Perceptual grouping ability in Williams syndrome: Evidence for deviant patterns of performance

Williams syndrome (WS) is a rare genetic disorder. At a cognitive level, this population display poor visuo-spatial cognition when compared to verbal ability. Within the visuo-spatial domain, it is now accepted that individuals with WS are able to perceive both local and global aspects of an image, albeit at a low level. The present study examines the manner in which local elements are grouped into a global whole in WS. Fifteen individuals with WS and 15 typically developing controls, matched for non-verbal ability, were presented with a matrix of local elements and asked whether these elements were perceptually grouped horizontally or vertically. The WS group were at the same level as the control group when grouping by luminance, closure, and alignment. However, their ability to group by shape, orientation and proximity was significantly poorer than controls. This unusual profile of grouping abilities in WS suggests that these individuals do not form a global percept in a typical manner

DHODH modulates transcriptional elongation in the neural crest and melanoma

Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma1. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation

Systems developmental biology: the use of ontologies in annotating models and in identifying gene function within and across species

Systems developmental biology is an approach to the study of embryogenesis that attempts to analyze complex developmental processes through integrating the roles of their molecular, cellular, and tissue participants within a computational framework. This article discusses ways of annotating these participants using standard terms and IDs now available in public ontologies (these are areas of hierarchical knowledge formalized to be computationally accessible) for tissues, cells, and processes. Such annotations bring two types of benefit. The first comes from using standard terms: This allows linkage to other resources that use them (e.g., GXD, the gene-expression [G-E] database for mouse development). The second comes from the annotation procedure itself: This can lead to the identification of common processes that are used in very different and apparently unrelated events, even in other organisms. One implication of this is the potential for identifying the genes underpinning common developmental processes in different tissues through Boolean analysis of their G-E profiles. While it is easiest to do this for single organisms, the approach is extendable to analyzing similar processes in different organisms. Although the full computational infrastructure for such an analysis has yet to be put in place, two examples are briefly considered as illustration. First, the early development of the mouse urogenital system shows how a line of development can be graphically formalized using ontologies. Second, Boolean analysis of the G-E profiles of the mesenchyme-to-epithelium transitions that take place during mouse development suggest Lhx1, Foxc1, and Meox1 as candidate transcription factors for mediating this process

Kidney disease in life-course socioeconomic context: the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Persons belonging to the working class or living in an adverse social environment at particular periods of their life course may have an increased risk of chronic kidney disease (CKD). METHODS: This hypothesis was examined among participants of the Life Course Socioeconomic Status Study, an ancillary study of the Atherosclerosis Risk in Communities Study, conducted in 2001 (mean age, 67.4 years; N = 12,631). CKD was defined by hospital discharge diagnosis and/or estimated glomerular filtration rate less than 45 mL/min/1.73 m(2) (<0.75 mL/s/1.73 m(2)). Social class was categorized as working class or non-working class at ages 30, 40, or 50 years. Area-level socioeconomic status was based on a composite of census scores during the same period. Adjusted odds ratios were obtained within strata of white and African-American race. RESULTS: The adjusted odds ratio of CKD for persons belonging to the working class versus non-working class at age 30 was 1.4 (95% confidence interval, 1.0 to 2.0) in whites and 1.9 (95% confidence interval, 1.1 to 3.0) in African Americans. Working class membership was associated with CKD, even at earlier stages of adult life, and class was associated more strongly with CKD than was education. Working class membership also suggested a stronger association with CKD among African Americans than whites, independent of diabetes and hypertension status. At later periods in the life course, area socioeconomic status was associated with CKD. CONCLUSION: Socioeconomic factors, including area socioeconomic status and social class, are associated with CKD and may account for some of the racial disparity in kidney disease.http://deepblue.lib.umich.edu/bitstream/2027.42/78575/1/ShohamVupputri2007_AmJKidneyDisease.pd

Large scale statistical inference of signaling pathways from RNAi and microarray data

