Second messenger/signal transduction pathways in major mood disorders: Moving from membrane to mechanism of action, part II: bipolar disorder

The etiopathogenesis and treatment of major mood disorders have historically focused on modulation of monoaminergic (serotonin, norepinephrine, dopamine) and amino acid [γ-aminobutyric acid (GABA), glutamate] receptors at the plasma membrane. Although the activation and inhibition of these receptors acutely alter local neurotransmitter levels, their neuropsychiatric effects are not immediately observed. This time lag implicates intracellular neuroplasticity as primary in the mechanism of action of antidepressants and mood stabilizers. The modulation of intracellular second messenger/signal transduction cascades affects neurotrophic pathways that are both necessary and sufficient for monoaminergic and amino acid–based treatments. In this review, we will discuss the evidence in support of intracellular mediators in the pathophysiology and treatment of preclinical models of despair and major depressive disorder (MDD). More specifically, we will focus on the following pathways: cAMP/PKA/CREB, neurotrophin-mediated (MAPK and others), p11, Wnt/Fz/Dvl/GSK3β, and NFκB/ΔFosB. We will also discuss recent discoveries with rapidly acting antidepressants, which activate the mammalian target of rapamycin (mTOR) and release of inhibition on local translation via elongation factor stimulation. Throughout this discourse, we will highlight potential intracellular targets for therapeutic intervention. Finally, future clinical implications are discussed

A First Look at the Auriga-California Giant Molecular Cloud With Herschel and the CSO: Census of the Young Stellar Objects and the Dense Gas

We have mapped the Auriga/California molecular cloud with the Herschel PACS and SPIRE cameras and the Bolocam 1.1 mm camera on the Caltech Submillimeter Observatory (CSO) with the eventual goal of quantifying the star formation and cloud structure in this Giant Molecular Cloud (GMC) that is comparable in size and mass to the Orion GMC, but which appears to be forming far fewer stars. We have tabulated 60 compact 70/160um sources that are likely pre-main-sequence objects and correlated those with Spitzer and WISE mid-IR sources. At 1.1 mm we find 18 cold, compact sources and discuss their properties. The most important result from this part of our study is that we find a modest number of additional compact young objects beyond those identified at shorter wavelengths with Spitzer. We also describe the dust column density and temperature structure derived from our photometric maps. The column density peaks at a few x 10^22 cm^-2 (N_H2) and is distributed in a clear filamentary structure along which nearly all the pre-main-sequence objects are found. We compare the YSO surface density to the gas column density and find a strong non-linear correlation between them. The dust temperature in the densest parts of the filaments drops to ~10K from values ~ 14--15K in the low density parts of the cloud. We also derive the cumulative mass fraction and probability density function of material in the cloud which we compare with similar data on other star-forming clouds.Comment: in press Astrophysical Journal, 201

The Luminosities of Protostars in the Spitzer c2d and Gould Belt Legacy Clouds

Motivated by the long-standing "luminosity problem" in low-mass star formation whereby protostars are underluminous compared to theoretical expectations, we identify 230 protostars in 18 molecular clouds observed by two Spitzer Space Telescope Legacy surveys of nearby star-forming regions. We compile complete spectral energy distributions, calculate Lbol for each source, and study the protostellar luminosity distribution. This distribution extends over three orders of magnitude, from 0.01 Lsun - 69 Lsun, and has a mean and median of 4.3 Lsun and 1.3 Lsun, respectively. The distributions are very similar for Class 0 and Class I sources except for an excess of low luminosity (Lbol < 0.5 Lsun) Class I sources compared to Class 0. 100 out of the 230 protostars (43%) lack any available data in the far-infrared and submillimeter (70 um < wavelength < 850 um) and have Lbol underestimated by factors of 2.5 on average, and up to factors of 8-10 in extreme cases. Correcting these underestimates for each source individually once additional data becomes available will likely increase both the mean and median of the sample by 35% - 40%. We discuss and compare our results to several recent theoretical studies of protostellar luminosities and show that our new results do not invalidate the conclusions of any of these studies. As these studies demonstrate that there is more than one plausible accretion scenario that can match observations, future attention is clearly needed. The better statistics provided by our increased dataset should aid such future work.Comment: Accepted for publication in AJ. 21 pages, 10 figures, 4 table

