Willed action and its impairment in schizophrenia

Schizophrenia is a disabling psychiatric disorder characterised by positive symptoms (those which the patients experience and are abnormal by their presence such as hallucinations) and negative signs (when the patients lack some element of normal behaviour such as poverty of speech). Frith (1992) suggested that some of the signs and symptoms of schizophrenia reflect a dysfunction of "willed" actions while the processes involved in "stimulus driven" actions remain largely intact. The patients can perform routine acts elicited by environmental stimuli, but have difficulty in producing spontaneous behaviour in the absence of external cues. The aim of this thesis is to examine this hypothesis using a variety of experimental paradigms and procedures to asses willed initiation and preparation as well as willed suppression of action in schizophrenia. The aim of Study 1 was to assess the initiation and preparation of willed actions in 10 patients with schizophrenia and 13 controls using reaction time (RT) tasks that differ in the degree to which they involve volitionally controlled versus stimulus-driven responses. Study 2 examined performance of 11 patients with schizophrenia and 13 normal controls on two motor tasks (placing pegs in a pegboard and repetitive index finger tapping) under unimanual, bimanual and dual task conditions. The aim of Study 3 was to examine the above hypothesis by measuring movement related potentials (MRPs) prior to self-initiated and externally-triggered movements in three groups: 6 patients with schizophrenia with high ratings of negative signs, 5 patients with of schizophrenia with high ratings of positive symptoms and 6 normal controls. Studies 4, 5 and 6 examined willed suppression. Go no-go RT tests have both a relevant stimulus requiring a response and to-be-ignored stimuli requiring the response to be withheld, i.e. response inhibition. The aim of Study 4 was to examine the ability to withhold a response in conditions with increased complexity of decision-making for identifying 'go' stimuli in 14 patients with schizophrenia and 12 normal controls. The aim of Study 5 was to examine the ability to withhold a response in conditions with greater dimensional overlap between the non-target no-go and the target go stimuli in 14 patients with schizophrenia and 12 normal controls. The patients were divided into two groups, the 'high symptom' group consisted of the 7 patients with ratings of positive symptoms higher than the group median of 9, and the 'low symptom' group consisted of the 7 patients with positive symptom ratings below 9. The patients with 'high symptom' ratings had slower RTs than the controls which were significant for the SRT conditions of both tasks, and approached significance for the CRT conditions of both tasks. The differences in SRT or CRT between the 'low symptom' group and the controls were not statistically significant for either task. In Study 5 the controls showed greater slowing between CRT1 and CRT2 than between CRT2 and CRT3, whereas the RTs of 'low symptom' patients did not differ at all between CRT1 and CRT2 and slowed greatly for CRT3. Both patient groups had slower response times than controls in the Hayling test, and produced significantly fewer words in the alternating word fluency task compared to the controls. Performance on the cognitive tasks correlated with performance on the no-go tasks. Negative priming refers to the slowing of reaction times that occurs when an ignored distractor stimulus in a first trial (prime) becomes the target stimulus in the subsequent trial (probe) (Tipper, 1985). Unlike normal controls, patients with schizophrenia fail to show significant negative priming, that is, the significant delay of reaction times on probe trials are not present (Beech et al., 1989; David, 1995). The aim of study 6 was to examine the spatial negative priming effect in schizophrenia using a new paradigm that allows the effects of perceptual mismatch on RT to be considered independently of any spatial negative priming effects. The patients with schizophrenia did not show any spatial negative priming in conditions with or without perceptual mismatch. These results constitute the first unequivocal demonstration of impaired inhibitory processes in schizophrenia based on reduced negative priming effects. These results provide some overall but not uniformly consistent support for the hypothesis that patients with schizophrenia have an impairment in willed action while stimulus driven action remains intact. (Abstract shortened by UMI.

Activation of the innate immune receptor Dectin-1 upon formation of a 'phagocytic synapse'.

