Activation-induced deoxycytidine deaminase (AID) co-transcriptional scanning at single-molecule resolution

Activation-induced deoxycytidine deaminase (AID) generates antibody diversity in B cells by initiating somatic hypermutation (SHM) and class-switch recombination (CSR) during transcription of immunoglobulin variable (IgV) and switch region (IgS) DNA. Using single-molecule FRET, we show that AID binds to transcribed dsDNA and translocates unidirectionally in concert with RNA polymerase (RNAP) on moving transcription bubbles, while increasing the fraction of stalled bubbles. AID scans randomly when constrained in an 8 nt model bubble. When unconstrained on single-stranded (ss) DNA, AID moves in random bidirectional short slides/hops over the entire molecule while remaining bound for ~5 min. Our analysis distinguishes dynamic scanning from static ssDNA creasing. That AID alone can track along with RNAP during transcription and scan within stalled transcription bubbles suggests a mechanism by which AID can initiate SHM and CSR when properly regulated, yet when unregulated can access non-Ig genes and cause cancer

Impact of offering cycle training in schools upon cycling behaviour: a natural experimental study.

BACKGROUND: England's national cycle training scheme, 'Bikeability', aims to give children in England the confidence to cycle more. There is, however, little evidence on the effectiveness of cycle training in achieving this. We therefore examined whether delivering Bikeability was associated with cycling frequency or with independent cycling. METHODS: We conducted a natural experimental study using information on children aged 10-11 years participating in the nationally-representative Millennium Cohort Study. We identified Cohort participants whose schools had offered Bikeability in 2011-2012 using operational Bikeability delivery data (children in London excluded, as delivery data not available). Our natural experimental design capitalised on the fact that Cohort participants were surveyed at different times during 2012 and were also offered Bikeability at different times during 2012. This allowed us to compare cycling levels between children whose schools delivered Bikeability before their survey interview ('intervention group', N = 2563) and an otherwise comparable group of children whose schools delivered Bikeability later in the year ('control group', N = 773). Parents reported whether their child had completed formal cycle training; their child's cycling frequency; whether their child ever made local cycling trips without an adult; and other child and family factors. We used Poisson regression with robust standard errors to examine whether cycling behaviour differed between the intervention and control groups. RESULTS: Children whose school had offered Bikeability were much more likely to have completed cycle training than the control group (68% vs. 28%, p < 0.001). There was, however, no evidence that delivering Bikeability in school was associated with cycling more often (49.0% cycling at least once per week in the intervention group vs. 49.6% in the control group; adjusted risk ratio 0.99, 95% CI 0.89, 1.10). There was likewise no evidence of an association with cycling independently (51.5% in the intervention group vs. 50.1% in the control group; adjusted risk ratio 0.97, 95% CI 0.89, 1.06). CONCLUSIONS: Offering high-quality cycle training free at the point of delivery in English schools encourages children to do cycle training, but we found no evidence of short-term effects on cycling frequency or independent cycling. Future evaluation should investigate longer-term effects on these and other stated Bikeability objectives such as increasing cycling safety.This study was funded by the Economic and Social Research Council (ESRC: grant no.ES/L013606/1). DO and EvS are also supported by the Medical Research Council (Unit Programme numbers MC_UU_12015/6; MC_UU_12015/7). The contributions of DO and EvS were undertaken under the auspices of the Centre for Diet and Activity Research (CEDAR), a UKCRC Public Health Research Centre of Excellence which is funded by the British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, the National Institute for Health Research, and the Wellcome Trust. The views presented here are those of the authors, and do not necessarily reflect those of the ESRC or the Department for TransportThis is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s12966-016-0356-

Eye-Tracking Causality

How do people make causal judgments? What role, if any, does counterfactual simulation play? Counterfactual theories of causal judgments predict that people compare what actually happened with what would have happened if the candidate cause had been absent. Process theories predict that people focus only on what actually happened, to assess the mechanism linking candidate cause and outcome. We tracked participants' eye movements while they judged whether one billiard ball caused another one to go through a gate or prevented it from going through. Both participants' looking patterns and their judgments demonstrated that counterfactual simulation played a critical role. Participants simulated where the target ball would have gone if the candidate cause had been removed from the scene. The more certain participants were that the outcome would have been different, the stronger the causal judgments. These results provide the first direct evidence for spontaneous counterfactual simulation in an important domain of high-level cognition

In vitro mutation artifacts after formalin fixation and error prone translesion synthesis during PCR

BACKGROUND: Clinical specimens are routinely fixed in 10% buffered formalin and paraffin embedded. Although DNA is commonly extracted from fixed tissues and amplified by PCR, the effects of formalin fixation are relatively unknown. Formalin fixation is known to impair PCR, presumably through damage that blocks polymerase elongation, but an insidious possibility is error prone translesion synthesis across sites of damage, producing in vitro artifactual mutations during PCR. METHODS: To better understand the consequences of fixation, DNA specimens extracted from fresh or fixed tissues were amplified with Taq DNA polymerase, and their PCR products were cloned and sequenced. RESULTS: Significantly more (3- to 4-fold) mutations were observed with fixed DNA specimens. The majority of mutations were transitions, predominantly at A:T base pairs, randomly distributed along the template. CONCLUSIONS: Formalin fixation appears to cause random base damage, which can be bridged during PCR by Taq DNA polymerase through error prone translesion synthesis. Fixed DNA is a damaged but "readable" template

