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Objectives This pilot study assessed whether frontal lobe transcranial direct current stimulation (tDCS) combined with complex walking rehabilitation is feasible, safe, and shows preliminary efficacy for improving walking and executive function. Materials and methods Participants were randomized to one of the following 18-session interventions: active tDCS and rehabilitation with complex walking tasks (Active/Complex); sham tDCS and rehabilitation with complex walking tasks (Sham/Complex); or sham tDCS and rehabilitation with typical walking (Sham/Typical). Active tDCS was delivered over F3 (cathode) and F4 (anode) scalp locations for 20 min at 2 mA intensity. Outcome measures included tests of walking function, executive function, and prefrontal activity measured by functional near infrared spectroscopy. Results Ninety percent of participants completed the intervention protocol successfully. tDCS side effects of tingling or burning sensations were low (average rating less than two out of 10). All groups demonstrated gains in walking performance based on within-group effect sizes (d ≥ 0.50) for one or more assessments. The Sham/Typical group showed the greatest gains for walking based on between-group effect sizes. For executive function, the Active/Complex group showed the greatest gains based on moderate to large between-group effect sizes (d = 0.52-1.11). Functional near-infrared spectroscopy (fNIRS) findings suggest improved prefrontal cortical activity during walking. Conclusions Eighteen sessions of walking rehabilitation combined with tDCS is a feasible and safe intervention for older adults. Preliminary effects size data indicate a potential improvement in executive function by adding frontal tDCS to walking rehabilitation. This study justifies future larger clinical trials to better understand the benefits of combining tDCS with walking rehabilitation.

Complex walking in older adults can be improved with task practice and might be further enhanced by pairing transcranial direct current stimulation (tDCS) to the dorsolateral prefrontal cortex. We tested the hypothesis that a single session of practice of a complex obstacle negotiation task paired with active tDCS in older adults would produce greater within-session improvements in walking performance and retention of gains, compared to sham tDCS and no tDCS conditions.A total of 50 older adults (mean age = 74.46 years ± 6.49) with self-reported walking difficulty were randomized to receive either active tDCS (active-tDCS group) or sham tDCS (sham-tDCS group) bilaterally to the dorsolateral prefrontal cortex or no tDCS (no-tDCS group). Each group performed ten practice trials of an obstacle negotiation task at their fastest safe speed. Retention of gains in walking performance was assessed with three trials conducted one week later. Within-session effects of practice and between-session retention effects on obstacle negotiation speed were examined.At the practice session, all three groups exhibited significant within-session gains in walking speed (p ≤ 0.005). However, the gains were significantly greater in the sham-tDCS group than in the active-tDCS and no-tDCS groups (p ≤ 0.03) and were comparable between the active-tDCS and no-tDCS groups (p = 0.89). At one-week follow-up, the active-tDCS group exhibited significant between-session retention of gains and continued "offline" improvement in walking speed (p = 0.005). The active-tDCS group showed significantly greater retention of gains than the no-tDCS (p = 0.02) but not the sham-tDCS group (p = 0.24).Pairing prefrontal active tDCS with a single session of obstacle negotiation practice may enhance one-week retention of gains in walking performance compared to no tDCS. However, the evidence is insufficient to suggest a benefit of active tDCS over sham tDCS for enhancing the gains in walking performance. Additional studies with a multisession intervention design and larger sample size are needed to further investigate these findings.The Clinicaltrials.gov registration number for the study is NCT03122236.

Objective To evaluate the incidence and durability of compensatory hypertrophy with solitary kidneys in the setting of those with multicystic dysplastic kidney (MCDK) or Wilms tumor (WT) status postnephrectomy. Patients and Methods We conducted a retrospective cohort study of patients with MCDK and WT. MCDK patients were verified by sonographic findings prenatally. WT patients entered our study at time of nephrectomy. We compared the natural history of hypertrophy between the 2 cohorts via renal length measurement. We performed linear regression to predict creatinine clearance from renal length after adjusting for age and cohort status (MCDK versus WT). Results Fifty-two patients (56%) were diagnosed with WT, and 71 patients (44%) with MCDK patients met study criteria with a median age of postnatal ultrasound at 1.6 months (interquartile range 0.5-3.6). The median (IQR) follow-up time was 7.5 years. At the time of nephrectomy, 25/52 (48%) of Wilms patients had contralateral hypertrophy, while at diagnosis 22/71 (31%) of MCDK patients had contralateral hypertrophy, P = .03. Contralateral hypertrophy was a consistent finding throughout follow-up. As renal length increases by 1 cm, glomerular filtration rate increased by 7.8 mL/min/m2 (95% confidence interval 1.8-13.8, P = .01). Conclusion Contralateral hypertrophy appears to be a compensatory mechanism for unilateral kidney pathology as demonstrated by MCDK and WT patients. Hypertrophy often occurs at the time of diagnosis and appears to be a permanent finding as children reach their teenage years. Additionally, in nonhydronephrotic kidneys, increases in renal length correlate with improvement in glomerular filtration rate. Overall, the majority of children with solitary kidneys demonstrate compensatory hypertrophy.

This paper sets out a logical and inclusive approach to measuring purpose. We advocate a three-stage process, the first of which anchors the purpose, mission and vision of the organisation in its governance. The second stage identifies the business metrics that derive from purpose in relation to inputs, outputs, outcomes and impacts. In the final stage, these reporting metrics are converted into monetary values through enterprise cost-based accounting and societal valuation. This three-step approach provides a coherent reporting framework against which critical decisions can be made. These decisions may be internal – enabling management to allocate scarce resources appropriately – or external, allowing investors and other critical stakeholders to assess the performance of a company against its stated purpose. We conclude by categorising existing measurement initiatives in relation to the three stages.

Varying the substrate temperature changes structural and magnetic properties of spinel ferrite Ni0.65Zn0.35Fe2O4 (NZFO) thin films. X-ray diffraction of films grown at different temperature display only (004) reflections, without any secondary peaks, showing growth orientation along the c-axis. We find an increase in crystalline quality of these thin films with the rise of substrate temperature. The surface topography of thin films grown at different growth temperatures reveal that these films are smooth with low roughness; however, the thin films grown at 800 °C exhibit lowest average and root mean square (rms) roughness among all thin films. We find iron and nickel to be more oxidized (greater Fe3+ and Ni3+ content) in films grown and annealed at 700 °C and 800 °C, compared to those films grown at lower temperatures. The magnetic moment is observed to increase with an increase of substrate temperature and all thin films possess high saturation magnetization and low coercive field at room temperature. Films grown at 800 °C exhibit a ferrimagnetic–paramagnetic phase transition well above room temperature. The observed large magnetizations with soft magnetic behavior in NZFO thin films above room temperature suggest potential applications in memory, spintronics, and multifunctional devices.

Tissue composition impacts the interpretation of magnetic resonance spectroscopy metabolite quantification. The goal of applying tissue correction is to decrease the dependency of metabolite concentrations on the underlying voxel tissue composition. Tissue correction strategies have different underlying assumptions to account for different aspects of the voxel tissue fraction. The most common tissue correction is the CSF-correction that aims to account for the cerebrospinal fluid (CSF) fraction in the voxel, in which it is assumed there are no metabolites. More recently, the α-correction was introduced to account for the different concentrations of GABA+ in gray matter and white matter. In this paper, we show that the selected tissue correction strategy can alter the interpretation of results using data from a healthy aging cohort with GABA+ measurements in a frontal and posterior voxel. In a frontal voxel, we show an age-related decline in GABA+ when either no tissue correction (R2= 0.25, p < 0.001) or the CSF-correction is applied (R2= 0.08, p < 0.01). When applying the α-correction to the frontal voxel data, we find no relationship between age and GABA+ (R2= 0.02, p = 0.15). However, with the α-correction we still find that cognitive performance is correlated with GABA+ (R2= 0.11, p < 0.01). These data suggest that in healthy aging, while there is normal atrophy in the frontal voxel, GABA+ in the remaining tissue is not decreasing on average. This indicates that the selection of tissue correction can significantly impact the interpretation of MRS results.

