Genetic Enhancers ofsem-5Define Components of the Gonad-Independent Guidance Mechanism Controlling Sex Myoblast Migration inCaenorhabditis elegansHermaphrodites

AbstractThe migrations of the sex myoblasts inCaenorhabditis eleganshermaphrodites involve two guidance mechanisms: a gonad-dependent attraction that confers precise positioning of the sex myoblasts and a gonad-independent mechanism that is sufficient for coarse positioning in the absence of the gonad (Thomaset al.,1990). Here we show that mutations inunc-53, unc-71,andunc-73disrupt sex myoblast positioning in the absence of the gonad, while they do not affect positioning in the presence of the gonad. Thus, mutations in these genes appear to compromise the gonad-independent mechanism without affecting motility or the gonad-dependent attraction. Mutations insem-5confer dramatic sex myoblast positioning defects in double mutant combinations withunc-53, unc-71,orunc-73mutations, even in the presence of the gonad. This suggests thatsem-5is required for the gonad-dependent attractive mechanism. Mutations inlet-60 rasandlet-341also confer sex myoblast migration defects in anunc-53background, implicating these genes in gonad-dependent positioning as well

Computational selection of inhibitors of Abeta aggregation and neuronal toxicity.

Alzheimer\u27s disease (AD) is characterized by the cerebral accumulation of misfolded and aggregated amyloid-beta protein (Abeta). Disease symptoms can be alleviated, in vitro and in vivo, by \u27beta-sheet breaker\u27 pentapeptides that reduce plaque load. However the peptide nature of these compounds, made them biologically unstable and unable to penetrate membranes with high efficiency. The main goal of this study was to use computational methods to identify small molecule mimetics with better drug-like properties. For this purpose, the docked conformations of the active peptides were used to identify compounds with similar activities. A series of related beta-sheet breaker peptides were docked to solid state NMR structures of a fibrillar form of Abeta. The lowest energy conformations of the active peptides were used to design three dimensional (3D)-pharmacophores, suitable for screening the NCI database with Unity. Small molecular weight compounds with physicochemical features and a conformation similar to the active peptides were selected, ranked by docking and biochemical parameters. Of 16 diverse compounds selected for experimental screening, 2 prevented and reversed Abeta aggregation at 2-3microM concentration, as measured by Thioflavin T (ThT) fluorescence and ELISA assays. They also prevented the toxic effects of aggregated Abeta on neuroblastoma cells. Their low molecular weight and aqueous solubility makes them promising lead compounds for treating AD

Assessing the Multiple Impacts of Extreme Hurricanes in Southern New England, USA

The southern New England coast of the United States is particularly vulnerable to land-falling hurricanes because of its east-west orientation. The impact of two major hurricanes on the city of Providence (Rhode Island, USA) during the middle decades of the 20th century spurred the construction of the Fox Point Hurricane Barrier (FPHB) to protect the city from storm surge flooding. Although the Rhode Island/Narragansett Bay area has not experienced a major hurricane for several decades, increased coastal development along with potentially increased hurricane activity associated with climate change motivates an assessment of the impacts of a major hurricane on the region. The ocean/estuary response to an extreme hurricane is simulated using a high-resolution implementation of the ADvanced CIRCulation (ADCIRC) model coupled to the Precipitation-Runoff Modeling System (PRMS). The storm surge response in ADCIRC is first verified with a simulation of a historical hurricane that made landfall in southern New England. The storm surge and the hydrological models are then forced with winds and rainfall from a hypothetical hurricane dubbed “Rhody”, which has many of the characteristics of historical storms that have impacted the region. Rhody makes landfall just west of Narragansett Bay, and after passing north of the Bay, executes a loop to the east and the south before making a second landfall. Results are presented for three versions of Rhody, varying in the maximum wind speed at landfall. The storm surge resulting from the strongest Rhody version (weak Saffir–Simpson category five) during the first landfall exceeds 7 m in height in Providence at the north end of the Bay. This exceeds the height of the FPHB, resulting in flooding in Providence. A simulation including river inflow computed from the runoff model indicates that if the Barrier remains closed and its pumps fail (for example, because of a power outage or equipment failure), severe flooding occurs north of the FPHB due to impoundment of the river inflow. These results show that northern Narragansett Bay could be particularly vulnerable to both storm surge and rainfall-driven flooding, especially if the FPHB suffers a power outage. They also demonstrate that, for wind-driven storm surge alone under present sea level conditions, the FPHB will protect Providence for hurricanes less intense than category five

Spermidine/spermine N1-acetyltransferase specifically binds to the integrin α9 subunit cytoplasmic domain and enhances cell migration

The integrin α9β1 is expressed on migrating cells, such as leukocytes, and binds to multiple ligands that are present at sites of tissue injury and inflammation. α9β1, like the structurally related integrin α4β1, mediates accelerated cell migration, an effect that depends on the α9 cytoplasmic domain. α4β1 enhances migration through reversible binding to the adapter protein, paxillin, but α9β1-dependent migration is paxillin independent. Using yeast two-hybrid screening, we identified the polyamine catabolizing enzyme spermidine/spermine N1-acetyltransferase (SSAT) as a specific binding partner of the α9 cytoplasmic domain. Overexpression of SSAT increased α9β1-mediated migration, and small interfering RNA knockdown of SSAT inhibited this migration without affecting cell adhesion or migration that was mediated by other integrin cytoplasmic domains. The enzyme activity of SSAT is critical for this effect, because a catalytically inactive version did not enhance migration. We conclude that SSAT directly binds to the α9 cytoplasmic domain and mediates α9-dependent enhancement of cell migration, presumably by localized effects on acetylation of polyamines or of unidentified substrates

