The phosphomimetic mutation of syndecan-4 binds and inhibits Tiam1 modulating Rac1 activity in PDZ interaction-dependent manner

The small GTPases of the Rho family comprising RhoA, Rac1 and Cdc42 function as molecular switches controlling several essential biochemical pathways in eukaryotic cells. Their activity is cycling between an active GTP-bound and an inactive GDP-bound conformation. The exchange of GDP to GTP is catalyzed by guanine nucleotide exchange factors (GEFs). Here we report a novel regulatory mechanism of Rac1 activity, which is controlled by a phosphomimetic (Ser179Glu) mutant of syndecan-4 (SDC4). SDC4 is a ubiquitously expressed transmembrane, heparan sulfate proteoglycan. In this study we show that the Ser179Glu mutant binds strongly Tiam1, a Rac1-GEF reducing Rac1-GTP by 3-fold in MCF-7 breast adenocarcinoma cells. Mutational analysis unravels the PDZ interaction between SDC4 and Tiam1 is indispensable for the suppression of the Rac1 activity. Neither of the SDC4 interactions is effective alone to block the Rac1 activity, on the contrary, lack of either of interactions can increase the activity of Rac1, therefore the Rac1 activity is the resultant of the inhibitory and stimulatory effects. In addition, SDC4 can bind and tether RhoGDI1 (GDP-dissociation inhibitor 1) to the membrane. Expression of the phosphomimetic SDC4 results in the accumulation of the Rac1-RhoGDI1 complex. Co-immunoprecipitation assays (co-IP-s) reveal that SDC4 can form complexes with RhoGDI1. Together, the regulation of the basal activity of Rac1 is fine tuned and SDC4 is implicated in multiple ways

Clinical trials update of the European Organization for Research and Treatment of Cancer Breast Cancer Group

The present clinical trial update consists of a review of two of eight current studies (the 10981-22023 AMAROS trial and the 10994 p53 trial) of the European Organization for Research and Treatment of Cancer Breast Cancer Group, as well as a preview of the MIND-ACT trial. The AMAROS trial is designed to prove equivalent local/regional control for patients with proven axillary lymph node metastasis by sentinel node biopsy if treated with axillary radiotherapy instead of axillary lymph node dissection, with reduced morbidity. The p53 trial started to assess the potential predictive value of p53 using a functional assay in yeast in patients with locally advanced/inflammatory or large operable breast cancer prospectively randomised to a taxane regimen versus a nontaxane regimen

Ethanol Distribution, Dispensing, and Use: Analysis of a Portion of the Biomass-to-Biofuels Supply Chain Using System Dynamics

The Energy Independence and Security Act of 2007 targets use of 36 billion gallons of biofuels per year by 2022. Achieving this may require substantial changes to current transportation fuel systems for distribution, dispensing, and use in vehicles. The U.S. Department of Energy and the National Renewable Energy Laboratory designed a system dynamics approach to help focus government action by determining what supply chain changes would have the greatest potential to accelerate biofuels deployment. The National Renewable Energy Laboratory developed the Biomass Scenario Model, a system dynamics model which represents the primary system effects and dependencies in the biomass-to-biofuels supply chain. The model provides a framework for developing scenarios and conducting biofuels policy analysis. This paper focuses on the downstream portion of the supply chain–represented in the distribution logistics, dispensing station, and fuel utilization, and vehicle modules of the Biomass Scenario Model. This model initially focused on ethanol, but has since been expanded to include other biofuels. Some portions of this system are represented dynamically with major interactions and feedbacks, especially those related to a dispensing station owner’s decision whether to offer ethanol fuel and a consumer’s choice whether to purchase that fuel. Other portions of the system are modeled with little or no dynamics; the vehicle choices of consumers are represented as discrete scenarios. This paper explores conditions needed to sustain an ethanol fuel market and identifies implications of these findings for program and policy goals. A large, economically sustainable ethanol fuel market (or other biofuel market) requires low end-user fuel price relative to gasoline and sufficient producer payment, which are difficult to achieve simultaneously. Other requirements (different for ethanol vs. other biofuel markets) include the need for infrastructure for distribution and dispensing and widespread use of high ethanol blends in flexible-fuel vehicles

Graphene Photonics and Optoelectronics

The richness of optical and electronic properties of graphene attracts enormous interest. Graphene has high mobility and optical transparency, in addition to flexibility, robustness and environmental stability. So far, the main focus has been on fundamental physics and electronic devices. However, we believe its true potential to be in photonics and optoelectronics, where the combination of its unique optical and electronic properties can be fully exploited, even in the absence of a bandgap, and the linear dispersion of the Dirac electrons enables ultra-wide-band tunability. The rise of graphene in photonics and optoelectronics is shown by several recent results, ranging from solar cells and light emitting devices, to touch screens, photodetectors and ultrafast lasers. Here we review the state of the art in this emerging field.Comment: Review Nature Photonics, in pres

