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The present study is aimed to identify the effect of gratitude as an adaptive regulating mechanism from suicidal ideation (SI) for veterans with mental illness (study 1) and student veterans with posttraumatic stress disorder (PTSD) symptoms (study 2) in the United States. Descriptive statistics and regression analyses were used to examine sociodemographic characteristics and relationships between gratitude and SI. Our study 1 consisted of 156 veterans with mental illness. The mean age for study 1 was 37.85. Our study 2 consisted of 232 student veterans with PTSD symptoms. The mean age for study 2 was 28.43. Higher gratitude scores in study 1 and study 2 were significantly associated with lower SI scores after adjusting for demographics and depression. This study partially supports the association between gratitude and SI in veterans with mental illness. Based on the results from this study, gratitude interventions may be effective in reducing SI when working with veterans with mental illness.

The cockroach allergen Bla g 1 forms a novel fold consisting of 12 amphipathic alpha-helices enclosing an exceptionally large hydrophobic cavity which was previously demonstrated to bind a variety of lipids. Since lipid-dependent immunoactivity is observed in numerous allergens, understanding the structural basis of this interaction could yield insights into the molecular determinants of allergenicity. Here, we report atomic modelling of Bla g 1 bound to both fatty-acid and phospholipids ligands, with 8 acyl chains suggested to represent full stoichiometric binding. This unusually high occupancy was verified experimentally, though both modelling and circular dichroism indicate that the general alpha-helical structure is maintained regardless of cargo loading. Fatty-acid cargoes significantly enhanced thermostability while inhibiting cleavage by cathepsin S, an endosomal protease essential for antigen processing and presentation; the latter of which was found to correlate to a decreased production of known T-cell epitopes. Both effects were strongly dependent on acyl chain length, with 18–20 carbons providing the maximal increase in melting temperature (~20 °C) while completely abolishing proteolysis. Diacyl chain cargoes provided similar enhancements to thermostability, but yielded reduced levels of proteolytic resistance. This study describes how the biophysical properties of Bla g 1 ligand binding and digestion may relate to antigen processing, with potential downstream implications for immunogenicity.

The mosquito protein AEG12 is up-regulated in response to blood meals and flavivirus infection though its function remained elusive. Here, we determine the three-dimensional structure of AEG12 and describe the binding specificity of acyl-chain ligands within its large central hydrophobic cavity. We show that AEG12 displays hemolytic and cytolytic activity by selectively delivering unsaturated fatty acid cargoes into phosphatidylcholine-rich lipid bilayers. This property of AEG12 also enables it to inhibit replication of enveloped viruses such as Dengue and Zika viruses at low micromolar concentrations. Weaker inhibition was observed against more distantly related coronaviruses and lentivirus, while no inhibition was observed against the nonenveloped virus adeno-associated virus. Together, our results uncover the mechanistic understanding of AEG12 function and provide the necessary implications for its use as a broad-spectrum therapeutic against cellular and viral targets.

Interleukins and neurotrophins levels are altered in the periphery of patients with major depression and suicidal behavior, however it is not clear if similar abnormalities occur in the central nervous system. Our objective was to examine the association of IL-6, IL-1β, BDNF, and GDNF levels between postmortem plasma, cerebrospinal fluid (CSF), and brain tissue in a heterogeneous diagnostic subject groups including normal controls, mood disorders only, mood disorders with AUD/SUD (alcohol abuse disorder, substance abuse disorder), and AUD/SUD without mood disorders. To address these questions we collected postmortem plasma (n = 29), CSF (n = 28), and brain (BA10) (n = 57) samples from individuals with mood disorder, mood disorder with AUD/SUD, AUD/SUD and normal controls. These samples were analyzed using a multiplex based luminex assay with a customized 4-plex cytokine/interleukins- IL-6, IL-1β, BDNF, and GDNF human acute phase based on xMAP technology platform. Protein levels were determined using a Luminex 200 instrument equipped with Xponent-analyzing software. We observed IL-6 (p = 2.1e-07), and GDNF (p = 0.046) were significantly correlated between brain and CSF. In addition, IL-6 (p = 0.031), were significantly correlated between brain and plasma. Overall diagnostic group analysis showed a significant difference with brain GDNF, p = 0.0106. Pairwise comparisons showed that GDNF level is—39.9 ± 12 pg/ml, p = 0.0106, was significantly higher than in the brains derived from mood disorders compared to normal controls, —23.8 ± 5.5 pg/ml, p = 0.034. Brain BDNF was higher in suicide (p = 0.0023), males compared to females (p = 0.017), and psychiatric medication treated vs. non-treated (p = 0.005) individuals. Overall, we demonstrate that blood IL-6, GDNF and BDNF could be informative peripheral biomarkers of brain biology associated with mood disorders, substance disorders, and suicide.

