The vascular targeting agent combretastatin-A4 and a novel cis-Restricted {beta}-Lactam Analogue, CA-432, induce apoptosis in human chronic myeloid leukemia cells and ex vivo patient samples including those displaying multidrug resistance

Combretastatin-A4 (CA-4) is a natural derivative of the African willow tree Combretum caffrum. CA-4 is one of the most potent antimitotic components of natural origin, but it is, however, intrinsically unstable. A novel series of CA-4 analogs incorporating a 3,4-diaryl-2-azetidinone (β-lactam) ring were designed and synthesized with the objective to prevent cis -trans isomerization and improve the intrinsic stability without altering the biological activity of CA-4. Evaluation of selected β-lactam CA-4 analogs demonstrated potent antitubulin, antiproliferative, and antimitotic effects in human leukemia cells. A lead β-lactam analog, CA-432, displayed comparable antiproliferative activities with CA-4. CA-432 induced rapid apoptosis in HL-60 acute myeloid leukemia cells, which was accompanied by depolymerization of the microtubular network, poly(ADP-ribose) polymerase cleavage, caspase-3 activation, and Bcl-2 cleavage. A prolonged G(2)M cell cycle arrest accompanied by a sustained phosphorylation of mitotic spindle checkpoint protein, BubR1, and the antiapoptotic proteins Bcl-2 and Bcl-x(L) preceded apoptotic events in K562 chronic myeloid leukemia (CML) cells. Molecular docking studies in conjunction with comprehensive cell line data rule out CA-4 and β-lactam derivatives as P-glycoprotein substrates. Furthermore, both CA-4 and CA-432 induced significantly more apoptosis compared with imatinib mesylate in ex vivo samples from patients with CML, including those positive for the T315I mutation displaying resistance to imatinib mesylate and dasatinib. In summary, synthetic intrinsically stable analogs of CA-4 that display significant clinical potential as antileukemic agents have been designed and synthesized.

Membrane fission is promoted by insertion of amphipathic helices and is restricted by crescent BAR domains

Shallow hydrophobic insertions and crescent-shaped BAR scaffolds promote membrane curvature. Here, we investigate membrane fission by shallow hydrophobic insertions quantitatively and mechanistically. We provide evidence that membrane insertion of the ENTH domain of epsin leads to liposome vesiculation, and that epsin is required for clathrin-coated vesicle budding in cells. We also show that BAR-domain scaffolds from endophilin, amphiphysin, GRAF, and β2-centaurin limit membrane fission driven by hydrophobic insertions. A quantitative assay for vesiculation reveals an antagonistic relationship between amphipathic helices and scaffolds of N-BAR domains in fission. The extent of vesiculation by these proteins and vesicle size depend on the number and length of amphipathic helices per BAR domain, in accord with theoretical considerations. This fission mechanism gives a new framework for understanding membrane scission in the absence of mechanoenzymes such as dynamin and suggests how Arf and Sar proteins work in vesicle scission.

Reflections of universal algebras into semilattices, their Galois theories, and related factorization systems

Estabelecemos uma condição suficiente para a preservação dos produtos finitos, pelo reflector de uma variedade de álgebras universais numa subvariedade, que é, também, condição necessária se a subvariedade for idempotente. Esta condição é estabelecida, seguidamente, num contexto mais geral e caracteriza reflexões para as quais a propriedade de ser semi-exacta à esquerda e a propriedade, mais forte, de ter unidades estáveis, coincidem. Prova-se que reflexões simples e semi-exactas à esquerda coincidem, no contexto das variedades de álgebras universais e caracterizam-se as classes do sistema de factorização derivado da reflexão. Estabelecem-se resultados que ajudam a caracterizar morfismos de cobertura e verticais-estáveis em álgebras universais e no contexto mais geral já referido. Caracterizam-se as classes de morfismos separáveis, puramente inseparáveis e normais. O estudo dos morfismos de descida de Galois conduz a condições suficientes para que o seu par kernel seja preservado pelo reflector.

