Synthèse de glycodendrimères contenant des résidus fucosides et galactosides pour tester les propriétés d'adhésion des lectines pa-IL et pa-IIL de pseudomonas aeruginosa

Le présent ouvrage traite d'une alternative médicale potentielle pour inhiber l'adhésion bactérienne de la bactérie Pseudomonas aeruginosa. Cette dernière possède deux lectines, dépendantes du calcium (PA-IL et PA-IlL), ayant chacune un site de reconnaissance spécifique aux galactoses et aux fucoses, respectivement. Chez les patients atteints de la fIbrose kystique, le gène CF transmembrane regulator (CFTR) a subi une mutation, ce qui occasionne une augmentation de la présence des résidus fucoses à la surface des cellules épithéliales pulmonaires. L'attachement de cette bactérie pathogène à la glycoprotéine CFTR est la principale cause de virulence de la maladie. Pour ce faire, il a été envisagé d'utiliser les dendrimères pour intervenir dans ce processus d'adhésion bactérienne. Les dendrimères sont une classe de macromolécules monodisperses dont l'architecture arborescente autour d'un coeur plurifonctionnel est souvent comparée à différentes organisations autour de nous. En modifiant l'extrémité de ces structures au moyen de différents groupes fonctionnels, il est possible de leur conférer certaines des propriétés recherchées. Plusieurs applications dans divers domaines ont démontré leur potentiel. Particulièrement du côté de la biologie, ces molécules sont souvent comparées à des protéines, de par leur taille et leur structure globulaire. Lors de l'incorporation de fonctions carbohydrates en périphérie, des recherches ont démontré leur potentiel d'action au niveau des interactions sucres-protéines dues à l'effet cluster (augmentation de l'affinité saccharide-ligand grâce à leur multivalence). Ainsi, pour tenter d'inhiber l'adhésion de la bactérie Pseudomonas aeruginosa à la glycoprotéine CFTR, des glycodendrimères fucosylés et/ou galactosylés en surface sont développés. Basées sur des voies synthétiques appropriées, ces structures sont synthétisées à partir de produits commerciaux sur lesquels des groupements azotures et propargyliques sont installés. Ces fonctions précises permettront d'utiliser la « click chemistry », très régiospécifique et versatile. Par la suite, des tests préliminaires en inhibition compétitive (tests ELLA) et de turbidimétrie ont démontré que les deux lectines de la bactérie Pseudomonas aeruginosa pouvaient interagir avec les unités carbohydrates présentes sur les dendrimères et former un précipité détectable à 490nm en fonction du temps. Ainsi, l'utilisation des dendrimères pour inhiber l'adhésion bactérienne pourrait représenter une thérapie alternative ou un complémentaire aux antibiotiques pour le traitement d'infections mortelles. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Chimie thérapeutique, Fibrose kystique, Pseudomonas aeruginosa, Glycomimétiques, L-fucose, Glycosidation, Cycloaddition 1,3-dipolaire, Métathèse croisée, Dihydroxylation asymétrique

Hematology and Plasma Chemistry as Indicators of Health and Ecological Status In Beluga Whales, Delphinapterus Leucas

