Combinatorics on Words. New Aspects on Avoidability, Defect Effect, Equations and Palindromes

In this thesis we examine four well-known and traditional concepts of combinatorics on words. However the contexts in which these topics are treated are not the traditional ones. More precisely, the question of avoidability is asked, for example, in terms of k-abelian squares. Two words are said to be k-abelian equivalent if they have the same number of occurrences of each factor up to length k. Consequently, k-abelian equivalence can be seen as a sharpening of abelian equivalence. This fairly new concept is discussed broader than the other topics of this thesis. The second main subject concerns the defect property. The defect theorem is a well-known result for words. We will analyze the property, for example, among the sets of 2-dimensional words, i.e., polyominoes composed of labelled unit squares. From the defect effect we move to equations. We will use a special way to define a product operation for words and then solve a few basic equations over constructed partial semigroup. We will also consider the satisfiability question and the compactness property with respect to this kind of equations. The final topic of the thesis deals with palindromes. Some finite words, including all binary words, are uniquely determined up to word isomorphism by the position and length of some of its palindromic factors. The famous Thue-Morse word has the property that for each positive integer n, there exists a factor which cannot be generated by fewer than n palindromes. We prove that in general, every non ultimately periodic word contains a factor which cannot be generated by fewer than 3 palindromes, and we obtain a classification of those binary words each of whose factors are generated by at most 3 palindromes. Surprisingly these words are related to another much studied set of words, Sturmian words.

Choosing the target loci : heat shock factors HSF1 and HSF2 as regulators of cell stress and development

Heat shock factors (HSFs) are an evolutionarily well conserved family of transcription factors that coordinate stress-induced gene expression and direct versatile physiological processes in eukaryote organisms. The essentiality of HSFs for cellular homeostasis has been well demonstrated, mainly through HSF1-induced transcription of heat shock protein (HSP) genes. HSFs are important regulators of many fundamental processes such as gametogenesis, metabolic control and aging, and are involved in pathological conditions including cancer progression and neurodegenerative diseases. In each of the HSF-mediated processes, however, the detailed mechanisms of HSF family members and their complete set of target genes have remained unknown. Recently, rapid advances in chromatin studies have enabled genome-wide characterization of protein binding sites in a high resolution and in an unbiased manner. In this PhD thesis, these novel methods that base on chromatin immunoprecipitation (ChIP) are utilized and the genome-wide target loci for HSF1 and HSF2 are identified in cellular stress responses and in developmental processes. The thesis and its original publications characterize the individual and shared target genes of HSF1 and HSF2, describe HSF1 as a potent transactivator, and discover HSF2 as an epigenetic regulator that coordinates gene expression throughout the cell cycle progression. In male gametogenesis, novel physiological functions for HSF1 and HSF2 are revealed and HSFs are demonstrated to control the expression of X- and Y-chromosomal multicopy genes in a silenced chromatin environment. In stressed human cells, HSF1 and HSF2 are shown to coordinate the expression of a wide variety of genes including genes for chaperone machinery, ubiquitin, regulators of cell cycle progression and signaling. These results highlight the importance of cell type and cell cycle phase in transcriptional responses, reveal the myriad of processes that are adjusted in a stressed cell and describe novel mechanisms that maintain transcriptional memory in mitotic cell division.

Characteristics of urban heat island (UHI) in a high latitude coastal city - a case study of Turku, SW Finland

The term urban heat island (UHI) refers to the common situation in which the city is warmer than its rural surroundings. In this dissertation, the local climate, and especially the UHI, of the coastal city of Turku (182,000 inh.), SW Finland, was studied in different spatial and temporal scales. The crucial aim was to sort out the urban, topographical and water body impact on temperatures at different seasons and times of the day. In addition, the impact of weather on spatiotemporal temperature differences was studied. The relative importance of environmental factors was estimated with different modelling approaches and a large number of explanatory variables with various spatial scales. The city centre is the warmest place in the Turku area. Temperature excess relative to the coldest sites, i.e. rural areas about 10 kilometers to the NE from the centre, is on average 2 °C. Occasionally, the UHI intensity can be even 10 °C. The UHI does not prevail continuously in the Turku area, but occasionally the city centre can be colder than its surroundings. Then the term urban cool island or urban cold island (UCI) is used. The UCI is most common in daytime in spring and in summer, whereas during winter the UHI prevails throughout the day. On average, the spatial temperature differences are largest in summer, whereas the single extreme values are often observed in winter. The seasonally varying sea temperature causes the shift of relatively warm areas towards the coast in autumn and inland in spring. In the long term, urban land use was concluded to be the most important factor causing spatial temperature differences in the Turku area. The impact was mainly a warming one. The impact of water bodies was emphasised in spring and autumn, when the water temperature was relatively cold and warm, respectively. The impact of topography was on average the weakest, and was seen mainly in proneness of relatively low-lying places for cold air drainage during night-time. During inversions, however, the impact of topography was emphasised, occasionally outperforming those of urban land use and water bodies.

