A high-content, multiplexed screen in human breast cancer cells identifies profilin-1 inducers with anti-migratory activities

Profilin-1 (Pfn-1) is a ubiquitously expressed actin-binding protein that is essential for normal cell proliferation and migration. In breast cancer and several other adenocarcinomas, Pfn-1 expression is downregulated when compared to normal tissues. Previous studies from our laboratory have shown that genetically modulating Pfn-1 expression significantly impacts proliferation, migration, and invasion of breast cancer cells in vitro, and mammary tumor growth, dissemination, and metastatic colonization in vivo. Therefore, small molecules that can modulate Pfn-1 expression could have therapeutic potential in the treatment of metastatic breast cancer. The overall goal of this study was to perform a multiplexed phenotypic screen to identify compounds that inhibit cell motility through upregulation of Pfn-1. Screening of a test cassette of 1280 compounds with known biological activities on an Oris™ Pro 384 cell migration platform identified several agents that increased Pfn-1 expression greater than two-fold over vehicle controls and exerted anti-migratory effects in the absence of overt cytotoxicity in MDA-MB-231 human breast cancer cells. Concentration-response confirmation and orthogonal follow-up assays identified two bona fide inducers of Pfn-1, purvalanol and tyrphostin A9, that confirmed in single-cell motility assays and Western blot analyses. SiRNA-mediated knockdown of Pfn-1 abrogated the inhibitory effect of tyrphostin A9 on cell migration, suggesting Pfn-1 is mechanistically linked to tyrphostin A9's anti-migratory activity. The data illustrate the utility of the high-content cell motility assay to discover novel targeted anti-migratory agents by integrating functional phenotypic analyses with target-specific readouts in a single assay platform. © 2014 Joy et al

Predictors of residential stability among homeless young adults : a cohort study.

Abstract : BACKGROUND: Homelessness episodes have been shown to be associated with serious health outcomes among youth. This study was undertaken to estimate the probability of reaching residential stability over time and to identify predictors of residential stability among homeless young adults aged 18 to 25 years. METHODS: A prospective cohort study was carried out in Montréal, Canada, between April 5(th) 2006 and January 21(th) 2009. Interviews conducted every three months included questions on life conditions and social and mental health factors that are known to influence residential trajectories. Residential status was determined, starting on the first day after recruitment; each follow-up day was classified as a homeless day or a housed day. A period of 90 days was used to define residential stability; therefore the main study outcome was the occurrence of the first consecutive 90 housed days during the follow-up period. Kaplan-Meier and Cox proportional-hazards regression analyses were conducted. RESULTS: Of the 359 participants, 284 reached 90 days of residential stability over the study period, representing an annual probability of 80.5 %. In multivariate analysis, youth who had a high school degree, had a formal sector activity, and those who had sought psychological help were more likely to reach residential stability. Being a man, injecting substances, and having an informal sector activity were associated with a decreased probability to reach residential stability. CONCLUSION: Exposure to factors related to opportunities that promote social integration increases the chance of reaching residential stability. On the other hand, factors related to high level of street entrenchment seem to interfere with stabilization. Maximum efforts should be made to prevent chronic homelessness among youth, targeting not only individual impairments but also hinging on services adapted to foster social connections among the youth

The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1.