We recently reported age-related increases in left precuneus cortical thickness (CT) in older adults with elevated total depressive symptoms. However, it is unclear whether abnormalities in precuneus surface area (SA) are also evident and whether specific symptom dimensions of depression moderated age effects on these measurements. Seventy-three adults completed the Beck Depression Inventory - 2nd edition (BDI-II) and underwent structural neuroimaging. Measures of CT and SA were extracted from the right and left precuneus via FreeSurfer. Regression models included regions of interest as dependent variables, with age, BDI-II subscale scores (e.g., affective, cognitive, and somatic symptoms), and their interactions as independent variables, controlling for mean hemispheric thickness (for CT) or total intracranial volume (for SA). A significant age × somatic symptom interaction was found for left precuneus CT, such that elevated levels of somatic symptoms were significantly associated with age-related cortical thinning. No depressive symptom dimensions moderated the relationship between age and SA, suggesting that CT may be a more sensitive measure of brain abnormalities in middle-aged to older adults with depressive symptoms.

Background Greater hippocampal volume is observed in healthy older adults after short-term structured exercise. Whether long-term exposure to real-world physical activity (PA) programs has similar effects for sedentary older adults with impaired mobility and comorbid conditions is not known. Hypothesis A long-term moderate intensity regimen of PA is related to larger volume of the hippocampus in older adults at risk for mobility disability. We further explore whether these associations are modified by factors known to be related to dementia. Methods Twenty-six sedentary adults at risk for mobility disability participated in a 24-month randomized intervention program of physical activity (PA, N = 10, age: 74.9 years, 7 women) or health education (HE, N = 16, age: 76.8 years, 14 women). Volumes of total hippocampus, dentate gyrus, and cornu ammonis were measured at baseline and at 24-month follow-up using 7-Tesla magnetic resonance imaging. Between-group volumetric differences at 24 months were adjusted for sessions attended and baseline volumes. The contribution of each dementia-related factor was tested separately for education, APOE, diabetes, cardiovascular diseases, white matter hyperintensities, and brain atrophy. Results Between-group differences were significant for left hippocampus, left cornu ammonis, and right hippocampus. Adjustment for regional baseline volume attenuated the associations to statistically nonsignificant for right hippocampus and left conru ammonis; associations for left hippocampus were robust for all adjustments. Results were similar after adjustment for dementia-related factors. Conclusions In this group of sedentary older adults there was a hippocampal response to a long-term program of moderate-intensity PA. Future studies should examine whether hippocampal response could explain the beneficial effects of PA on cognition for vulnerable older adults.

Gestational diabetes (GDM) is associated with adverse pregnancy and neonatal outcomes, increased risk for type 2 diabetes (T2D) and other long-term consequences for both the mother and the offspring. GDM is usually diagnosed around 24-28 weeks of gestation via a complicated sequence of glucose challenge tests (GCT) and repeated blood-work, contributing to increased costs and patient/provider burden. In this study we design a stochastic learning algorithm for GDM prediction with "dirty", unprocessed raw data comprising only the records of diagnostic codes generated during past medical encounters from a national US insurance claims database. In computing the Gestational-diabetes Comorbid Risk (GCoR) score, we use no laboratory test results, no medications, demographic, or familial information, and yet achieve a sensitivity greater than 83% at 95% specificity with the corresponding area under the receiver operating characteristic curve (AUC) of 96.87% and a positive predictive value (PPV) >53% at the first prenatal visit for low-risk patients (n=648,784). The AUCs when evaluated one, two and four months before the first prenatal visit is respectively 92.75%, 91.82% and 89.97% for the same cohort. For a general cohort with potentially high risk patients included (n=670,417) we achieve AUCs of 95.42% at the first prenatal visit, degrading to 89.24%, 88.06% and 86.08% at the subsequent time points. And for a high-risk cohort (n=104,946), we achieve AUCs of 94.83%, 89.31%, 87.51%, and 85.80% respectively. We significantly outperform reported tools, achieving a over 200% improvement in sensitivity at 95% specificity for the low risk cohort. Additionally, accurate GDM risk assessment months before pregnancy opens new intervention possibilities, including risk management through lifestyle changes, as well as delaying pregnancy briefly to reduce GDM risk. Additionally, subtle differences in comorbidity patterns suggest the possibility of reducing misdiagnosis of disorders that mimic GDM symptomology such as Cushing's disease, and tumors of the adrenal gland. Funding Statement: This work is funded in part by the Defense Advanced Research Projects Agency (DARPA) project #FP070943- 01-PR. The claims made in this study do not reflect the position or the policy of the US Government. DARPA had no role in the authors’ decision to pursue this specific research problem, or authoring this specific article. Declaration of Interests: Authors have no known conflict of interest. Ethics Approval Statement: The de-identified insurance claims used in this study was deemed exempt by the relevant Institutional Review Board.

BACKGROUND: Gamma-aminobutyric acid (GABA), the brain's principal inhibitory neurotransmitter, has been associated with perceptual and attentional functioning. Recent application of magnetic resonance spectroscopy (MRS) provides in vivo evidence for decreasing GABA concentrations during adulthood. It is unclear, however, how age-related decrements in cerebral GABA concentrations contribute to cognitive decline, or whether previously reported declines in cerebral GABA concentrations persist during healthy aging. We hypothesized that participants with higher GABA concentrations in the frontal cortex would exhibit superior cognitive function and that previously reported age-related decreases in cortical GABA concentrations continue into old age.METHODS: We measured GABA concentrations in frontal and posterior midline cerebral regions using a Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) 1H-MRS approach in 94 older adults without history or clinical evidence of mild cognitive impairment or dementia (mean age, 73 years). We administered the Montreal Cognitive Assessment to assess cognitive functioning.RESULTS: Greater frontal GABA concentrations were associated with superior cognitive performance. This relation remained significant after controlling for age, years of education, and brain atrophy. GABA concentrations in both frontal and posterior regions decreased as a function of age.CONCLUSIONS: These novel findings from a large, healthy, older population indicate that cognitive function is sensitive to cerebral GABA concentrations in the frontal cortex, and GABA concentration in frontal and posterior regions continue to decline in later age. These effects suggest that proton MRS may provide a clinically useful method for the assessment of normal and abnormal age-related cognitive changes and the associated physiological contributors.

Cancer and its treatment are frequently associated with cancer-related cognitive impairment (CRCI). While CRCI has been associated with linked to chemotherapy, there is increasing evidence that the condition may start prior to treatment and for some, remain unresolved after active treatment and into survivorship. Although the pathophysiology of the condition is complex, alterations in systemic cytokines, signaling molecules activated in response to infection or injury that trigger inflammation, are a possible mechanism linked to cognitive dysfunction in breast cancer and other conditions. Given the conflicting results in the literature, the lack of focus on domain specific cognitive testing, and the need for a longer time period given the multiple modalities of standard treatments for early-stage breast cancer, this longitudinal study was conducted to address these gaps. Methods We assessed 75 women with early-stage breast cancer at five points over two years, starting prior to the initial chemotherapy through 24 months after chemotherapy initiation. Measures included a validated computerized evaluation of domain-specific cognitive functioning and a 17-plex panel of plasma cytokines. Linear mixed-effects models were applied to test the relationships of clinical variables and cytokine concentrations to each cognitive domain. Results Levels and patterns of cytokine concentrations varied over time: six of the 17 cytokines (IL-6, IL-12, IL-17, G-CSF, MIPS-1β, and MCP-1) had the most variability. Some cytokine levels (e.g., IL-6) increased during chemotherapy but then decreased subsequently, while others (e.g., IL-17) consistently declined from baseline over time. There were multiple relationships among cytokines and cognition, which varied over time. At baseline, elevated concentrations of G-CSF and reduced concentrations of IL-17 were associated with faster psychomotor speed. At the second time-point (prior to the mid-chemotherapy), multiple cytokines had significant associations with psychomotor speed, complex attention, executive function, verbal memory, cognitive flexibility, composite memory and visual memory. Six months after chemotherapy initiation and at the one-year point, there were multiple, significant relationships among cytokines and multiple cognitive. At two years, fewer significant relationships were noted; however, lower concentrations of IL-7, a hematopoietic cytokine, were associated with better psychomotor speed, complex attention, and memory (composite, verbal and visual). MCP-1 was inversely associated with psychomotor speed and complex attention and higher levels of MIP-1β were related to better complex attention. Conclusion Levels and patterns of cytokines changed over time and demonstrated associations with domain-specific cognitive functioning that varied over time. The observed associations between cytokines and cognitive performance provides evidence that not only prototypical cytokines (i.e., IL-6, TNF-α, and IL1-β) but also cytokines from multiple classes may contribute to the inflammatory environment that is associated with cognitive dysfunction. Future studies to better delineate the cytokine changes, both individually and in networks, are needed to precisely assess a mechanistic link between cytokines and cognitive function in women receiving treatments for breast cancer.

