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Abstract The human microbiome emerges as a promising reservoir for diagnostic markers and therapeutics. Since host-associated microbiomes at various body sites differ and diseases do not occur in isolation, a comprehensive analysis strategy highlighting the full potential of microbiomes should include diverse specimen types and various diseases. To ensure robust data quality and comparability across specimen types and diseases, we employ standardized protocols to generate sequencing data from 1931 prospectively collected specimens, including from saliva, plaque, skin, throat, eye, and stool, with an average sequencing depth of 5.3 gigabases. Collected from 515 patients, these samples yield an average of 3.7 metagenomes per patient. Our results suggest significant microbial variations across diseases and specimen types, including unexpected anatomical sites. We identify 583 unexplored species-level genome bins (SGBs) of which 189 are significantly disease-associated. Of note, the existence of microbial resistance genes in one specimen was indicative of the same resistance genes in other specimens of the same patient. Annotated and previously undescribed SGBs collectively harbor 28,315 potential biosynthetic gene clusters (BGCs), with 1050 significant correlations to diseases. Our combinatorial approach identifies distinct SGBs and BGCs, emphasizing the value of pan-body pan-disease microbiomics as a source for diagnostic and therapeutic strategies.

Abstract Microglia-driven neuroinflammation plays an important role in the development of Alzheimer’s disease. Microglia activation is accompanied by the formation and chronic expression of TLR4 inflammarafts, defined as enlarged and cholesterol-rich lipid rafts serving as an assembly platform for TLR4 dimers and complexes of other inflammatory receptors. The secreted apoA-I binding protein (APOA1BP or AIBP) binds TLR4 and selectively targets cholesterol depletion machinery to TLR4 inflammaraft-expressing inflammatory, but not homeostatic microglia. Here we demonstrated that amyloid-beta (Aβ) induced formation of TLR4 inflammarafts in microglia in vitro and in the brain of APP/PS1 mice. Mitochondria in Apoa1bp −/− APP/PS1 microglia were hyperbranched and cupped, which was accompanied by increased reactive oxygen species and the dilated endoplasmic reticulum. The size and number of Aβ plaques and neuronal cell death were significantly increased, and the animal survival was decreased in Apoa1bp −/− APP/PS1 compared to APP/PS1 female mice. These results suggest that AIBP exerts control of TLR4 inflammarafts and mitochondrial dynamics in microglia and plays a protective role in Alzheimer’s disease associated oxidative stress and neurodegeneration.

Abstract Background The post-COVID syndrome (PCS) has a large impact on an individual’s daily life. The wide variety of symptoms in PCS patients and the fact that it is still relatively new makes it difficult for general practitioners (GPs) to recognize, diagnose and treat patients with PCS, leading to difficulties in assessing and fulfilling healthcare needs. It is largely unknown what the experiences of Dutch patients and GPs are with PCS and, therefore, we gained insight into the different aspects of living with PCS and the associated healthcare needs. Methods Semi-structured interviews were performed with 13 self-reported PCS patients (varying in sex, age, education, and health literacy) and 6 GPs (varying in gender, age, and type of practice) between January-July 2022. Patients and GPs were most likely unrelated (not in the same practices). The data have been analysed using the Thematic Analysis method. Results Experiences appeared to vary between two types of PCS patients that emerged during the interviews: (1) individuals with good pre-existing health status (PEHS) who are severely affected by PCS and have difficulty recovering and (2) individuals with poorer PEHS whose health became even poorer after COVID-19 infection. The interviews with PCS patients and GPs revealed two main themes, in which the types of patients differed: (1) aspects of living with PCS; individuals with good PEHS mainly experience symptoms when overstimulated, while individuals with poorer PEHS generally feel exhausted continuously. (2) Healthcare experiences; GPs emphasized that individuals with good PEHS seem to benefit from support in distributing their energy by careful planning of daily activities, whereas individuals with poorer PEHS require support in activation. Patients and GPs emphasised the importance of taking patients seriously and acknowledging their symptoms. Finally, the patients interviewed indicated that some GPs doubted the existence of PCS, resulting in insufficient recognition. Conclusion Awareness of the differences in needs and experiences of the two types of PCS patients could contribute to more appropriate care. Acknowledgement of PCS by GPs as a real syndrome is important for patients and plays an important role in coping with or recovering from PCS. A multidisciplinary person-centred approach is important and can be coordinated by a GP.

Abstract Raphid diatoms are one of the few eukaryotes capable of gliding motility, which is remarkably fast and allows for quasi-instantaneous directional reversals. Besides other mechanistic models, it has been suggested that an actomyosin system provides the force for diatom gliding. However, in vivo data on the dynamics of actin and myosin in diatoms are lacking. In this study, we demonstrate that the raphe-associated actin bundles required for diatom movement do not exhibit a directional turnover of subunits and thus their dynamics do not contribute directly to force generation. By phylogenomic analysis, we identified four raphid diatom-specific myosins in Craspedostauros australis (CaMyo51A-D) and investigated their in vivo localization and dynamics through GFP-tagging. Only CaMyo51B-D but not CaMyo51A exhibited coordinated movement during gliding, consistent with a role in force generation. The characterization of raphid diatom-specific myosins lays the foundation for unraveling the molecular mechanisms that underlie the gliding motility of diatoms.

Abstract Background The prevalence of childhood obesity and diabetes continues to rise in the United States (US), especially among minority populations. The objective of the Early Tracking of Childhood Health Determinants (ETCHED) study is to investigate the role of adverse fetal and early-life risk exposures that contribute to the development of childhood obesity and metabolic risk. Methods ETCHED is a longitudinal observational study of American Indian/Alaska Native (AI/AN) and Hispanic pregnant woman and their offspring. Pregnant mothers ≥ 18 years old are enrolled at a large public hospital system in the southwestern US. Enrolled mothers are followed through pregnancy, delivery, and the maternal/offspring dyad will be followed until the child’s 18th birthday. At each maternal visit, questionnaires assessing medical history, diet, physical activity, sleep, perceived stress, and socioeconomic and sociocultural information are obtained. Standard laboratory tests during maternal visits include glycemic measures, lipids, and renal function. Additional bio samples obtained include venous blood samples and cord blood for obesity/metabolic biomarkers and genetic/epigenetic testing, urinalysis, placental tissue for examining functional pathways, breast milk for metabolomics, and stool for metabolites and microbiome analysis. The offspring will have 6 infant/toddler visits at 6–12 weeks, 4 months, 6 months, 18 months, 2 and 3 years respectively. Thereafter, they will undergo comprehensive research visits (major visits) at 4–5 years, 6–9 years, 10–13 years, and 14–17 years. The major visits in children include detailed medical history, anthropometry, developmental assessment, socioeconomic and environmental assessments (food insecurity, family structure, and childcare), feeding and activity, biochemical tests, genetics/epigenetic testing, and ultrasound elastography. Electronic health records will be reviewed for additional clinical information. The primary analysis will constitute estimation of correlation coefficients between continuous variables. The planned study duration in this ongoing study is 23-years. Discussion This is a life course study that that will examine biological and environmental risk factors for obesity and cardiometabolic risk from the intrauterine period to early childhood and adolescence in a population with high-risk of obesity and type 2 diabetes in the United States. The ETCHED study would also provide a unique opportunity to combine multi-omics and clinical data to create novel integrative models to predict the cardiometabolic risk associated with childhood obesity and possibly identify etiopathogenetic mechanisms and future targets of intervention. Trial registration number ClinicalTrials.gov identifier: NCT03481829. Updated July 19, 2024, https://clinicaltrials.gov/study/NCT03481829?cond=ETCHED&rank=1 .