Working fluid selection and design of small-scale waste heat recovery systems based on organic Rankine cycles

Demand for the use of energy systems, entailing high efficiency as well as availability to harness renewable energy sources, is a key issue in order to tackling the threat of global warming and saving natural resources. Organic Rankine cycle (ORC) technology has been identified as one of the most promising technologies in recovering low-grade heat sources and in harnessing renewable energy sources that cannot be efficiently utilized by means of more conventional power systems. The ORC is based on the working principle of Rankine process, but an organic working fluid is adopted in the cycle instead of steam. This thesis presents numerical and experimental results of the study on the design of small-scale ORCs. Two main applications were selected for the thesis: waste heat re- covery from small-scale diesel engines concentrating on the utilization of the exhaust gas heat and waste heat recovery in large industrial-scale engine power plants considering the utilization of both the high and low temperature heat sources. The main objective of this work was to identify suitable working fluid candidates and to study the process and turbine design methods that can be applied when power plants based on the use of non-conventional working fluids are considered. The computational work included the use of thermodynamic analysis methods and turbine design methods that were based on the use of highly accurate fluid properties. In addition, the design and loss mechanisms in supersonic ORC turbines were studied by means of computational fluid dynamics. The results indicated that the design of ORC is highly influenced by the selection of the working fluid and cycle operational conditions. The results for the turbine designs in- dicated that the working fluid selection should not be based only on the thermodynamic analysis, but requires also considerations on the turbine design. The turbines tend to be fast rotating, entailing small blade heights at the turbine rotor inlet and highly supersonic flow in the turbine flow passages, especially when power systems with low power outputs are designed. The results indicated that the ORC is a potential solution in utilizing waste heat streams both at high and low temperatures and both in micro and larger scale appli- cations.

Heat storage rate and acute fatigue in rats

Thermal environmental stress can anticipate acute fatigue during exercise at a fixed intensity (%VO2max). Controversy exists about whether this anticipation is caused by the absolute internal temperature (Tint, ºC), by the heat storage rate (HSR, cal/min) or by both mechanisms. The aim of the present study was to study acute fatigue (total exercise time, TET) during thermal stress by determining Tint and HSR from abdominal temperature. Thermal environmental stress was controlled in an environmental chamber and determined as wet bulb globe temperature (ºC), with three environmental temperatures being studied: cold (18ºC), thermoneutral (23.1ºC) or hot (29.4ºC). Six untrained male Wistar rats weighing 260-360 g were used. The animals were submitted to exercise at the same time of day in the three environments and at two treadmill velocities (21 and 24 m/min) until exhaustion. After implantation of a temperature sensor and treadmill adaptation, the animals were submitted to a Latin square experimental design using a 2 x 3 factorial scheme (velocity and environment), with the level of significance set at P<0.05. The results showed that the higher the velocity and the ambient temperature, the lower was the TET, with these two factors being independent. This result indicated that fatigue was independently affected by both the increase in exercise intensity and the thermal environmental stress. Fatigue developed at different Tint and HSR showed the best inverse relationship with TET. We conclude that HSR was the main anticipating factor of fatigue.

