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Thermal intolerance may limit activity in hostile environments. After heat illness, two physiologically distinct phenotypes evolve: heat tolerant (HT) and heat intolerant (HI). The recognition that heat illness alters gene expression justified revisiting the established physiological concept of HI. We used a DNA microarray to examine the global transcriptional response in peripheral blood mononuclear cells (PMBCs) from HI and HT phenotypes, categorized 2-mo postheat injury using a functional physiological heat-tolerance test (HTT, 40°C)-Recovery (R, 24°C) protocol. The impact of recurrent heat stress was studied in vitro using peripheral blood mononuclear cells (PBMCs) from controls (participants with no history of heat injury), HI, and HT (categorized by functional HTT) with a customized NanoString array. There were significant differences under basal conditions between the HI and HT. HI were more immunological alerted. Almost no shared genes were found between end-HTT and recovery phases, suggesting vast cellular plasticity. In HI, mitochondrial function was dysregulated, canonical pathways associated with exercise endurance-NRF2 and insulin were downregulated, whereas AMPK and peroxisome proliferator-activated receptor (PPAR) were upregulated. HT exhibited reciprocal responses, suggesting that energy dysregulation found in HI interfered with performance in the heat. The endoplasmic-reticulum stress response was also suppressed in HI. In vitro HTT (43°C) abolished differences between HI and HT PBMCs including the HSPs genes, whereas controls showed profound HSPs upregulation.

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1) The first evidence of the beneficial impact of Long-Term-Heat-Acclimation (LTHA) on cardio-vascular compliance was the positive inotropic response and improved left ventricular (LV) compliance noted when isolated hearts from LTHA rats were studied. Human echo study demonstrates that passive HA affects the right ventricle and the atria as well. 2) There is a cross-talk between vascular and cardiac compliance. Vascular compliance per se is defined by central venous pressure-Blood volume relationship-Global Vascular Compliance (GVC). It is determined by the sum of the vascular compliance of the vessels in every organ in any physiological state, varies with LTHA and thus influences cardiac performance. LTHA improves endothelial function, increases NO (nitric oxide) production, in-turn stimulating alterations in ECM (extracellular matrix) via the TGF ß1-SMAD pathway. 3) LTHA is associated with transformation from fast to slow myosin, heat acclimation ischemic/hypoxic cross-tolerance and alterations in the extracellular matrix. 4) A human translational study demonstrated improved LV compliance following bypass surgery in LTHA subjects compared to controls. 5) Diastolic dysfunction and the impact of comorbidities with vascular and non- vascular origins are major contributors to the syndrome of heart failure with preserved ejection function (HFPEF). Unfortunately, there is a paucity of treatment modalities that improve diastolic dysfunction. 6) In the current mini-review we suggest that LTHA may be beneficial to HFPEF patients by remodeling cardiac compliance and vascular response.

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PURPOSE: Exercise is a valuable intervention modality for patients post-myocardial infarction (MI). Aerobic and resistance training are both commonly used separately in cardiac rehabilitation. However, the effect of aerobic interval exercise combined with alternating sets of resistance training (super-circuit training, SCT) on cardiac electrophysiologic and anthropometric measures had not been thoroughly investigated. AIM: The primary objective of this study was to compare the effectiveness of moderate-intensity continuous-aerobic training (CAT) vs. SCT on cardiac electrical measures (resting electrocardiographic, ECG; a nd heart rate variability, HRV) in patients' post-MI presenting reduced left ventricular function. Second, to examine its effect on anthropometric measures. MATERIAL AND METHODS: Twenty-nine men post-MI with reduced left ventricular function were assigned randomly to either 12 weeks of CAT (n = 15) or SCT (n = 14). CAT group performed moderate-intensity activity. SCT group performed high-intensity exercise, alternating between resistance and aerobic training. Differences between CAT and SCT groups were done using independent t-tests, paired t-tests and effect size (ES). RESULTS: Participants in both groups improved their HRV measures (increase in HFnu; p < 0.05; ES > 0.51) and ECG (reduction in QT-dispersion; p < 0.05; ES > 0.51). Only the SCT group had significant improvements in waist circumference (p < 0.05). CONCLUSION: Exercise improves cardiac electrical measures post-MI. However, in comparison to CAT, SCT may yield greater anthropometric changes. In order to have improvements in cardiac electrical stability, clinicians working with post-MI patients may use both CAT and SCT. However, SCT might result in greater improvements.