BACKGROUND AND OBJECTIVE: Of three first-line anti-tuberculosis (anti-TB) drugs, isoniazid is most commonly associated with hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, NAT2, CYP2E1, GSTM1and GSTT1, that code for drug-metabolizing enzymes. This study evaluated whether the polymorphisms in these enzymes were associated with an increased risk of anti-TB drug-induced hepatitis in patients and could potentially be used to identify patients at risk of liver injury. METHODS AND DESIGN: In a cross-sectional study, 2244 tuberculosis patients were assessed two months after the start of treatment. Anti-TB drug-induced liver injury (ATLI) was defined as an ALT, AST or bilirubin value more than twice the upper limit of normal. NAT2, CYP2E1, GSTM1 and GSTT1 genotypes were determined using the PCR/ligase detection reaction assays. RESULTS: 2244 patients were evaluated, there were 89 cases of ATLI, a prevalence of 4% 9 patients (0.4%) had ALT levels more than 5 times the upper limit of normal. The prevalence of ATLI was greater among men than women, and there was a weak association with NAT2*5 genotypes, with ATLI more common among patients with the NAT2*5*CT genotype. The sensitivity of the CT genotype for identifying patients with ATLI was 42% and the positive predictive value 5.9%. CT ATLI was more common among slow acetylators (prevalence ratio 2.0 (95% CI 0.95,4.20) )compared to rapid acetylators. There was no evidence that ATLI was associated with CYP2E1 RsaIc1/c1genotype, CYP2E1 RsaIc1/c2 or c2/c2 genotypes, or GSTM1/GSTT1 null genotypes. CONCLUSIONS: In Xinjiang Uyghur TB patients, liver injury was associated with the genetic variant NAT2*5, however the genetic markers studied are unlikely to be useful for screening patients due to the low sensitivity and low positive predictive values for identifying persons at risk of liver injury

Conflict and Livelihood Decisions in the Chittagong Hill Tracts of Bangladesh

__Abstract__ We analyse rural household livelihood and child school enrolment decisions in the post-conflict setting of the Chittagong Hill Tracts (CHT) region of Bangladesh. What makes this paper innovative is the use of current subjective perceptions regarding the possibility of violence in the future and past actual experiences of violence in explaining household economic decision-making. Preferences are endogenous in line with behavioural economics. Regression results show that heightened subjective perceptions of future violence and past actual experiences of conflict influence current consumption and child enrolment and could encourage risky mixed crop cultivation. The trauma emanating from past experiences combined with current high perceptions of risk of violence may induce bolder and riskier behaviour in line with prospect theories of risk. Furthermore, a postconflic

Nonthermal Emission from Star-Forming Galaxies

The detections of high-energy gamma-ray emission from the nearby starburst galaxies M82 & NGC253, and other local group galaxies, broaden our knowledge of star-driven nonthermal processes and phenomena in non-AGN star-forming galaxies. We review basic aspects of the related processes and their modeling in starburst galaxies. Since these processes involve both energetic electrons and protons accelerated by SN shocks, their respective radiative yields can be used to explore the SN-particle-radiation connection. Specifically, the relation between SN activity, energetic particles, and their radiative yields, is assessed through respective measures of the particle energy density in several star-forming galaxies. The deduced energy densities range from O(0.1) eV/cm^3 in very quiet environments to O(100) eV/cm^3 in regions with very high star-formation rates.Comment: 17 pages, 5 figures, to be published in Astrophysics and Space Science Proceeding

Shallow water marine sediment bacterial community shifts along a natural CO2 gradient in the Mediterranean Sea off Vulcano, Italy.

The effects of increasing atmospheric CO(2) on ocean ecosystems are a major environmental concern, as rapid shoaling of the carbonate saturation horizon is exposing vast areas of marine sediments to corrosive waters worldwide. Natural CO(2) gradients off Vulcano, Italy, have revealed profound ecosystem changes along rocky shore habitats as carbonate saturation levels decrease, but no investigations have yet been made of the sedimentary habitat. Here, we sampled the upper 2 cm of volcanic sand in three zones, ambient (median pCO(2) 419 μatm, minimum Ω(arag) 3.77), moderately CO(2)-enriched (median pCO(2) 592 μatm, minimum Ω(arag) 2.96), and highly CO(2)-enriched (median pCO(2) 1611 μatm, minimum Ω(arag) 0.35). We tested the hypothesis that increasing levels of seawater pCO(2) would cause significant shifts in sediment bacterial community composition, as shown recently in epilithic biofilms at the study site. In this study, 454 pyrosequencing of the V1 to V3 region of the 16S rRNA gene revealed a shift in community composition with increasing pCO(2). The relative abundances of most of the dominant genera were unaffected by the pCO(2) gradient, although there were significant differences for some 5 % of the genera present (viz. Georgenia, Lutibacter, Photobacterium, Acinetobacter, and Paenibacillus), and Shannon Diversity was greatest in sediments subject to long-term acidification (>100 years). Overall, this supports the view that globally increased ocean pCO(2) will be associated with changes in sediment bacterial community composition but that most of these organisms are resilient. However, further work is required to assess whether these results apply to other types of coastal sediments and whether the changes in relative abundance of bacterial taxa that we observed can significantly alter the biogeochemical functions of marine sediments

