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Abstract The oomycete Phytophthora palmivora infects the fruit of cacao trees (Theobroma cacao) causing black pod rot and reducing yields. Cacao genotypes vary in their resistance levels to P. palmivora, yet our understanding of how cacao fruit respond to the pathogen at the molecular level during disease establishment is limited. To address this issue, disease development and RNA-Seq studies were conducted on pods of seven cacao genotypes (ICS1, WFT, Gu133, Spa9, CCN51, Sca6 and Pound7) to better understand their reactions to the post-penetration stage of P. palmivora infection. The pod tissue-P. palmivora pathogen assay resulted in the genotypes being classified as susceptible (ICS1, WFT, Gu133 and Spa9) or resistant (CCN51, Sca6 and Pound7). The number of differentially expressed genes (DEGs) ranged from 1625 to 6957 depending on genotype. A custom gene correlation approach identified 34 correlation groups. De novo motif analysis was conducted on upstream promoter sequences of differentially expressed genes, identifying 76 novel motifs, 31 of which were over-represented in the upstream sequences of correlation groups and associated with gene ontology terms related to oxidative stress response, defense against fungal pathogens, general metabolism and cell function. Genes in one correlation group (Group 6) were strongly induced in all genotypes and enriched in genes annotated with defense-responsive terms. Expression pattern profiling revealed that genes in Group 6 were induced to higher levels in the resistant genotypes. An additional analysis allowed the identification of 17 candidate cis-regulatory modules likely to be involved in cacao defense against P. palmivora. This study is a comprehensive exploration of the cacao pod transcriptional response to P. palmivora spread after infection. We identified cacao genes, promoter motifs, and promoter motif combinations associated with post-penetration resistance to P. palmivora in cacao pods and provide this information as a resource to support future and ongoing efforts to breed P. palmivora-resistant cacao.

Up to the present study, only 8.5% of the 522 macroalgal species reported at the Azores have sequences deposited in GenBank and BOLD public repositories. The sequences of four genetic markers (cox1, rbcL, UPA, tufA) were obtained for recently collected samples from two Azorean islands. DNA barcode-assisted identification was conducted on newly generated and unpublished sequences from public repositories. A literature review of recently published studies, including the molecular identifications of Azorean macroalgae, was also performed. The results confirm the occurrence of 51 species (including subspecific ranks) and provide four new records, namely, three cryptogenic species (Olokunia boudouresquei, Padina gymnospora, and Ulva lacinulata) and one introduced species (Ulva australis). This study contributes 23 DNA barcodes generated for the first time to the Azores, which now has 10.5% of its marine flora represented in public repositories. Additionally, UPA sequences were generated for the first time for the five taxa.

The article discusses an algorithm capable of determining the substitution scheme of the investigated circuit and calculating the parameters of its elements without operator intervention, based on the admittance frequency characteristics. This algorithm enhances the functional capabilities of RLC meters and can be applied to solve practical problems related to identifying the substitution scheme of the investigated circuit. As an RLC meter measures the total resistance only at one or several fixed frequencies, obtaining an understanding of the substitution scheme from these measurements is challenging. To select the substitution scheme, an analysis of the impedance or admittance frequency characteristics is required. Typically, this analysis is performed manually and is time- consuming. The proposed algorithm automates the analysis of the admittance frequency characteristics. The algorithm associates values and the sequence of slopes of the admittance frequency characteristics with an array of known sequences and slope values for known substitution schemes. The calculation of substitution scheme parameters is based on the resonance frequencies and the heights of zero slopes. To minimize the impact of noise on result accuracy, a synchronous signal detection method is employed. The article introduces a criterion for assessing the algorithm's performance and conducts testing on several types of circuits. During testing, the relative error in calculating substitution scheme parameters was evaluated, with a maximum value not exceeding 6 %.

Abstract Prussian blue nanoparticle‐based photothermal therapy (PBNP‐PTT) is an effective tumor treatment capable of eliciting an antitumor immune response. Motivated by the ability of PBNP‐PTT to potentiate endogenous immune responses, we recently demonstrated that PBNP‐PTT could be used ex vivo to generate tumor‐specific T cells against glioblastoma (GBM) cell lines as an adoptive T cell therapy (ATCT). In this study, we further developed this promising T cell development platform. First, we assessed the phenotype and function of T cells generated using PBNP‐PTT. We observed that PBNP‐PTT facilitated CD8+ T cell expansion from healthy donor PBMCs that secreted IFNγ and TNFα and upregulated CD107a in response to engagement with target U87 cells, suggesting specific antitumor T cell activation and degranulation. Further, CD8+ effector and effector memory T cell populations significantly expanded after co‐culture with U87 cells, consistent with tumor‐specific effector responses. In orthotopically implanted U87 GBM tumors in vivo, PBNP‐PTT‐derived T cells effectively reduced U87 tumor growth and generated long‐term survival in >80% of tumor‐bearing mice by Day 100, compared to 0% of mice treated with PBS, non‐specific T cells, or T cells expanded from lysed U87 cells, demonstrating an enhanced antitumor efficacy of this ATCT platform. Finally, we tested the generalizability of our approach by generating T cells targeting medulloblastoma (D556), breast cancer (MDA‐MB‐231), neuroblastoma (SH‐SY5Y), and acute monocytic leukemia (THP‐1) cell lines. The resulting T cells secreted IFNγ and exerted increased tumor‐specific cytolytic function relative to controls, demonstrating the versatility of PBNP‐PTT in generating tumor‐specific T cells for ATCT.

Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome-edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.

