The transcription T-bet is required for optimal proinflammatory trafficking of CD4+ T cells

Background: The transcription factor T-bet is a critical regulator of Th1 effector function. Animals deficient in T-bet are protected from a variety of inflammatory diseases, including systemic lupus erythematosus and inflammatory arthritis. An essential function of Th1 cells is the ability to traffic appropriately to sites of inflammation, which is largely dependent on the expression of specific selectin ligands and chemokine receptors. We therefore hypothesised that T-bet would modulate lymphocyte trafficking in vitro and in vivo by direct regulation of both selectin binding and chemokine function. Methods: Balb/c mice deficient in, or transgenic for, T-bet had been generated previously. T-bet$^{-/-}$ × DO11.10 TCR and T-bet$^{-/-}$ × IFN$^{-/-}$ mice were generated by backcrossing for >10 generations. CD4$^+$ T cells were generated from primary lymph nodes from all these mice by positive selection and stimulation with appropriate antigen. Functional analysis used the following four methods: adoptive transfer into WT Balb/c mice, which were then injected with OVA, cells were harvested from the spleen, lymph node and peritoneum; selectin binding, interactions with immoblised P-selectin and E-selectin under conditions of laminar flow were examined in a parallel plate flow chamber; expression of selectin ligands, using flow cytometry, real-time PCR and 35S incorporation; and chemokine receptor expression and function, using flow cytometry, real-time PCR, transwell chemotaxis and endothelial binding under flow conditions. Results: Selective migration of T-bet$^{-/-}$ CD4$^+$ T cells in a Th1-dependent model of peritoneal inflammation was completely abrogated. Further investigation revealed that this effect was due to a 50% reduction in binding to P-selectin but not E-selectin under in vitro flow conditions and that this was as a result of impaired tyrosine sulfation of PSGL-1. In addition, mRNA and surface expression of CXCR3, but not CCR5, was reduced and this was associated with a reduction in both transwell chemotaxis and binding to endothelial cells. Retroviral transfer experiments of T-bet cDNA into T-bet$^{-/-}$ and T-bet$^{-/-}$ × IFN$^{-/-}$ cells demonstrated that these effects were independent of interferon. Conclusions: These data establish that T-bet imprints a specific migratory program onto developing CD4$^+$ cells via control of PSGL-1 sulfation (and thus P-selectin binding) and CXCR3 expression and function. Furthermore, as E-selectin and CCR5 binding are unimpaired, this reveals a level of control on trafficking of Th1 lymphocytes not recognised by previous paradigms

A behavioral comparison of male and female adults with high functioning autism spectrum conditions

Autism spectrum conditions (ASC) affect more males than females in the general population. However, within ASC it is unclear if there are phenotypic sex differences. Testing for similarities and differences between the sexes is important not only for clinical assessment but also has implications for theories of typical sex differences and of autism. Using cognitive and behavioral measures, we investigated similarities and differences between the sexes in age- and IQ-matched adults with ASC (high-functioning autism or Asperger syndrome). Of the 83 (45 males and 38 females) participants, 62 (33 males and 29 females) met Autism Diagnostic Interview-Revised (ADI-R) cut-off criteria for autism in childhood and were included in all subsequent analyses. The severity of childhood core autism symptoms did not differ between the sexes. Males and females also did not differ in self-reported empathy, systemizing, anxiety, depression, and obsessive-compulsive traits/symptoms or mentalizing performance. However, adult females with ASC showed more lifetime sensory symptoms (p = 0.036), fewer current socio-communication difficulties (p = 0.001), and more self-reported autistic traits (p = 0.012) than males. In addition, females with ASC who also had developmental language delay had lower current performance IQ than those without developmental language delay (p<0.001), a pattern not seen in males. The absence of typical sex differences in empathizing-systemizing profiles within the autism spectrum confirms a prediction from the extreme male brain theory. Behavioral sex differences within ASC may also reflect different developmental mechanisms between males and females with ASC. We discuss the importance of the superficially better socio-communication ability in adult females with ASC in terms of why females with ASC may more often go under-recognized, and receive their diagnosis later, than males

Protein trafficking through the endosomal system prepares intracellular parasites for a home invasion

Toxoplasma (toxoplasmosis) and Plasmodium (malaria) use unique secretory organelles for migration, cell invasion, manipulation of host cell functions, and cell egress. In particular, the apical secretory micronemes and rhoptries of apicomplexan parasites are essential for successful host infection. New findings reveal that the contents of these organelles, which are transported through the endoplasmic reticulum (ER) and Golgi, also require the parasite endosome-like system to access their respective organelles. In this review, we discuss recent findings that demonstrate that these parasites reduced their endosomal system and modified classical regulators of this pathway for the biogenesis of apical organelles

Exhaled volatile organic compounds in patients with non-small cell lung cancer: cross sectional and nested short-term follow-up study

