Attempts to detect retrotransposition and de novo deletion of Alus and other dispersed repeats at specific loci in the human genome

Dispersed repeat elements contribute to genome instability by de novo insertion and unequal recombination between repeats. To study the dynamics of these processes, we have developed single DNA molecule approaches to detect de novo insertions at a single locus and Alu-mediated deletions at two different loci in human genomic DNA. Validation experiments showed these approaches could detect insertions and deletions at frequencies below 10(-6) per cell. However, bulk analysis of germline (sperm) and somatic DNA showed no evidence for genuine mutant molecules, placing an upper limit of insertion and deletion rates of 2 x 10(-7) and 3 x 10(-7), respectively, in the individuals tested. Such re-arrangements at these loci therefore occur at a rate lower than that detectable by the most sensitive methods currently available

Antibody engineering & therapeutics, the annual meeting of the antibody society December 7-10, 2015, San Diego, CA, USA

The 26th Antibody Engineering & Therapeutics meeting, the annual meeting of The Antibody Society united over 800 participants from all over the world in San Diego from 6-10 December 2015. The latest innovations and advances in antibody research and development were discussed, covering a myriad of antibody-related topics by more than 100 speakers, who were carefully selected by The Antibody Society. As a prelude, attendees could join the pre-conference training course focusing, among others, on the engineering and enhancement of antibodies and antibody-like scaffolds, bispecific antibody engineering and adaptation to generate chimeric antigen receptor constructs. The main event covered 4 d of scientific sessions that included antibody effector functions, reproducibility of research and diagnostic antibodies, new developments in antibody-drug conjugates (ADCs), preclinical and clinical ADC data, new technologies and applications for bispecific antibodies, antibody therapeutics for non-cancer and orphan indications, antibodies to harness the cellular immune system, building comprehensive IgVH-gene repertoires through discovering, confirming and cataloging new germline IgVH genes, and overcoming resistance to clinical immunotherapy. The Antibody Society's special session focused on "Antibodies to watch" in 2016. Another special session put the spotlight on the limitations of the new definitions for the assignment of antibody international nonproprietary names introduced by the World Health Organization. The convention concluded with workshops on computational antibody design and on the promise and challenges of using next-generation sequencing for antibody discovery and engineering from synthetic and in vivo libraries

Associations between reliable changes in depression and changes in BMI, total body fatness and visceral adiposity during a 12-month weight loss trial.

We investigated associations between changes in depression and body composition over a 12-month weight loss trial. Of the 298 adults (BMI > 27 m/kg2), 219 with complete depression and body composition data were included. A 10-item Center for Epidemiologic Studies Depression Scale measured depression; dual-energy X-ray absorptiometry measured body composition. Multinomial logistic regression predicted reliable changes in depression by BMI, body fat (BF) and visceral adiposity (VAT). Multiplicative interaction terms tested modification by sex and ethnicity. Participants with increases in body composition were less likely to experience improvements in depression (BMI: RRR = 0.79 (0.68-0.91), p < 0.01; BF: RRR = 0.97 (0.94 - 0.99), p = 0.01; VAT: RRR = 0.99 (0.98-1.00), p = 0.02), but not worsening of depression (BMI: RRR = 1.29 (0.96-1.73), p = 0.10; BF: RRR = 1.04 (0.99-1.09), p = 0.15; VAT: RRR = 1.01 (1.00-1.03), p = 0.18). Sex and ethnicity interaction terms were not significant. However, the relationship was only significant among females, among non-Latinos for BMI and BF, and among Latinos for VAT. Our study supports the association between depression and obesity and highlights the need for longitudinal studies investigating VAT and depression in diverse ethnic groups

GPs’ strategies in exploring the preschool child’s wellbeing in the paediatric consultation

Background: Although General Practitioners (GPs) are uniquely placed to identify children with emotional, social, and behavioural problems, they succeed in identifying only a small number of them. The aim of this article is to explore the strategies, methods, and tools employed by GPs in the assessment of the preschool child’s emotional, mental, social, and behavioural health. We look at how GPs address parental care of the child in general and in situations where GPs have a particular awareness of the child. Method: Twenty-eight Danish GPs were purposively selected to take part in a qualitative study which combined focus-group discussions, observation of child consultations, and individual interviews with GPs. Results: Analysis of the data suggests that GPs have developed a set of methods, and strategies to assess the preschool child and parental care of the child. They look beyond paying narrow attention to the physical health of the child and they have expanded their practice to include the relations and interactions in the consultation room. The physical examination of the child continues to play a central role in doctor-child communication. Conclusion: The participating GPs’ strategies helped them to assess the wellbeing of the preschool child but they often find it difficult to share their impressions with parents

Cross-sectional analysis of educational inequalities in primary prevention statin use in UK Biobank.