Abstract Microphysiological systems provide the opportunity to model accelerated changes at the human tissue level in the extreme space environment. Spaceflight-induced muscle atrophy experienced by astronauts shares similar physiological changes to muscle wasting in older adults, known as sarcopenia. These shared attributes provide a rationale for investigating molecular changes in muscle cells exposed to spaceflight that may mimic the underlying pathophysiology of sarcopenia. We report the results from three-dimensional myobundles derived from muscle biopsies from young and older adults, integrated into an autonomous CubeLab™, and flown to the International Space Station (ISS) aboard SpaceX CRS-21 as part of the NIH/NASA funded Tissue Chips in Space program. Global transcriptomic RNA-Seq analyses comparing the myobundles in space and on the ground revealed downregulation of shared transcripts related to myoblast proliferation and muscle differentiation. The analyses also revealed downregulated differentially expressed gene pathways related to muscle metabolism unique to myobundles derived from the older cohort exposed to the space environment compared to ground controls. Gene classes related to inflammatory pathways were downregulated in flight samples cultured from the younger cohort compared to ground controls. Our muscle tissue chip platform provides an approach to studying the cell autonomous effects of spaceflight on muscle cell biology that may not be appreciated on the whole organ or organism level and sets the stage for continued data collection from muscle tissue chip experimentation in microgravity. We also report on the challenges and opportunities for conducting autonomous tissue-on-chip CubeLabTM payloads on the ISS.

This paper reviews the phosphate phases in meteorites and those measured by landed spacecraft, what they reveal about past igneous and aqueous conditions on Mars, and important implications for potential prebiotic chemistry, past habitability, and potential biosignatures that could be detected in samples returned from Mars. A review of the 378 martian meteorites as of 2023 indicate that of the two most common phosphate minerals in Mars meteorites, merrillite and apatites, the apatite composition is largely F- and Cl-rich, with shergottites containing more OH. The phosphate concentrations examined across multiple missions show a relatively narrow range of phosphate, with higher concentrations observed in the Mount Sharp Group in Gale crater and Wishstone at Gusev crater and lower concentrations observed at Jezero crater floor and Jezero fan. Possible secondary phosphates detected on Mars, including Fe phosphates at Jezero crater and Gusev crater and Ca- and Al-bearing secondary phosphates, temperatures of formation of secondary phases and their dissolution rates and solubilities are reviewed and summarized. Despite this wealth of information about phosphates on Mars, due to their fine scale and relatively low concentrations, Mars Sample Return is needed to better understand phosphate and its implications for the igneous, aqueous, and astrobiological history of Mars.

Abstract Differential gene expression in bulk transcriptomics data can reflect change of transcript abundance within a cell type and/or change in the proportions of cell types. Expression deconvolution methods can help differentiate these scenarios. BEDwARS is a Bayesian deconvolution method designed to address differences between reference signatures of cell types and corresponding true signatures underlying bulk transcriptomic profiles. BEDwARS is more robust to noisy reference signatures and outperforms leading in-class methods for estimating cell type proportions and signatures. Application of BEDwARS to dihydropyridine dehydrogenase deficiency identified the possible involvement of ciliopathy and impaired translational control in the etiology of the disorder.

Abstract Sex‐related differences in vital rates that drive population change reflect the basic life history of a species. However, for visually monomorphic bird species, determining the effect of sex on demographics can be a challenge. In this study, we investigated the effect of sex on apparent survival, recruitment, and breeding propensity in the Adélie penguin (Pygoscelis adeliae), a monochromatic, slightly size dimorphic species with known age, known sex, and known breeding history data collected during 1996–2019 (n = 2127 birds) from three breeding colonies on Ross Island, Antarctica. Using a multistate capture–mark–recapture maximum‐likelihood model, we estimated apparent survival (Ŝ), recapture (resighting) probability (p^), and the probability of transitioning among breeding states and moving between colonies (ψ̂; colony‐specific non‐juvenile pre‐breeders, breeders, and non‐breeders). Survival rate varied by breeding status and colony, but not sex, and pre‐breeders had higher survival rates than breeders and non‐breeders. Females had a higher probability of recruiting into the breeding population each year and may enter the breeding pool at younger ages. In contrast, both sexes had the same probability of breeding from year to year once they had recruited. Although we detected no direct sex effects on survival, the variation in recruitment probability and age‐at‐first reproduction, along with lower survival rates of breeders compared to pre‐breeders, likely leads to shorter lifespans for females. This is supported by our findings of a male‐biased mean adult sex ratio (ASR) of 1.4 males for every female (x̂ proportion of males = 0.57, SD = 0.07) across all colonies and years in this metapopulation. Our study illustrates how important it can be to disentangle sex‐related variation in population vital rates, particularly for species with complex life histories and demographic dynamics.

Abstract Background We examined the longitudinal association between (change in) physical activity (PA) with new onset of five risk factors of metabolic syndrome among 657 middle-aged adults (mean age 44.1 (standard deviation (SD) 8.6) years) who were free of the respective outcome at baseline, in a longitudinal cohort study spanning over 29 years. Methods Levels of habitual PA and sports-related PA were assessed by a self-reported questionnaire. Incident elevated waist circumference (WC), elevated triglycerides (TG), reduced high-density lipoprotein cholesterols (HDL), elevated blood pressure (BP), and elevated blood-glucose (BG) were assessed by physicians and by self-reported questionnaires. We calculated Cox proportional hazard ratio regressions and 95% confidence intervals. Results Over time, participants developed (cases of incident risk factor; mean (SD) follow-up time) elevated WC (234 cases; 12.3 (8.2) years), elevated TG (292 cases; 11.1 (7.8) years), reduced HDL (139 cases; 12.4 (8.1) years), elevated BP (185 cases; 11.4 (7.5) years), or elevated BG (47 cases; 14.2 (8.5) years). For PA variables at baseline, risk reductions ranging between 37 and 42% for reduced HDL levels were detected. Furthermore, higher levels of PA (≥ 16.6 METh per week) were associated with a 49% elevated risk for incident elevated BP. Participants who increased PA levels over time, had risk reductions ranging between 38 and 57% for elevated WC, elevated TG and reduced HDL. Participants with stable high amounts of PA from baseline to follow-up had risk reductions ranging between 45 and 87% for incident reduced HDL and elevated BG. Conclusions PA at baseline, starting PA engagement, maintaining and increasing PA level over time are associated with favorable metabolic health outcomes.