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Exposure to high ambient temperature is a stressor that influences both biological and behavioral functions and has been previously shown to have an extensive impact on brain structure and function. Physiological, cellular and behavioral responses to heat-stress (HS) (40-41 °C, 2 h) were evaluated in adult male Sprague-Dawley rats. The effect of HS exposure before predator-scent stress (PSS) exposure (i.e., HS preconditioning) was examined. Finally, a possible mechanism of HS-preconditioning to PSS was investigated. Immunohistochemical analyses of chosen cellular markers were performed in the hippocampus and in the hypothalamic paraventricular nucleus (PVN). Plasma corticosterone levels were evaluated, and the behavioral assessment included the elevated plus-maze (EPM) and the acoustic startle response (ASR) paradigms. Endogenous levels of heat shock protein (HSP)-70 were manipulated using an amino acid (L-glutamine) and a pharmacological agent (Doxazosin). A single exposure to an acute HS resulted in decreased body mass (BM), increased body temperature and increased corticosterone levels. Additionally, extensive cellular, but not behavioral changes were noted. HS-preconditioning provided behavioral resiliency to anxiety-like behavior associated with PSS, possibly through the induction of HSP-70. Targeting of HSP-70 is an attractive strategy for stress-related psychopathology treatment.

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NEW FINDINGS: What is the topic of this review? This review outlines the history of research on epigenetic adaptations to heat exposure. The perspective taken is that adaptations reflect properties of hormesis, whereby low, repeated doses of heat induce adaptation (acclimation/acclimatization); whereas brief, life-threatening exposures can induce maladaptive responses. What advances does it highlight? The epigenetic mechanisms underlying acclimation/acclimatization comprise specific molecular programmes on histones that regulate heat shock proteins transcriptionally and protect the organism from subsequent heat exposures, even after long delays. The epigenetic signalling underlying maladaptive responses might rely, in part, on extensive changes in DNA methylation that are sustained over time and might contribute to later health challenges. ABSTRACT: Epigenetics plays a strong role in molecular adaptations to heat by producing a molecular memory of past environmental exposures. Moderate heat, over long periods of time, induces an 'adaptive' epigenetic memory, resulting in a condition of 'resilience' to future heat exposures or cross-tolerance to other forms of toxic stress. In contrast, intense, life-threatening heat exposures, such as severe heat stroke, can result in a 'maladaptive' epigenetic memory that can place an organism at risk of later health complications. These cellular memories are coded by post-translational modifications of histones on the nucleosomes and/or by changes in DNA methylation. They operate by inducing changes in the level of gene transcription and therefore phenotype. The adaptive response to heat acclimation functions, in part, by facilitating transcription of essential heat shock proteins and exhibits a biphasic short programme (maintaining DNA integrity, followed by a long-term consolidation). The latter accelerates acclimation responses after de-acclimation. Although less studied, the maladaptive responses to heat stroke appear to be coded in long-lasting changes in DNA methylation near the promoter region of genes involved with basic cell function. Whether these memories are also encoded in histone modifications is not yet known. There is considerable evidence that both adaptive and maladaptive epigenetic responses to heat can be inherited, although most evidence comes from lower organisms. Future challenges include understanding the signalling mechanisms responsible and discovering new ways to promote adaptive responses while suppressing maladaptive responses to heat, as all life forms adapt to life on a warming planet.

