Involvement of Noradrenergic Neurotransmission in the Stress- but not Cocaine-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Role for β-2 Adrenergic Receptors

The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.p.) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and reestablished by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim (FS); 20–25°C water), or administration of the α-2 adrenergic receptor (AR) antagonists yohimbine (2 mg/kg, i.p.) or BRL44408 (5, 10 mg/kg, i.p.). To investigate the role of ARs, mice were administered the nonselective β-AR antagonist, propranolol (5, 10 mg/kg, i.p.), the α-1 AR antagonist, prazosin (1, 2 mg/kg, i.p.), or the α-2 AR agonist, clonidine (0.03, 0.3 mg/kg, i.p.) before reinstatement testing. Clonidine, prazosin, and propranolol failed to block cocaine-induced reinstatement. The low (0.03 mg/kg) but not high (0.3 mg/kg) clonidine dose fully blocked FS-induced reinstatement but not reinstatement by yohimbine. Propranolol, but not prazosin, blocked reinstatement by both yohimbine and FS, suggesting the involvement of β-ARs. The β-2 AR antagonist ICI-118551 (1 mg/kg, i.p.), but not the β-1 AR antagonist betaxolol (10 mg/kg, i.p.), also blocked FS-induced reinstatement. These findings suggest that stress-induced reinstatement requires noradrenergic signaling through β-2 ARs and that cocaine-induced reinstatement does not require AR activation, even though stimulation of central noradrenergic neurotransmission is sufficient to reinstate

Computational, Integrative, and Comparative Methods for the Elucidation of Genetic Coexpression Networks

Gene expression microarray data can be used for the assembly of genetic coexpression network graphs. Using mRNA samples obtained from recombinant inbred Mus musculus strains, it is possible to integrate allelic variation with molecular and higher-order phenotypes. The depth of quantitative genetic analysis of microarray data can be vastly enhanced utilizing this mouse resource in combination with powerful computational algorithms, platforms, and data repositories. The resulting network graphs transect many levels of biological scale. This approach is illustrated with the extraction of cliques of putatively coregulated genes and their annotation using gene ontology analysis and cis-regulatory element discovery. The causal basis for coregulation is detected through the use of quantitative trait locus mapping

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

TOI-954 B And K2-329 B: Short-Period Saturn-Mass Planets That Test Whether Irradiation Leads To Inflation

We report the discovery of two short-period Saturn-mass planets, one transiting the G subgiant TOI-954 (TIC 44792534, V = 10.343, T = 9.78) observed in TESS sectors 4 and 5 and one transiting the G dwarf K2-329 (EPIC 246193072, V = 12.70, K = 10.67) observed in K2 campaigns 12 and 19. We confirm and characterize these two planets with a variety of ground-based archival and follow-up observations, including photometry, reconnaissance spectroscopy, precise radial velocity, and high-resolution imaging. Combining all available data, we find that TOI-954 b has a radius of ${0.852}_{-0.062}^{+0.053}\,{R}_{{\rm{J}}}$and a mass of ${0.174}_{-0.017}^{+0.018}$MJ and is in a 3.68 day orbit, while K2-329 b has a radius of ${0.774}_{-0.024}^{+0.026}\,{R}_{{\rm{J}}}$and a mass of ${0.260}_{-0.022}^{+0.020}$MJ and is in a 12.46 day orbit. As TOI-954 b is 30 times more irradiated than K2-329 b but more or less the same size, these two planets provide an opportunity to test whether irradiation leads to inflation of Saturn-mass planets and contribute to future comparative studies that explore Saturn-mass planets at contrasting points in their lifetimes

Pathogenic variants in the Longitudinal Early‐onset Alzheimer's Disease Study cohort

IntroductionOne goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants.MethodsLEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study.ResultsPreviously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases.DiscussionResults suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases.HighlightsSequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research

Cerebrospinal fluid biomarkers in the Longitudinal Early‐onset Alzheimer's Disease Study

IntroductionOne goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD).MethodsCerebrospinal fluid (CSF) concentrations of Aβ1-40, Aβ1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated.ResultsBiomarkers were correlated with one another. Levels of CSF Aβ42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aβ42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure.DiscussionThis study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design

Like mother, like child : investigating perinatal and maternal health stress in post-medieval London.

Post-Medieval London (sixteenth-nineteenth centuries) was a stressful environment for the poor. Overcrowded and squalid housing, physically demanding and risky working conditions, air and water pollution, inadequate diet and exposure to infectious diseases created high levels of morbidity and low life expectancy. All of these factors pressed with particular severity on the lowest members of the social strata, with burgeoning disparities in health between the richest and poorest. Foetal, perinatal and infant skeletal remains provide the most sensitive source of bioarchaeological information regarding past population health and in particular maternal well-being. This chapter examined the evidence for chronic growth and health disruption in 136 foetal, perinatal and infant skeletons from four low-status cemetery samples in post-medieval London. The aim of this study was to consider the impact of poverty on the maternal-infant nexus, through an analysis of evidence of growth disruption and pathological lesions. The results highlight the dire consequences of poverty in London during this period from the very earliest moments of life

NASA's J-2X Engine Builds on the Apollo Program for Lunar Return Missions

In January 2006, NASA streamlined its U.S. Vision for Space Exploration hardware development approach for replacing the Space Shuttle after it is retired in 2010. The revised CLV upper stage will use the J-2X engine, a derivative of NASA s Apollo Program Saturn V s S-II and S-IVB main propulsion, which will also serve as the Earth Departure Stage (EDS) engine. This paper gives details of how the J- 2X engine effort mitigates risk by building on the Apollo Program and other lessons learned to deliver a human-rated engine that is on an aggressive development schedule, with first demonstration flight in 2010 and human test flights in 2012. It is well documented that propulsion is historically a high-risk area. NASA s risk reduction strategy for the J-2X engine design, development, test, and evaluation is to build upon heritage hardware and apply valuable experience gained from past development efforts. In addition, NASA and its industry partner, Rocketdyne, which originally built the J-2, have tapped into their extensive databases and are applying lessons conveyed firsthand by Apollo-era veterans of America s first round of Moon missions in the 1960s and 1970s. NASA s development approach for the J-2X engine includes early requirements definition and management; designing-in lessons learned from the 5-2 heritage programs; initiating long-lead procurement items before Preliminary Desi& Review; incorporating design features for anticipated EDS requirements; identifying facilities for sea-level and altitude testing; and starting ground support equipment and logistics planning at an early stage. Other risk reduction strategies include utilizing a proven gas generator cycle with recent development experience; utilizing existing turbomachinery ; applying current and recent main combustion chamber (Integrated Powerhead Demonstrator) and channel wall nozzle (COBRA) advances; and performing rigorous development, qualification, and certification testing of the engine system, with a philosophy of "test what you fly, and fly what you test". These and other active risk management strategies are in place to deliver the J-2X engine for LEO and lunar return missions as outlined in the U.S. Vision for Space Exploration