The nuclear modification factor
R
AA
and the azimuthal anisotropy coefficient
v
2
of prompt and nonprompt (i.e. those from decays of b hadrons)
J
/
ψ
mesons, measured from PbPb and pp collisions at
s
...NN
=
2.76
TeV
at the LHC, are reported. The results are presented in several event centrality intervals and several kinematic regions, for transverse momenta
p
T
>
6.5
GeV
/
c
and rapidity
|
y
|
<
2.4
, extending down to
p
T
=
3
GeV
/
c
in the
1.6
<
|
y
|
<
2.4
range. The
v
2
of prompt
J
/
ψ
is found to be nonzero, but with no strong dependence on centrality, rapidity, or
p
T
over the full kinematic range studied. The measured
v
2
of nonprompt
J
/
ψ
is consistent with zero. The
R
AA
of prompt
J
/
ψ
exhibits a suppression that increases from peripheral to central collisions but does not vary strongly as a function of either
y
or
p
T
in the fiducial range. The nonprompt
J
/
ψ
R
AA
shows a suppression which becomes stronger as rapidity or
p
T
increases. The
v
2
and
R
AA
of open and hidden charm, and of open charm and beauty, are compared.
Abstract We present the final data from the Sloan Digital Sky Survey (SDSS) Reverberation Mapping (RM) project, a precursor to the SDSS-V Black Hole Mapper RM program. This data set includes 11 yr ...photometric and 7 yr spectroscopic light curves for 849 broad-line quasars over a redshift range of 0.1 < z < 4.5 and a luminosity range of L bol = 10 44−47.5 erg s −1 , along with spectral and variability measurements. We report 23, 81, 125, and 110 RM lags (relative to optical continuum variability) for broad H α , H β , Mg ii , and C iv using the SDSS-RM sample, spanning much of the luminosity and redshift ranges of the sample. Using 30 low-redshift RM active galactic nuclei with dynamical-modeling black hole masses, we derive a new estimate of the average virial factor of log f = 0.62 ± 0.07 for the line dispersion measured from the rms spectrum. The intrinsic scatter of individual virial factors is 0.31 ± 0.07 dex, indicating a factor of 2 systematic uncertainty in RM black hole masses. Our lag measurements reveal significant R – L relations for H β and Mg ii at high redshift, consistent with the latest measurements based on heterogeneous samples. While we are unable to robustly constrain the slope of the R – L relation for C iv given the limited dynamic range in luminosity, we found substantially larger scatter in C iv lags at fixed L 1350 . Using the SDSS-RM lag sample, we derive improved single-epoch (SE) mass recipes for H β , Mg ii , and C iv , which are consistent with their respective RM masses as well as between the SE recipes from two different lines, over the luminosity range probed by our sample. The new H β and Mg ii recipes are approximately unbiased estimators at given RM masses, but there are systematic biases in the C iv recipe. The intrinsic scatter of SE masses around RM masses is ∼0.45 dex for H β and Mg ii , increasing to ∼0.58 dex for C iv .
Four hydrocarbon van der Waals potentials have been employed to obtain crystal unit cell dimensions and enthalpy sublimation values for two fullerenes, C
60 and C
70. The same force fields have also ...been employed in computing adsorption energies between a series of hydrocarbon molecules and a model graphite basal plane. The four hydrocarbon force fields are MM2, MM3, MM3hc, which is a new reparametrization of MM3 by the authors in earlier studies, and the potential of Williams and Starr. The MM3 and MM3hc force fields have been shown to offer the best agreement between the experimental and calculated crystal data for C
60 and C
70. In the graphite-adsorbate molecule computations, both charged and uncharged models for the four force fields have been tested to establish which model provides the most accurate structural and thermodynamic results. These calculations indicate that models with no charges are superior despite their deficiencies. For the adsorption of aliphatic molecules onto graphite, MM3hc yields closer agreement between experimental and calculated energies of adsorption than its counterparts, while its predictions for aromatic compounds are slightly less accurate than the MM2 and MM3 results. All force fields are similar in their predictions of structural arrangements of the adsorbate molecules on graphite. However, the computed structures disagree with experimental findings in several cases, underlining the inadequacy of simple analytical potential functions for graphite-hydrocarbon interactions.
Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. ...Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.
Type 2 diabetes is characterized by hyperglycemia and inflammation. Prostaglandin E2, which signals through four G protein-coupled receptors (EP1-4), is a mediator of inflammation and is upregulated ...in diabetes. We have shown previously that EP3 receptor blockade promotes β-cell proliferation and survival in isolated mouse and human islets ex vivo. Here, we analyzed whether systemic EP3 blockade could enhance β-cell mass and identity in the setting of type 2 diabetes using mice with a spontaneous mutation in the leptin receptor (Leprdb).
Four- or six-week-old, db/+, and db/db male mice were treated with an EP3 antagonist daily for two weeks. Pancreata were analyzed for α-cell and β-cell proliferation and β-cell mass. Islets were isolated for transcriptomic analysis. Selected gene expression changes were validated by immunolabeling of the pancreatic tissue sections.
EP3 blockade increased β-cell mass in db/db mice through enhanced β-cell proliferation. Importantly, there were no effects on α-cell proliferation. EP3 blockade reversed the changes in islet gene expression associated with the db/db phenotype and restored the islet architecture. Expression of the GLP-1 receptor was slightly increased by EP3 antagonist treatment in db/db mice. In addition, the transcription factor nuclear factor E2-related factor 2 (Nrf2) and downstream targets were increased in islets from db/db mice in response to treatment with an EP3 antagonist. The markers of oxidative stress were decreased.
The current study suggests that EP3 blockade promotes β-cell mass expansion in db/db mice. The beneficial effects of EP3 blockade may be mediated through Nrf2, which has recently emerged as a key mediator in the protection against cellular oxidative damage.
•Systemic blockade of EP3 in vivo in db/db mice increase beta-cell proliferation and mass.•EP3 blockade has no effect on alpha-cell proliferation.•EP3 blockade restores islet architecture and beta-cell identity genes in db/db mice.•Beta cell GLP-1 receptor expression is increased by EP3 blockade.•EP3 blockade activates the Nrf2 anti-oxidant pathway.
The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that ...TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure–activity relationship (SAR) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge.
Thesis (Ed. D.)--Illinois State University, 1969.
Title from title page screen, viewed Aug. 25, 2004. Dissertation Committee: Clayton Thomas (chair), Robert Hogan, Gary Ramseyer. Includes ...bibliographical references (leaves 122-131). Also available in print.
Mood instability is a core clinical feature of affective and psychotic disorders. In keeping with the Research Domain Criteria approach, it may be a useful construct for identifying biology that cuts ...across psychiatric categories. We aimed to investigate the biological validity of a simple measure of mood instability and evaluate its genetic relationship with several psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD), schizophrenia, attention deficit hyperactivity disorder (ADHD), anxiety disorder and post-traumatic stress disorder (PTSD). We conducted a genome-wide association study (GWAS) of mood instability in 53,525 cases and 60,443 controls from UK Biobank, identifying four independently associated loci (on chromosomes 8, 9, 14 and 18), and a common single-nucleotide polymorphism (SNP)-based heritability estimate of ~8%. We found a strong genetic correlation between mood instability and MDD (r
= 0.60, SE = 0.07, p = 8.95 × 10
) and a small but significant genetic correlation with both schizophrenia (r
= 0.11, SE = 0.04, p = 0.01) and anxiety disorders (r
= 0.28, SE = 0.14, p = 0.04), although no genetic correlation with BD, ADHD or PTSD was observed. Several genes at the associated loci may have a role in mood instability, including the DCC netrin 1 receptor (DCC) gene, eukaryotic translation initiation factor 2B subunit beta (eIF2B2), placental growth factor (PGF) and protein tyrosine phosphatase, receptor type D (PTPRD). Strengths of this study include the very large sample size, but our measure of mood instability may be limited by the use of a single question. Overall, this work suggests a polygenic basis for mood instability. This simple measure can be obtained in very large samples; our findings suggest that doing so may offer the opportunity to illuminate the fundamental biology of mood regulation.
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