Abstract Background Epilepsy remains a significant public health concern in Tanzania, with affected individuals enduring stigma, whether through actions or perceptions. Myths, misunderstandings, and misconceptions about epilepsy have persisted due to a multitude of factors. Here, we assessed attitudes and perceptions toward epilepsy in Mahenge. Methods A cross-sectional study utilising a mixed-methods approach was undertaken in eight villages in the Ulanga district of Mahenge, integrating a semi-structured questionnaire and focus group discussions (FGDs). The questionnaire involved 778 community members, and 15 FGDs were conducted (seven groups with people with epilepsy and eight without). Descriptive statistics, chi-square, and logistic regression were used for quantitative analysis, while we used NVivo version 14 for thematic analysis of qualitative data. Results Of 778 participants, over half were women (425, 54.6%) with a median age of 41 years (IQR: 30–55) and most had completed primary education (79.9%). The majority of participants were aware of epilepsy (96.8%), yet they displayed low knowledge (51%), negative attitudes (45.5%), and perceptions (42.1%) towards the disorder. A low level of understanding was significantly associated with negative attitudes (Adjusted Odds Ratio [AOR] = 1.89, 95%CI: 1.41–2.53) and perceptions (AOR = 3.22, 95%CI: 2.05–5.04) towards epilepsy. In the qualitative analysis, often hereditary factors and infections were named as causes of epilepsy, along with misconceptions involving witchcraft and divine punishment. There was also a misconception about the contagiousness of epilepsy. Traditional healers were often the initial point of treatment. Epilepsy-related stigma was evident, with individuals with epilepsy facing derogatory labels, social isolation, and barriers to education. Lastly, there was a lack of understanding regarding a possible association between epilepsy and onchocerciasis. Conclusions Despite high awareness of epilepsy, there is insufficient understanding, negative attitudes, and perceptions, including misconceptions and stigma about this neurologic condition. Community-based education programmes are essential for promoting proper healthcare-seeking behaviour and dispelling myths.

Abstract Background Incorporating genomic data into risk prediction has become an increasingly popular approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. Methods Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. Results The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p=0.006), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p

Abstract Background The relationship between the quality of inpatient versus outpatient obstetric postpartum recovery is under-explored. We examined the association between inpatient reported quality of recovery with outpatient global recovery, pain severity, pain interference, anxiety, and depression screening scores postpartum. Methods We conducted a multicenter observational cohort study of women in labor who underwent vaginal, operative vaginal, or intrapartum cesarean birth. Subjects completed baseline assessments of pain, social support, anxiety, and depression in early labor. We assessed the Obstetric Quality of Recovery-10 (ObsQoR-10) on the day of discharge and the ObsQoR-10, Global Health Scale (GHVAS; 0–100), Brief Pain Inventory (BPI), and the Edinburgh Postnatal Depression Scale (EPDS) on postpartum day seven. We hypothesized that the ObsQoR-10 scores at discharge would be useful in predicting postpartum day seven measures of recovery and postpartum depression screening scores. Results We consented 558 subjects, 551/558(98%) completed baseline assessments, 400/551(72%) completed the ObsQoR-10 tool, and 344/551(62%) completed an EPDS assessment. Median (1st, 3rd quartile) ObsQoR-10 scores were 78 (63, 90) at discharge and 85 (68,93) on postpartum day seven, (difference of 7 [99% CI 2 to 13], P 86 at discharge had a RR of 1.5 [95% CI 1.2 to 1.8], P

Long-term operation of the supporting surfaces of large-sized parts, in particular tubular units of thermal power plants, leads to the destruction of the contact surfaces. Moisture penetrates into the formed discontinuities, and the vibrations present in the equipment in use rapidly increase the gap, reaching values of 10–15 mm. The authors of this article proposed the application of a composite layer of multimetal 1018 material without performing additional preparatory operations, ensuring the mandatory penetration of the material into the body of the supporting surface. This depth provides additional stability by maintaining boundary conditions. To determine the rational thickness of the composite layer, mathematical modeling of static loading of samples with different thicknesses in a wide range of values (from 2 mm to 12 mm) was performed. It was determined that the effective implementation of the developed technology was possible due to an increase in the load-bearing capacity of the composite material by creating additional grooves, or artificially creating grooves by welding, in the body of the part with a depth of 2.5–3 mm. The optimal excess of the composite was 1.0–1.5 mm. The proposed technology increases the stability of the composite layer up to three times and allows restoration without the use of mechanical treatment. The increase in the maximum stress values was 770 MPa, compared to the standard technology of 205 MPa.

Zoo enclosure design, and housing and husbandry protocols, will always be a compromise between what a species has evolved to do and what is possible to offer in a human-created environment. For some species, behaviours that are commonly performed in the wild may be constrained by husbandry practices that are used for ease or aesthetics or are accepted conventions. As zoos place more emphasis on positive animal welfare states, zoo enclosures should be scrutinised to check that what is provided, in terms of useful space, appropriate replication of habitat features, and maximal potential for natural behaviour performance, is relevant to the species and individuals being housed. For some species, zoos need to grapple with tough questions where the answer may not seem immediately obvious to ensure they are continuously improving standards of care, opportunities for the performance of species-typical behaviours, and advancing the attainment of positive welfare states. Determining the importance of flight, for example, and what this behaviour adds to the quality of life of a zoo-housed bird, is an important question that needs addressing to truly advance aviculture and how we determine bird welfare. This paper provides questions that should be answered and poses measures of what flight means to a bird, to provide evidence for the development and evolution of zoo bird housing. If we can devise some way of asking the animals in our care what they need, we can more firmly support decisions made that surround enclosure design, and housing decisions. Ultimately, this means gathering evidence on whether birds like to fly (e.g., from birds in training or demonstration activities) by applying mixed methods approaches of behavioural analysis, data on wild ecology, qualitative behavioural assessment, and cognitive bias testing to develop a robust suite of tools to address avian welfare considerations. Avian welfare scientists should attempt to define what meaningful flight is (i.e., flight that truly suggests a bird is flying) in order to support guidelines on aviary dimensions, space allowance, and welfare outputs from birds in both flighted and flight-restricted populations, and to determine what is most appropriate for an individual species. Changing the term “best practice” husbandry guidelines to “better practice” husbandry guidelines would instil the importance of regular review and reassessment of housing and management suitability for a species to ensure such care regimes remain appropriate. With an increasingly welfare-savvy public visiting zoos, it is essential that we seek more evidence to support and justify how birds are kept and ultimately use such evidence to enact changes to practices that are shown to infringe on avian welfare.

Abstract Background Immune thrombocytopenia (ITP) is a common cause of severe thrombocytopenia in dogs. The pathogenesis of nonassociative, primary ITP (pITP) appears complex, with ill‐defined thrombopoietic response. Objectives Develop an immunoassay to measure plasma canine thrombopoietin (TPO) concentration and characterize TPO concentrations in dogs with pITP. Animals Forty‐one healthy dogs, 8 dogs in an induced ITP model (3 control, 5 ITP), and 58 pITP dogs. Methods Recombinant canine TPO (rcTPO) was purchased and its identity confirmed by mass spectrometry. Monoclonal antibodies were raised to rcTPO and used to configure a sandwich ELISA using streptavidin‐biotin detection. Assay performance, coefficients of variability, and healthy dog plasma TPO reference interval (RI) were determined, followed by assay of ITP samples. Results Assay dynamic range was 15 pg/mL (lower limit of detection) to 1000 pg/mL TPO, with limit of quantitation of 62 pg/mL. Plasma TPO RI was 0 to 158 pg/mL, with plasma TPO 6000 pg/mL. In contrast, only 2/58 pITP dogs had TPO values above RI. Conclusions and Clinical Importance Plasma TPO concentration is paradoxically low at diagnosis for most dogs with pITP. This finding suggests that ineffective thrombopoiesis contributes to thrombocytopenia in pITP dogs and supports evaluating TPO receptor agonist treatment as used for pITP in humans. The TPO assay provides a new tool to study thrombopoiesis in pITP and other thrombocytopenic syndromes in dogs.

Barley net form net blotch (NFNB) is a destructive foliar disease caused by Pyrenophora teres f. teres. Barley line CIho5791, which harbors the broadly effective chromosome 6H resistance gene Rpt5, displays dominant resistance to P. teres f. teres. To genetically characterize P. teres f. teres avirulence/virulence on the barley line CIho5791, we generated a P. teres f. teres mapping population using a cross between the Moroccan CIho5791-virulent isolate MorSM40-3 and the avirulent reference isolate 0-1. Full genome sequences were generated for 103 progenies. Saturated chromosome-level genetic maps were generated, and quantitative trait locus (QTL) mapping identified two major QTL associated with P. teres f. teres avirulence/virulence on CIho5791. The most significant QTL mapped to chromosome (Ch) 1, where the virulent allele was contributed by MorSM40-3. A second QTL mapped to Ch8; however, this virulent allele was contributed by the avirulent parent 0-1. The Ch1 and Ch8 loci accounted for 27 and 15% of the disease variation, respectively, and the avirulent allele at the Ch1 locus was epistatic over the virulent allele at the Ch8 locus. As a validation, we used a natural P. teres f. teres population in a genome-wide association study that identified the same Ch1 and Ch8 loci. We then generated a new reference quality genome assembly of parental isolate MorSM40-3 with annotation supported by deep transcriptome sequencing of infection time points. The annotation identified candidate genes predicted to encode small, secreted proteins, one or more of which are likely responsible for overcoming the CIho5791 resistance. [Figure: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 “No Rights Reserved” license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law, 2024.

