Influence of hip-flexion angle on hamstrings isokinetic activity in sprinters.

CONTEXT: Hamstrings strains are common and debilitating injuries in many sports. Most hamstrings exercises are performed at an inadequately low hip-flexion angle because this angle surpasses 70° at the end of the sprinting leg's swing phase, when most injuries occur. OBJECTIVE: To evaluate the influence of various hip-flexion angles on peak torques of knee flexors in isometric, concentric, and eccentric contractions and on the hamstrings-to-quadriceps ratio. DESIGN: Descriptive laboratory study. SETTING: Research laboratory. Patients and Other Participants: Ten national-level sprinters (5 men, 5 women; age = 21.2 ± 3.6 years, height = 175 ± 6 cm, mass = 63.8 ± 9.9 kg). Intervention(s): For each hip position (0°, 30°, 60°, and 90° of flexion), participants used the right leg to perform (1) 5 seconds of maximal isometric hamstrings contraction at 45° of knee flexion, (2) 5 maximal concentric knee flexion-extensions at 60° per second, (3) 5 maximal eccentric knee flexion-extensions at 60° per second, and (4) 5 maximal eccentric knee flexionextensions at 150° per second. Main Outcome Measure(s): Hamstrings and quadriceps peak torque, hamstrings-to-quadriceps ratio, lateral and medial hamstrings root mean square. RESULTS: We found no difference in quadriceps peak torque for any condition across all hip-flexion angles, whereas hamstrings peak torque was lower at 0° of hip flexion than at any other angle (P < .001) and greater at 90° of hip flexion than at 30° and 60° (P < .05), especially in eccentric conditions. As hip flexion increased, the hamstrings-to-quadriceps ratio increased. No difference in lateral or medial hamstrings root mean square was found for any condition across all hip-flexion angles (P > .05). CONCLUSIONS: Hip-flexion angle influenced hamstrings peak torque in all muscular contraction types; as hip flexion increased, hamstrings peak torque increased. Researchers should investigate further whether an eccentric resistance training program at sprint-specific hip-flexion angles (70° to 80°) could help prevent hamstrings injuries in sprinters. Moreover, hamstrings-to-quadriceps ratio assessment should be standardized at 80° of hip flexion.

Validation française de l'échelle d'expérience temporelle du plaisir [Validation of the Temporal Experience of Pleasure Scale (TEPS) in a French-speaking environment.]

INTRODUCTION: Anhedonia is defined as a diminished capacity to experience pleasant emotion and is commonly included among the negative symptoms of schizophrenia. However, if patients report experiencing a lower level of pleasure than controls, they report experiencing as much pleasure as controls with online measurements of emotion. OBJECTIVE: The Temporal Experience of Pleasure Scale (TEPS) measures pleasure experienced in the moment and in anticipation of future activities. The TEPS is an 18-item self-report measurement of anticipatory (10 items) and consummatory (eight items) pleasure. The goal of this paper is to assess the psychometric characteristics of the French translation of this scale. METHODS: A control sample was composed of 60 women and 22 men, with a mean age of 38.1 years (S.D.: 10.8). Thirty-six were without qualification and 46 with qualified professional diploma. A sample of 21 patients meeting DSM IV-TR criteria for schizophrenia was recruited among the community psychiatry service of the department of psychiatry in Lausanne. They were five women and 16 men; mean age was of 34.1 years (S.D.: 7.5). Ten obtained a professional qualification and 11 were without qualification. None worked in competitive employment. Their mean dose of chlorpromazine equivalent was 431mg (S.D.: 259). All patients were on atypical antipsychotics. The control sample fulfilled the TEPS and the Physical Anhedonia Scale (PAS). The patient sample fulfilled the TEPS and was independently rated on the Calgary Depression Scale and the Scale for Assessment of Negative Symptoms. For comparison with controls, patients were matched on age, sex and professional qualification. This required the supplementary recruitment of two control subjects. RESULTS: Results with the control sample indicate that the TEPS presents an acceptable internal validity with Crombach alphas of 0.84 for the total scale, 0.74 for the anticipatory pleasure scale and 0.79 for the consummatory pleasure scale. The confirmatory factor analysis indicated that the model is well adapted to our data (chi(2)/dl=1.333; df=134; p<0.0006; root mean square residual, RMSEA=0.064). External validity measured with the PAS showed R=-0.27 (p<0.05) for the consummatory scale and R=-0.26 for the total score. Comparisons between patients and matched controls indicated that patients were significantly lower than control on anticipatory pleasure (t=2.7, df(40), 2-tailed p=0.01; cohen's d=0.83) and on total score of the TEPS (t=2.8, df (40), 2-tailed p=0.01; cohen's d=0.87). The two samples did not differ on consummatory pleasure. The anticipatory pleasure factor and the total TEPS showed significant negative correlation with the SANS anhedonia, respectively R=-0.78 (p<0.01) for the anticipatory factor and R=-0.61 (p<0.01) for the total TEPS. There was also a negative correlation between the anticipatory factor and the SANS avolition of R=-0.50 (p<0.05). These correlations were maintained, with partial correlations controlling for depression and chlorpromazine equivalents. CONCLUSION: The results of this validation show that the French version of the TEPS has psychometric characteristics similar to the original version. These results highlight the discrepancy between results of direct or indirect report of experienced pleasure in patients with schizophrenia. Patients may have difficulties in anticipating the pleasure of future enjoyable activities, but not in experiencing pleasure once in an enjoyable activity. Medication and depression do not seems to modify our results, but this should be better controlled in a longitudinal study. The anticipatory versus consummatory pleasure distinction appears to be useful for the development of new psychosocial interventions, tailored to improve desire in patients suffering from schizophrenia. Major limitations of the study are the small size of patient sample and the under representation of men in the control sample.

