Reduced Functional Connectivity of Default Mode and Set-Maintenance Networks in Ornithine Transcarbamylase Deficiency.

BACKGROUND AND PURPOSE: Ornithine transcarbamylase deficiency (OTCD) is an X-chromosome linked urea cycle disorder (UCD) that causes hyperammonemic episodes leading to white matter injury and impairments in executive functioning, working memory, and motor planning. This study aims to investigate differences in functional connectivity of two resting-state networks-default mode and set-maintenance-between OTCD patients and healthy controls. METHODS: Sixteen patients with partial OTCD and twenty-two control participants underwent a resting-state scan using 3T fMRI. Combining independent component analysis (ICA) and region-of-interest (ROI) analyses, we identified the nodes that comprised each network in each group, and assessed internodal connectivity. RESULTS: Group comparisons revealed reduced functional connectivity in the default mode network (DMN) of OTCD patients, particularly between the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) node and bilateral inferior parietal lobule (IPL), as well as between the ACC/mPFC node and the posterior cingulate cortex (PCC) node. Patients also showed reduced connectivity in the set-maintenance network, especially between right anterior insula/frontal operculum (aI/fO) node and bilateral superior frontal gyrus (SFG), as well as between the right aI/fO and ACC and between the ACC and right SFG. CONCLUSION: Internodal functional connectivity in the DMN and set-maintenance network is reduced in patients with partial OTCD compared to controls, most likely due to hyperammonemia-related white matter damage. Because several of the affected areas are involved in executive functioning, it is postulated that this reduced connectivity is an underlying cause of the deficits OTCD patients display in this cognitive domain

Turbulence and Zonal-Flow Impact in the Madison Symmetric Torus in Quasi-Single Helicity

Reversed-Field Pinches (RFPs) operating in the Quasi-Single-Helicity (QSH) magnetic geometry exhibit significant improvements in confinement time as compared to standard discharges due to the efficient saturation of large-scale tearing modes. This modification to the magnetic geometry and profiles introduces new instabilities which drive transport. This work focuses on diagnosing the microinstabilities and microturbulence in a non-reversed Madison Symmetric Torus QSH experiment. Local gyrokinetic simulations are conducted with the GENE code to identify the dominant instabilities as ion-temperature-gradient (ITG) and density-gradient-driven trapped-electron-mode (TEM) at core and edge radial locations, respectively. It has been previously observed in the RFP (Williams PoP 2017) that residual tearing fluctuations in RFPs degrade zonal flows; the degree to which this affected turbulence and transport in that work depended on the driving instability. While initial investigations reveal strong zonal flow activity, an ad-hoc magnetic perturbation is employed to model magnetic fluctuations present in the RFP. These fluctuations degrade the zonal flow structure, resulting in a more substantial increase in electrostatic fluxes for the TEM-dominated position than for its ITG counterpart

Performance of the Spacecraft Propulsion Research Facility During Altitude Firing Tests of the Delta 3 Upper Stage

The Spacecraft Propulsion Research Facility at the NASA Lewis Research Center's Plum Brook Station was reactivated in order to conduct flight simulation ground tests of the Delta 3 cryogenic upper stage. The tests were a cooperative effort between The Boeing Company, Pratt and Whitney, and NASA. They included demonstration of tanking and detanking of liquid hydrogen, liquid oxygen and helium pressurant gas as well as 12 engine firings simulating first, second, and third burns at altitude conditions. A key to the success of these tests was the performance of the primary facility systems and their interfaces with the vehicle. These systems included the structural support of the vehicle, propellant supplies, data acquisition, facility control systems, and the altitude exhaust system. While the facility connections to the vehicle umbilical panel simulated the performance of the launch pad systems, additional purge and electrical connections were also required which were unique to ground testing of the vehicle. The altitude exhaust system permitted an approximate simulation of the boost-phase pressure profile by rapidly pumping the test chamber from 13 psia to 0.5 psia as well as maintaining altitude conditions during extended steady-state firings. The performance of the steam driven ejector exhaust system has been correlated with variations in cooling water temperature during these tests. This correlation and comparisons to limited data available from Centaur tests conducted in the facility from 1969-1971 provided insight into optimizing the operation of the exhaust system for future tests. Overall, the facility proved to be robust and flexible for vehicle space simulation engine firings and enabled all test objectives to be successfully completed within the planned schedule

Dietary Long-Chain Omega-3 Fatty Acids Are Related to Impulse Control and Anterior Cingulate Function in Adolescents

