Distinct functions of integrin alpha and beta subunit cytoplasmic domains in cell spreading and formation of focal adhesions.

Integrin-mediated cell adhesion often results in cell spreading and the formation of focal adhesions. We exploited the capacity of recombinant human alpha IIb beta 3 integrin to endow heterologous cells with the ability to adhere and spread on fibrinogen to study the role of integrin cytoplasmic domains in initiation of cell spreading and focal adhesions. The same constructs were also used to analyze the role of the cytoplasmic domains in maintenance of the fidelity of the integrin repertoire at focal adhesions. Truncation mutants of the cytoplasmic domain of alpha IIb did not interfere with the ability of alpha IIb beta 3 to initiate cell spreading and form focal adhesions. Nevertheless, deletion of the alpha IIb cytoplasmic domain allowed indiscriminate recruitment of alpha IIb beta 3 to focal adhesions formed by other integrins. Truncation of the beta 3 subunit cytoplasmic domain abolished cell spreading mediated by alpha IIb beta 3 and also abrogated recruitment of alpha IIb beta 3 to focal adhesions. This truncation also dramatically impaired the ability of alpha IIb beta 3 to mediate the contraction of fibrin gels. In contrast, the beta 3 subunit cytoplasmic truncation did not reduce the fibrinogen binding affinity of alpha IIb beta 3. Thus, the integrin beta 3 subunit cytoplasmic domain is necessary and sufficient for initiation of cell spreading and focal adhesion formation. Further, the beta 3 cytoplasmic domain is required for the transmission of intracellular contractile forces to fibrin gels. The alpha subunit cytoplasmic domain maintains the fidelity of recruitment of the integrins to focal adhesions and thus regulates their repertoire of integrins

Analysis of IL2/IL21 Gene Variants in Cholestatic Liver Diseases Reveals an Association with Primary Sclerosing Cholangitis

Background/Aims: The chromosome 4q27 region harboring IL2 and IL21 is an established risk locus for ulcerative colitis (UC) and various other autoimmune diseases. Considering the strong coincidence of primary sclerosing cholangitis (PSC) with UC and the increased frequency of other autoimmune disorders in patients with primary biliary cirrhosis (PBC), we investigated whether genetic variation in the IL2/IL21 region may also modulate the susceptibility to these two rare cholestatic liver diseases. Methods: Four strongly UC-associated single nucleotide polymorphisms (SNPs) within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block were genotyped in 124 PBC and 41 PSC patients. Control allele frequencies from 1,487 healthy, unrelated Caucasians were available from a previous UC association study. Results: The minor alleles of all four markers were associated with a decreased susceptibility to PSC (rs13151961: p = 0.013, odds ratio (OR) 0.34; rs13119723: p = 0.023, OR 0.40; rs6822844: p = 0.031, OR 0.41; rs6840978: p = 0.043, OR 0.46). Moreover, a haplotype consisting of the four minor alleles also had a protective effect on PSC susceptibility (p = 0.0084, OR 0.28). A haplotype of the four major alleles was independently associated with PSC when excluding the patients with concomitant inflammatory bowel disease (p = 0.033, OR 4.18). Conclusion: The IL2/IL21 region may be one of the highly suggestive but so far rarely identified shared susceptibility loci for PSC and UC. Copyright (C) 2011 S. Karger AG, Base

Alcohol-induced retrograde facilitation renders witnesses of crime less suggestible to misinformation

RATIONALE: Research has shown that alcohol can have both detrimental and facilitating effects on memory: intoxication can lead to poor memory for information encoded after alcohol consumption (anterograde amnesia) and may improve memory for information encoded before consumption (retrograde facilitation). This study examined whether alcohol consumed after witnessing a crime can render individuals less vulnerable to misleading post-event information (misinformation). METHOD: Participants watched a simulated crime video. Thereafter, one third of participants expected and received alcohol (alcohol group), one third did not expect but received alcohol (reverse placebo), and one third did not expect nor receive alcohol (control). After alcohol consumption, participants were exposed to misinformation embedded in a written narrative about the crime. The following day, participants completed a cued-recall questionnaire about the event. RESULTS: Control participants were more likely to report misinformation compared to the alcohol and reverse placebo group. CONCLUSION: The findings suggest that we may oversimplify the effect alcohol has on suggestibility and that sometimes alcohol can have beneficial effects on eyewitness memory by protecting against misleading post-event information

