Downregulation of CREB expression in Alzheimer's brain and in Aβ-treated rat hippocampal neurons

<p>Abstract</p> <p>Background</p> <p>Oxidative stress plays an important role in neuronal dysfunction and neuron loss in Alzheimer's brain. Previous studies have reported downregulation of CREB-mediated transcription by oxidative stress and Aβ. The promoter for CREB itself contains cyclic AMP response elements. Therefore, we examined the expression of CREB in the hippocampal neurons of Tg2576 mice, AD post-mortem brain and in cultured rat hippocampal neurons exposed to Aβ aggregates.</p> <p>Results</p> <p>Laser Capture Microdissection of hippocampal neurons from Tg2576 mouse brain revealed decreases in the mRNA levels of CREB and its target, BDNF. Immunohistochemical analysis of Tg2576 mouse brain showed decreases in CREB levels in hippocampus and cortex. Markers of oxidative stress were detected in transgenic mouse brain and decreased CREB staining was observed in regions showing abundance of astrocytes. There was also an inverse correlation between SDS-extracted Aβ and CREB protein levels in Alzheimer's post-mortem hippocampal samples. The levels of CREB-regulated BDNF and BIRC3, a caspase inhibitor, decreased and the active cleaved form of caspase-9, a marker for the intrinsic pathway of apoptosis, was elevated in these samples. Exposure of rat primary hippocampal neurons to Aβ fibrils decreased CREB promoter activity. Decrease in CREB mRNA levels in Aβ-treated neurons was reversed by the antioxidant, N-acetyl cysteine. Overexpression of CREB by adenoviral transduction led to significant protection against Aβ-induced neuronal apoptosis.</p> <p>Conclusions</p> <p>Our findings suggest that chronic downregulation of CREB-mediated transcription results in decrease of CREB content in the hippocampal neurons of AD brain which may contribute to exacerbation of disease progression.</p

Positive Selection Drives Preferred Segment Combinations during Influenza Virus Reassortment

Influenza A virus (IAV) has a segmented genome that allows for the exchange of genome segments between different strains. This reassortment accelerates evolution by breaking linkage, helping IAV cross species barriers to potentially create highly virulent strains. Challenges associated with monitoring the process of reassortment in molecular detail have limited our understanding of its evolutionary implications. We applied a novel deep sequencing approach with quantitative analysis to assess the in vitro temporal evolution of genomic reassortment in IAV. The combination of H1N1 and H3N2 strains reproducibly generated a new H1N2 strain with the hemagglutinin and nucleoprotein segments originating from H1N1 and the remaining six segments from H3N2. By deep sequencing the entire viral genome, we monitored the evolution of reassortment, quantifying the relative abundance of all IAV genome segments from the two parent strains over time and measuring the selection coefficients of the reassorting segments. Additionally, we observed several mutations coemerging with reassortment that were not found during passaging of pure parental IAV strains. Our results demonstrate how reassortment of the segmented genome can accelerate viral evolution in IAV, potentially enabled by the emergence of a small number of individual mutation

Positive Selection Drives Preferred Segment Combinations during Influenza Virus Reassortment

Influenza A virus (IAV) has a segmented genome that allows for the exchange of genome segments between different strains. This reassortment accelerates evolution by breaking linkage, helping IAV cross species barriers to potentially create highly virulent strains. Challenges associated with monitoring the process of reassortment in molecular detail have limited our understanding of its evolutionary implications. We applied a novel deep sequencing approach with quantitative analysis to assess the in vitro temporal evolution of genomic reassortment in IAV. The combination of H1N1 and H3N2 strains reproducibly generated a new H1N2 strain with the hemagglutinin and nucleoprotein segments originating from H1N1 and the remaining six segments from H3N2. By deep sequencing the entire viral genome, we monitored the evolution of reassortment, quantifying the relative abundance of all IAV genome segments from the two parent strains over time and measuring the selection coefficients of the reassorting segments. Additionally, we observed several mutations coemerging with reassortment that were not found during passaging of pure parental IAV strains. Our results demonstrate how reassortment of the segmented genome can accelerate viral evolution in IAV, potentially enabled by the emergence of a small number of individual mutation

