PathBeat. Number 13 (Winter 2012) University of Iowa Department of Pathology.

University of Iowa Department of Pathology newsletter.

Copy number variation of KIR genes influences HIV-1 control.

A genome-wide screen for large structural variants showed that a copy number variant (CNV) in the region encoding killer cell immunoglobulin-like receptors (KIR) associates with HIV-1 control as measured by plasma viral load at set point in individuals of European ancestry. This CNV encompasses the KIR3DL1-KIR3DS1 locus, encoding receptors that interact with specific HLA-Bw4 molecules to regulate the activation of lymphocyte subsets including natural killer (NK) cells. We quantified the number of copies of KIR3DS1 and KIR3DL1 in a large HIV-1 positive cohort, and showed that an increase in KIR3DS1 count associates with a lower viral set point if its putative ligand is present (p = 0.00028), as does an increase in KIR3DL1 count in the presence of KIR3DS1 and appropriate ligands for both receptors (p = 0.0015). We further provide functional data that demonstrate that NK cells from individuals with multiple copies of KIR3DL1, in the presence of KIR3DS1 and the appropriate ligands, inhibit HIV-1 replication more robustly, and associated with a significant expansion in the frequency of KIR3DS1+, but not KIR3DL1+, NK cells in their peripheral blood. Our results suggest that the relative amounts of these activating and inhibitory KIR play a role in regulating the peripheral expansion of highly antiviral KIR3DS1+ NK cells, which may determine differences in HIV-1 control following infection.

Does the physical disector method provide an accurate estimation of sensory neuron number in rat dorsal root ganglia?

The physical disector is a method of choice for estimating unbiased neuron numbers; nevertheless, calibration is needed to evaluate each counting method. The validity of this method can be assessed by comparing the estimated cell number with the true number determined by a direct counting method in serial sections. We reconstructed a 1/5 of rat lumbar dorsal root ganglia taken from two experimental conditions. From each ganglion, images of 200 adjacent semi-thin sections were used to reconstruct a volumetric dataset (stack of voxels). On these stacks the number of sensory neurons was estimated and counted respectively by physical disector and direct counting methods. Also, using the coordinates of nuclei from the direct counting, we simulate, by a Matlab program, disector pairs separated by increasing distances in a ganglion model. The comparison between the results of these approaches clearly demonstrates that the physical disector method provides a valid and reliable estimate of the number of sensory neurons only when the distance between the consecutive disector pairs is 60 microm or smaller. In these conditions the size of error between the results of physical disector and direct counting does not exceed 6%. In contrast when the distance between two pairs is larger than 60 microm (70-200 microm) the size of error increases rapidly to 27%. We conclude that the physical dissector method provides a reliable estimate of the number of rat sensory neurons only when the separating distance between the consecutive dissector pairs is no larger than 60 microm.

Selectome update: quality control and computational improvements to a database of positive selection.

Selectome (http://selectome.unil.ch/) is a database of positive selection, based on a branch-site likelihood test. This model estimates the number of nonsynonymous substitutions (dN) and synonymous substitutions (dS) to evaluate the variation in selective pressure (dN/dS ratio) over branches and over sites. Since the original release of Selectome, we have benchmarked and implemented a thorough quality control procedure on multiple sequence alignments, aiming to provide minimum false-positive results. We have also improved the computational efficiency of the branch-site test implementation, allowing larger data sets and more frequent updates. Release 6 of Selectome includes all gene trees from Ensembl for Primates and Glires, as well as a large set of vertebrate gene trees. A total of 6810 gene trees have some evidence of positive selection. Finally, the web interface has been improved to be more responsive and to facilitate searches and browsing.

Senecio pterophorus DC., a new alien species in the European mainland

Senecio pterophorus DC. is an erect, semilignose shrub (fig. 1) which grows up to 2 m high. Is a chamaephyte basipetal branch-shedder (ORSHAN, Plant pheno-morphological studies in Mediterranean type ecosystems: 210-211. 1989) whose new branches appear below inflorescences but not from the lower parts of the plant. Leaves lanceolate. Stems are annual and develop at their apex a great number of small (up to 15 mm in diameter) yellow capitula which are grouped in a corymbose-paniculated inflorescence (HARVEY & SONDER, Flora Capensis: Cape Colony, Caffraria & Port Natal 3: 386.1865).

