Neurocardiology: translational advancements and potential.

In our original white paper published in the The Journal of Physiology in 2016, we set out our knowledge of the structural and functional organization of cardiac autonomic control, how it remodels during disease, and approaches to exploit such knowledge for autonomic regulation therapy. The aim of this update is to build on this original blueprint, highlighting the significant progress which has been made in the field since and major challenges and opportunities that exist with regard to translation. Imbalances in autonomic responses, while beneficial in the short term, ultimately contribute to the evolution of cardiac pathology. As our understanding emerges of where and how to target in terms of actuators (including the heart and intracardiac nervous system (ICNS), stellate ganglia, dorsal root ganglia (DRG), vagus nerve, brainstem, and even higher centres), there is also a need to develop sensor technology to respond to appropriate biomarkers (electrophysiological, mechanical, and molecular) such that closed-loop autonomic regulation therapies can evolve. The goal is to work with endogenous control systems, rather than in opposition to them, to improve outcomes.

Comparison of distal extremity magnetic resonance imaging findings in Australian racing Standardbreds and Thoroughbreds.

INTRODUCTION: Foot-related lameness is common in Standardbred and Thoroughbred racehorses. Magnetic resonance imaging (MRI) provides information on both the soft tissue and osseous structures of the distal extremity. The aim of this study was to determine whether abnormalities identified on distal limb MRI differed between these two racehorse populations. MATERIALS AND METHODS: The records of Standardbred and Thoroughbred racehorse distal extremity MRI examinations conducted at Camden Equine Centre and Ballarat Veterinary Practice between 2013 and 2023 were retrieved. Horses were included if pain causing lameness had been localised to the foot using perineural or intra-articular analgesia. MRI abnormalities of the structures within the distal extremity were recorded and comparisons made between the two groups. RESULTS: There was a significant difference in the rate of occurrence of certain MRI abnormalities between the Thoroughbred and Standardbred racehorse populations, including distal phalangeal fractures, proximal phalangeal short tau inversion recovery (STIR) hyperintensity (distal aspect), the presence and severity of ungular cartilage ossification, abnormalities of the navicular bone distal border synovial invaginations/vascular channels and navicular bone distal border fragments. The presence of distal extremity STIR hyperintensity and fractures was significantly higher in Standardbred compared to Thoroughbred racehorses when these findings were grouped and considered in combination. CONCLUSION: There were many similarities in the distal extremity MRI abnormalities identified in lame Australian Standardbred and Thoroughbred racehorses. However, distal phalangeal fractures, ungular cartilage ossification and distal extremity STIR hyperintensity were identified in significantly more in Standardbred than Thoroughbred racehorses.

Multi-targeted action of rooibos may protect against ischaemic stroke-induced neurological deficit and endothelial dysfunction.

ETHNOPHARMACOLOGICAL RELEVANCE: Indigenous use communities in the Western Cape (South Africa) where Aspalathus linearis (Brum.f) R.Dahlgren - or rooibos - grows naturally, has a long history of using rooibos for medicinal purposes. Apart from its well-known antioxidant effect, the Cederberg community in particular has been using rooibos as a treatment for high blood pressure. Given the detrimental effects of high blood pressure on endothelial cells, rooibos may either directly or indirectly affect vascular health. This, together with more recent reports of neuroprotective effects, may position rooibos as complementary medicine in related vascular conditions such as ischaemic stroke. AIMS OF THE STUDY: The study aimed to evaluate the potential benefit of acute administration of unfermented rooibos, on vascular health in a larval zebrafish model of stroke. MATERIALS AND METHODS: Stroke was induced via 24-h ponatinib exposure, in the presence or absence of an aqueous solution of an ethanolic extract of unfermented Rooibos (GreenOxithin™). The magnitude of stroke was assessed by monitoring larval locomotion and thrombus formation. In terms of specific mechanisms probed, changes in redox status (MDA and TEAC), neurological markers (TH and NeuroD1) and endothelial health (tight/adhesion junction protein expression) were assessed. RESULTS: Rooibos treatment limited thrombus formation and prevented stroke-induced deficits on larval motility. In terms of redox status, rooibos treatment prevented lipid peroxidation 3 days after initial stroke induction, reducing the need for significant upregulation of endogenous antioxidant mechanisms. Stroke-induced changes in neuronal (NeuroD1 and TH) protein expression were normalized in the presence of rooibos, suggesting a neuroprotective role. In terms of tight junction proteins, stroke-related decreases in ZO-1 expression were again prevented by rooibos treatment. In addition, rooibos treatment may beneficially modulate levels of claudin-5 and VE-cadherin, to indirectly limit stroke-associated vascular dysfunction. CONCLUSIONS: Taken together, activity data and physiological assessments suggest that unfermented rooibos may indeed have benefit in the context of stroke, via action at multiple targets. Thus, current data further our understanding of the mechanisms of actions of rooibos and warrant future research to confirm sufficient bioavailability of rooibos in target tissues, in mammalian systems.