Background/Objectives: With aging, people commonly develop motor slowing (bradykinesia). Although this slowness with aging may be entirely related to degradation of the cerebral networks important in motor programing, it is possible that, at least in part, it may be a learned procedure for enhancing the accuracy and/or precision of movements. The goal of this study is to test these contradictory hypotheses. Methods: Twenty-four healthy adults, 12 younger than age 26 and 12 older than age 65 were asked to make alternative marks with a pen between a card centered in front of them and a series of circles distributed across a page. Performance was timed, and participants were instructed to complete the task as quickly as possible while not sacrificing accuracy for speed. The circle sizes and hand used varied by trial. Results: The older adults performed the task more slowly for all target circle diameters. As the circles decreased in size, the younger adults performed the task more rapidly than did the older participants, but the younger participants also had a greater decline in accuracy. Conclusions: During this aiming task, healthy older adults were less likely than younger adults to sacrifice accuracy for speed. Thus, at least in part, their slowing may be a learned adaptive strategy.

The neuropeptide oxytocin plays a role in social cognition and affective processing. The neural processes underlying these effects are not well understood. Modulation of connectivity strength between subcortical and cortical regions has been suggested as one possible mechanism. The current study investigated effects of intranasal oxytocin administration on resting-state functional connectivity between amygdala and medial prefrontal cortex (mPFC), as two central regions involved in social-cognitive and affective processing. Going beyond previous work that largely examined young male participants, our study comprised young and older men and women to identify age and sex variations in oxytocin's central processes. This approach was based on known hormonal differences among these groups and emerging evidence of sex differences in oxytocin's effects on amygdala reactivity and age-by-sex-modulated effects of oxytocin in affective processing. In a double-blind design, 79 participants were randomly assigned to self-administer either intranasal oxytocin or placebo before undergoing resting-state functional magnetic resonance imaging. Using a targeted region-to-region approach, resting-state functional connectivity strength between bilateral amygdala and mPFC was examined. Participants in the oxytocin compared to the placebo group and men compared to women had overall greater amygdala mPFC connectivity strength at rest. These main effects were qualified by a significant three-way interaction: while oxytocin compared to placebo administration increased resting-state amygdala mPFC connectivity for young women, oxytocin did not significantly modulate connectivity in the other age-by-sex subgroups. This study provides novel evidence of age-by-sex differences in how oxytocin modulates resting-state brain connectivity, furthering our understanding of how oxytocin affects brain networks at rest.

SummaryThe thymus provides a unique microenvironment enabling development and selection of T lymphocytes. Medullary thymic epithelial cells (mTECs) play a pivotal role in this process by facilitating negative selection of self-reactive thymocytes and the generation of Foxp3+ regulatory T cells. Although studies have highlighted the non-canonical nuclear factor κB (NF-κB) pathway as the key regulator of mTEC development, comprehensive understanding of the molecular pathways regulating this process still remains incomplete. Here, we demonstrate that the development of functionally competent mTECs is regulated by the histone deacetylase 3 (Hdac3). Although histone deacetylases are global transcriptional regulators, this effect is highly specific only to Hdac3, as neither Hdac1 nor Hdac2 inactivation caused mTEC ablation. Interestingly, Hdac3 induces an mTEC-specific transcriptional program independently of the previously recognized RANK-NFκB signaling pathway. Thus, our findings uncover yet another layer of complexity of TEC lineage divergence and highlight Hdac3 as a major and specific molecular switch crucial for mTEC differentiation.

Predictions of O_3, CO, total NO_y and individual NO_y species (NO, NO_2, HNO_3, PAN, alkyl nitrates and aerosol nitrate) from a fine resolution regional air quality modeling system for the South Coast Air Basin (SoCAB) and San Joaquin Valley Air Basin (SJVAB) of California are presented and evaluated for the 2008 ARCTAS-CARB campaign. The measurements of the chemical compounds from the fire plumes during the field campaign allow for the evaluation of the model's ability to simulate fire-influenced air masses as well. In general, the model successfully simulated the broad spatial distribution of chemical compounds in both air basins as well as the variation within the basins. Using inventories that reflect 2008 emissions levels, the model performed well in simulating NO_x (NO + NO_2) in SoCAB. Therefore, the under prediction of O_3 over these areas is more likely caused by uncertainties with the VOC emissions, chemistry, or discrepancies in the meteorology. The model did not capture the relatively high levels of O_3, and some reactive nitrogen species that were measured off shore of the SoCAB, indicating potential missing sources or the transport from on shore to off shore was not successfully captured. In SJVAB, the model had good performance in simulating different chemical compounds in the Fresno and Arvin areas. However, enhanced concentrations of O_3, NO_x, HNO_3 and PAN near dairy farms were significantly underestimated in the model. Negative biases also exist for O_3 and HNO_3 near oil fields, suggesting larger uncertainties associated with these emission sources. While the model simulated the total NO_y mixing ratios reasonably well, the prediction for partitioning between individual compounds showed larger uncertainties in the model simulation. Although the fire emissions inventory was updated to include the latest emissions estimates and speciation profiles, our model shows limited improvement in simulating the enhancement of O_3, CO, and PAN under fire impact as compared to a previous version of the modeling system. Further improvements in simulating fire emissions, especially the timing and the plume injection heights, are desired in order to better simulate the impact of fires.

Proton magnetic resonance spectroscopy (1H-MRS) is a noninvasive imaging technique that measures the concentration of metabolites in defined areas of the human brain in vivo. The underlying structure of natural metabolism-emotion relationships is unknown. Further, there is a wide range of between-person differences in metabolite concentration in healthy individuals, but the significance of this variation for understanding emotion in healthy humans is unclear. Here we investigated the relationship of two emotional constructs, agency and flexibility, with the metabolites glutamate and glutamine (Glx), N-acetylaspartate (tNAA), choline (Cho), creatine (tCr), and myo-inositol (Ins) in the right dorsal anterior cingulate cortex (dACC) in medically and psychiatrically healthy volunteers (N = 20, 9 female; mean age = 22.8 years, SD = 3.40). The dACC was selected because this region is an integrative hub involved in multiple brain networks of emotion, cognition and behavior. Emotional traits were assessed using the Multidimensional Personality Questionnaire Brief Form (MPQ-BF), an empirically derived self-report instrument with an orthogonal factor structure. Phenotypes evaluated were positive and negative agency (MPQ-BF Social Potency, Aggression), emotional and behavioral flexibility (MPQ-BF Absorption, Control-reversed), and positive and negative affect (MPQ-BF Social Closeness; Stress Reaction, Alienation). The resting concentration of tNAA in the dACC was robustly positively correlated with Absorption (r = +0.56, unadjusted p = .005), moderately positively correlated with Social Potency (r = +0.42, unadjusted p = .03), and robustly negatively correlated with Aggression (r = -0.59, unadjusted p = .003). Absorption and Aggression accounted for substantial variance in tNAA (R2 = 0.31, 0.35; combined R2 = 0.50), and survived correction for multiple comparisons (Holm-Bonferroni adjusted p = .032, 0.021, respectively). dACC Glx and Cho had modest relationships with behavioral flexibility and social affiliation that did not survive this multiple correction, providing effect sizes for future work. Principal Component Analysis (PCA) revealed a three-factor orthogonal solution indicating specific relationships between: 1) Glx and behavioral engagement; 2) Cho and affiliative bonding; and 3) tNAA and a novel dimension that we term neuroaffective reserves. Our results inform the neurobiology of agency and flexibility and lay the groundwork for understanding mechanisms of natural emotion using 1H-MRS.

Background Extracellular free water within cerebral white matter tissue has been shown to increase with age and pathology, yet the cognitive consequences of free water in typical aging prior to the development of neurodegenerative disease remains unclear. Understanding the contribution of free water to cognitive function in older adults may provide important insight into the neural mechanisms of the cognitive aging process. Methods A diffusion-weighted MRI measure of extracellular free water as well as a commonly used diffusion MRI metric (fractional anisotropy) along nine bilateral white matter pathways were examined for their relationship with cognitive function assessed by the NIH Toolbox Cognitive Battery in 47 older adults (mean age ​= ​74.4 years, SD ​= ​5.4 years, range ​= ​65–85 years). Probabilistic tractography at the 99th percentile level of probability (Tracts Constrained by Underlying Anatomy; TRACULA) was utilized to produce the pathways on which microstructural characteristics were overlaid and examined for their contribution to cognitive function independent of age, education, and gender. Results When examining the 99th percentile probability core white matter pathway derived from TRACULA, poorer fluid cognitive ability was related to higher mean free water values across the angular and cingulum bundles of the cingulate gyrus, as well as the corticospinal tract and the superior longitudinal fasciculus. There was no relationship between cognition and mean FA or free water-adjusted FA across the 99th percentile core white matter pathway. Crystallized cognitive ability was not associated with any of the diffusion measures. When examining cognitive domains comprising the NIH Toolbox Fluid Cognition index relationships with these white matter pathways, mean free water demonstrated strong hemispheric and functional specificity for cognitive performance, whereas mean FA was not related to age or cognition across the 99th percentile pathway. Conclusions Extracellular free water within white matter appears to increase with normal aging, and higher values are associated with significantly lower fluid but not crystallized cognitive functions. When using TRACULA to estimate the core of a white matter pathway, a higher degree of free water appears to be highly specific to the pathways associated with memory, working memory, and speeded decision-making performance, whereas no such relationship existed with FA. These data suggest that free water may play an important role in the cognitive aging process, and may serve as a stronger and more specific indicator of early cognitive decline than traditional diffusion MRI measures, such as FA.

Background: Despite more widely accessible combination antiretroviral therapy (cART), the human immunodeficiency virus type-1 (HIV) infection remains a global public health challenge. Even in treated and chronically HIV-infected (HIV+) individuals, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in-vivo may delineate the neuropathological processes underlying these deficits. However, to date, neuroimaging findings are inconsistent. Methods: We established the ENIGMA-HIV Working Group to retrospectively pool and harmonize heterogeneous data from 12 HIV neuroimaging studies across Africa, Asia, Australia, Europe, and North America. Volume estimates for eight subcortical brain regions were extracted from T1- weighted MRI from 1,044 HIV+ adults (aged 22-81 years; 72·4% on cART; 70·3% male; 41·6% with detectable viral load; dVL), to identify associations with plasma markers reflecting current immunosuppression (CD4+ T-cell counts) or dVL. Follow-up analyses stratified data by cART status and sex. Findings: After Bonferroni correction, lower current CD4+ counts were associated with smaller hippocampal (β=20·3 mm3 per 100 cells/mm3; p=0·0001) and thalamic volumes (β=29.3; p=0·003); in participants not on cART, they were associated with smaller putamen volumes (β=65·1; p=0·0009). dVLs were associated with smaller hippocampi (Cohen's d=0·24; p=0·0003) and amygdala (d=0·18; p=0·0058). Interpretation: In a globally representative population of HIV+ individuals, volumes of structures in the limbic system were consistently associated with current plasma markers. Deficits in these regions may represent a generalizable brain signature of HIV-infection in the cART era. Our findings support the role of viral suppression and immune restoration in maintaining brain health. Funding Statement: Funding for the ENIGMA Center for Worldwide Medicine Imaging and Genomics was provided by the NIH Big Data to Knowledge Program (BD2K; U54 EB020403). Additional funding for this work was provided by NIH grants R01AG059874 (NJ), R01MH117601 (NJ), T32AG058507 (TMN and CRKC), 5T32MH073526 (CRKC), MH083553 (CHH), MH19535 (CHH), R01HL095135 (KJK), MH095661 (TK), UL1RR033176 (TK), UL1TR000124 (TK), MH19535 (TK), NS080655 (BAN), K01AA025306 (ECP), R01HL095135 (CMS), U54MD007584 (CMS), K23MH095661 (ADT), K23AG032872 (VV), R01NS061696 (VV), K24MH098759 (VV), K01AG050707 (AJW), P01AA019072 (RAC), R01MH074368 (RAC), P30 AI042853 (RAC), and by R01MH085604 (RP). This study was also supported by the SA Medical Research Council (DJS), NHMRC APP568746 and APP1045400 (LAC), and the European Research Council Advanced Grant MedYMA 2011- 291080 (XP). Declaration of Interests: PMT, TMN, NJ, and CRKC received partial research support from Biogen, Inc., for work unrelated to the topic of this manuscript. BKN has received an honorarium from MedLink Neurology. VV has served as a consultant for Merck and ViiV Healthcare in the past 3 years, not related to this work. JA has received honoraria for participating in advisory meetings for ViiV Healthcare, Gilead, Merck, Roche and AbbVie. The remaining authors all declare no conflicts of interest. Ethics Approval Statement: Each study obtained approval from their local ethics committee or institutional review board; participants signed an informed consent form at each participating site.

Background: Despite more widely accessible combination antiretroviral therapy (cART), the human immunodeficiency virus type-1 (HIV) infection remains a global public health challenge. Even in treated and chronically HIV-infected (HIV+) individuals, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in-vivo may delineate the neuropathological processes underlying these deficits. However, to date, neuroimaging findings are inconsistent. Methods: We established the ENIGMA-HIV Working Group to retrospectively pool and harmonize heterogeneous data from 12 HIV neuroimaging studies across Africa, Asia, Australia, Europe, and North America. Volume estimates for eight subcortical brain regions were extracted from T1- weighted MRI from 1,044 HIV+ adults (aged 22-81 years; 72·4% on cART; 70·3% male; 41·6% with detectable viral load; dVL), to identify associations with plasma markers reflecting current immunosuppression (CD4+ T-cell counts) or dVL. Follow-up analyses stratified data by cART status and sex. Findings: After Bonferroni correction, lower current CD4+ counts were associated with smaller hippocampal (β=20·3 mm3 per 100 cells/mm3; p=0·0001) and thalamic volumes (β=29.3; p=0·003); in participants not on cART, they were associated with smaller putamen volumes (β=65·1; p=0·0009). dVLs were associated with smaller hippocampi (Cohen's d=0·24; p=0·0003) and amygdala (d=0·18; p=0·0058). Interpretation: In a globally representative population of HIV+ individuals, volumes of structures in the limbic system were consistently associated with current plasma markers. Deficits in these regions may represent a generalizable brain signature of HIV-infection in the cART-era. Our findings support the role of viral suppression and immune restoration in maintaining brain health. Funding Statement: Funding for the ENIGMA Center for Worldwide Medicine Imaging and Genomics was provided by the NIH Big Data to Knowledge Program (BD2K; U54 EB020403). Additional funding for this work was provided by NIH grants R01AG059874 (NJ), R01MH117601 (NJ), T32AG058507 (TMN and CRKC), 5T32MH073526 (CRKC), MH083553 (CHH), MH19535 (CHH), R01HL095135 (KJK), MH095661 (TK), UL1RR033176 (TK), UL1TR000124 (TK), MH19535 (TK), NS080655 (BAN), K01AA025306 (ECP), R01HL095135 (CMS), U54MD007584 (CMS), K23MH095661 (ADT), K23AG032872 (VV), R01NS061696 (VV), K24MH098759 (VV), K01AG050707 (AJW), P01AA019072 (RAC), R01MH074368 (RAC), P30 AI042853 (RAC), and by R01MH085604 (RP). This study was also supported by the SA Medical Research Council (DJS), NHMRC APP568746 and APP1045400 (LAC), and the European Research Council Advanced Grant MedYMA 2011- 291080 (XP). Declaration of Interests: PMT, TMN, NJ, and CRKC received partial research support from Biogen, Inc., for work unrelated to the topic of this manuscript. BKN has received an honorarium from MedLink Neurology. VV has served as a consultant for Merck and ViiV Healthcare in the past 3 years, not related to this work. JA has received honoraria for participating in advisory meetings for ViiV Healthcare, Gilead, Merck, Roche and AbbVie. The remaining authors all declare no conflicts of interest. Ethics Approval Statement: Each study obtained approval from their local ethics committee or institutional review board; participants signed an informed consent form at each participating site.