Impulse control, an emergent function modulated by the prefrontal cortex (PFC), helps to dampen risky behaviors during adolescence. Influences on PFC maturation during this period may contribute to variations in impulse control. Availability of omega-3 fatty acids, an essential dietary nutrient integral to neuronal structure and function, may be one such influence. This study examined whether intake of energy-adjusted long-chain omega-3 fatty acids [eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] was related to variation in impulse control and PFC activity during performance of an inhibitory task in adolescents (n = 87; 51.7% female, mean age 13.3 ± 1.1 years) enrolled in a longitudinal neuroimaging study. Intake of DHA + EPA was assessed using a food frequency questionnaire and adjusted for total energy intake. Inhibitory control was assessed using caregiver rating scale (BRIEF Inhibit subscale) and task performance (false alarm rate) on a Go/No-Go task performed during functional MRI. Reported intake of long-chain omega-3 was positively associated with caregiver ratings of adolescent ability to control impulses (p = 0.017) and there was a trend for an association between intake and task-based impulse control (p = 0.072). Furthermore, a regression of BOLD response within PFC during successful impulse control (Correct No-Go versus Incorrect No-Go) with energy-adjusted DHA + EPA intake revealed that adolescents reporting lower intakes display greater activation in the dorsal anterior cingulate, potentially suggestive of a possible lag in cortical development. The present results suggest that dietary omega-3 fatty acids are related to development of both impulse control and function of the dorsal anterior cingulate gyrus in normative adolescent development. Insufficiency of dietary omega-3 fatty acids during this developmental period may be a factor which hinders development of behavioral control

Baseline brain and behavioral factors distinguish adolescent substance initiators and non-initiators at follow-up

Background Earlier substance use (SU) initiation is associated with greater risk for the development of SU disorders (SUDs), while delays in SU initiation are associated with a diminished risk for SUDs. Thus, identifying brain and behavioral factors that are markers of enhanced risk for earlier SU has major public health import. Heightened reward-sensitivity and risk-taking are two factors that confer risk for earlier SU. Materials and methods We characterized neural and behavioral factors associated with reward-sensitivity and risk-taking in substance-naïve adolescents (N = 70; 11.1–14.0 years), examining whether these factors differed as a function of subsequent SU initiation at 18- and 36-months follow-up. Adolescents completed a reward-related decision-making task while undergoing functional MRI. Measures of reward sensitivity (Behavioral Inhibition System-Behavioral Approach System; BIS-BAS), impulsive decision-making (delay discounting task), and SUD risk [Drug Use Screening Inventory, Revised (DUSI-R)] were collected. These metrics were compared for youth who did [Substance Initiators (SI); n = 27] and did not [Substance Non-initiators (SN); n = 43] initiate SU at follow-up. Results While SI and SN youth showed similar task-based risk-taking behavior, SI youth showed more variable patterns of activation in left insular cortex during high-risk selections, and left anterior cingulate cortex in response to rewarded outcomes. Groups displayed similar discounting behavior. SI participants scored higher on the DUSI-R and the BAS sub-scale. Conclusion Activation patterns in the insula and anterior cingulate cortex may serve as a biomarker for earlier SU initiation. Importantly, these brain regions are implicated in the development and experience of SUDs, suggesting differences in these regions prior to substance exposure

Baseline brain and behavioral factors distinguish adolescent substance initiators and non-initiators at follow-up

BackgroundEarlier substance use (SU) initiation is associated with greater risk for the development of SU disorders (SUDs), while delays in SU initiation are associated with a diminished risk for SUDs. Thus, identifying brain and behavioral factors that are markers of enhanced risk for earlier SU has major public health import. Heightened reward-sensitivity and risk-taking are two factors that confer risk for earlier SU.Materials and methodsWe characterized neural and behavioral factors associated with reward-sensitivity and risk-taking in substance-naïve adolescents (N = 70; 11.1–14.0 years), examining whether these factors differed as a function of subsequent SU initiation at 18- and 36-months follow-up. Adolescents completed a reward-related decision-making task while undergoing functional MRI. Measures of reward sensitivity (Behavioral Inhibition System-Behavioral Approach System; BIS-BAS), impulsive decision-making (delay discounting task), and SUD risk [Drug Use Screening Inventory, Revised (DUSI-R)] were collected. These metrics were compared for youth who did [Substance Initiators (SI); n = 27] and did not [Substance Non-initiators (SN); n = 43] initiate SU at follow-up.ResultsWhile SI and SN youth showed similar task-based risk-taking behavior, SI youth showed more variable patterns of activation in left insular cortex during high-risk selections, and left anterior cingulate cortex in response to rewarded outcomes. Groups displayed similar discounting behavior. SI participants scored higher on the DUSI-R and the BAS sub-scale.ConclusionActivation patterns in the insula and anterior cingulate cortex may serve as a biomarker for earlier SU initiation. Importantly, these brain regions are implicated in the development and experience of SUDs, suggesting differences in these regions prior to substance exposure

