Oncogenic Gain of Function in Glioblastoma Is Linked to Mutant p53 Amyloid Oligomers.

Tumor-associated p53 mutations endow cells with malignant phenotypes, including chemoresistance. Amyloid-like oligomers of mutant p53 transform this tumor suppressor into an oncogene. However, the composition and distribution of mutant p53 oligomers are unknown and the mechanism involved in the conversion is sparse. Here, we report accumulation of a p53 mutant within amyloid-like p53 oligomers in glioblastoma-derived cells presenting a chemoresistant gain-of-function phenotype. Statistical analysis from fluorescence fluctuation spectroscopy, pressure-induced measurements, and thioflavin T kinetics demonstrates the distribution of oligomers larger than the active tetrameric form of p53 in the nuclei of living cells and the destabilization of native-drifted p53 species that become amyloid. Collectively, these results provide insights into the role of amyloid-like mutant p53 oligomers in the chemoresistance phenotype of malignant and invasive brain tumors and shed light on therapeutic options to avert cancer

Longitudinal impact of process-oriented guided inquiry learning on the attitudes, self-efficacy and experiences of pre-medical chemistry students

A follow-up study was conducted with foundation-year chemistry students who were taught in an inquiry- and role-based, small-group active learning environment in order to evaluate their attitudes, experiences and self-efficacy during pre-medical chemistry courses. The study adopted a mixedmethods research design that involved both experimental and comparison groups. Using the CAEQ (Chemistry Attitudes and Experiences Questionnaire) and the ASCI v2 (Attitude toward the Study of Chemistry Inventory), the findings of this study indicated that inquiry-based chemistry learning experience improves the students’ intellectual accessibility and emotional satisfaction as well as develops their self-efficacy levels while pursuing intensive pre-medical courses in chemistry. The results of the qualitative data analyses using a course experience questionnaire indicated that the process-oriented guided inquiry learning (POGIL) experience helped the students succeed in rigorous pre-medical chemistry courses and gained some process skills required in the medical programme as listed by the AAMC (American Association of Medical Colleges)

Services just for men? Insights from a national study of the well men services pilots.

Men continue to have a lower life expectancy in most countries compared to women. Explanations of this gendered health inequality tend to focus on male risk taking, unhealthy lifestyle choices and resistance to seeking help from health services. In the period 2005-2008 the Scottish Government funded a nationwide community health promotion programme aimed at improving men's health, called Well Men Service Pilots (henceforth WMS)

Computer-supported feedback message tailoring: Theory-informed adaptation of clinical audit and feedback for learning and behavior change

Background: Evidence shows that clinical audit and feedback can significantly improve compliance with desired practice, but it is unclear when and how it is effective. Audit and feedback is likely to be more effective when feedback messages can influence barriers to behavior change, but barriers to change differ across individual health-care providers, stemming from differences in providers' individual characteristics. Discussion: The purpose of this article is to invite debate and direct research attention towards a novel audit and feedback component that could enable interventions to adapt to barriers to behavior change for individual health-care providers: computer-supported tailoring of feedback messages. We argue that, by leveraging available clinical data, theory-informed knowledge about behavior change, and the knowledge of clinical supervisors or peers who deliver feedback messages, a software application that supports feedback message tailoring could improve feedback message relevance for barriers to behavior change, thereby increasing the effectiveness of audit and feedback interventions. We describe a prototype system that supports the provision of tailored feedback messages by generating a menu of graphical and textual messages with associated descriptions of targeted barriers to behavior change. Supervisors could use the menu to select messages based on their awareness of each feedback recipient's specific barriers to behavior change. We anticipate that such a system, if designed appropriately, could guide supervisors towards giving more effective feedback for health-care providers. Summary: A foundation of evidence and knowledge in related health research domains supports the development of feedback message tailoring systems for clinical audit and feedback. Creating and evaluating computer-supported feedback tailoring tools is a promising approach to improving the effectiveness of clinical audit and feedback

Contact Manifolds, Contact Instantons, and Twistor Geometry

Recently, Kallen and Zabzine computed the partition function of a twisted supersymmetric Yang-Mills theory on the five-dimensional sphere using localisation techniques. Key to their construction is a five-dimensional generalisation of the instanton equation to which they refer as the contact instanton equation. Subject of this article is the twistor construction of this equation when formulated on K-contact manifolds and the discussion of its integrability properties. We also present certain extensions to higher dimensions and supersymmetric generalisations.Comment: v3: 28 pages, clarifications and references added, version to appear in JHE

BRCA1 and BRCA2 mutations in a population-based study of male breast cancer

Background: The contribution of BRCA1 and BRCA2 to the incidence of male breast cancer (MBC) in the United Kingdom is not known, and the importance of these genes in the increased risk of female breast cancer associated with a family history of breast cancer in a male first-degree relative is unclear. Methods: We have carried out a population-based study of 94 MBC cases collected in the UK. We screened genomic DNA for mutations in BRCA1 and BRCA2 and used family history data from these cases to calculate the risk of breast cancer to female relatives of MBC cases. We also estimated the contribution of BRCA1 and BRCA2 to this risk. Results: Nineteen cases (20%) reported a first-degree relative with breast cancer, of whom seven also had an affected second-degree relative. The breast cancer risk in female first-degree relatives was 2.4 times (95% confidence interval [CI] = 1.4–4.0) the risk in the general population. No BRCA1 mutation carriers were identified and five cases were found to carry a mutation in BRCA2. Allowing for a mutation detection sensitivity frequency of 70%, the carrier frequency for BRCA2 mutations was 8% (95% CI = 3–19). All the mutation carriers had a family history of breast, ovarian, prostate or pancreatic cancer. However, BRCA2 accounted for only 15% of the excess familial risk of breast cancer in female first-degree relatives. Conclusion: These data suggest that other genes that confer an increased risk for both female and male breast cancer have yet to be found

Numerical Hermitian Yang-Mills Connections and Kahler Cone Substructure

We further develop the numerical algorithm for computing the gauge connection of slope-stable holomorphic vector bundles on Calabi-Yau manifolds. In particular, recent work on the generalized Donaldson algorithm is extended to bundles with Kahler cone substructure on manifolds with h^{1,1}>1. Since the computation depends only on a one-dimensional ray in the Kahler moduli space, it can probe slope-stability regardless of the size of h^{1,1}. Suitably normalized error measures are introduced to quantitatively compare results for different directions in Kahler moduli space. A significantly improved numerical integration procedure based on adaptive refinements is described and implemented. Finally, an efficient numerical check is proposed for determining whether or not a vector bundle is slope-stable without computing its full connection.Comment: 38 pages, 10 figure