Hormone replacement therapy increases levels of antibodies against heat shock protein 65 and certain species of oxidized low density lipoprotein

Hormone replacement therapy (HRT) reduces cardiovascular risks, although the initiation of therapy may be associated with transient adverse ischemic and thrombotic events. Antibodies against heat shock protein (Hsp) and oxidized low density lipoprotein (LDL) have been found in atherosclerotic lesions and plasma of patients with coronary artery disease and may play an important role in the pathogenesis of atherosclerosis. The aim of the present study was to assess the effects of HRT on the immune response by measuring plasma levels of antibodies against Hsp 65 and LDL with a low and high degree of copper-mediated oxidative modification of 20 postmenopausal women before and 90 days after receiving orally 0.625 mg equine conjugate estrogen plus 2.5 mg medroxyprogesterone acetate per day. HRT significantly increased antibodies against Hsp 65 (0.316 ± 0.03 vs 0.558 ± 0.11) and against LDL with a low degree of oxidative modification (0.100 ± 0.01 vs 0.217 ± 0.02) (P<0.05 and P<0.001, respectively, ANOVA). The hormone-mediated immune response may trigger an inflammatory response within the vessel wall and potentially increase plaque burden. Whether or not this immune response is temporary or sustained and deleterious requires further investigation.

Thermoregulation in hypertensive men exercising in the heat with water ingestion

Hydration is recommended in order to decrease the overload on the cardiovascular system when healthy individuals exercise, mainly in the heat. To date, no criteria have been established for hydration for hypertensive (HY) individuals during exercise in a hot environment. Eight male HY volunteers without another medical problem and 8 normal (NO) subjects (46 ± 3 and 48 ± 1 years; 78.8 ± 2.5 and 79.5 ± 2.8 kg; 171 ± 2 and 167 ± 1 cm; body mass index = 26.8 ± 0.7 and 28.5 ± 0.6 kg/m²; resting systolic (SBP) = 142.5 and 112.5 mmHg and diastolic blood pressure (DBP) = 97.5 and 78.1 mmHg, respectively) exercised for 60 min on a cycle ergometer (40% of VO2peak) with (500 ml 2 h before and 115 ml every 15 min throughout exercise) or without water ingestion, in a hot humid environment (30ºC and 85% humidity). Rectal (Tre) and skin (Tsk) temperatures, heart rate (HR), SBP, DBP, double product (DP), urinary volume (Vu), urine specific gravity (Gu), plasma osmolality (Posm), sweat rate (S R), and hydration level were measured. Data were analyzed using ANOVA in a split plot design, followed by the Newman-Keuls test. There were no differences in Vu, Posm, Gu and S R responses between HY and NO during heat exercise with or without water ingestion but there was a gradual increase in HR (59 and 51%), SBP (18 and 28%), DP (80 and 95%), Tre (1.4 and 1.3%), and Tsk (6 and 3%) in HY and NO, respectively. HY had higher HR (10%), SBP (21%), DBP (20%), DP (34%), and Tsk (1%) than NO during both experimental situations. The exercise-related differences in SBP, DP and Tsk between HY and NO were increased by water ingestion (P < 0.05). The results showed that cardiac work and Tsk during exercise were higher in HY than in NO and the difference between the two groups increased even further with water ingestion. It was concluded that hydration protocol recommended for NO during exercise could induce an abnormal cardiac and thermoregulatory responses for HY individuals without drug therapy.

Leishmania infantum heat shock protein 83 for the serodiagnosis of tegumentary leishmaniasis

The serologic assay is an important tool in the diagnosis of leishmaniasis. One of the most commonly used tests is enzyme-linked immunosorbent assay (ELISA). Since total Leishmania promastigotes are used as antigen in the routine assay, false-positive reactions are frequent due to cross-reaction with sera from other diseases, mainly Chagas' disease. Therefore, an antigen that determines less cross-reactivity has been pursued for the serodiagnosis of leishmaniasis. In the present study we analyzed the use of recombinant Leishmania infantum heat shock protein (Hsp) 83 in ELISA for the serodiagnosis of cutaneous (N = 12) and mucocutaneous leishmaniasis (N = 14) and we observed the presence of anti-L. infantum Hsp 83 antibodies in all samples as well as anti-Leishmania total antigen antibodies. When cross-reactivity was tested, chronic Chagas' disease patients (N = 10) did not show any reactivity. Therefore, we consider this L. infantum Hsp 83 to be a good antigen for routine use for serodiagnosis of tegumentary leishmaniasis.

