T cell autoreactivity is a hallmark of autoimmune diseases but can also benefit self-maintenance and foster tissue repair. Herein, we investigated whether heart-specific T cells exert salutary or ...detrimental effects in the context of myocardial infarction (MI), the leading cause of death worldwide. After screening more than 150 class-II-restricted epitopes, we found that myosin heavy chain alpha (MYHCA) was a dominant cardiac antigen triggering post-MI CD4+ T cell activation in mice. Transferred MYHCA614-629-specific CD4+ T (TCR-M) cells selectively accumulated in the myocardium and mediastinal lymph nodes (med-LN) of infarcted mice, acquired a Treg phenotype with a distinct pro-healing gene expression profile, and mediated cardioprotection. Myocardial Treg cells were also detected in autopsies from patients who suffered a MI. Noninvasive PET/CT imaging using a CXCR4 radioligand revealed enlarged med-LNs with increased cellularity in MI-patients. Notably, the med-LN alterations observed in MI patients correlated with the infarct size and cardiac function. Taken together, the results obtained in our study provide evidence showing that MI-context induces pro-healing T cell autoimmunity in mice and confirms the existence of an analogous heart/med-LN/T cell axis in MI patients.
Pseudomonas aeruginosa is a prevalent opportunistic human pathogen that, like other Gram-negative pathogens, secretes outer membrane vesicles. Vesicles are complex entities composed of a subset of ...envelope lipid and protein components that have been observed to interact with and be internalized by host cells. This study characterized the inflammatory responses to naturally produced P. aeruginosa vesicles and determined the contribution of vesicle Toll-like receptor (TLR) ligands and vesicle proteins to that response. Analysis of macrophage responses to purified vesicles by real-time PCR and enzyme-linked immunosorbent assay identified proinflammatory cytokines upregulated by vesicles. Intact vesicles were shown to elicit a profoundly greater inflammatory response than the response to purified lipopolysaccharide (LPS). Both TLR ligands LPS and flagellin contributed to specific vesicle cytokine responses, whereas the CpG DNA content of vesicles did not. Neutralization of LPS sensing demonstrated that macrophage responses to the protein composition of vesicles required the adjuvantlike activity of LPS to elicit strain specific responses. Protease treatment to remove proteins from the vesicle surface resulted in decreased interleukin-6 and tumor necrosis factor alpha production, indicating that the production of these specific cytokines may be linked to macrophage recognition of vesicle proteins. Confocal microscopy of vesicle uptake by macrophages revealed that vesicle LPS allows for binding to macrophage surfaces, whereas vesicle protein content is required for internalization. These data demonstrate that macrophage sensing of both LPS and protein components of outer membrane vesicles combine to produce a bacterial strain-specific response that is distinct from those triggered by individual, purified vesicle components.
Unmanned aerial vehicles (UAVs) have become a popular wildlife survey tool. Most research has focused on detecting wildlife using UAVs with less known about behavioral responses. We compared the ...behavioral responses of breeding blue-winged teal (Spatula discors) (n = 151) and northern shovelers (Spatula clypeata) (n = 46) on wetlands flown over with a rotary DJI Matrice 200 quadcopter and control wetlands without flights. Using a GoPro camera affixed to a spotting scope, we conducted focal individual surveys and recorded duck behaviors for 30 minutes before, during, and 30 minutes after UAV flights to determine if ducks flushed or changed in specific activities. We also conducted scan surveys during flights to examine flushing and movement on the entire wetland. Between 24 April and 27 May 2020, we conducted 42 paired (control and flown) surveys. Both teal and shovelers increased proportion of time engaged in overhead vigilance on flown wetlands from pre-flight to during flight (0.008 to 0.020 and 0.006 to 0.032 of observation time, respectively). Both species left the wetland more frequently during flights than ducks on control wetlands. Despite similarities between species, we observed marked differences in time each species spent on active (e.g., feeding, courtship, swimming), resting, and vigilant behaviors during flights. Overall, teal became less active during flights (0.897 to 0.834 of time) while shovelers became more active during this period (0.724 to 0.906 of time). Based upon scan surveys, ducks flushed in 38.1% of surveys while control wetlands only had a single (2.4%) flush during the flight time. We found launch distance was the most important predictor of whether ducks swam for cover or away from the UAV which could result in inaccurate counts. Ducks appear aware of UAVs during flights, but minimal behavioral shifts suggest negative fitness consequences are unlikely.
Misunderstandings about the influence of land-surface features on tornado frequency and other tornado-related misconceptions may affect how people prepare for and behave during hazardous weather ...events. This research uses a phone survey (n = 1804) to assess how participants in three regions of Tennessee perceive their local tornado characteristics (i.e., direction of travel, seasonality, and diurnal timing) and their belief in protection from land-surface features (i.e., hills, water bodies, and buildings). Region of residence influences most beliefs in local tornado characteristics, and demographic characteristics, specifically age and gender, also have some influence. Residents in hilly East Tennessee are more likely to believe they are protected by hills and underestimate the proportion of nocturnal tornadoes, while residents in West Tennessee are more likely to believe they are protected by water bodies, perhaps because of proximity to the Mississippi River. Outside of the typical severe-weather season, participants were uncertain of when tornadoes were likely to occur; specifically, they did not recognize their local wintertime tornado activity. Because public perceptions are related to local features, local organizations and personnel, for example National Weather Service offices and broadcast meteorologists, may be most helpful in dispelling these misconceptions.
