Rational Drug Design Directed at Blocking the Initial Signaling Events in Lipopolysaccharide-Induced Sepsis.

Systemic Inflammatory Response Syndrome (SIRS) is classified as an immune system response to an infectious state. If left untreated, SIRS leads to sepsis, septic shock, end-organ dysfunction, and death. As a patient progresses through these stages, associations of acute respiratory distress, disseminated intravascular coagulation, and acute renal failure persist, resulting in millions of deaths annually. Lipopolysaccharide (LPS), a bacterial endotoxin, is released into the blood stream, triggering SIRS. LPS is found in the outer cell-wall of Gram-negative bacteria and is responsible for initiation of a devastating cytokine storm. One of the regions of LPS, lipid A, is a polyacylated glucosamine disaccharide that is primarily responsible for the pathological response of the immune system. LPS interacts with a plasma-LPS binding protein (LBP) via the lipid A region. LPS-LBP signals the CD14 receptor found on phagocytes and Toll-like receptors (TLR4), which results in a signaling pathway for inflammatory molecules like cytokines, TNFα, among numerous others. Antibiotic treatments alone prove insufficient; with numerous research data indicating increased bacterial resistance. It has been demonstrated that compounds resembling the lipid A region can act as antagonist to LPS signaling and would de-activate the inflammatory cascade. Blocking this cascade of events, in conjunction with other known sepsis treatments, would prove beneficial to patient prognoses. Lipid A analogues have been developed which are antagonists of LPS signaling and do not activate the inflammatory cascade. The most interesting antagonistsare the monosaccharides, which demonstrate that the glucosamine nitrogen can be replaced by oxygen and acyl groups can be replaced by more robust ethers

Prolonged anxiety on habituation of the cold shock response

Variation in the cold shock response (CSR) can be explained by physiological factors, habituation; and possibly "psychological" influences. Acute anxiety on cold-water immersion (CWI) increases the magnitude of the CSR in unhabituated volunteers and eliminates the reduction in the response seen after habituation. Recently it was demonstrated that habituation of the CSR includes a significant perceptual component. When the threat of CWI scenario was reduced, anxiety associated with being immersed was also reduced. In contrast, prolonged anxiety during repeat CWIs may prevent habituation. Therefore, it was hypothesized that prolonged anxiety reduces the extent of CSR habituation

Lineage Reconstruction of In Vitro Identified Antigen-Specific Autoreactive B Cells from Adaptive Immune Receptor Repertoires

The emergence, survival, growth and maintenance of autoreactive (AR) B-cell clones, the hallmark of humoral autoimmunity, leave their footprints in B-cell receptor repertoires. Collecting IgH sequences related to polyreactive (PR) ones from adaptive immune receptor repertoire (AIRR) datasets make the reconstruction and analysis of PR/AR B-cell lineages possible. We developed a computational approach, named ImmChainTracer, to extract members and to visualize clonal relationships of such B-cell lineages. Our approach was successfully applied on the IgH repertoires of patients suffering from monogenic hypomorphic RAG1 and 2 deficiency (pRD) or polygenic systemic lupus erythematosus (SLE) autoimmune diseases to identify relatives of AR IgH sequences and to track their fate in AIRRs. Signs of clonal expansion, affinity maturation and class-switching events in PR/AR and non-PR/AR B-cell lineages were revealed. An extension of our method towards B-cell expansion caused by any trigger (e.g., infection, vaccination or antibody development) may provide deeper insight into antigen specific B-lymphogenesis

Beneficial Effects of Resistance Exercise on Glycemic Control Are Not Further Improved by Protein Ingestion