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The effect of 30 days of ß-alanine supplementation on neurophysiological responses of animals exposed to an acute heat stress (HS) was examined. Animals were randomized to one of three groups; exposed to HS (120 min at 40-41 °C) and fed a normal diet (EXP; n = 12); EXP and supplemented with ß-alanine (EXP + BA; n = 10); or not exposed (CTL; n = 10). Hippocampal (CA1, CA3 and DG) and hypothalamic (PVN) immunoreactive (ir) cell numbers of COX2, IBA-1, BDNF, NPY and HSP70 were analyzed. Three animals in EXP and one in EXP-BA did not survive the HS, however no significant difference (p = 0.146) was noted in survival rate in EXP + BA. The % change in rectal temperature was significantly lower (p = 0.04) in EXP + BA than EXP. Elevations (p's < 0.05) in COX-2, IBA-1 and HSP70 ir-cell numbers were noted in animals exposed to HS in all subregions. COX-2 ir-cell numbers were attenuated for EXP + BA in CA1 (p = 0.02) and PVN (p = 0.015) compared to EXP. No difference in COX-2 ir-cell numbers was noted between CTL and EXP + BA at CA1. BDNF-ir cell numbers in CA1, DG and PVN were reduced (p's < 0.05) during HS compared to CTL. No difference in BDNF-ir cell numbers was noted between EXP + BA and CTL in CA3 and PVN. NPY-ir density was reduced in exposed animals in all subregions, but NPY-ir density for EXP-BA was greater than EXP in CA3 (p < 0.001) and PVN (p = 0.04). ß-Alanine supplementation attenuated the thermoregulatory and inflammatory responses and maintained neurotrophin and neuropeptide levels during acute HS. Further research is necessary to determine whether ß-alanine supplementation can increase survival rate during a heat stress.

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Blood-contaminated fingermarks (FMs) found in violent crime scenes may directly connect the suspect to the crime by linking the FM to the suspect and the DNA from the blood to the victim. However, marks that are incomparable are considered "dead-evidence" as the link to the suspect is lost. In this study, a novel approach was attempted to uncover the trace amount of touch DNA of the suspect in such marks. We examined the effect of two enhancement methods, ninhydrin (NIN) and amido black (AB), on DNA recovery from blood-contaminated FMs. A total of 108 fingerprints were deposited in three sets of depleted blood prints, blood-contaminated FMs, and latent FMs. All FMs were developed by either NIN or AB, or left undeveloped as reference followed by the quantification of the total DNA amount. This work shows that while AB had a detrimental effect on the quantity of blood-derived DNA specifically, reducing it by half, no similar effect was observed for touch DNA in latent FMs. This reduction led to the alteration of the major-to-minor DNA profile ratio to 70:30, thus enabling to obtain two distinct DNA profiles of the suspect from the touch DNA as well as the victim's profile from the blood. From an operational perspective, the use of AB in crime scenes may have an added value to retrieve the crucial DNA profile of the suspect, thus resurrecting a "dead-evidence."

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Traumatic brain injury (TBI), caused by mechanical impact to the brain, is a leading cause of death and disability among young adults, with slow and often incomplete recovery. Preemptive treatment strategies may increase the injury resilience of high-risk populations such as soldiers and athletes. In this work, the xanthophyll carotenoid Astaxanthin was examined as a potential nutritional preconditioning method in mice (sabra strain) to increase their resilience prior to TBI in a closed head injury (CHI) model. The effect of Astaxanthin pretreatment on heat shock protein (HSP) dynamics and functional outcome after CHI was explored by gavage or free eating (in pellet form) for 2 weeks before CHI. Assessment of neuromotor function by the neurological severity score (NSS) revealed significant improvement in the Astaxanthin gavage-treated group (100 mg/kg, ATX) during recovery compared to the gavage-treated olive oil group (OIL), beginning at 24 h post-CHI and lasting throughout 28 days (p < 0.007). Astaxanthin pretreatment in pellet form produced a smaller improvement in NSS vs. posttreatment at 7 days post-CHI (p < 0.05). Cognitive and behavioral evaluation using the novel object recognition test (ORT) and the Y Maze test revealed an advantage for Astaxanthin administration via free eating vs. standard chow during recovery post-CHI (ORT at 3 days, p < 0.035; improvement in Y Maze score from 2 to 29 days, p < 0.02). HSP profile and anxiety (open field test) were not significantly affected by Astaxanthin. In conclusion, astaxanthin pretreatment may contribute to improved recovery post-TBI in mice and is influenced by the form of administration.