<p>Abstract</p> <p>Background</p> <p>The advent of RNA interference techniques enables the selective silencing of biologically interesting genes in an efficient way. In combination with DNA microarray technology this enables researchers to gain insights into signaling pathways by observing downstream effects of individual knock-downs on gene expression. These secondary effects can be used to computationally reverse engineer features of the upstream signaling pathway.</p> <p>Results</p> <p>In this paper we address this challenging problem by extending previous work by Markowetz <it>et al</it>., who proposed a statistical framework to score networks hypotheses in a Bayesian manner. Our extensions go in three directions: First, we introduce a way to omit the data discretization step needed in the original framework via a calculation based on <it>p</it>-values instead. Second, we show how prior assumptions on the network structure can be incorporated into the scoring scheme using regularization techniques. Third and most important, we propose methods to scale up the original approach, which is limited to around 5 genes, to large scale networks.</p> <p>Conclusion</p> <p>Comparisons of these methods on artificial data are conducted. Our proposed module network is employed to infer the signaling network between 13 genes in the ER-<it>α </it>pathway in human MCF-7 breast cancer cells. Using a bootstrapping approach this reconstruction can be found with good statistical stability.</p> <p>The code for the module network inference method is available in the latest version of the <it>R</it>-package <it>nem</it>, which can be obtained from the Bioconductor homepage.</p

The role of multiple marks in epigenetic silencing and the emergence of a stable bivalent chromatin state

We introduce and analyze a minimal model of epigenetic silencing in budding yeast, built upon known biomolecular interactions in the system. Doing so, we identify the epigenetic marks essential for the bistability of epigenetic states. The model explicitly incorporates two key chromatin marks, namely H4K16 acetylation and H3K79 methylation, and explores whether the presence of multiple marks lead to a qualitatively different systems behavior. We find that having both modifications is important for the robustness of epigenetic silencing. Besides the silenced and transcriptionally active fate of chromatin, our model leads to a novel state with bivalent (i.e., both active and silencing) marks under certain perturbations (knock-out mutations, inhibition or enhancement of enzymatic activity). The bivalent state appears under several perturbations and is shown to result in patchy silencing. We also show that the titration effect, owing to a limited supply of silencing proteins, can result in counter-intuitive responses. The design principles of the silencing system is systematically investigated and disparate experimental observations are assessed within a single theoretical framework. Specifically, we discuss the behavior of Sir protein recruitment, spreading and stability of silenced regions in commonly-studied mutants (e.g., sas2, dot1) illuminating the controversial role of Dot1 in the systems biology of yeast silencing.Comment: Supplementary Material, 14 page

Pain in patients with pancreatic cancer: prevalence, mechanisms, management and future developments

Pain affects approximately 80% of patients with pancreatic cancer, with half requiring strong opioid analgesia, namely: morphine-based drugs on step three of the WHO analgesic ladder (as opposed to the weak opioids: codeine and tramadol). The presence of pain is associated with reduced survival. This article reviews the literature regarding pain: prevalence, mechanisms, pharmacological, and endoscopic treatments and identifies areas for research to develop individualized patient pain management pathways. The online literature review was conducted through: PubMed, Clinical Key, Uptodate, and NICE Evidence. There are two principal mechanisms for pain: pancreatic duct obstruction and pancreatic neuropathy which, respectively, activate mechanical and chemical nociceptors. In pancreatic neuropathy, several histological, molecular, and immunological changes occur which correlate with pain including: transient receptor potential cation channel activation and mast cell infiltration. Current pain management is empirical rather etiology-based and is informed by the WHO analgesic ladder for first-line therapies, and then endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) in patients with resistant pain. For EUS-CPN, there is only one clinical trial reporting a benefit, which has limited generalizability. Case series report pancreatic duct stenting gives effective analgesia, but there are no clinical trials. Progress in understanding the mechanisms for pain and when this occurs in the natural history, together with assessing new therapies both pharmacological and endoscopic, will enable individualized care and may improve patients’ quality of life and survival