Integrative MicroRNA and Proteomic Approaches Identify Novel Osteoarthritis Genes and Their Collaborative Metabolic and Inflammatory Networks

BACKGROUND: Osteoarthritis is a multifactorial disease characterized by destruction of the articular cartilage due to genetic, mechanical and environmental components affecting more than 100 million individuals all over the world. Despite the high prevalence of the disease, the absence of large-scale molecular studies limits our ability to understand the molecular pathobiology of osteoathritis and identify targets for drug development. METHODOLOGY/PRINCIPAL FINDINGS: In this study we integrated genetic, bioinformatic and proteomic approaches in order to identify new genes and their collaborative networks involved in osteoarthritis pathogenesis. MicroRNA profiling of patient-derived osteoarthritic cartilage in comparison to normal cartilage, revealed a 16 microRNA osteoarthritis gene signature. Using reverse-phase protein arrays in the same tissues we detected 76 differentially expressed proteins between osteoarthritic and normal chondrocytes. Proteins such as SOX11, FGF23, KLF6, WWOX and GDF15 not implicated previously in the genesis of osteoarthritis were identified. Integration of microRNA and proteomic data with microRNA gene-target prediction algorithms, generated a potential "interactome" network consisting of 11 microRNAs and 58 proteins linked by 414 potential functional associations. Comparison of the molecular and clinical data, revealed specific microRNAs (miR-22, miR-103) and proteins (PPARA, BMP7, IL1B) to be highly correlated with Body Mass Index (BMI). Experimental validation revealed that miR-22 regulated PPARA and BMP7 expression and its inhibition blocked inflammatory and catabolic changes in osteoarthritic chondrocytes. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that obesity and inflammation are related to osteoarthritis, a metabolic disease affected by microRNA deregulation. Gene network approaches provide new insights for elucidating the complexity of diseases such as osteoarthritis. The integration of microRNA, proteomic and clinical data provides a detailed picture of how a network state is correlated with disease and furthermore leads to the development of new treatments. This strategy will help to improve the understanding of the pathogenesis of multifactorial diseases such as osteoarthritis and provide possible novel therapeutic targets

Integrative MicroRNA and Proteomic Approaches Identify Novel Osteoarthritis Genes and Their Collaborative Metabolic and Inflammatory Networks

BACKGROUND: Osteoarthritis is a multifactorial disease characterized by destruction of the articular cartilage due to genetic, mechanical and environmental components affecting more than 100 million individuals all over the world. Despite the high prevalence of the disease, the absence of large-scale molecular studies limits our ability to understand the molecular pathobiology of osteoathritis and identify targets for drug development. METHODOLOGY/PRINCIPAL FINDINGS: In this study we integrated genetic, bioinformatic and proteomic approaches in order to identify new genes and their collaborative networks involved in osteoarthritis pathogenesis. MicroRNA profiling of patient-derived osteoarthritic cartilage in comparison to normal cartilage, revealed a 16 microRNA osteoarthritis gene signature. Using reverse-phase protein arrays in the same tissues we detected 76 differentially expressed proteins between osteoarthritic and normal chondrocytes. Proteins such as SOX11, FGF23, KLF6, WWOX and GDF15 not implicated previously in the genesis of osteoarthritis were identified. Integration of microRNA and proteomic data with microRNA gene-target prediction algorithms, generated a potential "interactome" network consisting of 11 microRNAs and 58 proteins linked by 414 potential functional associations. Comparison of the molecular and clinical data, revealed specific microRNAs (miR-22, miR-103) and proteins (PPARA, BMP7, IL1B) to be highly correlated with Body Mass Index (BMI). Experimental validation revealed that miR-22 regulated PPARA and BMP7 expression and its inhibition blocked inflammatory and catabolic changes in osteoarthritic chondrocytes. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that obesity and inflammation are related to osteoarthritis, a metabolic disease affected by microRNA deregulation. Gene network approaches provide new insights for elucidating the complexity of diseases such as osteoarthritis. The integration of microRNA, proteomic and clinical data provides a detailed picture of how a network state is correlated with disease and furthermore leads to the development of new treatments. This strategy will help to improve the understanding of the pathogenesis of multifactorial diseases such as osteoarthritis and provide possible novel therapeutic targets