ABSTRACT
Compared to the Western diet, the Mediterranean diet has many known benefits for both mental health and physical health; however, little is known about the effect of these dietary patterns on perceived stress and mental distress. To assess the relationship between dietary patterns, perceived stress and mental wellbeing, an anonymous online questionnaire targeting adults 18 and older was distributed via several social media platforms and email listservs. The survey included demographic questions, the Food-Mood Questionnaire, the Perceived Stress Scale and the Kessler Psychological Distress scale (K-6). A total of 1591 participants completed the survey. The data was analyzed using Principal Component Analysis and Pearson Correlation Coefficient in SPSS version 28.0. The results showed significant negative correlations between perceived stress and mental distress with several components of the Mediterranean diet, such as whole grains, seafood, fruits, vegetables, and beans. Despite being attributed to the Western diet, meat produced a negative correlation with perceived stress and mental distress. However, significant positive correlations between perceived stress and mental distress and the Western diet, such as fast food and high glycemic index food, were detected. Our findings provide evidence that dietary patterns modulate the stress response and suggest that incorporating components of the Mediterranean diet is beneficial for mental wellbeing and stress reduction.
ABSTRACT
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 pCO2 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 pCO2 tolerance, we crossed pCO2-tolerant fathers with pCO2-sensitive mothers and vice versa, reared their offspring at control and elevated pCO2 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.
Subject(s)
Coral Reefs , Perciformes , Animals , Carbon Dioxide , Fishes/physiology , Hydrogen-Ion Concentration , Perciformes/genetics , Seawater/chemistryABSTRACT
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.
Subject(s)
CD8-Positive T-Lymphocytes , Interferon Type I , Lymphocytic Choriomeningitis , Lymphocytic choriomeningitis virus/physiology , Virus Replication/genetics , Animals , Antigens, CD/genetics , Antigens, CD/metabolism , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/pathology , Humans , Interferon Type I/genetics , Interferon Type I/metabolism , Lymphocytic Choriomeningitis/genetics , Lymphocytic Choriomeningitis/metabolism , Lymphocytic Choriomeningitis/pathology , Mice , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/metabolism , Lymphocyte Activation Gene 3 ProteinABSTRACT
The understanding of the detection threshold and behavioral response of fishes in response to crude oil is critical to predicting the effects of oil spills on wild fish populations. The Deepwater Horizon oil spill released approximately 4.9 million barrels of crude oil into the northern Gulf of Mexico in 2010, overlapping spatially and temporally with the habitat of many pelagic fish species. Yet, it is unknown whether highly migratory species, such as mahi-mahi (Coryphaena hippurus), might detect and avoid oil contaminated waters. We tested the ability of control and oil-exposed juvenile mahi-mahi (15-45 mm) to avoid two dilutions of crude oil in a two-channel flume. Control fish avoided the higher concentration (27.1 µg/L Σ50PAH), while oil-exposed (24 h, 18.0 µg/L Σ50PAH) conspecifics did not. Electro-olfactogram (EOG) data demonstrated that both control and oil-exposed (24 h, 14.5 µg/L Σ50PAH) juvenile mahi-mahi (27-85 mm) could detect crude oil as an olfactory cue and that oil-exposure did not affect the EOG amplitude or duration in response to oil or other cues. These results show that a brief oil exposure impairs the ability of mahi-mahi to avoid oil and suggests that this alteration likely results from injury to higher order central nervous system processing rather than impaired olfactory physiology.
Subject(s)
Perciformes , Petroleum Pollution , Petroleum , Polycyclic Aromatic Hydrocarbons , Water Pollutants, Chemical , Animals , Avoidance Learning , Embryo, Nonmammalian , Gulf of MexicoABSTRACT
In fishes, olfactory cues evoke behavioral responses that are crucial to survival; however, the receptors, olfactory sensory neurons, are directly exposed to the environment and are susceptible to damage from aquatic contaminants. In 2010, 4.9 million barrels of crude oil were released into the northern Gulf of Mexico from the Deepwater Horizon disaster, exposing marine organisms to this environmental contaminant. We examined the ability of bicolor damselfish (Stegastes partitus), exposed to the water accommodated fraction (WAF) of crude oil, to respond to chemical alarm cue (CAC) using a two-channel flume. Control bicolor damselfish avoided CAC in the flume choice test, whereas WAF-exposed conspecifics did not. This lack of avoidance persisted following 8 days of control water conditions. We then examined the physiological response to CAC, brine shrimp rinse, bile salt, and amino acid cues using the electro-olfactogram (EOG) technique and found that WAF-exposed bicolor damselfish were less likely to detect CAC as an olfactory cue but showed no difference in EOG amplitude or duration compared to controls. These data indicate that a sublethal WAF exposure directly modifies detection and avoidance of CAC beyond the exposure period and may suggest reduced predator avoidance behavior in oil-exposed fish in the wild.