Ecological succession of a Jurassic shallow-water ichthyosaur fall.

After the discovery of whale fall communities in modern oceans, it has been hypothesized that during the Mesozoic the carcasses of marine reptiles created similar habitats supporting long-lived and specialized animal communities. Here, we report a fully documented ichthyosaur fall community, from a Late Jurassic shelf setting, and reconstruct the ecological succession of its micro- and macrofauna. The early 'mobile-scavenger' and 'enrichment-opportunist' stages were not succeeded by a 'sulphophilic stage' characterized by chemosynthetic molluscs, but instead the bones were colonized by microbial mats that attracted echinoids and other mat-grazing invertebrates. Abundant cemented suspension feeders indicate a well-developed 'reef stage' with prolonged exposure and colonization of the bones prior to final burial, unlike in modern whale falls where organisms such as the ubiquitous bone-eating worm Osedax rapidly destroy the skeleton. Shallow-water ichthyosaur falls thus fulfilled similar ecological roles to shallow whale falls, and did not support specialized chemosynthetic communities

Phase structure of black branes in grand canonical ensemble

This is a companion paper of our previous work [1] where we studied the thermodynamics and phase structure of asymptotically flat black $p$-branes in a cavity in arbitrary dimensions $D$ in a canonical ensemble. In this work we study the thermodynamics and phase structure of the same in a grand canonical ensemble. Since the boundary data in two cases are different (for the grand canonical ensemble boundary potential is fixed instead of the charge as in canonical ensemble) the stability analysis and the phase structure in the two cases are quite different. In particular, we find that there exists an analog of one-variable analysis as in canonical ensemble, which gives the same stability condition as the rather complicated known (but generalized from black holes to the present case) two-variable analysis. When certain condition for the fixed potential is satisfied, the phase structure of charged black $p$-branes is in some sense similar to that of the zero charge black $p$-branes in canonical ensemble up to a certain temperature. The new feature in the present case is that above this temperature, unlike the zero-charge case, the stable brane phase no longer exists and `hot flat space' is the stable phase here. In the grand canonical ensemble there is an analog of Hawking-Page transition, even for the charged black $p$-brane, as opposed to the canonical ensemble. Our study applies to non-dilatonic as well as dilatonic black $p$-branes in $D$ space-time dimensions.Comment: 32 pages, 2 figures, various points refined, discussion expanded, references updated, typos corrected, published in JHEP 1105:091,201

Genome wide analysis of gene expression changes in skin from patients with type 2 diabetes

Non-healing chronic ulcers are a serious complication of diabetes and are a major healthcare problem. While a host of treatments have been explored to heal or prevent these ulcers from forming, these treatments have not been found to be consistently effective in clinical trials. An understanding of the changes in gene expression in the skin of diabetic patients may provide insight into the processes and mechanisms that precede the formation of non-healing ulcers. In this study, we investigated genome wide changes in gene expression in skin between patients with type 2 diabetes and non-diabetic patients using next generation sequencing. We compared the gene expression in skin samples taken from 27 patients (13 with type 2 diabetes and 14 non-diabetic). This information may be useful in identifying the causal factors and potential therapeutic targets for the prevention and treatment of diabetic related diseases