Cardiovascular diseases (CVDs) are often linked to ageing and are the major cause of death worldwide. The declined proliferation of adult stem cells in the heart often impedes its regenerative potential. Thus, an investigation of the proliferative potential of adult human cardiac stem cells (hCSCs) might be of great interest for improving cell-based treatments of cardiovascular diseases. The application of human blood serum was already shown to enhance hCSC proliferation and reduce senescence. Here, the underlying signalling pathways of serum-mediated hCSC proliferation were studied. We are the first to demonstrate the involvement of the transcription factor NF-κB in the serum-mediated proliferative response of hCSCs by utilizing the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC). RNA-Sequencing (RNA-Seq) revealed ATF6B, COX5B, and TNFRSF14 as potential targets of NF-κB that are involved in serum-induced hCSC proliferation.

We report on the first results for the second-order perturbation theory correction to the ground-state energy of a nuclear many-body system in a continuum quantum Monte Carlo calculation. Second-order (and higher) perturbative corrections are notoriously difficult to compute in most ab initio many-body methods, where the focus is usually on obtaining the ground-state energy. By mapping our calculation of the second-order energy correction to an evolution in imaginary time using the diffusion Monte Carlo method, we are able to calculate these nuclear corrections for the first time. After benchmarking our method in the few-body sector, we explore the effect of charge-independence-breaking terms in the nuclear Hamiltonian. We then employ that approach to investigate the many-body, perturbative, order-by-order convergence that is fundamental in modern theories of the nucleon-nucleon interaction derived from chiral effective field theory. We find cutoff-dependent perturbativeness between potentials at higher chiral order and also that the difference between leading order and next-to-leading order potentials is nonperturbative; both of these results have important implications for future nuclear many-body calculations. Our approach is quite general and promises to be of wide applicability.

ABSTRACT The oomycete pathogen Phytophthora palmivora, which causes black pod rot (BPR) on cacao (Theobroma cacao L.), is responsible for devastating yield losses worldwide. Genetic variation in resistance to Phytophthora spp. is well documented among cacao cultivars, but variation has also been observed in the incidence of BPR even among trees of the same cultivar. In light of evidence that the naturally occurring phyllosphere microbiome can influence foliar disease resistance in other host-pathogen systems, it was hypothesized that differences in the phyllosphere microbiome between two field accessions of the cultivar Gainesville II 164 could be responsible for their contrasting resistance to P. palmivora. Bacterial alpha diversity was higher but fungal alpha diversity was lower in the more resistant accession MITC-331, and the accessions harbored phyllosphere microbiomes with distinct community compositions. Six bacterial and 82 fungal amplicon sequence variants (ASVs) differed in relative abundance between MITC-333 and MITC-331, including bacterial putative biocontrol agents and a high proportion of fungal pathogens, and nine fungal ASVs were correlated with increased lesion development. The roles of contrasting light availability and host mineral nutrition, particularly potassium, are also discussed. Results of this preliminary study can be used to guide research into microbiome-informed integrated pest management strategies effective against Phytophthora spp. in cacao. IMPORTANCE Up to 40% of the world’s cacao is lost each year to diseases, the most devastating of which is black pod rot, caused by Phytophthora palmivora. Though disease resistance is often attributed to cacao genotypes (i.e., disease-resistant rootstocks), this study highlights the role of the microbiome in contributing to differences in resistance even among accessions of the same cacao cultivar. Future studies of plant-pathogen interactions may need to account for variation in the host microbiome, and optimizing the cacao phyllosphere microbiome could be a promising new direction for P. palmivora resistance research.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) can occur due to maternal IgG antibodies targeting platelet antigens, causing life-threatening bleeding in the neonate. However, the disease manifests itself in only a fraction of pregnancies, most commonly with anti-HPA-1a antibodies. We found that in particular, the core fucosylation in the IgG-Fc tail is highly variable in anti-HPA-1a IgG, which strongly influences the binding to leukocyte IgG-Fc receptors IIIa/b (FcγRIIIa/b). Currently, gold-standard IgG-glycoanalytics rely on complicated methods (e.g., mass spectrometry (MS)) that are not suited for diagnostic purposes. Our aim was to provide a simplified method to quantify the biological activity of IgG antibodies targeting cells. We developed a cellular surface plasmon resonance imaging (cSPRi) technique based on FcγRIII-binding to IgG-opsonized cells and compared the results with MS. The strength of platelet binding to FcγR was monitored under flow using both WT FcγRIIIa (sensitive to Fc glycosylation status) and mutant FcγRIIIa-N162A (insensitive to Fc glycosylation status). The quality of the anti-HPA-1a glycosylation was monitored as the ratio of binding signals from the WT versus FcγRIIIa-N162A, using glycoengineered recombinant anti-platelet HPA-1a as a standard. The method was validated with 143 plasma samples with anti-HPA-1a antibodies analyzed by MS with known clinical outcomes and tested for validation of the method. The ratio of patient signal from the WT versus FcγRIIIa-N162A correlated with the fucosylation of the HPA-1a antibodies measured by MS (r=-0.52). Significantly, FNAIT disease severity based on Buchanan bleeding score was similarly discriminated against by MS and cSPRi. In conclusion, the use of IgG receptors, in this case, FcγRIIIa, on SPR chips can yield quantitative and qualitative information on platelet-bound anti-HPA-1a antibodies. Using opsonized cells in this manner circumvents the need for purification of specific antibodies and laborious MS analysis to obtain qualitative antibody traits such as IgG fucosylation, for which no clinical test is currently available.