Combining heat stress and moderate hypoxia reduces cycling time to exhaustion without modifying neuromuscular fatigue characteristics.

PURPOSE: This study investigated the isolated and combined effects of heat [temperate (22 °C/30 % rH) vs. hot (35 °C/40 % rH)] and hypoxia [sea level (FiO2 0.21) vs. moderate altitude (FiO2 0.15)] on exercise capacity and neuromuscular fatigue characteristics. METHODS: Eleven physically active subjects cycled to exhaustion at constant workload (66 % of the power output associated with their maximal oxygen uptake in temperate conditions) in four different environmental conditions [temperate/sea level (control), hot/sea level (hot), temperate/moderate altitude (hypoxia) and hot/moderate altitude (hot + hypoxia)]. Torque and electromyography (EMG) responses following electrical stimulation of the tibial nerve (plantar-flexion; soleus) were recorded before and 5 min after exercise. RESULTS: Time to exhaustion was reduced (P < 0.05) in hot (-35 ± 15 %) or hypoxia (-36 ± 14 %) compared to control (61 ± 28 min), while hot + hypoxia (-51 ± 20 %) further compromised exercise capacity (P < 0.05). However, the effect of temperature or altitude on end-exercise core temperature (P = 0.089 and P = 0.070, respectively) and rating of perceived exertion (P > 0.05) did not reach significance. Maximal voluntary contraction torque, voluntary activation (twitch interpolation) and peak twitch torque decreased from pre- to post-exercise (-9 ± 1, -4 ± 1 and -6 ± 1 % all trials compounded, respectively; P < 0.05), with no effect of the temperature or altitude. M-wave amplitude and root mean square activity were reduced (P < 0.05) in hot compared to temperate conditions, while normalized maximal EMG activity did not change. Altitude had no effect on any measured parameters. CONCLUSION: Moderate hypoxia in combination with heat stress reduces cycling time to exhaustion without modifying neuromuscular fatigue characteristics. Impaired oxygen delivery or increased cardiovascular strain, increasing relative exercise intensity, may have also contributed to earlier exercise cessation.

