Subbarrel patterns in somatosensory cortical barrels can emerge from local dynamic instabilities

Complex spatial patterning, common in the brain as well as in other biological systems, can emerge as a result of dynamic interactions that occur locally within developing structures. In the rodent somatosensory cortex, groups of neurons called "barrels" correspond to individual whiskers on the contralateral face. Barrels themselves often contain subbarrels organized into one of a few characteristic patterns. Here we demonstrate that similar patterns can be simulated by means of local growth-promoting and growth-retarding interactions within the circular domains of single barrels. The model correctly predicts that larger barrels contain more spatially complex subbarrel patterns, suggesting that the development of barrels and of the patterns within them may be understood in terms of some relatively simple dynamic processes. We also simulate the full nonlinear equations to demonstrate the predictive value of our linear analysis. Finally, we show that the pattern formation is robust with respect to the geometry of the barrel by simulating patterns on a realistically shaped barrel domain. This work shows how simple pattern forming mechanisms can explain neural wiring both qualitatively and quantitatively even in complex and irregular domains. © 2009 Ermentrout et al

Anxiety and Depression in Adults with Autism Spectrum Disorder: A Systematic Review and Meta-analysis

Adults with autism spectrum disorder (ASD) are thought to be at disproportionate risk of developing mental health comorbidities, with anxiety and depression being considered most prominent amongst these. Yet, no systematic review has been carried out to date to examine rates of both anxiety and depression focusing specifically on adults with ASD. This systematic review and meta-analysis examined the rates of anxiety and depression in adults with ASD and the impact of factors such as assessment methods and presence of comorbid intellectual disability (ID) diagnosis on estimated prevalence rates. Electronic database searches for studies published between January 2000 and September 2017 identified a total of 35 studies, including 30 studies measuring anxiety (n = 26 070; mean age = 30.9, s.d. = 6.2 years) and 29 studies measuring depression (n = 26 117; mean age = 31.1, s.d. = 6.8 years). The pooled estimation of current and lifetime prevalence for adults with ASD were 27% and 42% for any anxiety disorder, and 23% and 37% for depressive disorder. Further analyses revealed that the use of questionnaire measures and the presence of ID may significantly influence estimates of prevalence. The current literature suffers from a high degree of heterogeneity in study method and an overreliance on clinical samples. These results highlight the importance of community-based studies and the identification and inclusion of well-characterized samples to reduce heterogeneity and bias in estimates of prevalence for comorbidity in adults with ASD and other populations with complex psychiatric presentations

An untargeted multi-technique metabolomics approach to studying intracellular metabolites of HepG2 cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin

<p>Abstract</p> <p>Background</p> <p><it>In vitro </it>cell systems together with omics methods represent promising alternatives to conventional animal models for toxicity testing. Transcriptomic and proteomic approaches have been widely applied <it>in vitro </it>but relatively few studies have used metabolomics. Therefore, the goal of the present study was to develop an untargeted methodology for performing reproducible metabolomics on <it>in vitro </it>systems. The human liver cell line HepG2, and the well-known hepatotoxic and non-genotoxic carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), were used as the <it>in vitro </it>model system and model toxicant, respectively.</p> <p>Results</p> <p>The study focused on the analysis of intracellular metabolites using NMR, LC-MS and GC-MS, with emphasis on the reproducibility and repeatability of the data. State of the art pre-processing and alignment tools and multivariate statistics were used to detect significantly altered levels of metabolites after exposing HepG2 cells to TCDD. Several metabolites identified using databases, literature and LC-nanomate-Orbitrap analysis were affected by the treatment. The observed changes in metabolite levels are discussed in relation to the reported effects of TCDD.</p> <p>Conclusions</p> <p>Untargeted profiling of the polar and apolar metabolites of <it>in vitro </it>cultured HepG2 cells is a valid approach to studying the effects of TCDD on the cell metabolome. The approach described in this research demonstrates that highly reproducible experiments and correct normalization of the datasets are essential for obtaining reliable results. The effects of TCDD on HepG2 cells reported herein are in agreement with previous studies and serve to validate the procedures used in the present work.</p

Unfolded protein response is an early, non-critical event during hepatic stellate cell activation.

Hepatic stellate cells activate upon liver injury and help at restoring damaged tissue by producing extracellular matrix proteins. A drastic increase in matrix proteins results in liver fibrosis and we hypothesize that this sudden increase leads to accumulation of proteins in the endoplasmic reticulum and its compensatory mechanism, the unfolded protein response. We indeed observe a very early, but transient induction of unfolded protein response genes during activation of primary mouse hepatic stellate cells in vitro and in vivo, prior to induction of classical stellate cell activation genes. This unfolded protein response does not seem sufficient to drive stellate cell activation on its own, as chemical induction of endoplasmic reticulum stress with tunicamycin in 3D cultured, quiescent stellate cells is not able to induce stellate cell activation. Inhibition of Jnk is important for the transduction of the unfolded protein response. Stellate cells isolated from Jnk knockout mice do not activate as much as their wild-type counterparts and do not have an induced expression of unfolded protein response genes. A timely termination of the unfolded protein response is essential to prevent endoplasmic reticulum stress-related apoptosis. A pathway known to be involved in this termination is the non-sense-mediated decay pathway. Non-sense-mediated decay inhibitors influence the unfolded protein response at early time points during stellate cell activation. Our data suggest that UPR in HSCs is differentially regulated between acute and chronic stages of the activation process. In conclusion, our data demonstrates that the unfolded protein response is a JNK1-dependent early event during hepatic stellate cell activation, which is counteracted by non-sense-mediated decay and is not sufficient to drive the stellate cell activation process. Therapeutic strategies based on UPR or NMD modulation might interfere with fibrosis, but will remain challenging because of the feedback mechanisms between the stress pathways