Audit report on the City of West Branch, Iowa for the year ended June 30, 2013

Audit report on the City of West Branch, Iowa for the year ended June 30, 2013

Persistent infection of arenaviruses : molecular mechanisms and pathogenesis

Arenaviruses are enveloped negative single strand RNA viruses that include a number of important human pathogens. The most prevalent human pathogen among the arenaviruses is the Old World arenavirus Lassa virus (LASV) which is endemic in West Africa from Senegal to Cameroon. LASV is the etiologic agent of a severe viral hemorrhagic fever named Lassa fever whose mortality rate can reach 30% in hospitalized patients. One of the hallmarks of fatal arenavirus infection in humans is the absence of an effective innate and adaptive immune response. In nature, arenaviruses are carried by rodents which represent the natural reservoirs as well as the vectors for transmission. In their natural rodent reservoir, arenaviruses have the ability to establish persistent infection without any overt signs and symptoms of pathology. We believe that the modulation of the host cell's innate immunity by arenaviruses is a key determinant for persistence in the natural host and for the pathogenesis in man. In this thesis, we studied the interaction of arenaviruses with two main branches of the host's innate anti-viral defense, the type I interferon (IFN) system and virus-induced mitochondrial apoptosis. The arenavirus nucleoprotein (NP) is responsible for the anti-IFN activity of arenaviruses. Specifically, NP blocks the activation and the nuclear translocation of the transcription factor interferon regulatory factor 3 (IRF3) which leads to type I IFN production. LASV and the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) NPs contain a 3'-5'exoribonuclease domain in the C terminal part that has been linked to the anti-IFN activity of NP. In the first project, we sought to identify cellular component(s) of the type I IFN induction pathway targeted by the viral NP. Our study revealed that LCMV NP prevents the activation of IRF3 by blocking phosphorylation of the transcription factor. We found that LCMV NP specifically targets the IRF-activating kinase IKKs, and this specific binding is conserved within the Arenaviridae. We could also demonstrate that LCMV NP associates with the kinase domain of IKKs involving NP's C-terminal region. Lastly, we showed that the binding of LCMV NP inhibits the kinase activity of IKKs. This study allowed the discovery of a new cellular interacting partner of arenavirus NP. This newly described association may play a role in the anti-IFN activity of arenaviruses but potentially also in other aspects of arenavirus infection. For the second project, we investigated the ability of arenaviruses to avoid and/or suppress mitochondrial apoptosis. As persistent viruses, arenaviruses evolved a "hit and stay" survival strategy where the apoptosis of the host cell would be deleterious. We found that LCMV does not induce mitochondrial apoptosis at any time during infection. Specifically, no caspase activity, no cytochrome c release from the mitochondria as well as no cleavage of poly (ADP-ribose) polymerase (PARP) were detected during LCMV infection. Interestingly, we found that virus-induced mitochondrial apoptosis remains fully functional in LCMV infected cells, while the induction of type IIFN is blocked. Since both type IIFN production and virus- induced mitochondrial apoptosis critically depend on the pattern recognition receptor (PRR) RIG-I, we examined the role of RIG-I in apoptosis in LCMV infected cells. Notably, virus- induced mitochondrial apoptosis in LCMV infected cells was found to be independent of RIG- I and MDA5, but still depended on MAVS. Our study uncovered a novel mechanism by which arenaviruses alter the host cell's pro-apoptotic signaling pathway. This might represent a strategy arenaviruses developed to maintain this branch of the innate anti-viral defense in absence of type I IFN response. Taken together, these results allow a better understanding of the interaction of arenaviruses with the host cell's innate immunity, contributing to our knowledge about pathogenic properties of these important viruses. A better comprehension of arenavirus virulence may open new avenues for vaccine development and may suggest new antiviral targets for therapeutic intervention against arenavirus infections. - Les arenavirus sont des virus enveloppés à ARN simple brin qui comportent un grand nombre de pathogènes humains. Le pathogène humain le plus important parmi les arenavirus est le virus de Lassa qui est endémique en Afrique de l'Ouest, du Sénégal au Cameroun. Le virus de Lassa est l'agent étiologique d'une fièvre