Modelling the evolution and spread of HIV immune escape mutants.

During infection with human immunodeficiency virus (HIV), immune pressure from cytotoxic T-lymphocytes (CTLs) selects for viral mutants that confer escape from CTL recognition. These escape variants can be transmitted between individuals where, depending upon their cost to viral fitness and the CTL responses made by the recipient, they may revert. The rates of within-host evolution and their concordant impact upon the rate of spread of escape mutants at the population level are uncertain. Here we present a mathematical model of within-host evolution of escape mutants, transmission of these variants between hosts and subsequent reversion in new hosts. The model is an extension of the well-known SI model of disease transmission and includes three further parameters that describe host immunogenetic heterogeneity and rates of within host viral evolution. We use the model to explain why some escape mutants appear to have stable prevalence whilst others are spreading through the population. Further, we use it to compare diverse datasets on CTL escape, highlighting where different sources agree or disagree on within-host evolutionary rates. The several dozen CTL epitopes we survey from HIV-1 gag, RT and nef reveal a relatively sedate rate of evolution with average rates of escape measured in years and reversion in decades. For many epitopes in HIV, occasional rapid within-host evolution is not reflected in fast evolution at the population level.

Predictors of death among patients who completed tuberculosis treatment: a population-based cohort study.

Background: Mortality among patients who complete tuberculosis (TB) treatment is still high among vulnerable populations. The objective of the study was to identify the probability of death and its predictive factors in a cohort of successfully treated TB patients. Methods: A population-based retrospective longitudinal study was performed in Barcelona, Spain. All patients who successfully completed TB treatment with culture-confirmation and available drug susceptibility testing between 1995 1997 were retrospectively followed-up until December 31, 2005 by the Barcelona TB Control Program. Socio-demographic, clinical, microbiological and treatment variables were examined. Mortality, TB Program and AIDS registries were reviewed. Kaplan-Meier and a Cox regression methods with time-dependent covariates were used for the survival analysis, calculating the hazard ratio (HR) with 95% confidence intervals (CI). Results: Among the 762 included patients, the median age was 36 years, 520 (68.2%) were male, 178 (23.4%) HIV-infected, and 208 (27.3%) were alcohol abusers. Of the 134 (17.6%) injecting drug users (IDU), 123 (91.8%) were HIV-infected. A total of 30 (3.9%) recurrences and 173 deaths (22.7%) occurred (mortality rate: 3.4/100 person-years of follow-up). The predictors of death were: age between 4160 years old (HR: 3.5; CI:2.15.7), age greater than 60 years (HR: 14.6; CI:8.924), alcohol abuse (HR: 1.7; CI:1.22.4) and HIV-infected IDU (HR: 7.9; CI:4.713.3). Conclusions: The mortality rate among TB patients who completed treatment is associated with vulnerable populations such as the elderly, alcohol abusers, and HIV-infected IDU. We therefore need to fight against poverty, and promote and develop interventions and social policies directed towards these populations to improve their survival.

Efficacious treatment of non-dermatophyte mould onychomycosis with topical amphotericin B.

BACKGROUND: Dermatophytes are the main cause of onychomycosis, but various non-dermatophyte moulds (NDMs) are often the infectious agents in abnormal nails. In particular, Fusarium spp. and other NDMs are mostly insensitive to standard onychomycosis treatment with topical agents as well as with oral terbinafine and itraconazole.¦OBJECTIVE: The aim of this work is to report the efficacy of a topical amphotericin B solution on NDM onychomycosis in a series of 8 patients resistant to multiple conventional topical and systemic treatments.¦METHODS: Treatment consisted in the application of an optimized amphotericin B solution once daily to the affected nails and surrounding tissue. No mechanical debridement or medications were allowed except for trimming excessively long nails or in some cases occasionally applying urea-based cream to soften thickened nail plates.¦RESULTS: Onychomycosis was clinically cured in all patients after a 12-month treatment. Mycological cure was obtained in all but 1 patient.¦CONCLUSIONS: Topical amphotericin B is an efficacious, safe, cheap and easy-to-apply treatment which should be considered as first-line therapy for NDM onychomycosis.

Recueil de deux traités de Mysticisme.

