324 research outputs found
Geodatabase Development to Support Hyperspectral Imagery Exploitation
Geodatabase development for coastal studies conducted by the Naval Research Laboratory (NRL) is essential to support the exploitation of hyperspectral imagery (HSI). NRL has found that the remote sensing and mapping science community benefits from coastal classifications that group coastal types based on similar features. Selected features in project geodatabases relate to significant biological and physical forces that shape the coast. The project geodatabases help researchers understand factors that are necessary for imagery post processing, especially those features having a high degree of temporal and spatial variability. NRL project geodatabases include a hierarchy of environmental factors that extend from shallow water bottom types and beach composition to inland soil and vegetation characteristics. These geodatabases developed by NRL allow researchers to compare features among coast types. The project geodatabases may also be used to enhance littoral data archives that are sparse. This paper highlights geodatabase development for recent remote sensing experiments in barrier island, coral, and mangrove coast types
An Environmental Science and Engineering Framework for Combating Antimicrobial Resistance
On June 20, 2017, members of the environmental engineering and science (EES) community convened at the Association of Environmental Engineering and Science Professors (AEESP) Biennial Conference for a workshop on antimicrobial resistance. With over 80 registered participants, discussion groups focused on the following topics: risk assessment, monitoring, wastewater treatment, agricultural systems, and synergies. In this study, we summarize the consensus among the workshop participants regarding the role of the EES community in understanding and mitigating the spread of antibiotic resistance via environmental pathways. Environmental scientists and engineers offer a unique and interdisciplinary perspective and expertise needed for engaging with other disciplines such as medicine, agriculture, and public health to effectively address important knowledge gaps with respect to the linkages between human activities, impacts to the environment, and human health risks. Recommendations that propose priorities for research within the EES community, as well as areas where interdisciplinary perspectives are needed, are highlighted. In particular, risk modeling and assessment, monitoring, and mass balance modeling can aid in the identification of “hot spots” for antibiotic resistance evolution and dissemination, and can help identify effective targets for mitigation. Such information will be essential for the development of an informed and effective policy aimed at preserving and protecting the efficacy of antibiotics for future generations
Reverberation Mapping of the Kepler-Field AGN KA1858+4850
KA1858+4850 is a narrow-line Seyfert 1 galaxy at redshift 0.078 and is among
the brightest active galaxies monitored by the Kepler mission. We have carried
out a reverberation mapping campaign designed to measure the broad-line region
size and estimate the mass of the black hole in this galaxy. We obtained 74
epochs of spectroscopic data using the Kast Spectrograph at the Lick 3-m
telescope from February to November of 2012, and obtained complementary V-band
images from five other ground-based telescopes. We measured the H-beta light
curve lag with respect to the V-band continuum light curve using both
cross-correlation techniques (CCF) and continuum light curve variability
modeling with the JAVELIN method, and found rest-frame lags of lag_CCF = 13.53
(+2.03, -2.32) days and lag_JAVELIN = 13.15 (+1.08, -1.00) days. The H-beta
root-mean-square line profile has a width of sigma_line = 770 +/- 49 km/s.
Combining these two results and assuming a virial scale factor of f = 5.13, we
obtained a virial estimate of M_BH = 8.06 (+1.59, -1.72) x 10^6 M_sun for the
mass of the central black hole and an Eddington ratio of L/L_Edd ~ 0.2. We also
obtained consistent but slightly shorter emission-line lags with respect to the
Kepler light curve. Thanks to the Kepler mission, the light curve of
KA1858+4850 has among the highest cadences and signal-to-noise ratios ever
measured for an active galactic nucleus; thus, our black hole mass measurement
will serve as a reference point for relations between black hole mass and
continuum variability characteristics in active galactic nuclei
An epigenetic blockade of cognitive functions in the neurodegenerating brain
Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer’s disease [superscript 1]. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge [superscript 2]. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer’s-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer’s disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.Stanley Medical Research InstituteNational Institute of Neurological Disorders and Stroke (U.S.) (RO1NS078839)Swiss National Science FoundationBard Richmond (Fellowship)Simons FoundationTheodor und Ida Herzog-Egli Foundatio
An architecture for consolidating multidimensional time-series data onto a common coordinate grid
Effect of race on prediction of brain amyloidosis by plasma Aβ42/Aβ40, phosphorylated tau, and neurofilament light
BACKGROUND AND OBJECTIVES: To evaluate whether plasma biomarkers of amyloid (Aβ42/Aβ40), tau (p-tau181 and p-tau231), and neuroaxonal injury (neurofilament light chain [NfL]) detect brain amyloidosis consistently across racial groups.