Innate immune cells must be able to distinguish between direct binding to microbes and detection of components shed from the surface of microbes located at a distance. Dectin-1 (also known as CLEC7A) is a pattern-recognition receptor expressed by myeloid phagocytes (macrophages, dendritic cells and neutrophils) that detects β-glucans in fungal cell walls and triggers direct cellular antimicrobial activity, including phagocytosis and production of reactive oxygen species (ROS). In contrast to inflammatory responses stimulated upon detection of soluble ligands by other pattern-recognition receptors, such as Toll-like receptors (TLRs), these responses are only useful when a cell comes into direct contact with a microbe and must not be spuriously activated by soluble stimuli. In this study we show that, despite its ability to bind both soluble and particulate β-glucan polymers, Dectin-1 signalling is only activated by particulate β-glucans, which cluster the receptor in synapse-like structures from which regulatory tyrosine phosphatases CD45 and CD148 (also known as PTPRC and PTPRJ, respectively) are excluded (Supplementary Fig. 1). The 'phagocytic synapse' now provides a model mechanism by which innate immune receptors can distinguish direct microbial contact from detection of microbes at a distance, thereby initiating direct cellular antimicrobial responses only when they are required

Bridging topological and functional information in protein interaction networks by short loops profiling

Protein-protein interaction networks (PPINs) have been employed to identify potential novel interconnections between proteins as well as crucial cellular functions. In this study we identify fundamental principles of PPIN topologies by analysing network motifs of short loops, which are small cyclic interactions of between 3 and 6 proteins. We compared 30 PPINs with corresponding randomised null models and examined the occurrence of common biological functions in loops extracted from a cross-validated high-confidence dataset of 622 human protein complexes. We demonstrate that loops are an intrinsic feature of PPINs and that specific cell functions are predominantly performed by loops of different lengths. Topologically, we find that loops are strongly related to the accuracy of PPINs and define a core of interactions with high resilience. The identification of this core and the analysis of loop composition are promising tools to assess PPIN quality and to uncover possible biases from experimental detection methods. More than 96% of loops share at least one biological function, with enrichment of cellular functions related to mRNA metabolic processing and the cell cycle. Our analyses suggest that these motifs can be used in the design of targeted experiments for functional phenotype detection.This research was supported by the Biotechnology and Biological Sciences Research Council (BB/H018409/1 to AP, ACCC and FF, and BB/J016284/1 to NSBT) and by the Leukaemia & Lymphoma Research (to NSBT and FF). SSC is funded by a Leukaemia & Lymphoma Research Gordon Piller PhD Studentship

Mixing of Active and Sterile Neutrinos

We investigate mixing of neutrinos in the $\nu$MSM (neutrino Minimal Standard Model), which is the MSM extended by three right-handed neutrinos. Especially, we study elements of the mixing matrix $\Theta_{\alpha I}$ between three left-handed neutrinos $\nu_\alpha$ ($\alpha = e,\mu,\tau$) and two sterile neutrinos $N_I$ ($I=2,3$) which are responsible to the seesaw mechanism generating the suppressed masses of active neutrinos as well as the generation of the baryon asymmetry of the universe (BAU). It is shown that $\Theta_{eI}$ can be suppressed by many orders of magnitude compared with $\Theta_{\mu I}$ and $\Theta_{\tau I}$, when the Chooz angle $\theta_{13}$ is large in the normal hierarchy of active neutrino masses. We then discuss the neutrinoless double beta decay in this framework by taking into account the contributions not only from active neutrinos but also from all the three sterile neutrinos. It is shown that $N_2$ and $N_3$ give substantial, destructive contributions when their masses are smaller than a few 100 MeV, and as a results $\Theta_{e I}$ receive no stringent constraint from the current bounds on such decay. Finally, we discuss the impacts of the obtained results on the direct searches of $N_{2,3}$ in meson decays for the case when $N_{2,3}$ are lighter than pion mass. We show that there exists the allowed region for $N_{2,3}$ with such small masses in the normal hierarchy case even if the current bound on the lifetimes of $N_{2,3}$ from the big bang nucleosynthesis is imposed. It is also pointed out that the direct search by using $\pi^+ \to e^+ + N_{2,3}$ and $K^+ \to e^+ + N_{2,3}$ might miss such $N_{2,3}$ since the branching ratios can be extremely small due to the cancellation in $\Theta_{eI}$, but the search by $K^+ \to \mu^+ + N_{2,3}$ can cover the whole allowed region by improving the measurement of the branching ratio by a factor of 5.Comment: 30 pages, 32 figure

