From Nonspecific DNA–Protein Encounter Complexes to the Prediction of DNA–Protein Interactions

©2009 Gao, Skolnick. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.doi:10.1371/journal.pcbi.1000341DNA–protein interactions are involved in many essential biological activities. Because there is no simple mapping code between DNA base pairs and protein amino acids, the prediction of DNA–protein interactions is a challenging problem. Here, we present a novel computational approach for predicting DNA-binding protein residues and DNA–protein interaction modes without knowing its specific DNA target sequence. Given the structure of a DNA-binding protein, the method first generates an ensemble of complex structures obtained by rigid-body docking with a nonspecific canonical B-DNA. Representative models are subsequently selected through clustering and ranking by their DNA–protein interfacial energy. Analysis of these encounter complex models suggests that the recognition sites for specific DNA binding are usually favorable interaction sites for the nonspecific DNA probe and that nonspecific DNA–protein interaction modes exhibit some similarity to specific DNA–protein binding modes. Although the method requires as input the knowledge that the protein binds DNA, in benchmark tests, it achieves better performance in identifying DNA-binding sites than three previously established methods, which are based on sophisticated machine-learning techniques. We further apply our method to protein structures predicted through modeling and demonstrate that our method performs satisfactorily on protein models whose root-mean-square Ca deviation from native is up to 5 Å from their native structures. This study provides valuable structural insights into how a specific DNA-binding protein interacts with a nonspecific DNA sequence. The similarity between the specific DNA–protein interaction mode and nonspecific interaction modes may reflect an important sampling step in search of its specific DNA targets by a DNA-binding protein

Effective Rheology of Bubbles Moving in a Capillary Tube

We calculate the average volumetric flux versus pressure drop of bubbles moving in a single capillary tube with varying diameter, finding a square-root relation from mapping the flow equations onto that of a driven overdamped pendulum. The calculation is based on a derivation of the equation of motion of a bubble train from considering the capillary forces and the entropy production associated with the viscous flow. We also calculate the configurational probability of the positions of the bubbles.Comment: 4 pages, 1 figur

Local Gene Regulation Details a Recognition Code within the LacI Transcriptional Factor Family

The specific binding of regulatory proteins to DNA sequences exhibits no clear patterns of association between amino acids (AAs) and nucleotides (NTs). This complexity of protein-DNA interactions raises the question of whether a simple set of wide-coverage recognition rules can ever be identified. Here, we analyzed this issue using the extensive LacI family of transcriptional factors (TFs). We searched for recognition patterns by introducing a new approach to phylogenetic footprinting, based on the pervasive presence of local regulation in prokaryotic transcriptional networks. We identified a set of specificity correlations –determined by two AAs of the TFs and two NTs in the binding sites– that is conserved throughout a dominant subgroup within the family regardless of the evolutionary distance, and that act as a relatively consistent recognition code. The proposed rules are confirmed with data of previous experimental studies and by events of convergent evolution in the phylogenetic tree. The presence of a code emphasizes the stable structural context of the LacI family, while defining a precise blueprint to reprogram TF specificity with many practical applications.Ministerio de Ciencia e Innovación, Spain (Formación de Profesorado Universitario fellowship)Ministerio de Ciencia e Innovación, Spain (grant BFU2008-03632/BMC)Madrid (Spain : Region) (grant CCG08-CSIC/SAL-3651

People and Things on the Move: Domestic Material Culture, Poverty and Mobility in Victorian London

© 2016, The Author(s). The development of what Mayne and Lawrence (Urban History 26: 325–48, 1999) termed “ethnographic” approaches to studying nineteenth-century households and urban communities has gathered momentum in recent years. As such research agendas have taken hold and been applied to new contexts, so critiques, methodological developments, and new intellectual and theoretical currents, have provided opportunities to enhance and develop approaches. This article contributes to this on-going process. Drawing upon household archaeological research on Limehouse, a poor neighborhood in Victorian London, and inspired by the theoretical insights provided by the “new mobilities paradigm,” it aims to place “mobility” as a central and enabling intellectual framework for understanding the relationships between people, place, and poverty. Poor communities in nineteenth-century cities were undeniably mobile and transient. Historians and archaeologists have often regarded this mobility as an obstacle to studying everyday life in such contexts. However, examining temporal routines and geographical movements across a variety of time frames and geographical scales, this article argues that mobility is actually key to understanding urban life and an important mechanism for interpreting the fragmented material and documentary traces left by poor households in the nineteenth-century metropolis.We are grateful to the UK’s Arts and Humanities Research Council who funded the research upon which this paper is based (Grant Reference AH/E002285/1): ‘Living in Victorian London: Towards a Material History of Everyday Domestic Life in the Nineteenth-Century Metropolis

The emergence of health inequalities in early adulthood: evidence on timing and mechanisms from a West of Scotland cohort

