Efficient Activation of Reconstructed Rat Embryos by Cyclin-Dependent Kinase Inhibitors

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Associations of Mail Survey Length and Layout With Response Rates.

We assess the association between survey layout and response rates (RRs) in the 2017 Medicare Advantage Consumer Assessment of Healthcare Providers and Systems mail survey. Among 438 Medicare Advantage plans surveyed by six vendors, there was latitude in survey layout, and plans could add up to 12 supplemental items. Regression models predicted survey response from survey characteristics (page count, number of supplemental items, and survey attractiveness), and beneficiary sociodemographics. Beneficiary-age-by-survey-characteristic interactions assessed whether survey characteristics were more strongly related to RRs among older beneficiaries. We found that surveys with more supplemental items and less attractive layouts had lower adjusted odds of response. RRs were more sensitive to format among older beneficiaries. The difference in adjusted RRs for the most favorable versus the least favorable survey design was 14.5%. For a 65-year-old, this difference was 13.6%; for an 80-year-old, it was 21.0%. These findings suggest that even within a relatively standardized survey, formatting can substantially influence RRs

Type 2 Diabetes as a Risk Factor for Dementia in Women Compared With Men: A Pooled Analysis of 2.3 Million People Comprising More Than 100,000 Cases of Dementia

Objective: Type 2 diabetes confers a greater excess risk of cardiovascular disease in women than in men. Diabetes is also a risk factor for dementia, but whether the association is similar in women and men remains unknown. We performed a meta-analysis of unpublished data to estimate the sex-specific relationship between women and men with diabetes with incident dementia. Research design and methods: A systematic search identified studies published prior to November 2014 that had reported on the prospective association between diabetes and dementia. Study authors contributed unpublished sex-specific relative risks (RRs) and 95% CIs on the association between diabetes and all dementia and its subtypes. Sex-specific RRs and the women-to-men ratio of RRs (RRRs) were pooled using random-effects meta-analyses. Results: Study-level data from 14 studies, 2,310,330 individuals, and 102,174 dementia case patients were included. In multiple-adjusted analyses, diabetes was associated with a 60% increased risk of any dementia in both sexes (women: pooled RR 1.62 [95% CI 1.45-1.80]; men: pooled RR 1.58 [95% CI 1.38-1.81]). The diabetes-associated RRs for vascular dementia were 2.34 (95% CI 1.86-2.94) in women and 1.73 (95% CI 1.61-1.85) in men, and for nonvascular dementia, the RRs were 1.53 (95% CI 1.35-1.73) in women and 1.49 (95% CI 1.31-1.69) in men. Overall, women with diabetes had a 19% greater risk for the development of vascular dementia than men (multiple-adjusted RRR 1.19 [95% CI 1.08-1.30]; P \u3c 0.001). Conclusions: Individuals with type 2 diabetes are at ∼60% greater risk for the development of dementia compared with those without diabetes. For vascular dementia, but not for nonvascular dementia, the additional risk is greater in women

Calcineurin/NFAT Signaling in Activated Astrocytes Drives Network Hyperexcitability in A\u3cem\u3eβ\u3c/em\u3e-Bearing Mice

Hyperexcitable neuronal networks are mechanistically linked to the pathologic and clinical features of Alzheimer\u27s disease (AD). Astrocytes are a primary defense against hyperexcitability, but their functional phenotype during AD is poorly understood. Here, we found that activated astrocytes in the 5xFAD mouse model were strongly associated with proteolysis of the protein phosphatase calcineurin (CN) and the elevated expression of the CN-dependent transcription factor nuclear factor of activated T cells 4 (NFAT4). Intrahippocampal injections of adeno-associated virus vectors containing the astrocyte-specific promoter Gfa2 and the NFAT inhibitory peptide VIVIT reduced signs of glutamate-mediated hyperexcitability in 5xFAD mice, measured in vivo with microelectrode arrays and ex vivo brain slices, using whole-cell voltage clamp. VIVIT treatment in 5xFAD mice led to increased expression of the astrocytic glutamate transporter GLT-1 and to attenuated changes in dendrite morphology, synaptic strength, and NMDAR-dependent responses. The results reveal astrocytic CN/NFAT4 as a key pathologic mechanism for driving glutamate dysregulation and neuronal hyperactivity during AD

Down Syndrome: Age-Dependence of PiB Binding in Postmortem Frontal Cortex Across the Lifespan