The Flow Country blanket bogs in the counties of Caithness and Sutherland (northern Scotland, UK) harbour internationally important populations of specialist open-bog breeding bird species. However, commercial afforestation carried out in the 1980s, involving the non-native tree species lodgepole pine (Pinus contorta) and sitka spruce (Picea sitchensis) covering over 67,000 hectares (ca. 17 %) of the peatland, has significantly affected bird assemblages within and around the plantations. We conducted a literature review to identify the avian winners and losers resulting from this transformation. Our synthesis of existing findings confirms that afforestation has led to changes in the availability of breeding and foraging habitat, alterations in inter- and intra-specific competition dynamics, and the creation of forest edge effects. Crucially, the open-bog bird assemblages have been largely replaced by woodland specialists and generalists. While 33 species (including five Red-listed Birds of Conservation Concern) are observed to benefit from afforestation, these gains are arguably of lower conservation value than the original open-bog assemblages (27 species including 11 Red-listed species). As a mean proportion of the British population range, the Flow Country has a significantly higher proportion of Amber and Green-listed loser species than winners. Understanding the changes in assemblages is crucial for informing future decisions regarding forest planting and re-planting, particularly in the context of the ongoing dual challenges of climate change and biodiversity loss. Further research is necessary to comprehend the effects of afforestation on populations of waterfowl associated with open water features present in the blanket bog landscape. Given the need for woodland creation, bird conservation would benefit from leaving naturally open habitats intact and siting new woodland in areas that were formerly naturally forested.

Abstract We explore the generalized holographic complexity of odd-dimensional Myers-Perry asymptotically Anti-de Sitter (MP-AdS) black holes with equal angular momenta within the “complexity equals anything” proposal. We begin by determining the codimension-one generalized volume complexity by finding the extremum of the generally covariant volume functional. Locally, we show that its late-time growth rate aligns with the critical momenta associated with the extremal hypersurfaces. Globally, we discover diverse phase transitions for the complexity at early times, including first-order, second-order, and multicritical transitions. An area law and a phase diagram are proposed to adapt to these phase behaviours, highlighting the effects of the black hole’s angular momentum. At zero time, we define the generalized holographic complexity of formation and examine its scaling relations for both large near-extremal MP-AdS black holes and static charged black holes. We find that the scaling behaviours of the generalized volume complexity of formation maintain uniformity with those of the original holographic complexity formulations, except in cases where the scalar functional defining the generalized holographic complexity is infinite in the vacuum limit or at spatial infinity. Additionally, we show that these findings can be applied to codimension-zero observables.

Abstract Background The utilization of genomic information to improve health outcomes is progressively becoming more common in clinical practice. Nonetheless, disparities persist in accessing genetic services among ethnic minorities, individuals with low socioeconomic status, and other vulnerable populations. The Rio Grande Valley (RGV) at the Texas-Mexico border is predominantly Hispanic/Latino with a high poverty rate and very limited access to genetic services. Funded by the National Center for Advancing Translational Sciences, Project GIVE (Genetic Inclusion by Virtual Evaluation) was launched in 2022 to reduce the time to diagnosis and increase provider knowledge of genomics in this region, with the goal of improving pediatric health outcomes. We describe our experience of establishing a virtual pediatric genomic service in this region to expeditiously identify, recruit, and evaluate pediatric patients with undiagnosed diseases. Methods We have utilized an innovative electronic health record (EHR) agnostic virtual telehealth and educational platform called Consultagene to receive referrals from healthcare providers in the RGV. Using this portal, genetic services, including virtual evaluation and genome sequencing (GS), are being delivered to children with rare diseases. The study has also integrated effective methods to involve and educate community providers through in-person meetings and Continuing Professional Education (CPE) events. Results The recruitment efforts have proven highly successful with the utilization of Consultagene in this medically underserved region. The project’s ongoing engagement efforts with local healthcare providers have resulted in progressively more referrals to the study over time, thus improving inclusion and access to genomic care in the RGV. Additionally, the curated CPE content has been well received by healthcare providers in the region. Conclusions Project GIVE study has allowed advanced genetic evaluation and delivery of GS through the virtual Consultagene portal, effectively circumventing the recognized socioeconomic and logistical barriers to accessing genetic services within this border community.

Abstract Background Lymphatic filariasis (LF) is a globally significant, vector-borne, neglected tropical disease that can result in severe morbidity and disability. As the World Health Organization (WHO) Global Programme to Eliminate Lymphatic Filariasis makes progress towards LF elimination, there is greater need to develop sensitive strategies for post-intervention surveillance. Molecular xenomonitoring (MX), the detection of pathogen DNA in vectors, may provide a sensitive complement to traditional human-based surveillance techniques, including detection of circulating filarial antigen and microfilaraemia (Mf). This study aims to explore the relationship between human Mf prevalence and the prevalence of polymerase chain reaction (PCR)-positive mosquitoes using MX. Methods This study compared Mf and MX results from a 2019 community-based survey conducted in 35 primary sampling units (PSUs) in Samoa. This study also investigated concordance between presence and absence of PCR-positive mosquitoes and Mf-positive participants at the PSU level, and calculated sensitivity and negative predictive values for each indicator using presence of any Mf-positive infection in humans or PCR-positive mosquitoes as a reference. Correlation between prevalence of filarial DNA in mosquitoes and Mf in humans was estimated at the PSU and household/trap level using mixed-effect Bayesian multilevel regression analysis. Results Mf-positive individuals were identified in less than half of PSUs in which PCR-positive mosquito pools were present (13 of 28 PSUs). Prevalence of PCR-positive mosquitoes (each species separately) was positively correlated with Mf prevalence in humans at the PSU level. Analysed at the species level, only Aedes polynesiensis demonstrated strong evidence of positive correlation (r) with human Mf prevalence at both PSU (r: 0.5, 95% CrI 0.1–0.8) and trap/household levels (r: 0.6, 95% CrI 0.2–0.9). Conclusions Findings from this study demonstrate that MX can be a sensitive surveillance method for identifying residual infection in low Mf prevalence settings. MX identified more locations with signals of transmission than Mf-testing. Strong correlation between estimated PCR-positive mosquitoes in the primary vector species and Mf in humans at small spatial scales demonstrates the utility of MX as an indicator for LF prevalence in Samoa and similar settings. Further investigation is needed to develop MX guidelines to strengthen the ability of MX to inform operational decisions. Graphical abstract

Abstract Background Jasminum sambac, a widely recognized ornamental plant prized for its aromatic blossoms, exhibits three flora phenotypes: single-petal (“SP”), double-petal (“DP”), and multi-petal (“MP”). The lack of detailed characterization and comparison of J. sambac mitochondrial genomes (mitogenomes) hinders the exploration of the genetic and structural diversity underlying the varying floral phenotypes in jasmine accessions. Results Here, we de novo assembled three mitogenomes of typical phenotypes of J. sambac, “SP”, “DP”, and “MP-hutou” (“HT”), with PacBio reads and the “HT” chloroplast (cp) genome with Illumina reads, and verified them with read mapping and fluorescence in situ hybridization (FISH). The three mitogenomes present divergent sub-genomic conformations, with two, two, and four autonomous circular chromosomes ranging in size from 35.7 kb to 405.3 kb. Each mitogenome contained 58 unique genes. Ribosome binding sites with conserved AAGAAx/AxAAAG motifs were detected upstream of uncanonical start codons TTG, CTG and GTG. The three mitogenomes were similar in genomic content but divergent in structure. The structural variations were mainly attributed to recombination mediated by a large (~ 5 kb) forward repeat pair and several short repeats. The three jasmine cp. genomes showed a well-conserved structure, apart from a 19.9 kb inversion in “HT”. We identified a 14.3 kb “HT”-specific insertion on Chr7 of the “HT” nuclear genome, consisting of two 7 kb chloroplast-derived fragments with two intact ndhH and rps15 genes, further validated by polymerase chain reaction (PCR). The well-resolved phylogeny suggests faster mitogenome evolution in J. sambac compared to other Oleaceae species and outlines the mitogenome evolutionary trajectories within Lamiales. All evidence supports that “DP” and “HT” evolved from “SP”, with “HT” being the most recent derivative of “DP”. Conclusion The comprehensive characterization of jasmine organelle genomes has added to our knowledge of the structural diversity and evolutionary trajectories behind varying jasmine traits, paving the way for in-depth exploration of mechanisms and targeted genetic research.

