multi-effect characteristics in NUD paradigms provide a compelling rationale for large, adequately powered, long-term, randomized controlled trials of GLP-1RAs in the treatment and prevention of NUD. The replicated effect on mitigating post-nicotine cessation weight gain is a differentiating feature of GLP-1RAs from extant proven therapies for NUD.

Depression is one of the most common psychiatric disorders and frequently accompanied by other mental disorders. There is therefore a need to develop and document new treatments that could have a beneficial effect in treating depression. A new treatment approach to depression that has produced encouraging results is metacognitive therapy (MCT). This paper provides a general introduction to the theory of MCT and especially of how to use MCT in treating depressive disorders. The treatment is illustrated with the clinical case of Andrew, and in the final part of this paper the current evidence for MCT for depression is presented.

Abstract Background A subdural hematoma is a type of traumatic brain injury that results from the rupture of the bridging veins. It often presents with various neurological deficits. The Kernohan–Woltman notch phenomenon (KWNP) is a rare complication associated with subdural hematomas, characterized by ipsilateral hemiparesis due to compression of the contralateral cerebral peduncle. Case presentation We present a case of a 30-year-old female with a left subdural hematoma who exhibited paradoxical ipsilateral hemiparesis and discuss the appearance of KWNP in the context of alcohol withdrawal. We also report on the appearance of delirium tremens 6 days after evacuation. Conclusion In our report, we effectively rule out other causes of ipsilateral hemiparesis such as cerebrovascular accident or mass effect, and demonstrate a rare presentation of KWNP in an uncommon demographic. Our report also demonstrates an incidental finding of delirium tremens that may have been delayed in presentation due to intubation. The findings contribute to further research on these uncommon neurological and psychiatric manifestations.

Abstract Information encountered in different events, such as people and objects, can be interlinked in memory. Such memory integration supports novel inferences about the world. This study investigates the role of episodic context on memory integration in two experiments using an associative inference task. Participants encoded events with overlapping (AB and BC) and non-overlapping associations (XY) presented in the same or different episodic contexts. Inference performance across events (AC) was tested in the absence (Experiment 1) and in the presence (Experiment 2) of the encoding context. Our data show that inferences across events encoded in the same context were more accurate, faster, and made with greater confidence compared to those encoded in different contexts. However, this effect was observed only when the context was presented during testing, suggesting that context enhances associative inferences by facilitating retrieval of events associated with that context. These findings demonstrate that revisiting the encoding context promotes memory integration by providing privileged access to contextually associated memory traces and facilitating their flexible recombination to form novel inferences.

Abstract Background Immunotherapy has improved survival for patients with advanced clear cell renal cell carcinoma (ccRCC), but resistance to therapy develops in most patients. We use cellular-resolution spatial transcriptomics in patients with immunotherapy naïve and exposed primary ccRCC tumors to better understand immunotherapy resistance. Results Spatial molecular imaging of tumor and adjacent stroma samples from 21 tumors suggests that viable tumors following immunotherapy harbor more stromal CD8 + T cells and neutrophils than immunotherapy naïve tumors. YES1 is significantly upregulated in immunotherapy exposed tumor cells. Spatial GSEA shows that the epithelial-mesenchymal transition pathway is spatially enriched and the associated ligand-receptor transcript pair COL4A1-ITGAV has significantly higher autocorrelation in the stroma after exposure to immunotherapy. More integrin αV + cells are observed in immunotherapy exposed stroma on multiplex immunofluorescence validation. Compared to other cancers in TCGA, ccRCC tumors have the highest expression of both COL4A1 and ITGAV. Assessing bulk RNA expression and proteomic correlates in CPTAC databases reveals that collagen IV protein is more abundant in advanced stages of disease. Conclusions Spatial transcriptomics of samples of 3 patient cohorts with cRCC tumors indicates that COL4A1 and ITGAV are more autocorrelated in immunotherapy-exposed stroma compared to immunotherapy-naïve tumors, with high expression among fibroblasts, tumor cells, and endothelium. Further research is needed to understand changes in the ccRCC tumor immune microenvironment and explore potential therapeutic role of integrin after immunotherapy treatment.

Abstract The physics of spin-orbit entangled magnetic moments of 4d and 5d transition metal ions on a honeycomb lattice has been much explored in the search for unconventional magnetic orders or quantum spin liquids expected for compass spin models, where different bonds in the lattice favour different orientations for the magnetic moments. Realising such physics with rare-earth ions is a promising route to achieve exotic ground states in the extreme spin-orbit limit; however, this regime has remained experimentally largely unexplored due to major challenges in materials synthesis. Here we report the successful synthesis of powders and single crystals of β-Na2PrO3, with 4f 1 Pr4+ j eff = 1/2 magnetic moments arranged on a hyperhoneycomb lattice with the same threefold coordination as the planar honeycomb. We find a strongly non-collinear magnetic order with highly dispersive gapped excitations that we argue arise from frustration between bond-dependent, anisotropic off-diagonal exchanges, a compass quantum spin model not explored experimentally so far. Our results show that rare-earth ions on threefold coordinated lattices offer a platform for the exploration of quantum compass spin models in the extreme spin-orbit regime, with qualitatively distinct physics from that of 4d and 5d Kitaev materials.

Abstract To increase antibody affinity against pathogens, positively selected GC-B cells initiate cell division in the light zone (LZ) of germinal centers (GCs). Among these, higher-affinity clones migrate to the dark zone (DZ) and vigorously proliferate by utilizing energy provided by oxidative phosphorylation (OXPHOS). However, it remains unknown how positively selected GC-B cells adapt their metabolism for cell division in the glycolysis-dominant, cell cycle arrest-inducing, hypoxic LZ microenvironment. Here, we show that microRNA (miR)−155 mediates metabolic reprogramming during positive selection to protect high-affinity clones. Mechanistically, miR-155 regulates H3K36me2 levels in hypoxic conditions by directly repressing the histone lysine demethylase, Kdm2a, whose expression increases in response to hypoxia. The miR-155-Kdm2a interaction is crucial for enhancing OXPHOS through optimizing the expression of vital nuclear mitochondrial genes under hypoxia, thereby preventing excessive production of reactive oxygen species and subsequent apoptosis. Thus, miR-155-mediated epigenetic regulation promotes mitochondrial fitness in high-affinity GC-B cells, ensuring their expansion and consequently affinity maturation.

Abstract Purpose The course of Vogt-Koyanagi-Harada (VKH) disease is typically assessed qualitatively using indocyanine green angiography (ICGA) and enhanced-depth imaging optical coherence tomography (EDI-OCT). However, a quantitative approach could improve accuracy and objectivity. The aim of this study was to assess the clinical value of the automated measurement capabilities of swept-source optical coherence tomography (SS-OCT) to measure choroidal thickness (quantitative approach) in chronic VKH. Methods Prospective, longitudinal case–control study at a tertiary university hospital involving 23 chronic VKH patients (9 convalescent and 14 quiescent) and 17 age-matched controls. Choroidal thickness was automatically measured with SS-OCT. Results Choroidal thinning and improved vision were associated with treatment while increasing thickness and worsening vision were associated with posterior relapse. Overall, 41.6% of asymptomatic (no change in visual acuity) recurrences in the convalescent group and 25% of recurrences in the quiescent group were detected by SS-OCT. All recurrences diagnosed by SS-OCT showed signs of inflammation on ICGA. Conclusions Automatic measurement of choroidal thickness with SS-OCT is a rapid, non-invasive method of detecting posterior segment recurrences and treatment response in VKH patients, and could reduce the need for angiography to monitor this disease.