Eutrophication and some European waters of restricted exchange

Regions of Restricted Exchange (RREs) are an important feature of the European coastline. They are historically preferred sites for human settlement and aquaculture and their ecosystems, and consequent human use, may be at risk from eutrophication. The OAERRE project (EVK3-CT1999-0002 concerns ‘Oceanographic Applications to Eutrophication in Regions of Restricted Exchange’. It began in July 2000, and studies six sites. Four of these sites are fjords: Kongsfjorden (west coast of Spitzbergen); Gullmaren (Skagerrak coast of Sweden); Himmerfj.arden (Baltic coast of Sweden); and the Firth of Clyde (west coast of Scotland). Two are bays sheltered by sand bars: Golfe de Fos (French Mediterranean); and Ria Formosa (Portuguese Algarve). Together they exemplify a range of hydrographic and enrichment conditions. The project aims to understand the physical, biogeochemical and biological processes, and their interactions, that determine the trophic status of these coastal marine RRE through the development of simple screening models to define, predict and assess eutrophication. This paper introduces the sites and describes the component parts of a basic screening model and its application to each site using historical data. The model forms the starting point for the OAERRE project and views an RRE as a well-mixed box, exchanging with the sea at a daily rate E determined by physical processes, and converting nutrient to phytoplankton chlorophyll at a fixed yield q: It thus uses nutrient levels to estimate maximum biomass; these preliminary results are discussed in relation to objective criteria used to assess trophic status. The influence of factors such as grazing and vertical mixing on key parameters in the screening model are further studied using simulations of a complex‘research’ model for the Firth of Clyde. The future development of screening models in general and within OAERRE in particular is discussed. In addition, the paper looks ahead with a broad discussion of progress in the scientific understanding of eutrophication and the legal and socioeconomic issues that need to be taken into account in managing the trophic status of RREs.

Broad and restricted scope of the concept of civil service: a multipolarização do conceito de publica nos modelos hibricos. A capacidade transformadora dos memorados de entendimento: Portugal e Irlanda

Analise do conceito de Função Publica, identificando, á partida, uma dicotomia conceptual, entre um modelo marcadamente continental(broad concept of civil service) e um modelo restrito(restricted scope of the concept of civil service), característico dos países anglo-saxónicos, aflorando a reforma da Administração Publica, na senda da New Public Management, como o caminho para a afirmação de modelos híbridos, com características de laboralização da Função Publica e de flexisegurança, que surgem como consequência da pulverização daquela dicotomia, revelando uma miscigenação entre os modelos iniciais e elementos externos, de acordo com as idiossincrasias de cada país. Posterior estudo de caso, versando sobre Portugal e a Irlanda , dois países que, são contrario do que a tradição anglo- saxónica da Irlanda faria adivinhar, partilham um conceito amplo de Função Publica(broad concept of Civil Service), apoiado num sistema de carreira(carrear sytem). Percorrerem, quase em simultâneo, o caminho de um regate económico-financeiro desenvolvido pelo Fundo Monetário Internacional, Banco Central Europeu e Comissão Europeia. Procurara investiga-se se o acordo firmado entre os dois países e a Troika, materializado nos respectivos Memorando de Entendimento e sucessivas revisões, no período compreendido entre 16 de Dezembro de 2010 e 31 de Dezembro de 2012, introduziu modificações nos respectivos modelos de Função Publica, designadamente forçando-os a uma aproximação do restricted scope of the concept of Civil Service e, com isso, projectando-os para a adopção de modelos híbridos.