Abstract SETANTA (Study of HEarT DiseAse and ImmuNiTy After COVID-19 in Ireland) study aimed to investigate symptom burden and incidence of cardiac abnormalities after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/COVID-19 and to correlate these results with biomarkers of immunological response and coagulation. SETANTA was a prospective, single-arm observational cross-sectional study condcuted in a primary practice setting, and prospectively registered with ClinicalTrials.gov (identifier: NCT04823182). Patients with recent COVID-19 infection (≥ 6 weeks and ≤ 12 months) were prospectively enrolled. Primary outcomes of interest were markers of cardiac injury detected by cardiac magnetic resonance imaging (CMR), which included left ventricular ejection fraction, late gadolinium enhancement and pericardial abnormalities, as well as relevant biomarkers testing immunological response and coagulopathy. 100 patients (n = 129 approached) were included, amongst which 64% were female. Mean age of the total cohort was 45.2 years. The median (interquartile range) time interval between COVID-19 infection and enrolment was 189 [125, 246] days. 83% of participants had at least one persistent symptom, while 96% had positive serology for prior SARS-CoV-2 infection. Late gadolinium enhancement, pericardial effusion, was present in 2.2% and 8.3% respectively, while left ventricular ejection fraction was below the normal reference limit in 17.4% of patients. Von Willebrand factor antigen was elevated in 32.7% of patients and Fibrinogen and D-Dimer levels were found to be elevated in 10.2% and 11.1% of patients, respectively. In a cohort of primary practice patients recently recovered from SARS-CoV-2 infection, prevalence of persistent symptoms and markers of abnormal coagulation were high, despite a lower frequency of abnormalities on CMR compared with prior reports of patients assessed in a hospital setting. Trial Registration: Clinicaltrials.gov, NCT04823182 (prospectively registered on 30th March 2021).

Abstract This study investigated gaze behavior during visuo-cognitive-motor tasks with a change of movement direction in glaucoma patients and healthy controls. Nineteen glaucoma patients (10 females, 9 males) and 30 healthy sighted controls (17 females, 13 males) participated in this cross-sectional study. Participants performed two visuo-cognitive-motor tasks with a change of movement direction: (i) the “Speed-Court-Test” that involved stepping on different sensors in response to a visual sign displayed on either a large or small screen (165″ and 55″, respectively); (ii) the “Trail-Walking-Test” that required walking to 15 cones labeled with numbers (1–8) or letters (A-G) in an alternately ascending order. During these tasks, the time needed for completing each task was determined and the gaze behavior (e.g., saccade duration, fixation duration) was recorded via eye tracking. Data were analyzed with repeated measures analyses of covariance (ANCOVA; GROUP × SCREEN) and one-way ANCOVA. No differences between groups were found for the time needed to complete the tasks. However, during the “Trail-Walking-Test”, the fixation duration was longer for glaucoma patients than for controls (p = 0.016, $${\upeta }_{\text{p}}^{2}$$ η p 2 = 0.131). Furthermore, during the “Speed-Court-Test”, there was a screen size effect. Irrespective of group, saccade amplitudes were lower (p

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, presenting a persisting global health burden. Neutrophils have a double-edged role in tumor progression exhibiting both pro-tumor and anti-tumor functions. CD71, also known as transferrin receptor 1, performs a critical role in cellular iron uptake and is highly expressed on proliferating cells, and especially on activated immune cells. CD71 is known to be elevated in various types of solid cancers and is associated with poor prognosis, however, the expression of CD71 on neutrophils in PDAC and its potential clinical impact is still unknown. Therefore, we analyzed CD71 on circulating neutrophils in PDAC and clinical control patients and found a significant increased expression in PDAC patients. High expression of CD71 on neutrophils in PDAC patients was associated with reduced outcome compared to low expression. CD71 on neutrophils correlated positively with the levels of proinflammatory cytokines IL-6, IFN-γ, and growth factor ligands CD40-L, and BAFF in plasma of PDAC patients. Finally, we have demonstrated that high expression of CD71 on neutrophils was also associated with an increased expression of CD39 and CD25 on circulating T-cells. Based on our findings, we hypothesize that CD71 on neutrophils is associated with tumor progression in PDAC. Further studies are required to investigate the distinct functionality of CD71 expressing neutrophils and their potential clinical application.

Abstract Background Plasma growth differentiation factor 15 (GDF15) and N‐terminal proB‐type natriuretic peptide (NT‐proBNP) are cardiovascular biomarkers that associate with a range of diseases. Epigenetic scores (EpiScores) for GDF15 and NT-proBNP may provide new routes for risk stratification. Results In the Generation Scotland cohort (N ≥ 16,963), GDF15 levels were associated with incident dementia, ischaemic stroke and type 2 diabetes, whereas NT-proBNP levels were associated with incident ischaemic heart disease, ischaemic stroke and type 2 diabetes (all PFDR 95%) with levels of GDF15 and NT-proBNP, respectively. EpiScores for GDF15 and NT-proBNP were trained in a subset of the population. The GDF15 EpiScore replicated protein associations with incident dementia, type 2 diabetes and ischaemic stroke in the Generation Scotland test set (hazard ratios (HR) range 1.36–1.41, PFDR

Abstract Background Cannabinoids such as cannabidiol (CBD) exhibit anti-inflammatory properties and have the potential to act as a therapeutic following mild traumatic brain injury. There is limited evidence available on the pharmacological, physiological and psychological effects of escalating CBD dosages in a healthy, male, university athlete population. Furthermore, no dosing regimen for CBD is available with implications of improving physiological function. This study will develop an optimal CBD dose based on the pharmacokinetic data in contact-sport athletes. The physiological and psychological data will be correlated to the pharmacokinetic data to understand the mechanism(s) associated with an escalating CBD dose. Methods/design Forty participants will receive escalating doses of CBD ranging from 5 mg CBD/kg/day to 30 mg CBD/kg/day. The CBD dose is escalated every two weeks in increments of 5 mg CBD/kg/day. Participants will provide blood for pharmacological assessments at each of the 10 visits. Participants will complete a physiological assessment at each of the visits, including assessments of cerebral hemodynamics, blood pressure, electrocardiogram, seismocardiogram, transcranial magnetic stimulation, and salivary analysis for genomic sequencing. Finally, participants will complete a psychological assessment consisting of sleep, anxiety, and pain-related questionnaires. Discussion This study will develop of an optimal CBD dose based on pharmacological, physiological, and psychological properties for future use during contact sport seasons to understand if CBD can help to reduce the frequency of mild traumatic injuries and enhance recovery. Trial registration Clinicaltrials.gov: NCT06204003.

Abstract Scarcity of structural and evolutionary information on protein complexes poses a challenge to deep learning-based structure modelling. We integrate experimental distance restraints obtained by crosslinking mass spectrometry (MS) into AlphaFold-Multimer, by extending AlphaLink to protein complexes. Integrating crosslinking MS data substantially improves modelling performance on challenging targets, by helping to identify interfaces, focusing sampling, and improving model selection. This extends to single crosslinks from whole-cell crosslinking MS, opening the possibility of whole-cell structural investigations driven by experimental data. We demonstrate this by revealing the molecular basis of iron homoeostasis in Bacillus subtilis.

Abstract Gulf War Illness (GWI) is a chronic multisymptom disorder that affects approximately 25–32% of Gulf War veterans and is characterized by a number of symptoms such as cognitive impairment, psychiatric disturbances, chronic fatigue and gastrointestinal distress, among others. While the exact etiology of GWI is unknown, it is believed to have been caused by toxic exposures encountered during deployment in combination with other factors such as stress. In the present study we sought to evaluate the hypothesis that exposure to the toxin permethrin could prime neuroinflammatory stress response and elicit psychiatric symptoms associated with GWI. Specifically, we developed a mouse model of GWI, to evaluate the effects of chronic permethrin exposure followed by unpredictable stress. We found that subjecting mice to 14 days of chronic permethrin exposure followed by 7 days of unpredictable stress resulted in the development of depression-like behavior. This behavioral change coincided with distinct alterations in the microglia phenotype, indicating microglial activation in the hippocampus. We revealed that blocking microglial activation through Gi inhibitory DREADD receptors in microglia effectively prevented the behavioral change associated with permethrin and stress exposure. To elucidate the transcriptional networks impacted within distinct microglia populations linked to depression-like behavior in mice exposed to both permethrin and stress, we conducted a single-cell RNA sequencing analysis using 21,566 single nuclei collected from the hippocampus of mice. For bioinformatics, UniCell Deconvolve was a pre-trained, interpretable, deep learning model used to deconvolve cell type fractions and predict cell identity across spatial datasets. Our bioinformatics analysis identified significant alterations in permethrin exposure followed by stress-associated microglia population, notably pathways related to neuronal development, neuronal communication, and neuronal morphogenesis, all of which are associated with neural synaptic plasticity. Additionally, we observed permethrin exposure followed by stress-mediated changes in signal transduction, including modulation of chemical synaptic transmission, regulation of neurotransmitter receptors, and regulation of postsynaptic neurotransmitter receptor activity, a known contributor to the pathophysiology of depression in a subset of the hippocampal pyramidal neurons in CA3 subregions. Our findings tentatively suggest that permethrin may prime microglia towards a state of inflammatory activation that can be triggered by psychological stressors, resulting in depression-like behavior and alterations of neural plasticity. These findings underscore the significance of synergistic interactions between multi-causal factors associated with GWI.