We present the final design of the Giant Magellan Telescope (GMT) Adaptive Secondary Mirrors System (ASMS), which comprises seven 1m class deformable mirrors segments plus seven hexapod positioners. Each deformable mirror is based on the well established contactless technology developed by AdOptica and already successfully deployed in several 8m class telescopes. The challenge for GMT is that the seven deformable mirrors will function as a single mirror. A subscale prototype made of 72 actuators has been produced to secure system final design: test setup and preliminary results are presented.

The Giant Magellan Telescope will be a 25.4-m visible and infrared telescope at Las Campanas Observatory. The optical design consists of 7 8.4-m primary mirror segments that reflect light to 7 secondary mirror segments in a doubly-segmented direct Gregorian configuration. Each mirror pair must be coaligned and co-boresighted. During operations, the alignment of the optical components will deflect due to variations in temperature, gravity-induced structure flexure of the mount, and, on a scale relevant to phasing, vibrations. The doubly-segmented nature and size of the GMT will create a novel set of challenges for initial assembly, integration, and verification and maintaining high-precision alignment of the optical elements during operations. GMT is developing a Telescope Metrology System that uses 3D laser metrology systems to decrease the complexity of alignment and increase observatory efficiency. This paper discusses the 4 subsystems of TMS as well as their operational modes.

Suicidality is one of the leading causes of death among young adults in the United States and represents a significant health problem worldwide. The suicide rate among adolescents in the United States has increased dramatically in the latest years and has been accompanied by considerable changes in youth suicide, especially among young girls. Henceforth, we need a good understanding of the risk factors contributing to suicidal behavior in youth. An explanatory model for suicidal behavior that links clinical and psychological risk factors to the underlying neurobiological, neuropsychological abnormalities related to suicidal behavior might predict to help identify treatment options and have empirical value. Our explanatory model proposes that developmental, biological factors (genetics, proteomics, epigenetics, immunological) and psychological or clinical (childhood adversities) may have causal relevance to the changes associated with suicidal behavior. In this way, our model integrates findings from several perspectives in suicidality and attempts to explain the relationship between various neurobiological, genetic, and clinical observations in suicide research, offering a comprehensive hypothesis to facilitate understanding of this complex outcome. Unraveling the knowledge of the complex interplay of psychological, biological, sociobiological, and clinical risk factors is highly essential, concerning the development of effective prevention strategy plans for suicidal ideation and suicide., Highlights • Suicidality, suicidal attempts in adolescents is currently one of the major concern in public and mental health issues worldwide. • Positive and Negative symptoms of suicide in adolescents. • Neuropsychology, neurobiology- neurochemical, neuroimmunological and sociobiological risk factors of suicidality in adolescents. • Early risk assessments and its impact on treatment strategies for suicide.

OBJECTIVES: Recently fructose has been linked to the development of Nonalcoholic Fatty Liver Disease (NAFLD), but the mechanisms behind the progression remain to be elucidated. Kupffer cells have been identified as regulators of hepatic inflammation and extracellular matrix (ECM) proteins. Activated macrophages are known to express tissue inhibitor of metalloproteinase (TIMP1), which inhibits matrix metalloproteinase 9 (MMP9) activity of reconstructing ECM which leads to fibrosis. In humans and mouse models, TIMP1 expression is positively correlated with the progression of NAFLD. Based on these findings, we hypothesize that fructose regulates TIMP1 gene expression in activated proinflammatory macrophages. METHODS: Using an in vitro model of J774 macrophages and primary Kupffer cells, cells were treated to induce an M1 phenotype in the presence of glucose or fructose. Cells were harvested for RNA and RT-PCR was conducted to measure ECM gene expression. Isolated Kupffer cells were collected from C57BL/6J mice fed a high fat diet (HFD) supplemented with 30% fructose or 30% glucose and analyzed for ECM expression. To examine fructose uptake and intra- and extracellular metabolites, mass spectrophotometry and nuclear magnetic resonance was conducted. RESULTS: Timp1 gene expression was significantly increased in J77.4 cells treated with fructose compared to glucose. Surprisingly, fructose treatment decreased Mmp9 gene expression. Likewise, fructose treatment increased TIMP1 protein expression in isolated Kupffer cells. In vivo, isolated hepatic macrophages from mice fed HF and high fructose diet had elevated Timp1 gene expression compared to mice fed high glucose diet. Extracellular levels of lactate decreased by 1.5-fold in fructose treated J77.4 cells compared to glucose. Metabolites involved in the TCA cycle and mitochondrial function were decreased when treated with fructose compared to glucose in non-activated macrophages. However, fructose treatment increased intracellular methanol and acetate levels in M1 macrophages compared to glucose. CONCLUSIONS: Our data suggest that fructose upregulates Timp1 expression and possibly decreases mitochondrial function while increasing acetate and methanol production, identifying new mechanisms by which fructose drives the progression of NAFLD. FUNDING SOURCES: Kenan Institute North Carolina University.