Abstract The Large Hadron Collider’s high luminosity era presents major computational challenges in the analysis of collision events. Large amounts of Monte Carlo (MC) simulation will be required to constrain the statistical uncertainties of the simulated datasets below these of the experimental data. Modelling of high-energy particles propagating through the calorimeter section of the detector is the most computationally intensive MC simulation task. We introduce a technique combining recent advancements in generative models and quantum annealing for fast and efficient simulation of high-energy particle-calorimeter interactions.

Abstract Background Antenatal iron and folic acid (IFA) supplementation remains an effective strategy in the prevention of maternal anemia and low birthweight and is universally recommended by WHO. However, uptake of IFA has varied globally due to challenges with acceptability, supply and distribution, counselling and knowledge, and access to health services. In Botswana, nearly one-third of pregnant women engaged in antenatal care do not receive IFA, despite it being standard of care. The objectives of this study were to assess knowledge of and barriers and facilitators to IFA supplementation before and during pregnancy. Methods We conducted qualitative interviews with two key stakeholder groups at two different levels—the individual level (pregnant women) and the service delivery level (health care providers). Here, we present results from interviews with pregnant women at two representative antenatal clinic sites in Botswana in 2022. Results Pregnant women were motivated to be healthy and were knowledgeable about the benefits of supplementation during pregnancy to mothers and their infants; however, women knew more about the benefits of iron than folic acid. Most women were in favor of receiving IFA supplementation prior to pregnancy and receiving fortified foods. Several key barriers were identified: lack of supplement availability in the clinics, poverty, side effects, number of tablets, and adherence. Approaches to overcome these barriers included improving supplement availability, improving health education, increasing supply of nutritious and fortified foods, backyard gardens, and increasing family and monetary support. Conclusions Our study identified a need to 1) increase the availability of supplementation at antenatal clinics and 2) improve education regarding supplementation to include information about the benefits of folic acid and other micronutrients. Implementation research is needed to ascertain whether increasing supply and improving education could increase utilization of supplementation during pregnancy, with the ultimate goal of improving maternal and infant outcomes.

Abstract Adeno-associated virus-based gene therapy is a promising avenue in heart failure treatment, but has shown limited cardiac virus uptake in humans, requiring new approaches for clinical translation. Using a Yorkshire swine ischemic heart failure model, we demonstrate significant improvement in gene uptake with temporary coronary occlusions assisted by mechanical circulatory support. We first show that mechanical support during coronary artery occlusions prevents hemodynamic deterioration (n = 5 female). Subsequent experiments show that coronary artery occlusions during gene delivery improve gene transduction, while adding coronary sinus occlusion (Stop-flow) further improves gene expression up to >1 million-fold relative to conventional intracoronary infusion. Complete survival during and after delivery (n = 10 female, n = 10 male) further indicates safety of the approach. Improved cardiac gene expression correlates with virus uptake without an increase in extra-cardiac expression. Stop-flow delivery of virus-sized gold nanoparticles exhibits enhanced endothelial adherence and uptake, suggesting a mechanism independent of virus biology. Together, utilizing mechanical support for cardiac gene delivery offers a clinically-applicable strategy for heart failure-targeted therapies.

Antimicrobial resistance (AMR) is a threat to animal and ecosystem health, agriculture, water, and sanitation systems, posing risks not only to human health, but also to society and the systems upon which it depends. Global health governance draws on the One Health (OH) approach to combat AMR. However, the effective implementation of these approaches faces several constraints, including governance and implementation challenges arising from the interconnected nature of AMR with other global health threats, as well as local and structural socioecological factors that affect policy outcomes, that are often overlooked in governance approaches. This article aims to clarify how scientific literature has situated OH-AMR governance responses in relation to six socioecological dimensions: global health threats, broader concerns, governance frameworks, socioeconomic factors, health equity, and environmental justice. Informed by an Urban Political Ecology (UPE) lens and guided by the Critical Interpretive Synthesis (CIS) methodology of Dixon-Woods et al., our critical interpretive synthesis identified 18 articles situating OH-AMR arrangements within these socioecological dimensions. The role of global governance frameworks in shaping state governance arrangements has rarely been the object of analysis in the selected studies. The synthesis highlights the connections between urbanization, AMR risks, global health threats, and broader ecological challenges, calling for a reassessment of current global and state governance approaches. The study also offers a case for the adoption of a UPE lens to address AMR and related global health challenges.

The soybean cyst nematode (SCN; Heterodera glycines) facilitates infection by secreting a repertoire of effector proteins into host cells to establish a permanent feeding site composed of a syncytium of root cells. Among the diverse proteins secreted by the nematode, we were specifically interested in identifying proteases to pursue our goal of engineering decoy substrates that elicit an immune response when cleaved by an SCN protease. We identified a cysteine protease that we named Cysteine Protease 1 (CPR1), which was predicted to be a secreted effector based on transcriptomic data obtained from SCN esophageal gland cells, the presence of a signal peptide, and the lack of transmembrane domains. CPR1 is conserved in all isolates of SCN sequenced to date, suggesting it is critical for virulence. Transient expression of CPR1 in Nicotiana benthamiana leaves suppressed cell death induced by a constitutively active nucleotide binding leucine-rich repeat protein, RPS5, indicating that CPR1 inhibits effector-triggered immunity. CPR1 localizes in part to the mitochondria when expressed in planta. Proximity-based labeling in transgenic soybean roots, co-immunoprecipitation, and cleavage assays identified a branched-chain amino acid aminotransferase from soybean (GmBCAT1) as a substrate of CPR1. Consistent with this, GmBCAT1 also localizes to mitochondria. Silencing of the CPR1 transcript in the nematode reduced penetration frequency in soybean roots, while the expression of CPR1 in soybean roots enhanced susceptibility. Our data demonstrates that CPR1 is a conserved effector protease with a direct target in soybean roots, highlighting it as a promising candidate for decoy engineering. [Figure: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Abstract Healthy aging often entails a decline in cognitive and motor functions, affecting independence and quality of life in older adults. Brain stimulation shows potential to enhance these functions, but studies show variable effects. Previous studies have tried to identify responders and non-responders through correlations between behavioral change and baseline parameters, but results lack generalization to independent cohorts. We propose a method to predict an individual’s likelihood of benefiting from stimulation, based on baseline performance of a sequential motor task. Our results show that individuals with less efficient learning mechanisms benefit from stimulation, while those with optimal learning strategies experience none or even detrimental effects. This differential effect, first identified in a public dataset and replicated here in an independent cohort, was linked to one’s ability to integrate task-relevant information and not age. This study constitutes a further step towards personalized clinical-translational interventions based on brain stimulation.

Abstract Background The elevated incidence of tuberculosis (TB) outbreaks in schools poses a significant challenge to prevention and control efforts in China. The commonality among most outbreaks is the failure to isolate patients at an early stage. Early isolation of TB cases is crucial for reducing the spread of TB within schools. This study aims to quantify the impact of different isolation proportions and durations on the attack rate of TB in schools. It explored the intervention effects of isolation measures in preventing and controlling TB in school settings. The goal is to provide insights that can serve as a reference for reducing the occurrence of TB outbreaks in schools. Methods We collected data from 4 school TB outbreaks. Susceptible-Exposed-Infected-Recovered (SEIR) model was used to fit the collected data and calculate transmissibility. Susceptible-Exposed-Infected-Quarantined-Recovered (SEIQR) model was employed to evaluate the effect of isolation. Effective reproduction numbers and cumulative incidence were used to quantify the transmissibility of TB. Results In the 4 outbreaks, the majority of student cases were distributed in high grades of high school and universities, with a widespread occurrence of significant intervention delays. The median ascending reproduction value for the 4 outbreaks was 18.44 [interquartile range: 15.40-20.11]. Isolating 100% of the patients at the first month could reduce the number of cases by 99.47%, 87.99%, 96.48%, and 99.16%, respectively. Conclusions This study suggests that high schools and universities may represent significant high-risk environments for TB outbreaks. Early detection and isolation of cases are important strategies that can help reduce the risk of TB outbreaks, with observed case reductions of up to 99.47% when implemented promptly.

