Régulation des hémicanaux de connexine 43 : implication dans la cardioprotection contre les lésions ischémiques

La connexine 43 (Cx43) est l’unité protéique de base dans la formation des canaux des jonctions gap (JG) responsables des échanges intercellulaires. Toutefois, elle forme aussi des canaux non-jonctionnels à large conductance, nommés hémicanaux (Hc), qui fournissent un accès entre l’intérieure des cellules et le milieu extracellulaire. Bien qu’ils soient beaucoup moins étudiés que les JG, on estime que les Hc restent normalement à l’état fermé, et ce, grâce à la phosphorylation des connexines qui les forment. Suite à un stress ischémique, les Cx43 se déphosphorylent et entraînent ainsi l’ouverture des Hc de Cx43 (HcCx43), un effet qui compromet la survie des cellules. La protéine kinase C (PKC) est l’enzyme de phosphorylation qui possède le plus grand nombre de sites de phosphorylation sur la Cx43 en comparaison avec les autres kinases. Ses fonctions dépendent de la mise en jeu d’un répertoire d’au moins 12 isoformes distinctes. Dans les cardiomyocytes, les isoformes de PKC participent au développement des réponses adaptées ou mésadaptées au stress ischémique. Malgré que la régulation des canaux de Cx43 par la PKC lors d’une ischémie soit bien documentée, il n’existe pas à l’heure actuelle de connaissances sur les effets fonctionnels spécifiques qu’exercent des différentes isoformes de PKC sur les HcCx43, ni sur la valeur thérapeutique de la modulation de ses derniers. Dans ce contexte, nous avons proposé que les HcCx43 sont régulés sélectivement et différentiellement par les différentes isoformes de PKC et que l’inhibition spécifique de ces hémicanaux peut protéger le coeur lors d’un événement ischémique. Le présent travail comporte trois études qui ont été entreprises spécialement dans le but de valider ces hypothèses. Dans la première étude, nous avons profité de l’expertise du laboratoire du Dr Baroudi dans la dissection des isoformes de PKC pour étudier le rôle fonctionnel de chacune d’elles dans la régulation des HcCx43 en utilisant une gamme unique de peptides synthétiques inhibiteurs et activateurs spécifiques des isoformes de PKC, en combinaison avec la technique du patch-clamp. Nous avons démontré, entre autre, que les HcCx43 sont particulièrement inhibés par l’isoforme PKC epsilon, connue pour son effet cardioprotecteur contre les dommages ischémiques lors d’un préconditionnement ischémique. Dans la deuxième étude, nous avons caractérisé l’effet d’un peptide synthétique mimétique structural de la Cx43 sur la fonction des HcCx43. En plus d’avoir élucidé ces effets sur les propriétés fonctionnelles du canal, nous avons démontré d’une manière directe et indéniable que le peptide Gap26 inhibe et spécifiquement les HcCx43 et que son administration in vitro (cardiomyocytes isolés) et ex vivo (coeur intact) confère à ces modèles expérimentaux une résistance importante contre le stress ischémique. Dans la troisième étude, nous avons investigué pour la première fois in vivo le potentiel de deux peptides uniques mimétiques structuraux de la Cx43, Gap26 et Gap27, dans la cardioprotection contre les lésions ischémiques lorsqu’ils sont administrés à basse dose sous forme d’un bolus intraveineux unique. Nous avons démontré que l’injection de ces peptides avant ou après la survenue de l’ischémie réduit significativement la taille de l’infarctus qui en résulte.En conclusion, l’ensemble de ces résultats révèlent le rôle bénéfique de l’inhibition des HcCx43 lors d’une ischémie et dévoilent un potentiel thérapeutique prometteux des mimétiques structuraux de Cx43 dans la prévention et le traitement de l’infarctus du myocarde.

Restricted dispersal reduces the strength of spatial density dependence in a tropical bird population

Spatial processes could play an important role in density-dependent population regulation because the disproportionate use of poor quality habitats as population size increases is widespread in animal populations-the so-called buffer effect. While the buffer effect patterns and their demographic consequences have been described in a number of wild populations, much less is known about how dispersal affects distribution patterns and ultimately density dependence. Here, we investigated the role of dispersal in spatial density dependence using an extraordinarily detailed dataset from a reintroduced Mauritius kestrel (Falco punctatus) population with a territorial (despotic) breeding system. We show that recruitment rates varied significantly between territories, and that territory occupancy was related to its recruitment rate, both of which are consistent with the buffer effect theory. However, we also show that restricted dispersal affects the patterns of territory occupancy with the territories close to release sites being occupied sooner and for longer as the population has grown than the territories further away. As a result of these dispersal patterns, the strength of spatial density dependence is significantly reduced. We conclude that restricted dispersal can modify spatial density dependence in the wild, which has implications for the way population dynamics are likely to be impacted by environmental change.