Un traité d'ontologie, écrit par un auteur anonyme, en l'année 988 de l'hégire (1580), dans le sanğak de Sirim, après qu'il eut fait une retraite de quarante jours auprès d'un sheïkh soufi célèbre, Mir Sektavar, surnommé Mohammed Beg, dont il répéta les doctrines et les théories. Cet opuscule traite des idiosyncrasies des quatre aspects entre lesquels les Mystiques divisent le monde : le monde de la Divinité, le monde de la Toute-puissance, le monde de la Souveraineté, le monde du Royaume, et des trois Discriminants (folio 1 verso) ; un traité, sans titre, qui fut écrit, évidemment par le même auteur, au mois de Rebiʿ premier 990, sur les instances répétées d'un de ses amis, le defterdar Hasan Čelebi, à Constantinople, sur les trois classes des hommes (folio 54 verso), déterminées par leurs rapports avec les degrés du monde, avec les stades du monde tangible (folio 47 verso), et étudiées dans une rédaction très diffuse.

Fatty acid amide hydrolase deficiency enhances intraplaque neutrophil recruitment in atherosclerotic mice.

OBJECTIVE: Endocannabinoid levels are elevated in human and mouse atherosclerosis, but their causal role is not well understood. Therefore, we studied the involvement of fatty acid amide hydrolase (FAAH) deficiency, the major enzyme responsible for endocannabinoid anandamide degradation, in atherosclerotic plaque vulnerability. METHODS AND RESULTS: We assessed atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) and ApoE(-/-)FAAH(-/-) mice. Before and after 5, 10, and 15 weeks on high-cholesterol diet, we analyzed weight, serum cholesterol, and endocannabinoid levels, and atherosclerotic lesions in thoracoabdominal aortas and aortic sinuses. Serum levels of FAAH substrates anandamide, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) were 1.4- to 2-fold higher in case of FAAH deficiency. ApoE(-/-)FAAH(-/-) mice had smaller plaques with significantly lower content of smooth muscle cells, increased matrix metalloproteinase-9 expression, and neutrophil content. Circulating and bone marrow neutrophil counts were comparable between both genotypes, whereas CXC ligand1 levels were locally elevated in aortas of FAAH-deficient mice. We observed enhanced recruitment of neutrophils, but not monocytes, to large arteries of ApoE(-/-) mice treated with FAAH inhibitor URB597. Spleens of ApoE(-/-)FAAH(-/-) mice had reduced CD4+FoxP3+regulatory T-cell content, and in vitro stimulation of splenocytes revealed significantly elevated interferon-γ and tumor necrosis factor-α production in case of FAAH deficiency. CONCLUSIONS: Increased anandamide and related FAAH substrate levels are associated with the development of smaller atherosclerotic plaques with high neutrophil content, accompanied by an increased proinflammatory immune response.

Iowa Department of Transportation Major Items - Preliminary Quantity Report, January 16, 2013; With Addendums

Weekly letting report.

Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues

MicroRNAs (miRNAs) are short non-coding RNA molecules playing regulatory roles by repressing translation or cleaving RNA transcripts. Although the number of verified human miRNA is still expanding, only few have been functionally described. However, emerging evidences suggest the potential involvement of altered regulation of miRNA in pathogenesis of cancers and these genes are thought to function as both tumours suppressor and oncogenes. In our study, we examined by Real-Time PCR the expression of 156 mature miRNA in colorectal cancer. The analysis by several bioinformatics algorithms of colorectal tumours and adjacent non-neoplastic tissues from patients and colorectal cancer cell lines allowed identifying a group of 13 miRNA whose expression is significantly altered in this tumor. The most significantly deregulated miRNA being miR-31, miR-96, miR-133b, miR-135b, miR-145, and miR-183. In addition, the expression level of miR-31 was correlated with the stage of CRC tumor. Our results suggest that miRNA expression profile could have relevance to the biological and clinical behavior of colorectal neoplasia.

Una experiencia didáctica con el collage

El punto de partida que Joan Miró estableció para realizar las dieciocho Pintures segons collage de 1933 nos sirven hoy para hacer una propuesta que permita pensar en algunas de las claves de la pintura contemporánea. Términos como la apropiación, la autoría o la subjetividad del artista se ponen en juego cuando se activa el dispositivo del collage como modelo. Aquí se plantea una actividad de aprendizaje que confronta el trabajo individual con el colectivo y que tiene como objetivo principal la reflexión sobre el lenguaje pictórico.

A multiplicity of factors contributes to selective RNA polymerase III occupancy of a subset of RNA polymerase III genes in mouse liver.