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Due to an unfortunate misunderstanding, the top part of Figures 2 and 3 are not correctly displayed. The original article has been corrected and the proper version of Figures 2 and 3 is also published here.

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Astaxanthin is a powerful carotenoid antioxidant prevalent in marine organisms and approved as a food supplement. Recent studies have demonstrated Astaxanthin's beneficial attributes in various health states. Following initial reports of potential heat protective properties in Astaxanthin supplemented rats, we present here results of a novel study examining the effect of Astaxanthin supplementation on the heat shock response in rats in relation to core temperature (Tc) and the ensuing physiological strain. Two hours of heat stress at 41 °C during which rats developed their thermoregulatory hyperthermic plateau resulted in progressive increases in HSP72 and HSP27 in the Astaxanthin (Oleoresin)-treated group but not in the control (Olive oil) group. Enhanced elevation in HSPs suggests that Astaxanthin supplementation may augment the cellular stress protective response to heat stress.

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Heatstroke (HS) is an acute, progressive life-threatening emergency. Animals, including military working dogs (IDFMWD), rapidly activate cytoprotective processes, e.g., heat shock proteins (HSPs) and antioxidative molecules, in response to heat stress. We hypothesized that serum HSPs (eHSP72) and oxidative stress markers would differ in IDFMWD with a history of HS compared with controls and thus could be used to detect susceptibility to recurrent HS. eHSPs concentration, oxidative stress markers, and systemic physiological parameters were studied in dogs with and without histories of HS, undergoing indoor or outdoor training. Treadmill physical performance tests (PPTs) were conducted indoors at 22 °C (groups C-I and HS-I) or outdoors under heat stress conditions of 36 °C; 60% humidity (groups C-O and HS-O). Pre-, immediately post-, and 45 min post-PPT heart rate (HR), respiratory rate, and rectal temperature (Tre) were recorded in all dogs. Likewise, blood samples were collected and eHSP72, venous blood gas analysis, and lactate and creatine kinase activity (CK) were assayed. Serum uric acid (sUA) and total serum redox potential (TRP) were measured only in the indoor group. Immediately post-PPT under both environmental conditions, Tre, HR, eHSP, sUA, and TRP (only measured in indoor PPT) significantly (P < 0.05) increased, whereas venous blood pH and bicarbonate decreased significantly (P < 0.05). Between groups comparisons demonstrated significant differences in basal HR and post-PPT Tre immediately after outdoor PPT. eHSP72 induction, CK, sUA, and serum TRP remained significantly higher in the HS group during post-PPT recovery. Taken together, animals with a history of HS have different results, and this signature of previous HS may predict altered heat sensitivity.

