Search

The muscarinic-cholinergic system is involved in the pathophysiology of bipolar disorder (BD), and contributes to attention and the top-down and bottom-up cognitive and affective mechanisms of emotional processing, functionally altered in BD. Emotion processing can be assessed by the ability to inhibit a response when the content of the image is emotional. Impaired regulatory capacity of cholinergic neurotransmission conferred by reduced M2-autoreceptor availability is hypothesized to play a role in elevated salience of negative emotional distractors in euthymic BD relative to individuals with no history of mood instability. Thirty-three euthymic BD type-I (DSM-V-TR) and 50 psychiatrically-healthy controls underwent functional magnetic resonance imaging (fMRI) and an emotion-inhibition paradigm before and after intravenous cholinergic challenge using the acetylcholinesterase inhibitor, physostigmine (1 mg), or placebo. Mood, accuracy, and reaction time on either recognizing or inhibiting a response associated with an image involving emotion and regional functional activation were examined for effects of cholinergic challenge physostigmine relative to placebo, prioritizing any interaction with the diagnostic group. Analyses revealed that (1) at baseline, impaired behavioral performance was associated with lower activation in the anterior cingulate cortex in BD relative to controls during emotion processing; (2) physostigmine (vs. placebo) affected behavioral performance during the inhibition of negative emotions, without altering mood, and increased activation in the posterior cingulate cortex in BD (vs. controls); (3) In BD, lower accuracy observed during emotion inhibition of negative emotions was remediated by physostigmine and was associated with cingulate cortex overactivation. Our findings implicate abnormal regulation of cholinergic neurotransmission in the cingulate cortices in BD, which may mediate exaggerated emotional salience processing, a core feature of BD.

Intelligence is a strong predictor of occupational achievement, quality of life and physical health. While variation in intelligence is strongly heritable and has been robustly associated with early environment and brain morphology, little is known about how these factors combine and interact to explain this variation in intelligence. To address this, we modelled the relationship between common genetic variation, grey matter volume, early life adversity and education and intelligence in a UK Biobank sample of 16,383 individuals using structural equation modelling. We tested the hypotheses that total grey matter volume would mediate the association between genetics and intelligence, and that early life adversity and educational attainment would moderate this relationship. Common genetic variation was estimated using a genome-wide polygenic score (PGS) of intelligence. Consistent with previous studies, we found that grey matter volume was a significant mediator of the relationship between PGS and intelligence, but only when early life adversity was included in the model. We further found that higher educational attainment in turn moderated the effects of adversity. These findings suggest an important interaction between genetic and environmental factors in the development of intellectual functioning.

Tobacco use is increasing among youth in the U.S. The current study seeks to develop and pilot test a universal group-based Youth Brief Tobacco Intervention (Y-BTI) plus mobile phone automated text messaging (ATM) for 9th grade students to both prevent initiation among non-users and promote cessation among current users.This study will use a sequential, multi-method research design beginning with mixed methods formative work with 9th grade students to adapt the existing young adult Brief Tobacco Intervention (BTI) for youth and develop automated text messages. The formative work with students will identify salient themes and strategies for the interventions and optimal delivery schedules for the ATM intervention. The second phase of the study evaluates the Y-BTI and ATM through a pilot cluster randomized controlled trial that compares four treatment combinations: (1) Y-BTI + ATM, (2) Y-BTI alone, (3) ATM alone, or (4) standard of care. The Y-BTI is a single session, group-based intervention delivered in schools. The ATM intervention will provide comparable content to the Y-BTI but be delivered via text messaging 3-5 times per week for four weeks.In order to curb the rise of tobacco use among youth, interventions that are easily implemented and disseminated need to be developed. We aim to build upon previous research by showing that a universal group-based Y-BTI and ATM are effective in reducing tobacco use among a 9th graders by preventing initiation among tobacco naïve youth and promoting cessation among current users.