Beta-amyloid (Aβ) deposition in brain accumulates as a function of age in people with Down syndrome (DS) with subsequent development into Alzheimer disease neuropathology, typically by 40 years of age. In vivo imaging using the Pittsburgh Compound B (PiB) ligand has facilitated studies linking Aβ, cognition, and dementia in DS. However, there are no studies of PiB binding across the lifespan in DS. The current study describes in vitro 3H-PiB binding in the frontal cortex of autopsy cases with DS compared to non-DS controls. Tissue from 64 cases included controls (N=25) and DS (N=39). In DS, 3H-PiB binding was significantly associated with age. After age 40 years in DS, 3H-PiB binding rose dramatically along with increasing individual variability. 3H-PiB binding correlated with the amount of Aβ42. Using fixed frontal tissue and fluorescent 6-CN-PiB, neuritic and cored plaques along with extensive cerebral amyloid angiopathy (CAA) showed 6-CN-PiB binding. These results suggest that cortical PiB binding as shown by positron emission tomography imaging reflects plaques and CAA in DS brain

Aeolian Remobilisation of Volcanic Ash: Outcomes of a Workshop in the Argentinian Patagonia

During explosive volcanic eruptions, large quantities of tephra can be dispersed and deposited over wide areas. Following deposition, subsequent aeolian remobilisation of ash can potentially exacerbate primary impacts on timescales of months to millennia. Recent ash remobilisation events (e.g., following eruptions of Cordón Caulle 2011; Chile, and Eyjafjallajökull 2010, Iceland) have highlighted this to be a recurring phenomenon with consequences for human health, economic sectors, and critical infrastructure. Consequently, scientists from observatories and Volcanic Ash Advisory Centers (VAACs), as well as researchers from fields including volcanology, aeolian processes and soil sciences, convened at the San Carlos de Bariloche headquarters of the Argentinian National Institute of Agricultural Technology to discuss the ?state of the art? for field studies of remobilised deposits as well as monitoring, modeling and understanding ash remobilisation. In this article, we identify practices for field characterisation of deposits and active processes, including mapping, particle characterisation and sediment traps. Furthermore, since forecast models currently rely on poorly-constrained dust emission schemes, we call for laboratory and field measurements to better parameterise the flux of volcanic ash as a function of friction velocity. While source area location and extent are currently the primary inputs for dispersion models, once emission schemes become more sophisticated and better constrained, other parameters will also become important (e.g., source material volume and properties, effective precipitation, type and distribution of vegetation cover, friction velocity). Thus, aeolian ash remobilisation hazard and associated impact assessment require systematic monitoring, including the development of a regularly-updated spatial database of resuspension source areas.Fil: Jarvis, Paul A.. Universidad de Ginebra. Facultad de Ciencias. Sección de Ciencias de la Tierra; SuizaFil: Bonadonna, Costanza. Universidad de Ginebra. Facultad de Ciencias. Sección de Ciencias de la Tierra; SuizaFil: Dominguez, Lucia. Universidad de Ginebra. Facultad de Ciencias. Sección de Ciencias de la Tierra; SuizaFil: Forte, Pablo Brian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Estudios Andinos "Don Pablo Groeber". Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Estudios Andinos "Don Pablo Groeber"; ArgentinaFil: Frischknecht, Corine. Universidad de Ginebra. Facultad de Ciencias. Sección de Ciencias de la Tierra; SuizaFil: Bran, Donaldo. Instituto Nacional de Tecnología Agropecuaria; ArgentinaFil: Aguilar, Rigoberto. No especifíca;Fil: Beckett, Frances. No especifíca;Fil: Elissondo, Manuela. Secretaría de Industria y Minería. Servicio Geológico Minero Argentino; ArgentinaFil: Gillies, John. Desert Research Institute; Estados UnidosFil: Kueppers, Ulrich. Ludwig Maximilians Universitat; AlemaniaFil: Merrison, Jonathan. University Aarhus. Institut for Fysik Og Astronomi; DinamarcaFil: Varley, Nick. Universidad de Colima; MéxicoFil: Wallace, Kristi L.. United States Geological Survey; Estados Unido

Regional differences in clonal Japanese knotweed revealed by chemometrics-linked attenuated total reflection Fourier-transform infrared spectroscopy

