Epigenetic Modifications Mediate Experience-Induced Neuroplasticity; Relevance to the Etiology and Treatment of Posttraumatic Stress Disorder

Covalent chemical modifications, including the acetylation of core histone proteins and methylation of cytosine in or near promoter regions of DNA, influence the efficiency with which genes are transcribed. Chemical modifications that regulate gene expression within postmitotic differentiated neurons can reflect environmental influences, including exposure to stress. These chemical modifications or “marks” may reflect downstream consequences of the transduction of extracellular chemical messengers, such as neurotransmitters, growth factors and hormones, by receptors located at the surface of the neuron or within the cell itself. The ability to decipher the epigenetic code may serve as a record of early childhood adversity that sensitizes to additional epigenetic changes caused by traumatic exposures in adulthood. Further, epigenetic therapeutic interventions may be possible that would attenuate the severity of adverse consequences associated with traumatic exposures in the child and adult. Ideally, targeted epigenetic therapeutic interventions would address stress-induced dysregulation of the hypothalamic-pituitary-adrenal axis and promote expression of therapeutically beneficial neuroplasticity factors

Experimental Assessment of Mouse Sociability Using an Automated Image Processing Approach

Mouse is the preferred model organism for testing drugs designed to increase sociability. We present a method to quantify mouse sociability in which the test mouse is placed in a standardized apparatus and relevant behaviors are assessed in three different sessions (called session I, II, and III). The apparatus has three compartments (see Figure 1), the left and right compartments contain an inverted cup which can house a mouse (called “stimulus mouse”). In session I, the test mouse is placed in the cage and its mobility is characterized by the number of transitions made between compartments. In session II, a stimulus mouse is placed under one of the inverted cups and the sociability of the test mouse is quantified by the amounts of time it spends near the cup containing the enclosed stimulus mouse vs. the empty inverted cup. In session III, the inverted cups are removed and both mice interact freely. The sociability of the test mouse in session III is quantified by the number of social approaches it makes toward the stimulus mouse and by the number of times it avoids a social approach by the stimulus mouse. The automated evaluation of the movie detects the nose of the test mouse, which allows the determination of all described sociability measures in session I and II (in session III, approaches are identified automatically but classified manually). To find the nose, the image of an empty cage is digitally subtracted from each frame of the movie and the resulting image is binarized to identify the mouse pixels. The mouse tail is automatically removed and the two most distant points of the remaining mouse are determined; these are close to nose and base of tail. By analyzing the motion of the mouse and using continuity arguments, the nose is identified. © 2016 Journal of Visualized Experiments

Attention to Gaze and Emotion in Schizophrenia

Objective: Individuals with schizophrenia have difficulty interpreting social and emotional cues such as facial expression, gaze direction, body position, and voice intonation. Nonverbal cues are powerful social signals but are often processed implicitly, outside the focus of attention. The aim of this research was to assess implicit processing of social cues in individuals with schizophrenia. Method: Patients with schizophrenia or schizoaffective disorder and matched controls performed a primary task of word classification with social cues in the background. Participants were asked to classify target words (LEFT/RIGHT) by pressing a key that corresponded to the word, in the context of facial expressions with eye gaze averted to the left or right. Results: Although facial expression and gaze direction were irrelevant to the task, these facial cues influenced word classification performance. Participants were slower to classify target words (e.g., LEFT) that were incongruent to gaze direction (e.g., eyes averted to the right) compared to target words (e.g., LEFT) that were congruent to gaze direction (e.g., eyes averted to the left), but this only occurred for expressions of fear. This pattern did not differ for patients and controls. Conclusion: The results showed that threat-related signals capture the attention of individuals with schizophrenia. These data suggest that implicit processing of eye gaze and fearful expressions is intact in schizophrenia

Experimental Implementation of the Deutsch-Jozsa Algorithm for Three-Qubit Functions using Pure Coherent Molecular Superpositions

The Deutsch-Jozsa algorithm is experimentally demonstrated for three-qubit functions using pure coherent superpositions of Li$_{2}$ rovibrational eigenstates. The function's character, either constant or balanced, is evaluated by first imprinting the function, using a phase-shaped femtosecond pulse, on a coherent superposition of the molecular states, and then projecting the superposition onto an ionic final state, using a second femtosecond pulse at a specific time delay

Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk.

Variation in the human leukocyte antigen (HLA) genes accounts for one-half of the genetic risk in type 1 diabetes (T1D). Amino acid changes in the HLA-DR and HLA-DQ molecules mediate most of the risk, but extensive linkage disequilibrium complicates the localization of independent effects. Using 18,832 case-control samples, we localized the signal to 3 amino acid positions in HLA-DQ and HLA-DR. HLA-DQβ1 position 57 (previously known; P = 1 × 10(-1,355)) by itself explained 15.2% of the total phenotypic variance. Independent effects at HLA-DRβ1 positions 13 (P = 1 × 10(-721)) and 71 (P = 1 × 10(-95)) increased the proportion of variance explained to 26.9%. The three positions together explained 90% of the phenotypic variance in the HLA-DRB1-HLA-DQA1-HLA-DQB1 locus. Additionally, we observed significant interactions for 11 of 21 pairs of common HLA-DRB1-HLA-DQA1-HLA-DQB1 haplotypes (P = 1.6 × 10(-64)). HLA-DRβ1 positions 13 and 71 implicate the P4 pocket in the antigen-binding groove, thus pointing to another critical protein structure for T1D risk, in addition to the HLA-DQ P9 pocket.This research utilizes resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. This work is supported in part by funding from the National Institutes of Health (5R01AR062886-02 (PIdB), 1R01AR063759 (SR), 5U01GM092691-05 (SR), 1UH2AR067677-01 (SR), R01AR065183 (PIWdB)), a Doris Duke Clinical Scientist Development Award (SR), the Wellcome Trust (JAT) and the National Institute for Health Research (JAT and JMMH), and a Vernieuwingsimpuls VIDI Award (016.126.354) from the Netherlands Organization for Scientific Research (PIWdB). TLL was supported by the German Research Foundation (LE 2593/1-1 and LE 2593/2-1).This is the accepted manuscript. The final version is available at http://www.nature.com/ng/journal/v47/n8/full/ng.3353.html

Mapping genetic variations to three- dimensional protein structures to enhance variant interpretation: a proposed framework

The translation of personal genomics to precision medicine depends on the accurate interpretation of the multitude of genetic variants observed for each individual. However, even when genetic variants are predicted to modify a protein, their functional implications may be unclear. Many diseases are caused by genetic variants affecting important protein features, such as enzyme active sites or interaction interfaces. The scientific community has catalogued millions of genetic variants in genomic databases and thousands of protein structures in the Protein Data Bank. Mapping mutations onto three-dimensional (3D) structures enables atomic-level analyses of protein positions that may be important for the stability or formation of interactions; these may explain the effect of mutations and in some cases even open a path for targeted drug development. To accelerate progress in the integration of these data types, we held a two-day Gene Variation to 3D (GVto3D) workshop to report on the latest advances and to discuss unmet needs. The overarching goal of the workshop was to address the question: what can be done together as a community to advance the integration of genetic variants and 3D protein structures that could not be done by a single investigator or laboratory? Here we describe the workshop outcomes, review the state of the field, and propose the development of a framework with which to promote progress in this arena. The framework will include a set of standard formats, common ontologies, a common application programming interface to enable interoperation of the resources, and a Tool Registry to make it easy to find and apply the tools to specific analysis problems. Interoperability will enable integration of diverse data sources and tools and collaborative development of variant effect prediction methods