The daily pollen forecast provides crucial information for allergic patients to avoid exposure to specific pollen. Pollen counts are typically measured with air samplers and analyzed with microscopy by trained experts. In contrast, this study evaluated the effectiveness of identifying the component pollens using the metabolites extracted from an air-sampled pollen mixture. Ambient air-sampled pollen from Munich in 2016 and 2017 was visually identified from reference pollens and extracts were prepared. The extracts were lyophilized, rehydrated in optimal NMR buffers, and filtered to remove large proteins. NMR spectra were analyzed for pollen associated metabolites. Regression and decision-tree based algorithms using the concentration of metabolites calculated from the NMR spectra outperformed algorithms using the NMR spectra themselves as input data for pollen identification. Categorical prediction algorithms trained for low, medium, high, and very high pollen count groups had accuracies of 74% for the tree, 82% for the grass, and 93% for the weed pollen count. Deep learning models using convolutional neural networks performed better than regression models using NMR spectral input, and were the overall best method in terms of relative error and classification accuracy (86% for tree, 89% for grass, and 93% for weed pollen count). This study demonstrates that NMR spectra of air-sampled pollen extracts can be used in an automated fashion to provide taxa and type-specific measures of the daily pollen count.

Background Phosphatidylethanol (PEth) is a metabolite of ethanol (EtOH), and its concentration in whole blood samples is a direct biomarker of alcohol consumption. Because PEth is also present in the brain and incorporated in lipid membranes, it can be used to classify deceased individuals on alcohol consumption status at the time of death. The purpose of this study was to detect PEth homologs in postmortem brains of individuals known to have had alcohol use disorder (AUD) and to determine the relationship between serum alcohol at the time of death and PEth in the cerebellum (CE) and orbital frontal cortex (OFC). Methods Postmortem brain was collected and stored according to standard protocol. Psychiatric symptoms experienced prior to death were obtained by next of kin psychological autopsy to categorize subjects. Thirty male subjects were chosen for analyses: 10 with AUD with positive serum EtOH levels present at time of autopsy (AUD-W), 10 with AUD without positive serum EtOH levels (AUD-WO), and 10 controls. PEth 16:0/18:1 and 16:0/18:2 were quantified in 50 mg of CE and OFC of human postmortem brain using HPLC and mass spectrometric detection (triple quadrupole). Results Results of this study were as follows: (i) PEth 16:0/18:1 and 16:0/18:2 were detected in the CE and OFC of all subjects diagnosed with AUD, (ii) PEth 16:0/18:1 levels were about 10-fold higher than PEth 16:0/18:2 in all subjects and both areas of brain, (iii) AUD-W subjects had higher PEth homolog levels in CE and OFC than controls and AUD-WO subjects, (iv) PEth 16:0/18:1, but not PEth 16:0/18:2, levels in CE and OFC of AUD-W subjects correlated significantly with serum EtOH levels at the time of death. Conclusions Quantification of combined PEth homolog levels in postmortem human brain is a good candidate as a diagnostic factor to classify drinking status, especially for those with AUD at the time of death. For alcohol research studies with postmortem brain, verification of drinking status is essential.

Vinculin is an essential adhesion protein that links membrane-bound integrin and cadherin receptors through their intracellular binding partners to filamentous actin, facilitating mechanotransduction. Here we present an 8.5-Å-resolution cryo-electron microscopy reconstruction and pseudo-atomic model of the vinculin tail (Vt) domain bound to F-actin. Upon actin engagement, the N-terminal “strap” and helix 1 are displaced from the Vt helical bundle to mediate actin bundling. We find that an analogous conformational change also occurs in the H1′ helix of the tail domain of metavinculin (MVt) upon actin binding, a muscle-specific splice isoform that suppresses actin bundling by Vt. These data support a model in which metavinculin tunes the actin bundling activity of vinculin in a tissue-specific manner, providing a mechanistic framework for understanding metavinculin mutations associated with hereditary cardiomyopathies.