Background Evidence is inconsistent as to whether or not there are health inequalities in adolescence according to socio-economic position (SEP) and whether or when they emerge in early adulthood. Despite the large health inequalities literature, few studies have simultaneously compared the relative importance of ?health selection? versus ?social causation? at this life-stage. This study followed a cohort through the youth-adult transition to: (1) determine whether, and if so, when, health inequalities became evident according to both class of origin and current SEP; (2) compare the importance of health selection and social causation mechanisms; and (3) investigate whether these phenomena vary by gender. Methods Data are from a West-of-Scotland cohort, surveyed five times between age 15 (in 1987, N=1,515, response=85%) and 36. Self-reported physical and mental health were obtained at each survey. SEP was based on parental occupational class at 15, a combination of own education or occupational status at 18 and own occupational class (with an additional non-employment category) at older ages. In respect of when inequalities emerged, we used the relative index of inequality to examine associations between both parental and own current SEP and health at each age. In respect of mechanisms, path models, including SEP and health at each age, investigated both inter and intra-generational paths from SEP to health (?causation?) and from health to SEP (?selection?). Analyses were conducted separately for physical and mental health, and stratified by gender. Results Associations between both physical and mental health and parental SEP were non-significant at every age. Inequalities according to own SEP emerged for physical health at 24 and for mental health at 30. There was no evidence of selection based on physical health, but some evidence of associations between mental health in early adulthood and later SEP (intra-generational selection). Paths indicated intra-generational (males) and inter-generational (females) social causation of physical health inequalities, and intra-generational (males and females) and inter-generational (females) social causation of mental health inequalities. Conclusions The results suggest complex and reciprocal relationships between SEP and health and highlight adolescence and early adulthood as a sensitive period for this process, impacting on future life-chances and health

Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy

Background Copy number variants (CNVs) have been linked to neurodevelopmental disorders such as intellectual disability (ID), autism, epilepsy and psychiatric disease. There are few studies of CNVs in patients with both ID and epilepsy. Methods We evaluated the range of rare CNVs found in 80 Welsh patients with ID or developmental delay (DD), and childhood-onset epilepsy. We performed molecular cytogenetic testing by single nucleotide polymorphism array or microarray-based comparative genome hybridisation. Results 8.8 % (7/80) of the patients had at least one rare CNVs that was considered to be pathogenic or likely pathogenic. The CNVs involved known disease genes (EHMT1, MBD5 and SCN1A) and imbalances in genomic regions associated with neurodevelopmental disorders (16p11.2, 16p13.11 and 2q13). Prompted by the observation of two deletions disrupting SCN1A we undertook further testing of this gene in selected patients. This led to the identification of four pathogenic SCN1A mutations in our cohort. Conclusions We identified five rare de novo deletions and confirmed the clinical utility of array analysis in patients with ID/DD and childhood-onset epilepsy. This report adds to our clinical understanding of these rare genomic disorders and highlights SCN1A mutations as a cause of ID and epilepsy, which can easily be overlooked in adults

Toxoplasma gondii-Induced Activation of EGFR Prevents Autophagy Protein-Mediated Killing of the Parasite

Toxoplasma gondii resides in an intracellular compartment (parasitophorous vacuole) that excludes transmembrane molecules required for endosome-lysosome recruitment. Thus, the parasite survives by avoiding lysosomal degradation. However, autophagy can re-route the parasitophorous vacuole to the lysosomes and cause parasite killing. This raises the possibility that T. gondii may deploy a strategy to prevent autophagic targeting to maintain the non-fusogenic nature of the vacuole. We report that T. gondii activated EGFR in endothelial cells, retinal pigment epithelial cells and microglia. Blockade of EGFR or its downstream molecule, Akt, caused targeting of the parasite by LC3(+) structures, vacuole-lysosomal fusion, lysosomal degradation and killing of the parasite that were dependent on the autophagy proteins Atg7 and Beclin 1. Disassembly of GPCR or inhibition of metalloproteinases did not prevent EGFR-Akt activation. T. gondii micronemal proteins (MICs) containing EGF domains (EGF-MICs; MIC3 and MIC6) appeared to promote EGFR activation. Parasites defective in EGF-MICs (MIC1 ko, deficient in MIC1 and secretion of MIC6; MIC3 ko, deficient in MIC3; and MIC1-3 ko, deficient in MIC1, MIC3 and secretion of MIC6) caused impaired EGFR-Akt activation and recombinant EGF-MICs (MIC3 and MIC6) caused EGFR-Akt activation. In cells treated with autophagy stimulators (CD154, rapamycin) EGFR signaling inhibited LC3 accumulation around the parasite. Moreover, increased LC3 accumulation and parasite killing were noted in CD154-activated cells infected with MIC1-3 ko parasites. Finally, recombinant MIC3 and MIC6 inhibited parasite killing triggered by CD154 particularly against MIC1-3 ko parasites. Thus, our findings identified EGFR activation as a strategy used by T. gondii to maintain the non-fusogenic nature of the parasitophorous vacuole and suggest that EGF-MICs have a novel role in affecting signaling in host cells to promote parasite survival

