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Behaviour and sensory performance of marine fishes are impaired at CO2 levels projected to occur in the ocean in the next 50-100 years, and there is limited potential for within-generation acclimation to elevated CO2 (refs , ). However, whether fish behaviour can acclimate or adapt to elevated CO2 over multiple generations remains unanswered. We tested for transgenerational acclimation of reef fish olfactory preferences and behavioural lateralization at moderate (656 μatm) and high (912 μatm) end-of-century CO2 projections. Juvenile spiny damselfish, Acanthochromis polyacanthus, from control parents (446 μatm) exhibited an innate avoidance to chemical alarm cue (CAC) when reared in control conditions. In contrast, juveniles lost their innate avoidance of CAC and even became strongly attracted to CAC when reared at elevated CO2 levels. Juveniles from parents maintained at mid-CO2 and high-CO2 levels also lost their innate avoidance of CAC when reared in elevated CO2, demonstrating no capacity for transgenerational acclimation of olfactory responses. Behavioural lateralization was also disrupted for juveniles reared under elevated CO2, regardless of parental conditioning. Our results show minimal potential for transgenerational acclimation in this fish, suggesting that genetic adaptation will be necessary to overcome the effects of ocean acidification on behaviour. [ABSTRACT FROM AUTHOR]

Background: Alpha-dystroglycan (α-DG) is a cell surface receptor providing a molecular link between the extracellular matrix (ECM) and the actin-based cytoskeleton. During its biosynthesis, α-DG undergoes specific and unusual Oglycosylation crucial for its function as a high-affinity cellular receptor for ECM proteins. Methodology/Principal Findings: We report that expression of functionally glycosylated α-DG during thymic development is tightly regulated in developing T cells and largely confined to CD4-CD8- double negative (DN) thymocytes. Ablation of DG in T cells had no effect on proliferation, migration or effector function but did reduce the size of the thymus due to a significant loss in absolute numbers of thymocytes. While numbers of DN thymocytes appeared normal, a marked reduction in CD4+CD8+ double positive (DP) thymocytes occurred. In the periphery mature naïve T cells deficient in DG showed bothnormal proliferation in response to allogeneic cells and normal migration, effector and memory T cell function when tested in acute infection of mice with either lymphocytic choriomeningitis virus (LCMV) or influenza virus. Conclusions/Significance: Our study demonstrates that DG function is modulated by glycosylation during T cell development in vivo and that DG is essential for normal development and differentiation of T cells. [ABSTRACT FROM AUTHOR]

This article explores the ways in which the inhabitants of early fourteenth‐century Albi fashioned individual and collective truths about their hated bishop, Bernard de Castanet. The article primarily focuses on a manuscript now held in the Vatican Secret Archive (Collectorie 404). This manuscript contains the written testimonies of those who asserted that among other nefarious activities, Castanet had improperly used imprisonment and torture against his enemies, had engaged in sexual misconduct and had interfered with the quotidian affairs of the Albigensians to an inordinate degree. This article explores the grievance of the citizens of Albi within the context of inquisitorial influence and practice. I argue that the testimonies of those who complained to the pope about Castanet's conduct both reveal the complex means by which evidence and truth were created and communicated in the early fourteenth‐century milieu, and provide us with important insights into the manufacture of testimonial authority, the historical use of rumour and the ways in which medieval people could choose to narrate past experiences. [ABSTRACT FROM PUBLISHER]

The paramyxovirus pneumonia virus of mice (PVM) is a rodent model of human respiratory syncytial virus (hRSV) pathogenesis. Here we characterized the PVM-specific CD8+ T-cell repertoire in susceptible C57BL/6 mice. In total, 15 PVM-specific CD8+ T-cell epitopes restricted by H-2Db and/or H-2Kb were identified. These data open the door for using widely profiled, genetically manipulated C57BL/6 mice to study the contribution of epitope-specific CD8+ T cells to PVM pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Lassa virus (LASV) is a BSL-4 restricted agent. To allow study of infection by LASV under BSL-2 conditions, we generated a recombinant virus in which the LASV glycoprotein (Gp) was placed on the backbone of lymphocytic choriomeningitis virus (LCMV) Cl13 nucleoprotein, Z and polymerase genes (rLCMV Cl13/LASV Gp). The recombinant virus displayed high tropism for dendritic cells following in vitro or in vivo infection. Inoculation of immunocompetent adults resulted in an acute infection, generation of virus-specific CD8+ T cells and clearance of the infection. Inoculation of newborn mice with rLCMV Cl13/LASV Gp resulted in a life-long persistent infection. Interestingly, adoptive transfer of rLCMV Cl13/LASV Gp immune memory cells into such persistently infected mice failed to purge virus but, in contrast, cleared virus from mice persistently infected with wt LCMV Cl13. [Copyright &y& Elsevier]

