LGP2 plays a critical role in sensitizing mda-5 to activation by double-stranded RNA.

The DExD/H box RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation associated gene-5 (mda-5) sense viral RNA in the cytoplasm of infected cells and activate signal transduction pathways that trigger the production of type I interferons (IFNs). Laboratory of genetics and physiology 2 (LGP2) is thought to influence IFN production by regulating the activity of RIG-I and mda-5, although its mechanism of action is not known and its function is controversial. Here we show that expression of LGP2 potentiates IFN induction by polyinosinic-polycytidylic acid [poly(I:C)], commonly used as a synthetic mimic of viral dsRNA, and that this is particularly significant at limited levels of the inducer. The observed enhancement is mediated through co-operation with mda-5, which depends upon LGP2 for maximal activation in response to poly(I:C). This co-operation is dependent upon dsRNA binding by LGP2, and the presence of helicase domain IV, both of which are required for LGP2 to interact with mda-5. In contrast, although RIG-I can also be activated by poly(I:C), LGP2 does not have the ability to enhance IFN induction by RIG-I, and instead acts as an inhibitor of RIG-I-dependent poly(I:C) signaling. Thus the level of LGP2 expression is a critical factor in determining the cellular sensitivity to induction by dsRNA, and this may be important for rapid activation of the IFN response at early times post-infection when the levels of inducer are low

Influence of long-range dipolar interactions on the phase stability and hysteresis shapes of ferroelectric and antiferroelectric multilayers

Phase transition and field driven hysteresis evolution of a two-dimensional Ising grid consisting of ferroelectric-antiferroelectric multilayers that take into account the long range dipolar interactions were simulated by a Monte-Carlo method. Simulations were carried out for a 1+1 bilayer and a 5+5 superlattice. Phase stabilities of components comprising the structures with an electrostatic-like coupling term were also studied. An electrostatic-like coupling, in the absence of an applied field, can drive the ferroelectric layers towards 180º domains with very flat domain interfaces mainly due to the competition between this term and the dipole-dipole interaction. The antiferroelectric layers do not undergo an antiferroelectric-to-ferroelectric transition under the influence of an electrostatic-like coupling between layers as the ferroelectric layer splits into periodic domains at the expense of the domain wall energy. The long-range interactions become significant near the interfaces. For high periodicity structures with several interfaces, the interlayer long-range interactions substantially impact the configuration of the ferroelectric layers while the antiferroelectric layers remain quite stable unless these layers are near the Neel temperature. In systems investigated with several interfaces, the hysteresis loops do not exhibit a clear presence of antiferroelectricity that could be expected in the presence of anti-parallel dipoles, i. e., the switching takes place abruptly. Some recent experimental observations in ferroelectric-antiferroelectric multilayers are discussed where we conclude that the different electrical properties of bilayers and superlattices are not only due to strain effects alone but also long-range interactions. The latter manifests itself particularly in superlattices where layers are periodically exposed to each other at the interfaces

Neurophysiological evidence for rapid processing of verbal and gestural information in understanding communicative actions

During everyday social interaction, gestures are a fundamental part of human communication. The communicative pragmatic role of hand gestures and their interaction with spoken language has been documented at the earliest stage of language development, in which two types of indexical gestures are most prominent: the pointing gesture for directing attention to objects and the give-me gesture for making requests. Here we study, in adult human participants, the neurophysiological signatures of gestural-linguistic acts of communicating the pragmatic intentions of naming and requesting by simultaneously presenting written words and gestures. Already at ~150 ms, brain responses diverged between naming and request actions expressed by word-gesture combination, whereas the same gestures presented in isolation elicited their earliest neurophysiological dissociations significantly later (at ~210 ms). There was an early enhancement of request-evoked brain activity as compared with naming, which was due to sources in the frontocentral cortex, consistent with access to action knowledge in request understanding. In addition, an enhanced N400-like response indicated late semantic integration of gesture-language interaction. The present study demonstrates that word-gesture combinations used to express communicative pragmatic intentions speed up the brain correlates of comprehension processes – compared with gesture-only understanding – thereby calling into question current serial linguistic models viewing pragmatic function decoding at the end of a language comprehension cascade. Instead, information about the social-interactive role of communicative acts is processed instantaneously

An interdisciplinary intervention for older Taiwanese patients after surgery for hip fracture improves health-related quality of life