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Objectives: To examine the supplementation effects of the xanthophyll carotenoid Astaxanthin on physical performance and exertional heat strain in humans. Design: A randomized double blind placebo controlled trial. Methods: Twenty two male participants (Age: 23.14 ± 3.5 y, height: 175 ± 6 cm, body mass: 69.6 ± 8.7 kg, % body fat: 16.8 ± 3.8) received placebo (PLA, n = 10) or Astaxanthin (ATX, n = 12) 12 mg/day Per os (P.O), for 30 days, and were tested pre and post-supplementation with a maximal oxygen uptake (VO2 Max) test and the heat tolerance test (HTT) (2 h walk at 40°C, 40% relative humidity (RH), 5 kph, 2% incline). NIH database registration no. NCT02088242. Gas exchange, Heart rate (HR), Relative perceived exertion (RPE), and blood lactate were measured during the VO2 Max test. Heart rate (HR), rectal (Trec), and skin (Tskin) temperatures, RPE, and sweat rate (SR) were monitored in the HTT. Serum heat shock protein 72 (HSP72), Creatine phospho-kinase (CPK), C-reactive protein (CRP), and lipid profile were measured before and after the test. Results: The rise in blood lactate caused by the VO2 Max test was significantly diminished in the ATX group (9.4 ± 3.1 and 13.0 ± 3.1 mmole*l-1 in the ATX and PLA groups, respectively P < 0.02), as was the change in oxygen uptake during recovery (-2.02 ± 0.64 and 0.83 ± 0.79% of VO2 Max in the ATX and PLA group, respectively, p = 0.001). No significant differences were observed in the anaerobic threshold or VO2 Max. In the HTT, no significant physiological or biochemical differences were observed (HR <120 bpm, Trec rose by ~1°C to <38°C, no difference in SR). Conclusions: Astaxanthin supplementation improved exercise recovery. No benefit was observed for ATX over PLA in response to heat stress. Further examination of Astaxanthin in higher exertional heat strain is required.

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[This corrects the article DOI: 10.1371/journal.pone.0188551.].

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INTRODUCTION: Exercise is considered a valuable nonpharmacological intervention modality in cardiac rehabilitation (CR) programs in patients with ischemic heart disease. The effect of aerobic interval exercise combined with alternating sets of resistance training (super-circuit training, SCT) on cardiac patients' with reduced left ventricular function, post-myocardial infarction (MI) has not been thoroughly investigated. AIM OF STUDY: to improve cardiac function with a novel method of combined aerobic-resistance circuit training in a randomized control trial by way of comparing the effectiveness of continuous aerobic training (CAT) to SCT on mechanical cardiac function. Secondary to compare their effect on aerobic fitness, manual strength, and quality of life in men post MI. Finally, to evaluate the safety and feasibility of SCT. METHODS: 29 men post-MI participants were randomly assigned to either 12-weeks of CAT (n = 15) or SCT (n = 14). Both groups, CAT and SCT exercised at 60%-70% and 75-85% of their heart rate reserve, respectively. The SCT group also engaged in intermittently combined resistance training. Primary outcome measure was echocardiography. Secondary outcome measures were aerobic fitness, strength, and quality of life (QoL). The effectiveness of the two training programs was examined via paired t-tests and Cohen's d effect size (ES). RESULTS: Post-training, only the SCT group presented significant changes in echocardiography (a reduction in E/e' and an increase in ejection fraction, P<0.05). Similarly, only the SCT group presented significant changes in aerobic fitness (an increase in maximal metabolic equivalent, P<0.05). In addition, SCT improvement in the physical component of QoL was greater than this observed in the CAT group. In both training programs, no adverse events were observed. CONCLUSION: Men post-MI stand to benefit from both CAT and SCT. However, in comparison to CAT, as assessed by echocardiography, SCT may yield greater benefits to the left ventricle mechanical function as well as to the patient's aerobic fitness and physical QoL. Moreover, the SCT program was found to be feasible as well as safe.

