Meier–Gorlin syndrome and Wolf–Hirschhorn syndrome: two developmental disorders highlighting the importance of efficient DNA replication for normal development and neurogenesis

Microcephaly represents one of the most obvious clinical manifestations of impaired neurogenesis. Defects in the DNA damage response, in DNA repair, and structural abnormalities in centrosomes, centrioles and the spindle microtubule network have all been demonstrated to cause microcephaly in humans. Work describing novel functional defects in cell lines from individuals with either Meier–Gorlin syndrome or Wolf–Hirschhorn syndrome highlight the significance of optimal DNA replication and S phase progression for normal human development, including neurogenesis. These findings illustrate how different primary defects in processes impacting upon DNA replication potentially influence similar phenotypic outcomes, including growth retardation and microcephaly. Herein, we will describe the nature of the S phase defects uncovered for each of these conditions and highlight some of the overlapping cellular features

Protocol for a phase IV, open-label feasibility study investigating non-invasive markers of hepatic fibrosis in people living with HIV-1 and non-alcoholic fatty liver disease randomised to receiving optimised background therapy (OBT) plus maraviroc or OBT alone

Introduction At least 30% of people living with HIV (PLWH) infection have non-alcoholic fatty liver disease (NAFLD), which has now become a leading cause of hepatic fibrosis and cirrhosis. Management is based largely on lifestyle modifications, which are difficult to achieve, and therapeutic options are urgently needed. Maraviroc (MVC), through antagonism of CCR5 receptors, may reduce hepatic fibrosis progression and could be an effective treatment for NAFLD. However, dosing is usually two times per day, unlike most currently recommended antiretroviral therapies. This study will investigate the feasibility and acceptability of addition of MVC to combination antiretroviral therapy in PLWH and NAFLD as a treatment for NAFLD. Methods and analysis This is a phase IV, randomised, open-label, non-invasive feasibility study. Sixty individuals with well-controlled HIV-1 and NAFLD will be recruited from UK HIV clinics and randomised 1:1 to receive either optimised background therapy (OBT) plus MVC or OBT alone. Follow-up will be every 24 weeks for 96 weeks. The primary outcome measures will include recruitment and retention rates, adverse events and adherence. Secondary outcomes will include changes in markers of hepatic fibrosis, including the Enhanced Liver Fibrosis score, median liver stiffness measurement and controlled attenuation parameter scores on Fibroscan, and quality of life assessments. Analyses will be performed according to intention-to-treat principles. For secondary outcomes, estimated differences and 95% CIs between the groups using a t-method will be presented for continuous variables and as exact 95% binomial CIs for categorical variables. Ethics and dissemination Ethical approval was obtained through the London Dulwich UK Research Ethics Committee (reference 17/LO/2093). Results will be disseminated both through community groups and peer-reviewed scientific literature

Oral-Facial-Digital syndrome Type I cells exhibit impaired DNA repair; unanticipated consequences of defective OFD1 outside of the cilia network

Defects in OFD1 underlie the clinically complex ciliopathy, Oral-Facial-Digital syndrome Type I (OFD Type I). Our understanding of the molecular, cellular and clinical consequences of impaired OFD1 originate from its characterised roles at the centrosome/basal body/cilia network. Nonetheless, the first described OFD1 interactors were components of the TIP60 histone acetyltransferase complex. We find that OFD1 can also localise to chromatin and its reduced expression is associated with mislocalization of TIP60 in patient-derived cell lines. TIP60 plays important roles in controlling DNA repair. OFD Type I cells exhibit reduced histone acetylation and altered chromatin dynamics in response to DNA double strand breaks (DSBs). Furthermore, reduced OFD1 impaired DSB repair via homologous recombination repair (HRR). OFD1 loss also adversely impacted upon the DSB-induced G2-M checkpoint, inducing a hypersensitive and prolonged arrest. Our findings show that OFD Type I patient cells have pronounced defects in the DSB-induced histone modification, chromatin remodelling and DSB-repair via HRR; effectively phenocopying loss of TIP60. These data extend our knowledge of the molecular and cellular consequences of impaired OFD1, demonstrating that loss of OFD1 can negatively impact upon important nuclear events; chromatin plasticity and DNA repair