Local modulation of glucocorticoid action in adipocytes regulates adiposity and systemic insulin sensitivity. However, the specific cofactors that mediate glucocorticoid receptor (GR) action in adipocytes remain unclear. Here we show that the silencing mediator of retinoid and thyroid hormone receptors (SMRT) is recruited to GR in adipocytes and regulates ligand-dependent GR function. Decreased SMRT expression in adipocytes in vivo increases expression of glucocorticoid-responsive genes. Moreover, adipocytes with decreased SMRT expression exhibit altered glucocorticoid regulation of lipolysis. We conclude that SMRT regulates the metabolic functions of GR in adipocytes in vivo. Modulation of GR-SMRT interactions in adipocytes represents a novel approach to control the local degree of glucocorticoid action and thus influence adipocyte metabolic function.

Background Reduced physical activity (PA) may be one factor that contributes to cognitive decline and dementia in heart failure (HF). Yet, the longitudinal relationship between PA and cognition in HF is poorly understood owing to limitations of past work, including single-time assessments of PA. This is the first study to examine changes in objectively measured PA and cognition over time in HF. Methods and Results At baseline and 12 weeks, 57 HF patients completed psychosocial self-report measures and a neuropsychological battery and wore an accelerometer for 7 days. At baseline, HF patients spent an average of 597.83 (SD 75.91) minutes per day sedentary. Steps per day declined from baseline to the 12-week follow-up; there was also a trend for declines in moderate-vigorous PA. Regression analyses controlling for sex, HF severity, and depressive symptoms showed that decreases in light ( P = .08) and moderate-vigorous ( P = .04) daily PA emerged as strong predictors of declines in attention/executive function over the 12-week period, but not of memory or language. Conclusions Reductions in daily PA predicted acute decline in attention/executive function in HF, but not of memory or language. Modifications to daily PA may attenuate cognitive decline, and prospective studies are needed to test this possibility.

Hypertension may increase risk for dementia possibly because of its association with decreased cortical thickness. Disturbed cerebral autoregulation is one plausible mechanism by which hypertension impacts the cerebral structure, but the associations among hypertension, brain perfusion, and cortical thickness are poorly understood. The current sample consisted of 58 older adults with varying levels of vascular disease. Diagnostic history of hypertension and antihypertensive medication status was ascertained through self-report, and when available, confirmed by medical record review. All participants underwent arterial spin labeling and T1-weighted magnetic resonance imaging to quantify total and regional cortical perfusion and thickness. Analysis of covariance adjusting for medical variables showed that participants with hypertension exhibited reduced temporal and occipital brain perfusion and total and regional cortical thickness relative to those without hypertension. The effects of hypertension on total brain perfusion remained unchanged even after adjustment for age, although no such pattern emerged for cortical thickness. Decreased total brain perfusion predicted reduced thickness of the total brain and of the frontal, temporal, and parietal lobe cortices. Antihypertensive treatment was not associated with total cerebral perfusion or cortical thickness. This study provides initial evidence for the adverse effects of a diagnostic history of hypertension on brain hypoperfusion and reduced cortical thickness. Longitudinal studies are needed to investigate the role of hypertension and its interaction with other contributing factors (eg, age) in the manifestation of cerebral hypoperfusion and reduced cortical thickness.

NDCX-II is a newly completed accelerator facility at LBNL, built to study ion-heated warm dense matter, as well as aspects of ion-driven targets and intense-beam dynamics for inertial-fusion energy. The baseline design calls for using 12 induction cells to accelerate 30–50 nC of Li + ions to 1.2 MeV. During commissioning, though, we plan to extend the source lifetime by extracting less total charge. Over time, we expect that NDCX-II will be upgraded to substantially higher energies, necessitating the use of heavier ions to keep a suitable deposition range in targets. For operational flexibility, the option of using a helium plasma source is also being investigated. Each of these options requires development of an alternate acceleration schedule. The schedules here are worked out with a fast-running 1-D particle-in-cell code ASP.

We review some previous results on electron-cloud dynamics and accumulation and the impact of electron clouds on ion beam dynamics, and assess these in the context of a magnetic-quadrupole-based heavy-ion fusion driver. We present a new analysis which exploits analytic solution of linearized envelope equations between accelerating gaps to derive a set of mapping equations which we use to extrapolate from previously obtained particle-simulation results for a beam transport system to an HIF driver.

Chronic systemic immune activation and inflammatory processes have been linked to brain dysfunction in medically stable HIV-infected people. We investigated the association between verbal memory performance and plasma concentrations of 13 cytokines measured using multiplexed bead array immunoassay in 74 HIV-seropositive individuals and 50 HIV-seronegative controls. Memory performance was positively related to levels of IL-8 and IFN-γ, and negatively related to IL-10 and IL-18 and to hepatitis C infection. Memory performance was not significantly related to HIV disease markers. The results indicate the importance of systemic immune and inflammatory markers to neurocognitive function in chronic and stable HIV disease.

Objectives To examine whether depression and apathy are independently associated with longitudinal trajectories of cortical atrophy in the entorhinal cortex compared with frontal subregions previously implicated in late-life mood disturbance. Methods Data from 334 participants classified as having mild cognitive impairment in the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed by using multilevel models for change adjusted for age, global cognitive status, and total intracranial volume at enrollment. Participants in ADNI were recruited from >50 clinical research sites in the United States and Canada. Depression and apathy were identified by informants using the Neuropsychiatric Inventory Questionnaire. Serial magnetic resonance imaging was performed on 1.5-Tesla scanners according to the standardized ADNI-1 protocol on an average of 5 occasions over an average of 30.5 months. Regional cortical thickness values were derived from longitudinal data processing in FreeSurfer version 4.4. Results Depression was associated with reduced cortical thickness in the entorhinal cortex at baseline and accelerated atrophy in the anterior cingulate cortex. Similar relationships between depression and the orbitofrontal cortex and between apathy and the anterior cingulate cortex were not significant. Conclusions In mild cognitive impairment, depression signs are a better marker of longitudinal cortical atrophy than apathy. Results are consistent with hypotheses that depression is an early sign of a more aggressive neurodegenerative process or that depression lowers brain reserve capacity, allowing for more rapid progression of Alzheimer disease neuropathology.

Reduced systemic perfusion and comorbid medical conditions are key contributors to adverse brain changes in heart failure (HF). Hypertension, the most common co-occurring condition in HF, accelerates brain atrophy in aging populations. However, the independent and interactive effects of blood pressure and systemic perfusion on brain structure in HF have yet to be investigated.Forty-eight older adults with HF underwent impedance cardiography to assess current systolic blood pressure status and cardiac index to quantify systemic perfusion. All participants underwent brain magnetic resonance imaging to quantify total brain, total and subcortical gray matter volume, and white matter hyperintensities (WMH) volume.Regression analyses adjusting for medical and demographic factors showed decreased cardiac index was associated with smaller subcortical gray matter volume (P .01), and higher systolic blood pressure predicted reduced total gray matter volume (P = .03). The combination of higher blood pressure and lower cardiac index exacerbated WMH (P = .048).Higher blood pressure and systemic hypoperfusion are associated with smaller brain volume, and these factors interact to exacerbate WMH in HF. Prospective studies are needed to clarify the effects of blood pressure on the brain in HF, including the role of long-term blood pressure fluctuations.