Abstract The current cholesterol guidelines recommend maintaining low levels of low-density lipoprotein cholesterol (LDL-C) in patients with coronary artery disease (CAD). However, recent studies have suggested that both very low and very high LDL-C levels may be associated with increased mortality in the general population. We utilized data from TriNetX, a global health research network, to investigate the association between LDL-C levels and all-cause mortality in patients with CAD. CAD patients were identified using the International Classification of Diseases, Tenth Revision (ICD-10) diagnosis code and stratified into six LDL-C categories:

Abstract Infectious disease is the result of interactions between host and pathogen and can depend on genetic variations in both. We conduct a genome-to-genome study of paired human and Mycobacterium tuberculosis genomes from a cohort of 1556 tuberculosis patients in Lima, Peru. We identify an association between a human intronic variant (rs3130660, OR = 10.06, 95%CI: 4.87 − 20.77, P = 7.92 × 10−8) in the FLOT1 gene and a subclavaluee of Mtb Lineage 2. In a human macrophage infection model, we observe hosts with the rs3130660-A allele exhibited stronger interferon gene signatures. The interacting strains have altered redox states due to a thioredoxin reductase mutation. We investigate this association in a 2020 cohort of 699 patients recruited during the COVID-19 pandemic. While the prevalence of the interacting strain almost doubled between 2010 and 2020, its infection is not associated with rs3130660 in this recent cohort. These findings suggest a complex interplay among host, pathogen, and environmental factors in tuberculosis dynamics.

Abstract Integrating diverse types of biological data is essential for a holistic understanding of cancer biology, yet it remains challenging due to data heterogeneity, complexity, and sparsity. Addressing this, our study introduces an unsupervised deep learning model, MOSA (Multi-Omic Synthetic Augmentation), specifically designed to integrate and augment the Cancer Dependency Map (DepMap). Harnessing orthogonal multi-omic information, this model successfully generates molecular and phenotypic profiles, resulting in an increase of 32.7% in the number of multi-omic profiles and thereby generating a complete DepMap for 1523 cancer cell lines. The synthetically enhanced data increases statistical power, uncovering less studied mechanisms associated with drug resistance, and refines the identification of genetic associations and clustering of cancer cell lines. By applying SHapley Additive exPlanations (SHAP) for model interpretation, MOSA reveals multi-omic features essential for cell clustering and biomarker identification related to drug and gene dependencies. This understanding is crucial for developing much-needed effective strategies to prioritize cancer targets.

Abstract Background The rapid establishment and persistence of latent HIV-1 reservoirs is one of the main obstacles towards an HIV cure. While antiretroviral therapy supresses viral replication, it does not eradicate the latent reservoir of HIV-1-infected cells. Recent evidence suggests that the human microbiome, particularly the gut microbiome, may have the potential to modulate the HIV-1 reservoir. However, literature is limited and the exact mechanisms underlying the role of the microbiome in HIV immunity and potential regulation of the viral reservoir remain poorly understood. Results Here, we review updated knowledge on the associations between the human microbiome and HIV reservoir across different anatomical sites, including the gut, the lungs and blood. We provide an overview of the predominant taxa associated with prominent microbiome changes in the context of HIV infection. Based on the current evidence, we summarize the main study findings, with specific focus on consistent bacterial and related byproduct associations. Specifically, we address the contribution of immune activation and inflammatory signatures on HIV-1 persistence. Furthermore, we discuss possible scenarios by which bacterial-associated inflammatory mediators, related metabolites and host immune signatures may modulate the HIV reservoir size. Finally, we speculate on potential implications of microbiome-based therapeutics for future HIV-1 cure strategies, highlighting challenges and limitations inherent in this research field. Conclusions Despite recent advances, this review underscores the need for further research to deepen the understanding of the complex interplay between the human microbiome and HIV reservoir. Further integrative multi-omics assessments and functional studies are crucial to test the outlined hypothesis and to identify potential therapeutic targets ultimately able to achieve an effective cure for HIV.

Abstract Background Prolactin, a hormone produced by the pituitary gland, regulates breast development and may contribute to breast cancer etiology. However, most epidemiologic studies of prolactin and breast cancer have been restricted to single, often small, study samples with limited exploration of effect modification. Methods The Biomarkers in Breast Cancer Risk Prediction consortium includes 8,279 postmenopausal women sampled from four prospective cohort studies, of whom 3,441 were diagnosed with invasive breast cancer after enrollment. Prolactin concentrations were measured for all study participants on plasma samples collected when all women were postmenopausal and before any breast cancer diagnosis using ELISA assays. Pooled, unconditional logistic regression models, adjusted for confounders, estimated odd ratios (OR) for associations of prolactin and postmenopausal breast cancer risk overall and stratified by breast cancer risk factors. Results Higher plasma prolactin concentrations were positively associated with postmenopausal breast cancer risk (> 13.2 ng/mL vs. 13.2 ng/mL vs.

Objective: Poorly differentiated thyroid carcinomas (PDTCs) are rare and aggressive head and neck malignancies with a poor prognosis. Systemic treatment for incurable PDTC consists of multi-kinase inhibitors (MKIs) based on extrapolation from the experience with radioiodine refractory differentiated thyroid cancer (DTC). Cabozantinib is an approved second-line MKI therapy for DTC, but there are limited data regarding the safety and efficacy of cabozantinib for PDTC. Methods: We conducted a single-institution, retrospective analysis of patients with PDTC who received cabozantinib in any line of therapy. Baseline demographics, disease characteristics, treatment history, toxicity, and clinical outcomes were abstracted from the electronic medical record. Median progression-free survival (PFS) and overall survival (OS) were primary endpoints and estimated using Kaplan–Meier methodology. Results: Seven patients with PDTC who received cabozantinib were included. 4/7 (57%) patients had a partial response to cabozantinib, while 2/7 (29%) had stable disease (SD) as their best response. The median time on treatment for cabozantinib was 10.53 months. The median PFS from the start of cabozantinib was 12.9 months, and median OS was 14.21 months. Most adverse events to treatment (5/6) were low grade. Two (29%) patients were alive at the date of the last follow-up. Conclusion: Cabozantinib is an effective and reasonably well-tolerated treatment option for patients with PDTC. Prospective studies are needed to further investigate the role of cabozantinib in the treatment of PDTC, alone and in combination with other agents, including checkpoint inhibitors.