Accelerating growth of human coastal populations at the global and continent levels: 2000-2018.

Current human population growth along Earth's coasts is on a collision path with anticipated consequences of increasing natural and anthropogenic induced coastal hazards. Using recently-available ambient, dasymetric data, we developed methods to estimate annual continental and global coastal populations from (2000-2018) measured horizontally from the shoreline inward. We found: (1) large concentrations of population in relatively small bands and regions along the coast (~ 2 billion within 50 km and ~ 1 billion within 10 km); (2) higher growth rates of coastal population than inland population (an addition of 463 million within 50 km and 233 million within 10 km); (3) strong influence of distance from the coast to predict population distribution; and (4) that macro population patterns and growth could be expressed and modeled as a power function at continental and global levels. Findings point to emerging macro population patterns along the coast as contributing to increasing anthropogenic effects on Earth systems and increasing human risks associated with sea-level rise, land subsidence, extreme weather, and public health. Reliable data tracking of the magnitude, spatial distribution and change of human populations in the coastal regions is essential for comprehensive coastal monitoring.

New functions of pirin proteins and a 2-ketoglutarate: Ferredoxin oxidoreductase ortholog in Bacteroides fragilis metabolism and their impact on antimicrobial susceptibility to metronidazole and amixicile.

The understanding of how central metabolism and fermentation pathways regulate antimicrobial susceptibility in the anaerobic pathogen Bacteroides fragilis is still incomplete. Our study reveals that B. fragilis encodes two iron-dependent, redox-sensitive regulatory pirin protein genes, pir1 and pir2. The mRNA expression of these genes increases when exposed to oxygen and during growth in iron-limiting conditions. These proteins, Pir1 and Pir2, influence the production of short-chain fatty acids and modify the susceptibility to metronidazole and amixicile, a new inhibitor of pyruvate: ferredoxin oxidoreductase in anaerobes. We have demonstrated that Pir1 and Pir2 interact directly with this oxidoreductase, as confirmed by two-hybrid system assays. Furthermore, structural analysis using AlphaFold2 predicts that Pir1 and Pir2 interact stably with several central metabolism enzymes, including the 2-ketoglutarate:ferredoxin oxidoreductases Kor1AB and Kor2CDAEBG. We used a series of metabolic mutants and electron transport chain inhibitors to demonstrate the extensive impact of bacterial metabolism on metronidazole and amixicile susceptibility. We also show that amixicile is an effective antimicrobial against B. fragilis in an experimental model of intra-abdominal infection. Our investigation led to the discovery that the kor2AEBG genes are essential for growth and have dual functions, including the formation of 2-ketoglutarate via the reverse TCA cycle. However, the metabolic activity that bypasses the function of Kor2AEBG following the addition of phospholipids or fatty acids remains undefined. Overall, our study provides new insights into the central metabolism of B. fragilis and its regulation by pirin proteins, which could be exploited for the development of new narrow-spectrum antimicrobials in the future.

Early-life gut bacterial community structure predicts disease risk and athletic performance in horses bred for racing.

