Investigating the Role of Gene-Gene Interactions in TB Susceptibility

Tuberculosis (TB) is the second leading cause of mortality from infectious disease worldwide. One of the factors involved in developing disease is the genetics of the host, yet the field of TB susceptibility genetics has not yielded the answers that were expected. A commonly posited explanation for the missing heritability of complex disease is gene-gene interactions, also referred to as epistasis. In this study we investigate the role of gene-gene interactions in genetic susceptibility to TB using a cohort recruited from a high TB incidence community from Cape Town, South Africa. Our discovery data set incorporates genotypes from a large a number of candidate gene studies as well as genome-wide data. After limiting our search space to pairs of putative TB susceptibility genes, as well as pairs of genes that have been curated in online databases as potential interactors, we use statistical modelling to identify pairs of interacting SNPs. We attempt to validate the top models identified in our discovery data set using an independent genome-wide TB case-control data set from The Gambia. A number of models were successfully validated, indicating that interplay between the NRG1 - NRG3, GRIK1 - GRIK3 and IL23R - ATG4C gene pairs may modify susceptibility to TB. Gene pairs involved in the NF-κB pathway were also identified in the discovery data set (SFTPD - NOD2, ISG15 - TLR8 and NLRC5 - IL12RB1), but could not be tested in the Gambian study group due to lack of overlapping data.     

Prevalence and Correlates of Client-Perpetrated Violence against Female Sex Workers in 13 Mexican Cities

Background

Globally, client-perpetrated violence against female sex workers (FSWs) has been associated with multiple health-related harms, including high-risk sexual behavior and increased exposure to HIV/STIs. This study examined correlates of client-perpetrated sexual, physical, and economic violence (e.g., robbery) against FSWs in 13 cities throughout Mexico.

Methods

FSWs (N = 1,089) who were enrolled in a brief, evidence-based, sexual risk reduction intervention for FSWs (Mujer Segura) were interviewed about their work context, including experiences of violence perpetrated by clients, sexual risk and substance use practices, financial need, and social supports. Three broad categories of factors (sociodemographic, work context, behavioral and social characteristics of FSWs) were examined as correlates of sexual, physical, and economic violence.

Results

The prevalence of different types of client-perpetrated violence against FSWs in the past 6 months was: sexual (11.7%), physical (11.8%), economic (16.9%), and any violence (22.6%). Greater financial need, self-identification as a street worker, and lower perceived emotional support were independently associated with all three types of violence. Alcohol use before or during sex with clients in the past month was associated with physical and sexual violence. Using drugs before or during sex with clients, injection drug use in the past month, and population size of city were associated with sexual violence only, and FSWs’ alcohol use score (AUDIT-C) was associated with economic violence only.

Conclusions

Correlates of client-perpetrated violence encompassed sociodemographic, work context, and behavioral and social factors, suggesting that approaches to violence prevention for FSWs must be multi-dimensional. Prevention could involve teaching FSWs strategies for risk avoidance in the workplace (e.g., avoiding use of alcohol with clients), enhancement of FSWs’ community-based supports, development of interventions that deliver an anti-violence curriculum to clients, and programs to address FSWs’ financial need by increasing their economic opportunities outside of the sex trade.     

Spatial and temporal localization of SPIRRIG and WAVE/SCAR reveal roles for these proteins in actin-mediated root hair development

Root hairs are single-cell protrusions that enable roots to optimize nutrient and water acquisition. These structures attain their tubular shapes by confining growth to the cell apex, a process called tip growth. The actin cytoskeleton and endomembrane systems are essential for tip growth; however, little is known about how these cellular components coordinate their activities during this process. Here, we show that SPIRRIG (SPI), a beige and Chediak Higashi domain-containing protein involved in membrane trafficking, and BRK1 and SCAR2, subunits of the WAVE/SCAR (W/SC) actin nucleating promoting complex, display polarized localizations in Arabidopsis thaliana root hairs during distinct developmental stages. SPI accumulates at the root hair apex via post-Golgi compartments and positively regulates tip growth by maintaining tip-focused vesicle secretion and filamentous-actin integrity. BRK1 and SCAR2 on the other hand, mark the root hair initiation domain to specify the position of root hair emergence. Consistent with the localization data, tip growth was reduced in spi and the position of root hair emergence was disrupted in brk1 and scar1234. BRK1 depletion coincided with SPI accumulation as root hairs transitioned from initiation to tip growth. Taken together, our work uncovers a role for SPI in facilitating actin-dependent root hair development in Arabidopsis through pathways that might intersect with W/SC.     