Introduction Cancer-related fatigue (CRF) is a frequent and burdensome sequela of cancer and cancer therapies. It can persist from months to years and has a substantial impact on patients’ quality of life and functioning. CRF is often still not adequately diagnosed and insufficiently treated. According to guideline recommendations, patients should be routinely screened for CRF from cancer diagnosis onwards. We will investigate how an effective screening should be designed regarding timing, frequency, screening type and cut-off points.Methods and analysis MERLIN is a longitudinal observational study that will include 300 patients with cancer at the beginning of cancer therapy. The main study centre is the National Center for Tumour Diseases Heidelberg, Germany. Patients answer five items to shortly screen for CRF at high frequency during their therapy and at lower frequency during the post-treatment phase for 18 months. Further, CRF is assessed at wider intervals based on the Cella criteria, the Brief Fatigue Inventory impact scale, the quality of life fatigue questionnaire (QLQ-FA12) and the fatigue and cognitive items of the quality of life core questionnaire (QLQ-C30), both of the European Organisation for Research and Treatment of Cancer. Important psychological, socio-demographical or medical factors, which may exacerbate CRF are assessed. All assessments are performed online. Receiver operating curves, areas under the curve, sensitivity, specificity, positive and negative predictive values and likelihood ratios will be calculated to determine optimal short screening modalities.Ethics and dissemination The study was approved by the ethics committee of the Medical Faculty of the Heidelberg University, Germany (approval number: S-336/2022). Written informed consent is obtained from all participants. The study is conducted in full conformance with the principles of the Declaration of Helsinki. Results will be published in peer-reviewed scientific journals, presented at conferences and communicated to clinical stakeholders to foster the implementation of an effective CRF management.Trial registration number ClinicalTrials.gov; registration number: NCT05448573.

IntroductionFailure to properly prepare the equine athlete for exercise and support post-exercise recovery is a contributing factor to physical breakdown and lameness. Equine physiotherapy was not introduced until the early twentieth century and has since evolved to allow for wearable therapies such as therapeutic boots to be accessible to a broad spectrum of equestrians. The purpose of this study was to evaluate the effects of ceramic boots, boots combining vibration and cryotherapy, and boots containing tourmaline on the performance of sport horses during jumping as well as to examine changes in vital signs in response to treatment.MethodsEight healthy horses received the 3 therapeutic boot treatments or a control (no boot) in a Latin square experiment for a period of 5 days each. Horses performed approximately 10 min of exercise through a jump chute for the 5 consecutive days and jump performance parameters were recorded during each exercise session. Therapeutics were applied in the morning prior to exercise per the manufacturer’s recommendation and were removed only for exercise.Results and DiscussionIn a Bayesian network analysis, changes in vital signs (heart rate, respiration, and temperature) were driven by individual animal, rather than boot treatment. Jump performance was influenced by boot treatment, physiological measurements, and individual animal. Therapeutic boots were associated with changes in conditional probabilities of numerous performance outcomes. This study indicates the use of wearable therapies may result in improved performance outcomes of sport horses in jumping exercises.

Summary: IgG antibodies are important mediators of vaccine-induced immunity through complement- and Fc receptor-dependent effector functions. Both are influenced by the composition of the conserved N-linked glycan located in the IgG Fc domain. Here, we compared the anti-Spike (S) IgG1 Fc glycosylation profiles in response to mRNA, adenoviral, and protein-based COVID-19 vaccines by mass spectrometry (MS). All vaccines induced a transient increase of antigen-specific IgG1 Fc galactosylation and sialylation. An initial, transient increase of afucosylated IgG was induced by membrane-encoding S protein formulations. A fucose-sensitive ELISA for antigen-specific IgG (FEASI) exploiting FcγRIIIa affinity for afucosylated IgG was used as an orthogonal method to confirm the LC-MS-based afucosylation readout. Our data suggest that vaccine-induced anti-S IgG glycosylation is dynamic, and although variation is seen between different vaccine platforms and individuals, the evolution of glycosylation patterns display marked overlaps.

Adipose tissue is an important secretory organ, but less is known about the secretory activity of perivascular fat. Here the authors use proteomics analysis on secretomes from perivascular fat to identify neuronal growth regulator 1 as an adipocyte-derived neurotrophic factor, whose decreased secretion in obesity results in a loss of sympathetic innervation of adipose depots in mice.

Abstract We examined the longitudinal association between physical activity (PA) and the risk of incident metabolic syndrome (MetS) among middle-aged, community-dwelling adults, including 591 individuals (314 females; mean (SD) age, 43.8 (8.5) years) who were free of MetS at baseline. Habitual and sports-related PA was assessed by a self-reported questionnaire. MetS was defined based on HDL-cholesterols, triglycerides, glucose or HbA1c, blood pressure, and waist circumference. We calculated Cox proportional hazard ratios (HR) and 95% confidence intervals (CI) using regression analyses. Over a mean follow-up of 12.5 years, 205 participants developed incident MetS. Four different sports-related PA measures were associated with a decreased risk of incident MetS: (1) Engaging in ≥ 75 min/week (HR 0.71, 95% CI 0.53–0.94), (2) maintaining a continuously high amount from baseline to follow-up of ≥ 75 min/week (HR 0.66, 95% CI 0.46–0.94), (3) starting from

The article discusses the clinical manifestations, pathomorphology, pathogenesis and various treatment methods of cervical radiculopathy (CR). Article points out diagnostic difficulties arising from the frequent discrepancy between clinical and neuroimaging data. The issues of choice of conservative and surgical treatment are discussed, based on the analysis of data from recent systematic reviews.In the absence of focal neurological symptoms, radicular compression is unlikely. The natural course of CR is favorable. Rehabilitation programs are used as the first line of treatment, including a combination of education, exercise, manual therapy, psychological and pharmacological methods. Drug therapy for CR starts with non-steroidal anti-inflammatory drugs administration; to achieve the effect quickly, it is possible to use aceclofenac (Aertal) in the form of a powder for suspension.