Launched in 2009, Keck Observatory’s Telescope Control System Upgrade (TCSU) project set out to improve Keck’s telescope pointing, tracking, and offsetting performance as well as increase maintainability and reliability. The project went online full time on the Keck 2 telescope in October 2017 and on the Keck 1 telescope in March 2018 after a notable delay due to a re-design of the azimuth and elevation encoder mounting systems. This paper discusses the details and challenges of implementing this large and complicated system while never requiring a shutdown of either telescope. The TCSU project replaced all of the major elements of the telescope controls, rotator and secondary mirror controls, and safety system. National Instrument’s reconfigurable I/O technology (i.e. NI RIO), with their embedded field programmable gate arrays (FPGAs), are used as the core of the telescope’s digital velocity control loop, structural filter, and tachometer filter. They were also used to create a monitoring and safety system for the rotator velocity controller as well as reading the newly installed tilt meters used to greatly improve pointing performance. Delta Tau’s family of “Brick” programmable multi-axis controllers, i.e. PMAC or BRICK, are used to control the rotator and secondary mirror. They enable better tuning and faster slew speeds for these subsystems. An Allen Bradley’s ControlLogix® controller and the family of FLEX™ Input/Output (IO) modules were used to create a distributed safety system able to handle a wide variety of signal types. This technology refresh based on commercial off the shelf equipment replaced much of our obsolete and custom equipment. A significant part of the project was the installation of new telescope azimuth and elevation position encoders based on Heidenhain’s 40 micron grading tape scales. Interpolated to a 10 nanometer resolution, the new encoders provide true 4 mas resolution in azimuth and 1 mas resolution in elevation. This is a big improvement to Keck’s position sensing when compared to the old rotary incremental encoders. The installation required a significant amount of mechanical infrastructure to house them. Additionally, two tilt meters were installed to sense the telescope’s varying vertical angle as a function of azimuth, mainly due to the azimuth bearing’s axial runout. The encoders and tilt meters are the primary reason for achieving the greatly improved pointing and tracking performance [1]. Finally, a switching solution using solid state relays and dual network switches was installed to provide seamless and rapid switching between the old and new control systems during commissioning. Although this component is a simple design and does not boast of any new technology, it is one of the key components that enabled the successful testing of the new equipment while keeping the old system operational as a backup for night time observing as well as for baseline performance comparisons. It allowed us to switch a variety of signal types and was very cost effective when compared to available products.

Synaptosomal Associated Protein-25 kilodaltons (SNAP-25) is an integral member of the SNARE complex. This complex is essential for calcium-triggered synaptic vesicular fusion and release of neurotransmitters into the synaptic cleft. In addition to neurotransmission, SNAP-25 is associated with insulin release, the regulation of intracellular calcium, and neuroplasticity. Because of SNAP-25's varied and crucial biological roles, the consequences of changes in this protein can be seen in both the central nervous system and the periphery. In this review, we will look at the published literature from human genetic, postmortem, and animal studies involving SNAP-25. The accumulated data indicate that SNAP-25 may be linked with some symptoms associated with a variety of psychiatric disorders. These disorders include bipolar disorder, schizophrenia, major depressive disorder, attention deficit hyperactivity disorder, autism, alcohol use disorder, and dementia. There are also data suggesting SNAP-25 may be involved with non-psychiatric seizures and metabolic disorders. We believe investigation of SNAP-25 is important for understanding both normal behavior and some aspects of the pathophysiology of behavior seen with psychiatric disorders. The wealth of information from both animal and human studies on SNAP-25 offers an excellent opportunity to use a bi-directional research approach. Hypotheses generated from genetically manipulated mice can be directly tested in human postmortem tissue, and, conversely, human genetic and postmortem findings can improve and validate animal models for psychiatric disorders.