Abstract Background The effects of intervention programs on health-related quality of life (HRQOL) of patients with hip fracture have not been well studied. We hypothesized that older patients with hip fracture who received our interdisciplinary intervention program would have better HRQOL than those who did not. Methods A randomized experimental design was used. Older patients with hip fracture (N = 162), 60 to 98 years old, from a medical center in northern Taiwan were randomly assigned to an experimental (n = 80) or control (n = 82) group. HRQOL was measured by the SF-36 Taiwan version at 1, 3, 6, and 12 months after discharge. Results The experimental group had significantly better overall outcomes in bodily pain (β = 9.38, p = 0.002), vitality (β = 9.40, p < 0.001), mental health (β = 8.16, p = 0.004), physical function (β = 16.01, p < 0.001), and role physical (β = 22.66, p < 0.001) than the control group at any time point during the first year after discharge. Physical-related health outcomes (physical functioning, role physical, and vitality) had larger treatment effects than emotional/mental- and social functioning-related health outcomes. Conclusions This interdisciplinary intervention program may improve health outcomes of elders with hip fracture. Our results may provide a reference for health care providers in countries using similar programs with Chinese/Taiwanese immigrant populations. Trial registration NCT01052636http://deepblue.lib.umich.edu/bitstream/2027.42/78259/1/1471-2474-11-225.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78259/2/1471-2474-11-225.pdfPeer Reviewe

Chronic joint disease caused by persistent Chikungunya virus infection is controlled by the adaptive immune response

Chikungunya virus (CHIKV) is a reemerging mosquito-borne pathogen that causes incapacitating disease in humans characterized by intense joint pain that can persist for weeks, months, or even years. Although there is some evidence of persistent CHIKV infection in humans suffering from chronic rheumatologic disease symptoms, little is known about chronic disease pathogenesis, and no specific therapies exist for acute or chronic CHIKV disease. To investigate mechanisms of chronic CHIKV-induced disease, we utilized a mouse model and defined the duration of CHIKV infection in tissues and the associated histopathological changes. Although CHIKV RNA was readily detectable in a variety of tissues very early after infection, CHIKV RNA persisted specifically in joint-associated tissues for at least 16 weeks. Inoculation of Rag1(−/−) mice, which lack T and B cells, resulted in higher viral levels in a variety of tissues, suggesting that adaptive immunity controls the tissue specificity and persistence of CHIKV infection. The presence of CHIKV RNA in tissues of wild-type and Rag1(−/−) mice was associated with histopathological evidence of synovitis, arthritis, and tendonitis; thus, CHIKV-induced persistent arthritis is not mediated primarily by adaptive immune responses. Finally, we show that prophylactic administration of CHIKV-specific monoclonal antibodies prevented the establishment of CHIKV persistence, whereas therapeutic administration had tissue-specific efficacy. These findings suggest that chronic musculoskeletal tissue pathology is caused by persistent CHIKV infection and controlled by adaptive immune responses. Our results have significant implications for the development of strategies to mitigate the disease burden associated with CHIKV infection in humans

A monoclonal antibody raised against bacterially expressed MPV17 sequences shows peroxisomal, endosomal and lysosomal localisation in U2OS cells

Recessive mutations in the MPV17 gene cause mitochondrial DNA depletion syndrome, a fatal infantile genetic liver disease in humans. Loss of function in mice leads to glomerulosclerosis and sensineural deafness accompanied with mitochondrial DNA depletion. Mutations in the yeast homolog Sym1, and in the zebra fish homolog tra cause interesting, but not obviously related phenotypes, although the human gene can complement the yeast Sym1 mutation. The MPV17 protein is a hydrophobic membrane protein of 176 amino acids and unknown function. Initially localised in murine peroxisomes, it was later reported to be a mitochondrial inner membrane protein in humans and in yeast. To resolve this contradiction we tested two new mouse monoclonal antibodies directed against the human MPV17 protein in Western blots and immunohistochemistry on human U2OS cells. One of these monoclonal antibodies showed specific reactivity to a protein of 20 kD absent in MPV17 negative mouse cells. Immunofluorescence studies revealed colocalisation with peroxisomal, endosomal and lysosomal markers, but not with mitochondria. This data reveal a novel connection between a possible peroxisomal/endosomal/lysosomal function and mitochondrial DNA depletion

Assessing the impact of a health intervention via user-generated Internet content