Effect of age and gender on sweat lactate and ammonia concentrations during exercise in the heat

The dependence of sweat composition and acidity on sweating rate (SR) suggests that the lower SR in children compared to adults may be accompanied by a higher level of sweat lactate (Lac-) and ammonia (NH3) and a lower sweat pH. Four groups (15 girls, 18 boys, 8 women, 8 men) cycled in the heat (42ºC, 20% relative humidity) at 50% VO2max for two 20-min bouts with a 10-min rest before bout 1 and between bouts. Sweat was collected into plastic bags attached to the subject's lower back. During bout 1, sweat from girls and boys had higher Lac- concentrations (23.6 ± 1.2 and 21.2 ± 1.7 mM; P < 0.05) than sweat from women and men (18.2 ± 1.9 and 14.8 ± 1.6 mM, respectively), but Lac- was weakly associated with SR (P > 0.05; r = -0.27). Sweat Lac- concentration dropped during exercise bout 2, reaching similar levels among all groups (overall mean = 13.7 ± 0.4 mM). Children had a higher sweat NH3 than adults during bout 1 (girls = 4.2 ± 0.4, boys = 4.6 ± 0.6, women = 2.7 ± 0.2, and men = 3.0 ± 0.2 mM; P < 0.05). This difference persisted through bout 2 only in females. On average, children's sweat pH was lower than that of adults (mean ± SEM, girls = 5.4 ± 0.2, boys = 5.0 ± 0.1, women = 6.2 ± 0.5, and men = 6.2 ± 0.4 for bout 1, and girls = 5.4 ± 0.2, boys = 6.5 ± 0.5, women = 5.2 ± 0.2, and men = 6.9 ± 0.4 for bout 2). This may have favored NH3 transport from plasma to sweat as accounted for by a significant correlation between sweat NH3 and H+ (r = 0.56). Blood pH increased from rest (mean ± SEM; 7.3 ± 0.02) to the end of exercise (7.4 ± 0.01) without differences among groups. These results, however, are representative of sweat induced by moderate exercise in the absence of acidosis.

Gentamicin-induced preconditioning of proximal tubular LLC-PK1 cells stimulates nitric oxide production but not the synthesis of heat shock protein

Nephrotoxicity is the main side effect of antibiotics such as gentamicin. Preconditioning has been reported to protect against injuries as ischemia/reperfusion. The objective of the present study was to determine the effect of preconditioning with gentamicin on LLC-PK1 cells. Preconditioning was induced in LLC-PK1 cells by 24-h exposure to 2.0 mM gentamicin (G/IU). After 4 or 15 days of preconditioning, cells were again exposed to gentamicin (2.0 mM) and compared to untreated control or G/IU cells. Necrosis and apoptosis were assessed by acridine orange and HOESCHT 33346. Nitric oxide (NO) and endothelin-1 were assessed by the Griess method and available kit. Heat shock proteins were analyzed by Western blotting. After 15 days of preconditioning, LLC-PK1 cells exhibited a significant decrease in necrosis (23.5 ± 4.3 to 6.5 ± 0.3%) and apoptosis (23.5 ± 4.3 to 6.5 ± 2.1%) and an increase in cell proliferation compared to G/IU. NO (0.177 ± 0.05 to 0.368 ± 0.073 µg/mg protein) and endothelin-1 (1.88 ± 0.47 to 2.75 ± 0.53 pg/mL) production significantly increased after 15 days of preconditioning compared to G/IU. No difference in inducible HSP 70, constitutive HSC 70 or HSP 90 synthesis in tubular cells was observed after preconditioning with gentamicin. The present data suggest that preconditioning with gentamicin has protective effects on proximal tubular cells, that involved NO synthesis but not reduction of endothelin-1 or production of HSP 70, HSC 70, or HSP 90. We conclude that preconditioning could be a useful tool to prevent the nephrotoxicity induced by gentamicin.

Effect of heat and moisture exchangers on the prevention of ventilator-associated pneumonia in critically ill patients

Ventilator-associated pneumonia (VAP) remains one of the major causes of infection in the intensive care unit (ICU) and is associated with the length of hospital stay, duration of mechanical ventilation, and use of broad-spectrum antibiotics. We compared the frequency of VAP 10 months prior to (pre-intervention group) and 13 months after (post-intervention group) initiation of the use of a heat and moisture exchanger (HME) filter. This is a study with prospective before-and-after design performed in the ICU in a tertiary university hospital. Three hundred and fourteen patients were admitted to the ICU under mechanical ventilation, 168 of whom were included in group HH (heated humidifier) and 146 in group HME. The frequency of VAP per 1000 ventilator-days was similar for both the HH and HME groups (18.7 vs 17.4, respectively; P = 0.97). Duration of mechanical ventilation (11 vs 12 days, respectively; P = 0.48) and length of ICU stay (11 vs 12 days, respectively; P = 0.39) did not differ between the HH and HME groups. The chance of developing VAP was higher in patients with a longer ICU stay and longer duration of mechanical ventilation. This finding was similar when adjusted for the use of HME. The use of HME in intensive care did not reduce the incidence of VAP, the duration of mechanical ventilation, or the length of stay in the ICU in the study population.

