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Social and endocrine correlates of immune function in meerkats: implications for the immunocompetence handicap hypothesis.
Social status can mediate effects on the immune system, with profound consequences for individual health; nevertheless, most investigators of status-related disparities in free-ranging animals have used faecal parasite burdens to proxy immune function in the males of male-dominant species. We instead use direct measures of innate immune function (complement and natural antibodies) to examine status-related immunocompetence in both sexes of a female-dominant species. The meerkat is a unique model for such a study because it is a cooperatively breeding species in which status-related differences are extreme, evident in reproductive skew, morphology, behaviour, communication and physiology, including that dominant females naturally express the greatest total androgen (androstenedione plus testosterone) concentrations. We found that, relative to subordinates, dominant animals had reduced serum bacteria-killing abilities; also, relative to subordinate females, dominant females had reduced haemolytic complement activities. Irrespective of an individual's sex or social status, androstenedione concentrations (but not body condition, age or reproductive activity) negatively predicted concurrent immunocompetence. Thus, dominant meerkats of both sexes are immunocompromised. Moreover, in female meerkats, androstenedione perhaps acting directly or via local conversion, may exert a double-edged effect of promoting dominance and reproductive success at the cost of increased parasitism and reduced immune function. Given the prominent signalling of dominance in female meerkats, these findings may relate to the immunocompetence handicap hypothesis (ICHH); however, our data would suggest that the endocrine mechanism underlying the ICHH need not be mediated solely by testosterone and might explain trade-offs in females, as well as in males
Social and endocrine correlates of immune function in meerkats : implications for the immunocompetence
Social status can mediate effects on the immune system, with
profound consequences for individual health; nevertheless,
most investigators of status-related disparities in freeranging
animals have used faecal parasite burdens to
proxy immune function in the males of male-dominant
species. We instead use direct measures of innate immune
function (complement and natural antibodies) to examine
status-related immunocompetence in both sexes of a femaledominant
species. The meerkat is a unique model for such
a study because it is a cooperatively breeding species in
which status-related differences are extreme, evident in
reproductive skew, morphology, behaviour, communication
and physiology, including that dominant females naturally
express the greatest total androgen (androstenedione
plus testosterone) concentrations. We found that, relative
to subordinates, dominant animals had reduced serum
bacteria-killing abilities; also, relative to subordinate females,
dominant females had reduced haemolytic complement
activities. Irrespective of an individual’s sex or social status, androstenedione concentrations (but not body condition, age or reproductive activity) negatively
predicted concurrent immunocompetence. Thus, dominant meerkats of both sexes are
immunocompromised. Moreover, in female meerkats, androstenedione perhaps acting directly
or via local conversion, may exert a double-edged effect of promoting dominance and reproductive
success at the cost of increased parasitism and reduced immune function. Given the prominent
signalling of dominance in female meerkats, these findings may relate to the immunocompetence
handicap hypothesis (ICHH); however, our data would suggest that the endocrine mechanism
underlying the ICHH need not be mediated solely by testosterone and might explain trade-offs in
females, as well as in males.This work was supported by the National Science Foundation (IOS-1021633 to C.M.D. and IOS-1601685 to
C.M.D. and K.N.S.) and the Duke University Graduate School (Judy C. Woodruff Fellowship, Fred and Barbara
Sutherland Fellowship and Katherine Goodman Stern Fellowship to K.N.S.). Vehicle costs in the field were supported
by Duke University (research funds to C.M.D.). We relied on records of individual life histories and access to a field
site maintained by the KalahariMeerkat Project (KMP). During the span of this study, the KMP was supported by the
European Research Council (Research grant no. 294494 to T.H.C.-B.), the University of Cambridge, the University of
Zurich, the Mammal Research Institute at the University of Pretoria and Duke University.http://rsos.royalsocietypublishing.orgam2019Mammal Research Institut
ABA triblock copolymers: from controlled synthesis to controlled function
The ABA amphiphilic block copolymers, poly(hydroxyethyl methacrylate-hlock-methylphenylsilane-block-hydroxyethyl methacrylate) (PHEMA-PMPS-PHEMA) and poly[oligo(ethylene glycol) methyl ether methacrylate-block-methylphenylsilane-block-oligo(ethylene glycol). methyl ether methacrylate] (POEGMA-PMPS-POEGMA) were successfully synthesised via atom transfer radical polymerisation (ATRP). Macroinitiators suitable for the ATRP of oligo(ethylene glycol) methyl ether methacrylate and 2-hydroxyethyl methacrylate were synthesised from the condensation reaction of alpha,omega-dihalopolymethylphenylsilane and 2'-hydroxyethyl 2-bromo-2-methylpropanoate. The copolymers were characterised using H-1 NMR and C-13 NMR spectroscopy and molecular weight characteristics were determined using size exclusion chromatography and H-1 NMR. The aggregation behaviour of some of the copolymers in water was studied using transmission and scanning electron microscopy and dynamic light scattering. These revealed the prevalent aggregate species to be micelles. Larger aggregates of 300-1000 nm diameter were also observed. The UV induced degradation of the aggregates was studied by UV-Vis spectroscopy. The thermal behaviour of selected copolymers was studied by differential scanning calorimetry and microphase separation of the two components was demonstrated
Circulating BMP9 Protects the Pulmonary Endothelium during Inflammation-induced Lung Injury in Mice.