Analysis of marriage registers, apprentice records, wills and insurance policies demonstrates that in the eighteenth century, the Thames, downstream from the Tower of London, was a major barrier to the development of strong business and marriage links between the residents on the north bank in Stepney, and those on the south bank in Surrey and Kent. Possible reasons for our findings are examined in the context of London's growth, migration patterns and business opportunities. The importance of Sun Fire Office insurance policies, in examining personal and commercial links between places far apart is emphasised. Suggestions are made for future research.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown.We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48 % male) derived from 15 distinct MRI scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers – the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

On 4 August 2016, DARPA conducted the final event of the Cyber Grand Challenge (CGC). The challenge in CGC was to build an autonomous system capable of playing in a capture-the-flag hacking competition. The final event pitted the systems from seven finalists against each other, with each system attempting to defend its own network services while proving vulnerabilities in other systems’ defended services. Xandra, our automated cyber reasoning system, took second place overall in the final event. Xandra placed first in security (preventing exploits), second in availability (keeping services operational and efficient), and fourth in evaluation (proving vulnerabilities in competitor services). Xandra also drew the least power of any of the competitor systems. In this article, we describe the high-level strategies applied by Xandra, their realization in Xandra’s architecture, the synergistic interplay between offense and defense, and finally, lessons learned via post-mortem analysis of the final event.

Seamen from Royal Navy ships were boarded in the 1740s with Betty Wright, a lodging-house keeper of Gosport, Hampshire. Her surviving account books together with the wills of hundreds of mariners o...

The Center of Excellence in Remote Sensing Education and Research (CERSER) program on the campus of Elizabeth City State University is currently partnering with the Science Gateways Community Institute (SGCI) which is led by the San Diego Supercomputing Center (SDSC). SGCI is divided into five sections to support members of the gateway community: Incubator, Extended Developer Support, Scientific Software Collaborative, Community Engagement & Exchange, and Workforce Development. Dr. Linda Hayden, the CERSER Principal Investigator, leads the Workforce Development Section. The Workforce Development goals are to increase the development pipeline of science gateway young professionals and educators with an emphasis on increasing involvement of students from underrepresented groups.As science today grows increasingly computer based, it poses challenges and opportunities for researchers. Scientists and engineers are turning to gateways to allow them to analyze, share, and understand large volumes of data more effectively. The existence of science and engineering gateways and the sophisticated cyberinfrastructure tools together can significantly improve the productivity of researchers. Most importantly, science gateways can give uniform access to the cyberinfrastructure that enables cutting-edge science.The goal of the science gateways team was to increase the interactivity of the SGCI Workforce Development section of the SGCI web site to attract potential members and publicize needed information. The proposed modifications for this project were completed utilizing HTML, CSS, and graphical modeling.

Variants at microRNA-137 (MIR137), one of the most strongly associated schizophrenia risk loci identified to date, are associated with poorer cognitive performance. As microRNA-137 is known to regulate the expression of ~1900 other genes, including several that are independently associated with schizophrenia, we tested whether this gene set was also associated with variation in cognition, brain structure and brain function. Our analysis was based on an empirically derived list of genes whose expression was altered by manipulation of MIR137 expression. This list was cross-referenced with genome-wide schizophrenia association data to construct individual polygenic scores. In a sample of 808 patients and 192 controls, we tested whether these risk scores were associated with altered performance on cognitive functions known to be affected in schizophrenia. A subgroup of healthy participants also underwent functional imaging during memory performance, and brain volume and cortical thickness and shape analysis was carried out in n=216 patients and healthy participants. Increased polygenic risk within the empirically derived miR-137 regulated gene score was associated with significantly lower performance measures of IQ, working memory and episodic memory. Analysis of the spatial working memory fMRI task further suggested that increased risk score (thresholded at P=10-5) was significantly associated with increased activation of the right inferior occipital gyrus. Finally, the MiR137 gene network was not associated with variation in cortical thickness or shape, nor was it associated with variation in hippocampal volume. While polygenic risk scores were associated with reduced whole brain volume, this finding did not survive correction for multiple testing. In conclusion, these data are consistent with emerging evidence that MIR137 associated risk for schizophrenia may relate, in part, to its broader downstream genetic effects on neurocognitive function.

