Conformational activation of ADAMTS13

A disintegrin and metalloprotease with thrombospondin motifs 13 (ADAMTS13) is a metalloprotease that regulates von Willebrand factor (VWF) function. ADAMTS13-mediated proteolysis is determined by conformational changes in VWF, but also may depend on its own conformational activation. Kinetic analysis of WT ADAMTS13 revealed ∼2.5-fold reduced activity compared with ADAMTS13 lacking its C-terminal tail (MDTCS) or its CUB1-2 domains (WTΔCUB1-2), suggesting that the CUB domains naturally limit ADAMTS13 function. Consistent with this suggestion, WT ADAMTS13 activity was enhanced ∼2.5-fold by preincubation with either an anti-CUB mAb (20E9) or VWF D4CK (the natural binding partner for the CUB domains). Furthermore, the isolated CUB1-2 domains not only bound MDTCS, but also inhibited activity by up to 2.5-fold. Interestingly, a gain-of-function (GoF) ADAMTS13 spacer domain variant (R568K/F592Y/R660K/Y661F/Y665F) was ∼2.5-fold more active than WT ADAMTS13, but could not be further activated by 20E9 mAb or VWF D4CK and was unable to bind or to be inhibited by the CUB1-2 domains, suggesting that the inhibitory effects of the CUB domains involve an interaction with the spacer domain that is disrupted in GoF ADAMTS13. Electron microscopy demonstrated a “closed” conformation of WT ADAMTS13 and suggested a more “open” conformation for GoF ADAMTS13. The cryptic spacer domain epitope revealed by conformational unfolding also represents the core antigenic target for autoantibodies in thrombotic thrombocytopenic purpura. We propose that ADAMTS13 circulates in a closed conformation, which is maintained by a CUB–spacer domain binding interaction. ADAMTS13 becomes conformationally activated on demand through interaction of its C-terminal CUB domains with VWF, making it susceptible to immune recognition

A multi-dating approach to age-modelling long continental records: The 135 ka El Cañizar de Villarquemado sequence (NE Spain)

We present the multidisciplinary dating approach - including radiocarbon, Uranium/Thorium series (U/Th), paleomagnetism, single-grain Optical Stimulated Luminescence (OSL), Infrared Stimulated Luminescence (IRSL) and tephrochronology - used for the development of an age model for the Cañizar de Villarquemado sequence (VIL) for the last ca. 135 ka. We describe the protocols used for each technique and discuss the positive and negative results, as well as their implications for interpreting the VIL sequence and for dating similar terrestrial records. In spite of the negative results of some techniques, particularly due to the absence of adequate sample material or inaccurate analytical precision, the multi-technique strategy employed here is essential to maximize the chances of obtaining robust age models in terrestrial sequences. The final Bayesian age model for VIL sequence includes 16 AMS 14C ages, 9 OSL ages and 5 previously published IRSL ages, and the accuracy and resolution of the model are improved by incorporating information related to changes in accumulation rate, as revealed by detailed sedimentological analyses. The main paleohydrological and vegetation changes in the sequence are coherent with global Marine Isotope Stage (MIS) 6 to 1 transitions since the penultimate Termination, although some regional idiosyncrasies are evident, such as higher moisture variability than expected, an abrupt inception of the last glacial cycle and a resilient response of vegetation in Mediterranean continental Iberia in both Terminations

A comparative evaluation of the process of developing and implementing an emergency department HIV testing program