Abstract Background Crimean-Congo haemorrhagic fever (CCHF) is a lethal acute viral zoonosis with a case fatality rate of 5–50%. Due to the potential of human-to human transmission of the disease, healthcare workers (HCWs) are at risk of occupational exposure to CCHF virus. Little is known about CCHF virus route of transmission and risks in Iranian HCWs. Therefore this study was designed to identify the routes of exposure to the CCHF virus among Iranian HCWs. Methods From Oct 2000 to Feb 2023, 96 CCHF suspected healthcare workers referred to national reference laboratory were tested for CCHF virus infection by the use of RT-PCR and IgM Capture Enzyme-Linked Immunosorbent Assay (MAC-ELISA) and exposure history of cases were investigated to determine the CCHF virus routes of transmission in nosocomial settings. Results Twelve CCHF confirmed cases were identified including seven nurses and five physicians, with the median age of 32.5 years (range 23–53 years) and the median incubation period of 6.8 days (range from 1 to 22 days). None of the cases reported a history of tick bite or close contact with tissues or animal blood. The cases were from Razavi Khorasan (seven cases), Sistan and Baluchistan (two cases), Isfahan (one case), South Khorasan (one case) and Fars (one case). Percutaneous exposure (needle stick) (three cases), mucosal exposure (blood splash in to face) (three cases) and skin contact with blood (three cases) constituted the most prevalent routes of transmission. Since 2013, no CCHF cases have been identified among Iranian HCWs. Conclusions In healthcare settings, physicians and nurses are at risk of nosocomial CCHF virus infection. The routes of transmission mainly include direct exposures via needle-stick, mucosal or direct contact with the skin to infected blood. Continuous education and implementation of infection prevention and control measures are key factors to minimize the incidence of healthcare related CCHF.

Abstract The Arenaviridae family of segmented RNA viruses contains nearly 70 species with several associated with fatal haemorrhagic fevers, including Lassa, Lujo and Junin viruses. Lymphocytic choriomeningitis arenavirus (LCMV) is associated with fatal neurologic disease in humans and additionally represents a tractable model for studying arenavirus biology. Within cultured cells, a high proportion of LCMV spread is between directly neighbouring cells, suggesting infectivity may pass through intercellular connections, bypassing the canonical extracellular route involving egress from the plasma membrane. Consistent with this, we visualized abundant actin- and tubulin-rich connections conjoining LCMV-infected and uninfected cells within cultures, resembling tunnelling nanotubes (TNTs). Within these TNT-like connections, confocal and STED microscopy identified puncta containing the major structural components of LCMV virions alongside genomic RNA, consistent with intercellular transit of assembled virions or ribonucleoprotein genome segments. Blocking the extracellular route of infection by adding potent LCMV neutralising antibody M28 to supernatants during infection revealed around 50% of LCMV transmission was via intercellular connections. These results show arenaviruses transmission is more complex than previously thought involving both extracellular and intercellular routes.

Abstract A combination of multiple genetic and environmental factors appear to be required to trigger the onset of amyotrophic lateral sclerosis (ALS). Early life environmental exposures have been reported to be risk factors for a variety of adult-onset diseases, so we used data from an online international ALS case–control questionnaire to estimate whether any of these could be risk factors for the clinical onset of ALS. Responses were obtained from 1,049 people aged 40 years or more, 568 with ALS and 481 controls. People with ALS were more likely to have been born and lived longer in a country area than in a city area, to have younger parents, and to have lower educational attainment and fewer years of education. No ALS-control differences were found in sibling numbers, birth order, adult height, birth weight, parent smoking, Cesarean delivery, or age of starting smoking. In conclusion, early life events and conditions may be part of a group of polyenvironmental risk factors that act together with polygenetic variants to trigger the onset of ALS. Reducing exposure to adverse environmental factors in early life could help to lower the risk of later developing ALS.

Abstract Altered hepatic glucose fluxes are critical during the pathogenesis of type 2 diabetes. G protein-coupled receptors represent important regulators of hepatic glucose production. Recent studies have shown that hepatocytes express GPCRs that can couple to G12/13, a subfamily of heterotrimeric G proteins that has attracted relatively little attention in the past. Here we show, by analyzing several mutant mouse strains, that selective activation of hepatocyte G12/13 signaling leads to pronounced hyperglycemia and that this effect involves the stimulation of the ROCK1-JNK signaling cascade. Using both mouse and human hepatocytes, we also show that activation of endogenous sphingosine-1-phosphate type 1 receptors strongly promotes glucose release in a G12/13-dependent fashion. Studies with human liver samples indicate that hepatic GNA12 (encoding Gα12) expression levels positively correlate with indices of insulin resistance and impaired glucose homeostasis, consistent with a potential pathophysiological role of enhanced hepatic G12/13 signaling.

Abstract Positional coding along the anterior-posterior axis is regulated by HOX genes, whose 3’ to 5’ expression correlates with location along this axis. The precise utilisation of HOX genes in different human cell types is not fully understood. Here, we use single-cell and spatial-transcriptomics, along with in-situ sequencing, to create a developmental atlas of the human fetal spine. We analyse HOX gene expression across cell types during development, finding that neural-crest derivatives unexpectedly retain the anatomical HOX code of their origin while also adopting the code of their destination. This trend is confirmed across multiple organs. In the axial plane of the spinal cord, we find distinct patterns in the ventral and dorsal domains, providing insights into motor pool organisation and loss of collinearity in HOXB genes. Our findings shed new light on HOX gene expression in the developing spine, highlighting a HOX gene ‘source code’ in neural-crest cell derivatives.

Abstract Harnessing quantum correlations can enable sensing beyond classical precision limits, with the realization of such sensors poised for transformative impacts across science and engineering. Real devices, however, face the accumulated impacts of noise and architecture constraints, making the design and success of practical quantum sensors challenging. Numerical and theoretical frameworks to optimize and analyze sensing protocols in their entirety are thus crucial for translating quantum advantage into widespread practice. Here, we present an end-to-end variational framework for quantum sensing protocols, where parameterized quantum circuits and neural networks form trainable, adaptive models for quantum sensor dynamics and estimation, respectively. The framework is general and can be adapted towards arbitrary qubit architectures, as we demonstrate with experimentally-relevant ansätze for trapped-ion and photonic systems, and enables to directly quantify the impacts that noise and finite data sampling. End-to-end variational approaches can thus underpin powerful design and analysis tools for practical quantum sensing advantage.

Daily vitamin B12 (VB12) requirements of humans can naturally be fulfilled by animal product consumption, especially products from ruminants because of bacteria dwelling in their rumen. Indeed, only bacteria can synthesize this vitamin. Milk is hence an excellent source of VB12. This cross-sectional study was undertaken to unravel factors, such as genetic variation, diet and cow characteristics, and milk production, explaining the large variation in milk VB12 concentration among cows by using an integrative approach. Milk samples from 2 consecutive milkings were collected from 3,533 Canadian Holstein cows (1,239 first, 932 second, and 1,362 third and more lactations) located in 99 herds with various feeding management. For the purpose of genetic variation analysis, pedigrees were traced back for 3 complete generations for each sire and dam. A total of 10,021 identities were used in the subsequent genetic analyses. Milk VB12 averaged 4.2 ng/mL with a range between 0.7 and 9.0 ng/mL. Dietary fiber (NDF from forage, dietary NDF, ADF, and lignin) increased and dietary components related to energy (NFC, starch, NEL, and percentage of concentrate) decreased VB12 in milk. Milk VB12 varied with DIM, with a similar pattern as milk fat and protein concentration lactation curves. Milk VB12 increased as age at calving increased. When disregarding the herd variance, the heritability value was 0.37, meaning that milk VB12 can be modified by genetic selection. The final model including factors related to the diet, animal characteristics and milk productivity, and genetic variation explained 79% (pseudo-R2) of the milk VB12 variation. When excluding the random effect of the cow (i.e., excluding the animal and genetic relationships), the pseudo-R2 dropped to 43%, reinforcing the importance of genetic variation in explaining milk VB12 variation. To our knowledge, the present study is the most comprehensive evaluation of factors affecting milk VB12 variation including the greatest number of cows from various lactation stages.

