In vivo modulation of cervicovaginal drug transporters and tissue distribution by film-released tenofovir and darunavir for topical prevention of HIV-1

We thank Gilead Science for provision of tenofovir and Janssen R&D Ireland for provision of darunavir. We thank members of the MOTIF consortium for useful discussions and exchange of ideas during the course of this study. We thank the technical staff of IDMIT, the animal care and veterinary staff at CEA, Fontenay-aux-Roses, France. Funding: this work was supported by the European Union's Seventh Programme for research, technological development and demonstration under grant agreement No 305316 as part of the MOTIF (Microbicides Formulation Through Innovative Formulation for Vaginal and Rectal Delivery) project. It has also the support of the “Investissements d’Avenir” French government program managed by the Agence Nationale de la Recherche under ANR-11-INBS-0008 funding for the Infectious Disease Models and Innovative Therapies (IDMIT, Fontenay-aux-Roses, France) infrastructure, and ANR-10-EQPX-02-01 funding for the FlowCyTech facility (IDMIT, Fontenay-aux-Roses, France).Peer reviewedPostprin

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of diseas

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease

Guided conjugate Bayesian clustering for uncovering rhythmically expressed genes

Background: An increasing number of microarray experiments produce time series of expression levels for many genes. Some recent clustering algorithms respect the time ordering of the data and are, importantly, extremely fast. The focus of this paper is the development of such an algorithm on a microarray data set consisting of 22,810 genes of the plant Arabidopsis thaliana measured at 13 time points over two days. Circadian rhythms control the timing of various physiological and metabolic processes and are regulated by genes acting in feedback loops. The aim is to cluster and classify the expression profiles in order to identify genes potentially involved in, and regulated by, the circadian clock. Results: A greedy search over time series of expression levels (where series are compared pairwise, the two most similar put in the same cluster and so forth) will get a fast result but will only explore a very limited number of the possible partitions of the profiles. We propose an improved, deterministic method based on a multi-step application of a conjugate Bayesian clustering algorithm. It allows the entire space to be searched more fully and intelligently. The values of the summary statistics are used to not only score clusters of genes, but also to guide the search of the vast partition space. By following this procedure, we are able to cluster genes that are known to be rhythmically expressed with genes of previously unknown function; thus suggesting potentially interesting targets for future experiments

Efficient utility-based clustering over high dimensional partition spaces

Because of the huge number of partitions of even a moderately sized dataset, even when Bayes factors have a closed form, in model-based clustering a comprehensive search for the highest scoring (MAP) partition is usually impossible. However, when each cluster in a partition has a signature and it is known that some signatures are of scientific interest whilst others are not, it is possible, within a Bayesian framework, to develop search algorithms which are guided by these cluster signatures. Such algorithms can be expected to find better partitions more quickly. In this paper we develop a framework within which these ideas can be formalized. We then briefly illustrate the efficacy of the proposed guided search on a microarray time coursed at a set where the clustering objective is to identify clusters of genes with different types of circadian expression profiles

The Effects of Marital Status, Fertility, and Bereavement on Adult Mortality in Polygamous and Monogamous Households : Evidence From the Utah Population Database

Although the associations among marital status, fertility, bereavement, and adult mortality have been widely studied, much less is known about these associations in polygamous households, which remain prevalent across much of the world. We use data from the Utah Population Database on 110,890 women and 106,979 men born up to 1900, with mortality follow-up into the twentieth century. We examine how the number of wife deaths affects male mortality in polygamous marriages, how sister wife deaths affect female mortality in polygamous marriages relative to the death of a husband, and how marriage order affects the mortality of women in polygamous marriages. We also examine how the number of children ever born and child deaths affect the mortality of men and women as well as variation across monogamous and polygamous unions. Our analyses of women show that the death of a husband and the death of a sister wife have similar effects on mortality. Marriage order does not play a role in the mortality of women in polygamous marriages. For men, the death of one wife in a polygamous marriage increases mortality to a lesser extent than it does for men in monogamous marriages. For polygamous men, losing additional wives has a dose-response effect. Both child deaths and lower fertility are associated with higher mortality. We consistently find that the presence of other kin in the household—whether a second wife, a sister wife, or children—mitigates the negative effects of bereavement

Retinitis Pigmentosa Mutants Provide Insight into the Role of the N-terminal Cap in Rhodopsin Folding, Structure, and Function

Autosomal dominant retinitis pigmentosa (ADRP) mutants (T4K, N15S, T17M, V20G, P23A/H/L, and Q28H) in the N-terminal cap of rhodopsin misfold when expressed in mammalian cells. To gain insight into the causes of misfolding and to define the contributions of specific residues to receptor stability and function, we evaluated the responses of these mutants to 11-cisretinal pharmacological chaperone rescue or disulfide bondmediated repair. Pharmacological rescue restored folding in all mutants, but the purified mutant pigments in all cases were thermo-unstable and exhibited abnormal photobleaching, metarhodopsin II decay, and G protein activation. As a complementary approach, we superimposed this panel of ADRP mutants onto a rhodopsin background containing a juxtaposed cysteine pair (N2C/D282C) that forms a disulfide bond. This approach restored folding in T4K, N15S, V20G, P23A, and Q28H but not T17M, P23H, or P23L. ADRP mutant pigments obtained by disulfide bond repair exhibited enhanced stability, and some also displayed markedly improved photobleaching and signal transduction properties. Our major conclusionisthat the N-terminal cap stabilizes opsin during biosynthesis and contributes to the dark-state stability of rhodopsin. Comparison of these two restorative approaches revealed that the correct position of the cap relative to the extracellular loops is also required for optimal photochemistry and efficient G protein activation. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc

Stray-field NMR diffusion q-space diffraction imaging of monodisperse coarsening foams

The technique of stray field diffusion NMR is adapted to study the diffusion properties of water in monodisperse wet foams. We show for the first time, that the technique is capable of observing q-space diffusion diffraction peaks in monodisperse aqueous foams with initial bubble sizes in the range of 50–85 μm. The position of the peak maximum can be correlated simply to the bubble size in the foam leading to a technique that can investigate the stability of the foam over time. The diffusion technique, together with supplementary spin-spin relaxation analysis of the diffusion data is used to follow the stability and coarsening behaviour of monodisperse foams with a water fraction range between 0.24 and 0.33. The monodisperse foams remain stable for a period of hours in terms of the initial bubble size. The duration of this stable period correlates to the initial size of the bubbles. Eventually the bubbles begin to coarsen and this is observed in changes in the position of the diffusion diffraction maxima

Expression of genes for drug transporters in the human female genital tract and modulatory effect of antiretroviral drugs

Acknowledgments: We wish to thank patients and surgical teams at the University of Siena and St Mary’s Hospital London for their generous contribution to this study. Darunavir was kindly provided by Janssen R&D Ireland, and tenofovir by Gilead Sciences. Funding: This study was supported by the European Commission grant MOTIF (Microbicide Optimization Through Innovative Formulation for Vaginal and Rectal Delivery), FP7-HEALTH-2012-305316 http://cordis.europa.eu/result/rcn/15853​0_en.html. Beneficiaries of MOTIF include the University of Aberdeen, the University of Siena, Microbiotec srl, Imperial College, and King’s College London. MICROBIOTEC srl provided support in the form of a salary for MAS, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD