Search

Pervasive and wide-ranging cognitive deficits are a core feature of schizophrenia and an important determinant of long-term functional outcome. The lack of sufficiently effective treatments for cognitive impairment associated with schizophrenia (CIAS) represents a major unmet need and a central roadblock towards recovery. This is partly due to the current therapeutic focus on clinical symptoms, and the relative neglect of cognitive impairments despite their functionally disabling effects. Furthermore, effective treatment is impeded by our limited knowledge of the complex pathophysiology, which gives rise to perturbed information processing. Here, we review mechanisms and effectiveness of available pharmacological and non-pharmacological treatments for CIAS. Current evidence indicates, that while techniques which broadly enhance neural plasticity show the greatest therapeutic potential, effect sizes are at best moderate. Among other reasons, this is due to a considerable heterogeneity of responses to individual interventions. Furthermore, we discuss how recent conceptual advances in operationalizing cognitive impairments based on cognitive neuroscience have the potential to address these issues and facilitate the development of novel treatment strategies for CIAS. This includes more clearly elucidating pathophysiological mechanisms in both humans and animal models, identifying new treatment targets as well as establishing biomarkers for a better prediction of treatment responses.

BackgroundWorking memory (WM) deficits in schizophrenia (SCZ) have been linked to impairments in the encoding phase that are associated with aberrant neuronal functioning. Similar abnormalities have been observed in unaffected first-degree relatives (REL) and are thus discussed as candidate endophenotypes. The process of WM consolidation – i.e. the formation of durable WM representations – is assumed to be impaired in SCZ, but no study has investigated WM consolidation and neuronal correlates of visual WM encoding in REL before.MethodWe examined whole-brain activation during the encoding phase with an event-related functional magnetic resonance imaging study design in 25 SCZ subjects, 22 REL subjects, and 25 healthy controls. Subjects performed a visual masked change detection task that assessed WM performance and consolidation.ResultsSCZ showed deficient WM performance indicating an impairment consolidation process, accompanied by broad neuronal hypoactivation, most prominently in frontal brain regions, as well as increased activity of the anterior cingulate during the encoding phase. REL showed decreased neuronal activity in the middle and medial frontal gyrus and increased activity in the precentral gyrus and insula during encoding, but no significant behavioral deficits were observed. In respect of given consolidation times, REL showed a shift from decreased frontal activity at short time intervals to increased frontal activity at longer time intervals.ConclusionsFindings suggest WM consolidation may be slowed in REL so that the deployment of compensatory neuronal resources during encoding is needed to assure proper WM performance. This supports the view of WM-related neuronal dysfunctions as a potential endophenotypic marker.

Early exposure to negative environmental impact shapes individual behavior and potentially contributes to any mental disease. We reported previously that accumulated environmental risk markedly decreases age at schizophrenia onset. Follow-up of matched extreme group individuals (≤1 vs. ≥3 risks) unexpectedly revealed that high-risk subjects had >5 times greater probability of forensic hospitalization. In line with longstanding sociological theories, we hypothesized that risk accumulation before adulthood induces violent aggression and criminal conduct, independent of mental illness. We determined in 6 independent cohorts (4 schizophrenia and 2 general population samples) pre-adult risk exposure, comprising urbanicity, migration, physical and sexual abuse as primary, and cannabis or alcohol as secondary hits. All single hits by themselves were marginally associated with higher violent aggression. Most strikingly, however, their accumulation strongly predicted violent aggression (odds ratio 10.5). An epigenome-wide association scan to detect differential methylation of blood-derived DNA of selected extreme group individuals yielded overall negative results. Conversely, determination in peripheral blood mononuclear cells of histone-deacetylase1 mRNA as 'umbrella mediator' of epigenetic processes revealed an increase in the high-risk group, suggesting lasting epigenetic alterations. Together, we provide sound evidence of a disease-independent unfortunate relationship between well-defined pre-adult environmental hits and violent aggression, calling for more efficient prevention. This work was supported by the Max Planck Society, the Max Planck Förderstiftung, the DFG (CNMPB), EXTRABRAIN EU-FP7, the Niedersachsen-Research Network on Neuroinfectiology (N-RENNT), and EU-AIMS. The research of EUAIMS receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115300, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013), from the EFPIA companies, and from Autism Speaks. Moreover, support from Centro de Investigación en Red de Salud Mental (CIBERSAM); Instituto de Salud Carlos III (PI16/00998), Comissionat per a Universitats i Recerca del DIUE (2014SGR1636) and Spanish Ministry of Economy and Competitiveness (ES-EUEpiBrain, SAF2015-71526-REDT) is gratefully acknowledged. We thank all subjects for participating in the study, and all the many colleagues who have contributed over the past decade to the GRAS data collection.

This paper examines the potential of value engineering (VE) as a problem-solving tool for addressing various challenges in the marine construction industry. Through a review of large numbers of challenging engineering problems in the marine environment, the authors identified various complications caused by dynamic and uncertain marine environments in both the prebid and postbid stages of construction projects. These unexpected challenges required the project team to identify optimal solutions in a comprehensive and efficient manner. In past construction projects, a 10-step approach was designed and used by the authors to identify solutions for unexpected engineering problems. The approach has three limitations: (1) it is an informal and time-consuming process involving possibly redundant communications and coordination; (2) it is not specific and detailed enough to ensure that the optimal solution is in fact considered and selected in a comprehensive and efficient manner; and (3) it does not integrate standard metrics other than the estimated cost that can be used to quantitatively evaluate the performance of a solution in terms of productivity, quality, safety, and environmental impact. This paper first presents the current 10-step process for solving marine construction problems and limitations of this process. The paper then describes the VE seven-step process and highlights how the VE process and the 10-step approach share the same structure. All steps in the VE process can find correspondences in the 10-step process, whereas VE methodology formalizes the value of a solution and quantitative performance metrics to harvest and evaluate ideas from groups of engineers in a more systematic manner. Based on this shared structure, the paper discusses how to augment the 10-step approach with the VE methodology to achieve more comprehensive and efficient problem solving. Using a case study, the authors explain how such augmentation can effectively integrate the knowledge and experience of groups of engineers with diverse backgrounds in marine construction. Finally, the paper suggests future directions for using VE for marine construction projects.

Overall Abstract: Converging behavioural and neuroimaging evidence indicates that an inability to regulate behaviour by working memory (WM) is a core feature of people with schizophrenia (PSZ) which significantly influences their level of recovery. WM dysfunction has also gained interest as a target of cognitive enhancement interventions and as an intermediate phenotype in the study of the genetic architecture of schizophrenia. These translational strategies critically depend upon a clear understanding of the underlying cognitive and neurophysiological disturbances. The aim of the symposium is to highlight current approaches to identify the pathophysiological mechanisms underlying WM deficits on both the microcircuit and the systems level. M. Ichinose will report cognitive modelling data showing that PSZ have elevated internal noise during perceptual processing, which was inversely correlated with WM precision. This indicates that ‘noisy’ perception contribute to impairments in WM and other cognitive domains. R. Bittner will present behavioural data from PSZ and imaging genetics fMRI data from a large cohort of healthy participants. The results of these studies indicate, that specific impairments in bottom-up attentional processes associated with genetic risk contribute to the dysfunction of working memory encoding in schizophrenia. A. Anticevic will present computational microcircuit models, resting state fMRI data and fMRI data using ketamine which provide evidence for a disturbed excitation-inhibition (E-I) balance and resulting in large scale dysconnectivity in schizophrenia in the context of working memory and other cognitive processes. The research presented in this symposium integrates computational, neuroanatomical, electrophysiological, pharmacological, genetic, behavioural and neuroimaging methods to connect pathophysiological mechanisms at the microcircuit level such as increased neuronal noise and an abnormal E-I balance to disturbances in large scale brain networks at the systems level and to behavioral impairment. Such an integrative approach promises to yield new insights into the pathophysiology of cognitive dysfunction in schizophrenia.

Construction engineering for major infrastructure projects covers a wide range of activities to evaluate and select the techniques for assembling materials and components. Construction engineering inherently presents a very challenging opportunity for creative design, particularly on infrastructure projects. This construction engineering activity can be described as one of creating and developing workable, cost-effective, low-risk technical solutions for an array of infrastructure construction problems that must be solved from the plans and specifications stage through facility completion. The purpose of this paper is to illustrate a 10-step construction engineering process and define important knowledge requirements to foster creative design solutions using four case studies, including (1) positioning and holding a concrete bridge caisson in a 7-knot tidal current for a 4-month period; (2) skidding a 55,000-t immersed tube tunnel element 200 m on dry land from casting site to launch site; (3) building a ...

Background Cognitive impairments including deficits in working memory are commonly observed in schizophrenia. A bottom-up attentional bias has been suggested for encoding visually salient yet irrelevant information. To date it is not known if this bias persists when additional top-down information in the form of a predictive cue is provided. We were motivated to clarify this issue. Methods 40 patients with schizophrenia were measured and matched with 40 healthy control participants. During a change detection task four Gabor patches (two flickering and two non-flickering) with varying orientations were shown and participants had to memorize the orientations of the Gabor patches. A colored fixation cross was displayed before the stimuli either cueing two (predictive cue) or all four (non-predictive cue) Gabor patch locations resulting in a 2 x 2 design of four conditions with the factors salience (flickering vs. non-flickering) and cue (predictive cue vs. non-predictive cue). During retrieval a single Gabor patch was displayed, and participants reported if the orientation was the same or had changed in that location. At the beginning of each block participants were instructed to either encode the flickering or non-flickering patches (targets) whose location could either be cued or uncued. In 80 % of trials, a target was probed during retrieval. Results Patients encoded less information than healthy controls in all four conditions. Both healthy controls and patients encoded more visually salient information than non-salient information, and performance was near chance level during non-target trials. Patients encoded significantly more information when a predictive cue was provided before encoding visually non-salient information. Discussion Patients were able to overcome their bottom-up attentional bias of encoding visually salient irrelevant information when provided with top-down information. These findings are in line with previous reports of a bottom-up attentional bias during working memory encoding in schizophrenia. We propose that this bias can be overcome by providing additional top-down information.

The Sutong Bridge across the lower Yangtze River in China will have, when completed, the longest span (1,088 m) and the highest towers (306 m) of any cable stayed span in the world. The foundations for this record setting span will also be record setting. They are located in water depths exceeding 30 m with maximum flows exceeding 3 m/sec. The soil at the site of the main pylons consists of layers of silty sands and silty clays extending to bed rock at 270 m below river elevation.This paper describes the innovative methods used by the team of foundation designers and constructors to support this record setting bridge at this very challenging site. This paper covers three specific topics related to the foundations of the Sutong Bridge: • Design and construction of the 131 drilled shafts (2.8/2.5 m diameter and 114/117 m long) under each of the two main pylons, including the post-grouting of all drilled shaft tips.• Design and construction of the scour protection for the two main pylons.• Constructi...

Computational e uid dynamics tools have been used extensively in the analysis and development of the X-43A Hyper-X Research Vehicle. A signiecant element of this analysis is the prediction of integrated vehicle aeropropulsive performance,which includes an integration of aerodynamic and propulsion eoweelds. Thedevelopment of the Mach7X-43Arequiredapree ightassessmentoflongitudinalandlateral-directionalaeropropulsivecharacteristics nearthetargeteight-testcondition.Thedevelopmentofthispree ightdatabasewasaccomplishedthroughextensive aerodynamic wind-tunnel testing and a combination of three-dimensional inviscid airframe calculations and cowlto-tail scramjet cycle analyses togenerate longitudinal performance increments between mission sequences. These increments were measured directly and validated through tests of the Hyper-X e ight engine and vehicle e owpath simulator in the NASA Langley Research Center 8-Foot High Temperature Tunnel. Predictions were reened with tip-to-tailNavier‐Stokescalculations,which alsoprovidedinformation onscramjetexhaustplumeexpansion inthe aftbody region. A qualitative assessment of lateral-directional stability characteristics was made through a series of tip-to-tail inviscid calculations, including a simulation of the powered scramjet eight-test condition. Additional comparisons with wind-tunnel forceand momentdataas well as surfacepressuremeasurements from theHyper-X e ight engine and vehicle eowpath simulator model and wind-tunnel testing were made to assess solution accuracy.

The establishment of a quasi-steady flow in a generic scramjet combustor was studied for the case of a time varying inflow to the combustor. Such transient flow is characteristic of the reflected shock tunnel and expansion tube test facilities. Several numerical simulations of hypervelocity flow through a straight duct combustor with either a side wall step fuel injector or a centrally located strut injector are presented. Comparisons were made between impulsively started but otherwise constant flow conditions (typical of the expansion tube or tailored operations of the reflected shock tunnel) and the relaxing flow produced by the 'undertailored' operations of the reflected shock tunnel. Generally the inviscid flow features, such as the shock pattern and pressure distribution, were unaffected by the time varying inlet conditions and approached steady state in approx. the times indicated by experimental correlations. However, viscous features, such as heat transfer and skin friction, were altered by the relaxing inlet flow conditions.