Effects of a 5-h hilly running on ankle plantar and dorsal flexor force and fatigability

This study aimed to examine the effects of a 5-h hilly run on ankle plantar (PF) and dorsal flexor (DF) force and fatigability. It was hypothesised that DF fatigue/fatigability would be greater than PF fatigue/fatigability. Eight male trail long distance runners (42.5 ± 5.9 years) were tested for ankle PF and DF maximal voluntary isokinetic contraction strength and fatigue resistance tests (percent decrement score), maximal voluntary and electrically evoked isometric contraction strength before and after the run. Maximal EMG root mean square (RMS(max)) and mean power frequency (MPF) values of the tibialis anterior (TA), gastrocnemius lateralis (GL) and soleus (SOL) EMG activity were calculated. The peak torque of the potentiated high- and low-frequency doublets and the ratio of paired stimulation peak torques at 10 Hz over 100 Hz (Db10:100) were analysed for PF. Maximal voluntary isometric contraction strength of PF decreased from pre- to post-run (-17.0 ± 6.2%; P < 0.05), but no significant decrease was evident for DF (-7.9 ± 6.2%). Maximal voluntary isokinetic contraction strength and fatigue resistance remained unchanged for both PF and DF. RMS(max) SOL during maximal voluntary isometric contraction and RMS(max) TA during maximal voluntary isokinetic contraction were decreased (P < 0.05) after the run. For MPF, a significant decrease for TA (P < 0.05) was found and the ratio Db10:100 decreased for PF (-6.5 ± 6.0%; P < 0.05). In conclusion, significant isometric strength loss was only detected for PF after a 5-h hilly run and was partly due to low-frequency fatigue. This study contradicted the hypothesis that neuromuscular alterations due to prolonged hilly running are predominant for DF.

The prediction of speed and incline in outdoor running in humans using accelerometry.

PURPOSE: To explore whether triaxial accelerometric measurements can be utilized to accurately assess speed and incline of running in free-living conditions. METHODS: Body accelerations during running were recorded at the lower back and at the heel by a portable data logger in 20 human subjects, 10 men, and 10 women. After parameterizing body accelerations, two neural networks were designed to recognize each running pattern and calculate speed and incline. Each subject ran 18 times on outdoor roads at various speeds and inclines; 12 runs were used to calibrate the neural networks whereas the 6 other runs were used to validate the model. RESULTS: A small difference between the estimated and the actual values was observed: the square root of the mean square error (RMSE) was 0.12 m x s(-1) for speed and 0.014 radiant (rad) (or 1.4% in absolute value) for incline. Multiple regression analysis allowed accurate prediction of speed (RMSE = 0.14 m x s(-1)) but not of incline (RMSE = 0.026 rad or 2.6% slope). CONCLUSION: Triaxial accelerometric measurements allows an accurate estimation of speed of running and incline of terrain (the latter with more uncertainty). This will permit the validation of the energetic results generated on the treadmill as applied to more physiological unconstrained running conditions.

Breakpoints in ventilation, cerebral and muscle oxygenation, and muscle activity during an incremental cycling exercise.

The aim of this study was to locate the breakpoints of cerebral and muscle oxygenation and muscle electrical activity during a ramp exercise in reference to the first and second ventilatory thresholds. Twenty-five cyclists completed a maximal ramp test on an electromagnetically braked cycle-ergometer with a rate of increment of 25 W/min. Expired gazes (breath-by-breath), prefrontal cortex and vastus lateralis (VL) oxygenation [Near-infrared spectroscopy (NIRS)] together with electromyographic (EMG) Root Mean Square (RMS) activity for the VL, rectus femoris (RF), and biceps femoris (BF) muscles were continuously assessed. There was a non-linear increase in both cerebral deoxyhemoglobin (at 56 ± 13% of the exercise) and oxyhemoglobin (56 ± 8% of exercise) concomitantly to the first ventilatory threshold (57 ± 6% of exercise, p > 0.86, Cohen's d < 0.1). Cerebral deoxyhemoglobin further increased (87 ± 10% of exercise) while oxyhemoglobin reached a plateau/decreased (86 ± 8% of exercise) after the second ventilatory threshold (81 ± 6% of exercise, p < 0.05, d > 0.8). We identified one threshold only for muscle parameters with a non-linear decrease in muscle oxyhemoglobin (78 ± 9% of exercise), attenuation in muscle deoxyhemoglobin (80 ± 8% of exercise), and increase in EMG activity of VL (89 ± 5% of exercise), RF (82 ± 14% of exercise), and BF (85 ± 9% of exercise). The thresholds in BF and VL EMG activity occurred after the second ventilatory threshold (p < 0.05, d > 0.6). Our results suggest that the metabolic and ventilatory events characterizing this latter cardiopulmonary threshold may affect both cerebral and muscle oxygenation levels, and in turn, muscle recruitment responses.