Abstract Background Adolescents with chronic medical conditions (CMC) use alcohol and marijuana at levels equal to or even greater than their peers without CMC and are more likely to initiate substance use at 14 years or younger. Approximately 33% of adolescents with CMC binge drink alcohol and 20% use marijuana. When using substances, adolescents with CMC are at elevated risk for problem use and adverse consequences given their medical conditions. Although there has recently been progress integrating substance use services into adult hospitals, there has been almost no implementation of standardized substance use services into pediatric hospitals for adolescents with CMC. Screening, Brief Intervention, and Referral to Treatment (SBIRT) for adolescents is an evidence-based, public health approach to promote the early detection and intervention of risky alcohol use in high-risk youth. This paper describes a study protocol combining two leading implementation science frameworks, the Consolidated Framework for Implementation Research (CFIR) and the Health Equity Implementation framework (HEIF), to engage pediatric hospital partners (hospital staff and clinicians, patients with CMC, and caregivers) to identify and specify contextual determinants of SBIRT implementation, which can be used to derive implementation strategies to optimize SBIRT adoption, reach, and fidelity. Method This study will use semi-structured interviews and focus groups with pediatric hospital partners (e.g., hospital staff and clinicians, adolescent patients, and caregivers) to identify SBIRT implementation determinants, using semi-structured interview and focus group guides that integrate CFIR and HEIF dimensions. Discussion Understanding implementation determinants is one of the first steps in the implementation science process. The use of two determinant frameworks highlighting a comprehensive set of determinants including health equity and justice will enable identification of barriers and facilitators that will then map on to strategies that address these factors. This study will serve as an essential precursor to further work evaluating the feasibility of and the degree of engagement with SBIRT among this vulnerable pediatric population.

Abstract Kelps are vital for marine ecosystems, yet the genetic diversity underlying their capacity to adapt to climate change remains unknown. In this study, we focused on the kelp Macrocystis pyrifera a species critical to coastal habitats. We developed a protocol to evaluate heat stress response in 204 Macrocystis pyrifera genotypes subjected to heat stress treatments ranging from 21 °C to 27 °C. Here we show that haploid gametophytes exhibiting a heat-stress tolerant (HST) phenotype also produced greater biomass as genetically similar diploid sporophytes in a warm-water ocean farm. HST was measured as chlorophyll autofluorescence per genotype, presented here as fluorescent intensity values. This correlation suggests a predictive relationship between the growth performance of the early microscopic gametophyte stage HST and the later macroscopic sporophyte stage, indicating the potential for selecting resilient kelp strains under warmer ocean temperatures. However, HST kelps showed reduced genetic variation, underscoring the importance of integrating heat tolerance genes into a broader genetic pool to maintain the adaptability of kelp populations in the face of climate change.

Abstract Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels could provide new insights into molecular mechanisms underlying neurodegenerative disorders. In this meta-analysis of genome-wide association studies (GWAS) of blood NfL levels from eleven cohorts of European ancestry, we identify two genome-wide significant loci at 16p12 (UMOD) and 17q24 (SLC39A11). We observe association of three loci at 1q43 (FMN2), 12q14, and 12q21 with blood NfL levels in the meta-analysis of African-American ancestry. In the trans-ethnic meta-analysis, we identify three additional genome-wide significant loci at 1p32 (FGGY), 6q14 (TBX18), and 4q21. In the post-GWAS analyses, we observe the association of higher NfL polygenic risk score with increased plasma levels of total-tau, Aβ-40, Aβ-42, and higher incidence of Alzheimer’s disease in the Rotterdam Study. Furthermore, Mendelian randomization analysis results suggest that a lower kidney function could cause higher blood NfL levels. This study uncovers multiple genetic loci of blood NfL levels, highlighting the genes related to molecular mechanism of neurodegeneration.

Abstract We examined the association between walkability and blood lipids in a nationally representative sample of 29,649 participants aged 3–79 years who participated in the Canadian Health Measures Survey (CHMS) cycles 1 to 6. We focused on seven lipid biomarkers: apolipoprotein A (Apo A), apolipoprotein B (Apo B), triglycerides (TG), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), total cholesterol (TC), and TC/HDL. Cross-sectional associations were analyzed using generalized linear mixed models incorporating survey-specific sampling weights. An increase in the Canadian Active Living Environments Index, a measure of neighborhood walkability, equivalent to the magnitude of its interquartile range (IQR) was associated with the following percentage (95% confidence intervals (CI)) changes in lipids: decreased TG, -2.85 (-4.77, -0.93) and TC/HDL, -1.68 (-2.80, -0.56), and increased HDL, 1.68 (0.93, 2.42). Significant effects were largely restricted to adults (aged 17 to 79). In the younger age group there were no significant associations between walkability and lipids in the fully adjusted model. Significant associations were more frequently seen in females than males. For females, fully adjusted significant inverse associations were observed for TG, LDL, and TC/HDL, and there were positive associations with HDL and Apo A. Canadians living in more walkable neighborhoods have more favorable lipid profiles, suggesting that the built environment has the potential to influence the risk profile for cardiovascular health, especially among adults and females.

Abstract Background Treatment decisions for persons with relapsing–remitting multiple sclerosis (RRMS) rely on clinical and radiological disease activity, the benefit-harm profile of drug therapy, and preferences of patients and physicians. However, there is limited evidence to support evidence-based personalized decision-making on how to adapt disease-modifying therapy treatments targeting no evidence of disease activity, while achieving better patient-relevant outcomes, fewer adverse events, and improved care. Serum neurofilament light chain (sNfL) is a sensitive measure of disease activity that captures and prognosticates disease worsening in RRMS. sNfL might therefore be instrumental for a patient-tailored treatment adaptation. We aim to assess whether 6-monthly sNfL monitoring in addition to usual care improves patient-relevant outcomes compared to usual care alone. Methods Pragmatic multicenter, 1:1 randomized, platform trial embedded in the Swiss Multiple Sclerosis Cohort (SMSC). All patients with RRMS in the SMSC for ≥ 1 year are eligible. We plan to include 915 patients with RRMS, randomly allocated to two groups with different care strategies, one of them new (group A) and one of them usual care (group B). In group A, 6-monthly monitoring of sNfL will together with information on relapses, disability, and magnetic resonance imaging (MRI) inform personalized treatment decisions (e.g., escalation or de-escalation) supported by pre-specified algorithms. In group B, patients will receive usual care with their usual 6- or 12-monthly visits. Two primary outcomes will be used: (1) evidence of disease activity (EDA3: occurrence of relapses, disability worsening, or MRI activity) and (2) quality of life (MQoL-54) using 24-month follow-up. The new treatment strategy with sNfL will be considered superior to usual care if either more patients have no EDA3, or their health-related quality of life increases. Data collection will be embedded within the SMSC using established trial-level quality procedures. Discussion MultiSCRIPT aims to be a platform where research and care are optimally combined to generate evidence to inform personalized decision-making in usual care. This approach aims to foster better personalized treatment and care strategies, at low cost and with rapid translation to clinical practice. Trial registration ClinicalTrials.gov NCT06095271. Registered on October 23, 2023

Abstract Invasive cervical cancers (ICC), caused by HPV infections, have a heterogeneous molecular landscape. We investigate the detection, timing, and HPV type specificity of somatic mutations in 3929 HPV-positive exfoliated cervical cell samples from individuals undergoing cervical screening in the U.S. using deep targeted sequencing in ICC cases, precancers, and HPV-positive controls. We discover a subset of hotspot mutations rare in controls (2.6%) but significantly more prevalent in precancers, particularly glandular precancer lesions (10.2%), and cancers (25.7%), supporting their involvement in ICC carcinogenesis. Hotspot mutations differ by HPV type, and HPV18/45-positive ICC are more likely to have multiple hotspot mutations compared to HPV16-positive ICC. The proportion of cells containing hotspot mutations is higher (i.e., higher variant allele fraction) in ICC and mutations are detectable up to 6 years prior to cancer diagnosis. Our findings demonstrate the feasibility of using exfoliated cervical cells for detection of somatic mutations as potential diagnostic biomarkers.