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The primary outcome of heat acclimation is increased thermotolerance, which stems from enhancement of innate cytoprotective pathways. These pathways produce "ON CALL" molecules that can combat stressors to which the body has never been exposed, via cross-tolerance mechanisms (heat acclimation-mediated cross-tolerance-HACT). The foundation of HACT lies in the sharing of generic stress signaling, combined with tissue/organ- specific protective responses. HACT becomes apparent when acclimatory homeostasis is achieved, lasts for several weeks, and has a memory. HACT differs from other forms of temporal protective mechanisms activated by exposure to lower "doses" of the stressor, which induce adaptation to higher "doses" of the same/different stressor; e.g., preconditioning, hormesis. These terms have been adopted by biochemists, toxicologists, and physiologists to describe the rapid cellular strategies ensuring homeostasis. HACT employs two major protective avenues: constitutive injury attenuation and abrupt post-insult release of help signals enhanced by acclimation. To date, the injury-attenuating features seen in all organs studied include fast-responding, enlarged cytoprotective reserves with HSPs, anti-oxidative, anti-apoptotic molecules, and HIF-1α nuclear and mitochondrial target gene products. Using cardiac ischemia and brain hypoxia models as a guide to the broader framework of phenotypic plasticity, HACT is enabled by a metabolic shift induced by HIF-1α and there are less injuries caused by Ca+2 overload, via channel or complex-protein remodeling, or decreased channel abundance. Epigenetic markers such as post-translational histone modification and altered levels of chromatin modifiers during acclimation and its decline suggest that dynamic epigenetic mechanisms controlling gene expression induce HACT and acclimation memory, to enable the rapid return of the protected phenotype. In this review the link between in vivo physiological evidence and the associated cellular and molecular mechanisms leading to HACT and its difference from short-acting cross-tolerance strategies will be discussed.

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BACKGROUND: Moderate exercise training has been shown to decrease sudden cardiac death post myocardial infarction. However, the effects of intensive exercise are still controversial. METHODS AND RESULTS: Fourteen myocardial-infarcted rats were divided into sedentary (n=8) and intensive training groups (n=6) and 18 sham control rats to sedentary (n=10) and intensive training groups (n=8). Heart rate variability was obtained at weeks 1 and 8. The inducibility of ventricular tachycardia/fibrillation was assessed in a Langendorff system. Fast Fourier transforms were applied on the recorded ventricular tachycardia/fibrillations. Training reduces low to high frequency ratio of heart rate variability at week 8 compared with that at week 1 (P<0.05). In isolated hearts, the probability for ventricular tachycardia/fibrillation was decreased from 4.5±0.8% in sedentary controls to 1.56±0.2% in intensive training controls (P<0.05) and from 13.5±2.1% in the sedentary group to 5.4±1.2% in the intensive training group (P<0.01). Moreover, the pacing current required for ventricular fibrillation induction in the trained groups was increased following exercise (P<0.05). Fast Fourier transform analysis of ECG findings revealed an exercise-induced ventricular fibrillation transition from a narrow, single-peak spectrum at 17 Hz in sedentary controls to a broader range of peaks ranging from 13 to 22 Hz in the intensive training controls. CONCLUSIONS: Intensive exercise in infarcted rats leads to reduced ventricular fibrillation propensity and is associated with normalization of refractoriness and intrinsic spatiotemporal electrical variations.

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Early recognition of acute kidney injury (AKI) is important, as therapy is potentially more efficacious if instituted early in the course of disease. Urinary heat shock protein-72 to urinary creatinine ratio (uHSP72/uCr) was assessed as a diagnostic and prognostic marker in AKI in dogs. Fifty-three dogs were enrolled in five groups: healthy controls (n=11), urinary tract infection (n=10), chronic kidney disease (CKD; n=11), AKI (n=13), and acute decompensating CKD (n=8). Urinary heat shock protein-72 to urinary creatinine ratio was highest in the AKI group (P<0.001 when compared to the control and urinary tract infection groups, individually; P>0.05 compared to each of the other two groups). The area under the curve (AUC) for the receiver operator characteristic (ROC) analysis of uHSP72/uCr to predict AKI, compared to the control group, was 0.97. A cutoff value of 0.20ng/mg corresponded to sensitivity and specificity of 100% and 82%, respectively. Urinary heat shock protein-72 to urinary creatinine ratio was significantly lower in dogs categorized as survivors vs. non-survivors of AKI; ROC AUC, 0.91 (95% confidence intervals, 0.74-1.0). Urinary heat shock protein-72 to urinary creatinine ratio is a potentially useful diagnostic and prognostic biomarker of AKI in dogs.

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