<p>Abstract</p> <p>Background</p> <p>The 2006 Centers for Disease Control and Prevention (CDC) HIV testing guidelines recommend screening for HIV infection in all healthcare settings, including the emergency department (ED). In urban areas with a high background prevalence of HIV, the ED has become an increasingly important site for identifying HIV infection. However, this public health policy has been operationalized using different models. We sought to describe the development and implementation of HIV testing programs in three EDs, assess factors shaping the adoption and evolution of specific program elements, and identify barriers and facilitators to testing.</p> <p>Methods</p> <p>We performed a qualitative evaluation using in-depth interviews with fifteen 'key informants' involved in the development and implementation of HIV testing in three urban EDs serving sizable racial/ethnic minority and socioeconomically disadvantaged populations. Testing program HIV prevalence ranged from 0.4% to 3.0%.</p> <p>Results</p> <p>Three testing models were identified, reflecting differences in the use of existing ED staff to offer and perform the test and disclose results. Factors influencing the adoption of a particular model included: whether program developers were ED providers, HIV providers, or both; whether programs took a targeted or non-targeted approach to patient selection; and the extent to which linkage to care was viewed as the responsibility of the ED. A common barrier was discomfort among ED providers about disclosing a positive HIV test result. Common facilitators were a commitment to underserved populations, the perception that testing was an opportunity to re-engage previously HIV-infected patients in care, and the support and resources offered by the medical setting for HIV-infected patients.</p> <p>Conclusions</p> <p>ED HIV testing is occurring under a range of models that emerge from local realities and are tailored to institutional strengths to optimize implementation and overcome provider barriers.</p

The Effect of Fluorine Doping on the Characteristic Behaviour of CdTe

Fluorine which is an n-type dopant of cadmium telluride thin films was included during growth from a cadmium nitrate [Cd(NO3)2Æ4H2O] bath using an electrodeposition technique. The fluorine concentration in the Cd(NO3)2Æ4H2O baths were varied between 0.5 ppm and 50 ppm in order to determine its effect on the optical, structural, morphological and electrical properties of the as-deposited and the post-growth-treated layers. These characterisations were carried out using x-ray diffraction, ultraviolet–visible spectrophotometry, scanning electron microscopy, energy dispersive x-rays spectroscopy, photoelectrochemical cell measurement, direct current conductivity measurement and fully fabricated device characterisation. The results are systematically reported in this paper

Scrambling for access: availability, accessibility, acceptability and quality of healthcare for lesbian, gay, bisexual and transgender people in South Africa

BACKGROUND: Sexual orientation and gender identity are social determinants of health for people identifying as lesbian, gay, bisexual and transgender (LGBT), and health disparities among sexual and gender minority populations are increasingly well understood. Although the South African constitution guarantees sexual and gender minority people the right to non-discrimination and the right to access to healthcare, homo- and transphobia in society abound. Little is known about LGBT people's healthcare experiences in South Africa, but anecdotal evidence suggests significant barriers to accessing care. Using the framework of the UN International Covenant on Economic, Social and Cultural Rights General Comment 14, this study analyses the experiences of LGBT health service users using South African public sector healthcare, including access to HIV counselling, testing and treatment. METHODS: A qualitative study comprised of 16 semi-structured interviews and two focus group discussions with LGBT health service users, and 14 individual interviews with representatives of LGBT organisations. Data were thematically analysed within the framework of the UN International Covenant on Economic, Social and Cultural Rights General Comment 14, focusing on availability, accessibility, acceptability and quality of care. RESULTS: All interviewees reported experiences of discrimination by healthcare providers based on their sexual orientation and/or gender identity. Participants recounted violations of all four elements of the UN General Comment 14: 1) Availability: Lack of public health facilities and services, both for general and LGBT-specific concerns; 2) Accessibility: Healthcare providers' refusal to provide care to LGBT patients; 3) Acceptability: Articulation of moral judgment and disapproval of LGBT patients' identity, and forced subjection of patients to religious practices; 4) Quality: Lack of knowledge about LGBT identities and health needs, leading to poor-quality care. Participants had delayed or avoided seeking healthcare in the past, and none had sought out accountability or complaint mechanisms within the health system. CONCLUSION: Sexual orientation and gender identity are important categories of analysis for health equity, and lead to disparities in all four dimensions of healthcare access as defined by General Comment 14. Discriminatory and prejudicial attitudes by healthcare providers, combined with a lack of competency and knowledge are key reasons for these disparities in South Africa