Physical fitness is an important correlate of structural and functional integrity of the brain in healthy adults. In heart failure (HF) patients, poor physical fitness may contribute to cognitive dysfunction and we examined the unique contribution of physical fitness to brain structural integrity among patients with HF.Sixty-nine HF patients performed the Modified Mini Mental State examination (3MS) and underwent brain magnetic resonance imaging. All participants completed the 2-minute step test (2MST), a brief measure of physical fitness. We examined the associations between cognitive performance, physical fitness, and three indices of global brain integrity: total cortical gray matter volume, total white matter volume, and whole brain cortical thickness.Regression analyses adjusting for demographic characteristics, medical variables (e.g., left ventricular ejection fraction), and intracranial volume revealed reduced performance on the 2MST were associated with decreased gray matter volume and thinner cortex (p.05). Follow up analyses showed that reduced gray matter volume and decreased cortical thickness were associated with poorer 3MS scores (p.05).Poor physical fitness is common in HF and associated with reduced structural brain integrity. Prospective studies are needed to elucidate underlying mechanisms for the influence of physical fitness on brain health in HF.

Cognitive impairment and brain injury are common in people with HIV/AIDS, even when viral replication is effectively suppressed with combined antiretroviral therapies (cART). Metabolic and structural abnormalities may promote cognitive decline, but we know little about how these measures relate in people on stable cART. Here we used tensor-based morphometry (TBM) to reveal the 3D profile of regional brain volume variations in 210 HIV+ patients scanned with whole-brain MRI at 1.5T (mean age: 48.6±8.4years; all receiving cART). We identified brain regions where the degree of atrophy was related to HIV clinical measures and cerebral metabolite levels assessed with magnetic resonance spectroscopy (MRS). Regional brain volume reduction was linked to lower nadir CD4+ count, with a 1–2% white matter volume reduction for each 25-point reduction in nadir CD4+. Even so, brain volume measured by TBM showed no detectable association with current CD4+ count, AIDS Dementia Complex (ADC) stage, HIV RNA load in plasma or cerebrospinal fluid (CSF), duration of HIV infection, antiretroviral CNS penetration-effectiveness (CPE) scores, or years on cART, after controlling for demographic factors, and for multiple comparisons. Elevated glutamate and glutamine (Glx) and lower N-acetylaspartate (NAA) in the frontal white matter, basal ganglia, and mid frontal cortex — were associated with lower white matter, putamen and thalamus volumes, and ventricular and CSF space expansion. Reductions in brain volumes in the setting of chronic and stable disease are strongly linked to a history of immunosuppression, suggesting that delays in initiating cART may result in imminent and irreversible brain damage.

The enzyme deoxyhypusine hydroxylase (DOHH) catalyzes the activation of eukaryotic translation initiation factor (eIF5A), a protein essential for cell growth. Using bioinformatic predictions and reporter gene assays, we have identified a 182-nt element within the DOHH 3'-untranslated region (3'-UTR) that contains a number of target sites for miR-331-3p and miR-642-5p. Quantitative RT-PCR studies demonstrated overexpression of DOHH mRNA and underexpression of miR-331-3p and miR-642-5p in several prostate cancer cell lines compared with normal prostate epithelial cells. Transient overexpression of miR-331-3p and/or miR-642-5p in DU145 prostate cancer cells reduced DOHH mRNA and protein expression and inhibited cell proliferation. We observed synergistic growth inhibition with the combination of miR-331-3p and miR-642-5p and mimosine, a pharmacological DOHH inhibitor. Finally, we identified a significant inverse relationship between the expression of miR-331-3p or miR-642-5p and DOHH in a cohort of human prostate cancer tissues. Our results suggest a novel role for miR-331-3p and miR-642-5p in the control of prostate cancer cell growth via the regulation of DOHH expression and eIF5A activity.

Objective Obesity is associated with poorer cognitive function and impulsivity, which may contribute to binge eating disorder (BED). The objective of this study was to compare cognitive function in morbidly obese individuals with and without BED. Method A total of 131 morbidly obese individuals (41 with past or present BED, 90 with no BED history) completed a computerized battery of cognitive tests including executive, memory, language, and attention. Results Both groups of participants evidenced high rates of cognitive impairment; however, no significant differences emerged between persons with and without BED on cognitive testing. Comparison of persons without BED, current BED, and past BED also yielded no differences. Discussion In the present sample, morbidly obese individuals with and without BED were clinically indistinguishable on tests of cognitive function. Our findings suggest that obesity, rather than binge eating, may be more directly related to cognition. Future studies should further examine this relationship because it might provide greater insight into the neural mechanisms for this BED.

The goals of this paper are to review the most popular methods of predictor selection in regression models, to explain why some fail when the number P of explanatory variables exceeds the number N of participants, and to discuss alternative statistical methods that can be employed in this case. We focus on penalized least squares methods in regression models, and discuss in detail two such methods that are well established in the statistical literature, the LASSO and Elastic Net. We introduce bootstrap enhancements of these methods, the BE-LASSO and BE-Enet, that allow the user to attach a measure of uncertainty to each variable selected. Our work is motivated by a multimodal neuroimaging dataset that consists of morphometric measures (volumes at several anatomical regions of interest), white matter integrity measures from diffusion weighted data (fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity) and clinical and demographic variables (age, education, alcohol and drug history). In this dataset, the number P of explanatory variables exceeds the number N of participants. We use the BE-LASSO and BE-Enet to provide the first statistical analysis that allows the assessment of neurocognitive performance from high dimensional neuroimaging and clinical predictors, including their interactions. The major novelty of this analysis is that biomarker selection and dimension reduction are accomplished with a view towards obtaining good predictions for the outcome of interest (i.e., the neurocognitive indices), unlike principal component analysis that are performed only on the predictors' space independently of the outcome of interest.

Cytokine disturbances have been linked to brain dysfunction among HIV-infected people. Past studies have not simultaneously examined a large set of cytokine measures and their relationships to HIV-associated neurocognitive deficits. We hypothesized that performance on measures of attention, and executive and psychomotor functions would be associated with plasma cytokine concentrations in HIV-infected individuals. Plasma samples drawn from 30 HIV-infected and 37 HIV seronegative individuals were analyzed via xMAP multiplexed bead array immunoassay to determine concentrations of thirteen cytokines. Performance on Trail Making A/B, Stroop Test, Letter Number Sequencing, Digit Symbol Coding, Symbol Search, and Grooved Pegboard tests was assessed. Statistical analyses were performed to examine group differences in cytokine concentrations, and associations between cytokine and HIV clinical variables and neurocognitive performance. Significant HIV effects were found on seven of the thirteen cytokines, primarily with respect to interleukins. HIV clinical factors (CD4 and HIV RNA levels, duration of illness, antiretroviral treatment) and hepatitis C status were associated with specific plasma cytokine concentrations. Neurocognitive measures were associated with cytokine concentrations, most consistently among the interleukins and IP-10. Generally, cytokine concentrations were among the strongest predictors of neurocognitive function relative to other clinical factors, which reinforces their potential importance in examining the neuropathological processes of HIV. The findings also point to the potential value of simultaneously examining a panel of biomarkers. The current results suggest that a complex relationship likely exists among cytokines [how?], and that these relationships are mediated not only by HIV infection, but also by antiretroviral treatment and other comorbid conditions.

Reduced cardiac output is associated with increased white matter hyperintensities (WMH) and executive dysfunction in older adults, which may be secondary to relations between systemic and cerebral perfusion. This study preliminarily describes the regional distribution of cerebral WMH in the context of a normal cerebral perfusion atlas and aims to determine if these variables are associated with reduced cardiac output. Thirty-two participants (72 ± 8 years old, 38% female) with cardiovascular risk factors or disease underwent structural MRI acquisition at 1.5 T using a standard imaging protocol that included FLAIR sequences. WMH distribution was examined in common anatomical space using voxel-based morphometry and as a function of normal cerebral perfusion patterns by overlaying a single photon emission computed tomography (SPECT) atlas. Doppler echocardiogram data was used to dichotomize the participants on the basis of low (n = 9) and normal (n = 23) cardiac output. Global WMH count and volume did not differ between the low and normal cardiac output groups; however, atlas-derived SPECT perfusion values in regions of hyperintensities were reduced in the low versus normal cardiac output group (p < 0.001). Our preliminary data suggest that participants with low cardiac output have WMH in regions of relatively reduced perfusion, while normal cardiac output participants have WMH in regions with relatively higher regional perfusion. This spatial perfusion distribution difference for areas of WMH may occur in the context of reduced systemic perfusion, which subsequently impacts cerebral perfusion and contributes to subclinical or clinical microvascular damage.

