Pharmacological activation of the nuclear receptor REV-ERB reverses cognitive deficits and reduces amyloid-β burden in a mouse model of Alzheimer’s disease

Alzheimer’s disease currently lacks treatment options that effectively reverse the biological/anatomical pathology and cognitive deficits associated with the disease. Loss of function of the nuclear receptor REV-ERB is associated with reduced cognitive function in mouse models. The effect of enhanced REV-ERB activity on cognitive function has not been examined. In this study, we tested the hypothesis that enhanced REV-ERB function may enhance cognitive function in a model of Alzheimer’s disease. We utilized the REV-ERB agonist SR9009 to pharmacologically activate the activity of REV-ERB in the SAMP8 mouse model of Alzheimer’s disease. SR9009 reversed cognitive dysfunction of an aged SAMP8 mouse in several behavioral assays including novel object recognition, T-maze foot shock avoidance, and lever press operant conditioning task assessments. SR9009 treatment reduced amyloid-β 1–40 and 1–42 levels in the cortex, which is consistent with improved cognitive function. Furthermore, SR9009 treatment led to increased hippocampal PSD-95, cortical synaptophysin expression and the number of synapses suggesting improvement in synaptic function. We conclude that REV-ERB is a potential target for treatment of Alzheimer’s disease.</div

Neutron-Capture Elements in the Early Galaxy: Insights from a Large Sample of Metal-Poor Giants

New abundances for neutron-capture (n-capture) elements in a large sample of metal-poor giants from the Bond survey are presented. The spectra were acquired with the KPNO 4-m echelle and coude feed spectrographs, and have been analyzed using LTE fine-analysis techniques with both line analysis and spectral synthesis. Abundances of eight n-capture elements (Sr, Y, Zr, Ba, La, Nd, Eu, Dy) in 43 stars have been derived from blue (lambda = 4070--4710, R~20,000, S/N ratio~100-200) echelle spectra and red (lambda = 6100--6180, R~22,000, S/N ratio~100-200) coude spectra, and the abundance of Ba only has been derived from the red spectra for an additional 27 stars. Overall, the abundances show clear evidence for a large star-to-star dispersion in the heavy element-to-iron ratios. The new data also confirm that at metallicities [Fe/H] <~ --2.4, the abundance pattern of the heavy (Z >= 56) n-capture elements in most giants is well-matched to a scaled Solar System r-process nucleosynthesis pattern. The onset of the main r-process can be seen at [Fe/H] ~ --2.9. Contributions from the s-process can first be seen in some stars with metallicities as low as [Fe/H] ~ --2.75, and are present in most stars with metallicities [Fe/H] > --2.3. The lighter n-capture elements (Sr-Y-Zr) are enhanced relative to the heavier r-process element abundances. Their production cannot be attributed solely to any combination of the Solar System r- and main s-processes, but requires a mixture of material from the r-process and from an additional n-capture process which can operate at early Galactic time.Comment: Text + 5 Tables and 11 Figures: Submitted to the Astrophysical Journa

Pennsylvania Folklife Vol. 9, No. 1

• Half-Timbering in American Architecture • The Strouse Dance • Schuylkill Boatmen and Their Ways • Some Early Phases of the Philadelphia Mummers\u27 Parade • Fantasticals • Joseph Henry Dubbs as a Folklorist • About the Authors • Horse Companies in Montgomery County • Books Not for Burninghttps://digitalcommons.ursinus.edu/pafolklifemag/1000/thumbnail.jp

Regulation of Expression of Citrate Synthase by the Retinoic Acid Receptor-Related Orphan Receptor α (RORα)

The retinoic acid receptor-related orphan receptor α (RORα) is a member of the nuclear receptor superfamily of transcription factors that plays an important role in regulation of the circadian rhythm and metabolism. Mice lacking a functional RORα display a range of metabolic abnormalities including decreased serum cholesterol and plasma triglycerides. Citrate synthase (CS) is a key enzyme of the citric acid cycle that provides energy for cellular function. Additionally, CS plays a critical role in providing citrate derived acetyl-CoA for lipogenesis and cholesterologenesis. Here, we identified a functional RORα response element (RORE) in the promoter of the CS gene. ChIP analysis demonstrates RORα occupancy of the CS promoter and a putative RORE binds to RORα effectively in an electrophoretic mobility shift assay and confers RORα responsiveness to a reporter gene in a cotransfection assay. We also observed a decrease in CS gene expression and CS enzymatic activity in the staggerer mouse, which has a mutation of in the Rora gene resulting in nonfunctional RORα protein. Furthermore, we found that SR1001 a RORα inverse agonist eliminated the circadian pattern of expression of CS mRNA in mice. These data suggest that CS is a direct RORα target gene and one mechanism by which RORα regulates lipid metabolism is via regulation of CS expression