Abstract Background Essential oils of Cymbopogon citratus and Hyptis suaveolens are known for their insecticidal properties, but remain ineffective against mosquitoes resistant to synthetic insecticides. In order to improve insecticidal properties of these plants, this study aimed to investigate the chemical composition and insecticidal activity against Anopheles gambiae mosquitoes of essential oil obtained by co-distillation of dry leaves of C. citratus and H. suaveolens. Methods Essential oils were extracted by hydrodistillation from dry leaves of C. citratus and H. suaveolens, separately, then from the mixture of the dry leaves of the two plants in mass ratio 50/50. Each pure essential oil and the mixture obtained either by co-distillation or by combining pure essential oils in volume ratio 50/50 were then analysed by GC/MS. All essential oils and Deltamethrin 0.05% (positive control) were tested on two species of mosquitoes of the genus Anopheles gambiae according to the World Health Organization standard methods. Results Essential oil obtained by co-distillation mainly contained piperitone (40.80%), 1,8-cineole (24.64%), p-menth-4(8)-ene (13.20%), limonene (6.09%) and α-pinene (4.73%). However, the mixture of pure essential oils of these two plants mostly contained geranial (20.74%), neral (16.42%), 1,8-cineole (19.79%), sabinene (6.03%) and β-pinene (3.87%). The essential oil of C. citratus mainly contained geranial (41.49%), neral (32.83%), β-myrcene (13.66%) and geraniol (3.49%) while the major constituents of essential oil of H. suaveolens were 1,8-cineole (39.58%), sabinene (12.06%), β-pinene (7.73%), α-terpinolene (6.72%) and (E)-caryophyllene (7.49%). At the dose of 1%, all essential oils, except that of H. suaveolens, induced about 100% of mortality on the sensitive species of An. gambiae. However, on the resistant species at the same dose, the essential oil obtained by co-distillation induced the highest mortality (53.44%). The essential oils of C. citratus, H. suaveolens and the mixture of the two pure essential oils caused respectively 2.47, 15.28 and 18.33% of mortality. The synthetic insecticide caused 100 and 14.84% of mortality respectively on the sensitive and resistant species of An. gambiae. Conclusion Essential oil obtained by co-distillation showed good insecticidal efficacy against a resistant species of An. gambiae and might constitute a new solution to fight against mosquitoes resistant to synthetic insecticides.

Abstract The present investigation aimed to assess the safety of photobiomodulation (PBM) on the oral carcinogenesis process induced by 4NQO, focusing on cell proliferation and apoptosis. Sixty-six Wistar rats received systemic 4NQO for 12 (n = 33) and 20 weeks (n = 33), divided into Control group, PBM 0.3 J, and PBM 1 J. Applications for PBM occurred three times a week. At weeks 12 and 20, the animals were euthanized. The immunoreactivity for anti-ROS1 and anti-p53 antibodies was also assessed. Statistical analysis was assessed by multiple t-tests, Kruskal-Wallis, and Spearman’s correlation. At 12 weeks, PBM 1 J group had nodular lesions, distinct from control and PBM 0.3 J groups (p = 0.005). At 20 weeks, nodular lesions were common in control and PBM 0.3 J groups. Histopathological characteristics did not significantly differ between groups at 12 (p = 0.30) and 20 weeks (p = 0.58). Epithelial dysplasia (n = 21) was common at 12 weeks. After 20 weeks, most of the cases revealed squamous cell carcinoma (n = 24). No differences were observed in the immunostaining of p53 and ROS1 among the control and experimental groups and there was no correlation of these proteins with clinicopathological data. During the carcinogenesis process, the PBM did not modify the development of oral lesions and the expression of proliferative and apoptosis proteins.

Abstract Objective Lower socioeconomic status (SES) is a risk factor for poorer pain-related outcomes. Further, the neighborhood environments of disadvantaged communities can create a milieu of increased stress and deprivation that adversely affects pain-related and other health outcomes. Socioenvironmental variables such as the Area Deprivation Index, which ranks neighborhoods based on socioeconomic factors could be used to capture environmental aspects associated with poor pain outcomes. However, it is unclear whether the ADI could be used as a risk assessment tool in addition to individual-level SES. Methods The current study investigated whether neighborhood-level disadvantage impacts knee pain-related outcomes above sociodemographic measures. Participants were 188 community-dwelling adults who self-identified as non-Hispanic Black or non-Hispanic White and reported knee pain. Area Deprivation Index (ADI; measure of neighborhood-level disadvantage) state deciles were derived for each participant. Participants reported educational attainment and annual household income as measures of SES, and completed several measures of pain and function: Short-form McGill Pain Questionnaire, Western Ontario and McMaster Universities Osteoarthritis Index, and Graded Chronic Pain Scale were completed, and movement-evoked pain was assessed following the Short Physical Performance Battery. Hierarchical linear regression analyses were used to assess whether environmental and sociodemographic measures (i.e., ADI 80/20 [80% least disadvantaged and 20% most disadvantaged]; education/income, race) were associated with pain-related clinical outcomes. Results Living in the most deprived neighborhood was associated with poorer clinical knee pain-related outcomes compared to living in less deprived neighborhoods (ps

Abstract Background Research highlights the intense physiological demands of thoroughbred racing on jockeys, with elevated heart rates and substantial oxygen uptake, confirming the rigorous physical nature of the sport, however, the cardiovascular changes resulting from the physical demands of thoroughbred racing remain unexplored in Australian jockeys. Therefore, the objective of this study was to compare measures of cardiac structure and function of professional Australian jockeys to that of the general population and to determine if there are differences in heart structure and function detected using echocardiography. Methods Forty-six jockeys and thirty-three participants from the general population underwent two-dimensional echocardiography, which included all standard views and measurements. Each measurement was compared between groups using a Mann-Whitney U test. Results Groups were matched for age (jockeys (35 ± 12 years) and controls (36 ± 13 years)). Jockeys were shorter (1.64 ± 0.07 m vs. 1.75 ± 0.09 m, p