Barriers to following dietary recommendations in Type 2 diabetes

Aims  To evaluate barriers to following dietary recommendations in patients with Type 2 diabetes. Methods  We conducted focus groups and surveys in urban and suburban VA and academic medical centres. For the written survey, a self-administered questionnaire was mailed to a random sample of 446 patients with diabetes. For the focus groups, six groups of patients with diabetes (three urban, three suburban) were conducted, with 6–12 participants in each group. The focus groups explored barriers across various types of diabetes self-management; we extracted all comments relevant to barriers that limited patients’ ability to follow a recommended diet. Results  The written survey measured the burden of diabetes therapies (on a seven-point rating scale). Moderate diet was seen as a greater burden than oral agents (median 1 vs. 0, P  = 0.001), but less of a burden than insulin (median 1 vs. 4, P  < 0.001). A strict diet aimed at weight loss was rated as being similarly burdensome to insulin (median 4 vs. 4, P  = NS). Despite this, self-reported adherence was much higher for both pills and insulin than it was for a moderate diet. In the focus groups, the most commonly identified barrier was the cost (14/14 reviews), followed by small portion sizes (13/14 reviews), support and family issues (13/14 reviews), and quality of life and lifestyle issues (12/14 reviews). Patients in the urban site, who were predominantly African-American, noted greater difficulties communicating with their provider about diet and social circumstances, and also that the rigid schedule of a diabetes diet was problematic. Conclusions  Barriers to adherence to dietary therapies are numerous, but some, such as cost, and in the urban setting, communication with providers, are potentially remediable. Interventions aimed at improving patients’ ability to modify their diet need to specifically address these areas. Furthermore, treatment guidelines need to consider patients’ preferences and barriers when setting goals for treatment. Diabet. Med. (2004)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73213/1/j.1464-5491.2004.01342.x.pd

A quick guide for building a successful bioinformatics community

“Scientific community” refers to a group of people collaborating together on scientific-research-related activities who also share common goals, interests, and values. Such communities play a key role in many bioinformatics activities. Communities may be linked to a specific location or institute, or involve people working at many different institutions and locations. Education and training is typically an important component of these communities, providing a valuable context in which to develop skills and expertise, while also strengthening links and relationships within the community. Scientific communities facilitate: (i) the exchange and development of ideas and expertise; (ii) career development; (iii) coordinated funding activities; (iv) interactions and engagement with professionals from other fields; and (v) other activities beneficial to individual participants, communities, and the scientific field as a whole. It is thus beneficial at many different levels to understand the general features of successful, high-impact bioinformatics communities; how individual participants can contribute to the success of these communities; and the role of education and training within these communities. We present here a quick guide to building and maintaining a successful, high-impact bioinformatics community, along with an overview of the general benefits of participating in such communities. This article grew out of contributions made by organizers, presenters, panelists, and other participants of the ISMB/ECCB 2013 workshop “The ‘How To Guide’ for Establishing a Successful Bioinformatics Network” at the 21st Annual International Conference on Intelligent Systems for Molecular Biology (ISMB) and the 12th European Conference on Computational Biology (ECCB)

Assessing the perceived impact of post Minamata amalgam phase down on oral health inequalities: a mixed-methods investigation

Background: Data from countries that have implemented a complete phase out of dental amalgam following the Minamata agreement suggest increased costs and time related to the placement of alternatives with consumers absorbing the additional costs. This aim of this study was to investigate the impact of a complete phase out of dental amalgam on oral health inequalities in particular for countries dependent on state run oral health services. Methods: A mixed methods component design quantitative and qualitative study in the United Kingdom. The quantitative study involved acquisition and analysis of datasets from NHS Scotland to compare trends in placement of dental amalgam and a survey of GDPs in Yorkshire, UK. The qualitative study involved analysis of the free text of the survey and a supplementary secondary analysis of semi-structured interviews and focus groups with GDPs (private and NHS), dental school teaching leads and NHS dental commissioners to understand the impact of amalgam phase down on oral health inequalities. Results: Time-trends for amalgam placement showed that there was a significant (p < 0.05) reduction in amalgam use compared with composites and glass ionomers. However dental amalgam still represented a large proportion (42%) of the restorations (circa 1.8 million) placed in the 2016–2017 financial year. Survey respondents suggest that direct impacts of a phase down were related to increased costs and time to place alternative restorations and reduced quality of care. This in turn would lead to increased tooth extractions, reduced access to care and privatisation of dental services with the greatest impact on deprived populations. Conclusion: Amalgam is still a widely placed material in state run oral health services. The complete phase down of dental amalgam poses a threat to such services and threatens to widen oral health inequalities. Our data suggest that a complete phase out is not currently feasible unless appropriate measures are in place to ensure cheaper, long-lasting and easy to use alternatives are available and can be readily adopted by primary care oral health providers