The capture of beluga whales, Delphinapterus leucas, for instrumentation or tagging afforded the opportunity to collect blood, which was analyzed to evaluate the animals' health and gain information on basic physiological systems. Here, we report on hematological and plasma chemical constituents in samples obtained from 183 belugas, 55 of which were handled during attempts to apply tracking instruments. The other 128 samples were either drawn from live belugas captured for exhibit in zoological parks or research or obtained from the fresh carcasses of whales taken by Inuit hunters. The data span a 15-year period beginning in 1983 and represent various beluga stocks in the Canadian Arctic. The majority of the specimens were collected during the summer or estuarine phase of the belugas' annual cycle. Comparisons by age group, sex, stock, season, and year revealed significant differences in most of the cellular and chemical constituents examined. These results demonstrate some of the variability that might be encountered when examining a "random" selection of belugas at a particular location and time. Immature-sized whales had higher leucocyte counts, electrolyte concentrations, enzyme activity, total protein, albumin, hemoglobin, and some metabolites than older animals. Sex alone was associated with few hematological and plasma chemical differences. Seasonal variation in thyroid hormone activity was linked to marked environmental changes associated with the transition from cold oceanic waters to relatively warm estuaries. Two belugas recaptured 19 and 24 days after instrumentation showed changes in leucocyte counts, hematocrit, and a variety of plasma chemical constituents, some of which indicate inflammation and a likely physiological response to handling and tagging stresses.On a profité du fait qu'on capturait des bélougas, Delphinapterus leucas, en vue de les équiper d'instruments ou de les marquer, pour prélever des échantillons de sang qu'on a ensuite analysés afin d'évaluer l'état de santé des individus et de collecter de l'information sur leurs grands systèmes physiologiques. Nous présentons ici un rapport sur les constituants hématologiques et chimiques du plasma dans des échantillons provenant de 183 bélougas, dont 55 ont été manipulés au cours de tentatives visant à les équiper d'instruments de poursuite. Les 128 autres échantillons ont été obtenus soit de bélougas vivants capturés en vue d'être placés dans des zoos ou pour la recherche, soit de carcasses fraîches de baleines prises par les chasseurs inuits. Les données couvrent une période de 15 ans, commençant en 1983, et représentent divers stocks de bélougas de l'océan Arctique canadien. La plupart des spécimens ont été recueillis durant l'été ou durant la phase estuarienne du cycle annuel du bélouga. Des comparaisons par groupe d'âge, sexe, stock, saison et année ont révélé des différences marquées dans la plupart des constituants cellulaires et chimiques examinés. Ces résultats font ressortir une certaine variabilité à laquelle on peut s'attendre quand on étudie un échantillon "aléatoire" de bélougas pris à un endroit et à un moment donnés. Par rapport à des individus plus âgés, les baleines qui n'avaient pas atteint leur taille adulte avaient un compte de globules blancs plus élevé, de même qu'une plus forte concentration d'électrolytes, une plus grande activité enzymatique, et un taux plus fort d'albumine, d'hémoglobine et de certains métabolites. Le sexe seul n'était associé qu'à quelques différences hématologiques et chimiques du plasma. Une variation saisonnière de l'activité des hormones thyroïdiennes était liée à des changements nets du milieu correspondant à la transition des eaux froides océaniques aux estuaires relativement chauds. Deux bélougas recapturés 19 et 24 jours après avoir été équipés d'instruments montraient des changements dans le compte de globules blancs, dans l'hématocrite et dans divers constituants chimiques du plasma, dont certains révèlent une inflammation et probablement une réaction physiologique au stress dû à la manipulation et au marquage

Developmental and Degenerative Cardiac Defects in the Taiwanese Mouse Model of Severe Spinal Muscular Atrophy

We would like to acknowledge the Microscopy and Histology Core Facility at the University of Aberdeen, Kevin Mackenzie, Debbie Wilkinson, Gillian Milne and Lucy Wight, for the use of their facilities. G.K.M. was funded by a research award from RGA awarded to S.H.P. E.S. was funded by a University of Aberdeen Elphinstone PhD Studentship and a research award from the Euan Macdonald Centre for Motor Neurone Disease Research. H.K.S. was funded by a Euan Macdonald Centre for Motor Neurone Disease Research PhD Studentship. S.H.P. is funded by Tenovus (Scotland), SMA Trust and Prinses Beatrix Spierfonds. T.H.G. is funded by SMA Trust (UK SMA Research Consortium Award), Muscular Dystrophy UK, and Anatomical Society (PhD Studentship).Peer reviewedPostprin

Are forested buffers an effective conservation strategy for riparian fauna? An assessment using meta-analysis

Historically, forested riparian buffers have been created to provide protection for aquatic organisms and aquatic ecosystem functions. Increasingly, new and existing riparian buffers are being used also to meet terrestrial conservation requirements. To test the effectiveness of riparian buffers for conserving terrestrial fauna, we conducted a meta-analysis using published data from 397 comparisons of species abundance in riparian buffers and unharvested (reference) riparian sites. The response of terrestrial species to riparian buffers was not consistent between taxonomic groups; bird and arthropod abundances were significantly greater in buffers relative to unharvested areas, whereas amphibian abundance decreased. Edge-preferring species were more abundant in buffer sites than reference sites, whereas species associated with interior habitat were not significantly different in abundance. The degree of buffer effect on animal abundance was unrelated to buffer width; wider buffers did not result in greater similarity between reference and buffer sites. However, responses to buffer treatment were more variable in buffers ,50 m wide, a commonly prescribed width in many management plans. Our results indicate that current buffer prescriptions do not maintain most terrestrial organisms in buffer strips at levels comparable to undisturbed sites

From polarization multipoles to higher-order coherences

We demonstrate that the multipoles associated with the density matrix are truly observable quantities that can be unambiguously determined from intensity moments. Given their correct transformation properties, these multipoles are the natural variables to deal with a number of problems in the quantum domain. In the case of polarization, the moments are measured after the light has passed through two quarter-wave plates, one half-wave plate, and a polarizing beam splitter for specific values of the angles of the wave plates. For more general two-mode problems, equivalent measurements can be performed. (C) 2022 Optical Society of Americ

Two cases of spinal muscular atrophy type II with eosinophilic oesophagitis.