Background: Repatriation of ST-segment elevation myocardial infarction (STEMI) patients after primary percutaneous coronary intervention (PPCI) is common in regional health care programs. We examined the short- and long-term safety of early repatriation after PPCI in stable STEMI patients. Methods: Consecutive stable STEMI patients undergoing PPCI between 2016 to 2018 in the Fraser Health Authority were included. Outcomes were compared between early and nonrepatriated cohorts. Co-primary outcomes were a composite of death, myocardial infarction, congestive heart failure, and stroke at 30 days and 1 year. Logistic regression analyses were performed to determine association between early repatriation and outcomes, and to assess impact of transfer to cardiologist- vs internist-based care centres. Results: A total of 788 patients were included, with 62% being repatriated early. Primary composite and individual outcomes rates were similar between both cohorts. Early repatriation was not an independent predictor of 30-day (odds ratio [OR] 0.93, 95% confidence interval [CI] 0.50-1.72; P = 0.82) or 1-year (OR 1.05, 95% CI 0.67-1.65; P = 0.8) primary outcome, or of 30-day (OR 1.35, 95% CI 0.41-4.47, P = 0.63) or 1-year (OR 1.03, 95% CI 0.44-2.40; P = 0.95) mortality. Among early repatriated patients, transfer to cardiologist- vs internist-based care centres was not an independent factor for 30-day (OR 1.07, 95% CI 0.45-2.54; P = 0.87) or 1-year (OR 1.17, 95% 0.55-2.50, P = 0.69) primary outcome. Conclusions: Early repatriation of stable STEMI patients after PPCI appears to be safe based on short- and long-term outcomes, and transfer to internist- vs cardiology-based centres did not affect outcomes. After PPCI, early repatriation allows for redistribution of stable STEMI patients to lower-acuity settings across regional hospitals. RéSUMé: Contexte: Le rapatriement des patients ayant eu un infarctus du myocarde avec élévation du segment ST (STEMI) après une intervention coronarienne percutanée primaire (ICPP) est une pratique courante des programmes régionaux de soins de santé. Nous avons examiné l’innocuité à court et à long terme du rapatriement précoce de patients avec STEMI stables après une ICPP. Méthodologie: Des patients avec STEMI stables ayant subi une ICPP entre 2016 et 2018 dans un centre de la Fraser Health Authority ont été inclus dans l’étude. Les résultats des cohortes rapatriées de façon précoce et non rapatriées ont été comparés. Les paramètres d’évaluation principaux représentaient un critère composite comprenant le décès, un infarctus du myocarde, une insuffisance cardiaque congestive et un AVC après 30 jours et après 1 an. Des analyses de régression logistique ont été réalisées pour déterminer le lien entre le rapatriement précoce des patients et les résultats ainsi que pour évaluer l’incidence du transfert de centres de cardiologie vers des centres de médecine interne. Résultats: L’étude a porté sur 788 patients au total, dont 62 % avaient été rapatriés de façon précoce. La fréquence des paramètres d’évaluation principaux pour le critère composite et les critères individuels était comparable entre les deux cohortes. Le rapatriement précoce n’était pas un facteur prédictif indépendant du paramètre d’évaluation principal composite à 30 jours (rapport de cotes [RC] 0,93, intervalle de confiance [IC] à 95 % 0,50-1,72; p = 0,82) ou à 1 an (RC 1,05, IC à 95 % 0,67-1,65; p = 0,8), ni de la mortalité à 30 jours (RC 1,35, IC à 95 % 0,41-4,47, p = 0,63) ou à 1 an (RC 1,03, IC à 95 % 0,44-2,40; p = 0,95). Dans le cas des patients rapatriés de façon précoce, le transfert d’un centre de cardiologie à un centre de médecine interne n’était pas un facteur prédictif indépendant du paramètre d’évaluation principal composé à 30 jours (RC 1,07, IC à 95 % 0,45-2,54; p = 0,87) ou à 1 an (RC 1,17, IC à 95 % 0,55-2,50, p = 0,69). Conclusions: Le rapatriement précoce des patients avec STEMI stables après une ICPP semble sécuritaire d’après les résultats obtenus à court et à long terme, et le transfert vers un centre de médecine interne par rapport à un centre de cardiologie n’a pas eu d’incidence sur les résultats. Après une ICPP, le rapatriement précoce permet une redistribution des patients avec STEMI stables vers des hôpitaux de soins actifs régionaux.

Magnesium (Mg) – based alloys are becoming attractive materials for medical applications as temporary bone implants for support of fracture healing, e.g. as a suture anchor. Due to their mechanical properties and biocompatibility, they may replace titanium or stainless-steel implants, commonly used in orthopedic field. Nevertheless, patient safety has to be assured by finding a long-term balance between metal degradation, osseointegration, bone ultrastructure adaptation and element distribution in organs. In order to determine the implant behavior and its influence on bone and tissues, we investigated two Mg alloys with gadolinium contents of 5 and 10 wt percent in comparison to permanent materials titanium and polyether ether ketone. The implants were present in rat tibia for 10, 20 and 32 weeks before sacrifice of the animal. Synchrotron radiation-based micro computed tomography enables the distinction of features like residual metal, degradation layer and bone structure. Additionally, X-ray diffraction and X-ray fluorescence yield information on parameters describing the bone ultrastructure and elemental composition at the bone-to-implant interface. Finally, with element specific mass spectrometry, the elements and their accumulation in the main organs and tissues are traced. The results show that Mg-xGd implants degrade in vivo under the formation of a stable degradation layer with bone remodeling similar to that of Ti after 10 weeks. No accumulation of Mg and Gd was observed in selected organs, except for the interfacial bone after 8 months of healing. Thus, we confirm that Mg-5Gd and Mg-10Gd are suitable material choices for bone implants.

The mosaic of plant stands in central Cameroon is home to nearly 100,000 sq. km of semi-deciduous moist, dense forests and grassy and shrubby savannahs. On the southern part of this area, at the confluence of Mbam and Sanaga rivers, we are witnessing a dynamic to the advantage of forests because of both natural and human factors. While the natural factors have already been well documented, the effects of the human activities need to be better studied. The present contribution has for objective to understand how the actions of peasant societies contribute to the construction of landscapes and particularly to the creation of forests in detriment of savannahs. It is question to determine the stages and mechanisms of this forest conquest which begins with the occurrence of groves and patches of forest in savannahs. The methodology uses botanical surveys and interviews with the population. Primarily linked to security, the concerns responsible for this landscape dynamics then became economic and now land-related. Originally planted and used around villages as a defensive hedge in the 19th century in the backdrop of tribal wars, the tree was thereafter used as firebreak and windbreak around houses and as support for agroforestry, for example by providing a shade for the cultivation of cocoa. It is also henceforth planted to signal the appropriation of a space. The combination of these factors leads to an afforestation of the savannah through groves surrounding huts, post-cultural groves and agroforestry groves.

Norovirus is the leading cause of acute gastroenteritis (AGE) worldwide. Norovirus outbreaks at military facilities can cause loss of training and working days and increased healthcare utilization, affecting force readiness. During 2013–2023, we enrolled 2,304 US military recruits from 4 basic training facilities to investigate AGE outbreaks among this population. Among enrollees, we detected norovirus in 433 (18.8%) AGE cases, and norovirus caused 49 AGE outbreaks during our longitudinal study. On average, each norovirus case-patient missed 1.2 training days due to illness, and 6.2% required infusion care. Whole-genome sequencing of selected samples from each outbreak produced full-length genomes (6,989–7,787 bp) for 39 samples. Norovirus GII.4 Sydney was the most (12/39, 30.8%) identified genotype over the study period. Phylogenetic and comparative genomic analyses revealed that several outbreak strains were responsible for causing >1 outbreak, even across different training sites. Our findings can inform infection control practices at military installations and overall norovirus vaccine development.

Aotearoa New Zealand's aquatic ecosystems are declining despite widespread awareness of mitigation needs. This study employs storytelling to address this issue, testing the role of the messenger in encouraging freshwater restoration in rural catchment communities. We quantified peer-to-peer knowledge exchange on three cognitive processes (retention and extraction of information, motivation to reproduce modelled restoration behaviour, and recall of acquired information), using ArcGIS® ‘StoryMaps’. We created two restoration stories; one told through the voice of a respected catchment group member known for leadership, and one through a collective catchment group voice. We surveyed freshwater community members (N = 82) before and after reading the stories, and one month later, and found that participants reading either catchment restoration story (1) accepted both the catchment collective and the respected individual member as a trusted source, and could therefore relate to either, and (2) thought the story was informative and contained new details, independent of the time span land holders have been actively restoring. While our study found no significant differences between individual or collective storytellers, it confirms the value of trusted messengers as restoration knowledge brokers in rural catchment communities, a critical step in value-led freshwater restoration at large scales.