We analyze detailed atmospheric gas/aerosol composition data acquired during the 2008 NASA ARCTAS (Arctic Research of the Composition of the Troposphere from Aircraft and Satellites) airborne campaign performed at high northern latitudes in spring (ARCTAS-A) and summer (ARCTAS-B) and in California in summer (ARCTAS-CARB). Biomass burning influences were widespread throughout the ARCTAS campaign. MODIS data from 2000 to 2009 indicated that 2008 had the second largest fire counts over Siberia and a more normal Canadian boreal forest fire season. Near surface arctic air in spring contained strong anthropogenic signatures indicated by high sulfate. In both spring and summer most of the pollution plumes transported to the Arctic region were from Europe and Asia and were present in the mid to upper troposphere and contained a mix of forest fire and urban influences. The gas/aerosol composition of the high latitude troposphere was strongly perturbed at all altitudes in both spring and summer. The reactive nitrogen budget was balanced with PAN as the dominant component. Mean ozone concentrations in the high latitude troposphere were only minimally perturbed (

Previous literature has reported effects of nicotine withdrawal on brain function during cognitive tasks such as verbal working memory (VWM). Mechanisms of these withdrawal effects have not been clearly identified. Functional neuroimaging offers an objective method to examine brain mechanisms associated with observable behavior and subjective reports. To investigate these mechanisms, 12 smokers were administered a 2-Back VWM challenge during two functional magnetic resonance imaging sessions. Participants abstained from smoking prior to both sessions; however, they applied a nicotine patch before one session and a placebo patch prior to the other. Among regions that exhibited a significant response to the 2-Back during either session, withdrawal was associated with significantly greater deactivation in left and right temporal poles and left medial frontal gyrus. The magnitude of task-related activation showed a significant inverse relationship to craving in the majority of regions during placebo administration. Also, individual brain responses varied more during placebo, suggesting inefficient neural processing. Results suggest that differences in brain response to a VWM challenge during abstinence may be attributed to increased craving. Further deactivation of regions associated with the default network (medial frontal and anterior temporal clusters) during the placebo condition suggests further suspension of default activity, possibly to compensate for inefficient neural processing.

Neonatal jaundice can be best understood as a balance between the production and elimination of bilirubin, with a multitude of factors and conditions affecting each of these processes. When an imbalance results because of an increase in circulating bilirubin (or the bilirubin load) to significantly high levels (severe hyperbilirubinemia), it may cause permanent neurologic sequelae (kernicterus). In most infants, an increase in bilirubin production (e.g., due to hemolysis) is the primary cause of severe hyperbilirubinemia, and thus reducing bilirubin production is a rational approach for its management. The situation can become critical in infants with an associated impaired bilirubin elimination mechanism as a result of a genetic deficiency and/or polymorphism. Combining information about bilirubin production and genetic information about bilirubin elimination with the tracking of bilirubin levels means that a relative assessment of jaundice risk might be feasible. Information on the level of bilirubin production and its rate of elimination may help to guide the clinical management of neonatal jaundice.

The silencing mediator of retinoid and thyroid hormone receptors (SMRT) serves as a corepressor for nuclear receptors and other factors. Recent evidence suggests that SMRT is an important regulator of metabolism, but its role in adipocyte function in vivo remains unclear. We generated heterozygous SMRT knock-out (SMRT(+/-)) mice to investigate the function of SMRT in the adipocyte and the regulation of adipocyte insulin sensitivity. We show that SMRT(+/-) mice are normal weight on a regular diet, but develop increased adiposity on a high-fat diet (HFD). The mechanisms underlying this phenotype are complex, but appear to be due to a combination of an increased number of smaller subcutaneous adipocytes as well as decreased leptin expression, resulting in greater caloric intake. In addition, adipogenesis of mouse embryonic fibroblasts (MEFs) derived from these mice was increased. However, adipocyte insulin sensitivity, measured by insulin-induced Akt phosphorylation and insulin-mediated suppression of lipolysis, was enhanced in SMRT(+/-) adipocytes. These finding suggest that SMRT regulates leptin expression and limits the ability of fat mass to expand with increased caloric intake, but that SMRT also negatively regulates adipocyte insulin sensitivity.

Molecular chaperones of the heat shock protein-90 (Hsp90) family promote cell survival, but the molecular requirements of this pathway in tumor progression are not understood. Here, we show that a mitochondria-localized Hsp90 chaperone, tumor necrosis factor receptor-associated protein-1 (TRAP-1), is abundantly and ubiquitously expressed in human high-grade prostatic intraepithelial neoplasia, Gleason grades 3 through 5 prostatic adenocarcinomas, and metastatic prostate cancer, but largely undetectable in normal prostate or benign prostatic hyperplasia in vivo. Prostate lesions formed in genetic models of the disease, including the transgenic adenocarcinoma of the mouse prostate and mice carrying prostate-specific deletion of the phosphatase tensin homolog tumor suppressor (Pten(pc-/-)), also exhibit high levels of TRAP-1. Expression of TRAP-1 in nontransformed prostatic epithelial BPH-1 cells inhibited cell death, whereas silencing of TRAP-1 in androgen-independent PC3 or DU145 prostate cancer cells by small interfering RNA enhanced apoptosis. Targeting TRAP-1 with a novel class of mitochondria-directed Hsp90 inhibitors, ie, Gamitrinibs, caused rapid and complete killing of androgen-dependent or -independent prostate cancer, but not BPH-1 cells, whereas reintroduction of TRAP-1 in BPH-1 cells conferred sensitivity to Gamitrinib-induced cell death. These data identify TRAP-1 as a novel mitochondrial survival factor differentially expressed in localized and metastatic prostate cancer compared with normal prostate. Targeting this pathway with Gamitrinibs could be explored as novel molecular therapy in patients with advanced prostate cancer.

Objective: Elderly patients with cardiovascular disease (CVD) often report cognitive difficulties including reduced cognitive processing speed and attention. On cross-sectional examination, such reports relate more closely to mood than to objective measures of cognitive performance, thus questioning the validity of subjective cognitive complaints as a marker of neurodegenerative processes. This study examined the longitudinal relationship among self-reported cognitive difficulties, depression, and performance on objective tests of global cognition in patients with CVD. Participants and Methods: Forty-seven patients with CVD (aged 55–85 years) completed a measure of perceived cognitive dysfunction (Cognitive Difficulties Scale [CDS]), a medical history questionnaire, the Dementia Rating Scale (DRS), and the Beck Depression Inventory (BDI) at baseline and 12 months later. Baseline brain imaging was available on a small subsample (N = 17). Results: Hierarchical linear regression revealed that increased report of cognitive difficulties at baseline was significantly associated with poorer DRS performance at follow-up (F [3, 43] = 4.45, p=0.008, CDS partial r=−0.30, p=0.048), independent of age, education, baseline DRS, and BDI scores. Greater perceived cognitive dysfunction at baseline also related to higher level of white matter lesions (r = 0.53, df=15, p=0.028). Conclusions: Self-reported cognitive difficulties may reflect early changes in cognitive aging that are difficult to detect using global cognitive screening measures at a single time point. However, these perceived difficulties relate to objectively measured cognitive decline over time. Thus, they may provide important clinical information about early neurodegenerative processes that should be carefully monitored.

The Heavy-Ion Fusion Sciences Virtual National Laboratory is pursuing an approach to target heating experiments in the warm-dense matter regime, using space-charge-dominated ion beams that are simultaneously longitudinally bunched and transversely focused. Longitudinal beam compression by large factors has been demonstrated in the Neutralized Drift Compression Experiment (NDCX) with controlled ramps and forced neutralization. Using an injected 30-mA K+ ion beam with initial kinetic energy 0.3 MeV, axial compression leading to ∼50-fold current amplification and simultaneous radial focusing to beam radii of a few mm have led to encouraging energy deposition approaching the intensities required for eV-range target heating experiments. We discuss the status of several improvements to our Neutralized Drift Compression Experiment and associated beam diagnostics that are under development to reach the necessary higher beam intensities, including (1) greater axial compression via a longer velocity ramp using a new bunching module with approximately twice the available volt seconds (Vs); (2) improved centroid control via beam steering dipoles to mitigate aberrations in the bunching module; (3) time-dependent focusing elements to correct considerable chromatic aberrations; and (4) plasma injection improvements to establish a plasma density always greater than the beam density, expected to be >1013 cm−3.