Pride and confidence at work: potential predictors of occupational health in a hospital setting

BACKGROUND: This study focuses on determinants of a healthy work environment in two departments in a Swedish university hospital. The study is based on previously conducted longitudinal studies at the hospital (1994–2001), concerning working conditions and health outcomes among health care personnel in conjunction with downsizing processes. Overall, there was a general negative trend in relation to mental health, as well as long-term sick leave during the study period. The two departments chosen for the current study differed from the general hospital trend in that they showed stable health development. The aim of the study was to identify and analyse experiential determinants of healthy working conditions. METHODS: Thematic open-ended interviews were carried out with seventeen managers and key informants, representing different groups of co-workers in the two departments. The interviews were transcribed verbatim and an inductive content analysis was made. RESULTS: In the two studied departments the respondents perceived that it was advantageous to belong to a small department, and to work in cooperation-oriented care. The management approaches described by both managers and co-workers could be interpreted as transformational, due to a strain of visionary, delegating, motivating, confirmative, supportive attitudes and a strongly expressed solution-oriented attitude. The daily work included integrated learning activities. The existing organisational conditions, approaches and attitudes promoted tendencies towards a work climate characterised by trust, team spirit and professionalism. In the description of the themes organisational conditions, approaches and climate, two core determinants, work-pride and confidence, for healthy working conditions were interpreted. Our core determinants augment the well-established concepts: manageability, comprehensiveness and meaningfulness. These favourable conditions seem to function as a buffer against the general negative effects of downsizing observed elsewhere in the hospital, and in the literature. CONCLUSION: Research illuminating health-promoting aspects is rather unusual. This study could be seen as explorative. The themes and core dimensions we found could be used as a basis for further intervention studies in similar health-care settings. The result could also be used in future health promotion studies in larger populations. One of the first steps in such a strategy is to formulate relevant questions, and we consider that this study contributes to this

Clinical aspects of sentinel node biopsy

Sentinel lymph node (SLN) biopsy requires validation by a backup axillary dissection in a defined series of cases before becoming standard practice, to establish individual and institutional success rates and the frequency of false negative results. At least 90% success in finding the SLN with no more than 5-10% false negative results is a reasonable goal for surgeons and institutions learning the technique. A combination of isotope and dye to map the SLN is probably superior to either method used alone, yet a wide variety of technical variations in the procedure have produced a striking similarity of results. Most breast cancer patients are suitable for SLN biopsy, and the large majority reported to date has had clinical stage T1-2N0 invasive breast cancers. SLN biopsy will play a growing role in patients having prophylactic mastectomy, and in those with 'high-risk' duct carcinoma in situ, microinvasive cancers, T3 disease, and neoadjuvant chemotherapy. SLN biopsy for the first time makes enhanced pathologic analysis of lymph nodes logistically feasible, at once allowing greater staging accuracy and less morbidity than standard methods. Retrospective data suggest that micrometastases identified in this way are prognostically significant, and prospective clinical trials now accruing promise a definitive answer to this issue

Force of tuberculosis infection among adolescents in a high HIV and TB prevalence community: a cross-sectional observation study

BACKGROUND: Understanding of the transmission dynamics of tuberculosis (TB) in high TB and HIV prevalent settings is required in order to develop effective intervention strategies for TB control. However, there are little data assessing incidence of TB infection in adolescents in these settings. METHODS: We performed a tuberculin skin test (TST) and HIV survey among secondary school learners in a high HIV and TB prevalence community. TST responses to purified protein derivative RT23 were read after 3 days. HIV-infection was assessed using Orasure(R) collection device and ELISA testing. The results of the HIV-uninfected participants were combined with those from previous surveys among primary school learners in the same community, and force of TB infection was calculated by age. RESULTS: The age of 820 secondary school participants ranged from 13 to 22 years. 159 participants had participated in the primary school surveys. At a 10 mm cut-off, prevalence of TB infection among HIV-uninfected and first time participants, was 54% (n = 334/620). HIV prevalence was 5% (n = 40/816). HIV infection was not significantly associated with TST positivity (p = 0.07). In the combined survey dataset, TB prevalence was 45% (n = 645/1451), and was associated with increasing age and male gender. Force of infection increased with age, from 3% to 7.3% in adolescents [greater than or equal to]20 years of age. CONCLUSIONS: We show a high force of infection among adolescents, positively associated with increasing age. We postulate this is due to increased social contact with infectious TB cases. Control of the TB epidemic in this setting will require reducing the force of infection