Vertical distribution, size and composition of the weed seedbank under various tillage and herbicide treatments in a sequence of industrial crops

Investigations were conducted during the 2003, 2004 and 2005 growing seasons in northern Greece to evaluate effects of tillage regime (mouldboard plough, chisel plough and rotary tiller), cropping sequence (continuous cotton, cotton-sugar beet rotation and continuous tobacco) and herbicide treatment on weed seedbank dynamics. Amaranthus spp. and Portulaca oleracea were the most abundant species, ranging from 76% to 89% of total weed seeds found in 0-15 and 15-30 cm soil depths during the 3 years. With the mouldboard plough, 48% and 52% of the weed seedbank was found in the 0-15 and 15-30 cm soil horizons, while approximately 60% was concentrated in the upper 15 cm soil horizon for chisel plough and rotary tillage. Mouldboard ploughing significantly buried more Echinochloa crus-galli seeds in the 15-30 cm soil horizon compared with the other tillage regimes. Total seedbank (0-30 cm) of P. oleracea was significantly reduced in cotton-sugar beet rotation compared with cotton and tobacco monocultures, while the opposite occurred for E. crus-galli. Total seed densities of most annual broad-leaved weed species (Amaranthus spp., P. oleracea, Solanum nigrum) and E. crus-galli were lower in herbicide treated than in untreated plots. The results suggest that in light textured soils, conventional tillage with herbicide use gradually reduces seed density of small seeded weed species in the top 15 cm over several years. In contrast, crop rotation with the early established sugar beet favours spring-germinating grass weed species, but also prevents establishment of summer-germinating weed species by the early developing crop canopy.

Real estate portfolio size and risk reduction

The reduction of portfolio risk is important to all investors but is particularly important to real estate investors as most property portfolios are generally small. As a consequence, portfolios are vulnerable to a significant risk of under-performing the market, or a target rate of return and so investors may be exposing themselves to greater risk than necessary. Given the potentially higher risk of underperformance from owning only a few properties, we follow the approach of Vassal (2001) and examine the benefits of holding more properties in a real estate portfolio. Using Monte Carlo simulation and the returns from 1,728 properties in the IPD database, held over the 10-year period from 1995 to 2004, the results show that increases in portfolio size offers the possibility of a more stable and less volatile return pattern over time, i.e. down-side risk is diminished with increasing portfolio size. Nonetheless, increasing portfolio size has the disadvantage of restricting the probability of out-performing the benchmark index by a significant amount. In other words, although increasing portfolio size reduces the down-side risk in a portfolio, it also decreases its up-side potential. Be that as it may, the results provide further evidence that portfolios with large numbers of properties are always preferable to portfolios of a smaller size.

Habitat fragmentation reduces genetic diversity and connectivity among toad populations in the Brazilian Atlantic Coastal Forest

Tropical rainforests are becoming increasingly fragmented and understanding the genetic consequences of fragmentation is crucial for conservation of their flora and fauna. We examined populations of the toad Rhinella ornata, a species endemic to Atlantic Coastal Forest in Brazil, and compared genetic diversity among small and medium forest fragments that were either isolated or connected to large forest areas by corridors. Genetic differentiation, as measured by F(ST), was not related to geographic distance among study sites and the size of the fragments did not significantly alter patterns of genetic connectivity. However, population genetic diversity was positively related to fragment size, thus haplotype diversity was lowest in the smallest fragments, likely due to decreases in population sizes. Spatial analyses of genetic discontinuities among groups of populations showed a higher proportion of barriers to gene flow among small and medium fragments than between populations in continuous forest. Our results underscore that even species with relatively high dispersal capacities may, over time, suffer the negative genetic effects of fragmentation, possibly leading to reduced fitness of population and cases of localized extinction. (C) 2008 Elsevier Ltd. All rights reserved.

