Exhaustive assignment of compositional bias reveals universally prevalent biased regions: analysis of functional associations in human and Drosophila

BACKGROUND: Compositionally biased (CB) regions are stretches in protein sequences made from mainly a distinct subset of amino acid residues; such regions are frequently associated with a structural role in the cell, or with protein disorder. RESULTS: We derived a procedure for the exhaustive assignment and classification of CB regions, and have applied it to thirteen metazoan proteomes. Sequences are initially scanned for the lowest-probability subsequences (LPSs) for single amino-acid types; subsequently, an exhaustive search for lowest probability subsequences (LPSs) for multiple residue types is performed iteratively until convergence, to define CB region boundaries. We analysed > 40,000 CB regions with > 20 million residues; strikingly, nine single-/double- residue biases are universally abundant, and are consistently highly ranked across both vertebrates and invertebrates. To home in subpopulations of CB regions of interest in human and D. melanogaster, we analysed CB region lengths, conservation, inferred functional categories and predicted protein disorder, and filtered for coiled coils and protein structures. In particular, we found that some of the universally abundant CB regions have significant associations to transcription and nuclear localization in Human and Drosophila, and are also predicted to be moderately or highly disordered. Focussing on Q-based biased regions, we found that these regions are typically only well conserved within mammals (appearing in 60–80% of orthologs), with shorter human transcription-related CB regions being unconserved outside of mammals; they are also preferentially linked to protein domains such as the homeodomain and glucocorticoid-receptor DNA-binding domain. In general, only ~40–50% of residues in these human and Drosophila CB regions have predicted protein disorder. CONCLUSION: This data is of use for the further functional characterization of genes, and for structural genomics initiatives

Suitability of PSA-detected localised prostate cancers for focal therapy: Experience from the ProtecT study

This article is available through a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. Copyright @ 2011 Cancer Research UK.Background: Contemporary screening for prostate cancer frequently identifies small volume, low-grade lesions. Some clinicians have advocated focal prostatic ablation as an alternative to more aggressive interventions to manage these lesions. To identify which patients might benefit from focal ablative techniques, we analysed the surgical specimens of a large sample of population-detected men undergoing radical prostatectomy as part of a randomised clinical trial. Methods: Surgical specimens from 525 men who underwent prostatectomy within the ProtecT study were analysed to determine tumour volume, location and grade. These findings were compared with information available in the biopsy specimen to examine whether focal therapy could be provided appropriately. Results: Solitary cancers were found in prostatectomy specimens from 19% (100 out of 525) of men. In addition, 73 out of 425 (17%) men had multiple cancers with a solitary significant tumour focus. Thus, 173 out of 525 (33%) men had tumours potentially suitable for focal therapy. The majority of these were small, well-differentiated lesions that appeared to be pathologically insignificant (38–66%). Criteria used to select patients for focal prostatic ablation underestimated the cancer's significance in 26% (34 out of 130) of men and resulted in overtreatment in more than half. Only 18% (24 out of 130) of men presumed eligible for focal therapy, actually had significant solitary lesions. Conclusion: Focal therapy appears inappropriate for the majority of men presenting with prostate-specific antigen-detected localised prostate cancer. Unifocal prostate cancers suitable for focal ablation are difficult to identify pre-operatively using biopsy alone. Most lesions meeting criteria for focal ablation were either more aggressive than expected or posed little threat of progression.National Institute for Health Researc

Prevalence and risk factors of restrictive spirometry in a cohort of Peruvian adults

INTRODUCTION: Few studies have described the prevalence of and lung function decline among those with a restrictive spirometric pattern (RSP) in low- and middle-income countries. METHODS: We analyzed prospective data from 3055 adults recruited across four diverse settings in Peru over a 3-year period. Multivariable logistic regression was used to study the association between the presence of restriction and associated risk factors. Multivariable linear mixed models were used to determine lung function decline. RESULTS: Among 3055 participants, the average age was 55.4 years (SD 12.4); 49% were male. Overall prevalence of RSP was 4.7%, ranging from 2.8% (Lima) to 6.9% (Tumbes). The odds of having RSP were higher among those who lived in a rural environment (OR 2.19, 95%CI 1.43–3.37), had a diagnosis of diabetes (OR 1.94, 95%CI 1.10–3.40) and among women (OR 2.09, 95%CI 1.41–3.09). When adjusting for baseline lung function, adults with RSP had accelerated decline in forced expiratory volume in 1 s (FEV1) compared with non-obstructed, non-restricted individuals. DISCUSSION: RSP is prevalent particularly among women and in individuals living in rural settings of Peru. When adjusted for baseline lung function, participants with RSP had accelerated rates of FEV1 decline. Our findings are consistent with the notion that RSP is an insidious inflammatory condition with deleterious effects of lung function decline

Formation of Supermassive Black Holes

Evidence shows that massive black holes reside in most local galaxies. Studies have also established a number of relations between the MBH mass and properties of the host galaxy such as bulge mass and velocity dispersion. These results suggest that central MBHs, while much less massive than the host (~ 0.1%), are linked to the evolution of galactic structure. In hierarchical cosmologies, a single big galaxy today can be traced back to the stage when it was split up in hundreds of smaller components. Did MBH seeds form with the same efficiency in small proto-galaxies, or did their formation had to await the buildup of substantial galaxies with deeper potential wells? I briefly review here some of the physical processes that are conducive to the evolution of the massive black hole population. I will discuss black hole formation processes for `seed' black holes that are likely to place at early cosmic epochs, and possible observational tests of these scenarios.Comment: To appear in The Astronomy and Astrophysics Review. The final publication is available at http://www.springerlink.co