Subject(s)
Petroleum Pollution , Petroleum , Water Pollutants, Chemical , Animals , Gulf of Mexico , SmellABSTRACT
Individuals with end-stage diabetic peripheral neuropathy present with decreased pain sensation. Transient receptor potential vanilloid type 1 (TRPV1) is implicated in pain signaling and resides on sensory dorsal root ganglion (DRG) neurons. We investigated the expression and functional activity of TRPV1 in DRG neurons of the Ins2+/Akita mouse at 9 months of diabetes using immunohistochemistry, live single cell calcium imaging, and whole-cell patch-clamp electrophysiology. 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence assay was used to determine the level of Reactive Oxygen Species (ROS) in DRGs. Although TRPV1 expressing neuron percentage was increased in Ins2+/Akita DRGs at 9 months of diabetes compared to control, capsaicin-induced Ca2+ influx was smaller in isolated Ins2+/Akita DRG neurons, indicating impaired TRPV1 function. Consistently, capsaicin-induced Ca2+ influx was decreased in control DRG neurons cultured in the presence of 25 mM glucose for seven days versus those cultured with 5.5 mM glucose. The high glucose environment increased cytoplasmic ROS accumulation in cultured DRG neurons. Patch-clamp recordings revealed that capsaicin-activated currents decayed faster in isolated Ins2+/Akita DRG neurons as compared to those in control neurons. We propose that in poorly controlled diabetes, the accelerated rate of capsaicin-sensitive TRPV1 current decay in DRG neurons decreases overall TRPV1 activity and contributes to peripheral neuropathy.
Subject(s)
Calcium/metabolism , Capsaicin/pharmacology , Diabetic Neuropathies/metabolism , Ganglia, Spinal/drug effects , Neurons/drug effects , Pain/metabolism , TRPV Cation Channels/metabolism , Animals , Diabetic Neuropathies/genetics , Diabetic Neuropathies/pathology , Disease Models, Animal , Fluoresceins/chemistry , Fluorescent Dyes/chemistry , Ganglia, Spinal/metabolism , Ganglia, Spinal/pathology , Gene Expression Regulation , Glucose/pharmacology , Ion Transport/drug effects , Male , Membrane Potentials/drug effects , Membrane Potentials/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurons/metabolism , Neurons/pathology , Optical Imaging , Pain/genetics , Pain/physiopathology , Patch-Clamp Techniques , Primary Cell Culture , Reactive Oxygen Species/metabolism , Single-Cell Analysis , TRPV Cation Channels/geneticsABSTRACT
The outcome of a viral infection reflects the balance between virus virulence and host susceptibility. The clone 13 (Cl13) variant of lymphocytic choriomeningitis virus--a prototype of Old World arenaviruses closely related to Lassa fever virus--elicits in C57BL/6 and BALB/c mice abundant negative immunoregulatory molecules, associated with T-cell exhaustion, negligible T-cell-mediated injury, and high virus titers that persist. Conversely, here we report that in NZB mice, despite the efficient induction of immunoregulatory molecules and high viremia, Cl13 generated a robust cytotoxic T-cell response, resulting in thrombocytopenia, pulmonary endothelial cell loss, vascular leakage, and death within 6-8 d. These pathogenic events required type I IFN (IFN-I) signaling on nonhematopoietic cells and were completely abrogated by IFN-I receptor blockade. Thus, IFN-I may play a prominent role in hemorrhagic fevers and other acute virus infections associated with severe vascular pathology, and targeting IFN-I or downstream effector molecules may be an effective therapeutic approach.