The Sutong Bridge across the lower Yangtze River in China will have, when completed, the longest span (1,088 m) and the highest towers (306 m) of any cable stayed bridge in the world. The foundations for this record-setting span are drilled shafts under each of the main pylons. The North Pylon is supported on 131 drilled shafts, 2.5 m diameter and 114 m long. The South Pylon is supported on 131 drilled shafts 2.5 m in diameter and 117 m long. The tips of all drilled shafts were post-grouted after an extensive test program confirmed significant increase in capacity with post-grouting. This paper presents a description of the post-grouting test program, the results obtained, and the construction methods used for post grouting of the production drilled shafts.

In construction of drilled shafts under water, placing concrete in the shafts is technically demanding and involves complex construction logistics. Past construction experience has demonstrated that high quality concrete can be placed in drilled shafts under water with a proper concrete mix and proper placement techniques. However, a significant number of failures have occurred which have resulted in excessive cost overruns and delays. These problems may have occurred because proper underwater concrete construction techniques have not been widely disseminated within the industry. This is a technical area where competent design and sound construction planning can achieve a significant reduction in both risk and cost. This paper will discuss some key technical issues in the concrete mix design, concrete production and placement for the drilled shaft construction. The paper also describes two lesson-learned case histories from drilled shaft construction projects.

The effects of repetitive transcranial magnetic stimulation (rTMS) on schizophrenic negative symptoms (NS) and EEG topography were investigated in this pilot study. 10 patients with predominant NS were treated with 10 Hz rTMS over the left dorsolateral prefrontal cortex for 5 days. For NS ratings, the Scale for the Assessment of Negative Symptoms (SANS) was used. Both ratings and EEG recordings were obtained pre- and post-rTMS. Electrical activity changes were computed by Low Resolution Brain Electromagnetic Tomography. SANS showed an improvement after rTMS, from 49.0 (SD: 10.7) to 44.7 (SD: 11.8) (means). EEG frequency bands were changed fronto-temporally (right) and were mainly decreases in delta- and beta- and increases in alpha1-activity, as well as decreases in beta-activity in the temporal and parieto-occipital regions (left). Although we are aware of the limitations of this study, we assume a slight improvement in NS. The EEG findings refer to a possible neurophysiologic correlate of their improvement after rTMS.

In recent years, the U.S. Army Corps of Engineers has launched major developments in underwater construction of locks and dams, using the so-called "in-the-wet" or "offsite prefabrication" construction method. This innovative method uses precast concrete modules as the in situ form into which tremie concrete or other infill material is placed directly without use of a cofferdam. The tremie concrete is designed to work in composite action with the precast concrete modules. Numerous in-depth investigations have been conducted by several Corps districts and their consultants to evaluate the feasibility of the in-the-wet method at various potential sites of U.S. inland waterways. These studies have shown that the innovative construction method can provide substantial benefits in cost, construction time, risk reduction, and facility utilization, while minimizing disruption to river traffic and reducing environmental impact.

Numerical simulations of 3D turbulent mixing and reacting flows have been systematically evaluated by comparison with experimental data and other numerical solutions to provide confidence in the General Aerodynamic Simulation Program (GASP) code version 1.3. Specifically, the GASP flow solver has been used to model high speed flow through scram jet combustors. Unit injector problems evaluated include (1) UVA staged sonic normal injection of air into Mach 2 air stream, (2) the VPI Mach 1.7 low angled (15 deg) flush wall helium injection into an unconfined Mach 6 'cold air' stream, and (3) the HYPULSE angled (30 deg) flush wall hydrogen injection into a Mach 6, high enthalpy (flight Mach 17 simulation) nitrogen and air test gases. Results of the numerical simulation for the first two test cases have been compared with detailed in-stream measurements and with SPARK CFD solutions. The results for the last two cases have been compared with measured wall pressure and heat flux data and with SPARK CFD solutions. The present GASP solutions compare favorably with both the experimental data and the SPARK solutions.

A simple method for predicting the axial distribution of supersonic combustor thrust potential is described. A complementary technique for illustrating the spatial evolution and distribution of thrust potential and loss mechanisms in reacting flows is developed. Wall jet cases and swept ramp injector cases for Mach 17 and Mach 13.5 flight enthalpy inflow conditions are numerically modeled and analyzed using these techniques. The visualization of thrust potential in the combustor for the various cases examined provides a unique tool for increasing understanding of supersonic combustor performance potential.