The proper name as starting point for basic reading skills

Does alphabetic-phonetic writing start with the proper name and how does the name affect reading and writing skills? Sixty 4- to 5½-year-old children from middle SES families with Dutch as their first language wrote their proper name and named letters. For each child we created unique sets of words with and without the child’s first letter of the name to test spelling skills and phonemic sensitivity. Name writing correlated with children’s knowledge of the first letter of the name and phonemic sensitivity for the sound of the first letter of the name. Hierarchical regression analysis makes plausible that both knowledge of the first letter’s name and phonemic sensitivity for this letter explain why name writing results in phonetic spelling with the name letter. Practical implications of the findings are discussed

Cerebral activations related to ballistic, stepwise interrupted and gradually modulated movements in parkinson patients

Patients with Parkinson's disease (PD) experience impaired initiation and inhibition of movements such as difficulty to start/stop walking. At single-joint level this is accompanied by reduced inhibition of antagonist muscle activity. While normal basal ganglia (BG) contributions to motor control include selecting appropriate muscles by inhibiting others, it is unclear how PD-related changes in BG function cause impaired movement initiation and inhibition at single-joint level. To further elucidate these changes we studied 4 right-hand movement tasks with fMRI, by dissociating activations related to abrupt movement initiation, inhibition and gradual movement modulation. Initiation and inhibition were inferred from ballistic and stepwise interrupted movement, respectively, while smooth wrist circumduction enabled the assessment of gradually modulated movement. Task-related activations were compared between PD patients (N = 12) and healthy subjects (N = 18). In healthy subjects, movement initiation was characterized by antero-ventral striatum, substantia nigra (SN) and premotor activations while inhibition was dominated by subthalamic nucleus (STN) and pallidal activations, in line with the known role of these areas in simple movement. Gradual movement mainly involved antero-dorsal putamen and pallidum. Compared to healthy subjects, patients showed reduced striatal/SN and increased pallidal activation for initiation, whereas for inhibition STN activation was reduced and striatal-thalamo-cortical activation increased. For gradual movement patients showed reduced pallidal and increased thalamo-cortical activation. We conclude that PD-related changes during movement initiation fit the (rather static) model of alterations in direct and indirect BG pathways. Reduced STN activation and regional cortical increased activation in PD during inhibition and gradual movement modulation are better explained by a dynamic model that also takes into account enhanced responsiveness to external stimuli in this disease and the effects of hyper-fluctuating cortical inputs to the striatum and STN in particular

Aquaporin 5 Polymorphisms and Rate of Lung Function Decline in Chronic Obstructive Pulmonary Disease

RATIONALE: Aquaporin-5 (AQP5) can cause mucus overproduction and lower lung function. Genetic variants in the AQP5 gene might be associated with rate of lung function decline in chronic obstructive pulmonary disease (COPD). METHODS: Five single nucleotide polymorphisms (SNPs) in AQP5 were genotyped in 429 European American individuals with COPD randomly selected from the NHLBI Lung Health Study. Mean annual decline in FEV(1) % predicted, assessed over five years, was calculated as a linear regression slope, adjusting for potential covariates and stratified by smoking status. Constructs containing the wildtype allele and risk allele of the coding SNP N228K were generated using site-directed mutagenesis, and transfected into HBE-16 (human bronchial epithelial cell line). AQP5 abundance and localization were assessed by immunoblots and confocal immunofluorescence under control, shear stress and cigarette smoke extract (CSE 10%) exposed conditions to test for differential expression or localization. RESULTS: Among continuous smokers, three of the five SNPs tested showed significant associations (0.02>P>0.004) with rate of lung function decline; no associations were observed among the group of intermittent or former smokers. Haplotype tests revealed multiple association signals (0.012>P>0.0008) consistent with the single-SNP results. In HBE16 cells, shear stress and CSE led to a decrease in AQP5 abundance in the wild-type, but not in the N228K AQP5 plasmid. CONCLUSIONS: Polymorphisms in AQP5 were associated with rate of lung function decline in continuous smokers with COPD. A missense mutation modulates AQP-5 expression in response to cigarette smoke extract and shear stress. These results suggest that AQP5 may be an important candidate gene for COPD

The challenges of transferring chronic illness patients to adult care: reflections from pediatric and adult rheumatology at a US academic center

<p>Abstract</p> <p>Background</p> <p>Little is known about the transfer of care process from pediatric to adult rheumatology for patients with chronic rheumatic disease. The purpose of this study is to examine changes in disease status, treatment and health care utilization among adolescents transferring to adult care at the University of California San Francisco (UCSF).</p> <p>Methods</p> <p>We identified 31 eligible subjects who transferred from pediatric to adult rheumatology care at UCSF between 1995–2005. Subject demographics, disease characteristics, disease activity and health care utilization were compared between the year prior to and the year following transfer of care.</p> <p>Results</p> <p>The mean age at the last pediatric rheumatology visit was 19.5 years (17.4–22.0). Subject diagnoses included systemic lupus erythematosus (52%), mixed connective tissue disease (16%), juvenile idiopathic arthritis (16%), antiphospholipid antibody syndrome (13%) and vasculitis (3%). Nearly 30% of subjects were hospitalized for disease treatment or management of flares in the year prior to transfer, and 58% had active disease at the time of transfer. In the post-transfer period, almost 30% of subjects had an increase in disease activity. One patient died in the post-transfer period. The median transfer time between the last pediatric and first adult rheumatology visit was 7.1 months (range 0.7–33.6 months). Missed appointments were common in the both the pre and post transfer period.</p> <p>Conclusion</p> <p>A significant percentage of patients who transfer from pediatric to adult rheumatology care at our center are likely to have active disease at the time of transfer, and disease flares are common during the transfer period. These findings highlight the importance of a seamless transfer of care between rheumatology providers.</p