Young Stellar Objects in the Gould Belt

We present the full catalog of Young Stellar Objects (YSOs) identified in the 18 molecular clouds surveyed by the Spitzer Space Telescope "cores to disks" (c2d) and "Gould Belt" (GB) Legacy surveys. Using standard techniques developed by the c2d project, we identify 3239 candidate YSOs in the 18 clouds, 2966 of which survive visual inspection and form our final catalog of YSOs in the Gould Belt. We compile extinction corrected SEDs for all 2966 YSOs and calculate and tabulate the infrared spectral index, bolometric luminosity, and bolometric temperature for each object. We find that 326 (11%), 210 (7%), 1248 (42%), and 1182 (40%) are classified as Class 0+I, Flat-spectrum, Class II, and Class III, respectively, and show that the Class III sample suffers from an overall contamination rate by background AGB stars between 25% and 90%. Adopting standard assumptions, we derive durations of 0.40-0.78 Myr for Class 0+I YSOs and 0.26-0.50 Myr for Flat-spectrum YSOs, where the ranges encompass uncertainties in the adopted assumptions. Including information from (sub)millimeter wavelengths, one-third of the Class 0+I sample is classified as Class 0, leading to durations of 0.13-0.26 Myr (Class 0) and 0.27-0.52 Myr (Class I). We revisit infrared color-color diagrams used in the literature to classify YSOs and propose minor revisions to classification boundaries in these diagrams. Finally, we show that the bolometric temperature is a poor discriminator between Class II and Class III YSOs.Comment: Accepted for publication in ApJS. 29 pages, 11 figures, 14 tables, 4 appendices. Full versions of data tables (to be published in machine-readable format by ApJS) available at the end of the latex source cod

Deep Vadose Zone-Applied Field Research Initiative Fiscal Year 2011 Annual Report

This annual report describes the background of the Deep Vadose Zone-Applied Field Research Initiative, and some of the programmatic approaches and transformational technologies in groundwater and deep vadose zone remediation developed during fiscal year 2011. The Department of Energy (DOE) Office of Technology Innovation and Development's (OTID) mission is to transform science into viable solutions for environmental cleanup. In 2010, OTID developed the Impact Plan, Science and Technology to Reduce the Life Cycle Cost of Closure to outline the benefits of research and development of the lifecycle cost of cleanup across the DOE complex. This plan outlines OTID's ability to reduce by $50 billion, the$200 billion life-cycle cost in waste processing, groundwater and soil, nuclear materials, and deactivation and decommissioning. The projected life-cycle costs and return on investment are based on actual savings realized from technology innovation, development, and insertion into remedial strategies and schedules at the Fernald, Mound, and Ashtabula sites. To achieve our goals, OTID developed Applied Field Research Initiatives to facilitate and accelerate collaborative development and implementation of new tools and approaches that reduce risk, cost and time for site closure. The primary mission of the Deep Vadose Zone-Applied Field Research Initiative (DVZ-AFRI) is to protect our nation's water resources, keeping them clean and safe for future generations. The DVZ-AFRI was established for the DOE to develop effective, science-based solutions for remediating, characterizing, monitoring, and predicting the behavior and fate of deep vadose zone contamination. Subsurface contaminants include radionuclides, metals, organics, and liquid waste that originated from various sources, including legacy waste from the nation's nuclear weapons complexes. The DVZ-AFRI project team is translating strategy into action by working to solve these complex challenges in a collaborative environment that leverages technology and scientific expertise from DOE, Pacific Northwest National Laboratory, CH2M HILL Plateau Remediation Company, and the broad scientific research community. As project manager for the DVZ-AFRI, I have had the privilege this past year to team with creative, talented members of the scientific community nationwide to develop effective long-term solutions to address deep vadose zone contamination. This report highlights how the DVZ-AFRI project team is delivering results by achieving significant programmatic accomplishments, and developing and field-testing transformational technologies to address the nation's most pressing groundwater and vadose zone contamination problems

