Language and theory of mind in autism spectrum disorder : the relationship between complement syntax and false belief task performance.

This study aimed to test the hypothesis that children with autism spectrum disorder (ASD) use their knowledge of complement syntax as a means of “hacking out” solutions to false belief tasks, despite lacking a representational theory of mind (ToM). Participants completed a “memory for complements” task, a measure of receptive vocabulary, and traditional location change and unexpected contents false belief tasks. Consistent with predictions, the correlation between complement syntax score and location change task performance was significantly stronger within the ASD group than within the comparison group. However, contrary to predictions, complement syntax score was not significantly correlated with unexpected contents task performance within either group. Possible explanations for this pattern of results are considered

Interacting with Fictions:The Role of Pretend Play in Theory of Mind Acquisition

Pretend play is generally considered to be a developmental landmark in Theory of Mind acquisition. The aim of the present paper is to offer a new account of the role of pretend play in Theory of Mind development. To this end I combine Hutto and Gallagher’s account of social cognition development with Matravers’ recent argument that the cognitive processes involved in engagement with narratives are neutral regarding fictionality. The key contribution of my account is an analysis of pretend play as interaction with fictions. I argue that my account offers a better explanation of existing empirical data on the development of children’s pretend play and Theory of Mind than the competing theories from Leslie, Perner and Harris

Structural insights into Clostridium perfringens delta toxin pore formation

Clostridium perfringens Delta toxin is one of the three hemolysin-like proteins produced by C. perfringens type C and possibly type B strains. One of the others, NetB, has been shown to be the major cause of Avian Nectrotic Enteritis, which following the reduction in use of antibiotics as growth promoters, has become an emerging disease of industrial poultry. Delta toxin itself is cytotoxic to the wide range of human and animal macrophages and platelets that present GM2 ganglioside on their membranes. It has sequence similarity with Staphylococcus aureus β-pore forming toxins and is expected to heptamerize and form pores in the lipid bilayer of host cell membranes. Nevertheless, its exact mode of action remains undetermined. Here we report the 2.4 Å crystal structure of monomeric Delta toxin. The superposition of this structure with the structure of the phospholipid-bound F component of S. aureus leucocidin (LukF) revealed that the glycerol molecules bound to Delta toxin and the phospholipids in LukF are accommodated in the same hydrophobic clefts, corresponding to where the toxin is expected to latch onto the membrane, though the binding sites show significant differences. From structure-based sequence alignment with the known structure of staphylococcal α-hemolysin, a model of the Delta toxin pore form has been built. Using electron microscopy, we have validated our model and characterized the Delta toxin pore on liposomes. These results highlight both similarities and differences in the mechanism of Delta toxin (and by extension NetB) cytotoxicity from that of the staphylococcal pore-forming toxins

Information resource preferences by general pediatricians in office settings: a qualitative study

BACKGROUND: Information needs and resource preferences of office-based general pediatricians have not been well characterized. METHODS: Data collected from a sample of twenty office-based urban/suburban general pediatricians consisted of: (a) a demographic survey about participants' practice and computer use, (b) semi-structured interviews on their use of different types of information resources and (c) semi-structured interviews on perceptions of information needs and resource preferences in response to clinical vignettes representing cases in Genetics and Infectious Diseases. Content analysis of interviews provided participants' perceived use of resources and their perceived questions and preferred resources in response to vignettes. RESULTS: Participants' average time in practice was 15.4 years (2–28 years). All had in-office online access. Participants identified specialist/generalist colleagues, general/specialty pediatric texts, drug formularies, federal government/professional organization Websites and medical portals (when available) as preferred information sources. They did not identify decision-making texts, evidence-based reviews, journal abstracts, medical librarians or consumer health information for routine office use. In response to clinical vignettes in Genetics and Infectious Diseases, participants identified Question Types about patient-specific (diagnosis, history and findings) and general medical (diagnostic, therapeutic and referral guidelines) information. They identified specialists and specialty textbooks, history and physical examination, colleagues and general pediatric textbooks, and federal and professional organizational Websites as information sources. Participants with access to portals identified them as information resources in lieu of texts. For Genetics vignettes, participants identified questions about prenatal history, disease etiology and treatment guidelines. For Genetics vignettes, they identified patient history, specialists, general pediatric texts, Web search engines and colleagues as information sources. For Infectious Diseases (ID) vignettes, participants identified questions about patients' clinical status at presentation and questions about disease classification, diagnosis/therapy/referral guidelines and sources of patient education. For ID vignettes, they identified history, laboratory results, colleagues, specialists and personal experience as information sources. CONCLUSION: Content analysis of office-based general pediatricians' responses to clinical vignettes provided a qualitative description of their perceptions of information needs and preferences for information resource for cases in Genetics and Infectious Diseases. This approach may provide complementary information for discovering practitioner's information needs and resource preferences in different contexts