Although primarily characterised by loss of motor neurons from the anterior horn of spinal cord and muscle atrophy, spinal muscular atrophy (SMA) is now recognised as a multi-systemic disorder. Here, we report two SMA Type II patients with eosinophilic oesophagitis (EoE), a rare, chronic immune/antigen-mediated condition. One patient presented with dysphagia and poor weight gain, and the second patient had symptoms of gastro-oesophageal reflux (GOR) and poor weight gain. In both patients, macroscopic observations during gastroscopy indicated typical signs of EoE, which were verified during histological examination of oesophageal biopsies. Given that there is a specific treatment strategy for EoE, these cases highlight the importance of considering this condition in clinical investigations - especially for patients with SMA - who have GOR, discomfort, and oral aversion

Interventions targeting glucocorticoid-Krüppel-like factor 15-branched-chain amino acid signaling improve disease phenotypes in spinal muscular atrophy mice

The circadian glucocorticoid-Krüppel-like factor 15-branched-chain amino acid (GC-KLF15-BCAA) signaling pathway is a key regulatory axis in muscle, whose imbalance has wide-reaching effects on metabolic homeostasis. Spinal muscular atrophy (SMA) is a neuromuscular disorder also characterized by intrinsic muscle pathologies, metabolic abnormalities and disrupted sleep patterns, which can influence or be influenced by circadian regulatory networks that control behavioral and metabolic rhythms. We therefore set out to investigate the contribution of the GC-KLF15-BCAA pathway in SMA pathophysiology of Taiwanese Smn−/−;SMN2 and Smn2B/− mouse models. We thus uncover substantial dysregulation of GC-KLF15-BCAA diurnal rhythmicity in serum, skeletal muscle and metabolic tissues of SMA mice. Importantly, modulating the components of the GC-KLF15-BCAA pathway via pharmacological (prednisolone), genetic (muscle-specific Klf15 overexpression) and dietary (BCAA supplementation) interventions significantly improves disease phenotypes in SMA mice. Our study highlights the GC-KLF15-BCAA pathway as a contributor to SMA pathogenesis and provides several treatment avenues to alleviate peripheral manifestations of the disease. The therapeutic potential of targeting metabolic perturbations by diet and commercially available drugs could have a broader implementation across other neuromuscular and metabolic disorders characterized by altered GC-KLF15-BCAA signaling

Plant conservation in the Anthropocene - challenges and future prospects

Despite the massive efforts that have been made to conserve plant diversity across the world during the past few decades, it is becoming increasingly evident that our current strategies are not sufficiently effective to prevent the continuing decline in biodiversity. As a recent report by the CBD indicates, current progress and commitments are insufficient to achieve the Aichi Biodiversity Targets by 2020. Threatened species lists continue to grow while the world's governments fail to meet biodiversity conservation goals. Clearly, we are failing in our attempts to conserve biodiversity on a sufficient scale. The reasons for this situation are complex, including scientific, technical, sociological, economic and political factors. The conservation community is divided about how to respond. Some believe that saving all existing biodiversity is still an achievable goal. On the other hand, there are those who believe that we need to accept that biodiversity will inevitably continue to be lost, despite all our conservation actions and that we must focus on what to save, why and where. It has also been suggested that we need a new approach to conservation in the face of the challenges posed by the Anthropocene biosphere which we now inhabit. Whatever view one holds on the above issues, it is clear that we need to review the effectiveness of our current conservation strategies, identify the limiting factors that are preventing the Aichi goals being met and at the same time take whatever steps are necessary to make our conservation protocols more explicit, operational and efficient so as to achieve the maximum conservation effect. This paper addresses the key issues that underlie our failure to meet agreed targets and discusses the necessary changes to our conservation approaches. While we can justifiably be proud of our many achievements and successes in plant conservation in the past 30 years, which have helped slow the rate of loss, unless we devise a more coherent, consistent and integrated global strategy in which both the effectiveness and limitations of our current policies, action plans and procedures are recognized, and reflect this in national strategies, and then embark on a much bolder and ambitious set of actions, progress will be limited and plant diversity will continue to decline