Abstract Objective Multiple sclerosis (MS) is a common demyelinating central nervous system disease. MRI methods that can quantify myelin loss are needed for trials of putative remyelinating agents. Quantitative magnetization transfer MRI introduced the macromolecule proton fraction (MPF), which correlates with myelin concentration. We developed an alternative approach, Simultaneous‐Multi‐Angular‐Relaxometry‐of‐Tissue (SMART) MRI, to generate MPF. Our objective was to test SMART‐derived MPF metric as a potential imaging biomarker of demyelination. Methods Twenty healthy control (HC), 11 relapsing–remitting MS (RRMS), 22 progressive MS (PMS), and one subject with a biopsied tumefactive demyelinating lesion were scanned at 3T using SMART MRI. SMART‐derived MPF metric was determined in normal‐appearing cortical gray matter (NAGM), normal‐appearing subcortical white matter (NAWM), and demyelinating lesions. MPF metric was evaluated for correlations with physical and cognitive test scores. Comparisons were made between HC and MS and between MS subtypes. Furthermore, correlations were determined between MPF and neuropathology in the biopsied person. Results SMART‐derived MPF in NAGM and NAWM were lower in MS than HC (p

Abstract Basal-like breast cancer (BLBC) is a highly aggressive breast cancer subtype frequently associated with poor prognosis. Due to the scarcity of targeted treatment options, conventional cytotoxic chemotherapies frequently remain the standard of care. Unfortunately, their efficacy is limited as BLBC malignancies rapidly develop resistant phenotypes. Using transcriptomic and proteomic approaches in human and murine BLBC cells, we aimed to elucidate the molecular mechanisms underlying the acquisition of aggressive and chemotherapy-resistant phenotypes in these mammary tumors. Specifically, we identified and characterized a novel short isoform of Roundabout Guidance Receptor 3 (ROBO3s), upregulated in BLBC in response to chemotherapy and encoding for a protein variant lacking the transmembrane domain. We established an important role for the ROBO3s isoform, mediating cancer stem cell properties by stimulating the Hippo-YAP signaling pathway, and thus driving resistance of BLBC cells to cytotoxic drugs. By uncovering the conservation of ROBO3s expression across multiple cancer types, as well as its association with reduced BLBC-patient survival, we emphasize its potential as a prognostic marker and identify a novel attractive target for anti-cancer drug development.

ABSTRACT: Injuries and plumage damage (PD) are important indicators of welfare. First priority in turkey fattening is to reduce injurious pecking, which includes aggressive pecking (agonistic behavior) and additionally severe feather pecking (SFP) and cannibalism with their multifactorial reasons. Still, there are few studies available evaluating different genotypes for their welfare status under organic conditions. The aim of this study was to investigate the effects of genotype and husbandry with 100% organic feeding (2 variants with different riboflavin content: V1 and V2) on injuries and PD. During rearing nonbeaktrimmed male turkeys of a slow- (Auburn, n = 256) and fast-growing (B.U.T.6, n = 128) genotype were kept in 2 indoor housing systems (without environmental enrichment (EE) = H1−, n = 144 and with EE = H2+, n = 240). During fattening 13 animals per pen of H2+ were relocated to a free-range system (H3 MS, n = 104). EE included pecking stones, elevated seating platforms and silage feeding. The study included five 4-wk feeding phases. At the end of each phase, injuries and PD were scored to assess animal welfare. Injury scores ranged from 0 (=no damage) to 3 (=severe damage) and PD from 0 to 4. Injurious pecking was observed from the 8th week onward (injuries: 16.5% and PD: 31.4%). Binary logistic regression models showed that both indicators were affected by genotype (each P < 0.001), husbandry (each P < 0.001), feeding (injuries P = 0.004; PD P = 0.003), and age (each P < 0.001). Auburn showed less injuries and PD than B.U.T.6. H1− had the fewest injuries and PD for Auburn animals compared to H2+ or H3 MS. In summary, the use of alternative genotypes (Auburn) in organic fattening improved welfare, but keeping them in free-range systems or in husbandry with EE, does not lead to a reduction of injurious pecking. Therefore, further studies are needed with more and changing enrichment materials, further management measures, changes in housing structure, and even more intensive animal care.

Heart failure with preserved ejection fraction (HFpEF) is a complex cardiovascular insufficiency syndrome presenting with an ejection fraction (EF) of greater than 50% along with different proinflammatory and metabolic co-morbidities. Despite previous work provided key insights into our understanding of HFpEF, effective treatments are still limited. In the current study we attempted to unravel the molecular basis of sex-dependent differences in HFpEF pathology. We analyzed left ventricular samples from 1-year-old female and male transgenic (TG) rats homozygous for the rat Ren-2 renin gene (mRen2) characterized with hypertension and diastolic dysfunction and compared it to age-matched female and male wild type rats (WT) served as control. Cardiomyocytes from female and male TG rats exhibited an elevated titin-based stiffness (Fpassive), which was corrected to control level upon treatment with reduced glutathione indicating titin oxidation. This was accompanied with high levels of oxidative stress in TG rats with more prominent effects in female group. In vitro supplementation with heat shock proteins (HSPs) reversed the elevated Fpassive indicating restoration of their cytoprotective function. Furthermore, the TG group exhibited high levels of proinflammatory cytokines with significant alterations in apoptotic and autophagy pathways in both sexes. Distinct alterations in the expression of several proteins between both sexes suggest their differential impact on disease development and necessitate distinct treatment options. Hence, our data suggested that oxidative stress and inflammation distinctly drive diastolic dysfunction and remodeling in female and male rats with HFpEF and that the sex-dependent mechanisms contribute to HF pathology.