A Second Look at the Association between Gender and Mortality on Antiretroviral Therapy

Objective: We assessed the association between gender and mortality on antiretroviral therapy (ART) using identical models with and without sex-specific categories for weight and hemoglobin. Design: Cohort study of adult patients on ART. Setting: GHESKIO Clinic in Port-au-Prince, Haiti. Participants: 4,717 ART-naïve adult patients consecutively enrolled on ART at GHESKIO from 2003 to 2008. Main Outcome Measure: Mortality on ART; multivariable analyses were conducted with and without sex-specific categories for weight and hemoglobin. Results: In Haiti, male gender was associated with mortality (OR 1.61; 95% CI: 1.30–2.00) in multivariable analyses with hemoglobin and weight included as control variables, but not when sex-specific interactions with hemoglobin and weight were used. Conclusions: If sex-specific categories are omitted, multivariable analyses indicate a higher risk of mortality for males vs. females of the same weight and hemoglobin. However, because males have higher normal values for weight and hemoglobin, the males in this comparison would generally have poorer health status than the females. This may explain why gender differences in mortality are sometimes observed after controlling for differences in baseline variables when gender-specific interactions with weight and hemoglobin are omitted

A framework for the development of a global standardised marine taxon reference image database (SMarTaR-ID) to support image-based analyses

Video and image data are regularly used in the field of benthic ecology to document biodiversity. However, their use is subject to a number of challenges, principally the identification of taxa within the images without associated physical specimens. The challenge of applying traditional taxonomic keys to the identification of fauna from images has led to the development of personal, group, or institution level reference image catalogues of operational taxonomic units (OTUs) or morphospecies. Lack of standardisation among these reference catalogues has led to problems with observer bias and the inability to combine datasets across studies. In addition, lack of a common reference standard is stifling efforts in the application of artificial intelligence to taxon identification. Using the North Atlantic deep sea as a case study, we propose a database structure to facilitate standardisation of morphospecies image catalogues between research groups and support future use in multiple front-end applications. We also propose a framework for coordination of international efforts to develop reference guides for the identification of marine species from images. The proposed structure maps to the Darwin Core standard to allow integration with existing databases. We suggest a management framework where high-level taxonomic groups are curated by a regional team, consisting of both end users and taxonomic experts. We identify a mechanism by which overall quality of data within a common reference guide could be raised over the next decade. Finally, we discuss the role of a common reference standard in advancing marine ecology and supporting sustainable use of this ecosystem

Fruit and vegetable intake and the risk of cardiovascular disease, total cancer and all-cause mortality – a systematic review and dose-response meta-analysis of prospective studies

Background: Questions remain about the strength and shape of the dose-response relationship between fruit and vegetable intake and risk of cardiovascular disease, cancer and mortality, and the effects of specific types of fruit and vegetables. We conducted a systematic review and meta-analysis to clarify these associations. Methods: PubMed and Embase were searched up to 29 September 2016. Prospective studies of fruit and vegetable intake and cardiovascular disease, total cancer and all-cause mortality were included. Summary relative risks (RRs) were calculated using a random effects model, and the mortality burden globally was estimated; 95 studies (142 publications) were included. Results: For fruits and vegetables combined, the summary RR per 200 g/day was 0.92 [95% confidence interval (CI): 0.90–0.94, I2 = 0%, n = 15] for coronary heart disease, 0.84 (95% CI: 0.76–0.92, I2 = 73%, n = 10) for stroke, 0.92 (95% CI: 0.90–0.95, I2 = 31%, n = 13) for cardiovascular disease, 0.97 (95% CI: 0.95–0.99, I2 = 49%, n = 12) for total cancer and 0.90 (95% CI: 0.87–0.93, I2 = 83%, n = 15) for all-cause mortality. Similar associations were observed for fruits and vegetables separately. Reductions in risk were observed up to 800 g/day for all outcomes except cancer (600 g/day). Inverse associations were observed between the intake of apples and pears, citrus fruits, green leafy vegetables, cruciferous vegetables, and salads and cardiovascular disease and all-cause mortality, and between the intake of green-yellow vegetables and cruciferous vegetables and total cancer risk. An estimated 5.6 and 7.8 million premature deaths worldwide in 2013 may be attributable to a fruit and vegetable intake below 500 and 800 g/day, respectively, if the observed associations are causal. Conclusions: Fruit and vegetable intakes were associated with reduced risk of cardiovascular disease, cancer and all-cause mortality. These results support public health recommendations to increase fruit and vegetable intake for the prevention of cardiovascular disease, cancer, and premature mortality