hémorragique sévère appelée fièvre de Lassa, et dont le taux de mortalité peut atteindre 30% chez les patients hospitalisés. L'une des caractéristiques principales des infections fatales à arenavirus chez l'Homme est l'absence de réponse immunitaire innée et adaptative. Dans la nature, les arenavirus sont hébergés par différentes espèces de rongeur, qui représentent à la fois les réservoirs naturels et les vecteurs de transmission des arenavirus. Dans leur hôte naturel, les arenavirus ont la capacité d'établir une infection persistante sans symptôme manifeste d'une quelconque pathologie. Nous pensons que la modulation de système immunitaire inné de la cellule hôte par les arenavirus est un paramètre clé pour la persistance au sein de l'hôte naturel, ainsi que pour la pathogenèse chez l'Homme. L'objectif de cette thèse était d'étudier l'interaction des arenavirus avec deux branches essentielles de la défense antivirale innée de la cellule hôte, le système interféron (IFN) de type I et l'apoptose. La nucléoprotéine virale (NP) est responsable de l'activité anti-IFN des arenavirus. Plus spécifiquement, la NP bloque 1'activation et la translocation nucléaire du facteur de transcription IRF3 qui conduit à la production des IFNs de type I. La NP du virus de Lassa et celle du virus de la chorioméningite lymphocytaire (LCMV), l'arénavirus prototypique, possèdent dans leur extrémité C-terminale un domaine 3'-5' exoribonucléase qui a été associé à l'activité anti-IFN de ces protéines. Dans un premier projet, nous avons cherché à identifier des composants cellulaires de la cascade de signalisation induisant la production d'IFNs de type I qui pourraient être ciblés par la NP virale. Nos recherches ont révélé que la NP de LCMV empêche 1'activation d'IRF3 en bloquant la phosphorylation du facteur de transcription. Nous avons découvert que la NP de LCMV cible spécifiquement la kinase IKKe, et que cette interaction spécifique est conservée à travers la famille des Arenaviridae. Notre étude a aussi permis de démontrer que la NP de LCMV interagit avec le domaine kinase d'IKKe et que l'extrémité C-terminale de la NP est impliquée. Pour finir, nous avons pu établir que l'association avec la NP de LCMV inhibe l'activité kinase d'IKKe. Cette première étude présente la découverte d'un nouveau facteur cellulaire d'interaction avec la NP des arenavirus. Cette association pourrait jouer un rôle dans l'activité anti-IFN des arénavirus, mais aussi potentiellement dans d'autres aspects des infections à arénavirus. Pour le second projet, nous nous sommes intéressés à la capacité des arénavirus à éviter et/ou supprimer l'apoptose mitochondriale. En tant que virus persistants, les arénavirus ont évolué vers une stratégie de survie "hit and stay" pour laquelle l'apoptose de la cellule hôte serait néfaste. Nous avons observé qu'à aucun moment durant l'infection LCMV n'induit l'apoptose mitochondriale. Spécifiquement, aucune activité de caspase, aucune libération mitochondriale de cytochrome c ainsi qu'aucun clivage de la polymerase poly(ADP-ribose) (PARP) n'a été détecté pendant l'infection à LCMV. Il est intéressant de noter que l'apoptose mitochondriale induite par les virus reste parfaitement fonctionnelle dans les cellules infectées par LCMV, alors que l'induction de la réponse IFN de type I est bloquée dans les mêmes cellules. La production des IFNs de type I et l'apoptose mitochondriale induite par les virus dépendent toutes deux du récepteur de reconnaissance de motifs moléculaires RIG-I. Nous avons, par conséquent, investigué le rôle de RIG-I dans l'apoptose qui a lieu dans les cellules infectées par LCMV lorsqu'on les surinfecte avec un autre virus pro-apoptotique. En particulier, l'apoptose mitochondriale induite par les surinfections s'est révélée indépendante de RIG-I et MDA5, mais dépendante de MAVS dans les cellules précédemment infectées par LCMV. Notre étude démontre ainsi l'existence d'un nouveau mécanisme par lequel les arénavirus altèrent la cascade de signalisation pro-apoptotique de la cellule hôte. Il est possible que les arénavirus aient développé une stratégie permettant de maintenir fonctionnelle cette branche de la défense antivirale innée en l'absence de réponse IFN de type I. En conclusion, ces résultats nous amènent à mieux comprendre l'interaction des arénavirus avec l'immunité innée de la cellule hôte, ce qui contribue aussi à améliorer notre connaissance des propriétés pathogéniques de ces virus. Une meilleure compréhension des facteurs de virulence des arénavirus permet, d'une part, le développement de vaccins et peut, d'autre part, servir de base pour la découverte de nouvelles cibles thérapeutiques utilisées dans le traitement des infections à arénavirus.