Abstract Coagulation factor XII (FXII) conveys various functions as an active protease that promotes thrombosis and inflammation, and as a zymogen via surface receptors like urokinase-type plasminogen activator receptor (uPAR). While plasma levels of FXII are increased in diabetes mellitus and diabetic kidney disease (DKD), a pathogenic role of FXII in DKD remains unknown. Here we show that FXII is locally expressed in kidney tubular cells and that urinary FXII correlates with kidney dysfunction in DKD patients. F12-deficient mice (F12 -/- ) are protected from hyperglycemia-induced kidney injury. Mechanistically, FXII interacts with uPAR on tubular cells promoting integrin β1-dependent signaling. This signaling axis induces oxidative stress, persistent DNA damage and senescence. Blocking uPAR or integrin β1 ameliorates FXII-induced tubular cell injury. Our findings demonstrate that FXII-uPAR-integrin β1 signaling on tubular cells drives senescence. These findings imply previously undescribed diagnostic and therapeutic approaches to detect or treat DKD and possibly other senescence-associated diseases.

Abstract Wildlife tagging provides critical insights into animal movement ecology, physiology, and behavior amid global ecosystem changes. However, the stress induced by capture, handling, and tagging can impact post-release locomotion and activity and, consequently, the interpretation of study results. Here, we analyze post-tagging effects on 1585 individuals of 42 terrestrial mammal species using collar-collected GPS and accelerometer data. Species-specific displacements and overall dynamic body acceleration, as a proxy for activity, were assessed over 20 days post-release to quantify disturbance intensity, recovery duration, and speed. Differences were evaluated, considering species-specific traits and the human footprint of the study region. Over 70% of the analyzed species exhibited significant behavioral changes following collaring events. Herbivores traveled farther with variable activity reactions, while omnivores and carnivores were initially less active and mobile. Recovery duration proved brief, with alterations diminishing within 4–7 tracking days for most species. Herbivores, particularly males, showed quicker displacement recovery (4 days) but slower activity recovery (7 days). Individuals in high human footprint areas displayed faster recovery, indicating adaptation to human disturbance. Our findings emphasize the necessity of extending tracking periods beyond 1 week and particular caution in remote study areas or herbivore-focused research, specifically in smaller mammals.

Abstract Drug-induced gene expression profiles can identify potential mechanisms of toxicity. We focus on obtaining signatures for cardiotoxicity of FDA-approved tyrosine kinase inhibitors (TKIs) in human induced-pluripotent-stem-cell-derived cardiomyocytes, using bulk transcriptomic profiles. We use singular value decomposition to identify drug-selective patterns across cell lines obtained from multiple healthy human subjects. Cellular pathways affected by cardiotoxic TKIs include energy metabolism, contractile, and extracellular matrix dynamics. Projecting these pathways to published single cell expression profiles indicates that TKI responses can be evoked in both cardiomyocytes and fibroblasts. Integration of transcriptomic outlier analysis with whole genomic sequencing of our six cell lines enables us to correctly reidentify a genomic variant causally linked to anthracycline-induced cardiotoxicity and predict genomic variants potentially associated with TKI-induced cardiotoxicity. We conclude that mRNA expression profiles when integrated with publicly available genomic, pathway, and single cell transcriptomic datasets, provide multiscale signatures for cardiotoxicity that could be used for drug development and patient stratification.

Abstract Recent advances in high-resolution mapping of spatial interactions among regulatory elements support the existence of complex topological assemblies of enhancers and promoters known as enhancer-promoter hubs or cliques. Yet, organization principles of these multi-interacting enhancer-promoter hubs and their potential role in regulating gene expression in cancer remain unclear. Here, we systematically identify enhancer-promoter hubs in breast cancer, lymphoma, and leukemia. We find that highly interacting enhancer-promoter hubs form at key oncogenes and lineage-associated transcription factors potentially promoting oncogenesis of these diverse cancer types. Genomic and optical mapping of interactions among enhancer and promoter elements further show that topological alterations in hubs coincide with transcriptional changes underlying acquired resistance to targeted therapy in T cell leukemia and B cell lymphoma. Together, our findings suggest that enhancer-promoter hubs are dynamic and heterogeneous topological assemblies with the potential to control gene expression circuits promoting oncogenesis and drug resistance.

Abstract Antimicrobial resistance (AMR) is a global health threat. This randomized controlled trial evaluates the impact of experiential virtual reality (VR) versus information provision via VR or leaflet on prudent antibiotic use. A total of 249 (239 analyzed) participants were randomized into three conditions: VR Information + Experience, VR Information, or Leaflet Information. All participants received AMR information, while those in the VR Information + Experience condition additionally engaged in a game, making treatment decisions for their virtual avatar’s infection. Participants in the VR Information + Experience condition showed a significant increase in prudent use intentions from baseline (d = 1.48). This increase was significantly larger compared to the VR Information (d = 0.50) and Leaflet Information (d = 0.79) conditions. The increase in intentions from baseline remained significant at follow-up in the VR Information + Experience condition (d = 1.25). Experiential VR communication shows promise for promoting prudent antibiotics use.

Abstract We consider the collective field theory description of the singlet sector of a free and massless matrix field in d dimensions. The k-local collective fields are functions of (d − 1)k + 1 coordinates. We provide a map between the collective fields and fields in the dual gravitational theory defined on AdS d+1 spacetime. The coordinates of the collective field have a natural interpretation: the k-local collective field is a field defined on an AdS d+1×S k−1×S(d−2)(k−2)×S d−3 spacetime. The modes of a harmonic expansion on the S k−1×S(d−2)(k−2)×S d−3 portion of the spacetime leads to the spinning bulk fields of the dual gravity theory.

Abstract Advances in cancer biology have highlighted metabolic reprogramming as an essential aspect of tumorigenesis and progression. However, recent efforts to study tumor metabolism in vivo have identified some disconnects between in vitro and in vivo biology. This is due, at least in part, to the simplified nature of cell culture models and highlights a growing need to utilize more physiologically relevant approaches to more accurately assess tumor metabolism. In this review, we outline the evolution of our understanding of cancer metabolism and discuss some discrepancies between in vitro and in vivo conditions. We describe how the development of physiological media, in combination with advanced culturing methods, can bridge the gap between in vitro and in vivo metabolism.

Abstract Background Available data suggest that general practitioners (GPs) in Germany use complementary and alternative medicine (CAM) modalities more frequently than GPs in many other countries. We investigated the country differences perceived by general practitioners who have worked in Germany and in one of four other European countries with regard to the role of complementary and alternative treatments in primary care. Methods In this qualitative study we conducted semi-structured interviews with 12 GPs who had worked both in Germany and Italy, the Netherlands, Norway or the United Kingdom (UK; n = 3 for each of the four countries). Participants were asked how they perceived and experienced country differences regarding health system, relevance of CAM modalities, the role of evidence-based medicine (EBM) and science, and how they handle so-called indeterminate situations. For the analysis, we followed a thematic analysis approach according to Braun and Clarke with focus on themes that cover CAM. Results Participants unanimously reported that they perceived CAM to be more relevant in general practice in Germany compared to the other countries. We identified four overarching themes in relation to the perceived reasons for these differences. Firstly, physicians with experiences in countries with a strong EBM and science orientation (Netherlands, Norway and the UK) considered the deeply ingrained view in national healthcare systems and GP communities that CAM modalities are not evidence-based as the main reason for the lower use of CAM by GPs. Secondly, extensive training of communication skills was cited as a reason that reduced the need for CAM in the Netherlands, Norway and the UK. Thirdly, differences in patient expectations and demands were perceived as a factor contributing to greater utilisation of CAM by German GPs compared to the other countries. Finally, country-specific reimbursement mechanisms were considered as a factor influencing the role of CAM in general practice. Conclusions The study results point to major differences between countries with regard to the role of CAM in GP care. Differences in basic attitudes in the discipline of general practice, patient expectations and system conditions appear to play an important role here.