METHODS: Individuals enrolled in studies of memory and aging who self-identified as African American (AA) were matched 1:1 to self-identified non-Hispanic White (NHW) individuals by age,
RESULTS: There were 76 matched pairs of AA and NHW participants (n = 152 total). For both AA and NHW groups, the median age was 68.4 years, 42% were
DISCUSSION: Models predicting brain amyloidosis using a high-performance plasma Aβ42/Aβ40 assay may provide an accurate and consistent measure of brain amyloidosis across AA and NHW groups, but models based on plasma p-tau181, p-tau231, and NfL may perform inconsistently and could result in disproportionate misdiagnosis of AA individuals
Crebinostat: A novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity
Long-term memory formation is known to be critically dependent upon de novo gene expression in the brain. As a consequence, pharmacological enhancement of the transcriptional processes mediating long-term memory formation provides a potential therapeutic strategy for cognitive disorders involving aberrant neuroplasticity. Here we focus on the identification and characterization of small molecule inhibitors of histone deacetylases (HDACs) as enhancers of CREB (cAMP response element-binding protein)-regulated transcription and modulators of chromatin-mediated neuroplasticity. Using a CREB reporter gene cell line, we screened a library of small molecules structurally related to known HDAC inhibitors leading to the identification of a probe we termed crebinostat that produced robust activation of CREB-mediated transcription. Further characterization of crebinostat revealed its potent inhibition of the deacetylase activity of recombinant class I HDACs 1, 2, 3, and class IIb HDAC6, with weaker inhibition of the class I HDAC8 and no significant inhibition of the class IIa HDACs 4, 5, 7, and 9. In cultured mouse primary neurons, crebinostat potently induced acetylation of both histone H3 and histone H4 as well as enhanced the expression of the CREB target gene Egr1 (early growth response 1). Using a hippocampus-dependent, contextual fear conditioning paradigm, mice systemically administered crebinostat for a ten day time period exhibited enhanced memory. To gain insight into the molecular mechanisms of memory enhancement by HDAC inhibitors, whole genome transcriptome profiling of cultured mouse primary neurons treated with crebinostat, combined with bioinformatic analyses of CREB-target genes, was performed revealing a highly connected protein–protein interaction network reflecting modules of genes important to synaptic structure and plasticity. Consistent with these findings, crebinostat treatment increased the density of synapsin-1 punctae along dendrites in cultured neurons. Finally, crebinostat treatment of cultured mouse primary neurons was found to upregulate Bdnf (brain-derived neurotrophic factor) and Grn (granulin) and downregulate Mapt (tau) gene expression—genes implicated in aging-related cognitive decline and cognitive disorders. Taken together, these results demonstrate that crebinostat provides a novel probe to modulate chromatin-mediated neuroplasticity and further suggests that pharmacological optimization of selective of HDAC inhibitors may provide an effective therapeutic approach for human cognitive disorders.National Institutes of Health (U.S.) (R01DA028301)National Institutes of Health (U.S.) (R01NS051874)Stanley Medical Research InstituteHoward Hughes Medical Institut
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Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.
We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition
Reduction in Phencyclidine Induced Sensorimotor Gating Deficits in the Rat Following Increased System Xc − Activity in the Medial Prefrontal Cortex
Rationale: Aspects of schizophrenia, including deficits in sensorimotor gating, have been linked to glutamate dysfunction and/or oxidative stress in the prefrontal cortex. System xc −, a cystine–glutamate antiporter, is a poorly understood mechanism that contributes to both cellular antioxidant capacity and glutamate homeostasis.
Objectives: Our goal was to determine whether increased system xc − activity within the prefrontal cortex would normalize a rodent measure of sensorimotor gating.
Methods: In situ hybridization was used to map messenger RNA (mRNA) expression of xCT, the active subunit of system xc −, in the prefrontal cortex. Prepulse inhibition was used to measure sensorimotor gating; deficits in prepulse inhibition were produced using phencyclidine (0.3–3 mg/kg, sc). N-Acetylcysteine (10–100 μM) and the system xc − inhibitor (S)-4-carboxyphenylglycine (CPG, 0.5 μM) were used to increase and decrease system xc − activity, respectively. The uptake of 14C-cystine into tissue punches obtained from the prefrontal cortex was used to assay system xc − activity.
Results: The expression of xCT mRNA in the prefrontal cortex was most prominent in a lateral band spanning primarily the prelimbic cortex. Although phencyclidine did not alter the uptake of 14C-cystine in prefrontal cortical tissue punches, intraprefrontal cortical infusion of N-acetylcysteine (10–100 μM) significantly reduced phencyclidine- (1.5 mg/kg, sc) induced deficits in prepulse inhibition. N-Acetylcysteine was without effect when coinfused with CPG (0.5 μM), indicating an involvement of system xc −.
Conclusions: These results indicate that phencyclidine disrupts sensorimotor gating through system xc − independent mechanisms, but that increasing cystine–glutamate exchange in the prefrontal cortex is sufficient to reduce behavioral deficits produced by phencyclidine
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