BACKGROUND: Non-invasive diagnostic strategies aimed at identifying biomarkers of lung cancer are of great interest for early cancer detection. The aim of this study was to set up a new method for identifying and quantifying volatile organic compounds (VOCs) in exhaled air of patients with non-small cells lung cancer (NSCLC), by comparing the levels with those obtained from healthy smokers and non-smokers, and patients with chronic obstructive pulmonary disease. The VOC collection and analyses were repeated three weeks after the NSCLC patients underwent lung surgery. METHODS: The subjects' breath was collected in a Teflon(® )bulb that traps the last portion of single slow vital capacity. The 13 VOCs selected for this study were concentrated using a solid phase microextraction technique and subsequently analysed by means of gas cromatography/mass spectrometry. RESULTS: The levels of the selected VOCs ranged from 10(-12 )M for styrene to 10(-9 )M for isoprene. None of VOCs alone discriminated the study groups, and so it was not possible to identify one single chemical compound as a specific lung cancer biomarker. However, multinomial logistic regression analysis showed that VOC profile can correctly classify about 80 % of cases. Only isoprene and decane levels significantly decreased after surgery. CONCLUSION: As the combination of the 13 VOCs allowed the correct classification of the cases into groups, together with conventional diagnostic approaches, VOC analysis could be used as a complementary test for the early diagnosis of lung cancer. Its possible use in the follow-up of operated patients cannot be recommended on the basis of the results of our short-term nested study

Elephants in pyjamas: testing the weak central coherence account of autism spectrum disorders using a syntactic disambiguation task

According to the weak central coherence (CC) account individuals with autism spectrum disorders (ASD) exhibit enhanced local processing and weak part-whole integration. CC was investigated in the verbal domain. Adolescents, recruited using a 2 (ASD status) by 2 (language impairment status) design, completed an aural forced choice comprehension task involving syntactically ambiguous sentences. Half the picture targets depicted the least plausible interpretation, resulting in longer RTs across groups. These were assumed to reflect local processing. There was no ASD by plausibility interaction and consequently little evidence for weak CC in the verbal domain when conceptualised as enhanced local processing. Furthermore, there was little evidence that the processing of syntactically ambiguous sentences differed as a function of ASD or language-impairment status

A Conceptual Analysis of Autistic Masking: Understanding the Narrative of Stigma and the Illusion of Choice

Autistic masking is an emerging research area that focuses on understanding the conscious or unconscious suppression of natural autistic responses and adoption of alternatives across a range of domains. It is suggested that masking may relate to negative outcomes for autistic people, including late/missed diagnosis, mental health issues, burnout, and suicidality. This makes it essential to understand what masking is, and why it occurs. In this conceptual analysis, we suggest that masking is an unsurprising response to the deficit narrative and accompanying stigma that has developed around autism. We outline how classical social theory (i.e., social identity theory) can help us to understand how and why people mask by situating masking in the social context in which it develops. We draw upon the literature on stigma and marginalization to examine how masking might intersect with different aspects of identity (e.g., gender). We argue that although masking might contribute toward disparities in diagnosis, it is important that we do not impose gender norms and stereotypes by associating masking with a “female autism phenotype.” Finally we provide recommendations for future research, stressing the need for increased understanding of the different ways that autism may present in different people (e.g., internalizing and externalizing) and intersectionality. We suggest that masking is examined through a sociodevelopmental lens, taking into account factors that contribute toward the initial development of the mask and that drive its maintenance

A literature-based similarity metric for biological processes

BACKGROUND: Recent analyses in systems biology pursue the discovery of functional modules within the cell. Recognition of such modules requires the integrative analysis of genome-wide experimental data together with available functional schemes. In this line, methods to bridge the gap between the abstract definitions of cellular processes in current schemes and the interlinked nature of biological networks are required. RESULTS: This work explores the use of the scientific literature to establish potential relationships among cellular processes. To this end we haveused a document based similarity method to compute pair-wise similarities of the biological processes described in the Gene Ontology (GO). The method has been applied to the biological processes annotated for the Saccharomyces cerevisiae genome. We compared our results with similarities obtained with two ontology-based metrics, as well as with gene product annotation relationships. We show that the literature-based metric conserves most direct ontological relationships, while reveals biologically sounded similarities that are not obtained using ontology-based metrics and/or genome annotation. CONCLUSION: The scientific literature is a valuable source of information from which to compute similarities among biological processes. The associations discovered by literature analysis are a valuable complement to those encoded in existing functional schemes, and those that arise by genome annotation. These similarities can be used to conveniently map the interlinked structure of cellular processes in a particular organism

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

Who is Responsible for Evaluating the Safety and Effectiveness of Medical Devices? The Role of Independent Technology Assessment

IntroductionThe global medical technology industry brings thousands of devices to market every year. However, significant gaps persist in the scientific literature, in the medical device approval process, and in the realm of postmarketing surveillance. Although thousands of drugs obtain approval only after review in randomized controlled trials, relatively few new medical devices are subject to comparable scrutiny.ObjectiveTo improve health outcomes, we must enhance our scrutiny of medical devices, and, without simply deferring to the Food and Drug Administration, we must ask ourselves: Who is responsible for evaluating the safety and effectiveness of medical devices?ConclusionsTechnology assessments by independent organizations are a part of the solution to this challenge and may motivate further research focused on patient outcomes