Rationale: Pulmonary endothelial permeability contributes to the high-permeability pulmonary edema that characterizes acute respiratory distress syndrome. Circulating BMP9 (bone morphogenetic protein 9) is emerging as an important regulator of pulmonary vascular homeostasis. Objectives:To determine whether endogenous BMP9 plays a role in preserving pulmonary endothelial integrity and whether loss of endogenous BMP9 occurs during LPS challenge. Methods: A BMP9-neutralizing antibody was administrated to healthy adult mice, and lung vasculature was examined. Potential mechanisms were delineated by transcript analysis in human lung endothelial cells. The impact of BMP9 administration was evaluated in a murine acute lung injury model induced by inhaled LPS. Levels of BMP9 were measured in plasma from patients with sepsis and from endotoxemic mice. Measurements and Main Results: Subacute neutralization of endogenous BMP9 in mice (N = 12) resulted in increased lung vascular permeability (P = 0.022), interstitial edema (P = 0.0047), and neutrophil extravasation (P = 0.029) compared with IgG control treatment (N = 6). In pulmonary endothelial cells, BMP9 regulated transcriptome pathways implicated in vascular permeability and cell-membrane integrity. Augmentation of BMP9 signaling in mice (N = 8) prevented inhaled LPS-induced lung injury (P = 0.0027) and edema (P < 0.0001). In endotoxemic mice (N = 12), endogenous circulating BMP9 concentrations were markedly reduced, the causes of which include a transient reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. In human patients with sepsis (N = 10), circulating concentratons of BMP9 were also markedly reduced (P < 0.0001). Conclusions: Endogenous circulating BMP9 is a pulmonary endothelial-protective factor, downregulated during inflammation. Exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in lung injury
Measurement of the cosmic ray spectrum above eV using inclined events detected with the Pierre Auger Observatory
A measurement of the cosmic-ray spectrum for energies exceeding
eV is presented, which is based on the analysis of showers
with zenith angles greater than detected with the Pierre Auger
Observatory between 1 January 2004 and 31 December 2013. The measured spectrum
confirms a flux suppression at the highest energies. Above
eV, the "ankle", the flux can be described by a power law with
index followed by
a smooth suppression region. For the energy () at which the
spectral flux has fallen to one-half of its extrapolated value in the absence
of suppression, we find
eV.Comment: Replaced with published version. Added journal reference and DO
Energy Estimation of Cosmic Rays with the Engineering Radio Array of the Pierre Auger Observatory
The Auger Engineering Radio Array (AERA) is part of the Pierre Auger
Observatory and is used to detect the radio emission of cosmic-ray air showers.
These observations are compared to the data of the surface detector stations of
the Observatory, which provide well-calibrated information on the cosmic-ray
energies and arrival directions. The response of the radio stations in the 30
to 80 MHz regime has been thoroughly calibrated to enable the reconstruction of
the incoming electric field. For the latter, the energy deposit per area is
determined from the radio pulses at each observer position and is interpolated
using a two-dimensional function that takes into account signal asymmetries due
to interference between the geomagnetic and charge-excess emission components.
