Systematic Multi-Domain Alzheimer's Risk Reduction Trial (SMARRT): Study Protocol.

This article describes the protocol for the Systematic Multi-domain Alzheimer's Risk Reduction Trial (SMARRT), a single-blind randomized pilot trial to test a personalized, pragmatic, multi-domain Alzheimer's disease (AD) risk reduction intervention in a US integrated healthcare delivery system. Study participants will be 200 higher-risk older adults (age 70-89 years with subjective cognitive complaints, low normal performance on cognitive screen, and ≥ two modifiable risk factors targeted by our intervention) who will be recruited from selected primary care clinics of Kaiser Permanente Washington, oversampling people with non-white race or Hispanic ethnicity. Study participants will be randomly assigned to a two-year Alzheimer's risk reduction intervention (SMARRT) or a Health Education (HE) control. Randomization will be stratified by clinic, race/ethnicity (non-Hispanic white versus non-white or Hispanic), and age (70-79, 80-89). Participants randomized to the SMARRT group will work with a behavioral coach and nurse to develop a personalized plan related to their risk factors (poorly controlled hypertension, diabetes with evidence of hyper or hypoglycemia, depressive symptoms, poor sleep quality, contraindicated medications, physical inactivity, low cognitive stimulation, social isolation, poor diet, smoking). Participants in the HE control group will be mailed general health education information about these risk factors for AD. The primary outcome is two-year cognitive change on a cognitive test composite score. Secondary outcomes include: 1) improvement in targeted risk factors, 2) individual cognitive domain composite scores, 3) physical performance, 4) functional ability, 5) quality of life, and 6) incidence of mild cognitive impairment, AD, and dementia. Primary and secondary outcomes will be assessed in both groups at baseline and 6, 12, 18, and 24 months

Design and development of a magnetically-driven ventricular assist device (MVAD): in vitro implementation in the fontan circulation

A rapidly testable novel Magnetically-Driven Ventricular Assist Device (MVAD) with no m ving parts that can be used to provide assistance to the cardiovascular circulation while reducing caval pressure in patients who have undergone the Fontan procedure to palliate the Hypoplastic Left Heart Syndrome (HLHS) is proposed and studied. A benchtop Mock Flow Loop (MFL) of the cardiovascular circulation with a Fontan total cavopulmonary connection (TCPC) is configured to validate this hypothesis. The MFL is based on a Lumped-Parameter Model (LPM) comprised of upper and lower systemic circulation as well as left and right pulmonary circulation compartments. Needle valves are used to accurately replicate vascular resistance (R) while compliance chambers are used to mimic vascular compliance (C). The MFL centerpiece is the truncated aortic arch with an implanted MVAD. A ferro-fluid solution is mixed in water to simulate magnetically-charged blood. The pulsating flow is induced by drawing the ferro-fluid from a main reservoir with a Harvard Apparatus Medical pump while the MVAD provides assistive momentum to the TCPC. Flow and pressure sensor data at specific points in the MFL are acquired via a National Instruments multichannel data acquisition board and processed using LabView. Different prototypes of the MVAD are tested to validate the hypothesis

The Time is Right for an Antarctic Biorepository Network

Antarctica is a central driver of the Earth’s climate and health. The Southern Ocean surrounding Antarctica serves as a major sink for anthropogenic CO2 and heat (1), and the loss of Antarctic ice sheets contributes significantly to sea level rise and will continue to do so as the loss of ice sheets accelerates, with sufficient water stores to raise sea levels by 58 m (2). Antarctica\u27s marine environment is home to a number of iconic species, and the terrestrial realm harbors a remarkable oasis for life, much of which has yet to be discovered (3). Distinctive oceanographic features of the Southern Ocean—including the Antarctic Circumpolar Current, the Antarctic Polar Front, and exceptional depths surrounding the continent—coupled with chronically cold temperatures have fostered the evolution of a vast number of uniquely coldadapted species, many of which are found nowhere else on the Earth (4). The Antarctic marine biota, for example, displays the highest level of species endemism on the Earth (5). However, warming, ocean acidification, pollution, and commercial exploitation threaten the integrity of Antarctic ecosystems (6). Understanding changes in the biota and its capacities for adaptation is imperative for establishing effective policies for mitigating the impacts of climate change and sustaining the Antarctic ecosystems that are vital to global health

