Calmodulin Binds a Highly Extended HIV-1 MA Protein That Refolds Upon Its Release

Calmodulin (CaM) expression is upregulated upon HIV-1 infection and interacts with proteins involved in viral processing, including the multifunctional HIV-1 MA protein. We present here the results of studies utilizing small-angle neutron scattering with contrast variation that, when considered in the light of earlier fluorescence and NMR data, show CaM binds MA in an extended open-clamp conformation via interactions with two tryptophans that are widely spaced in sequence and space. The interaction requires a disruption of the MA tertiary fold such that MA becomes highly extended in a long snakelike conformation. The CaM-MA interface is extensive, covering ∼70% of the length of the MA such that regions known to be important in MA interactions with critical binding partners would be impacted. The CaM conformation is semiextended and as such is distinct from the classical CaM-collapse about short α-helical targets. NMR data show that upon dissociation of the CaM-MA complex, either by the removal of Ca2+ or increasing ionic strength, MA reforms its native tertiary contacts. Thus, we observe a high level of structural plasticity in MA that may facilitate regulation of its activities via intracellular Ca2+-signaling during viral processing. © 2012 Biophysical Society

The Entropy for General Extremal Black Holes

We use the Kerr/CFT correspondence to calculate the entropy for all known extremal stationary and axisymmetric black holes. This is done with the help of two ansatzs that are general enough to cover all such known solutions. Considering only the contribution from the Einstein-Hilbert action to the central charge(s), we find that the entropy obtained by using Cardy's formula exactly matches with the Bekenstein-Hawking entropy.Comment: Minor corrections, section 5 refined, references added

Is Student Participation in School Governance a “Mission impossible”?

The civic mission of schools in nurturing political literature, critical thinking and participatory citizens has always been played down in Hong Kong schools. On one hand, teaching civic education has never been ranked high in the education agenda. On the other hand, because of the conservative nature of schools, students are rarely encouraged to participate in school governance for the enhancement of their citizenship development. Funded by the General Research Fund (GRF) in Hong Kong, the authors conducted a quantitative survey on students’ participation in school governance and their citizenship development in 2013 to explore 1) students’ conception of “good citizens”; 2) the level and scope of student participation in school governance; and 3) the facilitating and hindering factors influencing student participation. This paper is a report on the simple statistical results of the survey findings. With reference to Westheimer and Kahne’s typologies, the findings revealed that the students had an eclectic understanding of citizenship, with higher scores for Personally Responsible Citizen and lower scores for Participatory, Justice Oriented and Patriotic Citizen, reflecting a conservative orientation. Concerning the implementation of school civic mission through student participation in school governance, it was found that students were rarely allowed to engage in important school matters, such as formulation of school rules and discussion of the school development plan. Our findings also revealed that schools were more inclined to inform students and consult them rather than confer real participation and powers to them. The paper concludes that the current practice of student participation in school governance does not facilitate the nurturing of active participatory citizens, particularly of a Justice Oriented nature, and this is urgently needed for the democratic development of Hong Kong

Three-Fold Diffraction Symmetry in Epitaxial Graphene and the SiC Substrate

The crystallographic symmetries and spatial distribution of stacking domains in graphene films on SiC have been studied by low energy electron diffraction (LEED) and dark field imaging in a low energy electron microscope (LEEM). We find that the graphene diffraction spots from 2 and 3 atomic layers of graphene have 3-fold symmetry consistent with AB (Bernal) stacking of the layers. On the contrary, graphene diffraction spots from the buffer layer and monolayer graphene have apparent 6-fold symmetry, although the 3-fold nature of the satellite spots indicates a more complex periodicity in the graphene sheets.Comment: An addendum has been added for the arXiv version only, including one figure with five panels. Published paper can be found at http://link.aps.org/doi/10.1103/PhysRevB.80.24140

A Single-Arm, Proof-Of-Concept Trial of Lopimune (Lopinavir/Ritonavir) as a Treatment for HPV-Related Pre-Invasive Cervical Disease

BACKGROUND: Cervical cancer is the most common female malignancy in the developing nations and the third most common cancer in women globally. An effective, inexpensive and self-applied topical treatment would be an ideal solution for treatment of screen-detected, pre-invasive cervical disease in low resource settings. METHODS: Between 01/03/2013 and 01/08/2013, women attending Kenyatta National Hospital's Family Planning and Gynaecology Outpatients clinics were tested for HIV, HPV (Cervista®) and liquid based cervical cytology (LBC -ThinPrep®). HIV negative women diagnosed as high-risk HPV positive with high grade squamous intraepithelial lesions (HSIL) were examined by colposcopy and given a 2 week course of 1 capsule of Lopimune (CIPLA) twice daily, to be self-applied as a vaginal pessary. Colposcopy, HPV testing and LBC were repeated at 4 and 12 weeks post-start of treatment with a final punch biopsy at 3 months for histology. Primary outcome measures were acceptability of treatment with efficacy as a secondary consideration. RESULTS: A total of 23 women with HSIL were treated with Lopimune during which time no adverse reactions were reported. A maximum concentration of 10 ng/ml of lopinavir was detected in patient plasma 1 week after starting treatment. HPV was no longer detected in 12/23 (52.2%, 95%CI: 30.6-73.2%). Post-treatment cytology at 12 weeks on women with HSIL, showed 14/22 (63.6%, 95%CI: 40.6-82.8%) had no dysplasia and 4/22 (18.2%, 95%CI: 9.9-65.1%) were now low grade demonstrating a combined positive response in 81.8% of women of which 77.8% was confirmed by histology. These data are supported by colposcopic images, which show regression of cervical lesions. CONCLUSIONS: These results demonstrate the potential of Lopimune as a self-applied therapy for HPV infection and related cervical lesions. Since there were no serious adverse events or detectable post-treatment morbidity, this study indicates that further trials are clearly justified to define optimal regimes and the overall benefit of this therapy. TRIAL REGISTRATION: ISRCTN Registry 48776874