Salty aqueous solutions (brines) occur on Earth and may be prevalent elsewhere. Serpentinization represents a family of geochemical reactions where the hydration of olivine-rich rocks can release aqueous hydrogen, H _2(aq) , as a byproduct, and hydrogen is a known basal electron donor for terrestrial biology. While the effects of lithological differences on serpentinization products have been thoroughly investigated, effects focusing on compositional differences of the reacting fluid have received less attention. In this contribution, we investigate how the chemistry of seawater-derived brines affects the generation of biologically available hydrogen resulting from the serpentinization of harzburgite. We numerically investigate the serpentinization of ultramafic rocks at equilibrium with an array of brines at different water activities (a proxy for salt concentration in aqueous fluids and a determinant for habitability) derived from seawater evaporation. Because the existing supersaturation of aqueous calcium carbonate, a contributor to dissolved inorganic carbon (DIC) in natural seawater, cannot be captured in equilibrium calculations, we bookend our calculations by enabling and suppressing carbonate minerals when simulating serpentinization. We find that the extent of DIC supersaturation can provide an important control of hydrogen availability. Increased DIC becomes a major sink for hydrogen by producing formate and associated complexes when the reacting fluids are acidic enough to allow for CO _2. Indeed, H _2(aq) reduces CO _2(aq) to formate, leading to a hydrogen deficit. These conclusions provide additional insights into the habitability of brine systems, given their potential for serpentinization across diverse planetary bodies such as on Mars and ocean worlds.

The ageing phenotype is strongly driven by the exhaustion of adult stem cells (ASCs) and the accumulation of senescent cells. Cardiovascular diseases (CVDs) and heart failure (HF) are strongly linked to the ageing phenotype and are the leading cause of death. As the human heart is considered as an organ with low regenerative capacity, treatments targeting the rejuvenation of human cardiac stem cells (hCSCs) are of great interest. In this study, the beneficial effects of human blood serum on proliferation and senescence of hCSCs have been investigated at the molecular level. We show the induction of a proliferation-related gene expression response by human blood serum at the mRNA level. The concurrent differential expression of the TGFβ target and inhibitor genes indicates the participation of TGFβ signalling in this context. Surprisingly, the application of TGFβ1 as well as the inhibition of TGFβ type I and type II receptor (TGFβRI/II) signalling strongly increased the proliferation of hCSCs. Likewise, both human blood serum and TGFβ1 reduced the senescence in hCSCs. The protective effect of serum on senescence in hCSCs was enhanced by simultaneous TGFβRI/II inhibition. These results strongly indicate a dual role of TGFβ signalling in terms of the serum-mediated effects on hCSCs. Further analysis via RNA sequencing (RNA-Seq) revealed the participation of Ras-inactivating genes wherefore a prevention of hyperproliferation upon serum-treatment in hCSCs via TGFβ signalling and Ras-induced senescence is suggested. These insights may improve treatments of heart failure in the future.

Odor-guided navigation is fundamental to the survival and reproductive success of many flying insects. Despite its biological importance, the mechanics of how insects sense and interpret odor plumes in the presence of complex flow fields remain poorly understood. This study employs numerical simulations to investigate the influence of turbulence, wingbeat-induced flow, and Schmidt number on the structure and perception of odor plumes by flying insects. Using an in-house computational fluid dynamics solver based on the immersed-boundary method, we solve the three-dimensional Navier–Stokes equations to model the flow field. The solver is coupled with the equations of motion for passive flapping wings to emulate wingbeat-induced flow. The odor landscape is then determined by solving the odor advection–diffusion equation. By employing a synthetic isotropic turbulence generator, we introduce turbulence into the flow field to examine its impact on odor plume structures. Our findings reveal that both turbulence and wingbeat-induced flow substantially affect odor plume characteristics. Turbulence introduces fluctuations and perturbations in the plume, while wingbeat-induced flow draws the odorant closer to the insect’s antennae. Moreover, we demonstrate that the Schmidt number, which affects odorant diffusivity, plays a significant role in odor detectability. Specifically, at high Schmidt numbers, larger fluctuations in odor sensitivity are observed, which may be exploited by insects to differentiate between various odorant volatiles emanating from the same source. This study provides new insights into the complex interplay between fluid dynamics and sensory biology and behavior, enhancing our understanding of how flying insects successfully navigate using olfactory cues in turbulent environments.

Hepatocellular carcinoma (HCC) is a major global health concern, representing one of the leading causes of cancer-related deaths. Despite various treatment options, the prognosis for HCC patients remains poor, emphasizing the need for a deeper understanding of the factors contributing to HCC development. This study investigates the role of poly(ADP-ribosyl)ation in hepatocyte maturation and its impact on hepatobiliary carcinogenesis. A conditional Parg knockout mouse model was employed, utilizing Cre recombinase under the albumin promoter to target Parg depletion specifically in hepatocytes. The disruption of the poly(ADP-ribosyl)ating pathway in hepatocytes affects the early postnatal liver development. The inability of hepatocytes to finish the late maturation step that occurs early after birth causes intensive apoptosis and acute inflammation, resulting in hypertrophic liver tissue with enlarged hepatocytes. Regeneration nodes with proliferative hepatocytes eventually replace the liver tissue and successfully fulfill the liver function. However, early developmental changes predispose these types of liver to develop pathologies, including with a malignant nature, later in life. In a chemically induced liver cancer model, Parg-depleted livers displayed a higher tendency for hepatocellular carcinoma development. This study underscores the critical role of the poly(ADP-ribosyl)ating pathway in hepatocyte maturation and highlights its involvement in liver pathologies and hepatobiliary carcinogenesis. Understanding these processes may provide valuable insights into liver biology and liver-related diseases, including cancer.