Background: The aim of the present study was to investigate the association of fMRI blood oxygen–level dependent (BOLD) reactivity with the level of epigenetic methylation of SLC6A4 in blood DNA from a sample of healthy participants and patients with major depressive disorder (MDD). Methods: We investigated patients with MDD and healthy controls using fMRI and an emotional attention-shifting task. We assessed site-specific DNA methylation of a previously characterized SLC6A4 region in peripheral blood DNA using pyrosequencing. Results: Our study involved 25 patients with MDD and 35 healthy controls. Activation in the anterior insula elicited by negative emotional content was significantly positively associated with the degree of SLC6A4 methylation. Significantly negative associations were observed between activation in the posterior insula and the degree of SLC6A4 methylation when judging the geometry of pictures after seeing negative in contrast to positive emotional stimuli. Healthy controls with a high degree of SLC6A4 methylation depicted significantly more activity elicited by positive stimuli in limbic regions and more activity elicited by negative stimuli in limbic as well as cognitive control regions than those with a low degree of SLC6A4 methylation. Limitations: It is impossible to measure methylation directly in the brain and thus we assessed peripheral methylation of SLC6A4. Since the association was cross-sectional, no conclusion about cause and effect can be drawn. Conclusion: Our study provides further support to the hypothesis that particular DNA methylation states that are associated with brain function during emotion processing are detectable in the periphery.

The Sargasso Sea has been a ocean life habitat for millions of years, yet accurate assessment of the boundary area and detection of these relatively small sea surface features using Landsat series and Moderate resolution Imaging Spectroradiometer (MODIS) instruments have been found to have difficulty or even impossible due to lack of spatial resolution, coverage, recurring observance, and algorithm limitations to identify pelagic species of Sargassum. Sargassum rafts tend to be elongated, curved in the upwind direction and warmer than the surrounding ocean surface. Long weed ‘trails’ extending upwind from the rafts are evidence of plants dropping out and being left behind. Satellite data utilizing a simple ocean color indexes such as the floating algae Index and Normalized Differential Vegetation Index (NDVI) have been established to detect floating algae in open environments using MODIS instruments. Floating Algae Index (FAI) has shown advantages over the traditional NDVI and Enhanced Vegetation Index (EVI) because FAI is less sensitive to changes in environmental and observing conditions (aerosol type and thickness, solar/viewing geometry, and sun glint) and can see through thin clouds. The baseline subtraction method provides a simple yet effective means for atmospheric correction. The algorithms assisted in identifying the boundary area of the Sargasso Sea and the path of this floating alga past Cape Hatteras into the Atlantic Ocean. Due to the fact that similar spectral bands are available on many existing and planned satellite sensors such as Landsat series observations satellites, the NDVI and FIA concept was extendable to establish a long-term record of these ecologically biological dependent ocean plants.

This note draws attention to the online availability, since July 2012, of London's land tax registers and the increasing number of insurance policies for the pre-1800 period also online. The Bludwo...

The forthcoming Enterprise Act makes the Competition Commission (CC) determinative in relation to merger and market inquiries. It also introduces new competition-based tests, the rationale for which is examined. Several procedural aspects of the new regime are explored, in particular the need for economic guidance to be published on the application of the new tests. A number of key economic considerations are then examined, including market definition, oligopoly pricing, entry and the scope for different perspectives as between economic analysis and business practice.