Arenaviruses are a major cause of hemorrhagic fevers endemic to Sub-Saharan Africa and South America, and thus a major public health and medical concern. The prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is widely used as a model system for studying persistent and acute infections, as well as for gaining an understanding of mammalian immune function. When originally characterized three decades ago, the LCMV isolate, Armstrong, which causes an acute infection in adult mice, was found to differ from the LCMV Clone 13 strain that causes a persistent infection by two amino acid changes, one within the virus surface glycoprotein (GP1: F260L) and the other within the virus L polymerase (K1076Q). Mutation F260L was considered solely responsible for the exceptionally strong binding affinity of Clone 13 (L at GP1 260) to its cellular receptor, a-dystroglycan, which among cells of the immune system is preferentially expressed on dendritic cells, and consequently, alters dendritic cell function leading to viral persistence. Recently, we noted a previously overlooked nucleotide difference between these two strains that results in an additional amino acid change in GP1, N176D. To investigate the potential contribution of this newly identified mutation to the Clone 13 phenotype, we used reverse-genetics approaches to generate recombinant LCM viruses with each of these individual mutations. Phenotypic characterization of these rLCMV showed that mutation F260L, but not N176D, in the GP1 of LCMV is essential for mediating the long-term persistence of Clone 13 infections. This work emphasizes the importance of subtle differences in viral strains that determine disease outcomes. [ABSTRACT FROM AUTHOR]

Abstract: There is no known antiviral drug treatment that routinely terminates persistent virus infections. A recent provocative report indicated that low dosage of the sphingosine analog FTY720 caused lymphopenia in mice persistently infected with lymphocytic choriomeningitis virus (LCMV)-clone 13 (Cl 13) and induced viral clearance within 30 days post-treatment (Premenko-Lanier et al., 2008). However, we find that low dosage of FTY720 fails to purge LCMV-Cl 13 infection and does not induce lymphopenia in LCMV-Cl 13-infected mice. In fact, infection with non-persistent LCMV-Arm53b or with persistent LCMV-Cl 13 induces an equivalent lymphopenia, demonstrating that the quantity of circulating cells has little bearing on viral persistence. In addition, treatment with FTY720 or the sphingosine-1-phosphate receptor 1 (S1P1)-specific agonist, AUY954, does not alleviate T cell exhaustion and exacerbates disruption of the CD8+ T cells response following LCMV-Cl 13 infection. Therefore, treatment with a sphingosine analog does not ameliorate persistent LCMV-Cl 13 infection. [Copyright &y& Elsevier]

Understanding of T cell exhaustion and successful therapy to restore T cell function was first described using Clone (Cl) 13 variant selected from the lymphocytic choriomeningitis virus (LCMV) Armstrong (ARM) 53b parental strain. T cell exhaustion plays a pivotal role in both persistent infections and cancers of mice and humans. C57BL/6, BALB, SWR/J, A/J, 129, C3H, and all but one collaborative cross (CC) mouse strain following Cl 13 infection have immunosuppressed T cell responses, high PD-1, and viral titers leading to persistent infection and normal life spans. In contrast, the profile of FVB/N, NZB, PL/J, SL/J, and CC NZO mice challenged with Cl 13 is a robust T cell response, high titers of virus, PD-1, and Lag3 markers on T cells. These mice all die 7 to 9 d after Cl 13 infection. Death is due to enhanced pulmonary endothelial vascular permeability, pulmonary edema, collapse of alveolar air spaces, and respiratory failure. Pathogenesis involves abundant levels of Cl 13 receptor alpha-dystroglycan on endothelial cells, with high viral replication in such cells leading to immunopathologic injury. Death is aborted by blockade of interferon-1 (IFN-1) signaling or deletion of CD8 T cells. [ABSTRACT FROM AUTHOR]