Effects of propofol on damage of rat intestinal epithelial cells induced by heat stress and lipopolysaccharides

Gut-derived endotoxin and pathogenic bacteria have been proposed as important causative factors of morbidity and death during heat stroke. However, it is still unclear what kind of damage is induced by heat stress. In this study, the rat intestinal epithelial cell line (IEC-6) was treated with heat stress or a combination of heat stress and lipopolysaccharide (LPS). In addition, propofol, which plays an important role in anti-inflammation and organ protection, was applied to study its effects on cellular viability and apoptosis. Heat stress, LPS, or heat stress combined with LPS stimulation can all cause intestinal epithelial cell damage, including early apoptosis and subsequent necrosis. However, propofol can alleviate injuries caused by heat stress, LPS, or the combination of heat stress and LPS. Interestingly, propofol can only mitigate LPS-induced intestinal epithelial cell apoptosis, and has no protective role in heat-stress-induced apoptosis. This study developed a model that can mimic the intestinal heat stress environment. It demonstrates the effects on intestinal epithelial cell damage, and indicated that propofol could be used as a therapeutic drug for the treatment of heat-stress-induced intestinal injuries.

From Escherichia coli heat-stable enterotoxin to mammalian endogenous guanylin hormones

The isolation of heat-stable enterotoxin (STa) from Escherichia coli and cholera toxin from Vibrio cholerae has increased our knowledge of specific mechanisms of action that could be used as pharmacological tools to understand the guanylyl cyclase-C and the adenylyl cyclase enzymatic systems. These discoveries have also been instrumental in increasing our understanding of the basic mechanisms that control the electrolyte and water balance in the gut, kidney, and urinary tracts under normal conditions and in disease. Herein, we review the evolution of genes of the guanylin family and STa genes from bacteria to fish and mammals. We also describe new developments and perspectives regarding these novel bacterial compounds and peptide hormones that act in electrolyte and water balance. The available data point toward new therapeutic perspectives for pathological features such as functional gastrointestinal disorders associated with constipation, colorectal cancer, cystic fibrosis, asthma, hypertension, gastrointestinal barrier function damage associated with enteropathy, enteric infection, malnutrition, satiety, food preferences, obesity, metabolic syndrome, and effects on behavior and brain disorders such as attention deficit, hyperactivity disorder, and schizophrenia.

Hypertension is associated with greater heat exchange during exercise recovery in a hot environment

Individuals with systemic arterial hypertension have a higher risk of heat-related complications. Thus, the aim of this study was to examine the thermoregulatory responses of hypertensive subjects during recovery from moderate-intensity exercise performed in the heat. A total of eight essential hypertensive (H) and eight normotensive (N) male subjects (age=46.5±1.3 and 45.6±1.4 years, body mass index=25.8±0.8 and 25.6±0.6 kg/m2, mean arterial pressure=98.0±2.8 and 86.0±2.3 mmHg, respectively) rested for 30 min, performed 1 h of treadmill exercise at 50% of maximal oxygen consumption, and rested for 1 h after exercise in an environmental chamber at 38°C and 60% relative humidity. Skin and core temperatures were measured to calculate heat exchange parameters. Mean arterial pressure was higher in the hypertensive than in the normotensive subjects throughout the experiment (P<0.05, unpaired t-test). The hypertensive subjects stored less heat (H=-24.23±3.99 W·m−2vs N=-13.63±2.24 W·m−2, P=0.03, unpaired t-test), experienced greater variations in body temperature (H=-0.62±0.05°C vsN=-0.35±0.12°C, P=0.03, unpaired t-test), and had more evaporated sweat (H=-106.1±4.59 W·m−2vs N=-91.15±3.24 W·m−2, P=0.01, unpaired t-test) than the normotensive subjects during the period of recovery from exercise. In conclusion, essential hypertensive subjects showed greater sweat evaporation and increased heat dissipation and body cooling relative to normotensive subjects during recovery from moderate-intensity exercise performed in hot conditions.