Luminescent Charge-transfer Platinum(ii) Metallacycle

The photophysical and electrochemical properties of a platinum(II) diimine complex bearing the bidentate diacetylide ligand tolan-2,2\u27-diacetylide (tda), Pt(dbbpy)(tda) [dbbpy = 4,4\u27-di-tert-butyl-2,2\u27-bipyridine] (1), are compared with two reference compounds, Pt(dbbpy)(C CPh)(2) (2) and Pt(dppp)tda [dppp = 1,3-bis(diphenylphosphino)propane] (3), respectively, The X-ray crystal structure of 1 is reported, which illustrates the nearly perfect square planarity exhibited by this metallacycle. Chromophore 2 possesses low-lying charge-transfer excited states analogous to 1, whereas structure 3 lacks such excited states but features a low-lying platinum-perturbed tda intraligand triplet manifold. In CH2Cl2, 1 exhibits a broad emission centered at 562 nm at ambient temperature, similar to 2, but with a higher photoluminescence quantum yield and longer excited-state lifetime. In both instances, the photoluminescence is consistent with triplet-charge-transfer excited-state parentage. The rigidity imposed by the cyclic diacetylide ligand in 1 leads to a reduction in nonradiative decay, which enhances its room-temperature photophysical properties. By comparison, 3 radiates highly structured tda-localized triplet-state phosphorescence at room temperature. The 77 K emission spectrum of 1 in 4:1 EtOH/MeOH becomes structured and is quantitatively similar to that measured for 3 under the same conditions. Because the 77 K spectra are nearly identical, the emissions are assigned as (3)tda in nature, implying that the charge-transfer states are raised in energy, relative to the (3)tda levels in 1 in the low-temperature glass. Nanosecond transient absorption spectrometry and ultrafast difference spectra were determined for 1-3 in CH2Cl2 and DMF at ambient temperature. In 1 and 2, the major absorption transients are consistent with the one-electron reduced complexes, corroborated by reductive spectroelectrochemical measurements performed at room temperature. As 3 does not possess any charge-transfer character, excitation into the pi pi* transitions of the tda ligand generated transient absorptions in the relaxed excited state assigned to the ligand-localized triplet state. In all three cases, the excited-state lifetimes measured by transient absorption are similar to those measured by time-resolved photoluminescence, suggesting that the same excited states giving rise to the photoluminescence are responsible for the absorption transients. ESR spectroscopy of the anions 1(-) and 2(-) and reductive spectroelectrochemistry of 1 and 2 revealed a LUMO based largely on the pi* orbital of the dbbpy ligand. Time-dependent density functional theory calculations performed on 1-3 both in vacuum and in a CH2Cl2 continuum revealed the molecular orbitals, energies, dipole moments, and oscillator strengths for the various electronic transitions in these molecules. A Delta SCF-method-derived shift applied to the calculated transition energies in the solvent continuum yielded good agreement between theory and experiment for each molecule in this study

Sustaining The Saco Estuary: Final Report 2015

This study focuses on the Saco estuary, the tidal portion of the Saco River, which drains the largest watershed in southern Maine. With headwaters in the White Mountains of New Hampshire, the watershed encompasses more than 4,400 km2, and provides clean healthy drinking water to over 100,000 people living and working in communities in southern Maine. When the study began in 2009, very little was known about the ecology of the Saco estuary. Researchers at the University of New England and the Wells National Estuarine Research Reserve employed the process of collaborative learning to bring together people who care about the estuary in order to identify their concerns. A Stewardship Network composed of people employed by municipal, state and federal governments, water supply organizations and businesses, volunteers from municipal boards making land use decisions, land trusts, property owners and representatives from other organizations that are uniquely focused on the region was formed. The Stewardship Network helped to define the project goals and objectives, and provided input and guidance over the five-year project. This report explains what the researchers discovered about the ecology of the estuary, along with what they learned about its social and economic components. This baseline assessment contributes to the long-term goal of restoring and sustaining the structure and function of the estuary, and supports the efforts of government, businesses and local organizations that value the estuary and depend upon the natural services it provides

Deglutarylation of glutaryl-CoA dehydrogenase by deacylating enzyme SIRT5 promotes lysine oxidation in mice