The Spitzer Survey of Interstellar Clouds in the Gould Belt. VI. The Auriga-California Molecular Cloud observed with IRAC and MIPS

We present observations of the Auriga-California Molecular Cloud (AMC) at 3.6, 4.5, 5.8, 8.0, 24, 70 and 160 micron observed with the IRAC and MIPS detectors as part of the Spitzer Gould Belt Legacy Survey. The total mapped areas are 2.5 sq-deg with IRAC and 10.47 sq-deg with MIPS. This giant molecular cloud is one of two in the nearby Gould Belt of star-forming regions, the other being the Orion A Molecular Cloud (OMC). We compare source counts, colors and magnitudes in our observed region to a subset of the SWIRE data that was processed through our pipeline. Using color-magnitude and color-color diagrams, we find evidence for a substantial population of 166 young stellar objects (YSOs) in the cloud, many of which were previously unknown. Most of this population is concentrated around the LkHalpha 101 cluster and the filament extending from it. We present a quantitative description of the degree of clustering and discuss the fraction of YSOs in the region with disks relative to an estimate of the diskless YSO population. Although the AMC is similar in mass, size and distance to the OMC, it is forming about 15 - 20 times fewer stars.Comment: (30 pages, 17 figures (2 multipage figures), accepted for publication in ApJ

Rasagiline Effects on Glucose Metabolism, Cognition, and Tau in Alzheimer’s Dementia

Background: A Phase II proof of concept (POC) randomized clinical trial was conducted to evaluate the effects of rasagiline, a monoamine oxidase B (MAO-B) inhibitor approved for Parkinson disease, in mild to moderate Alzheimer\u27s disease (AD). The primary objective was to determine if 1 mg of rasagiline daily for 24 weeks is associated with improved regional brain metabolism (fluorodeoxyglucose–positron emission tomography [FDG-PET]) compared to placebo. Secondary objectives included measurement of effects on tau PET and evaluation of directional consistency of clinical end points. Methods: This was a double-blind, parallel group, placebo-controlled, community-based, three-site trial of 50 participants randomized 1:1 to receive oral rasagiline or placebo (NCT02359552). FDG-PET was analyzed for the presence of an AD-like pattern as an inclusion criterion and as a longitudinal outcome using prespecified regions of interest and voxel-based analyses. Tau PET was evaluated at baseline and longitudinally. Clinical outcomes were analyzed using an intention-to-treat (ITT) model. Results: Fifty patients were randomized and 43 completed treatment. The study met its primary end point, demonstrating favorable change in FDG-PET differences in rasagiline versus placebo in middle frontal (P \u3c 0.025), anterior cingulate (P \u3c 0.041), and striatal (P \u3c 0.023) regions. Clinical measures showed benefit in quality of life (P \u3c 0.04). Digit Span, verbal fluency, and Neuropsychiatric Inventory (NPI) showed non-significant directional favoring of rasagiline; no effects were observed in Alzheimer\u27s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or activities of daily living. Rasagiline was generally well tolerated with low rates of adverse events and notably fewer neuropsychiatric symptoms in the active treatment group. Discussion: These outcomes illustrate the potential benefits of rasagiline on clinical and neuroimaging measures in patients with mild to moderate AD. Rasagiline appears to affect neuronal activity in frontostriatal pathways, with associated clinical benefit potential warranting a more fully powered trial. This study illustrated the potential benefit of therapeutic repurposing and an experimental medicine proof-of-concept design with biomarkers to characterize patient and detect treatment response

Sedentary time in older men and women: an international consensus statement and research priorities