Actin: its cumbersome pilgrimage through cellular compartments

In this article, we follow the history of one of the most abundant, most intensely studied proteins of the eukaryotic cells: actin. We report on hallmarks of its discovery, its structural and functional characterization and localization over time, and point to present days’ knowledge on its position as a member of a large family. We focus on the rather puzzling number of diverse functions as proposed for actin as a dual compartment protein. Finally, we venture on some speculations as to its origin

Blood pressure and body mass index in an ethnically diverse sample of adolescents in Paramaribo, Suriname

<p>Abstract</p> <p>Background</p> <p>High blood pressure (BP) is now an important public health problem in non-industrialised countries. The limited evidence suggests ethnic inequalities in BP in adults in some non-industrialised countries. However, it is unclear whether these ethnic inequalities in BP patterns in adults reflect on adolescents. Hence, we assessed ethnic differences in BP, and the association of BP with body mass index (BMI) among adolescents aged 12–17 years in Paramaribo, Suriname.</p> <p>Methods</p> <p>Cross-sectional study with anthropometric and blood pressure measurements. A random sample of 855 adolescents (167 Hindustanis, 169 Creoles, 128 Javanese, 91 Maroons and 300 mixed-ethnicities) were studied. Ethnicity was based on self-reported ethnic origin.</p> <p>Results</p> <p>Among boys, Maroons had a lower age- and height-adjusted systolic BP than Creoles, and a lower diastolic BP than other ethnic groups. However, after further adjustment for BMI, only diastolic BP in Maroons was significantly lower than in Javanese (67.1 versus 70.9 mmHg). Creole boys had a lower diastolic BP than Hindustani (67.3 versus 70.2 mmHg) and Javanese boys after adjustment for age, height and BMI. Among girls, there were no significant differences in systolic BP between the ethnic groups. Maroon girls, however, had a lower diastolic BP (65.6 mmHg) than Hindustani (69.1 mmHg), Javanese (71.2 mmHg) and Mixed-ethnic (68.3 mmHg) girls, but only after differences in BMI had been adjusted for. Javanese had a higher diastolic BP than Creoles (71.2 versus 66.8 mmHg) and Mixed-ethnicity girls. BMI was positively associated with BP in all the ethnic groups, except for diastolic BP in Maroon girls.</p> <p>Conclusion</p> <p>The study findings indicate higher mean BP levels among Javanese and Hindustani adolescents compared with their African descent peers. These findings contrast the relatively low BP reported in Javanese and Hindustani adult populations in Suriname and underscore the need for public health measures early in life to prevent high BP and its sequelae in later life.</p

Computer-Based Interventions for Problematic Alcohol Use:a Review of Systematic Reviews

PURPOSE: The aim of this review is to provide an overview of knowledge and knowledge gaps in the field of computer-based alcohol interventions by (1) collating evidence on the effectiveness of computer-based alcohol interventions in different populations and (2) exploring the impact of four specified moderators of effectiveness: therapeutic orientation, length of intervention, guidance and trial engagement.  METHODS: A review of systematic reviews of randomized trials reporting on effectiveness of computer-based alcohol interventions published between 2005 and 2015.  RESULTS: Fourteen reviews met the inclusion criteria. Across the included reviews, it was generally reported that computer-based alcohol interventions were effective in reducing alcohol consumption, with mostly small effect sizes. There were indications that longer, multisession interventions are more effective than shorter or single session interventions. Evidence on the association between therapeutic orientation of an intervention, guidance or trial engagement and reductions in alcohol consumption is limited, as the number of reviews addressing these themes is low. None of the included reviews addressed the association between therapeutic orientation, length of intervention or guidance and trial engagement.  CONCLUSIONS: This review of systematic reviews highlights the mostly positive evidence supporting computer-based alcohol interventions as well as reveals a number of knowledge gaps that could guide future research in this field