Repeated sprinting on natural grass impairs vertical stiffness but does not alter plantar loading in soccer players.

This study aimed to determine changes in spring-mass model (SMM) characteristics, plantar pressures, and muscle activity induced by the repetition of sprints in soccer-specific conditions; i.e., on natural grass with soccer shoes. Thirteen soccer players performed 6 × 20 m sprints interspersed with 20 s of passive recovery. Plantar pressure distribution was recorded via an insole pressure recorder device divided into nine areas for analysis. Stride temporal parameters allowed to estimate SMM characteristics. Surface electromyographic activity was monitored for vastus lateralis, rectus femoris, and biceps femoris muscles. Sprint time, contact time, and total stride duration lengthened from the first to the last repetition (+6.7, +12.9, and +9.3%; all P < 0.05), while flight time, swing time, and stride length remained constant. Stride frequency decrease across repetitions approached significance (-6.8%; P = 0.07). No main effect of the sprint number or any significant interaction between sprint number and foot region was found for maximal force, mean force, peak pressure and mean pressure (all P > 0.05). Center of mass vertical displacement increased (P < 0.01) with time, together with unchanged (both P > 0.05) peak vertical force and leg compression. Vertical stiffness decreased (-15.9%; P < 0.05) across trials, whereas leg stiffness changes were not significant (-5.9%; P > 0.05). Changes in root mean square activity of the three tested muscles over sprint repetitions were not significant. Although repeated sprinting on natural grass with players wearing soccer boots impairs their leg-spring behavior (vertical stiffness), there is no substantial concomitant alterations in muscle activation levels or plantar pressure patterns.

Effects of a 5-h hilly running on ankle plantar and dorsal flexor force and fatigability.

This study aimed to examine the effects of a 5-h hilly run on ankle plantar (PF) and dorsal flexor (DF) force and fatigability. It was hypothesised that DF fatigue/fatigability would be greater than PF fatigue/fatigability. Eight male trail long distance runners (42.5 ± 5.9 years) were tested for ankle PF and DF maximal voluntary isokinetic contraction strength and fatigue resistance tests (percent decrement score), maximal voluntary and electrically evoked isometric contraction strength before and after the run. Maximal EMG root mean square (RMS(max)) and mean power frequency (MPF) values of the tibialis anterior (TA), gastrocnemius lateralis (GL) and soleus (SOL) EMG activity were calculated. The peak torque of the potentiated high- and low-frequency doublets and the ratio of paired stimulation peak torques at 10 Hz over 100 Hz (Db10:100) were analysed for PF. Maximal voluntary isometric contraction strength of PF decreased from pre- to post-run (-17.0 ± 6.2%; P < 0.05), but no significant decrease was evident for DF (-7.9 ± 6.2%). Maximal voluntary isokinetic contraction strength and fatigue resistance remained unchanged for both PF and DF. RMS(max) SOL during maximal voluntary isometric contraction and RMS(max) TA during maximal voluntary isokinetic contraction were decreased (P < 0.05) after the run. For MPF, a significant decrease for TA (P < 0.05) was found and the ratio Db10:100 decreased for PF (-6.5 ± 6.0%; P < 0.05). In conclusion, significant isometric strength loss was only detected for PF after a 5-h hilly run and was partly due to low-frequency fatigue. This study contradicted the hypothesis that neuromuscular alterations due to prolonged hilly running are predominant for DF.

EADock: docking of small molecules into protein active sites with a multiobjective evolutionary optimization.