The Giant Magellan Telescope (GMT) is an advanced Extremely Large Telescope and is being designed for broad wavelength coverage and maximum sensitivity in pursuit of several high priority cosmology science objectives. The GMT will use large primary mirror segments to provide well corrected wavefronts and a very fast optical system with a 20-arcminute diameter field of view. It will have a direct Gregorian optical prescription and deformable secondary mirrors to implement adaptive optics. The project timeline leads to initial commissioning with early instruments by 2023. The Systems Engineering group, along with the chief engineer, is developing and flowing down science and operational requirements and is the guardian of the performance budget. An integrated performance model of the telescope is being developed to support requirements derivation, performance assessment and trade studies that drive telescope architecture decisions. This model has four key elements; a structural plant model which exhibits the complex dynamics of the telescope; a controls model that models both controller dynamics and noise; an optics model to accurately demonstrate performance and optical feedback; and loads models to characterize various environmental loads. This paper will introduce the GMT integrated modeling architecture, but will focus on the specific tools and process developed to build the critical structural model. An efficient process was required to support the variety of required analyses, update frequency of underlying finite element models, and various project critical trade studies. The end-to-end process, from subsystem finite element models to a system level plant and Simulink block diagram has been achieved through development of a new MATLAB class with many useful functions. Functions are covered that combine the subsystem models, manipulate those models, and help them run efficiently in discrete and continuous time. Verification and version control are also discussed. Case study of wind is presented with preliminary performance results.

Aims The enzyme catechol-O-methyl transferase (COMT) plays a primary role in the metabolism of catecholamine neurotransmitters and is implicated in the modulation of cognitive and emotional responses. The best-characterized single nucleotide polymorphism (SNP) of the COMT gene consists of a valine (Val)-to-methionine (Met) substitution at codon 108/158. The Met-containing variant confers a marked reduction in COMT catalytic activity. We recently showed that the activity of recombinant COMT is positively regulated by the enzyme Met sulfoxide reductase (MSR), which counters the oxidation of Met residues of proteins. The current study was designed to assess whether brain COMT activity may be correlated to MSR in an allele-dependent fashion.

SNAP-25 is a neurotransmitter vesicular docking protein which has been associated with brain disorders such as attention deficit hyperactivity disorder, bipolar disorder and schizophrenia. In this project, we were interested if clinical factors are associated with differential SNAP-25 expression. We examined the SNAP-25 isoform mRNA and protein levels in postmortem cortex Brodmann's area 9 (BA9) and BA24 (n = 29). Subjects were divided by psychiatric diagnosis, clinical variables including mood state in the last week of life and lifetime impulsiveness. We found affected subjects with a diagnosis of alcohol use disorder (AUD) had a lower level of SNAP-25b BA24 protein compared to those without AUD. Hispanic subjects had lower levels of SNAP-25a, b and BA9 mRNA than Anglo-American subjects. Subjects who smoked had a total pan (total) SNAP-25 BA9/BA24 ratio. Subjects in the group with a low level of anxious-psychotic symptoms had higher SNAP-25a BA24 mRNA compared to normal controls, and both the high and low symptoms groups had higher pan (total) SNAP-25 BA9/BA24 ratios than normal controls. These data expand our understanding of clinical factors associated with SNAP-25. They suggest that SNAP-25 total and isoform levels may be useful biomarkers beyond limited neurological and psychiatric diagnostic categories.

The Thirty Meter Telescope (TMT) needs to maintain precise positioning of the optical elements to deliver unprecedented image quality. Any vibration from observatory sources must therefore be minimized; model-based analysis leads to maximum allowable forces from any individual source typically of order a Newton or less in the most sensitive frequency band. Careful attention throughout the design process is needed to ensure that these challenging requirements are satisfied. We focus here in particular on cogging forces from the azimuth motor drive. Each motor yields periodic tangential and vertical forces of order 100's of Newtons, with higher harmonics of the waveform potentially exciting telescope structural resonances. There are 56 drive motors, and appropriate phasing between them can ideally cancel most of the net torque or net vertical force. However, the moment created between non-collocated forces still produces image motion even if the net force cancels, and further, small errors in forcer positioning result in imperfect cancellation. We provide a general methodology for estimating total cogging forces and then present an example of the expected TMT performance impact from motor cogging placed in context with the larger challenge of demanding vibration requirement.