Strokes restricted to the insular cortex

Résumé: L'objectif de l'étude est de caractériser la manifestation clinique d'une atteinte vasculaire cérébrale ischémique aiguë limitée au cortex insulaire, région intrigante et méconnue du cerveau humain. Dans la pratique clinique, une atteinte vasculaire aiguë limitée à l'insula, sans compromission d'autres régions cérébrales, est exceptionnelle et sa manifestation clinique neurologique est souvent non reconnue. L'étude est focalisée sur quatre patients, inscrits dans le Lausanne Stroke Registry, présentant une nouvelle atteinte vasculaire cérébrale avec une lésion unique purement limitée au cortex insulaire, objectivée à l'aide de la résonance magnétique (IRM). L'étude a mis en évidence cinq manifestations cliniques principales : 1) Troubles de la sensibilité corporelle sont révélé chez trois patients avec une atteinte insulaire postérieure (deux avec un syndrome pseudothalamique, un avec un déficit à distribution partielle). 2) Un patient avec une lésion insulaire postérieure gauche présent des troubles du goût. 3) Un syndrome pseudovestibulaire avec vertiges non rotatoires, instabilité à la marche sans nystagmus, est mis en évidence chez trois patients avec une atteinte ischémique insulaire postérieure. 4) Un patient avec atteinte de l'insula postérieure droite présente des épisodes d'hypertension artérielle d'origine cryptique. 5) Des troubles neuropsychologiques tels qu'aphasie et dysarthrie sont détectés chez les patients avec une atteinte insulaire postérieure gauche, un épisode de somatoparaphrénie est rapporté avec une atteinte insulaire postérieure droite. En conclusion, les atteintes vasculaires cérébrales ischémiques aiguës limitées au cortex insulaire postérieur peuvent se manifester principalement avec un tableau clinique caractérisé par un syndrome pseudothalamique associé à une symptomatologie pseudovertigineuse. Les lésions insulaires postérieures peuvent se manifester avec une dysarthrie et des troubles du goût, une aphasie (gauche), une somatoparaphrénie et une dysfonction hypertensive (droite). L'étude n'a pas mis en évidence de dysphagie, reportée dans les atteintes insulaires antérieures. Abstract: Objective: To characterize clinically acute insular strokes from four patients with, a first ever acute stroke restricted to the insula on MRI. Methods: The authors studied the clinical presentation of four patients with a first ever acute stroke restricted to the insula on MRI. Results: The authors found five main groups of clinical presentations: 1) somatosensory deficits in three patients with posterior insular stroke (two with a transient pseudothalamic sensory syndrome, one with partial distribution); 2) gustatory disorder in a patient with left posterior insular infarct; 3) vestibular-like syndrome, with dizziness, gait instability, and tendency to fall, but no nystagmus, in three patients with posterior insular strokes; 4) cardiovascular disturbances, consisting of hypertensive episodes in a patient with a right posterior insular infarct; and 5) neuropsychological disorders, including aphasia (left posterior insula), dysarthria, and transient somatoparaphrenia (right posterior insula). Conclusion: Strokes restricted to the posterior insula may present with pseudothalamic sensory and vestibular-like syndromes as prominent clinical manifestations, but also dysarthria and aphasia (in left lesions), somatoparaphrenia (right lesions) and gustatory dysfunction and blood pressure with hypertensive episodes in right lesions; we did not find acute dysphagia reported in anterior, insular strokes.

Le suicide comme langage de l'oppression. Ethnographie d'un service d'urgences psychiatriques