Subject(s)
Interferon Type I/metabolism , Lassa Fever/virology , Vascular Diseases/virology , Animals , Bronchoalveolar Lavage , Cell Line , Cricetinae , Cytokines/metabolism , Female , Lassa virus , Lymphocytic Choriomeningitis/virology , Lymphocytic choriomeningitis virus/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred NZB , Mice, Transgenic , Signal Transduction , Stem Cells/chemistry , T-Lymphocytes, Cytotoxic/virology , Virus ActivationABSTRACT
A recent publication indicated that overexpression of Axl, a cellular receptor that negatively regulates Toll-like receptor signaling, enhanced the entry of viruses pseudotyped with the glycoprotein of lymphocytic choriomeningitis virus (LCMV) in vitro. In testing the biological relevance of these observations, we found differences in neither viral kinetics between LCMV infections of Axl(-/-) and wild-type mice nor T-cell responses prior to spontaneous viral clearance. Thus, Axl is not required for productive LCMV infection of mice.
Subject(s)
Arenaviridae Infections/physiopathology , Arenavirus/metabolism , Proto-Oncogene Proteins/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Virus Internalization , Animals , Arenavirus/physiology , Fluorescence , Mice , Mice, Inbred C57BL , Mice, Knockout , Proto-Oncogene Proteins/genetics , Receptor Protein-Tyrosine Kinases/genetics , Axl Receptor Tyrosine KinaseABSTRACT
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-2D(b) and/or H-2K(b) 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.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Murine pneumonia virus/immunology , Amino Acid Sequence , Animals , Antigens, Viral/genetics , Epitope Mapping , Epitopes, T-Lymphocyte/genetics , H-2 Antigens/metabolism , Histocompatibility Antigen H-2D/metabolism , Humans , Interferon-gamma/biosynthesis , Mice , Mice, Inbred C57BL , Murine pneumonia virus/genetics , Murine pneumonia virus/pathogenicity , Pneumovirus Infections/immunology , Pneumovirus Infections/virology , Viral Proteins/genetics , Viral Proteins/immunologyABSTRACT
We quantified CD8 T cells needed to cause type 1 diabetes and studied the anatomy of the CD8 T cell/beta (ß) cell interaction at the immunologic synapse. We used a transgenic model, in situ tetramer staining to distinguish antigen specific CD8 T cells from total T cells infiltrating islets and a variety of viral mutants selected for functional deletion(s) of various CD8 T cell epitopes. Twenty percent of CD8 T cells in the spleen were specific for all immunodominant and subdominant viral glycoprotein (GP) epitopes. CTLs to the immunodominant LCMV GP33-41 epitope accounted for 63% of the total (12.5% of tetramers). In situ hybridization analysis demonstrated only 1 to 2% of total infiltrating CD8 T cells were specific for GP33 CD8 T cell epitope, yet diabetes occurred in 94% of mice. The immunologic synapse between GP33 CD8 CTL and ß cell contained LFA-1 and perforin. Silencing both immunodominant epitopes (GP33, GP276-286) in the infecting virus led to a four-fold reduction in viral specific CD8 CTL responses, negligible lymphocyte infiltration into islets and absence of diabetes.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Diabetes Mellitus, Experimental/immunology , Diabetes Mellitus, Type 1/immunology , Immunodominant Epitopes/immunology , Insulin-Secreting Cells/immunology , Receptors, Antigen, T-Cell, alpha-beta/immunology , Animals , CD8-Positive T-Lymphocytes/pathology , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/pathology , Immunodominant Epitopes/genetics , Immunological Synapses/genetics , Immunological Synapses/immunology , Insulin-Secreting Cells/pathology , Mice , Mice, Transgenic , Receptors, Antigen, T-Cell, alpha-beta/geneticsABSTRACT
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, α-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.