Using genetic and morphological analysis to distinguish endangered taxa from their hybrids with the cultivated exotic pest plant <Emphasis Type="Italic">Lantana strigocamara</Emphasis> (syn: <Emphasis Type="Italic">Lantana camara</Emphasis>)

Because highly invasive species can rapidly assimilate rare taxa, we questioned whether two Florida endangered Lantana depressa varieties existed 21 years after Sanders documented their widespread hybridization with exotic Lantana strigocamara, and whether morphological traits could accurately discriminate genetic individuals. Stepwise discriminant analysis of morphological characters discriminated the three taxa, correctly classifying 98, 91, 89% of L. strigocamara, L. depressa var. depressa, and var. floridana. Hybrids blurred taxonomic distinctions of varieties and reduced classification accuracy by 7–17%. Species-specific Random Fragment Length Polymorphism (RFLP-PCR) confirmed hybridization has occurred. Intersimple Sequence Repeat (ISSR) fingerprints analyzed with STRUCTURE identified three groups indicating introgression. Morphological traits significantly, but weakly correlated with q ratios (P = 0.0001; r ² = 0.45). Although L. strigocamara introgression is widespread and ongoing, wild populations contain individuals that are predominantly L. depressa genome, supporting actions to remove adventive L. strigocamara, prevent its sale, and promote sales of genetically confirmed natives.     

Identification of two chromone phytoalexins in the sweet pea, Lathyrus odoratus

A major phytoalexin isolated from the Helminthosporium Carbonum-inoculated leaflets and pods of Lathyrus odoratus has been identified by spectroscopic procedures as 5,7-dihydroxy-3-ethylchromone (lathodoratin). Small amounts of the corresponding 7-O-methyl ether (methyl-lathodoratin) are also formed by this plant. Both compounds similarly occur as phytoalexins in the closely related legume L. hirsutus but are absent from the other Lathyrus species examined. The unusual 3-substitution of the chromone nucleus appears to be essential for fungitoxicity since the synthetic isomer 5,7-dihydroxy-2-ethylchromone is apparently inactive.     

Biosurfactant production and surface translocation are regulated by PlcR in Bacillus cereus ATCC 14579 under low-nutrient conditions

Bacillus cereus ATCC 14579 can respond to nutrient changes by adopting different forms of surface translocation. The B. cereus ATCC 14579 DeltaplcR mutant, but not the wild type, formed dendritic (branched) patterns on EPS [a low-nutrient medium that contains 7.0 g K(2)HPO(4), 3.0 g KH(2)PO(4), 0.1 g MgSO(4).7H(2)O, 0.1 g (NH(4))(2)SO(4), 0.01 g CaCl(2), 0.001 g FeSO(4), 0.1 g NaCl, 1.0 g glucose, and 125 mg yeast extract per liter] containing 0.7% agar. The dendritic patterns formed by sliding translocation of nonflagellated cells are enhanced under low-nutrient conditions and require sufficient production of a biosurfactant, which appears to be repressed by PlcR. The wild-type and complemented strains failed to slide on the surface of EPS agar because of the production of low levels of biosurfactant. Precoating EPS agar surfaces with surfactin (a biosurfactant produced by Bacillus subtilis) or biosurfactant purified from the DeltaplcR mutant rescued the ability of the wild-type and complemented strains to slide. When grown on a nutrient-rich medium like Luria-Bertani agar, both the wild-type and DeltaplcR mutant strains produced flagella. The wild type was hyperflagellated and elongated and exhibited swarming behavior, while the DeltaplcR mutant was multiflagellated and the cells often formed long chains but did not swarm. Thin-layer chromatography and mass spectrometry analyses suggested that the biosurfactant purified from the DeltaplcR mutant was a lipopeptide and had a mass of 1,278.1722 (m/z). This biosurfactant has hemolytic activity and inhibited the growth of several gram-positive bacteria.     

The effect of total starvation and very low energy diet in lean men on kinetics of whole body protein and five hepatic secretory proteins

It is unclear whether the rate of weight loss, independent of magnitude, affects whole body protein metabolism and the synthesis and plasma concentrations of specific hepatic secretory proteins. We examined 1) whether lean men losing weight rapidly (starvation) show greater changes in whole body protein kinetics, synthesis, and circulating concentrations of selected hepatic secretory proteins than those losing the same amount of weight more slowly [very low energy diet (VLED)]; and 2) whether plasma concentrations and synthetic rates of these proteins are related. Whole body protein kinetics were measured using [1-(13)C]leucine in 11 lean men (6 starvation, 5 VLED). Fractional and absolute synthetic rates of HDL-apolipoprotein A1 (apoA1), retinol binding protein, transthyretin, alpha(1)-antitrypsin (alpha(1)-AT), and transferrin were measured using a prime-constant intravenous infusion of [(13)C(2)]glycine. Compared with VLED group, the starvation group showed greater increases (at a 5% weight loss) in whole body protein oxidation (P < 0.05); fractional synthetic rates of HDL-apoA1 (25.3 vs. -1.52%; P = 0.003) and retinol binding protein (30.6 vs. 7.1%; P = 0.007); absolute synthetic rates of HDL-apoA1 (7.1 vs. -3.8 mg.kg(-1).day(-1); P = 0.003) and alpha(1)-AT (17.8 vs. 3.6 mg.kg(-1).day(-1); P = 0.02); and plasma concentration of alpha(1)-AT (P = 0.025). Relationships between synthetic rates and plasma concentrations varied between the secreted proteins. It is concluded that synthetic rates of hepatic secreted proteins in lean men are more closely related to the rate than the magnitude of weight loss. Changes in concentration of these secreted proteins can occur independently of changes in synthetic rates, and vice versa.