Abstract Background There is a growing interest in redesigning healthcare systems to increase access to and coordination across care settings for people with chronic conditions. We aim to gain a better understanding of the barriers faced by (1) children with chronic bronchial asthma, (2) adults with non-specific chronic back pain, and (3) older people with pre-existing mental illness/es in Austria’s fragmented social health insurance system. Methods Using a qualitative design, we conducted semi-structured interviews face-to-face and by telephone with health service providers, researchers, experts by experience (persons with lived/ personal experience, i.e., service users, patient advocates or family members/carers), and employees in public health administration between July and October 2019. The analysis and interpretation of data were guided by Levesque’s model of access, a conceptual framework used to evaluate access broadly according to different dimensions of accessibility to care: approachability, acceptability, availability and accommodation, affordability, and appropriateness. Results The findings from the 25 expert interviews were organised within Levesque’s conceptual framework. They highlight a lack of coordination and defined patient pathways, particularly at the onset of the condition, when seeking a diagnosis, and throughout the care process. On the supply side, patterns of poor patient-provider communication, lack of a holistic therapeutic approach, an urban-rural divide, strict separation between social care and the healthcare system and limited consultation time were among the barriers identified. On the demand side, patients’ ability to perceive a need and to subsequently seek and reach healthcare services was an important barrier, closely linked to a patient’s socio-economic status, health literacy and ability to pay. Conclusions While studies on unmet needs suggest a very low level of barriers to accessing health care in the Austrian context, our study highlights potential ‘invisible’ barriers. Barriers to healthcare access are of concern for patients with chronic conditions, underlining existing findings about the need to improve health services according to patients’ specific needs. Research on how to structure timely and integrated care independent of social and economic resources, continuity of care, and significant improvements in patient-centred communication and coordination of care would be paramount.

Abstract Background Many patients with metastatic breast cancer experience cancer- and treatment-related side effects that impair activities of daily living and negatively affect the quality of life. There is a need for interventions that improve quality of life by alleviating fatigue and other side effects during palliative cancer treatment. Beneficial effects of exercise have been observed in the curative setting, but, to date, comparable evidence in patients with metastatic breast cancer is lacking. The aim of this study is to assess the effects of a structured and individualized 9-month exercise intervention in patients with metastatic breast cancer on quality of life, fatigue, and other cancer- and treatment-related side effects. Methods The EFFECT study is a multinational, randomized controlled trial including 350 patients with metastatic breast cancer. Participants are randomly allocated (1:1) to an exercise or control group. The exercise group participates in a 9-month multimodal exercise program, starting with a 6-month period where participants exercise twice a week under the supervision of an exercise professional. After completing this 6-month period, one supervised session is replaced by one unsupervised session for 3 months. In addition, participants are instructed to be physically active for ≥30 min/day on all remaining days of the week, while being supported by an activity tracker and exercise app. Participants allocated to the control group receive standard medical care, general written physical activity advice, and an activity tracker, but no structured exercise program. The primary outcomes are quality of life (EORTC QLQ-C30, summary score) and fatigue (EORTC QLQ-FA12), assessed at baseline, 3, 6 (primary endpoint), and 9 months post-baseline. Secondary outcomes include physical fitness, physical performance, physical activity, anxiety, depression, pain, sleep problems, anthropometric data, body composition, and blood markers. Exploratory outcomes include quality of working life, muscle thickness, urinary incontinence, disease progression, and survival. Additionally, the cost-effectiveness of the exercise program is assessed. Adherence and safety are monitored throughout the intervention period. Discussion This large randomized controlled trial will provide evidence regarding the (cost-) effectiveness of exercise during treatment of metastatic breast cancer. If proven (cost-)effective, exercise should be offered to patients with metastatic breast cancer as part of standard care. Trial registration ClinicalTrials.gov NCT04120298 . Registered on October 9, 2019.

Introduction/Objectives: Primary care practice-based research networks (PBRNs) participated in a point of care (POC) device study funded by by the National Institutes of Health and led by the University of Massachusetts Chan Medical School (UMass) to speed the development, validation, and commercialization of POC tests to detect SARS-CoV-2. The purposes of this study were to describe the characteristics of participating PBRNs and their respective collaborators in this device trial and describe complications challenging its execution. Methods: Semi-structured interviews were conducted with lead personnel from participating PBRNs and UMass. Results: Four PBRNs and UMass were invited to participate and 3 PBRNs and UMass participated. This device trial recruited 321 subjects in 6 months; 65 subjects from PBRNs. Each PBRN and the academic medical center site enrolled and recruited subjects differently. Main challenges identified were having adequate clinic personnel to enroll and aid in consent and questionnaire completion, frequently changing inclusion/exclusion criteria, use of the digital electronic data collection platform, and having access to a −80°C freezer to store supplies. Discussion: This trial involved numerous researchers, primary care clinic leaders and staff, and academic center sponsored program staff and attorneys resulting in a resource-intensive endeavor to enroll 65 subjects in the real-world clinical setting of primary care PBRNs with the academic medical center enrolling the rest. Multiple obstacles to standing up the study were encountered by the PBRNS. Conclusions: Primary care PBRNs rely largely on the goodwill established between academic health centers and participating practices. For future investigations involving device studies, collaborating PBRN leaders should assess whether recruitment criteria may change, obtain detailed lists of equipment needed, and/or know if the study is likely to be halted suddenly to appropriately prepare their member practices.