The JCMT BISTRO Survey: Studying the Complex Magnetic Field of L43

We present observations of polarized dust emission at 850 μm from the L43 molecular cloud, which sits in the Ophiuchus cloud complex. The data were taken using SCUBA-2/POL-2 on the James Clerk Maxwell Telescope as a part of the BISTRO large program. L43 is a dense (NH 10 22 2 ~ –1023 cm−2) complex molecular cloud with a submillimeter-bright starless core and two protostellar sources. There appears to be an evolutionary gradient along the isolated filament that L43 is embedded within, with the most evolved source closest to the Sco OB2 association. One of the protostars drives a CO outflow that has created a cavity to the southeast. We see a magnetic field that appears to be aligned with the cavity walls of the outflow, suggesting interaction with the outflow. We also find a magnetic field strength of up to ∼160 ± 30 μG in the main starless core and up to ∼90 ± 40 μG in the more diffuse, extended region. These field strengths give magnetically super- and subcritical values, respectively, and both are found to be roughly trans-Alfvénic. We also present a new method of data reduction for these denser but fainter objects like starless cores

Filamentary Network and Magnetic Field Structures Revealed with BISTRO in the High-Mass Star-Forming Region NGC2264 : Global Properties and Local Magnetogravitational Configurations

We report 850 $\mu$m continuum polarization observations toward the filamentary high-mass star-forming region NGC 2264, taken as part of the B-fields In STar forming Regions Observations (BISTRO) large program on the James Clerk Maxwell Telescope (JCMT). These data reveal a well-structured non-uniform magnetic field in the NGC 2264C and 2264D regions with a prevailing orientation around 30 deg from north to east. Field strengths estimates and a virial analysis for the major clumps indicate that NGC 2264C is globally dominated by gravity while in 2264D magnetic, gravitational, and kinetic energies are roughly balanced. We present an analysis scheme that utilizes the locally resolved magnetic field structures, together with the locally measured gravitational vector field and the extracted filamentary network. From this, we infer statistical trends showing that this network consists of two main groups of filaments oriented approximately perpendicular to one another. Additionally, gravity shows one dominating converging direction that is roughly perpendicular to one of the filament orientations, which is suggestive of mass accretion along this direction. Beyond these statistical trends, we identify two types of filaments. The type-I filament is perpendicular to the magnetic field with local gravity transitioning from parallel to perpendicular to the magnetic field from the outside to the filament ridge. The type-II filament is parallel to the magnetic field and local gravity. We interpret these two types of filaments as originating from the competition between radial collapsing, driven by filament self-gravity, and the longitudinal collapsing, driven by the region's global gravity.Comment: Accepted for publication in the Astrophysical Journal. 43 pages, 32 figures, and 4 tables (including Appendix

Addressing climate change with behavioral science:A global intervention tournament in 63 countries

Effectively reducing climate change requires marked, global behavior change. However, it is unclear which strategies are most likely to motivate people to change their climate beliefs and behaviors. Here, we tested 11 expert-crowdsourced interventions on four climate mitigation outcomes: beliefs, policy support, information sharing intention, and an effortful tree-planting behavioral task. Across 59,440 participants from 63 countries, the interventions' effectiveness was small, largely limited to nonclimate skeptics, and differed across outcomes: Beliefs were strengthened mostly by decreasing psychological distance (by 2.3%), policy support by writing a letter to a future-generation member (2.6%), information sharing by negative emotion induction (12.1%), and no intervention increased the more effortful behavior-several interventions even reduced tree planting. Last, the effects of each intervention differed depending on people's initial climate beliefs. These findings suggest that the impact of behavioral climate interventions varies across audiences and target behaviors.</p