Subject(s)
Dendritic Cells/virology , Lymphocytic choriomeningitis virus/genetics , Phenotype , Point Mutation/genetics , Viral Fusion Proteins/genetics , Animals , Cell Line , Dendritic Cells/metabolism , Dystroglycans/metabolism , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Luminescent Measurements , Lymphocytic choriomeningitis virus/metabolism , Mice , Mice, Inbred C57BL , Virus InternalizationABSTRACT
Measles virus (MV), a member of the family Paramyxoviridae and an exclusively human pathogen, is among the most infectious viruses. A progressive fatal neurodegenerative complication, subacute sclerosing panencephalitis (SSPE), occurs during persistent MV infection of the CNS and is associated with biased hypermutations of the viral genome. The observed hypermutations of A-to-G are consistent with conversions catalyzed by the adenosine deaminase acting on RNA (ADAR1). To evaluate the role of ADAR1 in MV infection, we selectively disrupted expression of the IFN-inducible p150 ADAR1 isoform and found it caused embryonic lethality at embryo day (E) 11-E12. We therefore generated p150-deficient and WT mouse embryo fibroblast (MEF) cells stably expressing the MV receptor signaling lymphocyte activation molecule (SLAM or CD150). The p150(-/-) but not WT MEF cells displayed extensive syncytium formation and cytopathic effect (CPE) following infection with MV, consistent with an anti-MV role of the p150 isoform of ADAR1. MV titers were 3 to 4 log higher in p150(-/-) cells compared with WT cells at 21 h postinfection, and restoration of ADAR1 in p150(-/-) cells prevented MV cytopathology. In contrast to infection with MV, p150 disruption had no effect on vesicular stomatitis virus, reovirus, or lymphocytic choriomeningitis virus replication but protected against CPE resulting from infection with Newcastle disease virus, Sendai virus, canine distemper virus, and influenza A virus. Thus, ADAR1 is a restriction factor in the replication of paramyxoviruses and orthomyxoviruses.
Subject(s)
Adenosine Deaminase/genetics , Adenosine Deaminase/metabolism , Embryonic Development/genetics , Mutation/genetics , SSPE Virus/genetics , Subacute Sclerosing Panencephalitis/genetics , Virus Replication/genetics , Animals , Antigens, CD/metabolism , Cell Line , DNA Primers/genetics , Fluorescent Antibody Technique , Gene Knockout Techniques , Green Fluorescent Proteins , Mice , Mice, Inbred C57BL , Protein Isoforms/genetics , RNA-Binding Proteins , Receptors, Cell Surface/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signaling Lymphocytic Activation Molecule Family Member 1ABSTRACT
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.
Subject(s)
Internship and Residency , Adult , Humans , Problem-Based Learning , Mentors , Quality Improvement , Internal Medicine/education , CurriculumABSTRACT
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.
Subject(s)
Heart Failure/physiopathology , Heart Ventricles/diagnostic imaging , Precision Medicine/statistics & numerical data , Registries , Stroke Volume/physiology , Ventricular Function, Left/physiology , Echocardiography , Follow-Up Studies , Heart Failure/diagnosis , Heart Failure/epidemiology , Heart Ventricles/physiopathology , Humans , Incidence , Massachusetts/epidemiology , Prospective Studies , Proteomics/methodsABSTRACT
The extracellular ATP/adenosine axis in the tumor microenvironment (TME) has emerged as an important immune-regulatory pathway. Nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), otherwise known as CD39, is highly expressed in the TME, both on infiltrating immune cells and tumor cells across a broad set of cancer indications. CD39 processes pro-inflammatory extracellular ATP to ADP and AMP, which is then processed by Ecto-5'-nucleotidase/CD73 to immunosuppressive adenosine. Directly inhibiting the enzymatic function of CD39 via an antibody has the potential to unleash an immune-mediated anti-tumor response via two mechanisms: 1) increasing the availability of immunostimulatory extracellular ATP released by damaged and/or dying cells, and 2) reducing the generation and accumulation of suppressive adenosine within the TME. Tizona Therapeutics has engineered a novel first-in-class fully human anti-CD39 antibody, TTX-030, that directly inhibits CD39 ATPase enzymatic function with sub-nanomolar potency. Further characterization of the mechanism of inhibition by TTX-030 using CD39+ human melanoma cell line SK-MEL-28 revealed an uncompetitive allosteric mechanism (α < 1). The uncompetitive mechanism of action enables TTX-030 to inhibit CD39 at the elevated ATP concentrations reported in the TME. Maximal inhibition of cellular CD39 ATPase velocity was 85%, which compares favorably to results reported for antibody inhibitors to other enzyme targets. The allosteric mechanism of TTX-030 was confirmed via mapping the epitope to a region of CD39 distant from its active site, which suggests possible models for how potent inhibition is achieved. In summary, TTX-030 is a potent allosteric inhibitor of CD39 ATPase activity that is currently being evaluated in clinical trials for cancer therapy.
