Studies toward new anti-cancer strategies based on alpha-mannosidase inhibition.

Changes in the glycosylation pattern of cellular glycoproteins constitute a hallmark in human cancer and influence tumor progression, suggesting that inhibitors of selected glycosidases may control cancer progression. Following the studies on swainsonine, a natural inhibitor of Golgi alpha-mannosidase II, which highlighted the inhibition of cellular mannosidases as a potential innovative approach for the treatment of cancer, several dihydroxylated pyrrolidines and analogues were developed as new potent inhibitors of alpha-mannosidases II able to induce antiproliferative effects in human cancer cells.

Investigating the relationship between pollination strategies and the size-advantage model in zoophilous plants using the reproductive biology of Arum cylindraceum and other European Arum species as case studies

The size-advantage model (SAM) explains the temporal variation of energetic investment on reproductive structures (i.e. male and female gametes and reproductive organs) in long-lived hermaphroditic plants and animals. It proposes that an increase in the resources available to an organism induces a higher relative investment on the most energetically costly sexual structures. In plants, pollination interactions are known to play an important role in the evolution of floral features. Because the SAM directly concerns flower characters, pollinators are expected to have a strong influence on the application of the model. This hypothesis, however, has never been tested. Here, we investigate whether the identity and diversity of pollinators can be used as a proxy to predict the application of the SAM in exclusive zoophilous plants. We present a new approach to unravel the dynamics of the model and test it on several widespread Arum (Araceae) species. By identifying the species composition, abundance and spatial variation of arthropods trapped in inflorescences, we show that some species (i.e. A. cylindraceum and A. italicum) display a generalist reproductive strategy, relying on the exploitation of a low number of dipterans, in contrast to the pattern seen in the specialist A. maculatum (pollinated specifically by two fly species only). Based on the model presented here, the application of the SAM is predicted for the first two and not expected in the latter species, those predictions being further confirmed by allometric measures. We here demonstrate that while an increase in the female zone occurs in larger inflorescences of generalist species, this does not happen in species demonstrating specific pollinators. This is the first time that this theory is both proposed and empirically tested in zoophilous plants. Its overall biological importance is discussed through its application in other non-Arum systems.

Targeting Toll-Like Receptors: Promising Therapeutic Strategies for the Management of Sepsis-Associated Pathology and Infectious Diseases.

Toll-like receptors (TLRs) are pattern recognition receptors playing a fundamental role in sensing microbial invasion and initiating innate and adaptive immune responses. TLRs are also triggered by danger signals released by injured or stressed cells during sepsis. Here we focus on studies developing TLR agonists and antagonists for the treatment of infectious diseases and sepsis. Positioned at the cell surface, TLR4 is essential for sensing lipopolysaccharide of Gram-negative bacteria, TLR2 is involved in the recognition of a large panel of microbial ligands, while TLR5 recognizes flagellin. Endosomal TLR3, TLR7, TLR8, TLR9 are specialized in the sensing of nucleic acids produced notably during viral infections. TLR4 and TLR2 are favorite targets for developing anti-sepsis drugs, and antagonistic compounds have shown efficient protection from septic shock in pre-clinical models. Results from clinical trials evaluating anti-TLR4 and anti-TLR2 approaches are presented, discussing the challenges of study design in sepsis and future exploitation of these agents in infectious diseases. We also report results from studies suggesting that the TLR5 agonist flagellin may protect from infections of the gastrointestinal tract and that agonists of endosomal TLRs are very promising for treating chronic viral infections. Altogether, TLR-targeted therapies have a strong potential for prevention and intervention in infectious diseases, notably sepsis.

Comparaison de stratégies thérapeutiques dans la prise en charge de l'hypertension artérielle [Comparison of therapeutic strategies in the management of hypertension]

Guidelines for the treatment of hypertension recommend reducing blood pressure to below 140/90 mmHg. However, there is little to guide the clinician on which pharmacological strategy to pursue: monotherapy with stepped-care, sequential monotherapy, or the initial use of combination therapy. The STRATHE study was designed to clarify this issue by comparing the three strategies. A low-dose combination of perindopril/indapamide was significantly superior to either stepped-care or sequential monotherapy in terms of reducing systolic blood pressure and in the percentage of patients achieving normalisation without adverse effects. Pulse pressure showed a trend to greater reductions with the low-dose combination. Although there must be caution about extrapolating these results to other combinations, which may not have the same pharmacological properties, the STRATHE study has shown that initiating antihypertensive therapy with a low-dose combination has advantages over the two other classical therapeutic strategies.