Presymptomatic risk assessment for chronic non-communicable diseases

The prevalence of common chronic non-communicable diseases (CNCDs) far overshadows the prevalence of both monogenic and infectious diseases combined. All CNCDs, also called complex genetic diseases, have a heritable genetic component that can be used for pre-symptomatic risk assessment. Common single nucleotide polymorphisms (SNPs) that tag risk haplotypes across the genome currently account for a non-trivial portion of the germ-line genetic risk and we will likely continue to identify the remaining missing heritability in the form of rare variants, copy number variants and epigenetic modifications. Here, we describe a novel measure for calculating the lifetime risk of a disease, called the genetic composite index (GCI), and demonstrate its predictive value as a clinical classifier. The GCI only considers summary statistics of the effects of genetic variation and hence does not require the results of large-scale studies simultaneously assessing multiple risk factors. Combining GCI scores with environmental risk information provides an additional tool for clinical decision-making. The GCI can be populated with heritable risk information of any type, and thus represents a framework for CNCD pre-symptomatic risk assessment that can be populated as additional risk information is identified through next-generation technologies.Comment: Plos ONE paper. Previous version was withdrawn to be updated by the journal's pdf versio

Protecting eyewitness evidence: Examining the efficacy of a self-administered interview tool

Given the crucial role of eyewitness evidence, statements should be obtained as soon as possible after an incident. This is not always achieved due to demands on police resources. Two studies trace the development of a new tool, the Self-Administered Interview (SAI), designed to elicit a comprehensive initial statement. In Study 1, SAI participants reported more correct details than participants who provided a free recall account, and performed at the same level as participants given a Cognitive Interview. In Study 2, participants viewed a simulated crime and half recorded their statement using the SAI. After a delay of 1 week, all participants completed a free recall test. SAI participants recalled more correct details in the delayed recall task than control participants

On the interpretation of removable interactions: A survey of the field 33 years after Loftus

In a classic 1978 Memory &Cognition article, Geoff Loftus explained why noncrossover interactions are removable. These removable interactions are tied to the scale of measurement for the dependent variable and therefore do not allow unambiguous conclusions about latent psychological processes. In the present article, we present concrete examples of how this insight helps prevent experimental psychologists from drawing incorrect conclusions about the effects of forgetting and aging. In addition, we extend the Loftus classification scheme for interactions to include those on the cusp between removable and nonremovable. Finally, we use various methods (i.e., a study of citation histories, a questionnaire for psychology students and faculty members, an analysis of statistical textbooks, and a review of articles published in the 2008 issue of Psychology andAging) to show that experimental psychologists have remained generally unaware of the concept of removable interactions. We conclude that there is more to interactions in a 2 × 2 design than meets the eye

Application of site and haplotype-frequency based approaches for detecting selection signatures in cattle

<p>Abstract</p> <p>Background</p> <p>'Selection signatures' delimit regions of the genome that are, or have been, functionally important and have therefore been under either natural or artificial selection. In this study, two different and complementary methods--integrated Haplotype Homozygosity Score (|iHS|) and population differentiation index (F_ST)--were applied to identify traces of decades of intensive artificial selection for traits of economic importance in modern cattle.</p> <p>Results</p> <p>We scanned the genome of a diverse set of dairy and beef breeds from Germany, Canada and Australia genotyped with a 50 K SNP panel. Across breeds, a total of 109 extreme |iHS| values exceeded the empirical threshold level of 5% with 19, 27, 9, 10 and 17 outliers in Holstein, Brown Swiss, Australian Angus, Hereford and Simmental, respectively. Annotating the regions harboring clustered |iHS| signals revealed a panel of interesting candidate genes like SPATA17, MGAT1, PGRMC2 and ACTC1, COL23A1, MATN2, respectively, in the context of reproduction and muscle formation. In a further step, a new Bayesian F_ST-based approach was applied with a set of geographically separated populations including Holstein, Brown Swiss, Simmental, North American Angus and Piedmontese for detecting differentiated loci. In total, 127 regions exceeding the 2.5 per cent threshold of the empirical posterior distribution were identified as extremely differentiated. In a substantial number (56 out of 127 cases) the extreme F_STvalues were found to be positioned in poor gene content regions which deviated significantly (p < 0.05) from the expectation assuming a random distribution. However, significant F_STvalues were found in regions of some relevant genes such as SMCP and FGF1.</p> <p>Conclusions</p> <p>Overall, 236 regions putatively subject to recent positive selection in the cattle genome were detected. Both |iHS| and F_STsuggested selection in the vicinity of the Sialic acid binding Ig-like lectin 5 gene on BTA18. This region was recently reported to be a major QTL with strong effects on productive life and fertility traits in Holstein cattle. We conclude that high-resolution genome scans of selection signatures can be used to identify genomic regions contributing to within- and inter-breed phenotypic variation.</p