Calcium Phosphate Metabolism and Cardiovascular Disease in Patients with Chronic Kidney Disease

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73791/1/j.1525-139X.2003.160301.x.pd

Albumin-based cancer therapeutics for intraperitoneal drug delivery : a review

Albumin is a remarkable carrier protein with multiple cellular receptor and ligand binding sites, which are able to bind and transport numerous endogenous and exogenous compounds. The development of albumin-bound drugs is gaining increased importance in the targeted delivery of cancer therapy. Intraperitoneal (IP) drug delivery represents an attractive strategy for the local treatment of peritoneal metastasis (PM). PM is characterized by the presence of widespread metastatic tumor nodules on the peritoneum, mostly originating from gastro-intestinal or gynaecological cancers. Albumin as a carrier for chemotherapy holds considerable promise for IP delivery in patients with PM. Data from recent (pre)clinical trials suggest that IP albumin-bound chemotherapy may result in superior efficacy in the treatment of PM compared to standard chemotherapy formulations. Here, we review the evidence on albumin-bound chemotherapy with a focus on IP administration and its efficacy in PM

Implementation of routine outcome measurement in child and adolescent mental health services in the United Kingdom: a critical perspective

The aim of this commentary is to provide an overview of clinical outcome measures that are currently recommended for use in UK Child and Adolescent Mental Health Services (CAMHS), focusing on measures that are applicable across a wide range of conditions with established validity and reliability, or innovative in their design. We also provide an overview of the barriers and drivers to the use of Routine Outcome Measurement (ROM) in clinical practice

A Systematic Review of Online Sex Addiction and Clinical Treatments Using CONSORT Evaluation

Researchers have suggested that the advances of the Internet over the past two decades have gradually eliminated traditional offline methods of obtaining sexual material. Additionally, research on cybersex and/or online sex addictions has increased alongside the development of online technology. The present study extended the findings from Griffiths’ (2012) systematic empirical review of online sex addiction by additionally investigating empirical studies that implemented and/or documented clinical treatments for online sex addiction in adults. A total of nine studies were identified and then each underwent a CONSORT evaluation. The main findings of the present review provide some evidence to suggest that some treatments (both psychological and/or pharmacological) provide positive outcomes among those experiencing difficulties with online sex addiction. Similar to Griffiths’ original review, this study recommends that further research is warranted to establish the efficacy of empirically driven treatments for online sex addiction

Mosaic DNA imports with interspersions of recipient sequence after natural transformation of Helicobacter pylori

Helicobacter pylori colonizes the gastric mucosa of half of the human population, causing gastritis, ulcers, and cancer. H. pylori is naturally competent for transformation by exogenous DNA, and recombination during mixed infections of one stomach with multiple H. pylori strains generates extensive allelic diversity. We developed an in vitro transformation protocol to study genomic imports after natural transformation of H. pylori. The mean length of imported fragments was dependent on the combination of donor and recipient strain and varied between 1294 bp and 3853 bp. In about 10% of recombinant clones, the imported fragments of donor DNA were interrupted by short interspersed sequences of the recipient (ISR) with a mean length of 82 bp. 18 candidate genes were inactivated in order to identify genes involved in the control of import length and generation of ISR. Inactivation of the antimutator glycosylase MutY increased the length of imports, but did not have a significant effect on ISR frequency. Overexpression of mutY strongly increased the frequency of ISR, indicating that MutY, while not indispensable for ISR formation, is part of at least one ISR-generating pathway. The formation of ISR in H. pylori increases allelic diversity, and contributes to the uniquely low linkage disequilibrium characteristic of this pathogen

A single low-energy, iron-poor supernova as the source of metals in the star SMSS J 031300.36-670839.3

The element abundance ratios of four low-mass stars with extremely low metallicities indicate that the gas out of which the stars formed was enriched in each case by at most a few, and potentially only one low-energy, supernova. Such supernovae yield large quantities of light elements such as carbon but very little iron. The dominance of low-energy supernovae is surprising, because it has been expected that the first stars were extremely massive, and that they disintegrated in pair-instability explosions that would rapidly enrich galaxies in iron. What has remained unclear is the yield of iron from the first supernovae, because hitherto no star is unambiguously interpreted as encapsulating the yield of a single supernova. Here we report the optical spectrum of SMSS J031300.36- 670839.3, which shows no evidence of iron (with an upper limit of 10^-7.1 times solar abundance). Based on a comparison of its abundance pattern with those of models, we conclude that the star was seeded with material from a single supernova with an original mass of ~60 Mo (and that the supernova left behind a black hole). Taken together with the previously mentioned low-metallicity stars, we conclude that low-energy supernovae were common in the early Universe, and that such supernovae yield light element enrichment with insignificant iron. Reduced stellar feedback both chemically and mechanically from low-energy supernovae would have enabled first-generation stars to form over an extended period. We speculate that such stars may perhaps have had an important role in the epoch of cosmic reionization and the chemical evolution of early galaxies.Comment: 28 pages, 6 figures, Natur