Granulocyte Colony-stimulating Factor Reduces Mortality by Suppressing Ventricular Arrhythmias in Acute Phase of Myocardial Infarction in Rats

Our aim was to evaluate the effects of granulocyte colony-stimulating factor (G-CSF) on early cardiac arrhythmias after myocardial infarction (MI) and the impact on survival. Male Wistar rats received repeated doses of 50 mu g/kg G-CSF (MI-GCSF group) or vehicle (MI group) at 7, 3, and 1 days before surgery. MI was induced by permanent occlusion of left corollary artery. The electrocardiogram was obtained before occlusion and then for 30 minutes after surgery. Events and duration of ventricular arrhythmias were analyzed. The levels of connexin43 (Cx43) were measured by Western blot immediately before MI production. Survival was significantly increased in MI-GCSF pretreated group (74% versus 52.0% MI. P < 0.05). G-CSF pretreatment also significantly reduced the ventricular premature beats when compared with the untreated-MI group (201 +/- 47 versus 679 +/- 117, P < 0.05). The number and the duration of ventricular tachycardia were smaller in the MI-G-CSF group, as well as the number of ventricular fibrillation episodes (10% versus 69% in NIL P < 0.05). Cx43 levels were significantly increased by G-CSF treatment (1.27 +/- 0.13 versus 0.86 +/- 0.11; P < 0.05). The MI size 24 hours after occlusion was reduced by G-CSF pretreatment (36 +/- 3% versus 44 +/- 2% of left ventricle in MI group; P < 0.05). The increase of Cx43 expression in the heart may explain the reduced incidence in ventricular arrhythmias in the early phases after coronary artery occlusion in rats, thus increasing survival after MI.

The evidence that exercise during growth or adulthood reduces the risk of fragility fractures is weak

There has never been, and will never be, a randomized double-blind placebo-controlled trial demonstrating that exercise in youth, adulthood or old age reduces fragility or osteoporosis-related fractures in old age. The next level of evidence, a randomized, controlled but unblinded study with fractures as an end-point is feasible but has never been done. The basis for the belief that exercise reduces fractures is derived from lower levels of ‘evidence’, namely, retrospective and prospective observation cohort studies and case–control studies. These studies are at best hypothesis generating, never hypothesis testing. They are all subject to many systematic biases and should be interpreted with extreme scepticism. Surrogate measures of anti-fracture efficacy are the next level of evidence, such as the demonstration of a reduction in risk factors for falls, a reduction in falls, a reduction in fractures due to falls, an increase in peak bone size and mass, prevention of bone loss in midlife and restoration of bone mass and structure in old age.

Inhibition of inosine monophosphate dehydrogenase reduces adipogenesis and diet-induced obesity

We previously described a putative role for inosine monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme in de novo guanine nucleotide biosynthesis, in lipid accumulation. Here we present data which demonstrate that IMPDH activity is required for differentiation of preadipocytes into mature, lipid-laden adipocytes and maintenance of adipose tissue mass. In 3T3-L1 preadipocytes inhibition of IMPDH with mycophenolic acid (MPA) reduced intracellular GTP levels by 60% (p < 0.05) and blocked adipogenesis (p < 0.05). Co-treatment with guanosine, a substrate in the salvage pathway of nucleotide biosynthesis, restored GTP levels and adipogenesis demonstrating the specificity of these effects. Treatment of diet-induced obese mice with mycophenolate mofetil (MMF), the prodrug of MPA, for 28 days did not affect food intake or lean body mass but reduced body fat content (by 36%, p = 0.002) and adipocyte size (p = 0.03) and number. These data suggest that inhibition of IMPDH may represent a novel strategy to reduce adipose tissue mass.

An aqueous Chlorella extract inhibits IL-5 production by mast cells in vitro and reduces ovalbumin-induced eosinophil infiltration in the airway in mice in vivo

An aqueous extract of the edible microalga, Chlorella pyrenoidosa (CP) (1), has recently been tested for its immunomodulatory effects in a human clinical trial. Here, the CP extract was dialyzed and fractionated using Sephadex G 100 chromatography. The effects of a dialyzed aqueous CP extract, fraction 2, on mast cell mediator release in vitro and ovalbumin-induced allergic airway inflammation in vivo were examined. In vitro, treatment of mouse bone marrow-derived mast cells with 2 for 18 h significantly inhibited antigen (trinitrophenyl-BSA)-induced IL-5 production. In vivo, treatment of mice with 2 during ovalbumin sensitization and stimulation process significantly reduced eosinophil and neutrophil infiltration in the airways. Moreover, fractions obtained by size exclusion chromatography of 2 inhibited IgE-dependent cytokine GM-CSF production from human cord blood-derived mast cells. Taken together, these results suggest that 2 is composed of biopolymers with anti-allergic potential.

