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Host Genetics Predict Clinical Deterioration in HCV-Related Cirrhosis
Single nucleotide polymorphisms (SNPs) in the epidermal growth factor (EGF, rs4444903), patatin-like phospholipase domain-containing protein 3 (PNPLA3, rs738409) genes, and near the interleukin-28B (IL28B, rs12979860) gene are linked to treatment response, fibrosis, and hepatocellular carcinoma (HCC) in chronic hepatitis C. Whether these SNPs independently or in combination predict clinical deterioration in hepatitis C virus (HCV)-related cirrhosis is unknown. We genotyped SNPs in EGF, PNPLA3, and IL28B from liver tissue from 169 patients with biopsy-proven HCV cirrhosis. We estimated risk of clinical deterioration, defined as development of ascites, encephalopathy, variceal hemorrhage, HCC, or liver-related death using Cox proportional hazards modeling. During a median follow-up of 6.6 years, 66 of 169 patients experienced clinical deterioration. EGF non-AA, PNPLA3 non-CC, and IL28B non-CC genotypes were each associated with increased risk of clinical deterioration in age, sex, and race-adjusted analysis. Only EGF non-AA genotype was independently associated with increased risk of clinical deterioration (hazard ratio [HR] 2.87; 95% confidence interval [CI] 1.31–6.25) after additionally adjusting for bilirubin, albumin, and platelets. Compared to subjects who had 0–1 unfavorable genotypes, the HR for clinical deterioration was 1.79 (95%CI 0.96–3.35) for 2 unfavorable genotypes and 4.03 (95%CI 2.13–7.62) for unfavorable genotypes for all three loci (Ptrend<0.0001). In conclusion, among HCV cirrhotics, EGF non-AA genotype is independently associated with increased risk for clinical deterioration. Specific PNPLA3 and IL28B genotypes also appear to be associated with clinical deterioration. These SNPs have potential to identify patients with HCV-related cirrhosis who require more intensive monitoring for decompensation or future therapies preventing disease progression
4pi Models of CMEs and ICMEs
Coronal mass ejections (CMEs), which dynamically connect the solar surface to
the far reaches of interplanetary space, represent a major anifestation of
solar activity. They are not only of principal interest but also play a pivotal
role in the context of space weather predictions. The steady improvement of
both numerical methods and computational resources during recent years has
allowed for the creation of increasingly realistic models of interplanetary
CMEs (ICMEs), which can now be compared to high-quality observational data from
various space-bound missions. This review discusses existing models of CMEs,
characterizing them by scientific aim and scope, CME initiation method, and
physical effects included, thereby stressing the importance of fully 3-D
('4pi') spatial coverage.Comment: 14 pages plus references. Comments welcome. Accepted for publication
in Solar Physics (SUN-360 topical issue
Neutral H density at the termination shock: a consolidation of recent results
We discuss a consolidation of determinations of the density of neutral
interstellar H at the nose of the termination shock carried out with the use of
various data sets, techniques, and modeling approaches. In particular, we focus
on the determination of this density based on observations of H pickup ions on
Ulysses during its aphelion passage through the ecliptic plane. We discuss in
greater detail a novel method of determination of the density from these
measurements and review the results from its application to actual data. The H
density at TS derived from this analysis is equal to 0.087 \pm 0.022 cm-3, and
when all relevant determinations are taken into account, the consolidated
density is obtained at 0.09 \pm 0.022 cm-3. The density of H in CHISM based on
literature values of filtration factor is then calculated at 0.16 \pm 0.04
cm-3.Comment: Submitted to Space Science Review
Family and Neighbourhood Socioeconomic Inequalities in Childhood Trajectories of BMI and Overweight: Longitudinal Study of Australian Children