Glutathione deficit in schizophrenia: strategies to increase glutathione levels in " in vitro " and clinical studies

Summary: Decrease in glutathione (GSH) levels was observed in cerebrospinal fluid, prefrontal cortex and post-mortem striatum of schizophrenia patients. Evidences suggest a defect in GSH synthesis at the levels of the rate-limiting synthesizing enzyme, glutamate cysteine ligase (GCL). Indeed, polymorphisms in the gene of the modifier subunit of GCL (GCLM) was shown to be associated with the disease in three different populations, GCLM gene expression is decreaséd in fibroblasts from patients and the increase in GCL activity induced by an oxidative stress is lower in patients' fibroblasts compared to controls. GSH being a major antioxydant and redox regulator, its presence is of high importance for protecting cells against oxidative stress. The aim of the present work was to use various substances to increase GSH levels by diverse strategies. Since the synthesizing enzyme GCL is defective, bypassing this enzyme was the first strategy we used. GSH ethyl ester (GSHEE), a membrane permeable analog of GSH, succeeded in replenishing GSH levels in cultured neurons and astrocytes previously depleted in GSH by L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of GCL. GSHEE also abolished dopamine-induced decrease of NMDA-mediated calcium response observed in BSO-treated neurons. y-Glutamylcysteine ethyl ester (GCSE), a membrane permeable analog of the product of GCL, increased GSH levels only in astrocytes. The second strategy was to boost the defective enzyme GCL. While quercetin (flavonoid) could increase GSH levels only in astrocytes, curcumin (polyphenol) and tertbutylhydroquinone (quinone) were successful in both neurons and astrocytes, via an increase in the gene expression of the two subunits of GCL and, consequently, an increase in the activity of the enzyme. However, FK506, an immunosupressant, was unefficient. Treating astrocytes from GCLM KO mice showed that the modulatory subunit is necessary for the action of the substances. Finally, since cysteine is the limiting precursor in the synthesis of GSH, we hypothesized that we could increase GSH levels by providing more of this precursor. N-acetyl-cysteine (NAC), a cysteine donor, was administered to schizophrenia patients, using adouble-blind and cross-over protocol. NAC significantly improved the mismatch negativity (MMN), a component of the auditory evoked potentials, thought to reflect selective current flowing through open, unblocked NMDA channels. Considering that NMDA function is reduced when GSH levels are low, increasing these levels with NAC could improve NMDA function as reflected by the improvement in the generation of the MMN. Résumé: Les taux de glutathion (GSH) dans le liquide céphalo-rachidien, le cortex préfrontal ainsi que le striatum post-mortem de patients schizophrènes, sont diminués. L'enzyme limitante dans la synthèse du GSH, la glutamyl-cysteine ligase (GCL), est défectueuse. En effet, des polymorphismes dans le gène de la sous-unité modulatrice de GCL (GCLM) sont associés à la maladie, l'expression du gène GCLM est diminuée dans les fibroblastes de patients et, lors d'un stress oxidative, l'augmentation de l'activité de GCL est plus faible chez les patients que chez les contrôles. Le GSH étant un important antioxydant et régulateur du status redox, sa présence est primordiale afin de protéger les cellules contre les stress oxydatifs. Au cours du présent travail, une variété de substances ont été utilisées dans le but d'augmenter les taux de GSH. Passer outre l'enzyme de synthèse GCL qui est défectueuse fut la première stratégie utilisée. L'éthylester de GSH (GSHEE), un analogue du GSH qui pénètre la membrane cellulaire, a augmenté les taux de GSH dans des neurones et des astrocytes déficitaires en GSH dû au L-buthionine-(S,R)-sulfoximine (BSO), un inhibiteur du GCL. Dans ces neurones, le GSHEE a aussi aboli la diminution de la réponse NMDA, induite parla dopamine. L'éthyl-ester de y-glutamylcysteine (GCEE), un analogue du produit de la GCL qui pénètre la membrane cellulaire, a augmenté les taux de GSH seulement dans les astrocytes. La seconde stratégie était d'augmenter l'activité de l'enzyme GCL. Tandis que la quercétine (flavonoïde) n'a pu augmenter les taux de GSH que dans les astrocytes, la curcumin (polyphénol) et le tert-butylhydroquinone (quinone) furent efficaces dans les deux types de cellules, via une augmentation de l'expression des gènes des deux sous-unités de GCL et de l'activité de l'enzyme. Le FK506 (immunosupresseur) n' a démontré aucune efficacité. Traiter des astrocytes provenant de souris GCLM KO a permis d'observer que la sous-unité modulatoire est nécessaire à l'action des substances. Enfin, puisque la cysteine est le substrat limitant dans la synthèse du GSH, fournir plus de ce présurseur pourrait augmenter les taux de GSH. Nacétyl-cystéine (NAC), un donneur de cystéine, a été administrée à des schizophrènes, lors d'une étude en double-aveugle et cross-over. NAC a amélioré le mismatch negativity (MMN), un composant des potentials évoqués auditifs, qui reflète le courant circulant via les canaux NMDA. Puisque la fonctionnalité des R-NMDA est diminuée lorsque les taux de GSH sont bas, augmenter ces taux avec NAC pourrait améliorer la fonction des R-NMDA, réflété par une augmentation de l'amplitude du MMN.