Studies on ragweed and birch pollen extracts suggested that the adenosine content is an important factor in allergic sensitization. However, exposure levels from other pollens and considerations of geographic and seasonal factors have not been evaluated.This study compared the metabolite profile of pollen species important for allergic disease, specifically measured the adenosine content, and evaluated exposure to pollen-derived adenosine.An NMR metabolomics approach was used to measure metabolite concentrations in twenty-six pollen extracts. Pollen count data was analyzed from five cities to model exposure.A principal component analysis of the various metabolites identified by NMR showed that pollen extracts could be differentiated primarily by sugar content: glucose, fructose, sucrose, and myo-inositol. In extracts of 10 mg of pollen/ml, the adenosine was highest for grasses (45 μM) followed by trees (23 μM) and weeds (19 μM). Pollen count data showed that tree pollen was typically 5-10 times the amount of other pollens. At the daily peaks of tree, grass, and weed season the pollen-derived adenosine exposure per day is likely to only be 1.1, 0.11, and 0.12 μg, respectively. Seasonal models of pollen exposure and respiration suggest that it would be a rare event limited to tree pollen season for concentrations of pollen-derived adenosine to approach physiological levels.Sugar content and other metabolites may be useful in classifying pollens. Unless other factors create localized exposures that are very different from these models, pollen-derived adenosine is unlikely to be a major factor in allergic sensitization.

Deletions in the 16.6 kb mitochondrial genome have been implicated in numerous disorders that often display muscular and/or neurological symptoms due to the high-energy demands of these tissues. We describe a catalogue of 4489 putative mitochondrial DNA (mtDNA) deletions, including their frequency and relative read rate, using a combinatorial approach of mitochondria-targeted PCR, next-generation sequencing, bioinformatics, post-hoc filtering, annotation, and validation steps. Our bioinformatics pipeline uses MapSplice, an RNA-seq splice junction detection algorithm, to detect and quantify mtDNA deletion breakpoints rather than mRNA splices. Analyses of 93 samples from postmortem brain and blood found (i) the 4977 bp ‘common deletion’ was neither the most frequent deletion nor the most abundant; (ii) brain contained significantly more deletions than blood; (iii) many high frequency deletions were previously reported in MitoBreak, suggesting they are present at low levels in metabolically active tissues and are not exclusive to individuals with diagnosed mitochondrial pathologies; (iv) many individual deletions (and cumulative metrics) had significant and positive correlations with age and (v) the highest deletion burdens were observed in major depressive disorder brain, at levels greater than Kearns–Sayre Syndrome muscle. Collectively, these data suggest the Splice-Break pipeline can detect and quantify mtDNA deletions at a high level of resolution.

Axon outgrowth during development and neurotransmitter release depends on exocytotic mechanisms, although what protein machinery is common to or differentiates these processes remains unclear. Here we show that the neural t-SNARE (target-membrane-associated-soluble N-ethylmaleimide fusion protein attachment protein (SNAP) receptor) SNAP-25 is not required for nerve growth or stimulus-independent neurotransmitter release, but is essential for evoked synaptic transmission at neuromuscular junctions and central synapses. These results demonstrate that the development of neurotransmission requires the recruitment of a specialized SNARE core complex to meet the demands of regulated exocytosis.

Background Minority populations have been under-represented in mental health research studies. The systematic treatment enhancement program for bipolar disorder developed the Community Partners Program (CPP) to address this issue in a large, prospective treatment study of persons with bipolar disorder. Purpose The primary goal of CPP was to develop a community-based infrastructure for studying bipolar disorder that would enhance the ethnic/racial and socioeconomic diversity of participants. Methods Selected academic sites partnered with local clinics (n = 6 partnerships in five cities). This report describes the conceptualization, implementation, and qualitative evaluation of CPP, as well as quantitative analysis of clinical and sociodemographic differences between the samples recruited at academic versus community sites. Results Quantitative analysis of the 155 participants from the six partnerships revealed enrollment of 45% from minority populations (vs. 15% in academic sites). Significant sociodemographic differences were evident not only between academic and community sites, but within minority and non-minority groups across site types. Notably, clinical differences were not evident between participants from academic and community sites. Review of qualitative data suggests that certain factors around implementation of research protocols may enhance community participation. Conclusions Moving research recruitment and participation into community sites was more successful in increasing minority enrollment than efforts to attract such individuals to academic sites. Recommendations for creating and maintaining academic/community partnerships are given. Limitations Several important variables were not considered including mood severity, hospitalization, or treatment differences. Minority participants were grouped by combining African American and Hispanics, which may have obscured subgroup differences. A derivation of standard qualitative methods was used in this study. Clinical Trials 2009; 6: 344—354. http://ctj.sagepub.com