Missing steps in a staircase: a qualitative study of the perspectives of key stakeholders on the use of adaptive designs in confirmatory trials

Background Despite the promising benefits of adaptive designs (ADs), their routine use, especially in confirmatory trials, is lagging behind the prominence given to them in the statistical literature. Much of the previous research to understand barriers and potential facilitators to the use of ADs has been driven from a pharmaceutical drug development perspective, with little focus on trials in the public sector. In this paper, we explore key stakeholders’ experiences, perceptions and views on barriers and facilitators to the use of ADs in publicly funded confirmatory trials. Methods Semi-structured, in-depth interviews of key stakeholders in clinical trials research (CTU directors, funding board and panel members, statisticians, regulators, chief investigators, data monitoring committee members and health economists) were conducted through telephone or face-to-face sessions, predominantly in the UK. We purposively selected participants sequentially to optimise maximum variation in views and experiences. We employed the framework approach to analyse the qualitative data. Results We interviewed 27 participants. We found some of the perceived barriers to be: lack of knowledge and experience coupled with paucity of case studies, lack of applied training, degree of reluctance to use ADs, lack of bridge funding and time to support design work, lack of statistical expertise, some anxiety about the impact of early trial stopping on researchers’ employment contracts, lack of understanding of acceptable scope of ADs and when ADs are appropriate, and statistical and practical complexities. Reluctance to use ADs seemed to be influenced by: therapeutic area, unfamiliarity, concerns about their robustness in decision-making and acceptability of findings to change practice, perceived complexities and proposed type of AD, among others. Conclusions There are still considerable multifaceted, individual and organisational obstacles to be addressed to improve uptake, and successful implementation of ADs when appropriate. Nevertheless, inferred positive change in attitudes and receptiveness towards the appropriate use of ADs by public funders are supportive and are a stepping stone for the future utilisation of ADs by researchers

Body size and the risk of biliary tract cancer: a population-based study in China

Though obesity is an established risk factor for gall bladder cancer, its role in cancers of the extrahepatic bile ducts and ampulla of Vater is less clear, as also is the role of abdominal obesity. In a population-based case–control study of biliary tract cancer in Shanghai, China, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for biliary tract cancer in relation to anthropometric measures, including body mass index (BMI) at various ages and waist-to-hip ratio (WHR), adjusting for age, sex, and education. The study included 627 patients with biliary tract cancer (368 gall bladder, 191 bile duct, 68 ampulla of Vater) and 959 healthy subjects randomly selected from the population. A higher BMI at all ages, including early adulthood (ages 20–29 years), and a greater WHR were associated with an increased risk of gall bladder cancer. A high usual adult BMI (⩾25) was associated with a 1.6-fold risk of gall bladder cancer (95% CI 1.2–2.1, P for trend <0.001). Among subjects without gallstones, BMI was also positively associated with gall bladder cancer risk. Regardless of BMI levels, increasing WHR was associated with an excess risk of gall bladder cancer risk, with those having a high BMI (⩾25) and a high WHR (>0.90) having the highest risk of gall bladder cancer (OR=12.6, 95% CI 4.8–33.2), relative to those with a low BMI and WHR. We found no clear risk patterns for cancers of the bile duct and ampulla of Vater. These results suggest that both overall and abdominal obesity, including obesity in early adulthood, are associated with an increased risk of gall bladder cancer. The increasing prevalence of obesity and cholesterol stones in Shanghai seems at least partly responsible for the rising incidence of gall bladder cancer in Shanghai

Parkour as a donor sport for athletic development in youth team sports: insights through an ecological dynamics lens

Analyses of talent development in sport have identified that skill can be enhanced through early and continued involvement in donor sports which share affordances (opportunities for action) with a performer's main target sport. Aligning key ideas of the Athletic Skills Model and ecological dynamics theory, we propose how the sport of parkour could provide a representative and adaptive platform for developing athletic skill (e.g. coordination, timing, balance, agility, spatial awareness and muscular strength). We discuss how youth sport development programmes could be (re) designed to include parkour-style activities, in order to develop general athletic skills in affordance-rich environments. It is proposed that team sports development programmes could particularly benefit from parkour-style training since it is exploratory and adaptive nature shapes utilisation of affordances for innovative and autonomous performance by athletes. Early introduction to varied, relevant activities for development of athleticism and skill, in a diversified training programme, would provide impetus for a fundamental shift away from the early specialisation approach favoured by traditional theories of skill acquisition and expertise in sport