Assessing the effect of a health-oriented intervention by traditional epidemiological methods is commonly based only on population segments that use healthcare services. Here we introduce a complementary framework for evaluating the impact of a targeted intervention, such as a vaccination campaign against an infectious disease, through a statistical analysis of user-generated content submitted on web platforms. Using supervised learning, we derive a nonlinear regression model for estimating the prevalence of a health event in a population from Internet data. This model is applied to identify control location groups that correlate historically with the areas, where a specific intervention campaign has taken place. We then determine the impact of the intervention by inferring a projection of the disease rates that could have emerged in the absence of a campaign. Our case study focuses on the influenza vaccination program that was launched in England during the 2013/14 season, and our observations consist of millions of geo-located search queries to the Bing search engine and posts on Twitter. The impact estimates derived from the application of the proposed statistical framework support conventional assessments of the campaign

Functional MRI evidence for the decline of word retrieval and generation during normal aging

International audienceThis fMRI study aimed to explore the effect of normal aging on word retrieval and generation. The question addressed is whether lexical production decline is determined by a direct mechanism, which concerns the language operations or is rather indirectly induced by a decline of executive functions. Indeed, the main hypothesis was that normal aging does not induce loss of lexical knowledge, but there is only a general slowdown in retrieval mechanisms involved in lexical processing , due to possible decline of the executive functions. We used three tasks (verbal fluency, object naming , and semantic categorization). Two groups of participants were tested (Young, Y and Aged, A), without cognitive and psychiatric impairment and showing similar levels of vocabulary. Neuropsychological testing revealed that older participants had lower executive function scores, longer processing speeds, and tended to have lower verbal fluency scores. Additionally, older participants showed higher scores for verbal automa-tisms and overlearned information. In terms of behav-ioral data, older participants performed as accurate as younger adults, but they were significantly slower for the semantic categorization and were less fluent for verbal fluency task. Functional MRI analyses suggested that older adults did not simply activate fewer brain regions involved in word production, but they actually showed an atypical pattern of activation. Significant correlations between the BOLD (Blood Oxygen Level Dependent) signal of aging-related (A > Y) regions and cognitive scores suggested that this atypical pattern of the activation may reveal several compensatory mechanisms (a) to overcome the slowdown in retrieval, due to the decline of executive functions and processing speed and (b) to inhibit verbal automatic processes. The BOLD signal measured in some other aging-dependent regions did not correlate with the behavioral and neuro-psychological scores, and the overactivation of these uncorrelated regions would simply reveal dedifferentia-tion that occurs with aging. Altogether, our results suggest that normal aging is associated with a more difficult access to lexico-semantic operations and representations by a slowdown in executive functions, without any conceptual loss

An ethnographic investigation of maternity healthcare experience of immigrants in rural and urban Alberta, Canada

Background: Canada is among the top immigrant-receiving nations in the world. Immigrant populations may face structural and individual barriers in the access to and navigation of healthcare services in a new country. The aims of the study were to (1) generate new understanding of the processes that perpetuate immigrant disadvantages in maternity healthcare, and (2) devise potential interventions that might improve maternity experiences and outcomes for immigrant women in Canada. Methods: The study utilized a qualitative research approach that focused on ethnographic research design and data analysis contextualized within theories of organizational behaviour and critical realism. Data were collected over 2.5 years using focus groups and in-depth semistructured interviews with immigrant women (n = 34), healthcare providers (n = 29), and social service providers (n = 23) in a Canadian province. Purposive samples of each subgroup were generated, and recruitment and data collection – including interpretation and verification of translations – were facilitated through the hiring of community researchers and collaborations with key informants. Results: The findings indicate that (a) communication difficulties, (b) lack of information, (c) lack of social support (isolation), (d) cultural beliefs, e) inadequate healthcare services, and (f) cost of medicine/services represent potential barriers to the access to and navigation of maternity services by immigrant women in Canada. Having successfully accessed and navigated services, immigrant women often face additional challenges that influence their level of satisfaction and quality of care, such as lack of understanding of the informed consent process, lack of regard by professionals for confidential patient information, short consultation times, short hospital stays, perceived discrimination/stereotyping, and culture shock. Conclusions: Although health service organizations and policies strive for universality and equality in service provision, personal and organizational barriers can limit care access, adequacy, and acceptability for immigrant women. A holistic healthcare approach must include health informational packages available in different languages/media. Health care professionals who care for diverse populations must be provided with training in cultural competence, and monitoring and evaluation programs to ameliorate personal and systemic discrimination

Gender differences in coerced patients with schizophrenia

European Commission (Quality of life and Management of Living Resources Programme, contract number QLG4-CT- 2002-01036), Czech Ministry of Education research grant MSM002160849, and research grants PRVOUK–P26/LF1/4 and PRVOUK–P03/LF1/