Gut bacterial communities have a profound influence on the health of humans and animals. Early-life gut microbial community structure influences the development of immunological competence and susceptibility to disease. For the Thoroughbred racehorse, the significance of early-life microbial colonisation events on subsequent health and athletic performance is unknown. Here we present data from a three-year cohort study of horses bred for racing designed to explore interactions between early-life gut bacterial community structure, health events in later life and athletic performance on the racetrack. Our data show that gut bacterial community structure in the first months of life predicts the risk of specific diseases and athletic performance up to three years old. Foals with lower faecal bacterial diversity at one month old had a significantly increased risk of respiratory disease in later life which was also associated with higher relative abundance of faecal Pseudomonadaceae. Surprisingly, athletic performance up to three years old, measured by three different metrics, was positively associated with higher faecal bacterial diversity at one month old and with the relative abundance of specific bacterial families. We also present data on the impact of antibiotic exposure of foals during the first month of life. This resulted in significantly lower faecal bacterial diversity at 28 days old, a significantly increased risk of respiratory disease in later life and a significant reduction in average prize money earnings, a proxy for athletic performance. Our study reveals associations between early-life bacterial community profiles and health events in later life and it provides evidence of the detrimental impact of antimicrobial treatment in the first month of life on health and performance outcomes in later life. For the first time, this study demonstrates a relationship between early-life gut bacterial communities and subsequent athletic performance that has implications for athletes of all species including humans.

E-learning within the European cystic fibrosis society - A multidisciplinary cross-sectional survey.

BACKGROUND: Continuing professional development (CPD) is a component of practice that spans all disciplines within cystic fibrosis (CF). E-learning resources theoretically represent flexible, low cost and time efficient methods of CPD. We aimed to explore European Cystic Fibrosis Society (ECFS) members' and CF health professional communities' current views, experiences and perceptions of e-learning and the ECFS education platform (ECFS-EP). METHODS: An online cross-sectional survey was developed by the ECFS Education Committee and circulated via the ECFS conference, emails and within the society subgroups between June and September 2023. RESULTS: 547 responses were received from 58 countries; 57 % of responders were ECFS members. A wide range of specialities were represented from the multidisciplinary team including 36 % clinicians. The majority of respondents (63 %) spent 6 or more hours a week on their professional education. Online platforms were used either weekly (34 %) or monthly (37 %); 54 % of respondents had used the ECFS-EP and this was rated favourably overall, specifically for content quality. Preferred formats for education were articles and medium length (15-30 min) webinars. CONCLUSIONS: This multidisciplinary cohort survey illustrates contemporary practice and opinion relating to e-learning and the ECFS-EP. Strengths include the high number of responses and the wide range of countries and specialities represented. Results suggest the ECFS-EP is valued and highlights priority topics, preferred formats and opportunities to optimise awareness. Results support continued provision and oversight of high quality education via an online platform. Continued success will rely on learning from user experience and feedback to inform future practice.

Medical Students' Views of the Future in a Rapidly Changing World.

BACKGROUND AND OBJECTIVES: Physicians have long been considered valued members of a solid US health care system. Significant changes in medical education, health care, and society at-large suggest that current medical students may face a different future. To help guide educators and policy makers, we set out to understand medical students' perceptions of the future of health care and their place in it. METHODS: In year one of a longitudinal study, we conducted in-depth interviews of Case Western Reserve University medical students. A multidisciplinary team performed iterative thematic analyses and sampling until reaching saturation on major themes. RESULTS: Eleven medical student participants described social and health care issues as major influences on their professional futures. Concerns included health care system failings, unsustainable costs, climate change, demographic shifts, disinformation, and public distrust in health care. Students looked forward to team practice and using technology, data, and artificial intelligence in care delivery. They hoped for greater access and equity in health care, with a focus on prevention and social, behavioral, and environmental drivers of health. Most students expected to be employed rather than in private practice and sought time/flexibility for professional and personal interests. Paying off medical school debt and advocating for patients and change were priorities. Many saw primary care as important, but fewer envisioned it as their career path of choice. CONCLUSIONS: Medical students envision a future shaped by health care systems and social issues. These findings can inform those helping students prepare for uncertainty and rapid change in their careers, their lives, and the lives of their patients.

Understanding allostasis: Early-life self-regulation involves both up- and down-regulation of arousal.

