Salience Attribution and its Relationship to Cannabis-Induced Psychotic Symptoms

BACKGROUND: Cannabis is a widely used drug associated with increased risk for psychosis. The dopamine hypothesis of psychosis postulates that altered salience processing leads to psychosis. We therefore tested the hypothesis that cannabis users exhibit aberrant salience and explored the relationship between aberrant salience and dopamine synthesis capacity. METHODS: We tested 17 cannabis users and 17 age- and sex-matched non-user controls using the Salience Attribution Test (SAT), a probabilistic reward-learning task. Within users, cannabis-induced psychotic symptoms were measured with the Psychotomimetic States Inventory (PSI). Dopamine synthesis capacity, indexed as the influx rate constant Kicer, was measured in 10 users and 6 controls with 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine positron emission tomography. RESULTS: There was no significant difference in aberrant salience between the groups (F1,32 = 1.12, p=.30 [implicit]; F1,32=1.09, p=.30 [explicit]). Within users there was a significant positive relationship between cannabis-induced psychotic symptom severity and explicit aberrant salience scores (r=.61, p=.04) and there was a significant association between cannabis dependency/abuse status and high implicit aberrant salience scores (F1,15= 5.8, p=.03). Within controls, implicit aberrant salience was inversely correlated with whole striatal dopamine synthesis capacity (r=-.91, p=.01), whereas this relationship was non-significant within users (difference between correlations: Z=-2.05, p=.04). CONCLUSIONS: Aberrant salience is positively associated with cannabis-induced psychotic symptom severity, but is not seen in cannabis users overall. This is consistent with the hypothesis that the link between cannabis use and psychosis involves alterations in salience processing. Longitudinal studies are needed to determine whether these cognitive abnormalities are pre-existing or caused by long-term cannabis use

Asymmetric nexus between wages and productivity in the context of the global financial crisis

In the context of the breakdown of the wage-productivity nexus since the 2008–09 Global Financial Crisis, this study analyzes that nexus in the UK by accounting for potential asymmetries and nonlinearities. Employing a NARDL framework and data from 2000Q1 to 2018Q4, our key findings suggest that aggregate productivity and productivity within the retail sector have a significant and positive impact on aggregate wages and wages within the retail sector. However, there are important asymmetries and nonlinearities. The impact of productivity on wages in the retail sector is found to be many times smaller than that of aggregate productivity on aggregate wages across the economy as a whole. Economic growth, inflation and unemployment rates are found to have effects on wage growth over the short term. In the long run, it is productivity that is the sole statistically significant influence on wages. Our findings contribute to the debate on the productivity-wage nexus and have profound implications for the labour market and wage policies

Strain‐Promoted Cycloadditions in Lipid Bilayers Triggered by Liposome Fusion

Due to the variety of roles served by the cell membrane, its composition and structure are complex, making it difficult to study. Bioorthogonal reactions, such as the strain promoted azide-alkyne cycloaddition (SPAAC), are powerful tools for exploring the function of biomolecules in their native environment but have been largely unexplored within the context of lipid bilayers. Here, we developed a new approach to study the SPAAC reaction in liposomal membranes using azide- and strained alkyne-functionalized Förster resonance energy transfer (FRET) dye pairs. This study represents the first characterization of the SPAAC reaction between diffusing molecules inside liposomal membranes. Potential applications of this work include in situ bioorthogonal labeling of membrane proteins, improved understanding of membrane dynamics and fluidity, and the generation of new probes for biosensing assays

Differential production of type I IFN determines the reciprocal levels of IL-10 and proinflammatory cytokines produced by C57BL/6 and BALB/c macrophages