How do patients with inflammatory bowel disease want their biological therapy administered?

<p>Abstract</p> <p>Background</p> <p>Infliximab is usually administered by two monthly intravenous (iv) infusions, therefore requiring visits to hospital. Adalimumab is administered by self subcutaneous (sc) injections every other week. Both of these anti-TNF drugs appear to be equally efficacious in the treatment of Crohn's Disease and therefore the decision regarding which drug to choose will depend to some extent on patient choice, which may be based on the mode of administration.</p> <p>The aims of this study were to compare preferences in Inflammatory Bowel Disease (IBD) patients for two currently available anti-TNF agents and the reasons for their choices.</p> <p>Methods</p> <p>An anonymous questionnaire was distributed to IBD patients who had attended the Gastroenterology service (Ulster Hospital, Dundonald, Belfast, N. Ireland. UK) between January 2007 and December 2007. The patients were asked in a hypothetical situation if the following administering methods of anti-TNF drugs (intravenous or subcutaneous) were available, which drug route of administration would they choose.</p> <p>Results</p> <p>One hundred and twenty-five patients fulfilled the inclusion criteria and were issued questionnaires, of these 78 questionnaires were returned (62 percent response). The mean age of respondent was 44 years. Of the total number of respondents, 33 patients (42 percent) preferred infliximab and 19 patients (24 percent) preferred adalimumab (p = 0.07). Twenty-six patients (33 percent) did not indicate a preference for either biological therapy and were not included in the final analysis. The commonest reason cited for those who chose infliximab (iv) was: <it>"I do not like the idea of self-injecting," </it>(67 percent). For those patients who preferred adalimumab (sc) the commonest reason cited was: <it>"I prefer the convenience of injecting at home," </it>(79 percent). Of those patients who had previously been treated with an anti-TNF therapy (n = 10, all infliximab) six patients stated that they would prefer infliximab if given the choice in the future (p = 0.75).</p> <p>Conclusions</p> <p>There was a trend towards patient preference for infliximab (iv) treatment as opposed to adalimumab (sc) in patients with IBD. This difference may be due to the frequency of administration, mode of administration or differing 'times in the market-place', as infliximab had been approved for a longer period of time in Crohn's disease. Further studies are required in IBD patients to investigate whether patient choice will affect compliance, patient satisfaction and efficacy of treatment with anti-TNF therapies.</p

Fleeting Perceptual Experience and the Possibility of Recalling Without Seeing

We explore an intensely debated problem in neuroscience, psychology and philosophy: the degree to which the “phenomenological consciousness” of the experience of a stimulus is separable from the “access consciousness” of its reportability. Specifically, it has been proposed that these two measures are dissociated from one another in one, or both directions. However, even if it was agreed that reportability and experience were doubly dissociated, the limits of dissociation logic mean we would not be able to conclusively separate the cognitive processes underlying the two. We take advantage of computational modelling and recent advances in state-trace analysis to assess this dissociation in an attentional/experiential blink paradigm. These advances in state-trace analysis make use of Bayesian statistics to quantify the evidence for and against a dissociation. Further evidence is obtained by linking our finding to a prominent model of the attentional blink – the Simultaneous Type/Serial Token model. Our results show evidence for a dissociation between experience and reportability, whereby participants appear able to encode stimuli into working memory with little, if any, conscious experience of them. This raises the possibility of a phenomenon that might be called sight-blind recall, which we discuss in the context of the current experience/reportability debate