Ce travail s'intéresse à la problématique du suicide à partir de l'émergence en Suisse, vers la fin des années '90, de la prévention du suicide comme préoccupation sociale et politique. Au début, ce sont les milieux associatifs qui ont soulevé à cette question en percevant le suicide comme le reflet d'une souffrance d'origine sociale. Par la suite, la prévention du suicide est progressivement devenue une problématique de santé publique appréhendée essentiellement sous le registre médical comme étant le symptôme d'une pathologie psychiatrique. Après une première partie consacrée aux processus sociopolitiques et aux transformations morales touchant le suicide et sa prévention, ce travail approfondit, au travers d'un terrain ethnographique, la prise en charge des personnes présentant des problématiques suicidaires au sein d'un service d'urgences psychiatriques.Malgré une approche se voulant biopsychosociale, l'analyse des discours et des pratiques soignantes montre que la dimension sociale est largement négligée, conduisant à une médicalisation de situations de détresse qui sont principalement de nature sociale. En effet, parmi la population qui fréquente le service, on observe une surreprésentation de personnes issues des classes sociales défavorisées présentant souvent des trajectoires biographiques particulièrement difficiles. Au fil des entretiens avec les patients émerge une analyse voyant la souffrance psychique et la prise en charge psychiatrique comme étant aujourd'hui une manière d'obtenir une reconnaissance sociale et symbolique. Les problématiques suicidaires peuvent ainsi être interprétées comme une forme d'expression, un langage au travers duquel s'exprime la position sociale défavorisée.En adoptant une posture militante construite à partir de la réalité ethnographique, les problématiques suicidaires sont analysées comme l'expression d'une condition d'oppression liée à un cadre social et économique de plus en plus contraignant, à des rapports de pouvoir inégaux ainsi qu'à une lecture individualisante, médicalisante et pathologisante des problèmes sociaux.The present thesis discusses suicide prevention in Switzerland, which emerged as a social and political issue at the end of the '90s. At first, this question was taken up by associations considering suicide as a reflection of social suffering. Thereafter, suicide prevention gradually became a public health matter conceived with a medical approach as a symptom of a psychiatric disease. The first part of this work analyzes the sociopolitical process and moral transformations concerning suicide and its prevention. The second part is based on an ethnographic fieldwork conducted in a psychiatric emergency unit that attends people who have tried to attempt their life or consider doing it. Through the analysis of discourses and practices of the medical staff, this research shows that the social aspect of suicide is widely neglected, leading to a medicalization of social problems. In fact, amongst patients attending the emergency unit, there is an over-­-representation of people from disadvantaged classes having very difficult life stories. Interviews with patients also revealed that psychic suffering and psychiatric treatment is nowadays a way to get social and symbolical recognition. Suicidal problems can be understood as a language expressing a disadvantaged social position. By adopting a militant position constructed from the ethnographic reality, suicide is analyzed as the expression of an oppressed condition related to a more and more restricted social and economic situation, to unequal power relations as well as to an individualistic, medical and pathological interpretation of social problems.

Hierarchy and Expansiveness in Two-Dimensional Subshifts of Finite Type

Subshifts are sets of configurations over an infinite grid defined by a set of forbidden patterns. In this thesis, we study two-dimensional subshifts offinite type (2D SFTs), where the underlying grid is Z2 and the set of for-bidden patterns is finite. We are mainly interested in the interplay between the computational power of 2D SFTs and their geometry, examined through the concept of expansive subdynamics. 2D SFTs with expansive directions form an interesting and natural class of subshifts that lie between dimensions 1 and 2. An SFT that has only one non-expansive direction is called extremely expansive. We prove that in many aspects, extremely expansive 2D SFTs display the totality of behaviours of general 2D SFTs. For example, we construct an aperiodic extremely expansive 2D SFT and we prove that the emptiness problem is undecidable even when restricted to the class of extremely expansive 2D SFTs. We also prove that every Medvedev class contains an extremely expansive 2D SFT and we provide a characterization of the sets of directions that can be the set of non-expansive directions of a 2D SFT. Finally, we prove that for every computable sequence of 2D SFTs with an expansive direction, there exists a universal object that simulates all of the elements of the sequence. We use the so called hierarchical, self-simulating or fixed-point method for constructing 2D SFTs which has been previously used by Ga´cs, Durand, Romashchenko and Shen.

Le vieux caporal : drame en cinq actes. [suivi de] Diane de lys et de camélias, ou La femme du monde légère, liée à un homme bilieux qui n'entend pas la plaisanterie : grande parodie en 3 petits tableaux. Livr. 121 / par MM. Dumanoir et d'Ennery ; par MM. Delacour et Lambert Thiboust

Collection : Théâtre contemporain illustré ; 121e et 122e livraisons

Le vieux caporal : drame en cinq actes. [suivi de] Diane de lys et de camélias, ou La femme du monde légère, liée à un homme bilieux qui n'entend pas la plaisanterie : grande parodie en 3 petits tableaux. Livr. 122 / par MM. Dumanoir et d'Ennery ; par MM. Delacour et Lambert Thiboust

Collection : Théâtre contemporain illustré ; 121e et 122e livraisons