Purpose: To investigate the mechanisms underpinning modifications in glucose homeostasis and insulin sensitivity 24 h after a bout of resistance exercise (RE) with or without protein ingestion. Methods: Twenty-four healthy males were assigned to a control (CON; n = 8), exercise (EX; n = 8) or exercise plus protein condition (EX+PRO; n = 8). Muscle biopsy and blood samples were obtained at rest for all groups and immediately post-RE (75% 1RM, 8×10 repetitions of leg-press and extension exercise) for EX and EX+PRO only. At 24 h post-RE (or post-resting biopsy for CON), a further muscle biopsy was obtained. Participants then consumed an oral glucose load (OGTT) containing 2 g of [U-13C] glucose during an infusion of 6, 6-[2H2] glucose. Blood samples were obtained every 10 min for 2 h to determine glucose kinetics. EX+PRO ingested an additional 25 g of intact whey protein with the OGTT. A final biopsy sample was obtained at the end of the OGTT. Results: Fasted plasma glucose and insulin were similar for all groups and were not different immediately post- and 24 h post-RE. Following RE, muscle glycogen was 26±8 and 19±6% lower in EX and EX+PRO, respectively. During OGTT, plasma glucose AUC was lower for EX and EX+PRO (75.1±2.7 and 75.3±2.8 mmol·L-1:120 min, respectively) compared with CON (90.6±4.1 mmol·L-1:120 min). Plasma insulin response was 13±2 and 21±4% lower for EX and CON, respectively, compared with EX+PRO. Glucose disappearance from the circulation was ~12% greater in EX and EX+PRO compared with CON. Basal 24 h post-RE and insulin-stimulated PAS-AS160/TBC1D4 phosphorylation was greater for EX and EX+PRO. Conclusions: Prior RE improves glycemic control and insulin sensitivity through an increase in the rate at which glucose is disposed from the circulation. However, co-ingesting protein during a high-glucose load does not augment this response at 24 h post-exercise in healthy, insulin-sensitive individuals

Acute anxiety predicts components of the cold shock response on cold water immersion:toward an integrated psychophysiological model of acute cold water survival

Introduction: Drowning is a leading cause of accidental death. In cold-water, sudden skin cooling triggers the life-threatening cold shock response (CSR). The CSR comprises tachycardia, peripheral vasoconstriction, hypertension, inspiratory gasp, and hyperventilation with the hyperventilatory component inducing hypocapnia and increasing risk of aspirating water to the lungs. Some CSR components can be reduced by habituation (i.e., reduced response to stimulus of same magnitude) induced by 3–5 short cold-water immersions (CWI). However, high levels of acute anxiety, a plausible emotion on CWI: magnifies the CSR in unhabituated participants, reverses habituated components of the CSR and prevents/delays habituation when high levels of anxiety are experienced concurrent to immersions suggesting anxiety is integral to the CSR.Purpose: To examine the predictive relationship that prior ratings of acute anxiety have with the CSR. Secondly, to examine whether anxiety ratings correlated with components of the CSR during immersion before and after induction of habituation.Methods: Forty-eight unhabituated participants completed one (CON1) 7-min immersion in to cold water (15°C). Of that cohort, twenty-five completed four further CWIs that would ordinarily induce CSR habituation. They then completed two counter-balanced immersions where anxiety levels were increased (CWI-ANX) or were not manipulated (CON2). Acute anxiety and the cardiorespiratory responses (cardiac frequency [fc], respiratory frequency [fR], tidal volume [VT], minute ventilation [E]) were measured. Multiple regression was used to identify components of the CSR from the most life-threatening period of immersion (1st minute) predicted by the anxiety rating prior to immersion. Relationships between anxiety rating and CSR components during immersion were assessed by correlation.Results: Anxiety rating predicted the fc component of the CSR in unhabituated participants (CON1; p < 0.05, r = 0.536, r2= 0.190). After habituation immersions (i.e., cohort 2), anxiety rating predicted the fR component of the CSR when anxiety levels were lowered (CON2; p < 0.05, r = 0.566, r2= 0.320) but predicted the fc component of the CSR (p < 0.05, r = 0.518, r2= 0.197) when anxiety was increased suggesting different drivers of the CSR when anxiety levels were manipulated; correlation data supported these relationships.Discussion: Acute anxiety is integral to the CSR before and after habituation. We offer a new integrated model including neuroanatomical, perceptual and attentional components of the CSR to explain these data