The genomic loci occupied by RNA polymerase (RNAP) III have been characterized in human culture cells by genome-wide chromatin immunoprecipitations, followed by deep sequencing (ChIP-seq). These studies have shown that only ∼40% of the annotated 622 human tRNA genes and pseudogenes are occupied by RNAP-III, and that these genes are often in open chromatin regions rich in active RNAP-II transcription units. We have used ChIP-seq to characterize RNAP-III-occupied loci in a differentiated tissue, the mouse liver. Our studies define the mouse liver RNAP-III-occupied loci including a conserved mammalian interspersed repeat (MIR) as a potential regulator of an RNAP-III subunit-encoding gene. They reveal that synteny relationships can be established between a number of human and mouse RNAP-III genes, and that the expression levels of these genes are significantly linked. They establish that variations within the A and B promoter boxes, as well as the strength of the terminator sequence, can strongly affect RNAP-III occupancy of tRNA genes. They reveal correlations with various genomic features that explain the observed variation of 81% of tRNA scores. In mouse liver, loci represented in the NCBI37/mm9 genome assembly that are clearly occupied by RNAP-III comprise 50 Rn5s (5S RNA) genes, 14 known non-tRNA RNAP-III genes, nine Rn4.5s (4.5S RNA) genes, and 29 SINEs. Moreover, out of the 433 annotated tRNA genes, half are occupied by RNAP-III. Transfer RNA gene expression levels reflect both an underlying genomic organization conserved in dividing human culture cells and resting mouse liver cells, and the particular promoter and terminator strengths of individual genes.

Transplantation hépatique : introduction en Suisse d'un nouveau système d'allocation des organes [Liver transplantation: new organ allocation system in Switzerland]

This article describes the new organ allocation system for liver transplantation introduced in Switzerland on July 1, 2007. In its newly adopted transplantation law, Switzerland chose the MELD score (Model for end-stage liver disease), based on three laboratory values: total bilirubin, serum creatinine and INR. Advantages and limitations of the MELD score are discussed. Finally the West Switzerland joint liver transplantation program is briefly introduced. Cet article décrit le nouveau système d'allocation des organes pour la transplantation hépatique, qui a été introduit en Suisse depuis le 1er juillet 2007. En se dotant d'une nouvelle loi sur la transplantation en 2007, la Suisse a en effet opté pour le score MELD (Model for end-stage liver disease), c'est-à-dire un score calculable à partir de trois valeurs de laboratoire : bilirubine totale, créatinine et INR. Les avantages du MELD, mais aussi quelques inconvénients potentiels, sont brièvement décrits. Afin de clarifier le parcours du patient pour lequel une évaluation prétransplantation hépatique spécialisée est indiquée, une brève description du programme romand de transplantation hépatique est présentée.

A bio-inspired agent-based programming environment for pervasive platforms

Abstract in English : Ubiquitous Computing is the emerging trend in computing systems. Based on this observation this thesis proposes an analysis of the hardware and environmental constraints that rule pervasive platforms. These constraints have a strong impact on the programming of such platforms. Therefore solutions are proposed to facilitate this programming both at the platform and node levels. The first contribution presented in this document proposes a combination of agentoriented programming with the principles of bio-inspiration (Phylogenesys, Ontogenesys and Epigenesys) to program pervasive platforms such as the PERvasive computing framework for modeling comPLEX virtually Unbounded Systems platform. The second contribution proposes a method to program efficiently parallelizable applications on each computing node of this platform. Résumé en Français : Basée sur le constat que les calculs ubiquitaires vont devenir le paradigme de programmation dans les années à venir, cette thèse propose une analyse des contraintes matérielles et environnementale auxquelles sont soumises les plateformes pervasives. Ces contraintes ayant un impact fort sur la programmation des plateformes. Des solutions sont donc proposées pour faciliter cette programmation tant au niveau de l'ensemble des noeuds qu'au niveau de chacun des noeuds de la plateforme. La première contribution présentée dans ce document propose d'utiliser une alliance de programmation orientée agent avec les grands principes de la bio-inspiration (Phylogénèse, Ontogénèse et Épigénèse). Ceci pour répondres aux contraintes de programmation de plateformes pervasives comme la plateforme PERvasive computing framework for modeling comPLEX virtually Unbounded Systems . La seconde contribution propose quant à elle une méthode permettant de programmer efficacement des applications parallélisable sur chaque noeud de calcul de la plateforme

Ontogeny of Sleeping in Color - Linking melanism to sleep architecture and rhythmicity variation in wild barn owl nestlings