The major histocompatibility complex (MHC) is one of the most intensively investigated, genetically diverse regions of the genome. In its extended form, it encodes more than 400 genes critical to immunity but is also involved in many other functions. In 2009, three simultaneously published genome-wide association studies (GWAS) reported the first compelling evidence for involvement of the MHC in schizophrenia susceptibility. In this review, we describe the structure and function of the MHC, discuss some of the challenges for genetic analysis of the region, and provide an update on findings from GWAS studies before describing potential approaches to interpreting the role of the locus in schizophrenia etiology. The GWAS literature supports involvement of the MHC locus in schizophrenia susceptibility. Current evidence suggests that the MHC plays a more significant role in schizophrenia susceptibility than in other psychiatric disorders. Because of the substantial diversity at the locus, there are differences in the implicated risk variants between ancestral groups, as there are for many other disorders. This is somewhat different than the pattern emerging at other loci. The association findings presently capture large genomic regions, with at least some evidence to suggest that multiple signals may be involved. Based on notable successes in other disorders, we suggest approaches to refining association signals at the locus. Finally, we discuss that these genetic data may be used to understand how the MHC contributes to the complex etiology of schizophrenia.

Multiple-antenna systems have been shown to provide significant performance improvements over single-antenna systems. Theoretical analysis, simulation and experimental testing corroborate improvements in capacity and transmit power/energy savings. Unfortunately, co-located MIMO radios have numerous disadvantages compared to single-antenna radios; such as more complex RF and modem signal processing, inability to provide sufficient antenna spacing for soldier communication frequencies, increased radio size form factors and higher digital hardware power requirements. In this work, we propose to use simple and low cost single-antenna radios in “distributed groups” to form MIMO virtual arrays. Virtual arrays are created by “clusters” of single-antenna transmitters and receivers, respectively, each of which work cooperatively together and can be shown to provide many of the benefits of co-located MIMO systems. We used a 2×2 USRP-based MIMO OFDM system to perform field measurements with the objective to determine throughput and capacity performance compared to SISO OFDM. We compared performance by changing channel propagation environment, antenna spacing, RF frequency and propagation distance. In some channel environments, throughput gains (TPG) of 2X were found with range gain (RNG) of 2X compared to the same SISO OFDM system. We found that optimal antenna spacing may be environment dependent, which motivated us to develop a more general distributed MIMO system approach that could be utilized for field measurements in nearly any configuration desired. Subsequently, we developed a 2-transmit and (1–4)-receive distributed OFDM MIMO model suitable for single-antenna radios, with simulations that support a RNG of between 2.25X and 5.5X.

As the first gene to have achieved genome-wide significance for psychosis, ZNF804A has predictably been a subject of intense research activity. We review the evidence to date for the association between schizophrenia and the original risk variant rs1344706 identified as well as additional common and rare variants at this locus. We describe the still scant literature on the biological function of ZNF804A and discuss the efforts being made to characterize and refine the associated phenotype using imaging and neuropsychological approaches. We conclude that ZNF804A is robustly, if modestly, associated with schizophrenia risk, with much work still remaining to elucidate its role in schizophrenia biology.

Susceptibility to schizophrenia and bipolar disorder may involve a substantial, shared contribution from thousands of common genetic variants, each of small effect. Identifying whether risk variants map to specific molecular pathways is potentially biologically informative. We report a molecular pathway analysis using the single-nucleotide polymorphism (SNP) ratio test, which compares the ratio of nominally significant (P

A long-term frequency shift, with respect to TAI, has been observed in each of two hydrogen masers by direct frequency comparisons between them and primary cesium standards. The shift is attributed to an increase in the wall shift of the storage bulb in the maser. Depending on the storage bulb used, this increase was found to be between 3 × 10-13 and 8 × 10-13 per year. Possible reasons for the observed shift are discussed.