The enzyme catechol-O-methyltransferase (COMT), which catalyses the degradation of dopamine and norepinephrine, is posited to participate in the pathophysiology of bipolar disorder (BD) and schizophrenia. In support of this notion, rich evidence has documented that the severity of various BD and schizophrenia symptoms is moderated by rs4680, a single nucleotide polymorphism of the COMT gene featuring a valine (Val)-to-methionine (Met) substitution that results in lower catalytic activity. Nevertheless, the specific relevance of COMT enzymatic activity in the pathophysiology of BD and schizophrenia dimensions remains elusive.We measured COMT catalytic activity in post-mortem prefrontal cortices, striata and cerebella of schizophrenia and BD patients, as well as non-affected controls. These values were then correlated with rs4680 genotypes and psychopathology scores in the last week of life.No direct correlation between COMT activity and rs4680 genotypes was found; however, the severity of manic symptoms was highly correlated with COMT activity in the striatum, irrespective of the diagnostic group.These results suggest that COMT striatal activity, but not rs4680 genotype, may serve as a biomarker for manic symptoms. Future studies are warranted to confirm these findings and assess the neurobiological links between COMT striatal activity and manic symptoms.

Vinculin is an essential and abundant cytoskeletal protein localized to focal adhesions and cell-cell contacts, where it participates in the linkage of transmembrane receptors to the actin cytoskeleton to control cell survival and migration. Loss of vinculin results in increased cell migration, apoptotic resistance, and the acquisition of tumorigenic properties. Mutations in vinculin and its splice variant, metavinculin, are associated with cardiac disease. Vinculin consists of a head domain (Vh) and a tail domain (Vt) that form autoinhibitory interactions in its inactive state, but release upon activation, exposing phosphorylation, protein and phosphoinositol 4,5-bisphosphate (PIP2) binding sites. The interaction of vinculin with PIP2 is believed critical for its function, however, it is currently unclear how vinculin specifically recognizes PIP2 and regulates vinculin. Vt forms an antiparallel five-helix bundle with amino-terminal (NT) and carboxyl terminal (CT) extensions. While a crystal structure of an oligomerized Vt mutant complexed to a short chain PIP2 has recently been published (Chinthalapudi et al. (JCB, 2014)), the structure is incompatible with membrane insertion. We propose an alternative model using experimental data, molecular docking and dynamics simulations and provide validation of the model through biophysical and biochemical analyses. In our model, the PIP2 head group binds to the Vt basic collar, and promotes release of Vt's strap and CT to facilitate membrane insertion. The role of vinculin/PIP2 interaction in mediating vinculin activation, localization, cell migration, force sensing and transmission has also been characterized using cell microscopy, including super-resolution microscopy approaches, by examining WT and PIP2-deficient full length vinculin in knockout cells. Information derived from these analyses will result in an unprecedented understanding of vinculin function from the molecular to the cellular level and will enable us to build more comprehensive models of vinculin membrane interactions.

Nuclear magnetic resonance (NMR) has continued to evolve as a powerful method, with an increase in the number of pulse sequences and techniques available to study protein-protein interactions. In this chapter, a straightforward method to map a protein-protein interface and design a structural model is described, using chemical shift perturbation, paramagnetic relaxation enhancement, and data-driven docking.

A recent flight test program was undertaken to evaluate the Smart Adaptive Flight Effective Cue (SAFE-Cue) pilot-vehicle system loss of control mitigation concept. Three experienced test pilots participated in the flight test evaluations that were conducted using the Calspan Learjet In-Flight Simulator. While the focus of the program was to assess the SAFE-Cue system performance in the presence of failure/damage scenarios, the pilots were also exposed to the baseline aircraft configuration several times during their evaluations. The baseline configuration was designed to have Level 1 handling qualities for the sum-ofsines tracking and bank angle capture and hold tasks that were evaluated as part of the “blind” configurations presented to each pilot. Because of a mechanical issue, only two of the three pilots conducted the roll axis evaluations. From analysis of the test data it was clearly evident that the pilots employed disparate control strategies with one using an unexpected “bang-bang” technique that resulted in a sustained pilot-induced oscillation (PIO). Based on the resulting pilot comments and ratings, the “bang-bang” pilot did not recognize that he was in a sustained PIO. In contrast, the other pilot was able to achieve desired performance with no tendency for PIO. Using a variety of analysis approaches, the two baseline configuration runs were explored in detail to assess the observed differences. Analysis results revealed that both pilots provided lead compensation, however, there were significant differences in pilot input power and effective time delay. Over the course of one baseline configuration evaluation run, the “bang-bang” pilot fixated his input power at a single frequency with a significantly higher gain and an additional 100 msec of effective delay. A new time-varying PIO metric introduced herein clearly illustrates the observed differences in pilot behavior.