Effect of transformation mechanism (static or dynamic) on final ferrite grain size

A simple series of test was developed to highlight and compare the difference between the static strain induced transformation (SSIT) and the dynamic strain induced transformation (DSIT) mechanism in grain refinement and also to investigate the origin of the difference between the two mechanisms. The results showed that while the SSIT sets up a two-dimensional impingement among the ferrite grains, it cannot avoid their coarsening (normal growth). However, the DSIT forms a group of grains with a three-dimensional impingement which does not coarsen and maintains their fine size throughout the transformation, thereby, reduces the final average grain size.

Small seed size increases the potential for dispersal of wetland plants by ducks

1. Long-distance dispersal (LDD) is important in plants of dynamic and ephemeral habitats. For plants of dynamic wetland habitats, waterfowl are generally considered to be important LDD vectors. However, in comparison to the internal (endozoochorous) dispersal of terrestrial plants by birds, endozoochorous dispersal of wetland plants by waterfowl has received little attention. We quantified the capacity for endozoochorous dispersal of wetland plants by waterfowl and identified the mechanisms underlying successful dispersal, by comparing the dispersal capacities of a large number of wetland plant species.

2. We selected 23 common plant species from dynamic wetland habitats and measured their seed characteristics. We fed seeds of all species to mallards (Anas platyrhynchos), a common and highly omnivorous duck species, and quantified seed gut survival, gut passage speed and subsequent germination. We then used a simple model to calculate seed dispersal distances.

3. In total 21 of the 23 species can be dispersed by mallards, with intact seed retrieval and subsequent successful germination of up to 32% of the ingested seeds. The species that pass fastest through the digestive tract of the mallards are retrieved in the greatest numbers (up to 54%) and germinate best (up to 87%). These are the species with the smallest seeds. Seed coat thickness plays only a minor role in determining intact passage through the mallard gut, but determines if ingestion enhances or reduces germination in comparison to control seeds.

4. Model calculations estimate that whereas the largest seeds can hardly be dispersed by mallards, most seeds can be dispersed up to 780 km, and the smallest seeds up to 3000 km, by mallards during migration.

5. Synthesis. This study demonstrates the mechanism underlying successful endozoochorous dispersal of wetland plant seeds by mallards: small seed size promotes rapid, and hence intact and viable, passage through the mallard gut. Mallards can disperse wetland plant seeds of all but the largest-seeded species successfully in relatively large numbers (up to 32% of ingested seeds) over long distances (up to thousands of kilometres) and are therefore important dispersal vectors.

Modelling the combined effect of grain size and grain shape on plastic anisotropy of metals

Within each columnar grain of a metallic film, the resistance to dislocation glide varies in function of the orientation of the slip plane with regard to the grain long axis. Plastic slip is impeded across grain boundaries and this contributes to the anisotropy of the overall mechanical response. A simplified (Taylor-type) crystal plasticity model is proposed that accounts for such effect of grain shape on the slip system selection. Assuming that dislocation density gradients are normal to the grain boundaries, backstresses developed at the onset of plasticity are estimated based on two definitions of the effective grain boundary spacing ‘‘seen’’ by individual slip systems. The first one reduces to the mean area-to-perimeter ratio of cross-sections of the grain cut parallel to the slip plane. Closed-form expressions of the average backstresses developed inside grains with spheroidal shapes are introduced in the crystal hardening law. The model reproduces the very high plastic anisotropy of electro-deposited pure iron with a strong c-fiber and a refined columnar grain structure [Yoshinaga, N., Sugiura, N., Hiwatashi, S., Ushioda, K., Kada, O., 2008. Deep drawability of electro-deposited pure iron having an extremely sharp h111i//ND texture. ISIJ Int. 48, 667–670]. It also provides valid estimates of the texture development and the influence of grain size on the yield strength.

Additional Saturday rehabilitation improves functional independence and quality of life and reduces length of stay: a randomised controlled trial

Background

Many inpatients receive little or no rehabilitation on weekends. Our aim was to determine what effect providing additional Saturday rehabilitation during inpatient rehabilitation had on functional independence, quality of life and length of stay compared to 5 days per week of rehabilitation.

This was a multicenter, single-blind (assessors) randomized controlled trial with concealed allocation and 12-month follow-up conducted in two publically funded metropolitan inpatient rehabilitation facilities in Melbourne, Australia. Patients were eligible if they were adults (aged ≥18 years) admitted for rehabilitation for any orthopedic, neurological or other disabling conditions excluding those admitted for slow stream rehabilitation/geriatric evaluation and management. Participants were randomly allocated to usual care Monday to Friday rehabilitation (control) or to Monday to Saturday rehabilitation (intervention). The additional Saturday rehabilitation comprised physiotherapy and occupational therapy. The primary outcomes were functional independence (functional independence measure (FIM); measured on an 18 to 126 point scale), health-related quality of life (EQ-5D utility index; measured on a 0 to 1 scale, and EQ-5D visual analog scale; measured on a 0 to 100 scale), and patient length of stay. Outcome measures were assessed on admission, discharge (primary endpoint), and at 6 and 12 months post discharge.

