There is an epidemic of chronic kidney disease of unknown origin (CKDu) primarily affecting younger men in Central America, especially El Salvador and Nicaragua. The primary hypothesis has included heat stress and dehydration. Although medication usage is widely viewed as a likely contributor to kidney damage, the association with chronic kidney disease in Central America has not been fully explored. This study investigated medication usage, symptom presentation, and kidney function among 524 outdoor workers in agricultural and non-agricultural industries enrolled in the Mesoamerican Nephropathy Occupational Study (MANOS) led by Boston University researchers. An overview of the literature on the adverse effects of medication on renal function and thermoregulation, with a focus on medications considered in MANOS, was conducted. Medication usage and symptom presentation on both a short- and long-term timeframe were explored in relation to kidney function measured by estimated glomerular filtration rate. Long-term usage of NSAIDS and potassium supplements was significantly associated with kidney function. Neither short- or long-term uses of acetaminophen, the most commonly used medication, were associated with kidney function. While several self-reported health symptoms were significantly associated with lower kidney function in crude models, the associations’ significance levels lessened after adjusting for age, country, and industry. In contrast, symptoms of chistata (a local term for painful urination) and lower abdominal pain three months prior to data collection each significantly predicted higher kidney function. The results of this exploratory, cross-sectional study present an opportunity for further study on how medications and symptoms, related to both nephrotoxicity and heat stress, could be associated with kidney function.

This thesis sought to evaluate whether the increased risk of heat-related illness observed in black-African descendants stems from impairements in local- and whole-body heat loss responses in this ethnic group. To evaluate this, in separate studies local- (study 1) and whole–body (study 2) heat loss responses were compared in young men (18-30 y) of black-African (n=21) and Caucasian (n=21) descent, matched for physical characteristics and fitness and born and raised in the same temperate environment. In study 1, we compared nitric oxide-dependent skin blood flow and sweating responses in young men of black-African (n=10) and Caucasian (n=10) descent during rest, exercise, and recovery in the heat. Both groups rested for 10-min, and then performed 50-min of moderate-intensity exercise at 200 W/m2, followed by 30-min of recovery in hot-dry heat (35°C, 20% RH). Local cutaneous vascular conductance (CVC%max) and sweat rate (SR) were measured at two forearm skin sites treated with a) lactated-Ringer (Control), or b) 10 mM NG-nitro-L-arginine methyl ester (L‐NAME, NO synthase-inhibitor). L-NAME significantly reduced CVC%max throughout rest, exercise, and recovery in both groups (both p<0.001). However, there were no significant main effects for the NO contribution to CVC%max between groups (all p>0.500). L-NAME significantly reduced local SR in both groups (both p<0.050). The NO contribution to SR was similar between groups such that L-NAME reduced SR relative to control at 40 and 50 min into exercise (both p<0.050). In study 2, we assessed whole-body total heat loss (evaporative + dry heat exchange) in black-African (n=11) and Caucasian (n=11) men using direct calorimetry. Participants performed three, 30-min bouts of semi-recumbent cycling at fixed metabolic heat productions (and therefore matched heat loss requirements between groups) of 200 (light), 250 (moderate), and 300 W/m2 (vigorous), each followed by 15-min recovery, in dry heat (40°C, ~13% relative humidity). Across all exercise bouts, dry (p=0.435) and evaporative (p=0.600) heat exchange did not differ significantly between groups. As such, total heat loss during light, moderate and vigorous exercise was similar between groups (p=0.777), averaging ((mean (SD)); 177 (10), 217 (13) and 244 (20) W/m2 in men of black-African descent, and 172 (13), 212 (17) and 244 (17) W/m2 in Caucasian men. Accordingly, body heat storage across all exercise bouts (summation of metabolic heat production and total heat loss) was also similar between the black-African (568 (142) kJ) and Caucasian groups (623 (124) kJ; p=0.356). This thesis demonstrates that ethnicity does not influence NO-dependent cutaneous vasodilation and sweating in healthy, young black-African descent and Caucasian men during exercise in the heat. Furthermore, we extend upon these observations by showing no differences in whole-body dry and evaporative heat exchange and therefore body heat storage.