The development of a body comparison measure: the CoSS

Purpose This study reports on the development and validation of a brief and widely applicable measure of body comparison (the Comparison of Self-Scale—CoSS), which is a maintaining feature of eating disorders. Methods A sample of 412 adults completed the CoSS, an existing measure of aspects of body comparison, and eating pathology and associated states. Test–retest reliability was examined over 2 weeks. Results Exploratory factor analysis showed that 22 CoSS items loaded onto two factors, resulting in two scales—Appearance Comparison and Social Comparison—with strong internal consistency and test–retest reliability. Conclusions In clinical terms, the CoSS was superior to the existing measure of body comparison in accounting for depression and anxiety. Given that it is a relatively brief measure, the CoSS could be useful in the routine assessment of body comparison, and in formulating and treating individuals with body image concerns. However, the measure awaits full clinical validation

Why Rice Farmers Don't Sail: Coastal Subsistence Traditions and Maritime Trends in Early China

The Lower Yangtze River Valley is a key region for the early development of rice farming and the emergence of wet rice paddy field systems. Subsistence evidence from Neolithic sites in this area highlights the importance of freshwater wetlands for both plant and animal food resources. Early Neolithic rice cultivators looked inland, especially to wetlands and nearby woodlands, for their main protein sources. Links to the sea among these Neolithic populations are notably scarce. Due to the high yields of wet rice, compared with other staple crops as well as dryland rice, the wetland rice focused subsistence strategy of the Lower Yangtze would have supported high, and increasing, local population densities. Paddy agriculture demands labor input and water management on a large scale, which would have stimulated and reinforced trends towards more complex societies, such as that represented by Liangzhu in the lower Yangtze region. Population growth could have been largely absorbed locally, suggesting that population packing, not migration, was the dominant trend. Other case studies of agricultural dispersal, for the Korean Peninsula and Japan further illustrate the lack of correlation between the spread of rice agriculture and wet rice cultivation. Although wet rice cultivation was a pull factor that drew local populations towards increased density and increased social complexity, it did not apparently push groups to migrate outwards. Instead, the transition from wetland to rain fed rice cultivation systems and/or the integration of rice with rain fed millet crops are much more likely to have driven the demographic dynamics that underpin early farmer migrations and crop dispersal

Insights into the Molecular Basis of L-Form Formation and Survival in Escherichia coli

L-forms have been shown to occur among many species of bacteria and are suspected to be involved in persistent infections. Since their discovery in 1935, numerous studies characterizing L-form morphology, growth, and pathogenic potential have been conducted. However, the molecular mechanisms underlying the formation and survival of L-forms remain unknown. Using unstable L-form colonies of Escherichia coli as a model, we performed genome-wide transcriptome analysis and screened a deletion mutant library to study the molecular mechanisms involved in formation and survival of L-forms. Microarray analysis of L-form versus classical colonies revealed many up-regulated genes of unknown function as well as multiple over-expressed stress pathways shared in common with persister cells and biofilms. Mutant screens identified three groups of mutants which displayed varying degrees of defects in L-form colony formation. Group 1 mutants, which showed the strongest defect in L-form colony formation, belonged to pathways involved in cell envelope stress, DNA repair, iron homeostasis, outer membrane biogenesis, and drug efflux/ABC transporters. Four (Group 1) mutants, rcsB, a positive response regulator of colanic acid capsule synthesis, ruvA, a recombinational junction binding protein, fur, a ferric uptake regulator and smpA a small membrane lipoprotein were selected for complementation. Complementation of the mutants using a high-copy overexpression vector failed, while utilization of a low-copy inducible vector successfully restored L-form formation. This work represents the first systematic genetic evaluation of genes and pathways involved in the formation and survival of unstable L-form bacteria. Our findings provide new insights into the molecular mechanisms underlying L-form formation and survival and have implications for understanding the emergence of antibiotic resistance, bacterial persistence and latent infections and designing novel drugs and vaccines