The effect of head-to-head competition on behavioral thermoregulation, thermophysiological strain and performance during exercise in the heat

Background It has been suggested that pacing is a thermoregulatory behaviour. We investigated the effect of competition on pacing, performance and thermophysiological strain during exercise in the heat and the psychological factors mediating competition effects. Method Eighteen males (maximum oxygen uptake [VO2max] 3.69 [0.44] L min−1) undertook a preliminary 20-km cool (wet-bulb globe temperature [WBGT] 12 °C) cycling time trial (TT) and three experimental 20-km trials (balanced order): (i) cool TT (CoolSolo); (ii) hot (WBGT 26 °C) TT (HotSolo); (iii) hot head-to-head competition (HotH2H). During TTs, an avatar of the participant’s performance was visible. During HotH2H, participants believed they were competing against another participant, but the competitor’s avatar replicated their own preliminary (cool) TT.ResultsTTs (min:sec [SD]) slowed with increased ambient temperature [CoolSolo 35:31 (2:11) versus HotSolo 36:10 (2:26); p = 0.011]. This effect was negated by competition; performances were not different between HotH2H [35:17 (1:52)] and CoolSolo (p = 0.160) and were quicker in HotH2H versus HotSolo (p = 0.001). End-exercise rectal temperature, mean body temperature and physiological strain index were (p < 0.05) higher in HotH2H than either solo condition. Despite faster performance and greater thermophysiological strain, rating of perceived exertion (RPE), thermal comfort and sensation, and perceptual strain index were not different between HotH2H and HotSolo. The difference in end-exercise rectal temperature between HotH2H and HotSolo was related to pre-exercise anticipatory heart rate response (r = 0.608, p = 0.010) and participants’ propensity for deliberate risk-taking (B = 0.12, p < 0.001), whereas self-reported resilience predicted change in performance times between HotH2H versus HotSolo (B = − 9.40, p = 0.010). Conclusion Competition changes the relationship between perceived and actual thermophysiological state, altering behavioural thermoregulation and increasing thermophysiological strain; this could increase heat-illness risk. Psychophysiological and psychological measures may identify susceptible individuals

Biological controls for standardization and interpretation of adaptive immune receptor repertoire profiling

Use of adaptive immune receptor repertoire sequencing (AIRR-seq) has become widespread, providing new insights into the immune system with potential broad clinical and diagnostic applications. However, like many high-throughput technologies, it comes with several problems, and the AIRR Community was established to understand and help solve them. We, the AIRR Community's Biological Resources Working Group, have surveyed scientists about the need for standards and controls in generating and annotating AIRR-seq data. Here, we review the current status of AIRR-seq, provide the results of our survey, and based on them, offer recommendations for developing AIRR-seq standards and controls, including future work. Keywords: B-cell Receptor (BCR); IG; T-cell Receptor (TCR); TR; antibody; immunoglobulin; immunology; inflammation; next generation sequencing (NGS)

The Erotic and the Vulgar: Visual Culture and Organized Labor's Critique of U.S. Hegemony in Occupied Japan

This essay engages the colonial legacy of postwar Japan by arguing that the political cartoons produced as part of the postwar Japanese labor movement’s critique of U.S. cultural hegemony illustrate how gendered discourses underpinned, and sometimes undermined, the ideologies formally represented by visual artists and the organizations that funded them. A significant component of organized labor’s propaganda rested on a corpus of visual media that depicted women as icons of Japanese national culture. Japan’s most militant labor unions were propagating anti-imperialist discourses that invoked an engendered/endangered nation that accentuated the importance of union roles for men by subordinating, then eliminating, union roles for women