Orientador: Jose Luiz Moraes Vasconcelos / Resumo: O objetivo do experimento foi avaliar a temperatura vaginal em parâmetros produtivos e reprodutivos. Vacas Holandesas lactantes n = 641 (209 primíparas 36,9 ± 6,54 kg de leite / d; 432 multíparas 43,9 ± 9,77 kg de leite / d) tiveram a temperatura vaginal monitorada através de termômetros, anexados a um dispositivo intravaginal como parte de um protocolo de IATF. A temperatura vaginal foi registrada a cada 10 minutos durante três dias. A temperatura ambiente e a umidade relativa (ITU) foram mensuradas usando um termômetro externo colocado dentro do barracão. Os dados foram analisados com SAS 9.4 usando correlação de Pearson, ANOVA e regressão logística. Calculou-se o estresse térmico com base na porcentagem de tempo que a vaca ficou com uma temperatura vaginal ≥ 39,1°C (PCT). As vacas foram classificadas através de quartis (AltaPCT (3º quartil; PCT-60%) e BaixaPCT; PCT-16%) para PCT e o mediana para produção de leite, que eram diferentes para primíparas e multíparas. Houve uma baixa correlação entre ITU e produção de leite com PCT (r = 0,01), indicando maior variação na termorregulação. O BaixaPCT (22,4 e 13,9%) e o AltaPCT (12,6 e 9,7%) reduziram significativamente o P/AI no dia 30 e 52 pós-IA (P < 0,01) e sem interações com ordem, escore de condição corporal e ITU observados. A cor da pelagem e a espessura do couro não influenciaram o PCT (P > 0,1). Entretanto houve interação entre cor de pelagem, PCT e produção de leite, onde independente da PCT e produção de leite, vacas d... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

Orientador: José Fernando Garcia / Banca: Marcos Vinicius Gualberto Barbosa da Silva / Banca: Gisele Zoccal Mingoti / Banca: Guilherme de Paula Nogueira / Banca: Fabiano Antonio Cadioli / Resumo: RESUMO - Uma das questões mais interessantes que poderiam ser elucidadas empregando a análise de metilação em todo o genoma é como ela afeta a regulação da temperatura corporal em animais domésticos. A resposta a esta questão torna-se imperativa, particularmente no caso de bovinos de leite e corte, uma vez que as raças modernas mais populares descendem de ancestral comum, que derivou em duas subespécies (Bos taurus e Bos indicus) as quais respondem aos estímulos ambientais de formas opostas (raças de zonas temperadas ou adaptadas a regiões tropicais, respectivamente). Mapas de metilação do DNA genômico foram originados usando a técnica de RRBS à partir de células nucleadas do sangue de um grupo de bovinos Angus e Nelore puros, expostos ao estresse ambiental condicionado pelo calor. Os dados de metilação distribuídos ao longo dos cromossomos bovinos puderam ser representados graficamente, enfatizando padrão altamente homogêneo entre as amostras analisadas e a robustez do método. A cobertura de sequenciamento empregada foi suficientemente profunda (em todos os casos superior a 20 vezes o tamanho do genoma), permitindo concluir sobre a ocorrência de eventos de metilação do DNA possivelmente associados a alterações fisiológicas causadas pelo estresse térmico. A análise da metilação do DNA revelou 4.662 janelas metiladas diferencialmente (cada uma com 1.000 pares de bases), sendo a maioria (2.695) relacionada a diferenças entre as raças e não diretamente à resposta ao estresse tér... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: ABSTRACT - One of the most interesting questions that could be solved using genome-wide methylation analysis is how it affects the regulation of body temperature in domestic animals. The answer to this question becomes imperative, particularly in the case of dairy and beef cattle, since modern breeds more frequently descended from a common ancestor, derived in two subspecies (Bos taurus and Bos indicus), which respond to environmental stimuli of different forms (breeds of temperate zones and adapted to tropical regions, respectively). Genomic maps were originated using RRBS DNA methylation data from nucleated blood cells of a group of pure Angus and Nelore cattle exposed to environmental heat strees. Methylation data distributed along the bovine chromosomes could be represented graphically, emphasizing a highly homogeneous pattern between the analyzed samples and the robustness of the method. The sequencing coverage used was sufficiently deep (in all cases higher than 20 times the genome size) leading to the identification of DNA methylation events possibly associated with physiological changes caused by heat stress. The DNA methylation analysis showed a total of 4,662 differentially methylated windows (each with 1,000 base pairs), most of them (2,695) related to differences between breeds and not to the response to heat stress. Analysis of the 214 common windows (comprising 103 genes) revealed epigenetic signals related to the heat stress response and recovery, which were ma... (Complete abstract click electronic access below) / Doutor

