Targeted Assembly of Short Sequence Reads

As next-generation sequence (NGS) production continues to increase, analysis is becoming a significant bottleneck. However, in situations where information is required only for specific sequence variants, it is not necessary to assemble or align whole genome data sets in their entirety. Rather, NGS data sets can be mined for the presence of sequence variants of interest by localized assembly, which is a faster, easier, and more accurate approach. We present TASR, a streamlined assembler that interrogates very large NGS data sets for the presence of specific variants, by only considering reads within the sequence space of input target sequences provided by the user. The NGS data set is searched for reads with an exact match to all possible short words within the target sequence, and these reads are then assembled strin-gently to generate a consensus of the target and flanking sequence. Typically, variants of a particular locus are provided as different target sequences, and the presence of the variant in the data set being interrogated is revealed by a successful assembly outcome. However, TASR can also be used to find unknown sequences that flank a given target. We demonstrate that TASR has utility in finding or confirming ge-nomic mutations, polymorphism, fusion and integration events. Targeted assembly is a powerful method for interrogating large data sets for the presence of sequence variants of interest. TASR is a fast, flexible and easy to use tool for targeted assembly

PB.23: Effect of detector type on cancer detection in digital mammography

This work measured the effect that image quality associated with different detectors has on cancer detection in mammography using a novel method for changing the appearance of images.\ud \ud A set of 270 mammography cases (one view, both breasts) was acquired using five Hologic Selenias and two Hologic Dimensions X-ray units: 80 normal, 80 with simulated inserted subtle calcification clusters, 80 with subtle real noncalcification malignant lesions and 30 with benign lesions (biopsy proven). These 270 cases (Arm 1) were converted to appear as if they had been acquired on two other imaging systems: needle image plate computed radiography (CR) (Arm 2) and powder phosphor CR (Arm 3). Three experienced mammography readers marked the location of suspected cancers in the images and classified whether each lesion would require further investigation and the confidence in that decision. Performance was calculated as the area under curve (AUC) of the alternative free-response receiver operating characteristic curv

Monkey Steering Responses Reveal Rapid Visual-Motor Feedback

The neural mechanisms underlying primate locomotion are largely unknown. While behavioral and theoretical work has provided a number of ideas of how navigation is controlled, progress will require direct physiolgical tests of the underlying mechanisms. In turn, this will require development of appropriate animal models. We trained three monkeys to track a moving visual target in a simple virtual environment, using a joystick to control their direction. The monkeys learned to quickly and accurately turn to the target, and their steering behavior was quite stereotyped and reliable. Monkeys typically responded to abrupt steps of target direction with a biphasic steering movement, exhibiting modest but transient overshoot. Response latencies averaged approximately 300 ms, and monkeys were typically back on target after about 1 s. We also exploited the variability of responses about the mean to explore the time-course of correlation between target direction and steering response. This analysis revealed a broad peak of correlation spanning approximately 400 ms in the recent past, during which steering errors provoke a compensatory response. This suggests a continuous, visual-motor loop controls steering behavior, even during the epoch surrounding transient inputs. Many results from the human literature also suggest that steering is controlled by such a closed loop. The similarity of our results to those in humans suggests the monkey is a very good animal model for human visually guided steering

Pathological Investigation of Congenital Bicuspid Aortic Valve Stenosis, Compared with Atherosclerotic Tricuspid Aortic Valve Stenosis and Congenital Bicuspid Aortic Valve Regurgitation