Subject(s)
Adenosine Triphosphatases/drug effects , Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Apyrase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Antibodies, Monoclonal/chemistry , Antibody Affinity , Antineoplastic Agents/chemistry , Binding Sites, Antibody , Cell Line, Tumor , Enzyme Inhibitors/chemistry , HumansABSTRACT
Elevated seawater CO2 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 CO2 levels could affect the behaviour of large pelagic species. Here, we tested the effects of elevated CO2, 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 CO2 (~500 and ~1000 µatm pCO2) and temperature (21 °C and 25 °C). The effects of elevated CO2 were trait-specific with anxiety the only behaviour significantly affected. Juvenile S. lalandi reared at elevated CO2 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.
Subject(s)
Behavior, Animal , Carbon Dioxide/chemistry , Fishes/physiology , Seawater/chemistry , Animals , Anxiety , Hydrogen-Ion Concentration , Oceans and SeasABSTRACT
DC are a highly heterogeneous population that plays a critical role in host defense. We previously demonstrated that virus infection induces BM plasmacytoid DC (pDC) differentiation into CD11b(+) conventional DC (cDC) upon in vitro culture with Fms-like tyrosine kinase 3 ligand (Flt3L). Here we use immunoglobulin D-J rearrangements and pDC adoptive transfer to provide definitive proof supporting BM pDC conversion into CD11b(+) cDC during in vivo viral infection. We show that in vivo BM pDC conversion into CD11b(+) cDC relates to enhanced ability to prime virus-specific T cells. Furthermore, we demonstrate that in vivo pDC conversion does not rely on viral infection of BM pDC, but instead is mediated by type I IFN signaling. Finally, by exploiting recently identified pDC-specific Ab, we provide further characterizations of the BM pDC fraction that exhibits this broader developmental plasticity. Collectively, these data indicate that BM pDC actively contribute to the CD11b(+) cDC pool during in vivo viral infection and delineates molecular, functional, and phenotypic features of this novel developmental pathway.
Subject(s)
Bone Marrow/immunology , CD11b Antigen/immunology , Dendritic Cells/immunology , Lymphocytic choriomeningitis virus/immunology , Animals , Antigen Presentation/immunology , Interferon Type I/immunology , Mice , Mice, Inbred C57BLABSTRACT
We explored the mechanism of action of CD39 antibodies that inhibit ectoenzyme CD39 conversion of extracellular ATP (eATP) to AMP and thus potentially augment eATP-P2-mediated proinflammatory responses. Using syngeneic and humanized tumor models, we contrast the potency and mechanism of anti-CD39 mAbs with other agents targeting the adenosinergic pathway. We demonstrate the critical importance of an eATP-P2X7-ASC-NALP3-inflammasome-IL18 pathway in the antitumor activity mediated by CD39 enzyme blockade, rather than simply reducing adenosine as mechanism of action. Efficacy of anti-CD39 activity was underpinned by CD39 and P2X7 coexpression on intratumor myeloid subsets, an early signature of macrophage depletion, and active IL18 release that facilitated the significant expansion of intratumor effector T cells. More importantly, anti-CD39 facilitated infiltration into T cell-poor tumors and rescued anti-PD-1 resistance. Anti-human CD39 enhanced human T-cell proliferation and Th1 cytokine production and suppressed human B-cell lymphoma in the context of autologous Epstein-Barr virus-specific T-cell transfer. SIGNIFICANCE: Overall, these data describe a potent and novel mechanism of action of antibodies that block mouse or human CD39, triggering an eATP-P2X7-inflammasome-IL18 axis that reduces intratumor macrophage number, enhances intratumor T-cell effector function, overcomes anti-PD-1 resistance, and potentially enhances the efficacy of adoptive T-cell transfer.This article is highlighted in the In This Issue feature, p. 1631.
Subject(s)
Adenosine Triphosphate/metabolism , Antineoplastic Agents, Immunological/administration & dosage , Apyrase/antagonists & inhibitors , Inflammasomes/metabolism , Neoplasms/drug therapy , Animals , Antineoplastic Agents, Immunological/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Male , Mice , Neoplasm Transplantation , Neoplasms/immunology , Receptors, Purinergic P2X7/metabolism , Signal TransductionABSTRACT
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 CO2, and to test how these responses are influenced by variations in tolerance to elevated CO2 exhibited by the parents. Within-generation responses in gene expression to end-of-century predicted CO2 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 CO2 conditions. Our results show that both parental variation in tolerance and cross-generation exposure to elevated CO2 are crucial factors in determining the response of reef fish to changing ocean chemistry.