Optimal performance lies at intermediate autonomic arousal, but no previous research has examined whether the emergence of endogenous control associates with changes in children's up-regulation from hypo-arousal, as well as down-regulation from hyper-arousal. We used wearables to take day-long recordings from N = 58, 12-month-olds (60% white/58% female); and, in the same infants, we measured self-regulation in the lab with a still-face paradigm. Overall, our findings suggest that infants who showed more self-regulatory behaviors in the lab were more likely to actively change their behaviors in home settings moment-by-moment "on the fly" following changes in autonomic arousal, and that these changes result in up- as well as down-regulation. Implications for the role of atypical self-regulation in later psychopathology are discussed.

Tobacco smoking and tooth loss in adults and elderly in Brazil: a populational-based cross-sectional study.

OBJECTIVES: To determine the association between smoking and tooth loss in individuals aged 18 years or more living in Brazil. METHODS: Secondary analysis of the 2019 Brazilian National Health Survey data. The outcome was self-reported tooth loss, and the main independent variable was tobacco smoking. Family income, schooling, sex and age were covariates. Multiple linear regression analysis determined the association between tobacco smoking and the number of missing teeth and then the average number of missing teeth was predicted according to smoking status. RESULTS: The mean number of missing teeth in 88,531 individuals aged 18 or more was 7.7 (95%CI: 7.6-7.8). At least one missing tooth was identified in 72.0% (95%CI: 71.4-72.6) of the population, 21.3% (95%CI: 20.9-21.7) had a non-functional dentition, 14.2% (95%CI: 13.9-14.6) had severe tooth loss and 10.3% (95%CI: 10.0-10.6) were edentulous. The adjusted regression coefficients for number of missing teeth showed that current or former smokers, individuals with low family income and schooling, older age and females exhibited higher tooth loss. Current and former smokers had 1.40 (95%CI: 1.35-1.46) and 1.13 (95%CI: 0.54-0.98) times more lost teeth than never smokers, respectively. CONCLUSIONS: Both tooth loss and smoking are common in Brazilians and are associated. Unfavorable socioeconomic status and demographic factors also predict tooth loss.

Dissipative systems fractionally coupled to a bath.

Quantum diffusion is a major topic in condensed-matter physics, and the Caldeira-Leggett model has been one of the most successful approaches to study this phenomenon. Here, we generalize this model by coupling the bath to the system through a Liouville fractional derivative. The Liouville fractional Langevin equation is then derived in the classical regime, without imposing a non-Ohmic macroscopic spectral function for the bath. By investigating the short- and long-time behavior of the mean squared displacement, we show that this model is able to describe a large variety of anomalous diffusion. Indeed, we find ballistic, sub-ballistic, and super-ballistic behavior for short times, whereas for long times, we find saturation and sub- and super-diffusion.

Posttraumatic stress disorder is characterized by functional dysregulation of dermal fibroblasts.

Incidence of mental health disorders are rising in modernity, with psychological stress linked to a propensity for developing various chronic diseases due to a relative inability of the body to counter the allostatic load on cellular level. Despite these high rates of comorbidities associated with posttraumatic stress disorder (PTSD), there is still a lack of understanding in terms of the peripheral effects of PTSD on tissue level. Therefore, the purpose of this study was to profile basal dermal fibroblast functional status in PTSD using a wide range of markers involved in the cell-to-cell communication facilitated by fibroblasts. Primary dermal fibroblasts derived from patients diagnosed with PTSD (n = 11) and matched trauma exposed controls (i.e. who did not develop PTSD, n = 10) were cultured using standard techniques. The patients and controls were matched based on age, sex, body-mass index (BMI) and lifestyle. The growth rate, population doubling time, cell surface marker expression (CD31, FNDC5) (flow cytometry), secretome (TIMP-2, MMP-9) (ELISAs), intracellular signalling capacity (Fluo-4 Ca2+ flux) and gene expression (IL-6, IL-10, PTX-3, iNOS, Arg1) were compared between groups. The data illustrated significant PTSD-associated fibroblast conditioning resulting in a blunted signalling capacity. This observation highlights the importance of including tissue-specific investigations in future studies focused on elucidating the association between PTSD and subsequent risk for somatic disease.

Is Seeing Believing? Hallmark Movie Viewership and Relationship Beliefs.