The function of sleep remains unknown. To gain insight into the function of sleep in natural conditions, I assessed variation in sleep architecture and its link with fitness-related phenotypic traits. I considered melanin-based coloration because its underlying genetic basis is very well known giving an opportunity to examine whether some genes pleiotropically regulate both coloration and sleep. The melanocortin system is known to generate covariation between melanin-based coloration and other phenotypes like behaviour, physiology and life history traits. I investigated whether this system of genes could participate in the co-expression of coloration and sleep. I carried out a study with nestling barn owls (Tyto alba) in order to tackle the potential link between variation in color traits and the ontogeny of sleep under natural conditions. For this I established a suitable method for recording the brain activity (electroencephalogram) of owls in nature. Birds are especially interesting, because they convergently evolved sleep states similar to those exhibited by mammals. As in mammals, I found that in owlets time spent in rapid eye movement (REM) sleep declines with age, a relationship thought to eflect developmental changes in the brain. Thus this developmental trajectory appears to reflect a fundamental feature of sleep. Additionally, I discovered an association between a gene involved in melanism expressed in the feather follicles (proprotein convertase subtilisin/kexin type 2, PCSK2) and the age-related changes in sleep in the brain. Nestlings with higher expression levels of PCSK2 showed a more precocial pattern of sleep development and a higher degree of melanin-based coloration compared to nestlings with lower PCSK2 expression. Also sleep architecture and the development of rhythmicity in brain and physical activity was related to plumage traits of the nestlings and their biological parents. This pattern during ontogeny might reflect differences in life l history strategies, antipredator behaviour and developmental pace. Therefore, differently colored individuals may differentially deal with trade-offs between the costs and benefits of sleep which in turn lead to differences in brain organization and ultimately fitness. These results should stimulate evolutionary biologists to consider sleep as a major life history trait. Résumé La fonction du sommeil reste inconnue. Afin d'acquérir une meilleur compréhension de la fonction du sommeil dans les conditions naturelles, j'ai analysé la variation dans l'architecture du sommeil et son lien avec d'autres traits phénotypiques liés au succès reproducteur (fitness). J'ai choisi et examiné la coloration mélanique, car ses bases génétiques sont bien connues et il est ainsi possible d'étudier si certains gènes, de façon pléiotropique régulent à la fois la coloration et le sommeil. J'ai exploré si ce système génétique était impliqué dans la co-expression de la coloration et du sommeil. J'ai effectué mon étude sur des poussins de chouette effraie (Tyto alba) en condition naturelle, pour rechercher ce lien potentiel entre la variation de la coloration et l'ontogenèse du sommeil. Dans ce but, j'ai établi une méthodologie permettant d'enregistrer l'activité cérébrale (électroencéphalogramme) des chouettes dans la nature. Les oiseaux sont particulièrement intéressants car ils ont développé, par évolution convergente, des phases de sommeil similaires à celles des mammifères. De manière semblable à ce qui a été montré chez les mammifères, j'ai découvert que le temps passé dans le sommeil paradoxal diminue avec l'âge des poussins. On pense que ceci est dû aux changements développementaux au niveau du cerveau. Cette trajectoire développementale semble refléter une caractéristique fondamentale du sommeil. J'ai également découvert une association entre l'un des gènes impliqué dans le mélanisme, exprimé dans les follicules plumeux (proprotein convertase subtilisin/kexin type 2, PCSK2), et les changements dans la structure du sommeil avec l'âge. Les poussins ayant un niveau d'expression génétique élevé de la PCSK2 présentent une structure du sommeil plus précoce et un taux de coloration dû à la mélanine plus élevé que des poussins avec un niveau d'expression moindre de la PCSK2. L'architecture du sommeil et le développement de la rythmicité dans le cerveau ainsi que l'activité physique sont également liés à la coloration des plumes des poussins et pourraient ainsi refléter des différences de stratégies d'histoire de vie, de comportements anti-prédateur et de vitesses développementales. Ainsi, des individus de coloration différente sembleraient traiter différemment les coûts et les bénéfices du sommeil, ce qui aurait des conséquences sur l'organisation cérébrale et pour finir, sur le succès reproducteur. Ces résultats devraient encourager les biologistes évolutionnistes à considérer le sommeil comme un important trait d'histoire de vie. Zusammenfassung Die Funktion von Schlaf ist noch unbekannt. Um mehr Einsicht in diese unter natürlichen Bedingungen zu bekommen, habe ich die Variation in der Schlafarchitektur und die Verknüpfung mit phänotypischen Merkmalen, die mit der Fitness zusammenhängen, studiert. Ich habe mir melanin-basierte Färbung angesehen, da die zugrunde liegende genetische Basis bekannt ist und somit die Möglichkeit gegeben ist, zu untersuchen, ob einige Gene beides regulieren, Färbung und Schlaf. Das melanocortin System generiert eine Kovariation zwischen melanin-basierter Färbung und anderen phänotypischer Merkmale wie Verhalten, Physiologie und Überlebensstrategien. Ich habe untersucht, ob dieses Gensystem an einer gleichzeitigen Steuerung von Färbung und Schlaf beteiligt ist. Dazu habe ich Schleiereulen (Tyto alba) studiert um einen möglichen Zusammenhang zwischen der Variation in der Pigmentierung und der Entwicklung des Schlafs unter natürlichen Bedingungen zu entdecken. Für diese Studie entwickelte ich eine Methode um die Gehirnaktivität (Elektroenzephalogramm) bei Eulen in der Natur aufzunehmen. Vögel sind besonders interessant, da sie die gleichen Schlafstadien aufweisen wie Säugetiere und diese unabhängig konvergent entwickelt haben. Genauso wie bei Säugetieren nahm die Dauer des sogenannten ,,rapid eye movement" (REM) - Schlafes mit zunehmendem Alter ab. Es wird angenommen, dass dieser Zusammenhang die Entwicklung des Gehirns widerspiegelt. Daher scheint dieses Entwicklungsmuster ein fundamentaler Aspekt von Schlaf zu sein. Zusätzlich entdeckte ich einen Zusammenhang zwischen der Aktivität eines Gens in den Federfollikeln (proprotein convertase subtilisin/kexin type 2, PCSK2), das für die Ausprägung schwarzer Punkte auf den Federn der Eulen verantwortlich ist, und den altersabhängigen Änderungen im Schlafmuster im Gehirn. Küken mit höherer Aktivität von PCSK2 zeigten eine frühreifere Schlafentwicklung und eine dunklere Färbung als Küken mit niedriger PCSK2 Aktivität. Die Architekture des Schlafes und die Entwicklung der Rhythmik im Gehirn und die der physischen Aktivität ist mit der Färbung des Gefieders von den Küken und ihren Eltern verknüpft. Dieses Muster während der Entwicklung kann Unterschiede in Überlebensstrategien, Feindabwehrverhalten und in der Entwicklungsgeschwindigkeit reflektieren. Unterschiedlich gefärbte Individuen könnten unterschiedliche Strategien haben um zwischen den Kosten und Nutzen von Schlaf zu entscheiden, was zu Unterschieden in der Gehirnstruktur führen kann und letztendlich zur Fitness. Diese Ergebnisse sollten Evolutionsbiologen stimulieren Schlaf als einen wichtigen Bestandteil des Lebens zu behandeln.

