A Ku Bridge over Broken DNA

AbstractThe Ku heterodimer is essential for the nonhomologous end-joining pathway of DNA double-strand break repair; it both protects the broken ends and recruits some of the many proteins required to complete repair. The recently determined structure of Ku provides insights into how it can both bind to the DNA ends and allow access by the other proteins required to rejoin them

RAG1/2-Mediated Resolution of Transposition Intermediates Two Pathways and Possible Consequences

AbstractDuring B and T cell development, the RAG1/RAG2 protein complex cleaves DNA at conserved recombination signal sequences (RSS) to initiate V(D)J recombination. RAG1/2 has also been shown to catalyze transpositional strand transfer of RSS-containing substrates into target DNA to form branched DNA intermediates. We show that RAG1/2 can resolve these intermediates by two pathways. RAG1/2 catalyzes hairpin formation on target DNA adjacent to transposed RSS ends in a manner consistent with a model leading to chromosome translocations. Alternatively, disintegration removes transposed donor DNA from the intermediate. At high magnesium concentrations, such as are present in mammalian cells, disintegration is the favored pathway of resolution. This may explain in part why RAG1/2-mediated transposition does not occur at high frequency in cells

Hearing-Related Health Among Adult American Indians From a Pacific Northwest Tribe

INTRODUCTION: Hearing loss and tinnitus are common in most populations, although few data have addressed hearing-related health among tribal members and the need for public health interventions. METHODS: This cross-sectional study examined prevalence and risk factors for hearing loss and tinnitus among 217 adults in a Pacific Northwest tribe. Frequency measures were conducted for difficulty hearing certain sounds and hearing aid use. In 2006, risk factors were examined for two outcomes-hearing loss and tinnitus-with analysis conducted in the same year. RESULTS: Although self-reported hearing loss was more common in men (24%) than women (13%), a larger percentage of women compared with men reported difficulty hearing certain sounds. Only 8% of study participants reported hearing aid use. After age adjustment, significant noise exposure was associated with hearing loss (OR=8.30, 95% CI=1.84, 37.52). The overall prevalence of tinnitus was 33% (similar in men and women). After adjusting for age, the odds of tinnitus in individuals with more than four ear infections was 4.77 (95% CI=1.89, 12.02) times the odds in those who never had an ear infection. Tinnitus was also associated with significant noise exposure (OR=2.24, 95% CI=1.28, 6.73) even after age adjustment. CONCLUSIONS: Increasing age and significant noise exposure were associated with hearing loss in this tribe. Tinnitus was associated with significant noise exposure and history of otitis media, even after age adjustment. Public health efforts are needed to improve hearing-related health in this tribe through messages about noise exposure and use of hearing protection

Cracking the DNA Code for V(D)J Recombination

To initiate V(D) J recombination for generating the adaptive immune response of vertebrates, RAG1/2 recombinase cleaves DNA at a pair of recombination signal sequences, the 12- and 23-RSS. We have determined crystal and cryo-EM structures of RAG1/2 with DNA in the pre-reaction and hairpinforming complexes up to 2.75 angstrom resolution. Both protein and DNA exhibit structural plasticity and undergo dramatic conformational changes. Coding-flank DNAs extensively rotate, shift, and deform for nicking and hairpin formation. Two intertwined RAG1 subunits crisscross four times between the asymmetric pair of severely bent 12/23-RSS DNAs. Location-sensitive bending of 60 degrees and 150 degrees in 12- and 23-RSS spacers, respectively, must occur for RAG1/2 to capture the nonamers and pair the hep-tamers for symmetric double-strand breakage. DNA pairing is thus sequence-context dependent and structure specific, which partly explains the "beyond 12/23'' restriction. Finally, catalysis in crystallo reveals the process of DNA hairpin formation and its stabilization by interleaved base stacking.116Ysciescopu

Experimental evidence for Tayler instability in a liquid metal column

In the current-driven, kink-type Tayler instability (TI) a sufficiently strong azimuthal magnetic field becomes unstable against non-axisymmetric perturbations. The TI has been discussed as a possible ingredient of the solar dynamo mechanism and a source of the helical structures in cosmic jets. It is also considered as a size limiting factor for liquid metal batteries. We report on a liquid metal TI experiment using a cylindrical column of the eutectic alloy GaInSn to which electrical currents of up to 8 kA are applied. We present results of external magnetic field measurements that indicate the occurrence of the TI in good agreement with numerical predictions. The interference of TI with the competing large scale convection, resulting from Joule heating, is also discussed.Comment: 4 pages, 5 figure