We randomly assigned 996 adults (mean (SD) age 74 (13) years) to Monday to Saturday rehabilitation (n = 496) or usual care Monday to Friday rehabilitation (n = 500). Relative to admission scores, intervention group participants had higher functional independence (mean difference (MD) 2.3, 95% confidence interval (CI) 0.5 to 4.1, P = 0.01) and health-related quality of life (MD 0.04, 95% CI 0.01 to 0.07, P = 0.009) on discharge and may have had a shorter length of stay by 2 days (95% CI 0 to 4, P = 0.1) when compared to control group participants. Intervention group participants were 17% more likely to have achieved a clinically significant change in functional independence of 22 FIM points or more (risk ratio (RR) 1.17, 95% CI 1.03 to 1.34) and 18% more likely to have achieved a clinically significant change in health-related quality of life (RR 1.18, 95% CI 1.04 to 1.34) on discharge compared to the control group. There was some maintenance of effect for functional independence and health-related quality of life at 6-month follow-up but not at 12-month follow-up. There was no difference in the number of adverse events between the groups (incidence rate ratio = 0.81, 95% CI 0.61 to 1.08).

Providing an additional day of rehabilitation improved functional independence and health-related quality of life at discharge and may have reduced length of stay for patients receiving inpatient rehabilitation. 

Resistive vibration exercise reduces lower limb muscle atrophy during 56-day bed-rest

OBJECTIVES: The current study aimed to examine the effectiveness of a resistive vibration exercise countermeasure during prolonged bed-rest in preventing lower-limb muscle atrophy. METHODS: 20 male subjects underwent 56-days of bed-rest and were assigned to either an inactive control, or a countermeasure group which performed high-load resistive exercises (including squats, heel raises and toe raises) with whole-body vibration. Magnetic resonance imaging of the lower-limbs was performed at two-weekly intervals. Volume of individual muscles was calculated. RESULTS: Countermeasure exercise reduced atrophy in the triceps surae and the vastii muscles (F>3.0, p<.025). Atrophy of the peroneals, tibialis posterior and toe flexors was less in the countermeasure-subjects, though statistical evidence for this was weak (F

Resistive simulated weightbearing exercise with whole body vibration reduces lumbar spine deconditioning in bed-rest

STUDY DESIGN: Randomized controlled trial. OBJECTIVE: Determine the effectiveness a resistive exercise countermeasure with whole-body vibration in relation to lumbo-pelvic muscle and spinal morphology changes during simulated spaceflight (bed-rest). SUMMARY OF BACKGROUND DATA: Spinal lengthening, flattening of the spinal curves, increases in disc size, and muscle atrophy are commonly seen in spaceflight simulation. This may represent a risk for low back injury. Consideration of exercise countermeasures against these changes is critical for success of long-term spaceflight missions. METHODS: Twenty healthy male subjects underwent 8-weeks of bed-rest with 6-months follow-up and were randomly allocated to an inactive control or countermeasure exercise group. Magnetic resonance imaging of the lumbo-pelvic region was conducted at regular time-points during and after bed-rest. Using uniplanar images at L4, cross-sectional areas of the multifidus, lumbar erector spinae, quadratus lumborum, psoas, anterolateral abdominal, and rectus abdominis muscles were measured. Sagittal scans were used to assess lumbar spine morphology (length, sagittal disc area and height, and intervertebral angles). RESULTS: The countermeasure group exhibited less multifidus muscle atrophy (P = 0.024) and its atrophy did not persist long-term as in the control group (up to 3-months; P < 0.006). Spinal lengthening (P = 0.03) and increases in disc area (P = 0.041) were also reduced. Significant partial correlations (P < 0.001) existed between spinal morphology and muscle cross-sectional area changes. CONCLUSION: The resistive vibration exercise countermeasure reduced, but did not entirely prevent, multifidus muscle atrophy and passive spinal tissue deconditioning during bed-rest. Atrophy of the multifidus muscles was persistent long-term in the inactive subjects. Future work could consider closer attention to spinal posture during exercise and optimizing exercise dose.