R4220 --> 687.12 --> The connection between stress and eating patterns has been extensively studied; however, the reverse association between dietary factors and perceived stress is still a gap in the literature. In particular, the effect of omega‐3 fatty acids on perceived stress is little known. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega‐3 fatty acids that play major roles in the nervous system. Therefore, the aim of this study was to assess the relationship between intake of omega‐3 fatty acids rich food, perceived stress and mental distress. It is hypothesized that a diet high in omega‐3 will have a negative correlation with mental distress and perceived stress. An anonymous online survey, consisting of the validated Food‐Mood Questionnaire, Kessler‐6 and Perceived Stress Scale, was distributed to participants 18 years and older through various means, including email and social media platforms. A total of 1591 individuals completed the survey. Data was analyzed using Spearman's Rho correlation and Principal Component Analysis, in SPSS Version 25.0. Our results indicated that a diet high in omega‐3 fatty acids, specifically flax seeds and nuts (p <0.01), fish oil supplements (p <.05) and fatty fish such as salmon (p <.01) negatively correlated with perceived stress. Additionally, our results suggest that flax seeds and nuts (p <0.01) as well as fish (p <0.01) negatively correlated with mental distress. Collectively, the results of this study suggest that a diet high in omega 3 fatty acids may reduce perceived stress and improve mental wellbeing. [ABSTRACT FROM AUTHOR]

During persistent viral infections, chronic immune activation, negative immune regulator expression, an elevated interferon signature, and lymphoid tissue destruction correlate with disease progression. We demonstrated that blockade of type I interferon (IFN-I) signaling using an IFN-I receptor neutralizing antibody reduced immune system activation, decreased expression of negative immune regulatory molecules, and restored lymphoid architecture in mice persistently infected with lymphocytic choriomeningitis virus. IFN-I blockade before and after establishment of persistent virus infection resulted in enhanced virus clearance and was CD4 T cell-dependent. Hence, we demonstrate a direct causal link between IFN-I signaling, immune activation, negative immune regulator expression, lymphoid tissue disorganization, and virus persistence. Our results suggest that therapies targeting IFN-I may help control persistent virus infections. [ABSTRACT FROM AUTHOR]

Organisms' responses to environmental changes involve complex, coordinated responses of multiple tissues and potential parental influences. Here using a multi-tissue approach we determine how variation in parental behavioural tolerance and exposure to elevated CO 2 influences the developmental and intergenerational molecular responses of their offspring in the coral reef fish Acanthochromis polyacanthus to future ocean acidification (OA) conditions. Gills and liver showed the highest transcriptional response to OA in juvenile fish regardless of parental OA conditioning, while the brain and liver showed the greatest intergenerational acclimation signals. Developmentally induced signals of OA, such as altered neural function in the brain, were restored to control levels after intergenerational exposure. Intergenerational CO 2 exposure also enabled the offspring to adjust their metabolic processes, potentially allowing them to better meet the energetic demands of a high CO 2 environment. Furthermore, offspring of OA-exposed parents differentially expressed a new complement of genes, which may facilitate intergenerational acclimatory responses. A genetic component of intergenerational plasticity also played a crucial role, with the parental behavioural phenotype largely determining the offspring's transcriptional signals. Overall, our results reveal tissue-specific transcriptional changes underlying intergenerational plastic responses to elevated CO 2 exposure, enhancing understanding of organismal acclimation to OA throughout the whole body., Competing Interests: Competing interests All authors declare they have no competing interests. Ethical approval Sample collection was carried out following all institutional and national law guidelines. The experiment was completed under James Cook University ethics approval A1828., (© 2024. The Author(s).)

Introduction: Quality improvement (QI) training is an essential component of resident medical education and a part of the ACGME core competencies. We present our residency's evidence-based QI curriculum, which outlines key components identified in the literature for successful QI education., Methods: Our curriculum included a mandatory five-part longitudinal educational series during ambulatory education sessions for second-year residents. Modeled after the Institute for Healthcare Improvement model for improvement and taught by a chief resident, our curriculum introduced residents to key QI concepts through case-based, just-in-time didactics and applied experiential learning via concurrent resident-led longitudinal QI projects. Residents received structured, multilayer mentorship from a faculty mentor in their field of interest and the chief resident of quality and patient safety. Their work-in-progress projects were presented to faculty QI experts and institutional leadership for additional feedback and mentorship., Results: Since 2016, a total of 234 internal medicine residents have completed our QI curriculum and developed 67 QI projects, which have been presented at various local, regional, and national conferences. In the 2 most recent academic years, Quality Improvement Knowledge Application Tool Revised (QIKAT-R) scores significantly increased from 4.6 precurriculum to 6.3 postcurriculum ( p < .001)., Discussion: A longitudinal, experiential, and mentored QI curriculum teaches residents QI skill sets through incorporating mechanisms associated with successful educational initiatives and adult learning theory. Our QIKAT-R results and project output show that our curriculum is associated with improved trainee QI knowledge and systems-level improvements., (© 2023 Xiang et al.)