Extreme genetic fragility of the HIV-1 capsid

Genetic robustness, or fragility, is defined as the ability, or lack thereof, of a biological entity to maintain function in the face of mutations. Viruses that replicate via RNA intermediates exhibit high mutation rates, and robustness should be particularly advantageous to them. The capsid (CA) domain of the HIV-1 Gag protein is under strong pressure to conserve functional roles in viral assembly, maturation, uncoating, and nuclear import. However, CA is also under strong immunological pressure to diversify. Therefore, it would be particularly advantageous for CA to evolve genetic robustness. To measure the genetic robustness of HIV-1 CA, we generated a library of single amino acid substitution mutants, encompassing almost half the residues in CA. Strikingly, we found HIV-1 CA to be the most genetically fragile protein that has been analyzed using such an approach, with 70% of mutations yielding replication-defective viruses. Although CA participates in several steps in HIV-1 replication, analysis of conditionally (temperature sensitive) and constitutively non-viable mutants revealed that the biological basis for its genetic fragility was primarily the need to coordinate the accurate and efficient assembly of mature virions. All mutations that exist in naturally occurring HIV-1 subtype B populations at a frequency >3%, and were also present in the mutant library, had fitness levels that were >40% of WT. However, a substantial fraction of mutations with high fitness did not occur in natural populations, suggesting another form of selection pressure limiting variation in vivo. Additionally, known protective CTL epitopes occurred preferentially in domains of the HIV-1 CA that were even more genetically fragile than HIV-1 CA as a whole. The extreme genetic fragility of HIV-1 CA may be one reason why cell-mediated immune responses to Gag correlate with better prognosis in HIV-1 infection, and suggests that CA is a good target for therapy and vaccination strategies

Follow-up of phase I trial of adalimumab and rosiglitazone in FSGS: III. Report of the FONT study group

Abstract Background Patients with resistant primary focal segmental glomerulosclerosis (FSGS) are at high risk of progression to chronic kidney disease stage V. Antifibrotic agents may slow or halt this process. We present outcomes of follow-up after a Phase I trial of adalimumab and rosiglitazone, antifibrotic drugs tested in the Novel Therapies in Resistant FSGS (FONT) study. Methods 21 patients -- 12 males and 9 females, age 16.0 ± 7.5 yr, and estimated GFR (GFRe) 121 ± 56 mL/min/1.73 m2 -- received adalimumab (n = 10), 24 mg/m2 every 14 days or rosiglitazone (n = 11), 3 mg/m2 per day for 16 weeks. The change in GFRe per month prior to entry and after completion of the Phase I trial was compared. Results 19 patients completed the 16-week FONT treatment phase. The observation period pre-FONT was 18.3 ± 10.2 months and 16.1 ± 5.7 months after the study. A similar percentage of patients, 71% and 56%, in the rosiglitazone and adalimumab cohorts, respectively, had stabilization in GFRe, defined as a reduced negative slope of the line plotting GFRe versus time without requiring renal replacement therapy after completion of the FONT treatment period (P = 0.63). Conclusion Nearly 50% of patients with resistant FSGS who receive novel antifibrotic agents may have a legacy effect with delayed deterioration in kidney function after completion of therapy. Based on this proof-of-concept preliminary study, we recommend long-term follow-up of patients enrolled in clinical trials to ascertain a more comprehensive assessment of the efficacy of experimental treatments