Translating a set of disease regions into insight about pathogenic mechanisms requires not only the ability to identify the key disease genes within them, but also the biological relationships among those key genes. Here we describe a statistical method, Gene Relationships Among Implicated Loci (GRAIL), that takes a list of disease regions and automatically assesses the degree of relatedness of implicated genes using 250,000 PubMed abstracts. We first evaluated GRAIL by assessing its ability to identify subsets of highly related genes in common pathways from validated lipid and height SNP associations from recent genome-wide studies. We then tested GRAIL, by assessing its ability to separate true disease regions from many false positive disease regions in two separate practical applications in human genetics. First, we took 74 nominally associated Crohn's disease SNPs and applied GRAIL to identify a subset of 13 SNPs with highly related genes. Of these, ten convincingly validated in follow-up genotyping; genotyping results for the remaining three were inconclusive. Next, we applied GRAIL to 165 rare deletion events seen in schizophrenia cases (less than one-third of which are contributing to disease risk). We demonstrate that GRAIL is able to identify a subset of 16 deletions containing highly related genes; many of these genes are expressed in the central nervous system and play a role in neuronal synapses. GRAIL offers a statistically robust approach to identifying functionally related genes from across multiple disease regions—that likely represent key disease pathways. An online version of this method is available for public use (http://www.broad.mit.edu/mpg/grail/)., Author Summary Modern genetic studies, including genome-wide surveys for disease-associated loci and copy number variation, provide a list of critical genomic regions that play an important role in predisposition to disease. Using these regions to understand disease pathogenesis requires the ability to first distinguish causal genes from other nearby genes spuriously contained within these regions. To do this we must identify the key pathways suggested by those causal genes. In this manuscript we describe a statistical approach, Gene Relationships Across Implicated Loci (GRAIL), to achieve this task. It starts with genomic regions and identifies related subsets of genes involved in similar biological processes—these genes highlight the likely causal genes and the key pathways. GRAIL uses abstracts from the entirety of the published scientific literature about the genes to look for potential relationships between genes. We apply GRAIL to four very different phenotypes. In each case we identify a subset of highly related genes; in cases where false positive regions are present, GRAIL is able to separate out likely true positives. GRAIL therefore offers the potential to translate disease genomic regions from unbiased genomic surveys into the key processes that may be critical to the disease.

This paper compares the performance of network coding to a baseline protocol that uses OLSR, SPF and NORM. The performance of each protocol suite is characterized in a three-hour militarily-relevant network topology using five (emulated) applications: video, voice, file transfer, situation awareness and messaging. Network coding provides comparable performance while using substantially less bandwidth. Simplified example scenarios are presented to provide insight into the reasons for network codingpsilas improved performance.

Radio Frequency Identification (RFID) technology is being widely applied within logistical supply chains to keep track of items and their containers from the point of manufacture all the way to the point of item use. The systems that provide this tracking capability consist of inexpensive electronic tags which are affixed to the items and containers, readers which extract data from these tags as they pass along the supply chain, data collection points where the data that has been read is aggregated, a communications system that connects the readers to the collection points and the collection points to each other, and a data base with accompanying software that can provide useful interpretations of the data that is being collected by the system. There are several applications of this technology with potential for enhancing military operations. For example, consider the preparation of a small unit of action about to embark on a mission that requires a collection of specialized equipment to be distributed among the unit individuals. Each item in the collection could be tagged before each individual is equipped. At the mission "jumping-off" point, each individual could be scanned by a reader to verify that they have the required equipment for the mission. In addition, the leader of the mission could periodically scan his individual soldiers to determine their equipment complement at any time during the mission.

Primary cesium frequency standards realized as cesium fountains offer the prospect of frequency accuracy in the 10-15 range, or better. Active hydrogen masers are good candidates for the source of a local time scale to disseminate frequency at this level of accuracy after calibration by a cesium fountain that operates intermittently. We develop a procedure for evaluating the frequency uncertainty associated with the resulting calibrated time scale. We apply the procedure to the expected performance of masers and cesium fountains, and find that current hydrogen masers can be used to deliver frequency uncertainties of less than 10-15, and might be used to approach 10-16. The procedure is appropriate to use, for example, when reporting uncertainties for cesium fountain average frequencies delivered to assist the International Bureau of Weights and Measures (BIPM) in steering International Atomic Time (TAI).