Knowledge of adaptive potential is crucial to predicting the impacts of ocean acidification (OA) on marine organisms. In the spiny damselfish, Acanthochromis polyacanthus , individual variation in behavioural tolerance to elevated pCO 2 has been observed and is associated with offspring gene expression patterns in the brain. However, the maternal and paternal contributions of this variation are unknown. To investigate parental influence of behavioural pCO 2 tolerance, we crossed pCO 2 -tolerant fathers with pCO 2 -sensitive mothers and vice versa, reared their offspring at control and elevated pCO 2 levels, and compared the juveniles' brain transcriptional programme. We identified a large influence of parental phenotype on expression patterns of offspring, irrespective of environmental conditions. Circadian rhythm genes, associated with a tolerant parental phenotype, were uniquely expressed in tolerant mother offspring, while tolerant fathers had a greater role in expression of genes associated with histone binding. Expression changes in genes associated with neural plasticity were identified in both offspring types: the maternal line had a greater effect on genes related to neuron growth while paternal influence impacted the expression of synaptic development genes. Our results confirm cellular mechanisms involved in responses to varying lengths of OA exposure, while highlighting the parental phenotype's influence on offspring molecular phenotype.

Introduction: Patients with heart failure (HF) are classically categorised by left ventricular ejection fraction (LVEF). Efforts to predict outcomes and response to specific therapy among LVEF-based groups may be suboptimal, in part due to the underlying heterogeneity within clinical HF phenotypes. A multidimensional characterisation of ambulatory patients with and without HF across LVEF groups is needed to better understand and manage patients with HF in a more precise manner., Methods and Analysis: To date, the first cohort of 1313 out of total planned 3000 patients with and without HF has been enroled in this single-centre, longitudinal observational cohort study. Baseline and 1-year follow-up blood samples and clinical characteristics, the presence and duration of comorbidities, serial laboratory, echocardiographic data and images and therapy information will be obtained. HF diagnosis, aetiology of disease, symptom onset and clinical outcomes at 1 and 5 years will be adjudicated by a team of clinicians. Clinical outcomes of interest include all-cause mortality, cardiovascular mortality, all-cause hospitalisation, cardiovascular hospitalisation, HF hospitalisation, right-sided HF and acute kidney injury. Results from the Preserved versus Reduced Ejection Fraction Biomarker Registry and Precision Medicine Database for Ambulatory Patients with Heart Failure (PREFER-HF) trial will examine longitudinal clinical characteristics, proteomic, metabolomic, genomic and imaging data to better understand HF phenotypes, with the ultimate goal of improving precision medicine and clinical outcomes for patients with HF., Ethics and Dissemination: Information gathered in this research will be published in peer-reviewed journals. Written informed consent for PREFER-HF was obtained from all participants. All study procedures were approved by the Mass General Brigham Institutional Review Board in Boston, Massachusetts and performed in accordance with the Declaration of Helsinki (Protocol Number: 2016P000339)., Trial Registration Number: PREFER-HF ClinicalTrials.gov identifier: NCT03480633., Competing Interests: Competing interests: JLJ is a Trustee of the American College of Cardiology, has received grant support from Roche Diagnostics, Novartis Pharmaceuticals and Abbott Diagnostics, consulting income from Abbott Diagnostics, Janssen, Novartis and Roche Diagnostics, and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer and Takeda. HKG has received research grant support from Roche Diagnostics, Jana Care, Ortho Clinical, Novartis, Pfizer, Alnylam, Akcea; consulting income from Amgen, Eko, Merck, Roche Diagnostics, Radiometer, Pfizer; Stock ownership for Eko; Research payments for clinical endpoint committees from Radiometer. She has also received research payment for clinical endpoint committees from Baim Institute for Clinical Research for Abbott, Siemens and Beckman Coulter., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Elevated seawater CO 2 can cause a range of behavioural impairments in marine fishes. However, most studies to date have been conducted on small benthic species and very little is known about how higher oceanic CO 2 levels could affect the behaviour of large pelagic species. Here, we tested the effects of elevated CO 2 , and where possible the interacting effects of high temperature, on a range of ecologically important behaviours (anxiety, routine activity, behavioural lateralization and visual acuity) in juvenile yellowtail kingfish, Seriola lalandi. Kingfish were reared from the egg stage to 25 days post-hatch in a full factorial design of ambient and elevated CO 2 (~500 and ~1000 μatm pCO 2 ) and temperature (21 °C and 25 °C). The effects of elevated CO 2 were trait-specific with anxiety the only behaviour significantly affected. Juvenile S. lalandi reared at elevated CO 2 spent more time in the dark zone during a standard black-white test, which is indicative of increased anxiety. Exposure to high temperature had no significant effect on any of the behaviours tested. Overall, our results suggest that juvenile S. lalandi are largely behaviourally tolerant to future ocean acidification and warming. Given the ecological and economic importance of large pelagic fish species more studies investigating the effect of future climate change are urgently needed., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The impacts of ocean acidification will depend on the ability of marine organisms to tolerate, acclimate and eventually adapt to changes in ocean chemistry. Here, we use a unique transgenerational experiment to determine the molecular response of a coral reef fish to short-term, developmental and transgenerational exposure to elevated CO 2 , and to test how these responses are influenced by variations in tolerance to elevated CO 2 exhibited by the parents. Within-generation responses in gene expression to end-of-century predicted CO 2 levels indicate that a self-amplifying cycle in GABAergic neurotransmission is triggered, explaining previously reported neurological and behavioural impairments. Furthermore, epigenetic regulator genes exhibited a within-generation specific response, but with some divergence due to parental phenotype. Importantly, we find that altered gene expression for the majority of within-generation responses returns to baseline levels following parental exposure to elevated CO 2 conditions. Our results show that both parental variation in tolerance and cross-generation exposure to elevated CO 2 are crucial factors in determining the response of reef fish to changing ocean chemistry.