Abstract Background Child maltreatment (CM) can have devastating and potentially lifelong effects for those affected and is a major contributor to mental health problems. To tackle public health problems it is crucial to have reliable data on CM. The aim of this study is to assess the prevalence and predictors of CM in a nationwide sample of the German population of young adults. Methods The study population (young adults aged 18 to 31 years) stems from the KiGGS Cohort study, the longitudinal branch of the German Health Interview and Examination Survey for children and adolescents. This sample meets the criteria of the United Nations Sustainable Development Goals (SDG) indicator 16.2.3. The data was collected between 2014 and 2017. CM were assessed with the Childhood Trauma Questionnaire (CTQ) in. In addition, socio-demographic variables and other known risk factors for CM were assessed. A total of 6433 (47.8% female) participants were included in the analyses. Binary logistic regression analyses were used to investigate predictors of maltreatment subtypes. Ordinal regression was used to examine their association with experience of multiple forms of CM. Results Overall, 18.4% (f: 20.9%, m: 16.1%) of the participants reported having experienced at least one type of CM; 6.7% (f: 8.8%, m: 4.8%) reported experiences of emotional abuse, 3.7% (f: 3.9%, m: 3.5%) physical abuse, 3.5% (f: 5.3%, m: 1.7%) sexual abuse, 9.0% (f: 9.9%, m: 8.2%) emotional neglect and 8.6% (f: 8.5%, m: 8.7%) physical neglect. Gender, subjective social status, education and household dysfunction (e.g. living with an individual who is using substances) emerged as significant predictors for different types of CM. Additionally, all these factors were significant risk factors for experiencing cumulative CM. Conclusions CM is common in the German population, with almost one in five people experiencing at least one type of CM. The results reveal important risk factors for the occurrence of CM. In particular, people with lower social status and those who grew up in dysfunctional households are at higher risk of CM. Greater support for this vulnerable population may reduce the prevalence of CM.

Abstract Background Prescribing errors put an enormous burden on health and the economy, claiming implementation of effective methods to prevent/reduce them. Polypharmacy regimens (five or more drugs) are highly prone to unacknowledged prescribing errors, since the complex network of drug-drug interactions, guidelines and contraindications is challenging to be adequately evaluated in the prescription phase, especially if different doctors are involved. Clinical decision support systems aimed at polypharmacy evaluation may be crucial to recognize and correct prescribing errors. Methods A commercial clinical decision support system (Drug-PIN®) was applied to estimate the frequency of unrecognized prescribing errors in a group of 307 consecutive patients accessing the hospital pre-admission service of the Sant’Andrea Hospital of Rome, Italy, in the period April-June 2023. Drug-PIN® is a two-step system, first scoring the risk (low, moderate or high) associated with a certain therapy-patient pair, then allowing therapy optimization by medications exchanges. We defined prescribing errors as cases where therapy optimization could achieve consistent reduction of the Drug-PIN® calculated risk. Results Polypharmacy was present in 205 patients, and moderate to high risk for medication harm was predicted by Drug-PIN® in 91 patients (29.6%). In 58 of them (63.7%), Drug-PIN® guided optimization of the therapy could be achieved, with a statistically significant reduction of the calculated therapy-associated risk score. Patients whose therapy cannot be improved have a statistically significant higher number of used drugs. Considering the overall study population, the rate of avoidable prescribing errors was 18.89%. Conclusions Results suggest that computer-aided evaluation of medication-associated harm could be a valuable and actionable tool to identify and prevent prescribing errors in polypharmacy. We conducted the study in a Hospital pre-admission setting, which is not representative of the general population but represents a hotspot to intercept fragile population, where a consistent fraction of potentially harmful polypharmacy regimens could be promptly identified and corrected by systematic use of adequate clinical decision support tools.

Abstract Background Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor-β (TGF-β) superfamily that has gained considerable attention over the last decade for its observed ability to reverse age-related deterioration of multiple tissues, including the heart. Yet as many researchers have struggled to confirm the cardioprotective and anti-aging effects of GDF11, the topic has grown increasingly controversial, and the field has reached an impasse. We postulated that a clearer understanding of GDF11 could be gained by investigating its health effects at the population level. Methods and results We employed a comprehensive strategy to interrogate results from genome-wide association studies in population Biobanks. Interestingly, phenome-wide association studies (PheWAS) of GDF11 tissue-specific cis-eQTLs revealed associations with asthma, immune function, lung function, and thyroid phenotypes. Furthermore, PheWAS of GDF11 genetic variants confirmed these results, revealing similar associations with asthma, immune function, lung function, and thyroid health. To complement these findings, we mined results from transcriptome-wide association studies, which uncovered associations between predicted tissue-specific GDF11 expression and the same health effects identified from PheWAS analyses. Conclusions In this study, we report novel relationships between GDF11 and disease, namely asthma and hypothyroidism, in contrast to its formerly assumed role as a rejuvenating factor in basic aging and cardiovascular health. We propose that these associations are mediated through the involvement of GDF11 in inflammatory signaling pathways. Taken together, these findings provide new insights into the health effects of GDF11 at the population level and warrant future studies investigating the role of GDF11 in these specific health conditions.

Abstract Background ​​The genus Fusarium poses significant threats to food security and safety worldwide because numerous species of the fungus cause destructive diseases and/or mycotoxin contamination in crops. The adverse effects of climate change are exacerbating some existing threats and causing new problems. These challenges highlight the need for innovative solutions, including the development of advanced tools to identify targets for control strategies. Description In response to these challenges, we developed the Fusarium Protein Toolkit (FPT), a web-based tool that allows users to interrogate the structural and variant landscape within the Fusarium pan-genome. The tool displays both AlphaFold and ESMFold-generated protein structure models from six Fusarium species. The structures are accessible through a user-friendly web portal and facilitate comparative analysis, functional annotation inference, and identification of related protein structures. Using a protein language model, FPT predicts the impact of over 270 million coding variants in two of the most agriculturally important species, Fusarium graminearum and F. verticillioides. To facilitate the assessment of naturally occurring genetic variation, FPT provides variant effect scores for proteins in a Fusarium pan-genome based on 22 diverse species. The scores indicate potential functional consequences of amino acid substitutions and are displayed as intuitive heatmaps using the PanEffect framework. Conclusion FPT fills a knowledge gap by providing previously unavailable tools to assess structural and missense variation in proteins produced by Fusarium. FPT has the potential to deepen our understanding of pathogenic mechanisms in Fusarium, and aid the identification of genetic targets for control strategies that reduce crop diseases and mycotoxin contamination. Such targets are vital to solving the agricultural problems incited by Fusarium, particularly evolving threats resulting from climate change. Thus, FPT has the potential to contribute to improving food security and safety worldwide.

Abstract Background Clostridium autoethanogenum is an acetogenic bacterium that autotrophically converts carbon monoxide (CO) and carbon dioxide (CO2) gases into bioproducts and fuels via the Wood–Ljungdahl pathway (WLP). To facilitate overall carbon capture efficiency, the reaction stoichiometry requires supplementation of hydrogen at an increased ratio of H2:CO to maximize CO2 utilization; however, the molecular details and thus the ability to understand the mechanism of this supplementation are largely unknown. Results In order to elucidate the microbial physiology and fermentation where at least 75% of the carbon in ethanol comes from CO2, we established controlled chemostats that facilitated a novel and high (11:1) H2:CO uptake ratio. We compared and contrasted proteomic and metabolomics profiles to replicate continuous stirred tank reactors (CSTRs) at the same growth rate from a lower (5:1) H2:CO condition where ~ 50% of the carbon in ethanol is derived from CO2. Our hypothesis was that major changes would be observed in the hydrogenases and/or redox-related proteins and the WLP to compensate for the elevated hydrogen feed gas. Our analyses did reveal protein abundance differences between the two conditions largely related to reduction–oxidation (redox) pathways and cofactor biosynthesis, but the changes were more minor than we would have expected. While the Wood–Ljungdahl pathway proteins remained consistent across the conditions, other post-translational regulatory processes, such as lysine-acetylation, were observed and appeared to be more important for fine-tuning this carbon metabolism pathway. Metabolomic analyses showed that the increase in H2:CO ratio drives the organism to higher carbon dioxide utilization resulting in lower carbon storages and accumulated fatty acid metabolite levels. Conclusions This research delves into the intricate dynamics of carbon fixation in C. autoethanogenum, examining the influence of highly elevated H2:CO ratios on metabolic processes and product outcomes. The study underscores the significance of optimizing gas feed composition for enhanced industrial efficiency, shedding light on potential mechanisms, such as post-translational modifications (PTMs), to fine-tune enzymatic activities and improve desired product yields.

