Modeling the functional genomics of autism using human neurons.

Human neural progenitors from a variety of sources present new opportunities to model aspects of human neuropsychiatric disease in vitro. Such in vitro models provide the advantages of a human genetic background combined with rapid and easy manipulation, making them highly useful adjuncts to animal models. Here, we examined whether a human neuronal culture system could be utilized to assess the transcriptional program involved in human neural differentiation and to model some of the molecular features of a neurodevelopmental disorder, such as autism. Primary normal human neuronal progenitors (NHNPs) were differentiated into a post-mitotic neuronal state through addition of specific growth factors and whole-genome gene expression was examined throughout a time course of neuronal differentiation. After 4 weeks of differentiation, a significant number of genes associated with autism spectrum disorders (ASDs) are either induced or repressed. This includes the ASD susceptibility gene neurexin 1, which showed a distinct pattern from neurexin 3 in vitro, and which we validated in vivo in fetal human brain. Using weighted gene co-expression network analysis, we visualized the network structure of transcriptional regulation, demonstrating via this unbiased analysis that a significant number of ASD candidate genes are coordinately regulated during the differentiation process. As NHNPs are genetically tractable and manipulable, they can be used to study both the effects of mutations in multiple ASD candidate genes on neuronal differentiation and gene expression in combination with the effects of potential therapeutic molecules. These data also provide a step towards better understanding of the signaling pathways disrupted in ASD

Effectiveness of physiotherapy exercise following hip arthroplasty for osteoarthritis: a systematic review of clinical trials

Background: Physiotherapy has long been a routine component of patient rehabilitation following hip joint replacement. The purpose of this systematic review was to evaluate the effectiveness of physiotherapy exercise after discharge from hospital on function, walking, range of motion, quality of life and muscle strength, for osteoarthritic patients following elective primary total hip arthroplasty. Methods: Design: Systematic review, using the Cochrane Collaboration Handbook for Systematic Reviews of Interventions and the Quorom Statement. Database searches: AMED, CINAHL, EMBASE, KingsFund, MEDLINE, Cochrane library (Cochrane reviews, Cochrane Central Register of Controlled Trials, DARE), PEDro, The Department of Health National Research Register. Handsearches: Physiotherapy, Physical Therapy, Journal of Bone and Joint Surgery (Britain) Conference Proceedings. No language restrictions were applied. Selection: Trials comparing physiotherapy exercise versus usual/standard care, or comparing two types of relevant exercise physiotherapy, following discharge from hospital after elective primary total hip replacement for osteoarthritis were reviewed. Outcomes: Functional activities of daily living, walking, quality of life, muscle strength and range of hip joint motion. Trial quality was extensively evaluated. Narrative synthesis plus meta-analytic summaries were performed to summarise the data. Results: 8 trials were identified. Trial quality was mixed. Generally poor trial quality, quantity and diversity prevented explanatory meta-analyses. The results were synthesised and meta-analytic summaries were used where possible to provide a formal summary of results. Results indicate that physiotherapy exercise after discharge following total hip replacement has the potential to benefit patients. Conclusion: Insufficient evidence exists to establish the effectiveness of physiotherapy exercise following primary hip replacement for osteoarthritis. Further well designed trials are required to determine the value of post discharge exercise following this increasingly common surgical procedure

Underperforming policy networks : the biopesticides network in the United Kingdom

Loosely integrated and incomplete policy networks have been neglected in the literature. They are important to consider in terms of understanding network underperformance. The effective delivery and formulation of policy requires networks that are not incomplete or underperforming. The biopesticides policy network in the United Kingdom is considered and its components identified with an emphasis on the lack of integration of retailers and environmental groups. The nature of the network constrains the actions of its agents and frustrates the achievement of policy goals. A study of this relatively immature policy network also allows for a focus on network formation. The state, via an external central government department, has been a key factor in the development of the network. Therefore, it is important to incorporate such factors more systematically into understandings of network formation. Feedback efforts from policy have increased interactions between productionist actors but the sphere of consumption remains insufficiently articulated

Differential Effect of Viable Versus Necrotic Neutrophils on Mycobacterium tuberculosis Growth and Cytokine Induction in Whole Blood.