Executive Order Number Eighty-Four February, 2014

In this order the governor declares that volunteerism is an integral part of Iowa's future and well-being and creates the Governor's Council on National Service in Iowa.

The Escherichia coli RuvB branch migration protein forms double hexameric rings around DNA.

The RuvB protein is induced in Escherichia coli as part of the SOS response to DNA damage. It is required for genetic recombination and the postreplication repair of DNA. In vitro, the RuvB protein promotes the branch migration of Holliday junctions and has a DNA helicase activity in reactions that require ATP hydrolysis. We have used electron microscopy, image analysis, and three-dimensional reconstruction to show that the RuvB protein, in the presence of ATP, forms a dodecamer on double-stranded DNA in which two stacked hexameric rings encircle the DNA and are oriented in opposite directions with D6 symmetry. Although helicases are ubiquitous and essential for many aspects of DNA repair, replication, and transcription, three-dimensional reconstruction of a helicase has not yet been reported, to our knowledge. The structural arrangement that is seen may be common to other helicases, such as the simian virus 40 large tumor antigen.

ISBN (international standard book number) -an international perspective

Esitelmä Suomen ISBN-keskus 30 vuotta -juhlassa Helsingin yliopistossa 7.11.2002

Executive Order Number Eighty-Five March, 2014

In this order the governor declares that accountability, openness and transparency are essential to the efficient operation of state government and in the best interest of taxpayers as relates to personnel settlement agreements.

Densité urbaine et psychose - est-ce que vivre en ville rend schizophrène [Urban density and psychosis - does living in a city cause schizophrenia?].

While it has often been stated that prevalence of schizophrenia is the same around the world, many publications have shown this illness is twice more frequent in urban areas. Although many hypotheses have been proposed, the mechanisms explaining this phenomenon are still unknown. Besides potential biological explanations, a certain number of hypotheses emerging from social sciences have recently enriched the debate. This article reviews the literature related to this issue and describes the development of a research projects conducted in collaboration between the Institut of Geography at the University of Neuchâtel, the Department of Psychiatry at the Lausanne University and the Swiss branch of ISPS, a society promoting the psychological treatment of schizophrenia and other psychoses.

Improved multiple-locus variable-number tandem-repeat assay for Staphylococcus aureus genotyping, providing a highly informative technique together with strong phylogenetic value.

We describe an improved multiple-locus variable-number tandem-repeat (VNTR) analysis (MLVA) scheme for genotyping Staphylococcus aureus. We compare its performance to those of multilocus sequence typing (MLST) and spa typing in a survey of 309 strains. This collection includes 87 epidemic methicillin-resistant S. aureus (MRSA) strains of the Harmony collection, 75 clinical strains representing the major MLST clonal complexes (CCs) (50 methicillin-sensitive S. aureus [MSSA] and 25 MRSA), 135 nasal carriage strains (133 MSSA and 2 MRSA), and 13 published S. aureus genome sequences. The results show excellent concordance between the techniques' results and demonstrate that the discriminatory power of MLVA is higher than those of both MLST and spa typing. Two hundred forty-two genotypes are discriminated with 14 VNTR loci (diversity index, 0.9965; 95% confidence interval, 0.9947 to 0.9984). Using a cutoff value of 45%, 21 clusters are observed, corresponding to the CCs previously defined by MLST. The variability of the different tandem repeats allows epidemiological studies, as well as follow-up of the evolution of CCs and the identification of potential ancestors. The 14 loci can conveniently be analyzed in two steps, based upon a first-line simplified assay comprising a subset of 10 loci (panel 1) and a second subset of 4 loci (panel 2) that provides higher resolution when needed. In conclusion, the MLVA scheme proposed here, in combination with available on-line genotyping databases (including http://mlva.u-psud.fr/), multiplexing, and automatic sizing, can provide a basis for almost-real-time large-scale population monitoring of S. aureus.