Three-dimensional finite rate chemistry solutions are performed on a single fuel injector configuration. The results are compared with limited experimental data obtained from the HYPULSE expansion tube facility at simulated flight Mach 17 flow conditions. All comparisons, except for wall heat flux, were in excellent agreement. Key findings from this study are useful in interpretation of the experimental measurements.

This paper demonstrates the successful application of CFD to modeling an external burning flowfield. The study used the 2D, 3D, and PNS versions of the SPARK code. Various grids, boundary conditions, and ignition methodologies have been employed. Flameholding was achieved through the use of a subsonic outflow condition and a hot block located behind the step to ignite the fuel. Since the resulting burning produces a large subsonic region downstream of the cowl, this entire surface can be pressurized to the level of the back pressure. An evaluation of interactions between the ramjet exhaust and the external burning products demonstrate the complexity of this design issue. Ths code is now capable of evaluating the external burning effectiveness for flight vehicles using simple injector schemes, and the methodology can be readily applied to other external burning designs.

This paper presents a summary of design studies from the 'open' literature which illustrate the level of effort and the use of computational fluid dynamics (CFD) to support the National Aerospace Plane (NASP) X-30 design. CFD plays a major role in the NASP program, particularly for the very high speed regions (Mach greater than 10) where wind tunnels cannot fully simulate the flow, and flow field measurements are difficult to obtain. Full simulation (nose-to-tail analysis) of the NASP flow field, both internal and external, is discussed.

The foundations for I-205 North Channel crossing of the Columbia River are two types, large spread footings with seals bearing directly on dense conglomerate and double bell shaped footings supported on bearing pile driven into the conglomerate. The methods used to construct these two types of foundations consist of two unique and separate cofferdam systems. The first system utilizes 100 feet long interlocking H-pile sections to form a cofferdam 145 feet by 59 feet by 100 feet deep. The use of these interlocking sections allows a designed dewatered depth of 62 feet with only two support points for the entire wall. The second system utilizes two bell shaped steel forms, stiffened to withstand a hydrostatic head of 54 feet. The larger of these two forms is 83 feet by 66 feet in plan by 62 feet high and weighs 450 tons. These forms, except for the top 14 feet, are one solid welded unit which was set and stripped in one piece.

The underlying cellular mechanisms of catatonia, an executive “psychomotor” syndrome that is observed across neuropsychiatric diseases, have remained obscure. In humans and mice, reduced expression of the structural myelin protein CNP is associated with catatonic signs in an age-dependent manner, pointing to the involvement of myelin-producing oligodendrocytes. Here, we showed that the underlying cause of catatonic signs is the low-grade inflammation of white matter tracts, which marks a final common pathway in Cnp-deficient and other mutant mice with minor myelin abnormalities. The inhibitor of CSF1 receptor kinase signaling PLX5622 depleted microglia and alleviated the catatonic symptoms of Cnp mutants. Thus, microglia and low-grade inflammation of myelinated tracts emerged as the trigger of a previously unexplained mental condition. We observed a very high (25%) prevalence of individuals with catatonic signs in a deeply phenotyped schizophrenia sample (n = 1095). Additionally, we found the loss-of-function allele of a myelin-specific gene (CNP rs2070106-AA) associated with catatonia in 2 independent schizophrenia cohorts and also associated with white matter hyperintensities in a general population sample. Since the catatonic syndrome is likely a surrogate marker for other executive function defects, we suggest that microglia-directed therapies may be considered in psychiatric disorders associated with myelin abnormalities.

Design and analysis of the NASP depends heavily upon developing the critical technology areas that cover the entire engineering design of the vehicle. These areas include materials, structures, propulsion systems, propellants, integration of airframe and propulsion systems, controls, subsystems, and aerodynamics areas. Currently, verification of many of the classical engineering tools relies heavily on computational fluid dynamics. Advances are being made in the development of CFD codes to accomplish nose-to-tail analyses for hypersonic aircraft. Additional details involving the partial development, analysis, verification, and application of the CFL3D code and the SPARK combustor code are discussed. A nonequilibrium version of CFL3D that is presently being developed and tested is also described. Examples are given of portion calculations for research hypersonic aircraft geometries and comparisons with experiment data show good agreement.