4,541 research outputs found
Total Synthesis of (±)-Actinophyllic Acid
During a search for new natural product structures as potential leads for developing agents for treating cardiovascular disorders, Quinn, Carroll, and co-workers reported in 2005 the isolation and relative configuration of actinophyllic acid (1).1 This structurally unique indole alkaloid was obtained from the leaves of the tree Alstonia actinophylla collected on the Cape York Peninsula, Far North Queensland, Australia. It was identified in a coupled CPU/ hippuricase assay as an inhibitor of carboxypeptidase U (CPU), an endogenous inhibitor of the process the body uses to clear fibrin clots (fibrinolysis).2 The structure of actinophyllic acid (1) is unique becausethe1-azabicyclo[4.4.2]dodecaneand1-azabicyclo[4.2.1]nonane fragments that define its structure are found in no other indole alkaloid. We report herein the first total synthesis of (()-actinophyllic acid (1) by a route that is sufficiently concise that it would be suitable for production of gram quantities of the natura
Setdb1 histone methyltransferase regulates mood-related behaviors and expression of the NMDA receptor subunit NR2B
Histone methyltransferases specific for the histone H3-lysine 9 residue, including Setdb1 (Set domain, bifurcated 1)/Eset/Kmt1e are associated with repressive chromatin remodeling and expressed in adult brain, but potential effects on neuronal function and behavior remain unexplored. Here, we report that transgenic mice with increased Setdb1 expression in adult forebrain neurons show antidepressant-like phenotypes in behavioral paradigms for anhedonia, despair, and learned helplessness. Chromatin immunoprecipitation in conjunction with DNA tiling arrays (ChIP-chip) revealed that genomic occupancies of neuronal Setdb1 are limited t
First Observation of the Rare Decay Mode K-long -> e+ e-
In an experiment designed to search for and study very rare two-body decay
modes of the K-long, we have observed four examples of the decay K-long -> e+
e-, where the expected background is 0.17+-0.10 events. This observation
translates into a branching fraction of 8.7^{+5.7}_{-4.1} X 10^{-12},
consistent with recent theoretical predictions. This result represents by far
the smallest branching fraction yet measured in particle physics.Comment: 9 pages, 3 figure
An Integrated-Photonics Optical-Frequency Synthesizer
Integrated-photonics microchips now enable a range of advanced
functionalities for high-coherence applications such as data transmission,
highly optimized physical sensors, and harnessing quantum states, but with
cost, efficiency, and portability much beyond tabletop experiments. Through
high-volume semiconductor processing built around advanced materials there
exists an opportunity for integrated devices to impact applications cutting
across disciplines of basic science and technology. Here we show how to
synthesize the absolute frequency of a lightwave signal, using integrated
photonics to implement lasers, system interconnects, and nonlinear frequency
comb generation. The laser frequency output of our synthesizer is programmed by
a microwave clock across 4 THz near 1550 nm with 1 Hz resolution and
traceability to the SI second. This is accomplished with a heterogeneously
integrated III/V-Si tunable laser, which is guided by dual
dissipative-Kerr-soliton frequency combs fabricated on silicon chips. Through
out-of-loop measurements of the phase-coherent, microwave-to-optical link, we
verify that the fractional-frequency instability of the integrated photonics
synthesizer matches the reference-clock instability for a 1
second acquisition, and constrain any synthesis error to while
stepping the synthesizer across the telecommunication C band. Any application
of an optical frequency source would be enabled by the precision optical
synthesis presented here. Building on the ubiquitous capability in the
microwave domain, our results demonstrate a first path to synthesis with
integrated photonics, leveraging low-cost, low-power, and compact features that
will be critical for its widespread use.Comment: 10 pages, 6 figure
Aerodynamic investigations of ventilated brake discs.
The heat dissipation and performance of a ventilated brake disc strongly depends
on the aerodynamic characteristics of the flow through the rotor passages. The
aim of this investigation was to provide an improved understanding of ventilated
brake rotor flow phenomena, with a view to improving heat dissipation, as well
as providing a measurement data set for validation of computational fluid
dynamics methods. The flow fields at the exit of four different brake rotor
geometries, rotated in free air, were measured using a five-hole pressure probe
and a hot-wire anemometry system. The principal measurements were taken using
two-component hot-wire techniques and were used to determine mean and unsteady
flow characteristics at the exit of the brake rotors. Using phase-locked data
processing, it was possible to reveal the spatial and temporal flow variation
within individual rotor passages. The effects of disc geometry and rotational
speed on the mean flow, passage turbulence intensity, and mass flow were
determined. The rotor exit jet and wake flow were clearly observed as
characterized by the passage geometry as well as definite regions of high and
low turbulence. The aerodynamic flow characteristics were found to be reasonably
independent of rotational speed but highly dependent upon rotor geometry
Biochemical adaptations of the retina and retinal pigment epithelium support a metabolic ecosystem in the vertebrate eye
Here we report multiple lines of evidence for a comprehensive model of energy metabolism in the vertebrate eye. Metabolic flux, locations of key enzymes, and our finding that glucose enters mouse and zebrafish retinas mostly through photoreceptors support a conceptually new model for retinal metabolism. In this model, glucose from the choroidal blood passes through the retinal pigment epithelium to the retina where photoreceptors convert it to lactate. Photoreceptors then export the lactate as fuel for the retinal pigment epithelium and for neighboring Mu ̈ ller glial cells. We used human retinal epithelial cells to show that lactate can suppress consumption of glucose by the retinal pigment epithelium. Suppression of glucose consumption in the retinal pigment epithelium can increase the amount of glucose that reaches the retina. This framework for understanding metabolic relationships in the vertebrate retina provides new insights into the underlying causes of retinal disease and age-related vision loss
Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.
BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.
METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.
RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.
CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function
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