The Hallmark Channel, a highly watched cable network, is known for its consistently idealistic portrayals of romantic relationships. Despite its popularity, no research has examined whether increased viewership of Hallmark movies covaries with endorsement of relationship beliefs. According to cultivation theory, what we watch impacts our beliefs and perceptions of reality. Additionally, the Differential Susceptibility to Media Effects Model (DSMM) proposes that certain variables, such as developmental (i.e., age, relationship length) and dispositional factors (e.g., attachment style, gender), may make certain viewers more or less susceptible to the effects of media viewership. Based on this grounding, the main purpose of this study was to determine if watching more Hallmark movies is associated with endorsing certain beliefs about romantic relationships and opposite-sex friendships when controlling for several susceptibility factors. A nationwide sample of heterosexual, married participants (N = 279) completed measures of Romantic Beliefs, Implicit Theories of Relationships, and beliefs about opposite-sex friendships and reported on their media consumption. More frequent Hallmark movie viewership was associated with increased endorsement of several relationship beliefs, above and beyond susceptibility factors (e.g., attachment, relationship length) and daily television consumption. Specifically, greater Hallmark movie viewership was positively associated with greater endorsement of multiple unrealistic relationship beliefs, destiny beliefs, and believing that opposite-sex friendships are problematic. The findings of the current study provide further support for cultivation theory and DSMM.

Comparing environmental impacts of deep-seabed and land-based mining: A defensible framework.

The crises of climate change and biodiversity loss are interlinked and must be addressed jointly. A proposed solution for reducing reliance on fossil fuels, and thus mitigating climate change, is the transition from conventional combustion-engine to electric vehicles. This transition currently requires additional mineral resources, such as nickel and cobalt used in car batteries, presently obtained from land-based mines. Most options to meet this demand are associated with some biodiversity loss. One proposal is to mine the deep seabed, a vast, relatively pristine and mostly unexplored region of our planet. Few comparisons of environmental impacts of solely expanding land-based mining versus extending mining to the deep seabed for the additional resources exist and for biodiversity only qualitative. Here, we present a framework that facilitates a holistic comparison of relative ecosystem impacts by mining, using empirical data from relevant environmental metrics. This framework (Environmental Impact Wheel) includes a suite of physicochemical and biological components, rather than a few selected metrics, surrogates, or proxies. It is modified from the "recovery wheel" presented in the International Standards for the Practice of Ecological Restoration to address impacts rather than recovery. The wheel includes six attributes (physical condition, community composition, structural diversity, ecosystem function, external exchanges and absence of threats). Each has 3-5 sub attributes, in turn measured with several indicators. The framework includes five steps: (1) identifying geographic scope; (2) identifying relevant spatiotemporal scales; (3) selecting relevant indicators for each sub-attribute; (4) aggregating changes in indicators to scores; and (5) generating Environmental Impact Wheels for targeted comparisons. To move forward comparisons of land-based with deep seabed mining, thresholds of the indicators that reflect the range in severity of environmental impacts are needed. Indicators should be based on clearly articulated environmental goals, with objectives and targets that are specific, measurable, achievable, relevant, and time bound.

Severe Tick-Borne Encephalitis (TBE) in a Patient with X-Linked Agammaglobulinemia; Treatment with TBE Virus IgG Positive Plasma, Clinical Outcome and T Cell Responses.

PURPOSE: A patient with X-linked agammaglobulinemia (XLA) and severe tick-borne encephalitis (TBE) was treated with TBE virus (TBEV) IgG positive plasma. The patient's clinical response, humoral and cellular immune responses were characterized pre- and post-infection. METHODS: ELISA and neutralisation assays were performed on sera and TBEV PCR assay on sera and cerebrospinal fluid. T cell assays were conducted on peripheral blood the patient and five healthy vaccinated controls. RESULTS: The patient was admitted to the hospital with headache and fever. He was not vaccinated against TBE but receiving subcutaneous IgG-replacement therapy (IGRT). TBEV IgG antibodies were low-level positive (due to scIGRT), but the TBEV IgM and TBEV neutralisation tests were negative. During hospitalisation his clinical condition deteriorated (Glasgow coma scale 3/15) and he was treated in the ICU with corticosteroids and external ventricular drainage. He was then treated with plasma containing TBEV IgG without apparent side effects. His symptoms improved within a few days and the TBEV neutralisation test converted to positive. Robust CD8+ T cell responses were observed at three and 18-months post-infection, in the absence of B cells. This was confirmed by tetramers specific for TBEV. CONCLUSION: TBEV IgG-positive plasma given to an XLA patient with TBE without evident adverse reactions may have contributed to a positive clinical outcome. Similar approaches could offer a promising foundation for researching therapeutic options for patients with humoral immunodeficiencies. Importantly, a robust CD8+ T cell response was observed after infection despite the lack of B cells and indicates that these patients can clear acute viral infections and could benefit from future vaccination programs.