A wide range of protein acyl modifications has been identified on enzymes across various metabolic processes; however, the impact of these modifications remains poorly understood. Protein glutarylation is a recently identified modification that can be nonenzymatically driven by glutaryl-CoA. In mammalian systems, this unique metabolite is only produced in the lysine and tryptophan oxidative pathways. To better understand the biology of protein glutarylation, we studied the relationship between enzymes within the lysine/tryptophan catabolic pathways, protein glutarylation, and regulation by the deglutarylating enzyme sirtuin 5 (SIRT5). Here, we identify glutarylation on the lysine oxidation pathway enzyme glutaryl-CoA dehydrogenase (GCDH) and show increased GCDH glutarylation when glutaryl-CoA production is stimulated by lysine catabolism. Our data reveal that glutarylation of GCDH impacts its function, ultimately decreasing lysine oxidation. We also demonstrate the ability of SIRT5 to deglutarylate GCDH, restoring its enzymatic activity. Finally, metabolomic and bioinformatic analyses indicate an expanded role for SIRT5 in regulating amino acid metabolism. Together, these data support a feedback loop model within the lysine/tryptophan oxidation pathway in which glutaryl-CoA is produced, in turn inhibiting GCDH function via glutaryl modification of GCDH lysine residues and can be relieved by SIRT5 deacylation activity

Genome-wide association study of antidepressant treatment resistance in a population-based cohort using health service prescription data and meta-analysis with GENDEP

Antidepressants demonstrate modest response rates in the treatment of major depressive disorder (MDD). Despite previous genome-wide association studies (GWAS) of antidepressant treatment response, the underlying genetic factors are unknown. Using prescription data in a population and family-based cohort (Generation Scotland: Scottish Family Health Study; GS:SFHS), we sought to define a measure of (a) antidepressant treatment resistance and (b) stages of antidepressant resistance by inferring antidepressant switching as non-response to treatment. GWAS were conducted separately for antidepressant treatment resistance in GS:SFHS and the Genome-based Therapeutic Drugs for Depression (GENDEP) study and then meta-analysed (meta-analysis n = 4213, cases = 358). For stages of antidepressant resistance, a GWAS on GS:SFHS only was performed (n = 3452). Additionally, we conducted gene-set enrichment, polygenic risk scoring (PRS) and genetic correlation analysis. We did not identify any significant loci, genes or gene sets associated with antidepressant treatment resistance or stages of resistance. Significant positive genetic correlations of antidepressant treatment resistance and stages of resistance with neuroticism, psychological distress, schizotypy and mood disorder traits were identified. These findings suggest that larger sample sizes are needed to identify the genetic architecture of antidepressant treatment response, and that population-based observational studies may provide a tractable approach to achieving the necessary statistical power

Inhibition of proteasome activity by the dietary flavonoid apigenin is associated with growth inhibition in cultured breast cancer cells and xenografts

Abstract Introduction Proteasome inhibition is an attractive approach to anticancer therapy and may have relevancy in breast cancer treatment. Natural products, such as dietary flavonoids, have been suggested as natural proteasome inhibitors with potential use for cancer prevention and therapeutics. We previously reported that apigenin, a flavonoid widely distributed in many fruits and vegetables, can inhibit proteasome activity and can induce apoptosis in cultured leukemia Jurkat T cells. Whether apigenin has proteasome-inhibitory activity in the highly metastatic human breast MDA-MB-231 cells and xenografts, however, is unknown. Methods MDA-MB-231 breast cancer cell cultures and xenografts were treated with apigenin, followed by measurement of reduced cellular viability/proliferation, proteasome inhibition, and apoptosis induction. Inhibition of the proteasome was determined by levels of the proteasomal chymotrypsin-like activity, by ubiquitinated proteins, and by accumulation of proteasome target proteins in extracts of the treated cells or tumors. Apoptotic cell death was measured by capase-3/caspase-7 activation, poly(ADP-ribose) polymerase cleavage, and immunohistochemistry for terminal nucleotidyl transferase-mediated nick end labeling positivity. Results We report for the first time that apigenin inhibits the proteasomal chymotrypsin-like activity and induces apoptosis not only in cultured MDA-MB-231 cells but also in MDA-MB-231 xenografts. Furthermore, while apigenin has antibreast tumor activity, no apparent toxicity to the tested animals was observed. Conclusion We have shown that apigenin is an effective proteasome inhibitor in cultured breast cancer cells and in breast cancer xenografts. Furthermore, apigenin induces apoptotic cell death in human breast cancer cells and exhibits anticancer activities in tumors. The results suggest its potential benefits in breast cancer prevention and treatment