BACKGROUND: Studies show the potential deterioration of brain vascularization and probable involvement of hypertension in Alzheimer disease (AD). OBJECTIVE: The objective was to evaluate the potential impact of hypertension on cerebral vascular flows in a sample of Alzheimer's patients. METHODS: 19 patients with AD, including 10 with hypertension (aHT+) and 9 without hypertension (aHT-) were recruited. They underwent clinical evaluation and phase-contrast MRI protocol for flow assessment. Cerebral arterial flow distributions were evaluated using kurtosis and skewness indices at the intracranial and extracranial levels. RESULTS: No significant differences were found in the mean arterial flow, pulse flow and kurtosis between the levels in the AD aHT+ population. There was a significant difference in skewness between extra- and intracranial levels (p = 0.01). No significant differences were found in the mean arterial flow between the levels in the AD aHT- population. A significant difference was observed in the pulse flow (p = 0.03), kurtosis (p = 0.02) and skewness (p = 0.008) between the levels. At the extracranial level we did not find any significant differences in the mean arterial flow, pulse flow or skewness between aHT+ and aHT-. There was a significant difference in kurtosis at the extracranial level between the aHT+ and aHT- (p = 0.03). At the intracranial level, there were no significant differences in all parameters. CONCLUSION: Results showed a difference between cerebral vasculature in AD for aHT+ and aHT- groups. This is probably related to the loss of arterial compliance induced by the degradation of the vascular system.

Hemibiotrophic fungi in the genus Colletotrichum employ a biotrophic phase to invade host epidermal cells followed by a necrotrophic phase to spread through neighboring mesophyll and epidermal cells. We used serial block face-scanning electron microscopy (SBF-SEM) to compare subcellular changes that occur in Medicago sativa (alfalfa) cotyledons during infection by Colletotrichum destructivum (compatible on M. sativa) and C. higginsianum (incompatible on M. sativa). Three-dimensional reconstruction of serial images revealed that alfalfa epidermal cells infected with C. destructivum undergo massive cytological changes during the first 60 h following inoculation to accommodate extensive intracellular hyphal growth. Conversely, inoculation with the incompatible species C. higginsianum resulted in no successful penetration events and frequent formation of papilla-like structures and cytoplasmic aggregates beneath attempted fungal penetration sites. Further analysis of the incompatible interaction using focused ion beam-scanning electron microscopy (FIB-SEM) revealed the formation of large multivesicular body-like structures that appeared spherical and were not visible in compatible interactions. These structures often fused with the host plasma membrane, giving rise to paramural bodies that appeared to be releasing extracellular vesicles (EVs). Isolation of EVs from the apoplastic space of alfalfa leaves at 60 h postinoculation showed significantly more vesicles secreted from alfalfa infected with incompatible fungus compared with compatible fungus, which in turn was more than produced by noninfected plants. Thus, the increased frequency of paramural bodies during incompatible interactions correlated with an increase in EV quantity in apoplastic wash fluids. Together, these results suggest that EVs and paramural bodies contribute to immunity during pathogen attack in alfalfa. [Figure: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Abstract Background Glycosphingolipids (GSLs) are membrane lipids composed of a ceramide backbone linked to a glycan moiety. Ganglioside biosynthesis is a part of the GSL metabolism, which involves sequential reactions catalyzed by specific enzymes that in part have a poor substrate specificity. GSLs are deregulated in cancer, thus playing a role as potential biomarkers for personalized therapy or subtype classification. However, the analysis of GSL profiles is complex and requires dedicated technologies, that are currently not included in the commonly utilized high-throughput assays adopted in contexts such as molecular tumor boards. Methods In this study, we developed a method to discriminate the enzyme activity among the four series of the ganglioside metabolism pathway by incorporating transcriptome data and topological information of the metabolic network. We introduced three adjustment options for reaction activity scores (RAS) and demonstrated their application in both exploratory and comparative analyses by applying the method on neuroblastic tumors (NTs), encompassing neuroblastoma (NB), ganglioneuroblastoma (GNB), and ganglioneuroma (GN). Furthermore, we interpreted the results in the context of earlier published GSL measurements in the same tumors. Results By adjusting RAS values using a weighting scheme based on network topology and transition probabilities (TPs), the individual series of ganglioside metabolism can be differentiated, enabling a refined analysis of the GSL profile in NT entities. Notably, the adjustment method we propose reveals the differential engagement of the ganglioside series between NB and GNB. Moreover, MYCN gene expression, a well-known prognostic marker in NTs, appears to correlate with the expression of therapeutically relevant gangliosides, such as GD2. Using unsupervised learning, we identified subclusters within NB based on altered GSL metabolism. Conclusion Our study demonstrates the utility of adjusting RAS values in discriminating ganglioside metabolism subtypes, highlighting the potential for identifying novel cancer subgroups based on sphingolipid profiles. These findings contribute to a better understanding of ganglioside dysregulation in NT and may have implications for stratification and targeted therapeutic strategies in these tumors and other tumor entities with a deregulated GSL metabolism.

Abstract Background It is estimated that 1 in 4 stroke survivors will experience a second stroke. Educating patients about risk factors for stroke and a generally healthier lifestyle may help prevent recurrent strokes, which are a burden on society and the healthcare system. The goals of this paper were to investigate the estimated level of knowledge of stroke patients regarding their disease, the methods of information commonly used in clinical practice, the topics that should be included in an educational program aimed at improving health knowledge among stroke survivors, and how such a program could be delivered with the help of technology-based education (i.e., information delivered by digital platforms such as smartphones or rehabilitation technologies). Methods We performed a survey among health professionals working with stroke patients in Switzerland. Results 161 health professionals of different backgrounds took part in the survey, and 94 completed it. According to the results, only 33% of healthcare professionals thought that patients were well informed about stroke one month after stroke onset. These findings suggest that there is room for improvement in how stroke patients are educated about stroke, risk factors, and prevention. Additionally, it was highlighted that technology is not commonly used in clinical practice to support patients’ education, although this is an acceptable method for healthcare professionals. The results also helped to identify key topics to be included in an educational program and recommendations for implementing such a program in rehabilitation technologies. Conclusions This work allowed gaining more insight into healthcare professionals’ opinions on the potential of technology-based education and key aspects to consider when implementing it to support health and prevention knowledge after stroke.

Abstract In recent years, the building sector has become more conscious of sustainability, and the use of phase change materials (PCMs) in concrete has gained more attraction. Integration of PCM with building facades is a successful method to reduce energy consumption and improve human comfort. However, no single PCM can work in an all-weather scenario. Hence, in this research work, an attempt is made to select a suitable PCM for Chennai city, India, and this methodology can be employed at any geographical location. The PCM tile is designed by including certain features to increase the thermal conductivity of the PCM zone. The optimum design of the PCM tile is achieved through multi-objective optimization techniques. L27 orthogonal array is employed, and all the tests were conducted through validated numerical simulation. Redesigned PCM tile includes a PCM layer of 2 cm thickness with a 10% mix of copper nanoparticles covered by plaster. Redesigned PCM tile reduces the peak indoor temperature by 6.62℃ compared with conventional roof systems.

Abstract Development of new vaccines tailored for difficult-to-target diseases is hampered by a lack of diverse adjuvants for human use, and none of the currently available adjuvants induce Th17 cells. Here, we develop a liposomal adjuvant, CAF®10b, that incorporates Mincle and Toll-like receptor 9 agonists. In parallel mouse and non-human primate studies comparing to CAF® adjuvants already in clinical trials, we report species-specific effects of adjuvant composition on the quality and magnitude of the responses. When combined with antigen, CAF®10b induces Th1 and Th17 responses and protection against a pulmonary infection with Mycobacterium tuberculosis in mice. In non-human primates, CAF®10b induces higher Th1 responses and robust Th17 responses detectable after six months, and systemic and pulmonary Th1 and Th17 recall responses, in a sterile model of local recall. Overall, CAF®10b drives robust memory antibody, Th1 and Th17 vaccine-responses via a non-mucosal immunization route across both rodent and primate species.