In recent years, protein-ligand docking has become a powerful tool for drug development. Although several approaches suitable for high throughput screening are available, there is a need for methods able to identify binding modes with high accuracy. This accuracy is essential to reliably compute the binding free energy of the ligand. Such methods are needed when the binding mode of lead compounds is not determined experimentally but is needed for structure-based lead optimization. We present here a new docking software, called EADock, that aims at this goal. It uses an hybrid evolutionary algorithm with two fitness functions, in combination with a sophisticated management of the diversity. EADock is interfaced with the CHARMM package for energy calculations and coordinate handling. A validation was carried out on 37 crystallized protein-ligand complexes featuring 11 different proteins. The search space was defined as a sphere of 15 A around the center of mass of the ligand position in the crystal structure, and on the contrary to other benchmarks, our algorithm was fed with optimized ligand positions up to 10 A root mean square deviation (RMSD) from the crystal structure, excluding the latter. This validation illustrates the efficiency of our sampling strategy, as correct binding modes, defined by a RMSD to the crystal structure lower than 2 A, were identified and ranked first for 68% of the complexes. The success rate increases to 78% when considering the five best ranked clusters, and 92% when all clusters present in the last generation are taken into account. Most failures could be explained by the presence of crystal contacts in the experimental structure. Finally, the ability of EADock to accurately predict binding modes on a real application was illustrated by the successful docking of the RGD cyclic pentapeptide on the alphaVbeta3 integrin, starting far away from the binding pocket.

Reticulocyte dynamic and hemoglobin variability in hemodialysis patients treated with Darbepoetin alfa and C.E.R.A.: a randomized controlled trial.

BACKGROUND: In a simulation based on a pharmacokinetic model we demonstrated that increasing the erythropoiesis stimulating agents (ESAs) half-life or shortening their administration interval decreases hemoglobin variability. The benefit of reducing the administration interval was however lessened by the variability induced by more frequent dosage adjustments. The purpose of this study was to analyze the reticulocyte and hemoglobin kinetics and variability under different ESAs and administration intervals in a collective of chronic hemodialysis patients. METHODS: The study was designed as an open-label, randomized, four-period cross-over investigation, including 30 patients under chronic hemodialysis at the regional hospital of Locarno (Switzerland) in February 2010 and lasting 2 years. Four subcutaneous treatment strategies (C.E.R.A. every 4 weeks Q4W and every 2 weeks Q2W, Darbepoetin alfa Q4W and Q2W) were compared with each other. The mean square successive difference of hemoglobin, reticulocyte count and ESAs dose was used to quantify variability. We distinguished a short- and a long-term variability based respectively on the weekly and monthly successive difference. RESULTS: No difference was found in the mean values of biological parameters (hemoglobin, reticulocytes, and ferritin) between the 4 strategies. ESAs type did not affect hemoglobin and reticulocyte variability, but C.E.R.A induced a more sustained reticulocytes response over time and increased the risk of hemoglobin overshooting (OR 2.7, p = 0.01). Shortening the administration interval lessened the amplitude of reticulocyte count fluctuations but resulted in more frequent ESAs dose adjustments and in amplified reticulocyte and hemoglobin variability. Q2W administration interval was however more favorable in terms of ESAs dose, allowing a 38% C.E.R.A. dose reduction, and no increase of Darbepoetin alfa. CONCLUSIONS: The reticulocyte dynamic was a more sensitive marker of time instability of the hemoglobin response under ESAs therapy. The ESAs administration interval had a greater impact on hemoglobin variability than the ESAs type. The more protracted reticulocyte response induced by C.E.R.A. could explain both, the observed higher risk of overshoot and the significant increase in efficacy when shortening its administration interval.Trial registrationClinicalTrials.gov NCT01666301.