Skeletal muscle is a highly adaptable tissue that comprises approximately 40% of total body weight while accounting for up to 90% of whole-body oxygen consumption and energy expenditure during exercise. The loss of skeletal muscle protein and subsequent decrease in muscle mass (atrophy) that accompanies disuse results primarily from a decrease in intracellular protein synthesis combined with an increase in proteolytic activity. Interestingly, these processes of skeletal muscle atrophy are amplified by changes in mitochondrial capacity, with evidence suggesting that the maintenance of mitochondria during periods of disuse protects skeletal muscle against atrophy. Remarkably, rodents with denervated muscle are protected against muscle atrophy following whole-body heat stress. The mechanism of protection appears to be tied to the observed increases in heat shock protein (HSP) and PGC-1α, which accompany the heat stress. Without any published observations as to whether such heat-induced protection against muscle atrophy would translate to human muscle, the aim of this project was to determine the extent to which deep tissue heating (via pulsed shortwave diathermy) might provide protection against skeletal muscle atrophy.

<p>RNA-directed DNA methylation (RdDM) is a process by which epigenetic silencing is maintained at the boundary between genes and flanking transposable elements. In maize, RdDM is dependent on <i>Mediator of Paramutation 1 (Mop1</i>), a putative RNA dependent RNA polymerase. Here I show that although RdDM is essential for the maintenance of DNA methylation of a silenced <i>MuDR</i> transposon in maize, a loss of that methylation does not result in a restoration of activity of that element. Instead, heritable maintenance of silencing is maintained by histone modifications. At one terminal inverted repeat (TIR) of the element, heritable silencing is mediated via H3K9 and H3K27 dimethylation, even in the absence of DNA methylation. At the second TIR, heritable silencing is mediated by H3K27 trimethylation, a mark normally associated with somatically inherited gene silencing. I find that a brief exposure of high temperature in a <i>mop1</i> mutant rapidly reverses both of these modifications in conjunction with a loss of transcriptional silencing. These reversals are heritable, even in <i>mop1</i> wild type progeny in which methylation is restored at both TIRs. These observations suggest that DNA methylation is neither necessary to maintain silencing, nor is it sufficient to initiate silencing once it has been reversed. To leverage the specificity of our observations made at bench, I also performed a transcriptome analysis in <i>mop1</i> mutants under heat. I found that a substantial number of genes as well as a subset of TEs are reactivated in <i>mop1</i> mutants under heat, which is consistent with the effects I observed on <i>MuDR</i>. Interestingly, I found that <i>mop1</i>-specific reactivation of TEs is closely correlated with changes in expression of nearby genes, most of which are involved in metabolic transportation and sensing. This suggests that one function of <i>MOP1</i> is to prevent inappropriate expression of genes in this pathway when they are close to TEs. Taken together, my work will provide an opportunity to better understand the causes and consequences of TE silencing and reactivation, as well as the effects of TEs on gene regulation under stress conditions.</p>

Le stress thermique résulte d'une exposition à une température située au-delà de la plage optimale pour un organisme. L’impact du stress thermique est variable selon son intensité, allant d’un effet bénéfique à la mort de l’organisme. Mon travail de thèse a établi un modèle de stress thermique aigu (aHS pour acute Heat Stress) chez C. elegans et a étudié ses effets sur l'homéostasie cellulaire, le développement des vers et la réponse autophagique. Un aHS au cours du 4ème stade larvaire induit un retard de développement, mais aucune létalité ni stérilité. Ce stress de développement entraîne la fragmentation massive mais transitoire des mitochondries, la formation d'agrégats dans la matrice et la diminution de la respiration mitochondriale. En outre, l’aHS déclenche un flux autophagique associé à des événements de mitophagie dans de nombreux tissus et en particulier dans l'épiderme. Nous avons montré que la réponse autophagique à l’aHS était protectrice pour les animaux. De plus, nous avons découvert que dans l’épiderme, les mitochondries sont les principaux sites de biogenèse des autophagosomes, en conditions physiologique et en aHS. Nous avons également constaté que la protéine DRP-1 (dynamin related protein 1) est impliquée dans le processus de mitophagie induite par l'aHS. Chez les animaux mutants drp-1 soumis au aHS, la fission mitochondriale est impossible, l’autophagie est induite mais les autophagosomes sont anormaux et agrégés sur la mitochondrie. À partir de ces données, nous proposons que DRP-1 participe au contrôle de la qualité des mitochondries stressées en coordonnant la fission mitochondriale et la biogenèse des autophagosomes. J'ai également étudié plusieurs protéines pouvant être impliquées dans les zones de contact entre le réticulum endoplasmique et les mitochondries, ainsi que leurs rôles sur la morphologie mitochondriale et l'autophagie, dans des conditions physiologiques ou d’aHS. De plus, nous avons développé de nouveaux outils pour analyser les sites de contact ER-mitochondries. / Heat stress results from an exposure to a temperature beyond the optimum range of an organism. The impact of heat stress can range from beneficial to lethal due to the severity of stress. My thesis work established an acute heat stress (aHS) model in C. elegans and studied its effects on cell homeostasis, worm development and autophagy response. aHS during the 4th larval stage induces a developmental delay but no lethality or sterility. This developmental stress results in the massive but transitory fragmentation of mitochondria, the formation of aggregates in the matrix and the decrease of mitochondrial respiration. In addition, aHS triggers an active autophagy flux associated to mitophagy events in many tissues and particularly in epidermis. We showed that the autophagy response upon aHS is protective for the animals. Moreover, we discovered that in the epidermis, the mitochondria are the major sites for autophagosome biogenesis in both standard and aHS. We also found that the dynamin related protein DRP-1 is involved in aHS-induced mitophagy process. In drp-1 animals submitted to aHS, mitochondrial fission is unable to achieve, and despite autophagy induction the autophagosomes cluster and elongate abnormally on mitochondria. From these data, we propose that DRP-1 is involved in the quality control of stressed mitochondria by coordinating mitochondrial fission and autophagosomes biogenesis. I also studied several proteins which may be involved in contact zones between endoplasmic reticulum and mitochondria, and their roles on mitochondrial morphology and autophagy, in physiological or aHS conditions. Furthermore, we have developed new tools for further studying the ER-mitochondria contact sites.