Mobility enhancement among older adults 75 + in rural areas: Study protocol of the MOBILE randomized controlled trial

Background: Maintaining mobility in old age is crucial for healthy ageing including delaying the onset and progress of frailty. However, the extent of an individuals' mobility relies largely on their personal, social, and environmental resources as outlined in the Life-Space Constriction Model. Recent studies mainly focus on facilitating habitual out-of-home mobility by fostering one type of resources only. The MOBILE trial aims at testing whether tablet-assisted motivational counselling enhances the mobility of community-dwelling older adults by addressing personal, social, and environmental resources. Methods: In the MOBILE randomized controlled trial, we plan to enrol 254 community-dwelling older adults aged 75 and older from Havelland, a rural area in Germany. The intervention group will receive a tablet-assisted motivational counselling at the participant's home and two follow-up telephone sessions. Main focus of the counselling sessions lays on setting and adapting individual mobility goals and applying action planning and habit formation strategies by incorporating the personal social network and regional opportunities for engaging in mobility related activities. The control group will receive postal general health information. The primary mobility outcome is time out-of-home assessed by GPS (GPS.Rec2.0-App) at three points in time (baseline, after one month, and after three months for seven consecutive days each). Secondary outcomes are the size of the GPS-derived life-space convex hull, self-reported life-space mobility (LSA-D), physical activity (IPAQ), depressive symptoms (GDS), frailty phenotype, and health status (SF-12). Discussion: The MOBILE trial will test the effect of a motivational counselling intervention on out-of-home mobility in community-dwelling older adults. Novel aspects of the MOBILE trial include the preventive multi-level intervention approach in combination with easy-to-use technology. The ecological approach ensures low-threshold implementation, which increases the benefit for the people in the region

Differences Between US and UK Adults in Stroke Preparedness: Evidence From Parallel Population-Based Community Surveys

Background and Purpose—Although time-dependent treatment is available, most people delay contacting emergency medical services for stroke. Given differences in the healthcare system and public health campaigns, exploring between-country differences in stroke preparedness may identify novel ways to increase acute stroke treatment.  Methods—A survey was mailed to population-based samples in Ingham County, Michigan, US (n=2500), and Newcastle upon Tyne, UK (n=2500). Surveys included stroke perceptions and stroke/nonstroke scenarios to assess recognition and response to stroke. Between-country differences and associations with stroke preparedness were examined usingttests and linear mixed models.  Results—Overall response rate was 27.4%. The mean age of participants was 55 years, and 58% were female. US participants were better in recognizing stroke (70% versus 63%, d=0.27) and were more likely to call emergency medical services (55% versus 52%, d=0.11). After controlling for demographics and comorbidities, US participants remained more likely to recognize stroke but were not more likely to respond appropriately. A greater belief that medical treatment can help with stroke and understanding of stroke was associated with improved stroke recognition and response.  Conclusions—Overall, stroke recognition and response were moderate. US participants were modestly better at recognising stroke, although there was little difference in response to stroke. Future stroke awareness interventions could focus more on stroke outcome expectations and developing a greater understanding of stroke among the public

The stroke ‘Act FAST’ campaign: Remembered but not understood?

Background: The stroke awareness raising campaign ‘Act FAST' (Face, Arms, Speech: Time to call Emergency Medical Services) has been rolled out in multiple waves in England, but impact on stroke recognition and response remains unclear. Purpose: The purpose of this study was to test whether providing knowledge of the FAST acronym through a standard Act FAST campaign leaflet increases accurate recognition and response in stroke-based scenario measures. Methods: This is a population-based, cross-sectional survey of adults in Newcastle upon Tyne, UK, sampled using the electoral register, with individuals randomized to receive a questionnaire and Act FAST leaflet (n = 2500) or a questionnaire only (n = 2500) in 2012. Campaign message retention, stroke recognition, and response measured through 16 scenario-based vignettes were assessed. Data were analyzed in 2013. Results: Questionnaire return rate was 32·3% (n = 1615). No differences were found between the leaflet and no-leaflet groups in return rate or demographics. Participants who received a leaflet showed better campaign recall (75·7% vs. 68·2%, P = 0·003) and recalled more FAST mnemonic elements (66·1% vs. 45·3% elements named correctly, P < 0·001). However, there were no between-group differences for stroke recognition and response to stroke-based scenarios (P > 0·05). Conclusions: Despite greater levels of recall of specific ‘Act FAST' elements among those receiving the Act FAST leaflet, there was no impact on stroke recognition and response measures