Abstract While liquid environments with high salt content are of broad interest to the Earth and Planetary Science communities, instruments face challenges in detecting organics in hypersaline samples due to the effects of salts. Therefore, technology to desalt samples before analysis by these instruments would be enabling for liquid sampling on missions to Mars or ocean worlds. Electrodialysis (ED) removes salt from aqueous solutions by applying an electric potential across a series of ion‐selective membranes, and is demonstrated to retain a significant percentage of dissolved organic molecules (DOM) in marine samples. However, current electrodialysis systems used for DOM recovery are too large for deployment on missions or for use in terrestrial fieldwork. Here, we present the design and evaluation of the Miniature Robotic Electrodialysis (MR ED) system, which is approximately 1/20th the size of heritage instruments and processes as little as 50 mL of sample at a time. We present tests of the instrument efficiency and DOM recovery using lab‐created solutions as well as natural samples taken from an estuary of the Skidaway River (Savannah, GA) (Verity, 2002) and from South Bay Saltworks (San Diego, CA) (Roseman & Watry, 2008; Survey, 2011). Our results show that the MR ED system removed 97%–99% of the salts in most samples, with an average DOC recovery range from 53% to 77%, achieving similar capability to tabletop instruments. This work both demonstrates MR ED as a possible field instrument and increases the technology readiness level of miniaturized electrodialysis systems for future missions.

Abstract. The mediatization of several high-profile cases of sexual abuse in sports has sensitized a larger public for the problem of interpersonal violence against athletes. This article provides an overview of what is already known on the prevalence of different forms of interpersonal violence in sports, associated personal, organizational and cultural risk factors, and the psychopathological consequences of interpersonal violence. Throughout the article, areas where more research is needed are highlighted. It is concluded that evidence-based psychiatric and psychotherapeutic prevention, intervention and care programs that are tailored to the specific needs of athletes are needed to safeguard mental health in sports.

Abstract The numerical understanding of cichlids and stingrays was examined regarding addition and subtraction abilities within the number space of one to five. Experiments were conducted as two-alternative forced-choice experiments, using a delayed matching to sample technique. On each trial, fish had to perform either an addition or subtraction, based on the presentation of two-dimensional objects in two distinct colors, with the color signaling a particular arithmetic process. Six cichlids and four stingrays successfully completed training and recognized specific colors as symbols for addition and subtraction. Cichlids needed more sessions than stingrays to reach the learning criterion. Transfer tests showed that learning was independent of straightforward symbol memorization. Individuals did not just learn to pick the highest or lowest number presented based on the respective color; instead, learning was specific to adding or subtracting ‘one’. Although group results were significant for both species in all tests, individual results varied. Addition was learned more easily than subtraction by both species. While cichlids learned faster than stingrays, and more cichlids than stingrays learned the task, individual performance of stingrays exceeded that of cichlids. Previous studies have provided ample evidence that fish have numerical abilities on par with those of other vertebrate and invertebrate species tested, a result that is further supported by the findings of the current study.

Powerplants frequently use river water for cooling, subsequently discharging warm effluent. Some of these plants can cycle on and off rapidly based on electricity demand, resulting in dramatic temperature fluctuations in the receiving waters. To understand the impacts on resident fish populations in the Upper Mississippi River, we (i) assessed the effects of rapid water cooling on three native fish species; (ii) investigated whether smallmouth bass (Micropterus dolomieu) behavior favored movement into thermal plumes when given a choice of cooler or ambient water; and (iii) tracked native M. dolomieu with acoustic tags and recorded core body temperature during the thermal cycling process of a steam electric powerplant. In cold shock experiments, mortality was associated with rapid temperature declines and dependent on the final (cold) holding temperature. The species or developmental stage of the tested organism did not affect survival. When given a choice between warm and ambient waters, M. dolomieu exhibited little inclination to acclimate to the warmer water and instead “self-regulated” by moving in and out of the warm water plume. This finding was supported by telemetry data on M. dolomieu. The core temperature of the fish never increased more than 2 °C above the ambient (upstream) Mississippi River temperature, even during warm effluent discharge.

Background & aimsBody composition (BC) changes with age and is associated with morbidity and mortality. A physically active lifestyle influences BC and represents an important predictor of successful aging. To emphasize this, the World Health Organization established activity recommendations for all age groups. We describe BC during adulthood using a cross-sectional sample from a German community and investigate the associations between physical activity (PA), physical fitness (PF), and BC.MethodsData from 329 men and women aged 35 to 86 years were analyzed. PA was measured by questionnaire and classified into sport activity and habitual activity. PF was measured through physical performance tests and BC by bioelectrical impedance analysis. Fat mass index (FMI) and fat-free mass index (FFMI) were calculated to represent height-adjusted BC. Associations between PA, PF, and BC were analyzed using linear regression models.ResultsFor both sexes, strength was positively associated with FFMI (♂: ß = 0.313; ♀: ß = 0.213) and phase angle (♂: ß = 0.357; ♀: ß = 0.409). For FMI, a significant negative association with strength was found only in women (ß = -0.189). Cardiorespiratory fitness showed a negative association with FMI (ß = -0.312) and FFMI (ß = -0.201) for men, while in women a positive association was found for FFMI (ß = 0.186). For coordination, a significant association with FMI was observed only in women (ß = -0.190). Regarding PA only one significant relationship between sport activity and FMI among women (ß = -0.170) was found.ConclusionsIn our sample, PF was closer related to BC than PA. Strength and cardiorespiratory fitness were the strongest predictors for BC. This supports the World Health Organization's activity recommendations to include both resistance and endurance training in the weekly sports program to maintain a healthy BC.