Post-exercise parasympathetic reactivation and sensibility to hypoxia

Introduction Exposure to hypoxia leads to several reactions of the organism, which try to compensate the reduced oxygen level in the blood. Acute response is characterized by an increase in pulmonary ventilation (Hypoxia Ventilatory Response, HVR) and in cardiac output (cardiac response to hypoxia). Heart rate (HR) at rest and during exercise is higher at high altitude than at sea level, whereas HRmax is lower. These cardiac adaptations are partially explained by an increased sympathetic stimulation associated with a reduced parasympathetic tone (12). The precise mechanisms of HRmax decline in acute hypoxia are however still to be identified, although several hypothesis have been suggested, such as a direct effect of hypoxia on the electrophysiological properties, an influence of skeletal maximal VO2 or a modulation of the autonomic nervous system (8). Some authors have reported that endurance trained athletes present an increased sensitivity to hypoxia shown by a large reduction in VO2max and an important decrease in arterial saturation. (9,11, 13) A hypoxia test can assess the sensibility of chemoreceptors to the reduction of oxygen by calculating hypoxic ventilatory and cardiac responses, knowing that low sensibility is correlated with poor acclimatization. Two parameters results from the differences in ventilation (and heart rate) divided by the difference in the arterial oxygen saturation between normoxia and hypoxia (18). Objective The hypothesis tested by this study is that parasympathetic reactivation after moderate effort in hypoxic condition can be used as a marker of individual sensibility to hypoxia. Parasympathetic reactivation is a marker of vagal tone that predict endurance capacity and aerobic fitness (2,7). Methods Subjects This study uses data obtained from two groups of athletes participating into two larger studies about adaptation to hypoxia. One group is composed of elite athletes (Swiss ski mountaineering team), the other one of mid-level athletes (ski mountaineering amateurs). The particularity of this target population is that they often train at high altitude, and therefore could show a better response to hypoxia than athleltes of other disciplines. Protocol The athletes performed a submaximal exercise (6min run at 9 km/h, flat) followed by 10 min of seated rest either in an hypoxic chamber (simulated altitude of 3000m) or in normoxic conditions. During the resting phase parasympathetic reactivation was assessed by beat-to-beat HR measurements.A test of tolerance to altitude was also performed. Analysis Parasympathetic reactivation, assessed by the calculation of the root mean square of successive differences in the R-R intervals (RMSSD)(4), is compared to individual responses at altitude, in order to appreciate the correlation between the two phenomena.

The effect of workplace smoking bans on heart rate variability and pulse wave velocity of non-smoking hospitality workers

OBJECTIVES: To investigate the effect of a change in second-hand smoke (SHS) exposure on heart rate variability (HRV) and pulse wave velocity (PWV), this study utilized a quasi-experimental setting when a smoking ban was introduced. METHODS: HRV, a quantitative marker of autonomic activity of the nervous system, and PWV, a marker of arterial stiffness, were measured in 55 non-smoking hospitality workers before and 3-12 months after a smoking ban and compared to a control group that did not experience an exposure change. SHS exposure was determined with a nicotine-specific badge and expressed as inhaled cigarette equivalents per day (CE/d). RESULTS: PWV and HRV parameters significantly changed in a dose-dependent manner in the intervention group as compared to the control group. A one CE/d decrease was associated with a 2.3 % (95 % CI 0.2-4.4; p = 0.031) higher root mean square of successive differences (RMSSD), a 5.7 % (95 % CI 0.9-10.2; p = 0.02) higher high-frequency component and a 0.72 % (95 % CI 0.40-1.05; p < 0.001) lower PWV. CONCLUSIONS: PWV and HRV significantly improved after introducing smoke-free workplaces indicating a decreased cardiovascular risk.

EADock : design of a new molecular docking algorithm and some of its applications

