Synaptic and transcriptionally downregulated genes are associated with cortical thickness differences in autism.

Differences in cortical morphology-in particular, cortical volume, thickness and surface area-have been reported in individuals with autism. However, it is unclear what aspects of genetic and transcriptomic variation are associated with these differences. Here we investigate the genetic correlates of global cortical thickness differences (ΔCT) in children with autism. We used Partial Least Squares Regression (PLSR) on structural MRI data from 548 children (166 with autism, 295 neurotypical children and 87 children with ADHD) and cortical gene expression data from the Allen Institute for Brain Science to identify genetic correlates of ΔCT in autism. We identify that these genes are enriched for synaptic transmission pathways and explain significant variation in ΔCT. These genes are also significantly enriched for genes dysregulated in the autism post-mortem cortex (Odd Ratio (OR) = 1.11, Pcorrected  10-14), driven entirely by downregulated genes (OR = 1.87, Pcorrected  10-15). We validated the enrichment for downregulated genes in two independent data sets: Validation 1 (OR = 1.44, Pcorrected = 0.004) and Validation 2 (OR = 1.30; Pcorrected = 0.001). We conclude that transcriptionally downregulated genes implicated in autism are robustly associated with global changes in cortical thickness variability in children with autism

Reduction of Pavlovian bias in schizophrenia: Enhanced effects in clozapine-administered patients

The negative symptoms of schizophrenia (SZ) are associated with a pattern of reinforcement learning (RL) deficits likely related to degraded representations of reward values. However, the RL tasks used to date have required active responses to both reward and punishing stimuli. Pavlovian biases have been shown to affect performance on these tasks through invigoration of action to reward and inhibition of action to punishment, and may be partially responsible for the effects found in patients. Forty-five patients with schizophrenia and 30 demographically-matched controls completed a four-stimulus reinforcement learning task that crossed action ("Go" or "NoGo") and the valence of the optimal outcome (reward or punishment-avoidance), such that all combinations of action and outcome valence were tested. Behaviour was modelled using a six-parameter RL model and EEG was simultaneously recorded. Patients demonstrated a reduction in Pavlovian performance bias that was evident in a reduced Go bias across the full group. In a subset of patients administered clozapine, the reduction in Pavlovian bias was enhanced. The reduction in Pavlovian bias in SZ patients was accompanied by feedback processing differences at the time of the P3a component. The reduced Pavlovian bias in patients is suggested to be due to reduced fidelity in the communication between striatal regions and frontal cortex. It may also partially account for previous findings of poorer "Go-learning" in schizophrenia where "Go" responses or Pavlovian consistent responses are required for optimal performance. An attenuated P3a component dynamic in patients is consistent with a view that deficits in operant learning are due to impairments in adaptively using feedback to update representations of stimulus value

Zur Problematik der Kapazitaetsberechnung von Flugbetriebsflaechen auf Flugplaetzen

SIGLECopy held by FIZ Karlsruhe; available from UB/TIB Hannover / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

DRD3 gene and striatum in autism spectrum disorder

A single-nucleotide polymorphism (SNP) of the DRD3 gene (rs167771) was recently associated with autism spectrum disorders (ASD). Different polymorphisms of rs167771 corresponded to varying degrees of stereotyped behaviour. As DRD3 receptors are relatively overexpressed in the striatum, we investigated whether striatal volume was related to these polymorphisms in autism. We assessed volumes of caudate nucleus and putamen in 86 participants with ASD (mean age 15.3 years). MANCOVA showed an association between alleles of the rs167771 SNP and the volume of striatal structures. Furthermore, greater caudate nucleus volume correlated with stereotyped behaviour. These findings support a relationship between DRD3 gene SNPs, striatum and stereotyped behaviour in ASD

Psychopathological symptoms associated with synthetic cannabinoid use: a comparison with natural cannabis

Background: Synthetic cannabinoids (SCs) are a class of new psychoactive substances that have been rapidly evolving around the world throughout recent years. Many different synthetic cannabinoid analogues are on the consumer market and sold under misleading names, like “spice” or “incense.” A limited number of studies have reported serious health effects associated with SC use. In this study, we compared clinical and subclinical psychopathological symptoms associated with SC use and natural cannabis (NC) use. Methods: A convenience sample of 367 NC and SC users was recruited online, including four validated psychometric questionnaires: The Drug Use Disorders Identification Test (DUDIT), Insomnia Severity Index (ISI), Altman Mania Scale (Altman), and Brief Symptom Inventory (BSI). The two groups were compared with analysis of variance (ANOVA) and covariance (ANCOVA), chi2 tests, and logistic regression when appropriate. Results: The SC user group did not differ in age from the NC user group (27.7 years), but contained less females (21% and 30%, respectively). SC users scored higher than NC users on all used psychometric measures, indicating a higher likelihood of drug abuse, sleep problems, (hypo)manic symptoms, and the nine dimensions comprising the BSI, somatization, obsessive-compulsive behavior, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism. Odds ratios (95% CI) for the SC user group vs NC user group were, respectively, drug dependence 3.56 (1.77–7.16), (severe) insomnia 5.01 (2.10–11.92), (hypo-)mania 5.18 (2.04–13.14), and BSI psychopathology 5.21 (2.96–9.17). Discussion: This study shows that SC use is associated with increased mental health symptomatology compared to NC use

Cooperative function of CCR7 and lymphotoxin in the formation of a lymphoma-permissive niche within murine secondary lymphoid organs

Lymphoma cell survival and progression is putatively dependent on a specific microanatomical localisation within secondary lymphoid organs. Despite compelling data correlating homeostatic chemokine receptor expression and human lymphoma pathogenesis, genetic models that either mimic lymphoma dissemination or dissect a crosstalk of lymphoma and stromal cells are missing. Applying the genetically tractable Emu-Myc transgenic mouse model, we show that the chemokine receptor CCR7 regulates Emu-Myc lymphoma homing to lymph nodes and distinctive microanatomic sites of the spleen. CCR7-controlled access of lymphoma cells to the splenic T cell zone led to a significant survival advantage compared to CCR7-deficient lymphoma cells which were excluded from this zone. Within the niche, lymphoma cells stimulated a reciprocal crosstalk with gp38(+) fibroblastic reticular cells. This reciprocal cooperation program was mediated by lymphoma B cell-presented lymphotoxin which acted on lymphotoxin beta receptor-bearing stromal cells followed by alteration of stromal cellular composition. Crosstalk inhibition by lymphotoxin alpha deletion and by employing a lymphotoxin beta receptor-immunoglobulin fusion protein impaired lymphoma growth. Thus, abrogation of CCR7-governed migration and of sustained lymphotoxin signaling could provide new targets in lymphoma therapy