In BTK, phosphorylated Y223 in the SH3 domain mirrors catalytic activity, but does not influence biological function.

ABSTRACT: Bruton's tyrosine kinase (BTK) is an enzyme needed for B-cell survival, and its inhibitors have become potent targeted medicines for the treatment of B-cell malignancies. The initial activation event of cytoplasmic protein-tyrosine kinases is the phosphorylation of a conserved regulatory tyrosine in the catalytic domain, which in BTK is represented by tyrosine 551. In addition, the tyrosine 223 (Y223) residue in the SRC homology 3 (SH3) domain has, for more than 2 decades, generally been considered necessary for full enzymatic activity. The initial recognition of its potential importance stems from transformation assays using nonlymphoid cells. To determine the biological significance of this residue, we generated CRISPR-Cas-mediated knockin mice carrying a tyrosine to phenylalanine substitution (Y223F), maintaining aromaticity and bulkiness while prohibiting phosphorylation. Using a battery of assays to study leukocyte subsets and the morphology of lymphoid organs, as well as the humoral immune responses, we were unable to detect any difference between wild-type mice and the Y223F mutant. Mice resistant to irreversible BTK inhibitors, through a cysteine 481 to serine substitution (C481S), served as an additional immunization control and mounted similar humoral immune responses as Y223F and wild-type animals. Collectively, our findings suggest that phosphorylation of Y223 serves as a useful proxy for phosphorylation of phospholipase Cγ2 (PLCG2), the endogenous substrate of BTK. However, in contrast to a frequently held conception, this posttranslational modification is dispensable for the function of BTK.

Integrative phylogenetic, phylogeographic and morphological characterisation of the Unio crassus species complex reveals cryptic diversity with important conservation implications.

The global decline of freshwater mussels and their crucial ecological services highlight the need to understand their phylogeny, phylogeography and patterns of genetic diversity to guide conservation efforts. Such knowledge is urgently needed for Unio crassus, a highly imperilled species originally widespread throughout Europe and southwest Asia. Recent studies have resurrected several species from synonymy based on mitochondrial data, revealing U. crassus to be a complex of cryptic species. To address long-standing taxonomic uncertainties hindering effective conservation, we integrate morphometric, phylogenetic, and phylogeographic analyses to examine species diversity within the U. crassus complex across its entire range. Phylogenetic analyses were performed using cytochrome c oxidase subunit I (815 specimens from 182 populations) and, for selected specimens, whole mitogenome sequences and Anchored Hybrid Enrichment (AHE) data on âˆ¼ 600 nuclear loci. Mito-nuclear discordance was detected, consistent with mitochondrial DNA gene flow between some species during the Pliocene and Pleistocene. Fossil-calibrated phylogenies based on AHE data support a Mediterranean origin for the U. crassus complex in the Early Miocene. The results of our integrative approach support 12 species in the group: the previously recognised Unio bruguierianus, Unio carneus, Unio crassus, Unio damascensis, Unio ionicus, Unio sesirmensis, and Unio tumidiformis, and the reinstatement of five nominal taxa: Unio desectusstat. rev., Unio gontieriistat. rev., Unio mardinensisstat. rev., Unio nanusstat. rev., and Unio vicariusstat. rev. Morphometric analyses of shell contours reveal important morphospace overlaps among these species, highlighting cryptic, but geographically structured, diversity. The distribution, taxonomy, phylogeography, and conservation of each species are succinctly described.