Abstract Creativity is typically operationalized as divergent thinking (DT) ability, a form of higher-order cognition which relies on memory, attention, and other component processes. Despite recent advances, creativity neuroscience lacks a unified framework to model its complexity across neural, genetic, and cognitive scales. Using task-based fMRI from two independent samples and MVPA, we identified a neural pattern that predicts DT, validated through cognitive decoding, genetic data, and large-scale resting-state fMRI. Our findings reveal that DT neural patterns span brain regions associated with diverse cognitive functions, with positive weights in the default mode and frontoparietal control networks and negative weights in the visual network. The high correlation with the primary gradient of functional connectivity suggests that DT involves extensive integration from concrete sensory information to abstract, higher-level cognition, distinguishing it from other advanced cognitive functions. Moreover, neurobiological analyses show that the DT pattern is positively correlated with dopamine-related neurotransmitters and genes influencing neurotransmitter release, advancing the neurobiological understanding of creativity.

Abstract Tropospheric ozone impacts health, climate, and ecosystems. Effective ozone mitigation policies are challenged by limited quantitative understanding of national versus transboundary contributions to surface ozone. This study uses a chemical transport model with a source apportionment algorithm to analyze ozone contributions across Europe from 2015 to 2017 during peak ozone season. We quantify country-level ozone production and imported ozone, distinguishing contributions from 35 European countries, neighboring countries, seas, and hemispheric influences. Results show substantial contributions from outside the 35 European countries, with hemispheric contributions playing a significant role. European contributions are crucial during high ozone episodes, especially from Germany, France, Italy, the UK, Poland, and Spain. Spain, northern Italy, and northwest France are identified as areas where national precursor reductions would be more effective in improving national air quality. Furthermore, 25 of the 35 European countries studied are net importers of cumulative ozone mass, with the Netherlands, Belgium, and the UK acting as major exporters. These findings highlight the need for comprehensive air quality policies and cross-border cooperation.

Abstract Objective This study used real-world observational data to compare profiles of patients receiving different first-line treatment for hormone receptor positive (ER+), HER2 negative, metastatic breast cancer (MBC): CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) versus ET alone. Method From a nationwide electronic health record-derived Flatiron Health de-identified database including 280 US cancer clinics, we identified patients with hormone receptor positive, HER2 negative, metastatic breast cancer receiving 1st -line therapy with ET alone or CDK4/6i plus ET between February 2015 and November 2021. Patient sociodemographic status, MBC treatment regimen and outcomes were the focus of this analysis. Patient characteristics were compared using t-tests and chi-square tests. Logistic regression analysis was performed to examine the association of patient characteristics with the likelihood of receiving 1st -line CDK4/6i plus ET vs. ET alone. Kaplan-Meier method and Cox proportional hazards were used to test the impact of 1st -line treatment regimen on real-world progression-free survival (PFS) and overall survival (OS). Baseline characteristics were balanced using inverse probability weighting (IPW). Results The study population included 3,917 patients receiving CDK4/6i plus ET (n = 2170) and ET alone (n = 1747) for their MBC. Compared to patients receiving ET alone, those receiving CDK4/6i plus ET were younger (mean age 66.8 vs. 68.6, p

Abstract Background NEK10, a serine/threonine/tyrosine kinase belonging to the NEK (NIMA-related kinases) family, has been associated with diverse cellular processes. However, no specific target pathways have been identified. Our previous work knocking down NEK10 in HeLa cells suggested a functional association with mitochondria, as we observed altered mitochondrial morphology, mitochondrial oxygen consumption, mtDNA integrity, and reactive oxygen species levels. Methods To better understand this association, we studied human HAP1 cells fully knockout for NEK10 and confirmed that NEK10 has an important role in mitochondrial homeostasis. We performed the study of mitochondrial respiration, mitochondrial morphology, mitochondrial mass, and mtDNA analysis. Additionally, we showed proteome and phosphoproteome data of crude mitochondrial fraction of Parental and NEK10 KO cells using liquid chromatography-mass spectrometry (LC–MS/MS). Results In the absence of NEK10 several mitochondrial functions were disturbed. Moreover, proteome and phosphoproteome analyses of mitochondrial fractions showed that NEK10 alters the threonine phosphorylation status of several mitochondrial/endoplasmic reticulum components, including HSP60, NDUFB4, and TOM20. These changes impacted the steady-state levels of a larger group of proteins, preferentially involving respiratory complexes and autophagy pathways. Conclusion We concluded that NEK10 plays a key role in mitochondrial function, possibly by modulating the phosphorylation status of mitochondrial proteins.

Abstract Background Since the implementation of universal antiretroviral therapy, kidney transplantation (K-Tx) has become a valuable option for treatment of end-stage kidney disease for people with HIV (PWH) with similar patient and graft survival as compared to HIV-uninfected patients. Little is known about the hazards and manifestations of infectious disease (ID) events occurring in kidney transplant recipients with HIV. Methods Using linked information collected in the Swiss HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study (STCS), we described in-depth demographical and clinical characteristics of PWH who received a K-Tx since 2008. Further, we performed recurrent time to event analyses to understand whether HIV was an independent risk factor for ID events. Results Overall, 24 PWH with 57 ID events were included in this study (100% match of SHCS to STCS). Of these, 17 (70.8%) patients had at least one ID event: 22 (38.6%) viral (HIV not counted), 18 (31.6%) bacterial, one (1.8%) fungal and 16 (28.1%) probable infections. Most ID events affected the respiratory tract (25, 37.3%) or the urinary tract (13, 19.4%). Pathogen types and infection sites were similar in PWH and a matched control group of HIV-uninfected patients. HIV was not an independent risk factor for ID events (adjusted hazard ratio 0.94, p = 0.9). Conclusion By linking data from two large national Swiss cohorts, we provided in-depth information on ID events in PWH receiving a K-Tx in Switzerland. HIV infection was not associated with an increased hazard for ID events after K-Tx.

Abstract The oxalate-carbonate pathway (OCP) involves degradation of soil oxalate to carbonate. To exploit and manage this natural mineralization of assimilated atmospheric CO2 into stable carbonates, improved understanding of this complex biotransformation process is needed. A strain of oxalate-degrading bacteria, Azospirillum sp. OX-1, was isolated from soil, and its secondary products of calcium oxalate degradation were analyzed and characterized using SEM, XRD, TG/DTG-DTA and FTIR-spectroscopy. The molecular mechanism of calcium oxalate degradation was also analyzed using proteomics. The results showed, for the first time, that OX-1 could not only degrade calcium oxalate to calcium carbonate, but also that the process was accompanied by synthesis of methane. Proteomic analysis demonstrated that OX-1 has a dual enzyme system for calcium oxalate degradation, using formyl-CoA transferase (FRC) and thiamine pyrophosphate (ThDP)-dependent oxalyl-CoA decarboxylase (OXC) to form calcium carbonate. Up-regulated expression of enzymes related to methane synthesis was also detected during calcium oxalate degradation. Since methane is also a potent greenhouse gas, these new results suggest that the utility of exploiting the OCP to reduce atmospheric CO2 must be re-evaluated and that further studies should be conducted to reveal how widespread the methane producing capacity of strain OX-1 is in other bacteria and soil environments.