The enzyme catechol-O-methyltransferase (COMT) plays a primary role in the metabolism of catecholamine neurotransmitters and is implicated in the modulation of cognitive and emotional responses. The best characterized single nucleotide polymorphism (SNP) of the COMT gene consists of a valine (Val)-to-methionine (Met) substitution at codon 108/158. The Met-containing variant confers a marked reduction in COMT catalytic activity. We recently showed that the activity of recombinant COMT is positively regulated by the enzyme Met sulphoxide reductase (MSR), which counters the oxidation of Met residues of proteins. The current study was designed to assess whether brain COMT activity may be correlated to MSR in an allele-dependent fashion.COMT and MSR activities were measured from post-mortem samples of prefrontal cortices, striata and cerebella of 32 subjects by using catechol and dabsyl-Met sulphoxide as substrates, respectively. Allelic discrimination of COMT Val(108/185) Met SNP was performed using the Taqman 5'nuclease assay.Our studies revealed that, in homozygous carriers of Met, but not Val alleles, the activity of COMT and MSR was significantly correlated throughout all tested brain regions.These results suggest that the reduced enzymatic activity of Met-containing COMT may be secondary to Met sulphoxidation and point to MSR as a key molecular determinant for the modulation of COMT activity.

Background Psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BP) are projected to lead the global disease burden within the next decade. Several lines of evidence suggest that epigenetic- or genetic-mediated dysfunction is frequently present in these disorders. To date, the inheritance patterns have been complicated by the problem of integrating epigenomic and transcriptomic factors that have yet to be elucidated. Therefore, there is a need to build a comprehensive database for storing epigenomic and transcriptomic data relating to psychiatric disorders. Description We have developed the PD_NGSAtlas, which focuses on the efficient storage of epigenomic and transcriptomic data based on next-generation sequencing and on the quantitative analyses of epigenetic and transcriptional alterations involved in psychiatric disorders. The current release of the PD_NGSAtlas contains 43 DNA methylation profiles and 37 transcription profiles detected by MeDIP-Seq and RNA-Seq, respectively, in two distinct brain regions and peripheral blood of SZ, BP and non-psychiatric controls. In addition to these data that were generated in-house, we have included, and will continue to include, published DNA methylation and gene expression data from other research groups, with a focus on psychiatric disorders. A flexible query engine has been developed for the acquisition of methylation profiles and transcription profiles for special genes or genomic regions of interest of the selected samples. Furthermore, the PD_NGSAtlas offers online tools for identifying aberrantly methylated and expressed events involved in psychiatric disorders. A genome browser has been developed to provide integrative and detailed views of multidimensional data in a given genomic context, which can help researchers understand molecular mechanisms from epigenetic and transcriptional perspectives. Moreover, users can download the methylation and transcription data for further analyses. Conclusions The PD_NGSAtlas aims to provide storage of epigenomic and transcriptomic data as well as quantitative analyses of epigenetic and transcriptional alterations involved in psychiatric disorders. The PD_NGSAtlas will be a valuable data resource and will enable researchers to investigate the pathophysiology and aetiology of disease in detail. The database is available at http://bioinfo.hrbmu.edu.cn/pd_ngsatlas/. Electronic supplementary material The online version of this article (doi:10.1186/s12920-014-0071-z) contains supplementary material, which is available to authorized users.

Vinculin is an essential cytoskeletal protein that is a prominent component of focal adhesions and adherens junctions. It exists in an autoinhibited conformation that masks interactions of ligands with the head (Vh) and tail (Vt) domain. Upon activation, vinculin functions as a scaffold to regulate cellular events resulting in cell migration, cell survival and embryogenesis. Vinculin null cells display tumorigenic properties and mutation or loss of vinculin is associated with cardiac disease. The interaction between vinculin and actin plays a pivotal role in linking transmembrane receptors to the cytoskeleton, which, in turn, is important for controlling cellular cell morphology, force transmission and motility. Binding of F-actin to Vt causes a conformational change that induces formation of a cryptic dimer necessary for actin filament bundling, however, the conformational change that occurs and dimer that is formed is unknown. It is also unclear how vinculin recognizes PIP2, inserts into membranes and is regulated by this interaction. We have now obtained a sub-nanometer resolution reconstruction of the Vt/actin complex which sheds light on actin-induced conformational changes necessary for vinculin dimerization and actin filament bundling, and have integrated computational and experimental approaches to generate and test models for the actin-induced vinculin dimer and vinculin/PIP2 membrane interaction and assess their significance in vinculin function both in vitro and in cells.