Pioneering studies into the effects of elevated CO 2 on the behaviour of reef fishes often tested high-CO 2 reared fish using control water in the test arena. While subsequent studies using rearing treatment water (control or high CO 2 ) in the test arena have confirmed the effects of high CO 2 on a range of reef fish behaviours, a further investigation into the use of different test water in the experimental arena is warranted. Here, we used a fully factorial design to test the effect of rearing treatment water (control or high CO 2 ) and experimental test water (control or high CO 2 ) on antipredator responses of larval reef fishes. We tested antipredator behaviour in larval clownfish Amphiprion percula and ambon damselfish Pomacentrus amboinensis , two species that have been used in previous high CO2 experiments. Specifically, we tested if: (1) using control or high CO 2 water in a two channel flume influenced the response of larval clownfish to predator odour; and (2) using control or high CO 2 water in the test arena influenced the escape response of larval damselfish to a startle stimulus. Finally, (3) because the effects of high CO 2 on fish behaviour appear to be caused by altered function of the GABA-A neurotransmitter we tested if antipredator behaviours were restored in clownfish treated with a GABA antagonist (gabazine) in high CO 2 water. Larval clownfish reared from hatching in control water (496 µatm) strongly avoided predator cue whereas larval clownfish reared from hatching in high CO 2 (1,022 µatm) were attracted to the predator cue, as has been reported in previous studies. There was no effect on fish responses of using either control or high CO 2 water in the flume. Larval damselfish reared for four days in high CO 2 (1,051 µatm) exhibited a slower response to a startle stimulus and slower escape speed compared with fish reared in control conditions (464 µatm). There was no effect of test water on escape responses. Treatment of high-CO 2 reared clownfish with 4 mg l -1 gabazine in high CO 2 seawater restored the normal response to predator odour, as has been previously reported with fish tested in control water. Our results show that using control water in the experimental trials did not influence the results of previous studies on antipredator behaviour of reef fishes and also supports the results of novel experiments conducted in natural reef habitat at ambient CO 2 levels., Competing Interests: The authors declare there are no competing interestes