Abstract: Background: Japanese knotweed (R. japonica var japonica) is one of the world’s 100 worst invasive species, causing crop losses, damage to infrastructure, and erosion of ecosystem services. In the UK, this species is an all-female clone, which spreads by vegetative reproduction. Despite this genetic continuity, Japanese knotweed can colonise a wide variety of environmental habitats. However, little is known about the phenotypic plasticity responsible for the ability of Japanese knotweed to invade and thrive in such diverse habitats. We have used attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy, in which the spectral fingerprint generated allows subtle differences in composition to be clearly visualized, to examine regional differences in clonal Japanese knotweed. Results: We have shown distinct differences in the spectral fingerprint region (1800–900 cm− 1) of Japanese knotweed from three different regions in the UK that were sufficient to successfully identify plants from different geographical regions with high accuracy using support vector machine (SVM) chemometrics. Conclusions: These differences were not correlated with environmental variations between regions, raising the possibility that epigenetic modifications may contribute to the phenotypic plasticity responsible for the ability of R. japonica to invade and thrive in such diverse habitats

Combinatorial CRISPR-Cas9 screens for de novo mapping of genetic interactions.

We developed a systematic approach to map human genetic networks by combinatorial CRISPR-Cas9 perturbations coupled to robust analysis of growth kinetics. We targeted all pairs of 73 cancer genes with dual guide RNAs in three cell lines, comprising 141,912 tests of interaction. Numerous therapeutically relevant interactions were identified, and these patterns replicated with combinatorial drugs at 75% precision. From these results, we anticipate that cellular context will be critical to synthetic-lethal therapies

Impact of the Alzheimer's Disease Neuroimaging Initiative, 2004 to 2014

INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative (ADNI) was established in 2004 to facilitate the development of effective treatments for Alzheimer's disease (AD) by validating biomarkers for AD clinical trials. METHODS: We searched for ADNI publications using established methods. RESULTS: ADNI has (1) developed standardized biomarkers for use in clinical trial subject selection and as surrogate outcome measures; (2) standardized protocols for use across multiple centers; (3) initiated worldwide ADNI; (4) inspired initiatives investigating traumatic brain injury and post-traumatic stress disorder in military populations, and depression, respectively, as an AD risk factor; (5) acted as a data-sharing model; (6) generated data used in over 600 publications, leading to the identification of novel AD risk alleles, and an understanding of the relationship between biomarkers and AD progression; and (7) inspired other public-private partnerships developing biomarkers for Parkinson's disease and multiple sclerosis. DISCUSSION: ADNI has made myriad impacts in its first decade. A competitive renewal of the project in 2015 would see the use of newly developed tau imaging ligands, and the continued development of recruitment strategies and outcome measures for clinical trials

Next-Generation Sequencing of HIV-1 Single Genome Amplicons

The analysis of HIV-1 sequences has helped understand the viral molecular epidemiology, monitor the development of antiretroviral drug resistance, and design candidate vaccines. The introduction of single genome amplification (SGA) has been a major advancement in the field, allowing for the characterization of multiple sequences per patient while preserving linkage among polymorphisms in the same viral genome copy. Sequencing of SGA amplicons is performed by capillary Sanger sequencing, which presents low throughput, requires a high amount of template, and is highly sensitive to template/primer mismatching. In order to meet the increasing demand for HIV-1 SGA amplicon sequencing, we have developed a platform based on benchtop next-generation sequencing (NGS) (IonTorrent) accompanied by a bioinformatics pipeline capable of running on computer resources commonly available at research laboratories. During assay validation, the NGS-based sequencing of 10 HIV-1 env SGA amplicons was fully concordant with Sanger sequencing. The field test was conducted on plasma samples from 10 US Navy and Marine service members with recent HIV-1 infection (sampling interval: 2005-2010; plasma viral load: 5,884-194,984 copies/ml). The NGS analysis of 101 SGA amplicons (median: 10 amplicons/individual) showed within-individual viral sequence profiles expected in individuals at this disease stage, including individuals with highly homogeneous quasispecies, individuals with two highly homogeneous viral lineages, and individuals with heterogeneous viral populations. In a scalability assessment using the Ion Chef automated system, 41/43 tested env SGA amplicons (95%) multiplexed on a single Ion 318 chip showed consistent gene-wide coverage \u3e50×. With lower sample requirements and higher throughput, this approach is suitable to support the increasing demand for high-quality and cost-effective HIV-1 sequences in fields such as molecular epidemiology, and development of preventive and therapeutic strategies