Variations in DNA methylation of interferon gamma and programmed death 1 in allograft rejection after kidney transplantation

Background: The role of DNA methylation in the regulation of the anti-donor-directed immune response after organ transplantation is unknown. Here, we studied the methylation of two mediators of the immune response: the pro-inflammatory cytokine interferon γ (IFNγ) and the inhibitory receptor programmed death 1 (PD1) in naïve and memory CD8+ T cell subsets in kidney transplant recipients receiving immunosuppressive medication. Both recipients experiencing an episode of acute allograft rejection (rejectors) as well as recipients without rejection (non-rejectors) were included. Results: CpGs in the promoter regions of both IFNγ and PD1 were significantly (p < 0.001) higher methylated in the naïve CD8+ T cells compared to the memory T cell subsets. The methylation status of both IFNγ and PD1 inversely c

Solitosynthesis of Q-balls

We study the formation of Q-balls in the early universe, concentrating on potentials with a cubic or quartic attractive interaction. Large Q-balls can form via solitosynthesis, a process of gradual charge accretion, provided some primordial charge assymetry and initial ``seed'' Q-balls exist. We find that such seeds are possible in theories in which the attractive interaction is of the form $A H \psi^* \psi$, with a light ``Higgs'' mass. Condensate formation and fragmentation is only possible for masses $m_\psi$ in the sub-eV range; these Q-balls may survive untill present.Comment: 9 pages, 1 figur

Tooth-surface-specific Effects of Xylitol: Randomized Trial Results

The Xylitol for Adult Caries Trial was a three-year, double-blind, multi-center, randomized clinical trial that evaluated the effectiveness of xylitol vs. placebo lozenges in the prevention of dental caries in caries-active adults. The purpose of this secondary analysis was to investigate whether xylitol lozenges had a differential effect on cumulative caries increments on different tooth surfaces. Participants (ages 21-80 yrs) with at least one follow-up visit (n = 620) were examined at baseline, 12, 24, and 33 months. Negative binomial and zero-inflated negative binomial regression models were used to estimate incidence rate ratios (IRR) for xylitol’s differential effect on cumulative caries increments on root and coronal surfaces and, among coronal surfaces, on smooth (buccal and lingual), occlusal, and proximal surfaces. Participants in the xylitol arm developed 40% fewer root caries lesions (0.23 D2FS/year) than those in the placebo arm (0.38 D2FS/year; IRR = 0.60; 95% CI [0.44, 0.81]; p < .001). There was no statistically significant difference between xylitol and control participants in the incidence of smooth-surface caries (p = .100), occlusal-surface caries (p = .408), or proximal-surface caries (p = .159). Among these caries-active adults, xylitol appears to have a caries-preventive effect on root surfaces (ClinicalTrials.gov NCT00393055)

Rare variants in optic disc area gene CARD10 enriched in primary open-angle glaucoma

Background: Genome-wide association studies (GWAS) have identified association of common alleles with primary open-angle glaucoma (POAG) and its quantitative endophenotypes near numerous genes. This study aims to determine whether rare pathogenic variants in these disease-associated genes contribute to POAG. Methods: Participants fulfilled strict inclusion criteria of advanced POAG at a young age of diagnosis. Myocilin mutation carriers were excluded using direct sequencing. Whole exome sequencing was performed on 187 glaucoma cases and 103 local screened nonglaucoma controls then joint-called with exomes of 993 previously sequenced Australian controls. GWAS-associated genes were assessed for enrichment of rare predicted pathogenic variants in POAG. Significantly enriched genes were compared against Exome Aggregation Consortium (ExAC) public control. Results: Eighty-six GWAS disease or trait-associated glaucoma genes were captured and sequenced. CARD10 showed enrichment after Bonferroni correction for rare variants in glaucoma cases (OR = 13.2, P = 6.94 × 10−5) with mutations identified in 4.28% of our POAG cohort compared to 0.27% in controls. CARD10 was significantly associated with optic disc parameters in previous GWAS. The whole GWAS gene set showed no enrichment in POAG overall (OR = 1.12, P = 0.51). Conclusion: We report here an enrichment of rare predicted pathogenic coding variants within a GWAS-associated locus in POAG (CARD10). These findings indicate that both common and rare pathogenic coding variants in CARD10 may contribute to POAG pathogenesis.Tiger Zhou, Emmanuelle Souzeau, Shiwani Sharma, Owen M. Siggs, Ivan Goldberg, Paul R. Healey, Stuart Graham, Alex W. Hewitt, David A. Mackey, Robert J. Casson, John Landers, Richard Mills, Jonathan Ellis, Paul Leo, Matthew A. Brown, Stuart MacGregor, Kathryn P. Burdon and Jamie E. Crai