Consent for Use of Clinical Leftover Biosample: A Survey among Chinese Patients and the General Public

Background: Storage of leftover biosamples generates rich biobanks for future studies, saving time and money and limiting physical impact to sample donors. Objective: To investigate the attitudes of Chinese patients and the general public on providing consent for storage and use of leftover biosamples. Design, Setting and Participants: Cross-sectional surveys were conducted among randomly selected patients admitted to a Shanghai city hospital (n = 648) and members of the general public (n = 492) from May 2010 to July 2010. Main Outcome Measures: Face-to-face interviews collected respondents-report of their willingness to donate residual biosample, trust in medical institutions, motivation for donation, concerns of donated sample use, expectations for research results return, and so on. Results: The response rate was 83.0%. Of the respondents, 89.1 % stated that they completely understood or understood most of questions. Willingness to donate residual sample was stated by 64.7%, of which 16.7 % desired the option to withdraw their donations anytime afterwards. Only 42.3 % of respondents stated they ‘‘trust’ ’ or ‘‘strongly trust’ ’ medical institutions, the attitude of trusting or strongly trusting medical institutions were significantly associated with willingness to donate in the general public group.(p,0.05) The overall assent rate for future research without specific consents was als

P-hydroxyphenylpyruvate, an intermediate of the Phe/Tyr catabolism, improves mitochondrial oxidative metabolism under stressing conditions and prolongs survival in rats subjected to profound hemorrhagic shock

The aim of this study was to test the effect of a small volume administration of p-hydroxyphenylpyruvate (pHPP) in a rat model of profound hemorrhagic shock and to assess a possible metabolic mechanism of action of the compound. The results obtained show that hemorrhaged rats treated with 2-4% of the estimated blood volume of pHPP survived significantly longer (p<0.001) than rats treated with vehicle. In vitro analysis on cultured EA.hy 926 cells demonstrated that pHPP improved cell growth rate and promoted cell survival under stressing conditions. Moreover, pHPP stimulated mitochondria-related respiration under ATP-synthesizing conditions and exhibited antioxidant activity toward mitochondria-generated reactive oxygen species. The compound effects reported in the in vitro and in vivo analyses were obtained in the same millimolar concentration range. These data disclose pHPP as an efficient energetic substrates-supplier to the mitochondrial respiratory chain as well as an antioxidant supporting the view that the compound warrants further evaluation as a therapeutic agent. © 2014 Cotoia et al

Comparing composite likelihood methods based on pairs for spatial Gaussian random fields

In the last years there has been a growing interest in proposing methods for estimating covariance functions for geostatistical data. Among these, maximum likelihood estimators have nice features when we deal with a Gaussian model. However maximum likelihood becomes impractical when the number of observations is very large. In this work we review some solutions and we contrast them in terms of loss of statistical efficiency and computational burden. Specifically we focus on three types of weighted composite likelihood functions based on pairs and we compare them with the method of covariance tapering. Asymptotic properties of the three estimation methods are derived. We illustrate the effectiveness of the methods through theoretical examples, simulation experiments and by analyzing a data set on yearly total precipitation anomalies at weather stations in the United States.In the last years there has been a growing interest in proposing methods for estimating covariance functions for geostatistical data. Among these, maximum likelihood estimators have nice features when we deal with a Gaussian model. However maximum likelihood becomes impractical when the number of observations is very large. In this work we review some solutions and we contrast them in terms of loss of statistical efficiency and computational burden. Specifically we focus on three types of weighted composite likelihood functions based on pairs and we compare them with the method of covariance tapering. Asymptotic properties of the three estimation methods are derived. We illustrate the effectiveness of the methods through theoretical examples, simulation experiments and by analyzing a data set on yearly total precipitation anomalies at weather stations in the United States