The thesis deals with the airing of stable objects, especially the stables for dairy cows.

This thesis evaluated physiological responses of young and older adults during extreme heat events and the extent to which commonly recommended heat-health guidelines (indoor temperature limits) and heat mitigation strategies (cooling centres) are effective at limiting hyperthermia and cardiovascular burden. A multidisciplinary narrative review and three experimental studies were conducted. In the review, the mechanisms by which aging impairs the regulation of body temperature and hemodynamic stability, and how they may contribute to the increased risk of heat-related mortality and morbidity in older adults, were summarized. A lack of ecologically minded study designs in previous research evaluating the physiological responses supporting homeostasis and health during heat stress (i.e., body temperature regulation and cardiovascular stability) was also identified. The three experiments were therefore designed as day-long (8-9 hour) extreme heat simulations to 1) evaluate age-related alterations in thermoregulatory and cardiovascular function during peak heat conditions; 2) assess how these responses translate to indoor environments; and 3) quantify the effectiveness of cooling centers, a widely recommended heat mitigation strategy, for limiting hyperthermia and cardiovascular burden. In the first study, healthy older adults (age: 64-78 years; n=19) stored 87 kJ [95% confidence limits: 33, 141] more heat than their younger (age: 19-31 years; n=20) counterparts (328 [71] kJ vs. 241 [SD: 87]; P<0.001) during the first three hours of a 9-hour exposure to extreme heat (40°C and 15% relative humidity). This resulted in a 0.4°C [0.2, 0.6] greater increase in body core temperature in the older adults that was maintained throughout exposure (1.0 [0.3] vs 0.6 [0.3]°C; P<0.001). These findings were extended in the second study, wherein it was demonstrated that healthy older adults (age: 66-78 years, n=8) exhibit progressive elevations in body temperatures (P<0.001) and attenuations in cardiovascular autonomic function (P<0.001) during 8 hours of rest in conditions representative of those experienced indoors during extreme heat events. These ranged from an actively cooled environment (22°C), through indoor temperature thresholds recommended by Toronto Public Health (26°C) and the World Health Organization (31°C), to poorly insulated and ventilated homes and/or dwellings without access to air conditioning (36°C; 45% relative humidity in all conditions). In the third study, it was shown that short-term exposure to a cool environment midway through (hours 5-6) a day-long (9 hour) simulated heat event reduced core temperature in a group of healthy older adults (age: 67-78 years; n=8) by 0.8°C [0.6, 1.0] compared to an age-matched group not removed from the heat (from study 1). Despite this, core temperature rose rapidly upon return to the heat and was statistically equivalent in both groups by the end of exposure (37.8 [0.3] vs 37.9 [0.3]°C; P=0.011). The findings of this thesis indicate that even healthy older adults experience sustained elevations in body temperature and cardiovascular burden during extreme heat events and that commonly recommended heat-health guidelines (indoor temperature limits) and mitigation strategies (cooling centres) may not provide adequate protection. Collectively, this work represents a considerable advance in our understanding of the physiological burden experienced by older adults during hot weather and extreme heat events.

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