Model-independent search for CP violation in D0→K−K+π−π+ and D0→π−π+π+π− decays

A search for CP violation in the phase-space structures of D0 and View the MathML source decays to the final states K−K+π−π+ and π−π+π+π− is presented. The search is carried out with a data set corresponding to an integrated luminosity of 1.0 fb−1 collected in 2011 by the LHCb experiment in pp collisions at a centre-of-mass energy of 7 TeV. For the K−K+π−π+ final state, the four-body phase space is divided into 32 bins, each bin with approximately 1800 decays. The p-value under the hypothesis of no CP violation is 9.1%, and in no bin is a CP asymmetry greater than 6.5% observed. The phase space of the π−π+π+π− final state is partitioned into 128 bins, each bin with approximately 2500 decays. The p-value under the hypothesis of no CP violation is 41%, and in no bin is a CP asymmetry greater than 5.5% observed. All results are consistent with the hypothesis of no CP violation at the current sensitivity

Search for the lepton-flavor-violating decays Bs0→e±μ∓ and B0→e±μ∓

A search for the lepton-flavor-violating decays Bs0→e±μ∓ and B0→e±μ∓ is performed with a data sample, corresponding to an integrated luminosity of 1.0  fb-1 of pp collisions at √s=7  TeV, collected by the LHCb experiment. The observed number of Bs0→e±μ∓ and B0→e±μ∓ candidates is consistent with background expectations. Upper limits on the branching fractions of both decays are determined to be B(Bs0→e±μ∓)101  TeV/c2 and MLQ(B0→e±μ∓)>126  TeV/c2 at 95% C.L., and are a factor of 2 higher than the previous bounds

Branching fraction and CP asymmetry of the decays B+→K0Sπ+ and B+→K0SK+

An analysis of B+ → K0 Sπ+ and B+ → K0 S K+ decays is performed with the LHCb experiment. The pp collision data used correspond to integrated luminosities of 1 fb−1 and 2 fb−1 collected at centre-ofmass energies of √ s = 7 TeV and √ s = 8 TeV, respectively. The ratio of branching fractions and the direct CP asymmetries are measured to be B(B+ → K0 S K+ )/B(B+ → K0 Sπ+ ) = 0.064 ± 0.009 (stat.) ± 0.004 (syst.), ACP(B+ → K0 Sπ+ ) = −0.022 ± 0.025 (stat.) ± 0.010 (syst.) and ACP(B+ → K0 S K+ ) = −0.21 ± 0.14 (stat.) ± 0.01 (syst.). The data sample taken at √ s = 7 TeV is used to search for B+ c → K0 S K+ decays and results in the upper limit ( fc · B(B+ c → K0 S K+ ))/( fu · B(B+ → K0 Sπ+ )) < 5.8 × 10−2 at 90% confidence level, where fc and fu denote the hadronisation fractions of a ¯b quark into a B+ c or a B+ meson, respectively

Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia

The interaction of germline variation and somatic cancer driver mutations is underinvestigated. Here we describe the genomic mitochondrial landscape in adult acute myeloid leukaemia (AML) and show that rare variants affecting the nuclear- and mitochondriallyencoded complex I genes show near-mutual exclusivity with somatic driver mutations affecting isocitrate dehydrogenase 1 (IDH1), but not IDH2 suggesting a unique epistatic relationship. Whereas AML cells with rare complex I variants or mutations in IDH1 or IDH2 all display attenuated mitochondrial respiration, heightened sensitivity to complex I inhibitors including the clinical-grade inhibitor, IACS-010759, is observed only for IDH1-mutant AML. Furthermore, IDH1 mutant blasts that are resistant to the IDH1-mutant inhibitor, ivosidenib, retain sensitivity to complex I inhibition. We propose that the IDH1 mutation limits the flexibility for citrate utilization in the presence of impaired complex I activity to a degree that is not apparent in IDH2 mutant cells, exposing a mutation-specific metabolic vulnerability. This reduced metabolic plasticity explains the epistatic relationship between the germline complex I variants and oncogenic IDH1 mutation underscoring the utility of genomic data in revealing metabolic vulnerabilities with implications for therapy.Mahmoud A. Bassal, Saumya E. Samaraweera, Kelly Lim, Brooks A. Bernard, Sheree Bailey, Satinder Kaur, Paul Leo, John Toubia, Chloe Thompson-Peach, Tran Nguyen, Kyaw Ze Ya Maung, Debora A. Casolari, Diana G. Iarossi, Ilaria S. Pagani, Jason Powell, Stuart Pitson, Siria Natera, Ute Roessner, Ian D. Lewis, Anna L. Brown, Daniel G. Tenen, Nirmal Robinson, David M. Ross, Ravindra Majeti, Thomas J. Gonda, Daniel Thomas, Richard J. D, Andre

A study of CP violation in B-+/- -> DK +/- and B-+/- -> D pi(+/-) decays with D -> (KSK +/-)-K-0 pi(-/+) final states

A first study of CP violation in the decay modes B-+/- -> [(KSK +/-)-K-0 pi(-/+)](D)h(+/-) and B-+/- -> [(KSK +/-)-K-0 pi(-/+)](D)h(+/-), where h labels a K or pi meson and D labels a D-0 or (D) over bar (0) meson, is performed. The analysis uses the LHCb data set collected in pp collisions, corresponding to an integrated luminosity of 3 fb(-1). The analysis is sensitive to the CP-violating CKM phase gamma through seven observables: one charge asymmetry in each of the four modes and three ratios of the charge-integrated yields. The results are consistent with measurements of gamma using other decay modes