•First systematic case analysis of climate-related non-economic loss and damage..•Intangible losses, damages and at-risk sentiments are pervasive across the world.•Most accounts about lived ...experiences with harm are from rich (not poor) countries..•Epistemological injustices underrepresent intangible harm among the poorest people.•Personal stories humanize loss and are an urgent wake-up call for policy makers.
A situated and socially engaged science of loss arising from climate change takes people’s lived experiences with risk and harm as its fundamental starting point. It foregrounds what losses occur, where and how, which of these losses matter most to people and why, and whether or not such losses are considered acceptable and potentially reversible. However, obtaining such insight is difficult if the many things people value, across space and time, are intangible, i.e. they cannot and perhaps should not be quantified, and hence are often overlooked and omitted. This is the case, for instance, for the symbolic and affective dimensions of culture and place, such as sense of belonging, personal and collective notions of identity, and ways of knowing and making sense of the world, all of which are already undermined by climate change. Here, we perform the first systematic comparative analysis of people-centered and place-specific experiences with climate-related harm to people’s values that are largely intangible and non-commensurable. We draw upon >100 published case studies from around the world to make visible and concrete what matters most to people and what is at stake in the context of climate-related hazards and impacts. We show that the same threats can produce vastly different outcomes, ranging from reversible damages to irreversible losses and anticipated future risks, across numerous value dimensions, for indigenous and non-indigenous families, communities, and countries at all levels of development. Through this analysis, we also empirically validate dimensions of harm that have been produced and reproduced in the literature, albeit often devoid of distinct substance, lived experiences, and intrinsic significance. We end by discussing ethical implications of the ‘one thousand ways’ to encounter harm and offer recommendations to overcome methodological challenges in advancing a science of loss grounded in place.
To diminish heart failure development after acute myocardial infarction (AMI), several preclinical studies have focused on influencing the inflammatory processes in the healing response post-AMI. The ...initial purpose of this healing response is to clear cell debris of the injured cardiac tissue and to eventually resolve inflammation and support scar tissue formation. This is a well-balanced reaction. However, excess inflammation can lead to infarct expansion, adverse ventricular remodeling and thereby propagate heart failure development. Different macrophage subtypes are centrally involved in both the promotion and resolution phase of inflammation. Modulation of macrophage subset polarization has been described to greatly affect the quality and outcome of healing after AMI. Therefore, it is of great interest to reveal the process of macrophage polarization to support the development of therapeutic targets. The current review summarizes (pre)clinical studies that demonstrate essential molecules involved in macrophage polarization that can be modulated and influence cardiac healing after AMI.
Background Peripheral leukocytes in patients with atopic dermatitis (AD) have elevated phosphodiesterase-4 activity, which is associated with production of proinflammatory mediators. OPA-15406 is a ...phosphodiesterase-4 inhibitor with high selectivity for phosphodiesterase-4-B. Objectives We sought to assess effectiveness and tolerability of topical OPA-15406 in patients with AD. Methods This was a randomized, double-blind, vehicle-controlled, phase-II study. Patients 10 to 70 years of age with mild or moderate AD received topical OPA-15406 0.3% (n = 41), OPA-15406 1% (n = 43), or vehicle (n = 37) twice daily for 8 weeks. Results The primary end point, Investigator Global Assessment of Disease Severity score of 0 or 1 with greater than or equal to 2-grade reduction, was met at week 4 in the OPA-15406 1% group ( P = .0165 vs vehicle). Mean percentage improvement from baseline Eczema Area and Severity Index score for OPA-15406 1% was notable in week 1 (31.4% vs 6.0% for vehicle; P = .0005), even larger in week 2 (39.0% vs 3.0%; P = .0001), and persisted for 8 weeks. Visual analog scale pruritus scores improved from moderate to mild within the first week in the OPA-15406 1% group (36.4% mean change; P = .0011). OPA-15406 levels in blood were negligible. Incidence of adverse events was low, with most events mild in intensity. Limitations Further confirmatory phase-III studies are required. Conclusion OPA-15406 ointment may provide an effective therapeutic modality for patients with mild to moderate AD.
Genomic resources are becoming available for Pisum but to link these to phenotypic diversity requires well marked populations segregating for relevant traits. Here we describe two such resources. Two ...recombinant inbred populations, derived from wide crosses in Pisum are described. One high resolution mapping population involves cv Caméor, for which the first pea whole genome assembly was obtained, crossed to JI0281, a basally divergent P. sativum sativum landrace from Ethiopia. The other is an inter sub-specific cross between P. s. sativum and the independently domesticated P. s. abyssinicum. The corresponding genetic maps provide information on chromosome level sequence assemblies and identify structural differences between the genomes of these two Pisum subspecies. In order to visualise chromosomal translocations that distinguish the mapping parents, we created a simplified version of Threadmapper to optimise it for interactive 3-dimensional display of multiple linkage groups. The genetic mapping of traits affecting seed coat roughness and colour, plant height, axil ring pigmentation, leaflet number and leaflet indentation enabled the definition of their corresponding genomic regions. The consequence of structural rearrangement for trait analysis is illustrated by leaf serration. These analyses pave the way for identification of the underlying genes and illustrate the utility of these publicly available resources. Segregating inbred populations derived from wide crosses in Pisum, together with the associated marker data, are made publicly available for trait dissection. Genetic analysis of these populations is informative about chromosome scale assemblies, structural diversity in the pea genome and has been useful for the fine mapping of several discrete and quantitative traits.
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