Pattern recognition receptors detect microbial products and induce cytokines, which shape the immunological response. IL-12, TNF-alpha, and IL-1 beta are proinflammatory cytokines, which are essential for resistance against infection, but when produced at high levels they may contribute to immunopathology. In contrast, IL-10 is an immunosuppressive cytokine, which dampens proinflammatory responses, but it can also lead to defective pathogen clearance. The regulation of these cytokines is therefore central to the generation of an effective but balanced immune response. In this study, we show that macrophages derived from C57BL/6 mice produce low levels of IL-12, TNF-alpha, and IL-1 beta, but high levels of IL-10, in response to TLR4 and TLR2 ligands LPS and Pam3CSK4, as well as Burkholderia pseudomallei, a Gram-negative bacterium that activates TLR2/4. In contrast, macrophages derived from BALB/c mice show a reciprocal pattern of cytokine production. Differential production of IL-10 in B. pseudomallei and LPS-stimulated C57BL/6 and BALB/c macrophages was due to a type I IFN and ERK1/2-dependent, but IL-27-independent, mechanism. Enhanced type I IFN expression in LPS-stimulated C57BL/6 macrophages was accompanied by increased STAT1 and IFN regulatory factor 3 activation. Furthermore, type I IFN contributed to differential IL-1 beta and IL-12 production in B. pseudomallei and LPS-stimulated C57BL/6 and BALB/c macrophages via both IL-10-dependent and -independent mechanisms. These findings highlight key pathways responsible for the regulation of pro- and anti-inflammatory cytokines in macrophages and reveal how they may differ according to the genetic background of the host.his work was supported by The Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001126), the U.K. Medical Research Council (FC001126), and the Wellcome Trust (FC001126) since April 1, 2015 and before that by U.K. Medical Research Council Grant MRC U117565642 and also by European Research Council Grant 294682-TB-PATH (Crick 10127). A.H. was additionally funded by a U.K. Medical Research Council Centenary Award. M.S. was funded by Fundação para a Ciência e Tecnologia, Portugal Grant FCT-ANR/BIM-MEC/ 0007/2013. M.S. is an associate Fundação para a Ciência e Tecnologia, Portugal investigator.info:eu-repo/semantics/publishedVersio

Mesolimbic Dopamine Function Is Related to Salience Network Connectivity: An Integrative Positron Emission Tomography and Magnetic Resonance Study

BACKGROUND: A wide range of neuropsychiatric disorders, from schizophrenia to drug addiction, involve abnormalities in both the mesolimbic dopamine system and the cortical salience network. Both systems play a key role in the detection of behaviorally relevant environmental stimuli. Although anatomical overlap exists, the functional relationship between these systems remains unknown. Preclinical research has suggested that the firing of mesolimbic dopamine neurons may activate nodes of the salience network, but in vivo human research is required given the species-specific nature of this network. METHODS: We employed positron emission tomography to measure both dopamine release capacity (using the D2/3 receptor ligand 11C-PHNO, n = 23) and dopamine synthesis capacity (using 18F-DOPA, n = 21) within the ventral striatum. Resting-state functional magnetic resonance imaging was also undertaken in the same individuals to investigate salience network functional connectivity. A graph theoretical approach was used to characterize the relationship between dopamine measures and network connectivity. RESULTS: Dopamine synthesis capacity was associated with greater salience network connectivity, and this relationship was particularly apparent for brain regions that act as information-processing hubs. In contrast, dopamine release capacity was associated with weaker salience network connectivity. There was no relationship between dopamine measures and visual and sensorimotor networks, indicating specificity of the findings. CONCLUSIONS: Our findings demonstrate a close relationship between the salience network and mesolimbic dopamine system, and they are relevant to neuropsychiatric illnesses in which aberrant functioning of both systems has been observed

Coastal risk mitigation by green infrastructure in Latin America

This paper aims to highlight the prevailing experiences of Latin America and to clarify what ‘green infrastructure’ entails in addition to describing seven case studies from a range of coastal ecosystems (wetlands, coastal dunes, beaches and coral reefs) at scales varying from local to regional. The case studies are categorised according to their degree of naturalness (nature-based, engineered ecosystems, soft engineering, ecologically enhanced hard infrastructure and de-engineering). Generally, the implementation of green infrastructure projects aims to increase resilience, enhance the provision of ecosystem services, recover biodiversity, reduce the negative effects of hard infrastructure and implement corrective measures. The greatest benefits of these projects relate to the creation of multi-functional spaces, which often combine the above advantages with improved opportunities for recreation and/or economic activities. It is hoped that this paper will disseminate the experience in green infrastructure among academics and practitioners and stimulate wider adoption of green infrastructure projects and good practices

A concept for trial institutions focussing on randomised controlled trials in surgery