Neutrophils exert both positive and negative influences on the host response to tuberculosis, but the mechanisms by which these differential effects are mediated are unknown. We studied the impact of live and dead neutrophils on the control of Mycobacterium tuberculosis using a whole blood bioluminescence-based assay, and assayed supernatant cytokine concentrations using Luminex™ technology and ELISA. CD15+ granulocyte depletion from blood prior to infection with M. tuberculosis-lux impaired control of mycobacteria by 96 h, with a greater effect than depletion of CD4+, CD8+, or CD14+ cells (p < 0.001). Augmentation of blood with viable granulocytes significantly improved control of mycobacteria by 96 h (p = 0.001), but augmentation with necrotic granulocytes had the opposite effect (p = 0.01). Both augmentations decreased supernatant concentrations of tumor necrosis factor and interleukin (IL)-12 p40/p70, but necrotic granulocyte augmentation also increased concentrations of IL-10, G-CSF, GM-CSF, and CCL2. Necrotic neutrophil augmentation reduced phagocytosis of FITC-labeled M. bovis BCG by all phagocytes, whereas viable neutrophil augmentation specifically reduced early uptake by CD14+ cells. The immunosuppressive effect of dead neutrophils required necrotic debris rather than supernatant. We conclude that viable neutrophils enhance control of M. tuberculosis in blood, but necrotic neutrophils have the opposite effect-the latter associated with induction of IL-10, growth factors, and chemoattractants. Our findings suggest a mechanism by which necrotic neutrophils may exert detrimental effects on the host response in active tuberculosis.Wellcome Trust (087754 to DL, 097684 to NB, 104803 and 203135 to RW, FC00110218 to Francis Crick Institute); Cancer Research UK (FC00110218 to Francis Crick Institute); Medical Research Council UK (FC00110218 to Francis Crick Institute); European Union (FP7-HEALTH-F3-2012-305578 to RW); National Research Foundation of South Africa (96841 to RW) and Barts Charity (MGU0292)

A flexible component-based robot control architecture for hormonal modulation of behaviour and affect

This document is the Accepted Manuscritpt of a paper published in Proceedings of 18th Annual Conference, TAROS 2017, Guildford, UK, July 19–21, 2017. Under embargo. Embargo end date: 20 July 2018. The final publication is available at Springer via https://link.springer.com/chapter/10.1007%2F978-3-319-64107-2_36. © 2017 Springer, Cham.In this paper we present the foundations of an architecture that will support the wider context of our work, which is to explore the link between affect, perception and behaviour from an embodied perspective and assess their relevance to Human Robot Interaction (HRI). Our approach builds upon existing affect-based architectures by combining artificial hormones with discrete abstract components that are designed with the explicit consideration of influencing, and being receptive to, the wider affective state of the robot

Distinguishing Asthma Phenotypes Using Machine Learning Approaches.

Asthma is not a single disease, but an umbrella term for a number of distinct diseases, each of which are caused by a distinct underlying pathophysiological mechanism. These discrete disease entities are often labelled as asthma endotypes. The discovery of different asthma subtypes has moved from subjective approaches in which putative phenotypes are assigned by experts to data-driven ones which incorporate machine learning. This review focuses on the methodological developments of one such machine learning technique-latent class analysis-and how it has contributed to distinguishing asthma and wheezing subtypes in childhood. It also gives a clinical perspective, presenting the findings of studies from the past 5 years that used this approach. The identification of true asthma endotypes may be a crucial step towards understanding their distinct pathophysiological mechanisms, which could ultimately lead to more precise prevention strategies, identification of novel therapeutic targets and the development of effective personalized therapies