Sedentary time is a modifiable determinant of poor health, and in older adults, reducing sedentary time may be an important first step in adopting and maintaining a more active lifestyle. The primary purpose of this consensus statement is to provide an integrated perspective on current knowledge and expert opinion pertaining to sedentary behaviour in older adults on the topics of measurement, associations with health outcomes, and interventions. A secondary yet equally important purpose is to suggest priorities for future research and knowledge translation based on gaps identified. A five-step Delphi consensus process was used. Experts in the area of sedentary behaviour and older adults (n=15) participated in three surveys, an in-person consensus meeting, and a validation process. The surveys specifically probed measurement, health outcomes, interventions, and research priorities. The meeting was informed by a literature review and conference symposium, and it was used to create statements on each of the areas addressed in this document. Knowledge users (n=3) also participated in the consensus meeting. Statements were then sent to the experts for validation. It was agreed that self-report tools need to be developed for understanding the context in which sedentary time is accumulated. For health outcomes, it was agreed that the focus of sedentary time research in older adults needs to include geriatric-relevant health outcomes, that there is insufficient evidence to quantify the dose-response relationship, that there is a lack of evidence on sedentary time from older adults in assisted facilities, and that evidence on the association between sedentary time and sleep is lacking. For interventions, research is needed to assess the impact that reducing sedentary time, or breaking up prolonged bouts of sedentary time has on geriatric-relevant health outcomes. Research priorities listed for each of these areas should be considered by researchers and funding agencies

The frequency of osteogenic activities and the pattern of intermittence between periods of physical activity and sedentary behaviour affects bone mineral content: the cross-sectional NHANES study

BACKGROUND: Sedentary behaviours, defined as non exercising seated activities, have been shown to have deleterious effects on health. It has been hypothesised that too much sitting time can have a detrimental effect on bone health in youth. The aim of this study is to test this hypothesis by exploring the association between objectively measured volume and patterns of time spent in sedentary behaviours, time spent in specific screen-based sedentary pursuits and bone mineral content (BMC) accrual in youth. METHODS: NHANES 2005–2006 cycle data includes BMC of the femoral and spinal region via dual-energy X-ray absorptiometry (DEXA), assessment of physical activity and sedentary behaviour patterns through accelerometry, self reported time spent in screen based pursuits (watching TV and using a computer), and frequency of vigorous playtime and strengthening activities. Multiple regression analysis, stratified by gender was performed on N = 671 males and N = 677 females aged from 8 to 22 years. RESULTS: Time spent in screen-based sedentary behaviours is negatively associated with femoral BMC (males and females) and spinal BMC (females only) after correction for time spent in moderate and vigorous activity. Regression coefficients indicate that an additional hour per day of screen-based sitting corresponds to a difference of −0.77 g femoral BMC in females [95% CI: -1.31 to −0.22] and of −0.45 g femoral BMC in males [95% CI: -0.83 to −0.06]. This association is attenuated when self-reported engagement in regular (average 5 times per week) strengthening exercise (for males) and vigorous playing (for both males and females) is taken into account. Total sitting time and non screen-based sitting do not appear to have a negative association with BMC, whereas screen based sedentary time does. Patterns of intermittence between periods of sitting and moderate to vigorous activity appears to be positively associated with bone health when activity is clustered in time and inter-spaced with long continuous bouts of sitting. CONCLUSIONS: Some specific sedentary pursuits (screen-based) are negatively associated with bone health in youth. This association is specific to gender and anatomical area. This relationship between screen-based time and bone health is independent of the total amount of physical activity measured objectively, but not independent of self-reported frequency of strengthening and vigorous play activities. The data clearly suggests that the frequency, rather than the volume, of osteogenic activities is important in counteracting the effect of sedentary behaviour on bone health. The pattern of intermittence between sedentary periods and activity also plays a role in bone accrual, with clustered short bouts of activity interspaced with long periods of sedentary behaviours appearing to be more beneficial than activities more evenly spread in time