The incidence and prevalence of diabetes in patients with serious mental illness in North West Wales: Two cohorts, 1875–1924 & 1994–2006 compared

<p>Abstract</p> <p>Background</p> <p>Against a background of interest in rates of diabetes in schizophrenia and related psychoses and claims that data from historical periods demonstrate a link that antedates modern antipsychotics, we sought to establish the rate of diabetes in first onset psychosis and subsequent prevalence in historical and contemporary cohorts.</p> <p>Methods</p> <p>Analysis of two epidemiologically complete databases of individuals admitted for mental illness. 3170 individuals admitted to the North Wales Asylum between 1875–1924 and tracked over 18,486 patient years and 394 North West Wales first admissions for schizophrenia and related psychoses between 1994 and 2006 and tracked after treatment.</p> <p>Results</p> <p>The prevalence of Type 2 diabetes among patients with psychoses at time of first admission in both historical and contemporary samples was 0%. The incidence of diabetes remained 0% in the historical sample throughout 15 years of follow-up but rose in the contemporary sample after 3, 5 and 6 years of treatment with an incidence rate double the expected population rate so that the 15 year prevalence is likely to be over 8%.</p> <p>Conclusion</p> <p>No association was found between diabetes and serious mental illness, but there may be an association between diabetes and treatment.</p

A classification-based framework for predicting and analyzing gene regulatory response

BACKGROUND: We have recently introduced a predictive framework for studying gene transcriptional regulation in simpler organisms using a novel supervised learning algorithm called GeneClass. GeneClass is motivated by the hypothesis that in model organisms such as Saccharomyces cerevisiae, we can learn a decision rule for predicting whether a gene is up- or down-regulated in a particular microarray experiment based on the presence of binding site subsequences ("motifs") in the gene's regulatory region and the expression levels of regulators such as transcription factors in the experiment ("parents"). GeneClass formulates the learning task as a classification problem — predicting +1 and -1 labels corresponding to up- and down-regulation beyond the levels of biological and measurement noise in microarray measurements. Using the Adaboost algorithm, GeneClass learns a prediction function in the form of an alternating decision tree, a margin-based generalization of a decision tree. METHODS: In the current work, we introduce a new, robust version of the GeneClass algorithm that increases stability and computational efficiency, yielding a more scalable and reliable predictive model. The improved stability of the prediction tree enables us to introduce a detailed post-processing framework for biological interpretation, including individual and group target gene analysis to reveal condition-specific regulation programs and to suggest signaling pathways. Robust GeneClass uses a novel stabilized variant of boosting that allows a set of correlated features, rather than single features, to be included at nodes of the tree; in this way, biologically important features that are correlated with the single best feature are retained rather than decorrelated and lost in the next round of boosting. Other computational developments include fast matrix computation of the loss function for all features, allowing scalability to large datasets, and the use of abstaining weak rules, which results in a more shallow and interpretable tree. We also show how to incorporate genome-wide protein-DNA binding data from ChIP chip experiments into the GeneClass algorithm, and we use an improved noise model for gene expression data. RESULTS: Using the improved scalability of Robust GeneClass, we present larger scale experiments on a yeast environmental stress dataset, training and testing on all genes and using a comprehensive set of potential regulators. We demonstrate the improved stability of the features in the learned prediction tree, and we show the utility of the post-processing framework by analyzing two groups of genes in yeast — the protein chaperones and a set of putative targets of the Nrg1 and Nrg2 transcription factors — and suggesting novel hypotheses about their transcriptional and post-transcriptional regulation. Detailed results and Robust GeneClass source code is available for download from