Abstract Intratumoral injections have the potential for enhanced cancer treatment efficacy while reducing costs and systemic exposure. However, intratumoral drug injections can result in substantial off-target leakage and are invisible under standard imaging modalities like ultrasound (US) and x-ray. A thermosensitive poloxamer-based gel for drug delivery was developed that is visible using x-ray imaging (computed tomography (CT), cone beam CT, fluoroscopy), as well as using US by means of integrating perfluorobutane-filled microbubbles (MBs). MBs content was optimized using tissue mimicking phantoms and ex vivo bovine livers. Gel formulations less than 1% MBs provided gel depositions that were clearly identifiable on US and distinguishable from tissue background and with minimal acoustic artifacts. The cross-sectional areas of gel depositions obtained with US and CT imaging were similar in studies using ex vivo bovine liver and postmortem in situ swine liver. The gel formulation enhanced multimodal image-guided navigation, enabling fusion of ultrasound and x-ray/CT imaging, which may enhance targeting, definition of spatial delivery, and overlap of tumor and gel. Although speculative, such a paradigm for intratumoral drug delivery might streamline clinical workflows, reduce radiation exposure by reliance on US, and boost the precision and accuracy of drug delivery targeting during procedures. Imageable gels may also provide enhanced temporal and spatial control of intratumoral conformal drug delivery.

Abstract Monel K-500 is a high-performance superalloy composed of nickel and copper, renowned for its exceptional strength, hardness, and resistance to corrosion. To machine this material more precisely and accurately, Electrical Discharge Machining (EDM) is one of the best choices. In EDM, material removal rate (MRR) and electrode wear rate (EWR) are crucial performance parameters that are often conflicting in nature. These parameters depend on several input variables, including peak current (Ip), pulse on time (Ton), duty cycle (Tau), and servo voltage (SV). Optimizing the EDM process is essential for enhancing performance. In this research, a set of experiments were conducted using EDM on Monel K500 alloy to determine the optimal process parameters. The Box–Behnken design was used to prepare the experimental design matrix. Utilizing the experimental data, a second-order mathematical model was developed using Response Surface Methodology (RSM). R2 value is found to be 99.40% and 96.60% for MRR and EWR RSM-based prediction model, respectively. High value of R2 is indicated is indicated good adequacy for prediction. The mathematical model further used in multi-objective dragonfly algorithm (MODA): a new meta-heuristic optimization technique to solve multi-objective optimization problem of EDM. The MODA is a very useful technique to achieve optimal solutions from the multi decision criteria. Utilizing this technique, a set of non-dominated solutions was obtained. Further, the TOPSIS method was used to determine the most desirable optimal solution, which was found to be 0.0135 mm3/min for EWR and 6.968 mm3/min for MRR. These results were obtained when the optimal process parameters were selected as Ip = 6 A, Ton = 200 µs, Tau = 12, and SV = 41.6 V. Operators can machine Monel K500 by selecting the above-mentioned optimal parameters to achieve the best performance.

Abstract Physical exercise induces acute psychophysiological responses leading to chronic adaptations when the exercise stimulus is applied repeatedly, at sufficient time periods, and with appropriate magnitude. To maximize long-term training adaptations, it is crucial to control and manipulate the external load and the resulting psychophysiological strain. Therefore, scientists have developed a theoretical framework that distinguishes between the physical work performed during exercise (i.e., external load/intensity) and indicators of the body's psychophysiological response (i.e., internal load/intensity). However, the application of blood flow restriction (BFR) during exercise with low external loads/intensities (e.g., ≤ 30% of the one-repetition-maximum, ≤ 50% of maximum oxygen uptake) can induce physiological and perceptual responses, which are commonly associated with high external loads/intensities. This current opinion aimed to emphasize the mismatch between external and internal load/intensity when BFR is applied during exercise. In this regard, there is evidence that BFR can be used to manipulate both external load/intensity (by reducing total work when exercise is performed to exhaustion) and internal load/intensity (by leading to higher physiological and perceptual responses compared to exercise performed with the same external load/intensity without BFR). Furthermore, it is proposed to consider BFR as an additional exercise determinant, given that the amount of BFR pressure can determine not only the internal but also external load/intensity. Finally, terminological recommendations for the use of the proposed terms in the scientific context and for practitioners are given, which should be considered when designing, reporting, discussing, and presenting BFR studies, exercise, and/or training programs.

Abstract Background School-based water, sanitation and hygiene (WASH) may improve the health and attendance of schoolchildren, particularly post-menarcheal girls, but existing evidence is mixed. We examined the impact of an urban school-based WASH programme (Project WISE) on child health and attendance. Methods The WISE cluster-randomised trial, conducted in 60 public primary schools in Addis Ababa, Ethiopia over one academic year, enrolled 2–4 randomly selected classes per school (~ 100 pupils) from grades 2 to 8 (aged 7–16) in an ‘open cohort’. Schools were assigned 1:1 by stratified randomisation to receive the intervention during the 2021/2022 or the 2022/2023 academic year (waitlist control). The intervention included improvements to drinking water storage, filtration and access, handwashing stations and behaviour change promotion. Planned sanitation improvements were not realised. At four unannounced classroom visits post-intervention (March–June 2022), enumerators recorded primary outcomes of roll-call absence, and pupil-reported respiratory illness and diarrhoea in the past 7 days among pupils present. Analysis was by intention-to-treat. Results Of 83 eligible schools, 60 were randomly selected and assigned. In total, 6229 eligible pupils were enrolled (median per school 101.5; IQR 94–112), 5987 enrolled at study initiation (23rd November–22nd December 2021) and the remaining 242 during follow-up. Data were available on roll-call absence for 6166 pupils (99.0%), and pupil-reported illness for 6145 pupils (98.6%). We observed a 16% relative reduction in odds of pupil-reported respiratory illness in the past 7 days during follow-up in intervention vs. control schools (aOR 0.84; 95% CI 0.71–1.00; p = 0.046). There was no evidence of effect on pupil-reported diarrhoea in the past 7 days (aOR 1.15; 95% CI 0.84–1.59; p = 0.39) nor roll-call absence (aOR 1.07; 95% 0.83–1.38; p = 0.59). There was a small increase in menstrual care self-efficacy (aMD 3.32 on 0–100 scale; 95% CI 0.05–6.59), and no evidence of effects on other secondary outcomes. Conclusions This large-scale intervention to improve school WASH conditions city-wide had a borderline impact on pupil-reported respiratory illness but no effect on diarrhoeal disease nor pupil absence. Future research should establish relationships between WASH-related illness, absence and other educational outcomes. Trial registration ClinicalTrials.gov, number NCT05024890.

Abstract Streptococcus mitis is a leading cause of infective endocarditis (IE). However, our understanding of the genomic epidemiology and pathogenicity of IE-associated S. mitis is hampered by low IE incidence. Here we use whole genome sequencing of 129 S. mitis bloodstream infection (BSI) isolates collected between 2001–2016 from clinically diagnosed IE cases in the UK to investigate genetic diversity, antimicrobial resistance, and pathogenicity. We show high genetic diversity of IE-associated S. mitis with virtually all isolates belonging to distinct lineages indicating no predominance of specific lineages. Additionally, we find a highly variable distribution of known pneumococcal virulence genes among the isolates, some of which are overrepresented in disease when compared to carriage strains. Our findings suggest that S. mitis in patients with clinically diagnosed IE is not primarily caused by specific hypervirulent or antimicrobial resistant lineages, highlighting the accidental pathogenic nature of S. mitis in patients with clinically diagnosed IE.

Abstract Climate warming disproportionately impacts countries in the Global South by increasing extreme heat exposure. However, geographic disparities in adaptation capacity are unclear. Here, we assess global inequality in green spaces, which urban residents critically rely on to mitigate outdoor heat stress. We use remote sensing data to quantify daytime cooling by urban greenery in the warm seasons across the ~500 largest cities globally. We show a striking contrast, with Global South cities having ~70% of the cooling capacity of cities in the Global North (2.5 ± 1.0 °C vs. 3.6 ± 1.7 °C). A similar gap occurs for the cooling adaptation benefits received by an average resident in these cities (2.2 ± 0.9 °C vs. 3.4 ± 1.7 °C). This cooling adaptation inequality is due to discrepancies in green space quantity and quality between cities in the Global North and South, shaped by socioeconomic and natural factors. Our analyses further suggest a vast potential for enhancing cooling adaptation while reducing global inequality.