Nonorographic generation of Arctic polar stratospheric clouds during

[1] During December 1999, polar stratospheric clouds (PSCs) were observed in the absence of conditions conducive to generation by topographic gravity waves. The possibility is explored that PSCs can be generated by inertia gravity waves (IGW) radiating from breaking synoptic-scale Rossby waves on the polar front jet. The aerosol features on 7 and 12 December are selected for comparison with theory and with simulations using the University of Wisconsin Nonhydrostatic Modeling System (UWNMS). Consistent with Rossby adjustment theory, a common feature in the UWNMS simulations is radiation of IGW from the tropopause polar front jet, especially from sectors which are evolving rapidly in the Rossby wave breaking process. Packets of gravity wave energy radiate upward and poleward into the cold pool, while individual wave crests propagate poleward and downward, causing mesoscale variations in vertical motion and temperature. On 12 December the eastbound DC-8 lidar observations exhibited a fairly uniform field of six waves in aerosol enhancement in the 14-20 km layer, consistent with vertical displacement by a field of IGW propagating antiparallel to the flow, with characteristic horizontal and vertical wavelengths of $300 and$10 km. UWNMS simulations show emanation of a field of IGW upward and southwestward from a northward incursion of the polar front jet. The orientation and evolution of the aerosol features on 7 December are consistent with a single PSC induced by an IGW packet propagating from a breaking Rossby wave over western Russia toward the northeast into the coldest part of the base of the polar vortex, with characteristic period $9 hours, vertical wavelength$12 km, and horizontal wavelength $1000 km. Linear theory shows that for both of these cases, IGW energy propagates upward at$1 km/hour and horizontally at $100 km/hour, with characteristic trace speed$30 m/s. The spatial orientation of the PSC along IGW phase lines is contrasted with the nearly horizontal filamentary structures in the PSC, which are indicative of flow streamlines. It is suggested that vertical displacement is a crucial factor in determining whether a PSC will form and that most PSCs are relatable to specific synoptic and mesoscale motions

Nonorographic generation of Arctic polar stratospheric clouds during

[1] During December 1999, polar stratospheric clouds (PSCs) were observed in the absence of conditions conducive to generation by topographic gravity waves. The possibility is explored that PSCs can be generated by inertia gravity waves (IGW) radiating from breaking synoptic-scale Rossby waves on the polar front jet. The aerosol features on 7 and 12 December are selected for comparison with theory and with simulations using the University of Wisconsin Nonhydrostatic Modeling System (UWNMS). Consistent with Rossby adjustment theory, a common feature in the UWNMS simulations is radiation of IGW from the tropopause polar front jet, especially from sectors which are evolving rapidly in the Rossby wave breaking process. Packets of gravity wave energy radiate upward and poleward into the cold pool, while individual wave crests propagate poleward and downward, causing mesoscale variations in vertical motion and temperature. On 12 December the eastbound DC-8 lidar observations exhibited a fairly uniform field of six waves in aerosol enhancement in the 14-20 km layer, consistent with vertical displacement by a field of IGW propagating antiparallel to the flow, with characteristic horizontal and vertical wavelengths of $300 and$10 km. UWNMS simulations show emanation of a field of IGW upward and southwestward from a northward incursion of the polar front jet. The orientation and evolution of the aerosol features on 7 December are consistent with a single PSC induced by an IGW packet propagating from a breaking Rossby wave over western Russia toward the northeast into the coldest part of the base of the polar vortex, with characteristic period $9 hours, vertical wavelength$12 km, and horizontal wavelength $1000 km. Linear theory shows that for both of these cases, IGW energy propagates upward at$1 km/hour and horizontally at $100 km/hour, with characteristic trace speed$30 m/s. The spatial orientation of the PSC along IGW phase lines is contrasted with the nearly horizontal filamentary structures in the PSC, which are indicative of flow streamlines. It is suggested that vertical displacement is a crucial factor in determining whether a PSC will form and that most PSCs are relatable to specific synoptic and mesoscale motions

New Rare Earth Element Abundance Distributions for the Sun and Five r-Process-Rich Very Metal-Poor Stars

We have derived new abundances of the rare-earth elements Pr, Dy, Tm, Yb, and Lu for the solar photosphere and for five very metal-poor, neutron-capture r-process-rich giant stars. The photospheric values for all five elements are in good agreement with meteoritic abundances. For the low metallicity sample, these abundances have been combined with new Ce abundances from a companion paper, and reconsideration of a few other elements in individual stars, to produce internally-consistent Ba, rare-earth, and Hf (56<= Z <= 72) element distributions. These have been used in a critical comparison between stellar and solar r-process abundance mixes.Comment: 48 pages, 11 figures, 12 tables: To appear in the Astrophysical Journal Supplemen

Mapping adipose and muscle tissue expression quantitative trait loci in African Americans to identify genes for type 2 diabetes and obesity

Relative to European Americans, type 2 diabetes (T2D) is more prevalent in African Americans (AAs). Genetic variation may modulate transcript abundance in insulin-responsive tissues and contribute to risk; yet published studies identifying expression quantitative trait loci (eQTLs) in African ancestry populations are restricted to blood cells. This study aims to develop a map of genetically regulated transcripts expressed in tissues important for glucose homeostasis in AAs, critical for identifying the genetic etiology of T2D and related traits. Quantitative measures of adipose and muscle gene expression, and genotypic data were integrated in 260 non-diabetic AAs to identify expression regulatory variants. Their roles in genetic susceptibility to T2D, and related metabolic phenotypes were evaluated by mining GWAS datasets. eQTL analysis identified 1,971 and 2,078 cis-eGenes in adipose and muscle, respectively. Cis-eQTLs for 885 transcripts including top cis-eGenes CHURC1, USMG5, and ERAP2, were identified in both tissues. 62.1% of top cis-eSNPs were within ±50kb of transcription start sites and cis-eGenes were enriched for mitochondrial transcripts. Mining GWAS databases revealed association of cis-eSNPs for more than 50 genes with T2D (e.g. PIK3C2A, RBMS1, UFSP1), gluco-metabolic phenotypes, (e.g. INPP5E, SNX17, ERAP2, FN3KRP), and obesity (e.g. POMC, CPEB4). Integration of GWAS meta-analysis data from AA cohorts revealed the most significant association for cis-eSNPs of ATP5SL and MCCC1 genes, with T2D and BMI, respectively. This study developed the first comprehensive map of adipose and muscle tissue eQTLs in AAs (publically accessible at https://mdsetaa.phs.wakehealth.edu) and identified genetically-regulated transcripts for delineating genetic causes of T2D, and related metabolic phenotypes