The spatial integral over the signal distribution gives a direct measurement of
the energy transferred from the primary cosmic ray into radio emission in the
AERA frequency range. We measure 15.8 MeV of radiation energy for a 1 EeV air
shower arriving perpendicularly to the geomagnetic field. This radiation energy
-- corrected for geometrical effects -- is used as a cosmic-ray energy
estimator. Performing an absolute energy calibration against the
surface-detector information, we observe that this radio-energy estimator
scales quadratically with the cosmic-ray energy as expected for coherent
emission. We find an energy resolution of the radio reconstruction of 22% for
the data set and 17% for a high-quality subset containing only events with at
least five radio stations with signal.Comment: Replaced with published version. Added journal reference and DO
Measurement of the Radiation Energy in the Radio Signal of Extensive Air Showers as a Universal Estimator of Cosmic-Ray Energy
We measure the energy emitted by extensive air showers in the form of radio
emission in the frequency range from 30 to 80 MHz. Exploiting the accurate
energy scale of the Pierre Auger Observatory, we obtain a radiation energy of
15.8 \pm 0.7 (stat) \pm 6.7 (sys) MeV for cosmic rays with an energy of 1 EeV
arriving perpendicularly to a geomagnetic field of 0.24 G, scaling
quadratically with the cosmic-ray energy. A comparison with predictions from
state-of-the-art first-principle calculations shows agreement with our
measurement. The radiation energy provides direct access to the calorimetric
energy in the electromagnetic cascade of extensive air showers. Comparison with
our result thus allows the direct calibration of any cosmic-ray radio detector
against the well-established energy scale of the Pierre Auger Observatory.Comment: Replaced with published version. Added journal reference and DOI.
Supplemental material in the ancillary file
Stratification of asthma phenotypes by airway proteomic signatures
© 2019 Background: Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy in prediction of treatment responses and a need for better understanding of the underlying mechanisms. Objective: We sought to identify molecular subphenotypes of asthma defined by proteomic signatures for improved stratification. Methods: Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyze the proteomes of sputum supernatants from 246 participants (206 asthmatic patients) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms. Results: Analysis of the sputum proteome resulted in 10 clusters (ie, proteotypes) based on similarity in proteomic features, representing discrete molecular subphenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined 3 of these as highly eosinophilic, 3 as highly neutrophilic, and 2 as highly atopic with relatively low granulocytic inflammation. For each of these 3 phenotypes, logistic regression analysis identified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms. Conclusion: This study provides further stratification of asthma currently classified based on quantification of granulocytic inflammation and provided additional insight into their underlying mechanisms, which could become targets for novel therapies
Is it feasible and safe to wake cardiac arrest patients receiving mild therapeutic hypothermia after 12 hours to enable early neuro-prognostication. The Therapeutic Hypothermia and eArly Waking (THAW) trial protocol
Mild therapeutic hypothermia (MTH 33°C) post out-of-hospital cardiac arrest (OHCA) is widely accepted as standard of care. However, uncertainty remains around the dose and therapy duration. OHCA patients are usually kept sedated±paralyzed and ventilated for the first 24–36 hours, which allows for targeted temperature management, but makes neurological prognostication challenging. The aim of this study is to investigate the feasibility and safety of assessing the unconscious OHCA patient after 12 hours for early waking/extubation while continuing to provide MTH for 24 hours, and fever prevention for 72 hours by using an intravenous temperature management (IVTM) system and established conscious MTH anti-shiver regimens. This is a single-center, prospective, non-randomized observational study that will compare the results of early awakening (at 12 hours) with historical controls. A total of 50 consecutive unconscious survivors of OHCA, treated with MTH, who meet the Therapeutic Hypothermia and eArly Waking (THAW) inclusion criteria will be enrolled. The patient will receive MTH by using IVTM. After 12 hours of MTH, patients will be assessed by using strict clinical criteria to determine suitability for early waking and extubation. Once awake and extubated, MTH will continue for 24 hours with skin counter-warming and anti-shiver regimen followed fever prevention up to 72 hours. All patients will have serial electroencephalogram (EEG), somatic sensory potential, and neuro-biomarkers performed on admission to intensive care unit, 6 and 12 hours, then every 24 hours until 72 hours. The study has been approved by the National Research Ethics Service, Health Research Authority
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