Reducing Intimate and Paying Partner Violence Against Women Who Exchange Sex in Mongolia

Women who exchange sex for money or other goods, that is, female sex workers, are at increased risk of experiencing physical and sexual violence from both paying and intimate partners. Exposure to violence can be exacerbated by alcohol use and HIV/STI risk. The purpose of this study is to examine the efficacy of a HIV/STI risk reduction and enhanced HIV/STI risk reduction intervention at decreasing paying and intimate partner violence against Mongolian women who exchange sex and engage in harmful alcohol use. Women are recruited and randomized to either (a) four sessions of a relationship-based HIV/STI risk reduction intervention (n = 49), (b) the same HIV/STI risk reduction intervention plus two additional motivational interviewing sessions (n = 58), or (c) a four session control condition focused on wellness promotion (n = 59). All the respondents complete assessments at baseline (preintervention) as well as at immediate posttest, 3 and 6 months postintervention. A multilevel logistic model finds that women who participated in the HIV/STI risk reduction group (OR = 0.14, p < .00), HIV/STI risk reduction and motivational interview group (OR = 0.46, p = .02), and wellness (OR = 0.20, p < .00) group reduced their exposure to physical and sexual violence in the past 90 days. No significant differences in effects are observed between conditions. This study demonstrates the efficacy of a relationship-based HIV/STI risk reduction intervention, a relationship-based HIV/STI risk reduction intervention combined with motivational interviewing, and a wellness promotion intervention in reducing intimate and paying partner violence against women who exchange sex in Mongolia. The findings have significant implications for the impact of minimal intervention and the potential role of peer networks and social support in reducing women’s experiences of violence in resource poor settings

Fibromodulin Is Essential for Fetal-Type Scarless Cutaneous Wound Healing

In contrast to adult and late-gestation fetal skin wounds, which heal with scar, early-gestation fetal skin wounds display a remarkable capacity to heal scarlessly. Although the underlying mechanism of this transition from fetal-type scarless healing to adult-type healing with scar has been actively investigated for decades, in utero restoration of scarless healing in late-gestation fetal wounds has not been reported. In this study, using loss- and gain-of-function rodent fetal wound models, we identified that fibromodulin (Fm) is essential for fetal-type scarless wound healing. In particular, we found that loss of Fm can eliminate the ability of early-gestation fetal rodents to heal without scar. Meanwhile, administration of fibromodulin protein (FM) alone was capable of restoring scarless healing in late-gestation rat fetal wounds, which naturally heal with scar, as characterized by dermal appendage restoration and organized collagen architectures that were virtually indistinguishable from those in age-matched unwounded skin. High Fm levels correlated with decreased transforming growth factor (TGF)-β1 expression and scarless repair, while low Fm levels correlated with increased TGF-β1 expression and scar formation. This study represents the first successful in utero attempt to induce scarless repair in late-gestation fetal wounds by using a single protein, Fm, and highlights the crucial role that the FM–TGF-β1 nexus plays in fetal-type scarless skin repair. © 2016 American Society for Investigative Patholog

Inhibition of αvβ5 Integrin Attenuates Vascular Permeability and Protects against Renal Ischemia-Reperfusion Injury

Ischemia-reperfusion injury (IRI) is a leading cause of AKI. This common clinical complication lacks effective therapies and can lead to the development of CKD. The αvβ5 integrin may have an important role in acute injury, including septic shock and acute lung injury. To examine its function in AKI, we utilized a specific function-blocking antibody to inhibit αvβ5 in a rat model of renal IRI. Pretreatment with this anti-αvβ5 antibody significantly reduced serum creatinine levels, diminished renal damage detected by histopathologic evaluation, and decreased levels of injury biomarkers. Notably, therapeutic treatment with the αvβ5 antibody 8 hours after IRI also provided protection from injury. Global gene expression profiling of post-ischemic kidneys showed that αvβ5 inhibition affected established injury markers and induced pathway alterations previously shown to be protective. Intravital imaging of post-ischemic kidneys revealed reduced vascular leak with αvβ5 antibody treatment. Immunostaining for αvβ5 in the kidney detected evident expression in perivascular cells, with negligible expression in the endothelium. Studies in a three-dimensional microfluidics system identified a pericyte-dependent role for αvβ5 in modulating vascular leak. Additional studies showed αvβ5 functions in the adhesion and migration of kidney pericytes in vitro Initial studies monitoring renal blood flow after IRI did not find significant effects with αvβ5 inhibition; however, future studies should explore the contribution of vasomotor effects. These studies identify a role for αvβ5 in modulating injury-induced renal vascular leak, possibly through effects on pericyte adhesion and migration, and reveal αvβ5 inhibition as a promising therapeutic strategy for AKI