Congenital bicuspid aortic valve (CBAV) is the main cause of aortic stenosis (AS) in young adults. However, the histopathological features of AS in patients with CBAV have not been fully investigated.We examined specimens of aortic valve leaflets obtained from patients who had undergone aortic valve re/placement at our institution for severe AS with CBAV (n = 24, CBAV-AS group), severe AS with tricuspid aortic valve (n = 24, TAV-AS group), and severe aortic regurgitation (AR) with CBAV (n = 24, CBAV-AR group). We compared the histopathological features among the three groups. Pathological features were classified using semi-quantitative methods (graded on a scale 0 to 3) by experienced pathologists without knowledge of the patients' backgrounds. The severity of inflammation, neovascularization, and calcium and cholesterol deposition did not differ between the CBAV-AS and TAV-AS groups, and these four parameters were less marked in the CBAV-AR group than in the CBAV-AS (all p<0.01). Meanwhile, the grade of valvular fibrosis was greater in the CBAV-AS group, compared with the TAV-AS and CBAV-AR groups (both p<0.01). In AS patients, thickness of fibrotic lesions was greater on the aortic side than on the ventricular side (both p<0.01). Meanwhile, thickness of fibrotic lesions was comparable between the aortic and ventricular sides in CBAV-AR patients (p = 0.35).Valvular fibrosis, especially on the aortic side, was greater in patients with CBAV-AS than in those without, suggesting a difference in the pathogenesis of AS between CBAV and TAV

Gender specific factors associated with having stopped smoking among in-school adolescents in Ukraine: results from the Global Youth Tobacco Survey 2005

<p>Abstract</p> <p>Background</p> <p>The prevalence of cigarette smoking in Ukraine is different between genders and is among the highest in the world. There is need to identify gender-specific factors that are associated with having stopped smoking among adolescents.</p> <p>Findings</p> <p>We used data from the Ukraine Global Youth Tobacco Survey 2005. We carried out a backward stepwise logistic regression analysis with having stopped smoking as the outcome.</p> <p>Altogether, 2800 adolescents reported having ever smoked cigarettes. Overall 64.1% (63.4% male, and 65.5% female) adolescents reported having stopped smoking. Male adolescents who stated that smoking decreases body weight were 25% more likely, while female adolescents were 9% less likely to stop smoking. While male adolescents who received support on how to stop smoking from a family member were 7% less likely, female adolescents were 60% more likely to stop smoking. Furthermore, while male adolescents who received a lecture on the harmful effects of smoking were 10% less likely, female adolescents were 9% more likely to stop smoking. Finally both male and female adolescents who were sure or most probably that they would not smoke a cigarette offered to them by their best friends were more likely, and those adolescents who were sure that smoking is harmful to health were less likely to stop smoking.</p> <p>Conclusions</p> <p>Our study has identified some factors that are associated with having quit smoking that are gender-specific. We believe public health programs targeting adolescent smoking should consider these factors in their design and implementation of gender sensitive interventions.</p

Computer-assisted mammographic imaging

Computer-assisted mammography imaging comprises computer-based analysis of digitized images resulting in prompts aiding mammographic interpretation and computerized stereotactic localization devices which improve location accuracy. The commercial prompting systems available are designed to draw attention to mammographic abnormalities detected by algorithms based on symptomatic practise in North America. High sensitivity rates are important commercially but result in increased false prompt rates, which are known to distract radiologists. A national shortage of breast radiologists in the UK necessitates evaluation of such systems in a population breast screening programme to determine effectiveness in increasing cancer detection and feasibility of implementation

Biomarkers in dementia: clinical utility and new directions.

Imaging, cerebrospinal fluid (CSF) and blood-based biomarkers have the potential to improve the accuracy by which specific causes of dementia can be diagnosed in vivo, provide insights into the underlying pathophysiology, and may be used as inclusion criteria and outcome measures for clinical trials. While a number of imaging and CSF biomarkers are currently used for each of these purposes, this is an evolving field, with numerous potential biomarkers in varying stages of research and development. We review the currently available biomarkers for the three most common forms of neurodegenerative dementia, and give an overview of research techniques that may in due course make their way into the clinic

SALL4 Expression in Gonocytes and Spermatogonial Clones of Postnatal Mouse Testes