[Voyage en Italie : 1824-1830]. , [Vue générale, avec le Château neuf] : [vue d'ensemble] : [dessin] / [Henri Labrouste]

Référence bibliographique : Weigert, 223

Integrative molecular bioinformatics study of human adrenocortical tumors : microRNA, tissue-specific target prediction, and pathway analysis.

MicroRNAs (miRs) are involved in the pathogenesis of several neoplasms; however, there are no data on their expression patterns and possible roles in adrenocortical tumors. Our objective was to study adrenocortical tumors by an integrative bioinformatics analysis involving miR and transcriptomics profiling, pathway analysis, and a novel, tissue-specific miR target prediction approach. Thirty-six tissue samples including normal adrenocortical tissues, benign adenomas, and adrenocortical carcinomas (ACC) were studied by simultaneous miR and mRNA profiling. A novel data-processing software was used to identify all predicted miR-mRNA interactions retrieved from PicTar, TargetScan, and miRBase. Tissue-specific target prediction was achieved by filtering out mRNAs with undetectable expression and searching for mRNA targets with inverse expression alterations as their regulatory miRs. Target sets and significant microarray data were subjected to Ingenuity Pathway Analysis. Six miRs with significantly different expression were found. miR-184 and miR-503 showed significantly higher, whereas miR-511 and miR-214 showed significantly lower expression in ACCs than in other groups. Expression of miR-210 was significantly lower in cortisol-secreting adenomas than in ACCs. By calculating the difference between dCT(miR-511) and dCT(miR-503) (delta cycle threshold), ACCs could be distinguished from benign adenomas with high sensitivity and specificity. Pathway analysis revealed the possible involvement of G2/M checkpoint damage in ACC pathogenesis. To our knowledge, this is the first report describing miR expression patterns and pathway analysis in sporadic adrenocortical tumors. miR biomarkers may be helpful for the diagnosis of adrenocortical malignancy. This tissue-specific target prediction approach may be used in other tumors too.