A game theoretical approach to the algebraic counterpart of the Wagner hierarchy

La hiérarchie de Wagner constitue à ce jour la plus fine classification des langages ω-réguliers. Par ailleurs, l'approche algébrique de la théorie de langages formels montre que ces ensembles ω-réguliers correspondent précisément aux langages reconnaissables par des ω-semigroupes finis pointés. Ce travail s'inscrit dans ce contexte en fournissant une description complète de la contrepartie algébrique de la hiérarchie de Wagner, et ce par le biais de la théorie descriptive des jeux de Wadge. Plus précisément, nous montrons d'abord que le degré de Wagner d'un langage ω-régulier est effectivement un invariant syntaxique. Nous définissons ensuite une relation de réduction entre ω-semigroupes pointés par le biais d'un jeu infini de type Wadge. La collection de ces structures algébriques ordonnée par cette relation apparaît alors comme étant isomorphe à la hiérarchie de Wagner, soit un quasi bon ordre décidable de largeur 2 et de hauteur ω. Nous exposons par la suite une procédure de décidabilité de cette hiérarchie algébrique : on décrit une représentation graphique des ω-semigroupes finis pointés, puis un algorithme sur ces structures graphiques qui calcule le degré de Wagner de n'importe quel élément. Ainsi le degré de Wagner de tout langage ω-régulier peut être calculé de manière effective directement sur son image syntaxique. Nous montrons ensuite comment construire directement et inductivement une structure de n''importe quel degré. Nous terminons par une description détaillée des invariants algébriques qui caractérisent tous les degrés de cette hiérarchie. Abstract The Wagner hierarchy is known so far to be the most refined topological classification of ω-rational languages. Also, the algebraic study of formal languages shows that these ω-rational sets correspond precisely to the languages recognizable by finite pointed ω-semigroups. Within this framework, we provide a construction of the algebraic counterpart of the Wagner hierarchy. We adopt a hierarchical game approach, by translating the Wadge theory from the ω-rational language to the ω-semigroup context. More precisely, we first show that the Wagner degree is indeed a syntactic invariant. We then define a reduction relation on finite pointed ω-semigroups by means of a Wadge-like infinite two-player game. The collection of these algebraic structures ordered by this reduction is then proven to be isomorphic to the Wagner hierarchy, namely a well-founded and decidable partial ordering of width 2 and height $\omega^\omega$. We also describe a decidability procedure of this hierarchy: we introduce a graph representation of finite pointed ω-semigroups allowing to compute their precise Wagner degrees. The Wagner degree of every ω-rational language can therefore be computed directly on its syntactic image. We then show how to build a finite pointed ω-semigroup of any given Wagner degree. We finally describe the algebraic invariants characterizing every Wagner degree of this hierarchy.

A situated analysis of football goalkeepers' experiences in critical game situations.

This study described elite football (soccer) goalkeepers' activity and performance in critical game situations. The 11 best French players (M age = 15.5 yr., SD = 0.5) participated in the study. Interviews focused on goalkeepers' experiences were conducted to identify meaningful events involved in failed actions. Players formulated 23 critical game situations. Verbatim encoding using a thematic analysis indicated that four main categories (coming off the line, goal-line clearance, one-on-one, and diving) represented the most critical situations encountered during matches. The relations among experience and action, inner states, background, attention contents, and intentions were elucidated. The discussion is grounded on the properties of such critical game situations and their implications for improving goalkeepers' performance.

Defining ecological strategies in neuroprosthetics.

Neurological disorders disrupt the equilibrium within the brain and spinal cord ecosystems. Ecology reuses, recycles, and reduces to help maintain the balance across ecosystems. Likewise, neuroprosthetics can help the brain help itself with ecoprosthetic designs that integrate the principles of the "three 'R's."

Preventive and therapeutic strategies in critically ill patients with highly resistant bacteria.

The antibiotic pipeline continues to diminish and the majority of the public remains unaware of this critical situation. The cause of the decline of antibiotic development is multifactorial and currently most ICUs are confronted with the challenge of multidrug-resistant organisms. Antimicrobial multidrug resistance is expanding all over the world, with extreme and pandrug resistance being increasingly encountered, especially in healthcare-associated infections in large highly specialized hospitals. Antibiotic stewardship for critically ill patients translated into the implementation of specific guidelines, largely promoted by the Surviving Sepsis Campaign, targeted at education to optimize choice, dosage, and duration of antibiotics in order to improve outcomes and reduce the development of resistance. Inappropriate antimicrobial therapy, meaning the selection of an antibiotic to which the causative pathogen is resistant, is a consistent predictor of poor outcomes in septic patients. Therefore, pharmacokinetically/pharmacodynamically optimized dosing regimens should be given to all patients empirically and, once the pathogen and susceptibility are known, local stewardship practices may be employed on the basis of clinical response to redefine an appropriate regimen for the patient. This review will focus on the most severely ill patients, for whom substantial progress in organ support along with diagnostic and therapeutic strategies markedly increased the risk of nosocomial infections.