<p>Abstract</p> <p>Background</p> <p>Although considered the reference standard for generating valid scientific evidence of a treatment's benefits and harms, the number of Randomised Controlled Trials (RCT) comparing surgical techniques remains low. Much effort has been made in order to overcome methodological issues and improve quality of RCTs in surgery. To the present there has been, however, only little emphasis on development and maintenance of institutions for implementation of adequately designed and conducted surgical RCTs.</p> <p>Mehods/Design</p> <p>Description of the developments in surgical RCT infrastructure in Germany between 2001 and 2006. Cross sectional evaluation of completed and ongoing surgical RCTs within the German Surgical Society and the Clinical Study Centre, Department of Surgery, University of Heidelberg.</p> <p>Results</p> <p>Foundation of a national Clinical Trial Centre (CTC) for the organisation of multi-centre RCTs in the surgical setting (Study Center of the German Surgical Society, SDGC). Establishment of a network of CTCs with affiliated Clinical Sites (CSs) to enhance patient recruitment and shorten the duration of RCTs. Since its foundation four surgical RCTs with a total sample size of 1650 patients (1006 of these randomised) have been supervised by the SDGC with 35 CSs involved in patient recruitment. Five further CTCs were set up in 2006. Together with their affiliated CSs a network has been organised providing improved conditions for the conduction of surgical RCTs.</p> <p>Conclusion</p> <p>Improvement of infrastructure substantially facilitates integration of RCTs into routine surgical practice. A network of collaborating CTCs and CSs can provide an adequate infrastructure for the conduction of multi-centre RCTs.</p

Accelerating the Gillespie τ-Leaping Method Using Graphics Processing Units

The Gillespie τ-Leaping Method is an approximate algorithm that is faster than the exact Direct Method (DM) due to the progression of the simulation with larger time steps. However, the procedure to compute the time leap τ is quite expensive. In this paper, we explore the acceleration of the τ-Leaping Method using Graphics Processing Unit (GPUs) for ultra-large networks ( reaction channels). We have developed data structures and algorithms that take advantage of the unique hardware architecture and available libraries. Our results show that we obtain a performance gain of over 60x when compared with the best conventional implementations

13C-phenylalanine breath test detects altered phenylalanine kinetics in schizophrenia patients

Phenylalanine is an essential amino acid required for the synthesis of catecholamines including dopamine. Altered levels of phenylalanine and its metabolites in blood and cerebrospinal fluid have been reported in schizophrenia patients. This study attempted to examine for the first time whether phenylalanine kinetics is altered in schizophrenia using L-[1-13C]phenylalanine breath test (13C-PBT). The subjects were 20 chronically medicated schizophrenia patients (DSM-IV) and the same number of age- and sex-matched controls. 13C-phenylalanine (99 atom% 13C; 100 mg) was administered orally and the breath 13CO2 /12CO2 ratio was monitored for 120 min. The possible effect of antipsychotic medication (risperidone (RPD) or haloperidol (HPD) treatment for 21 days) on 13C-PBT was examined in rats. Body weight (BW), age and diagnostic status were significant predictors of the area under the curve of the time course of Δ13CO2 (‰) and the cumulative recovery rate (CRR) at 120 min. A repeated measures analysis of covariance controlled for age and BW revealed that the patterns of CRR change over time differed between the patients and controls and that Δ13CO2 was lower in the patients than in the controls at all sampling time points during the 120 min test, with an overall significant difference between the two groups. Chronic administration of RPD or HPD had no significant effect on 13C-PBT indices in rats. Our results suggest that 13C-PBT is a novel laboratory test that can detect altered phenylalanine kinetics in chronic schizophrenia patients. Animal experiments suggest that the observed changes are unlikely to be attributable to antipsychotic medication

Measuring Reciprocity in High Functioning Children and Adolescents with Autism Spectrum Disorders

Few instruments have been developed that measure impairments in reciprocity, a defining feature of autism. We introduce a new test assessing the quality of reciprocal behaviour: the interactive drawing test (IDT). Children and adolescents (n = 49) with and without high functioning autism spectrum disorders (HFASD) were invited to collaborate with an experimenter in making a joint drawing. Within both groups the performance on collaborative reciprocity improved with age. However, compared to the control group, HFASD participants showed less collaborative and more basic reciprocal behaviour and preferred to draw their own objects. They were less tolerant of the experimenter’s input as well. Performance on the IDT was independent of estimated verbal IQ. Reciprocal behaviour in self-initiated objects corresponded with more parental reported autistic traits, while reciprocal behaviour in other-initiated objects corresponded with less autistic traits. The findings of this study suggest that IDT is a promising instrument to assess reciprocity