3 Summary 3. 1 English The pharmaceutical industry has been facing several challenges during the last years, and the optimization of their drug discovery pipeline is believed to be the only viable solution. High-throughput techniques do participate actively to this optimization, especially when complemented by computational approaches aiming at rationalizing the enormous amount of information that they can produce. In siiico techniques, such as virtual screening or rational drug design, are now routinely used to guide drug discovery. Both heavily rely on the prediction of the molecular interaction (docking) occurring between drug-like molecules and a therapeutically relevant target. Several softwares are available to this end, but despite the very promising picture drawn in most benchmarks, they still hold several hidden weaknesses. As pointed out in several recent reviews, the docking problem is far from being solved, and there is now a need for methods able to identify binding modes with a high accuracy, which is essential to reliably compute the binding free energy of the ligand. This quantity is directly linked to its affinity and can be related to its biological activity. Accurate docking algorithms are thus critical for both the discovery and the rational optimization of new drugs. In this thesis, a new docking software aiming at this goal is presented, EADock. It uses a hybrid evolutionary algorithm with two fitness functions, in combination with a sophisticated management of the diversity. EADock is interfaced with .the CHARMM package for energy calculations and coordinate handling. A validation was carried out on 37 crystallized protein-ligand complexes featuring 11 different proteins. The search space was defined as a sphere of 15 R around the center of mass of the ligand position in the crystal structure, and conversely to other benchmarks, our algorithms was fed with optimized ligand positions up to 10 A root mean square deviation 2MSD) from the crystal structure. This validation illustrates the efficiency of our sampling heuristic, as correct binding modes, defined by a RMSD to the crystal structure lower than 2 A, were identified and ranked first for 68% of the complexes. The success rate increases to 78% when considering the five best-ranked clusters, and 92% when all clusters present in the last generation are taken into account. Most failures in this benchmark could be explained by the presence of crystal contacts in the experimental structure. EADock has been used to understand molecular interactions involved in the regulation of the Na,K ATPase, and in the activation of the nuclear hormone peroxisome proliferatoractivated receptors a (PPARa). It also helped to understand the action of common pollutants (phthalates) on PPARy, and the impact of biotransformations of the anticancer drug Imatinib (Gleevec®) on its binding mode to the Bcr-Abl tyrosine kinase. Finally, a fragment-based rational drug design approach using EADock was developed, and led to the successful design of new peptidic ligands for the a5ß1 integrin, and for the human PPARa. In both cases, the designed peptides presented activities comparable to that of well-established ligands such as the anticancer drug Cilengitide and Wy14,643, respectively. 3.2 French Les récentes difficultés de l'industrie pharmaceutique ne semblent pouvoir se résoudre que par l'optimisation de leur processus de développement de médicaments. Cette dernière implique de plus en plus. de techniques dites "haut-débit", particulièrement efficaces lorsqu'elles sont couplées aux outils informatiques permettant de gérer la masse de données produite. Désormais, les approches in silico telles que le criblage virtuel ou la conception rationnelle de nouvelles molécules sont utilisées couramment. Toutes deux reposent sur la capacité à prédire les détails de l'interaction moléculaire entre une molécule ressemblant à un principe actif (PA) et une protéine cible ayant un intérêt thérapeutique. Les comparatifs de logiciels s'attaquant à cette prédiction sont flatteurs, mais plusieurs problèmes subsistent. La littérature récente tend à remettre en cause leur fiabilité, affirmant l'émergence .d'un besoin pour des approches plus précises du mode d'interaction. Cette précision est essentielle au calcul de l'énergie libre de liaison, qui est directement liée à l'affinité du PA potentiel pour la protéine cible, et indirectement liée à son activité biologique. Une prédiction précise est d'une importance toute particulière pour la découverte et l'optimisation de nouvelles molécules actives. Cette thèse présente un nouveau logiciel, EADock, mettant en avant une telle précision. Cet algorithme évolutionnaire hybride utilise deux pressions de sélections, combinées à une gestion de la diversité sophistiquée. EADock repose sur CHARMM pour les calculs d'énergie et la gestion des coordonnées atomiques. Sa validation a été effectuée sur 37 complexes protéine-ligand cristallisés, incluant 11 protéines différentes. L'espace de recherche a été étendu à une sphère de 151 de rayon autour du centre de masse du ligand cristallisé, et contrairement aux comparatifs habituels, l'algorithme est parti de solutions optimisées présentant un RMSD jusqu'à 10 R par rapport à la structure cristalline. Cette validation a permis de mettre en évidence l'efficacité de notre heuristique de recherche car des modes d'interactions présentant un RMSD inférieur à 2 R par rapport à la structure cristalline ont été classés premier pour 68% des complexes. Lorsque les cinq meilleures solutions sont prises en compte, le taux de succès grimpe à 78%, et 92% lorsque la totalité de la dernière génération est prise en compte. La plupart des erreurs de prédiction sont imputables à la présence de contacts cristallins. Depuis, EADock a été utilisé pour comprendre les mécanismes moléculaires impliqués dans la régulation de la Na,K ATPase et dans l'activation du peroxisome proliferatoractivated receptor a (PPARa). Il a également permis de décrire l'interaction de polluants couramment rencontrés sur PPARy, ainsi que l'influence de la métabolisation de l'Imatinib (PA anticancéreux) sur la fixation à la kinase Bcr-Abl. Une approche basée sur la prédiction des interactions de fragments moléculaires avec protéine cible est également proposée. Elle a permis la découverte de nouveaux ligands peptidiques de PPARa et de l'intégrine a5ß1. Dans les deux cas, l'activité de ces nouveaux peptides est comparable à celles de ligands bien établis, comme le Wy14,643 pour le premier, et le Cilengitide (PA anticancéreux) pour la seconde.