OBJECTIVE: Identify whether participants with lower education are less likely to report taking statins for primary cardiovascular prevention than those with higher education, but an equivalent increase in underlying cardiovascular risk. METHODS: Using data from a large prospective cohort study, UK Biobank, we calculated a QRISK3 cardiovascular risk score for 472 097 eligible participants with complete data on self-reported educational attainment and statin use (55% female participants; mean age 56 years). We used logistic regression to explore the association between (i) QRISK3 score and (ii) educational attainment on self-reported statin use. We then stratified the association between QRISK3 score and statin use, by educational attainment to test for interactions. RESULTS: There was evidence of an interaction between QRISK3 score and educational attainment. Per unit increase in QRISK3 score, more educated individuals were more likely to report taking statins. In women with ≤7 years of schooling, a one unit increase in QRISK3 score was associated with a 7% higher odds of statin use (OR 1.07, 95% CI 1.07 to 1.07). In women with ≥20 years of schooling, a one unit increase in QRISK3 score was associated with an 14% higher odds of statin use (OR 1.14, 95% CI 1.14 to 1.15). Comparable ORs in men were 1.04 (95% CI 1.04 to 1.05) for ≤7 years of schooling and 1.08 (95% CI 1.08, 1.08) for ≥20 years of schooling. CONCLUSION: Per unit increase in QRISK3 score, individuals with lower educational attainment were less likely to report using statins, likely contributing to health inequalities

Transit Timing and Duration Variations for the Discovery and Characterization of Exoplanets

Transiting exoplanets in multi-planet systems have non-Keplerian orbits which can cause the times and durations of transits to vary. The theory and observations of transit timing variations (TTV) and transit duration variations (TDV) are reviewed. Since the last review, the Kepler spacecraft has detected several hundred perturbed planets. In a few cases, these data have been used to discover additional planets, similar to the historical discovery of Neptune in our own Solar System. However, the more impactful aspect of TTV and TDV studies has been characterization of planetary systems in which multiple planets transit. After addressing the equations of motion and parameter scalings, the main dynamical mechanisms for TTV and TDV are described, with citations to the observational literature for real examples. We describe parameter constraints, particularly the origin of the mass/eccentricity degeneracy and how it is overcome by the high-frequency component of the signal. On the observational side, derivation of timing precision and introduction to the timing diagram are given. Science results are reviewed, with an emphasis on mass measurements of transiting sub-Neptunes and super-Earths, from which bulk compositions may be inferred.Comment: Revised version. Invited review submitted to 'Handbook of Exoplanets,' Exoplanet Discovery Methods section, Springer Reference Works, Juan Antonio Belmonte and Hans Deeg, Eds. TeX and figures may be found at https://github.com/ericagol/TTV_revie

Vulnerability of drug‐resistant EML4‐ALK rearranged lung cancer to transcriptional inhibition

A subset of lung adenocarcinomas is driven by the EML4‐ALK translocation. Even though ALK inhibitors in the clinic lead to excellent initial responses, acquired resistance to these inhibitors due to on‐target mutations or parallel pathway alterations is a major clinical challenge. Exploring these mechanisms of resistance, we found that EML4‐ALK cells parental or resistant to crizotinib, ceritinib or alectinib are remarkably sensitive to inhibition of CDK7/12 with THZ1 and CDK9 with alvocidib or dinaciclib. These compounds robustly induce apoptosis through transcriptional inhibition and downregulation of anti‐apoptotic genes. Importantly, alvocidib reduced tumour progression in xenograft mouse models. In summary, our study takes advantage of the transcriptional addiction hypothesis to propose a new treatment strategy for a subset of patients with acquired resistance to first‐, second‐ and third‐generation ALK inhibitors