Synergistic interactions between XPC and p53 mutations in double-mutant mice: neural tube abnormalities and accelerated UV radiation-induced skin cancer

AbstractThe significance of DNA repair to human health has been well documented by studies on xeroderma pigmentosum (XP) patients, who suffer a dramatically increased risk of cancer in sun-exposed areas of their skin [1,2]. This autosomal recessive disorder has been directly associated with a defect in nucleotide excision–repair (NER) [1,2]. Like human XP individuals, mice carrying homozygous mutations in XP genes manifest a predisposition to skin carcinogenesis following exposure to ultraviolet (UV) radiation [3–5]. Recent studies have suggested that, in addition to roles in apoptosis [6] and cell-cycle checkpoint control [7] in response to DNA damage, p53 protein may modulate NER [8]. Mutations in the p53 gene have been observed in 50% of all human tumors [9] and have been implicated in both the early [10] and late [11] stages of skin cancer. To examine the consequences of a combined deficiency of the XPC and the p53 proteins in mice, we generated double-mutant animals. We document a spectrum of neural tube defects in XPC p53 mutant embryos. Additionally, we show that, following exposure to UV-B radiation, XPC p53 mutant mice have more severe solar keratosis and suffer accelerated skin cancer compared with XPC mutant mice that are wild-type with respect to p53

On the modification of the Efimov spectrum in a finite cubic box

Three particles with large scattering length display a universal spectrum of three-body bound states called "Efimov trimers''. We calculate the modification of the Efimov trimers of three identical bosons in a finite cubic box and compute the dependence of their energies on the box size using effective field theory. Previous calculations for positive scattering length that were perturbative in the finite volume energy shift are extended to arbitrarily large shifts and negative scattering lengths. The renormalization of the effective field theory in the finite volume is explicitly verified. Moreover, we investigate the effects of partial wave mixing and study the behavior of shallow trimers near the dimer energy. Finally, we provide numerical evidence for universal scaling of the finite volume corrections.Comment: 21 pages, 8 figures, published versio

Efimov physics from the functional renormalization group

Few-body physics related to the Efimov effect is discussed using the functional renormalization group method. After a short review of renormalization in its modern formulation we apply this formalism to the description of scattering and bound states in few-body systems of identical bosons and distinguishable fermions with two and three components. The Efimov effect leads to a limit cycle in the renormalization group flow. Recently measured three-body loss rates in an ultracold Fermi gas $^6$Li atoms are explained within this framework. We also discuss briefly the relation to the many-body physics of the BCS-BEC crossover for two-component fermions and the formation of a trion phase for the case of three species.Comment: 28 pages, 13 figures, invited contribution to a special issue of "Few-Body Systems" devoted to Efimov physics, published versio

Constraints on the Nucleon Strange Form Factors at Q^2 ~ 0.1 GeV^2

We report the most precise measurement to date of a parity-violating asymmetry in elastic electron-proton scattering. The measurement was carried out with a beam energy of 3.03 GeV and a scattering angle =6 degrees, with the result A_PV = -1.14 +/- 0.24 (stat) +/- 0.06 (syst) parts per million. From this we extract, at Q^2 = 0.099 GeV^2, the strange form factor combination G_E^s + 0.080 G_M^s = 0.030 +/- 0.025 (stat) +/- 0.006 (syst) +/- 0.012 (FF) where the first two errors are experimental and the last error is due to the uncertainty in the neutron electromagnetic form factor. This result significantly improves current knowledge of G_E^s and G_M^s at Q^2 ~0.1 GeV^2. A consistent picture emerges when several measurements at about the same Q^2 value are combined: G_E^s is consistent with zero while G_M^s prefers positive values though G_E^s=G_M^s=0 is compatible with the data at 95% C.L.Comment: minor wording changes for clarity, updated references, dropped one figure to improve focu

Clinical and molecular characterization of patients with YWHAG‐related epilepsy

Objective YWHAG variant alleles have been associated with a rare disease trait whose clinical synopsis includes an early onset epileptic encephalopathy with predominantly myoclonic seizures, developmental delay/intellectual disability, and facial dysmorphisms. Through description of a large cohort, which doubles the number of reported patients, we further delineate the spectrum of YWHAG-related epilepsy. Methods We included in this study 24 patients, 21 new and three previously described, with pathogenic/likely pathogenic variants in YWHAG. We extended the analysis of clinical, electroencephalographic, brain magnetic resonance imaging, and molecular genetic information to 24 previously published patients. Results The phenotypic spectrum of YWHAG-related disorders ranges from mild developmental delay to developmental and epileptic encephalopathy (DEE). Epilepsy onset is in the first 2 years of life. Seizure freedom can be achieved in half of the patients (13/24, 54%). Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. A genotype–phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains (90% vs. 19%, p < .001). Significance This study suggests that pathogenic YWHAG variants cause a wide range of clinical presentations with variable severity, ranging from mild developmental delay to DEE. In this allelic series, a genotype–phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe

Search for jet extinction in the inclusive jet-pT spectrum from proton-proton collisions at s=8 TeV

Published by the American Physical Society under the terms of the Creative Commons Attribution 3.0 License. Further distribution of this work must maintain attribution to the author(s) and the published articles title, journal citation, and DOI.The first search at the LHC for the extinction of QCD jet production is presented, using data collected with the CMS detector corresponding to an integrated luminosity of 10.7  fb−1 of proton-proton collisions at a center-of-mass energy of 8 TeV. The extinction model studied in this analysis is motivated by the search for signatures of strong gravity at the TeV scale (terascale gravity) and assumes the existence of string couplings in the strong-coupling limit. In this limit, the string model predicts the suppression of all high-transverse-momentum standard model processes, including jet production, beyond a certain energy scale. To test this prediction, the measured transverse-momentum spectrum is compared to the theoretical prediction of the standard model. No significant deficit of events is found at high transverse momentum. A 95% confidence level lower limit of 3.3 TeV is set on the extinction mass scale

Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings

Background:Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.Methods and Findings:1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure.An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62-1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12-2.04; p = 0.007).Conclusion: EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen.Trial Registration:http://www.ClinicalTrials.gov NCT00084136

Searches for electroweak neutralino and chargino production in channels with Higgs, Z, and W bosons in pp collisions at 8 TeV

Searches for supersymmetry (SUSY) are presented based on the electroweak pair production of neutralinos and charginos, leading to decay channels with Higgs, Z, and W bosons and undetected lightest SUSY particles (LSPs). The data sample corresponds to an integrated luminosity of about 19.5 fb(-1) of proton-proton collisions at a center-of-mass energy of 8 TeV collected in 2012 with the CMS detector at the LHC. The main emphasis is neutralino pair production in which each neutralino decays either to a Higgs boson (h) and an LSP or to a Z boson and an LSP, leading to hh, hZ, and ZZ states with missing transverse energy (E-T(miss)). A second aspect is chargino-neutralino pair production, leading to hW states with E-T(miss). The decays of a Higgs boson to a bottom-quark pair, to a photon pair, and to final states with leptons are considered in conjunction with hadronic and leptonic decay modes of the Z and W bosons. No evidence is found for supersymmetric particles, and 95% confidence level upper limits are evaluated for the respective pair production cross sections and for neutralino and chargino mass values