Background:Socioeconomic inequalities in longitudinal patterning of childhood overweight could cause marked differentials in total burden by adulthood. This study aims to determine timing and strength of the association between socioeconomic status (SES) and children's body mass index (BMI) in the pre- and primary school years, and to examine socioeconomic differences in overweight trajectories across childhood.Methods:Participants were 4949 children from the Longitudinal Study of Australian Children. BMI was measured at four biennial waves starting at age 4-5 years in 2004. Developmental trajectories of childhood overweight were identified with latent class analyses. Composite variables of family and neighbourhood SES were used.Results:Socioeconomic differences in mean BMI z-scores already present at age 4-5 more than doubled by age 10-11 years, reflecting decreasing mean BMI among advantaged rather than increasing means among disadvantaged children. Latent class analysis identified children with 'stable normal weight' (68%), and with 'persistent' (15%), 'late-onset' (14%), and 'resolving' overweight (3%). Risks of persistent and late-onset childhood overweight were highest among low SES families (e.g. most disadvantaged quintile: ORpersistent= 2.51, 95%CI: 1.83-3.43), and only partly explained by birth weight and parental overweight. Relationships with neighbourhood SES were weaker and attenuated fully on adjustment for family SES. No socioeconomic gradient was observed for resolving overweight.Conclusions:Childhood has become the critical period when socioeconomic inequalities in overweight emerge and strengthen. Although targeting disadvantaged children with early overweight must be a top priority, the presence of childhood overweight even among less-disadvantaged families suggests only whole-society approaches will eliminate overweight-associated morbidity
Difference in expression between AQP1 and AQP5 in porcine endometrium and myometrium in response to steroid hormones, oxytocin, arachidonic acid, forskolin and cAMP during the mid-luteal phase of the estrous cycle and luteolysis
BACKGROUND: Recently, we demonstrated in vitro that AQP1 and AQP5 in the porcine uterus are regulated by steroid hormones (P4, E2), arachidonic acid (AA), forskolin (FSK) and cAMP during the estrous cycle. However, the potential of the porcine separated uterine tissues, the endometrium and myometrium, to express these AQPs remains unknown. Thus, in this study, the responses of AQP1 and AQP5 to P4, E2 oxytocin (OT), AA, FSK and cAMP in the porcine endometrium and myometrium were examined during the mid-luteal phase of the estrous cycle and luteolysis.METHODS: Real-time PCR and western blot analysis.RESULTS: Progesterone up-regulated the expression of AQP1/AQP5 mRNAs and proteins in the endometrium and myometrium, especially during luteolysis. Similarly, E2 also stimulated the expression of both AQPs, but only in the endometrium. AA led to the upregulation of AQP1/AQP5 in the endometrium during luteolysis. In turn, OT increased the expression of AQP1/AQP5 mRNAs and proteins in the myometrium during mid-luteal phase. Moreover, a stimulatory effect of forskolin and cAMP on the expression of AQP1/AQP5 mRNAs and proteins in the endometrium and myometrium dominated during luteolysis, but during the mid-luteal phase their influence on the expression of these AQPs was differentiated depending on the type of tissue and the incubation duration.CONCLUSIONS: These results seem to indicate that uterine tissues; endometrium and myometrium, exhibit their own AQP expression profiles in response to examined factors. Moreover, the responses of AQP1/AQP5 at mRNA and protein levels to the studied factors in the endometrium and myometrium are more pronounced during luteolysis. This suggests that the above effects of the studied factors are connected with morphological and physiological changes taking place in the pig uterus during the estrous cycle.</p
Evidence for the h_b(1P) meson in the decay Upsilon(3S) --> pi0 h_b(1P)
Using a sample of 122 million Upsilon(3S) events recorded with the BaBar
detector at the PEP-II asymmetric-energy e+e- collider at SLAC, we search for
the spin-singlet partner of the P-wave chi_{bJ}(1P) states in the
sequential decay Upsilon(3S) --> pi0 h_b(1P), h_b(1P) --> gamma eta_b(1S). We
observe an excess of events above background in the distribution of the recoil
mass against the pi0 at mass 9902 +/- 4(stat.) +/- 2(syst.) MeV/c^2. The width
of the observed signal is consistent with experimental resolution, and its
significance is 3.1sigma, including systematic uncertainties. We obtain the
value (4.3 +/- 1.1(stat.) +/- 0.9(syst.)) x 10^{-4} for the product branching
fraction BF(Upsilon(3S)-->pi0 h_b) x BF(h_b-->gamma eta_b).Comment: 8 pages, 4 postscript figures, submitted to Phys. Rev. D (Rapid
Communications
Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics
A detailed study is presented of the expected performance of the ATLAS
detector. The reconstruction of tracks, leptons, photons, missing energy and
jets is investigated, together with the performance of b-tagging and the
trigger. The physics potential for a variety of interesting physics processes,
within the Standard Model and beyond, is examined. The study comprises a series
of notes based on simulations of the detector and physics processes, with
particular emphasis given to the data expected from the first years of
operation of the LHC at CERN