The geography of recent genetic ancestry across Europe

The recent genealogical history of human populations is a complex mosaic formed by individual migration, large-scale population movements, and other demographic events. Population genomics datasets can provide a window into this recent history, as rare traces of recent shared genetic ancestry are detectable due to long segments of shared genomic material. We make use of genomic data for 2,257 Europeans (the POPRES dataset) to conduct one of the first surveys of recent genealogical ancestry over the past three thousand years at a continental scale. We detected 1.9 million shared genomic segments, and used the lengths of these to infer the distribution of shared ancestors across time and geography. We find that a pair of modern Europeans living in neighboring populations share around 10-50 genetic common ancestors from the last 1500 years, and upwards of 500 genetic ancestors from the previous 1000 years. These numbers drop off exponentially with geographic distance, but since genetic ancestry is rare, individuals from opposite ends of Europe are still expected to share millions of common genealogical ancestors over the last 1000 years. There is substantial regional variation in the number of shared genetic ancestors: especially high numbers of common ancestors between many eastern populations likely date to the Slavic and/or Hunnic expansions, while much lower levels of common ancestry in the Italian and Iberian peninsulas may indicate weaker demographic effects of Germanic expansions into these areas and/or more stably structured populations. Recent shared ancestry in modern Europeans is ubiquitous, and clearly shows the impact of both small-scale migration and large historical events. Population genomic datasets have considerable power to uncover recent demographic history, and will allow a much fuller picture of the close genealogical kinship of individuals across the world.Comment: Full size figures available from http://www.eve.ucdavis.edu/~plralph/research.html; or html version at http://ralphlab.usc.edu/ibd/ibd-paper/ibd-writeup.xhtm

Health service utilization patterns of primary care patients with osteoarthritis

Contains fulltext : 53455.pdf ( ) (Open Access)BACKGROUND: To assess factors associated with visits to GPs, orthopaedists, and non-physician practitioners of complementary medicine (alternative practitioners) by primary care patients with osteoarthritis (OA). METHODS: Cross-sectional survey among 1250 consecutively addressed patients from 75 primary care practices in Germany. All patients suffered from OA of the knee or hip according to ACR criteria. They received questionnaires collecting sociodemographic data, data about health service utilisation, prescriptions, comorbidities. They also included established instruments as the Arthritis Impact Measurement Scale (AIMS2-SF) to assess disease-specific quality of life and the Patient Health Questionnaire (PHQ-9) to assess depression. Hierarchical stepwise multiple linear regression models were used to reveal significant factors influencing health service utilization. RESULTS: 1021 of 1250 (81.6%) questionnaires were returned. Nonrespondents did not differ from participants. Factors associated with health service use (HSU) varied between providers of care. Not being in a partnership, achieving a high score on the PHQ-9, increased pain severity reflected in the "symptom" scale of the AIMS2-SF, and an increased number of drug prescriptions predicted a high frequency of GP visits. The PHQ-9 score was also a predictor for visits to orthopaedists, as were previous GP contacts, a high score in the "symptom" scale as well as a high score in the "lower limb scale" of the AIMS2-SF. Regarding visits to alternative practitioners, a high score in the AIMS -"social" scale was a positive predictor as older people were less likely to visit them. CONCLUSION: Our results emphasize the need for awareness of psychological factors contributing to the use of health care providers. Addressing the revealed factors associated with HSU appropriately may lead to decreased health care utilization. But further research is needed to assess how this can be done successfully

European admixture on the Micronesian island of Kosrae: lessons from complete genetic information

The architecture of natural variation present in a contemporary population is a result of multiple population genetic forces, including population bottleneck and expansion, selection, drift, and admixture. We seek to untangle the contribution of admixture to genetic diversity on the Micronesian island of Kosrae. Toward this goal, we used a complete genetic approach by combining a dense genome-wide map of 100 000 single-nucleotide polymorphisms (SNPs) with data from uniparental markers from the mitochondrial genome and the nonrecombining portion of the Y chromosome. These markers were typed in ∼3200 individuals from Kosrae, representing 80% of the adult population of the island. We developed novel software that uses SNP data to delineate ancestry for individual segments of the genome. Through this analysis, we determined that 39% of Kosraens have some European ancestry. However, the vast majority of admixed individuals (77%) have European alleles spanning less than 10% of their genomes. Data from uniparental markers show most of this admixture to be male, introduced in the late nineteenth century. Furthermore, pedigree analysis shows that the majority of European admixture on Kosrae is because of the contribution of one individual. This approach shows the benefit of combining information from autosomal and uniparental polymorphisms and provides new methodology for determining ancestry in a population