Effects of prior short multiple-sprint exercises with different intersprint recoveries on the slow component of oxygen uptake during high-intensity exercise.

This study compares the effects of two short multiple-sprint exercise (MSE) (6 × 6 s) sessions with two different recovery durations (30 s or 180 s) on the slow component of oxygen uptake ([Formula: see text]O(2)) during subsequent high-intensity exercise. Ten male subjects performed a 6-min cycling test at 50% of the difference between the gas exchange threshold and [Formula: see text]O(2peak) (Δ50). Then, the subjects performed two MSEs of 6 × 6 s separated by two intersprint recoveries of 30 s (MSE(30)) and 180 s (MSE(180)), followed 10 min later by the Δ50 (Δ50(30) and Δ50(180), respectively). Electromyography (EMG) activities of the vastus medialis and lateralis were measured throughout each exercise bout. During MSE(30), muscle activity (root mean square) increased significantly (p ≤ 0.04), with a significant leftward-shifted median frequency of the power density spectrum (MDF; p ≤ 0.01), whereas MDF was significantly rightward-shifted during MSE(180) (p = 0.02). The mean [Formula: see text]O(2) value was significantly higher in MSE(30) than in MSE(180) (p < 0.001). During Δ50(30), [Formula: see text]O(2) and the deoxygenated hemoglobin ([HHb]) slow components were significantly reduced (-27%, p = 0.02, and -34%, p = 0.003, respectively) compared with Δ50. There were no significant modifications of the [Formula: see text]O(2) slow component in Δ50(180) compared with Δ50 (p = 0.32). The neuromuscular and metabolic adaptations during MSE(30) (preferential activation of type I muscle fibers evidenced by decreased MDF and a greater aerobic metabolism contribution to the required energy demands), but not during MSE(180), may lead to reduced [Formula: see text]O(2) and [HHb] slow components, suggesting an alteration in motor units recruitment profile (i.e., change in the type of muscle fibers recruited) and (or) an improved muscle O(2) delivery during subsequent exercise.

Electromyographic, cerebral, and muscle hemodynamic responses during intermittent, isometric contractions of the biceps brachii at three submaximal intensities.

This study examined the electromyographic, cerebral and muscle hemodynamic responses during intermittent isometric contractions of biceps brachii at 20, 40, and 60% of maximal voluntary contraction (MVC). Eleven volunteers completed 2 min of intermittent isometric contractions (12/min) at an elbow angle of 90° interspersed with 3 min rest between intensities in systematic order. Surface electromyography (EMG) was recorded from the right biceps brachii and near infrared spectroscopy (NIRS) was used to simultaneously measure left prefrontal and right biceps brachii oxyhemoglobin (HbO2), deoxyhemoglobin (HHb), and total hemoglobin (Hbtot). Transcranial Doppler ultrasound was used to measure middle cerebral artery velocity (MCAv) bilaterally. Finger photoplethysmography was used to record beat-to-beat blood pressure and heart rate. EMG increased with force output from 20 to 60% MVC (P < 0.05). Cerebral HbO2 and Hbtot increased while HHb decreased during contractions with differences observed between 60% vs. 40% and 20% MVC (P < 0.05). Muscle HbO2 decreased while HHb increased during contractions with differences being observed among intensities (P < 0.05). Muscle Hbtot increased from rest at 20% MVC (P < 0.05), while no further change was observed at 40 and 60% MVC (P > 0.05). MCAv increased from rest to exercise but was not different among intensities (P > 0.05). Force output correlated with the root mean square EMG and changes in muscle HbO2 (P < 0.05), but not changes in cerebral HbO2 (P > 0.05) at all three intensities. Force output declined by 8% from the 1st to the 24th contraction only at 60% MVC and was accompanied by systematic increases in RMS, cerebral HbO2 and Hbtot with a leveling off in muscle HbO2 and Hbtot. These changes were independent of alterations in mean arterial pressure. Since cerebral blood flow and oxygenation were elevated at 60% MVC, we attribute the development of fatigue to reduced muscle oxygen availability rather than impaired central neuronal activation.