Small electrodes were installed in the outer-midplane edge of NSTX to attempt to control the local width of the scrape-off layer (SOL) by creating an outward E(pol)xB flow. When the applied voltage between electrodes was 90 V, the density between these electrodes increased by a factor of 3-10 over a radial width of similar to 4 cm. Thus a local control of the SOL plasma density was obtained. (C) 2009 Elsevier B.V. All rights reserved.

We investigate by first-principles calculations the effect of ferrous iron, Fe 2+ , on the structure and the equation of state of MgSiO 3 post-perovskite. We find that ferrous iron is high-spin over the pressure range of the mantle assuming a ferromagnetic structure. The bulk modulus and the specific volume increase with the addition of ferrous iron to MgSiO 3 . We find that Fe partitions preferentially to post-perovskite and broadens the two-phase pressure range.

A high-order finite-volume algorithm is developed for the Fokker-Planck Operator (FPO) describing Coulomb collisions in strongly magnetized plasmas. The algorithm uses a generic fourth-order reconstruction scheme on an unstructured grid in the velocity space spanned by parallel velocity and magnetic moment. By analytically mapping between different coordinates, it produces an accurate and density-conserving numerical FPO for an arbitrary choice of velocity space coordinates. A linearized FPO in constants-of-motion coordinates is implemented as an example of the present algorithm combined with a cut-cell merging procedure. Numerical tests include the thermalization of a test distribution with a background Maxwellian at a different temperature, and the return to isotropy for a distribution initialized with a velocity space loss-cone. Utilization of the method for a nonlinear FPO is straightforward but requires evaluation of the Trubnikov-Rosenbluth potentials.

Elevated body mass index (BMI) is associated with adverse neurocognitive outcome in adults, including reduced neuropsychological test performance. It is unknown whether this relationship also exists in children and adolescents. A total of 478 children and adolescents (age 6-19) without significant medical or psychiatric history provided demographic information and completed a computerized cognitive test battery. Participants were categorized using clinical criteria into underweight, normal weight, at risk for overweight and overweight groups based on age and gender. Partial correlation and MANCOVA analyses adjusting for age and intellectual function found no relationship between BMI and cognitive test performance in the full sample. However, analyses performed separately by gender showed that underweight females exhibited poorer memory performance than other female BMI groups. These findings suggest that elevated BMI is not associated with cognitive function in healthy children and adolescents, though underweight might be a risk factor for reduced memory performance in females. Further work is needed to clarify the inconsistent findings between adults and minors.

Studies of verbal working memory (VWM) report that performance declines as the phonemic similarity of stimuli increases. To determine how phonological similarity affects brain function during VWM, "standard" and "similarity" versions of the 2-Back task were presented to 34 healthy participants during functional magnetic resonance imaging (FMRI). Letter consonants presented during similarity blocks rhymed, while consonants did not rhyme during standard blocks. Empirical ROIs were identified from significant 2-Back-related activity observed during either condition. A priori ROIs were selected from functional neuroimaging literature on phonological processing. Although VWM-related activity was not modulated by similarity in any of four regions recruited (dorsolateral prefrontal, posterior parietal, anterior insular, and supplementary motor cortices), four of five regions of deactivation exhibited significantly greater deactivation during the similarity compared to the standard condition (posterior cingulate, paracentral lobule, posterior insula, and parahippocampal gyrus). In a priori phonological processing-related ROIs, similarity did not affect observed increases in activity (supplementary motor area, Broca's area, and cerebellum), while two of the three regions exhibiting decreased activity (near Wernicke's area and Heschel's Gyrus) also exhibited more deactivation during similarity. Accuracy was lower during the similarity 2-Back, positively related to activity within recruited VWM-related ROIs, and inversely related to activity in regions of VWM-related deactivation. Based on known functions of these ROIs, we conclude that language, audition, and self-reflection processes may disengage during phonological interference, while activity levels are maintained in regions recruited during VWM processing. Similarity effects likely include suspension of attention to unrelated and distracting processes to improve concentration.

Increased carotid artery intima-media thickness (IMT) is a non-invasive marker of systemic arterial disease. Increased IMT has been associated with atherosclerosis, abnormal arterial mechanics, myocardial infarction, and stroke. Given evidence of a relationship between cardiovascular health and attention-executive-psychomotor functioning, the purpose of this study was to examine IMT in relation to neuropsychological test performance in patients with a variety of cardiovascular diagnoses.One hundred and nine participants, ages 55 to 85, underwent neuropsychological assessment and B-mode ultrasound of the left common carotid artery. IMT was calculated using an automated algorithm based on a validated edge-detection technique. The relationship between IMT and measures of language, memory, visual-spatial abilities and attention-executive-psychomotor functioning was modeled using hierarchical linear regression analyses adjusted for age, education, sex, cardiovascular risk, current systolic blood pressure, and history of coronary artery disease (CAD).Increased IMT was associated with significantly lower performance in the attention-executive-psychomotor domain (IMT beta=-0.26, p.01), independent of age, education, sex, cardiovascular risk, current systolic blood pressure, and CAD (F(10,100)=3.61, p.001). IMT was not significantly related to language, memory, or visual-spatial abilities.Our findings suggest that, in patients with cardiovascular disease, IMT may be associated with the integrity of frontal subcortical networks responsible for attention-executive-psychomotor performance. Future studies are needed to clarify the mechanisms by which IMT affects cognition and examine potential interactions between increased IMT and other measures of cardiovascular health such as blood pressure variability, cardiac systolic performance, and systemic perfusion.

The high-current experiment (HCX) at LBNL is a driver scale single beam injector that provides a 1 MeV K + ion beam current of 0.18 A for 5 μs. It transports high-current beams with large fill factor (ratio of the maximum beam envelope radius to the beam pipe radius) and low emittance growth that are required to keep the cost of the power plant competitive and to satisfy the target requirements of focusing ion beams to high-power density. Beam interaction with the background gas and walls desorbs electrons that can multiply and accumulate, creating an electron cloud. This ubiquitous effect grows at higher fill factors and degrades the quality of the beam. We review simulations and diagnostics tools used to measure electron production, accumulation and its properties.

Electron-clouds and rising desorbed gas pressure limit the performance of many existing accelerators and, potentially, that of future accelerators including heavy-ion warm-dense matter and fusion drivers. For the latter, self-consistent simulation of the interaction of the heavy-ion beam(s) with the electron-cloud is necessary. To this end, we have merged the two codes WARP (HIF accelerator code) and POSINST (high-energy e-cloud build-up code), and added modules for neutral gas molecule generation, gas ionization, and electron tracking algorithms in magnetic fields with large time steps. The new tool is being benchmarked against the High-Current Experiment (HCX) and good agreement has been achieved. The simulations have also aided diagnostic interpretation and have identified unanticipated physical processes. We present the ''roadmap'' describing the different modules and their interconnections, along with detailed comparisons with HCX experimental results, as well as a preliminary application to the modeling of electron clouds in the Large Hadron Collider.

For self-consistent ion-beam simulations including electron motion, it is desirable to be able to follow electron dynamics accurately without being constrained by the electron cyclotron timescale. To this end, we have developed a particle-advance that interpolates between full particle dynamics and drift motion. By making a proper choice of interpolation parameter, simulation particles experience physically correct parallel dynamics, drift motion, and gyroradius when the timestep is large compared to the cyclotron period, though the effective gyrofrequency is artificially low; in the opposite timestep limit, the method approaches a conventional Boris particle push. By combining this scheme with a Poisson solver that includes an interpolated form of the polarization drift in the dielectric response, the mover's utility can be extended to higher-density problems where the plasma frequency of the species being advanced exceeds its cyclotron frequency. We describe a series of tests of the mover and its application to simulation of electron clouds in heavy-ion accelerators.