Photo-affinity labelling and biochemical analyses identify the target of trypanocidal simplified natural product analogues
This work was supported by the Leverhulme Trust (Grant number RL2012-025). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Current drugs to treat African sleeping sickness are inadequate and new therapies are urgently required. As part of a medicinal chemistry programme based upon the simplification of acetogenin-type ether scaffolds, we previously reported the promising trypanocidal activity of compound 1 , a bis-tetrahydropyran 1,4-triazole (B-THP-T) inhibitor. This study aims to identify the protein target(s) of this class of compound in Trypanosoma brucei to understand its mode of action and aid further structural optimisation. We used compound 3 , a diazirine- and alkyne-containing bi-functional photo-affinity probe analogue of our lead B-THP-T, compound 1 , to identify potential targets of our lead compound in the procyclic form T. brucei. Bi-functional compound 3 was UV cross-linked to its target(s) in vivo and biotin affinity or Cy5.5 reporter tags were subsequently appended by Cu(II)-catalysed azide-alkyne cycloaddition. The biotinylated protein adducts were isolated with streptavidin affinity beads and subsequent LC-MSMS identified the FoF1-ATP synthase (mitochondrial complex V) as a potential target. This target identification was confirmed using various different approaches. We show that (i) compound 1 decreases cellular ATP levels (ii) by inhibiting oxidative phosphorylation (iii) at the FoF1-ATP synthase. Furthermore, the use of GFP-PTP-tagged subunits of the FoF1-ATP synthase, shows that our compounds bind specifically to both the α- and β-subunits of the ATP synthase. The FoF1-ATP synthase is a target of our simplified acetogenin-type analogues. This mitochondrial complex is essential in both procyclic and bloodstream forms of T. brucei and its identification as our target will enable further inhibitor optimisation towards future drug discovery. Furthermore, the photo-affinity labeling technique described here can be readily applied to other drugs of unknown targets to identify their modes of action and facilitate more broadly therapeutic drug design in any pathogen or disease model.Publisher PDFPeer reviewe
Cross Sections for the Reactions e+e- --> K+ K- pi+pi-, K+ K- pi0pi0, and K+ K- K+ K- Measured Using Initial-State Radiation Events
We study the processes e+e- --> K+ K- pi+pi-gamma, K+ K- pi0pi0gamma, and K+
K- K+ K-gamma, where the photon is radiated from the initial state. About
84000, 8000, and 4200 fully reconstructed events, respectively, are selected
from 454 fb-1 of BaBar data. The invariant mass of the hadronic final state
defines the \epem center-of-mass energy, so that the K+ K- pi+pi- data can be
compared with direct measurements of the e+e- --> K+ K- pi+pi- reaction. No
direct measurements exist for the e+e- --> K+ K-pi0pi0 or e+e- --> K+ K-K+ K-
reactions, and we present an update of our previous result with doubled
statistics. Studying the structure of these events, we find contributions from
a number of intermediate states, and extract their cross sections. In
particular, we perform a more detailed study of the e+e- --> phi(1020)pipigamma
reaction, and confirm the presence of the Y(2175) resonance in the phi(1020)
f0(980) and K+K-f0(980) modes. In the charmonium region, we observe the J/psi
in all three final states and in several intermediate states, as well as the
psi(2S) in some modes, and measure the corresponding product of branching
fraction and electron width.Comment: 35 pages, 42 figure
Study of Upsilon(3S,2S) -> eta Upsilon(1S) and Upsilon(3S,2S) -> pi+pi- Upsilon(1S) hadronic trasitions
We study the Upsilon(3S,2S)->eta Upsilon(1S) and Upsilon(3S,2S)->pi+pi-
Upsilon(1S) transitions with 122 million Upsilon(3S) and 100 million
Upsilon(2S) mesons collected by the BaBar detector at the PEP-II asymmetric
energy e+e- collider. We measure B[Upsilon(2S)->eta
Upsilon(1S)]=(2.39+/-0.31(stat.)+/-0.14(syst.))10^-4 and Gamma[Upsilon(2S)->eta
Upsilon(1S)]/Gamma[Upsilon(2S)-> pi+pi-
Upsilon(1S)]=(1.35+/-0.17(stat.)+/-0.08(syst.))10^-3. We find no evidence for
Upsilon(3S)->eta Upsilon(1S) and obtain B[Upsilon(3S)->eta Upsilon(1S)]<1.0
10^-4 and Gamma[Upsilon(3S)->eta Upsilon(1S)]/Gamma[Upsilon(3S)->pi+pi-
Upsilon(1S)]<2.3 10^-3 as upper limits at the 90% confidence level. We also
provide improved measurements of the Upsilon(2S) - Upsilon(1S) and Upsilon(3S)
- Upsilon(1S) mass differences, 562.170+/-0.007(stat.)+/-0.088(syst.) MeV/c^2
and 893.813+/-0.015(stat.)+/-0.107(syst.) MeV/c^2 respectively.Comment: 8 pages, 16 encapsulated postscript figures, submitted to Phys.Rev.
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