Effectiveness of interventions aimed at improving physical and psychological outcomes of fall-related injuries in people with dementia: a narrative systematic review

Background: The annual prevalence of falls in people with dementia ranges from 47 to 90%. Falls are a common reason for hospital admission in people with dementia, and there is limited research evidence regarding the care pathways experienced by this population. In addition to immediate management of an injury, prevention of further falls is likely to be an important part of any successful intervention. This review aims to assess the effectiveness of interventions for improving the physical and psychological wellbeing of people with dementia who have sustained a fall-related injury. Methods: Systematic review methodologies were employed utilising searches across multiple databases (MEDLINE, CENTRAL, Health Management Information Consortium, EMBASE, CINAHL, Web of Science, Allied and Complementary Medicine Database, and Physiotherapy Evidence Database (PEDro)) and citation chaining. Studies including people with a known diagnosis of dementia living in the community and who present at health services with a fall, with or without injury, were included. Outcomes of interest included mobility, recurrent falls, activities of daily living, length of hospital stay, and post-discharge residence. Results were independently reviewed and quality assessed by two researchers, and data extracted using a customised form. A narrative synthesis was performed due to heterogeneity of the included studies. Results: Seven studies were included. Interventions clustered into three broad categories: multidisciplinary in-hospital post-surgical geriatric assessment; pharmaceuticals; and multifactorial assessment. Multidisciplinary care and early mobilisation showed short-term improvements for some outcomes. Only an annual administration of zoledronic acid showed long-term reduction in recurrent falls. Conclusions: Due to high heterogeneity across the studies, definitive conclusions could not be reached. Most post-fall interventions were not aimed at patients with dementia and have shown little efficacy regardless of cognitive status. Minor improvements to some quality of life indicators were shown, but these were generally not statistically significant. Conclusions were also limited due to most studies addressing hip fracture; the interventions provided for this type of injury may not be suitable for other types of fractures or soft tissue injuries, or for use in primary care

Behavioural Risk Factors in Mid-Life Associated with Successful Ageing, Disability, Dementia and Frailty in Later Life: A Rapid Systematic Review.

BACKGROUND: Smoking, alcohol consumption, poor diet and low levels of physical activity significantly contribute to the burden of illness in developed countries. Whilst the links between specific and multiple risk behaviours and individual chronic conditions are well documented, the impact of these behaviours in mid-life across a range of later life outcomes has yet to be comprehensively assessed. This review aimed to provide an overview of behavioural risk factors in mid-life that are associated with successful ageing and the primary prevention or delay of disability, dementia, frailty and non-communicable chronic conditions. METHODS: A literature search was conducted to identify cohort studies published in English since 2000 up to Dec 2014. Multivariate analyses and a minimum follow-up of five years were required for inclusion. Two reviewers screened titles, abstracts and papers independently. Studies were assessed for quality. Evidence was synthesised by mid-life behavioural risk for a range of late life outcomes. FINDINGS: This search located 10,338 individual references, of which 164 are included in this review. Follow-up data ranged from five years to 36 years. Outcomes include dementia, frailty, disability and cardiovascular disease. There is consistent evidence of beneficial associations between mid-life physical activity, healthy ageing and disease outcomes. Across all populations studied there is consistent evidence that mid-life smoking has a detrimental effect on health. Evidence specific to alcohol consumption was mixed. Limited, but supportive, evidence was available relating specifically to mid-life diet, leisure and social activities or health inequalities. CONCLUSIONS: There is consistent evidence of associations between mid-life behaviours and a range of late life outcomes. The promotion of physical activity, healthy diet and smoking cessation in all mid-life populations should be encouraged for successful ageing and the prevention of disability and chronic disease.This work was funded by the National Institute for Health and Care Excellence (NICE), invitation to tender reference DDER 42013, and supported by the National Institute for Health Research School for Public Health Research. The scope of the work was defined by NICE and the protocol was agreed with NICE prior to the start of work. The funders had no role in data analysis, preparation of the manuscript or decision to publish.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pone.014440

Alignment of the ALICE Inner Tracking System with cosmic-ray tracks

37 pages, 15 figures, revised version, accepted by JINSTALICE (A Large Ion Collider Experiment) is the LHC (Large Hadron Collider) experiment devoted to investigating the strongly interacting matter created in nucleus-nucleus collisions at the LHC energies. The ALICE ITS, Inner Tracking System, consists of six cylindrical layers of silicon detectors with three different technologies; in the outward direction: two layers of pixel detectors, two layers each of drift, and strip detectors. The number of parameters to be determined in the spatial alignment of the 2198 sensor modules of the ITS is about 13,000. The target alignment precision is well below 10 micron in some cases (pixels). The sources of alignment information include survey measurements, and the reconstructed tracks from cosmic rays and from proton-proton collisions. The main track-based alignment method uses the Millepede global approach. An iterative local method was developed and used as well. We present the results obtained for the ITS alignment using about 10^5 charged tracks from cosmic rays that have been collected during summer 2008, with the ALICE solenoidal magnet switched off.Peer reviewe