The spermatogenic lineage is established after birth when gonocytes migrate to the basement membrane of seminiferous tubules and give rise to spermatogonial stem cells (SSC). In adults, SSCs reside within the population of undifferentiated spermatogonia (Aundiff) that expands clonally from single cells (Asingle) to form pairs (Apaired) and chains of 4, 8 and 16 Aaligned spermatogonia. Although stem cell activity is thought to reside in the population of Asingle spermatogonia, new research suggests that clone size alone does not define the stem cell pool. The mechanisms that regulate self-renewal and differentiation fate decisions are poorly understood due to limited availability of experimental tools that distinguish the products of those fate decisions. The pluripotency factor SALL4 (sal-like protein 4) is implicated in stem cell maintenance and patterning in many organs during embryonic development, but expression becomes restricted to the gonads after birth. We analyzed the expression of SALL4 in the mouse testis during the first weeks after birth and in adult seminiferous tubules. In newborn mice, the isoform SALL4B is expressed in quiescent gonocytes at postnatal day 0 (PND0) and SALL4A is upregulated at PND7 when gonocytes have colonized the basement membrane and given rise to spermatogonia. During steady-state spermatogenesis in adult testes, SALL4 expression overlapped substantially with PLZF and LIN28 in Asingle, Apaired and Aaligned spermatogonia and therefore appears to be a marker of undifferentiated spermatogonia in mice. In contrast, co-expression of SALL4 with GFRα1 and cKIT identified distinct subpopulations of Aundiff in all clone sizes that might provide clues about SSC regulation. Collectively, these results indicate that 1) SALL4 isoforms are differentially expressed at the initiation of spermatogenesis, 2) SALL4 is expressed in undifferentiated spermatogonia in adult testes and 3) SALL4 co-staining with GFRα1 and cKIT reveals distinct subpopulations of Aundiff spermatogonia that merit further investigation. © 2013 Gassei, Orwig

Extending colonic mucosal microbiome analysis - Assessment of colonic lavage as a proxy for endoscopic colonic biopsies

This study was supported through GI Research funds and MRC Grant Ref: MR/M00533X/1 to GH.Peer reviewedPublisher PD

The Pharmacogenetics of Statin Therapy on Clinical Events: No Evidence that Genetic Variation Affects Statin Response on Myocardial Infarction

Background: The pharmacogenetic effect on cardiovascular disease reduction in response to statin treatment has only been assessed in small studies. In a pharmacogenetic genome wide association study (GWAS) analysis within the Genomic Investigation of Statin Therapy (GIST) consortium, we investigated whether genetic variation was associated with the response of statins on cardiovascular disease risk reduction. Methods: The investigated endpoint was incident myocardial infarction (MI) defined as coronary heart disease death and definite and suspect non-fatal MI. For imputed single nucleotide polymorphisms (SNPs), regression analysis was performed on expected allelic dosage and meta-analysed with a fixed-effects model, inverse variance weighted meta-analysis. All SNPs with p-values <5.0 × 10(−4) in stage 1 GWAS meta-analysis were selected for further investigation in stage-2. As a secondary analysis, we extracted SNPs from the Stage-1 GWAS meta-analysis results based on predefined hypotheses to possibly modifying the effect of statin therapy on MI. Results: In stage-1 meta-analysis (eight studies, n = 10,769, 4,212 cases), we observed no genome-wide significant results (p < 5.0 × 10(−8)). A total of 144 genetic variants were followed-up in the second stage (three studies, n = 1,525, 180 cases). In the combined meta-analysis, no genome-wide significant hits were identified. Moreover, none of the look-ups of SNPs known to be associated with either CHD or with statin response to cholesterol levels reached Bonferroni level of significance within our stage-1 meta-analysis. Conclusion: This GWAS analysis did not provide evidence that genetic variation affects statin response on cardiovascular risk reduction. It does not appear likely that genetic testing for predicting effects of statins on clinical events will become a useful tool in clinical practice