Combined QCD and electroweak analysis of HERA data

A simultaneous fit of parton distribution functions (PDFs) and electroweak parameters to HERA data on deep inelastic scattering is presented. The input data are the neutral current and charged current inclusive cross sections which were previously used in the QCD analysis leading to the HERAPDF2.0 PDFs. In addition, the polarisation of the electron beam was taken into account for the ZEUS data recorded between 2004 and 2007. Results on the vector and axial-vector couplings of the Z boson to u- and d-type quarks, on the value of the electroweak mixing angle and the mass of the W boson are presented. The values obtained for the electroweak parameters are in agreement with Standard Model predictions.Comment: 32 pages, 10 figures, accepted by Phys. Rev. D. Small corrections from proofing process and small change to Fig. 12 and Table

Limits on the effective quark radius from inclusive epep scattering at HERA

The high-precision HERA data allows searches up to TeV scales for Beyond the Standard Model contributions to electron-quark scattering. Combined measurements of the inclusive deep inelastic cross sections in neutral and charged current $ep$ scattering corresponding to a luminosity of around 1 fb$^{-1}$ have been used in this analysis. A new approach to the beyond the Standard Model analysis of the inclusive $ep$ data is presented; simultaneous fits of parton distribution functions together with contributions of "new physics" processes were performed. Results are presented considering a finite radius of quarks within the quark form-factor model. The resulting 95% C.L. upper limit on the effective quark radius is $0.43\cdot 10^{-16}$ cm.Comment: 10 pages, 4 figures, accepted by Phys. Lett.

Search for a narrow baryonic state decaying to pKS0{pK^0_S} and pˉKS0{\bar{p}K^0_S} in deep inelastic scattering at HERA

A search for a narrow baryonic state in the $pK^0_S$ and $\bar{p}K^0_S$ system has been performed in $ep$ collisions at HERA with the ZEUS detector using an integrated luminosity of 358 pb$^{-1}$ taken in 2003-2007. The search was performed with deep inelastic scattering events at an $ep$ centre-of-mass energy of 318 GeV for exchanged photon virtuality, $Q^2$, between 20 and 100 $\rm{} GeV^{2}$. Contrary to evidence presented for such a state around 1.52 GeV in a previous ZEUS analysis using a sample of 121 pb$^{-1}$ taken in 1996-2000, no resonance peak was found in the $p(\bar{p})K^0_S$ invariant-mass distribution in the range 1.45-1.7 GeV. Upper limits on the production cross section are set.Comment: 16 pages, 4 figures, accepted by Phys. Lett. B. Minor changes from journal reviewing process, including a small correction to figure

Measurement of the cross-section ratio sigma_{psi(2S)}/sigma_{J/psi(1S)} in deep inelastic exclusive ep scattering at HERA

The exclusive deep inelastic electroproduction of $\psi(2S)$ and $J/\psi(1S)$ at an $ep$ centre-of-mass energy of 317 GeV has been studied with the ZEUS detector at HERA in the kinematic range $2 < Q^2 < 80$ GeV$^2$, $30 < W < 210$ GeV and $|t| < 1$ GeV$^2$, where $Q^2$ is the photon virtuality, $W$ is the photon-proton centre-of-mass energy and $t$ is the squared four-momentum transfer at the proton vertex. The data for $2 < Q^2 < 5$ GeV$^2$ were taken in the HERA I running period and correspond to an integrated luminosity of 114 pb$^{-1}$. The data for $5 < Q^2 < 80$ GeV$^2$ are from both HERA I and HERA II periods and correspond to an integrated luminosity of 468 pb$^{-1}$. The decay modes analysed were $\mu^+\mu^-$ and $J/\psi(1S) \,\pi^+\pi^-$ for the $\psi(2S)$ and $\mu^+\mu^-$ for the $J/\psi(1S)$. The cross-section ratio $\sigma_{\psi(2S)}/\sigma_{J/\psi(1S)}$ has been measured as a function of $Q^2, W$ and $t$. The results are compared to predictions of QCD-inspired models of exclusive vector-meson production.Comment: 24 pages, 8 figure

Measurement of neutral current e+/-p cross sections at high Bjorken x with the ZEUS detector

The neutral current e+/-p cross section has been measured up to values of Bjorken x of approximately 1 with the ZEUS detector at HERA using an integrated luminosity of 187 inv. pb of e-p and 142 inv. pb of e+p collisions at sqrt(s) = 318GeV. Differential cross sections in x and Q2, the exchanged boson virtuality, are presented for Q2 geq 725GeV2. An improved reconstruction method and greatly increased amount of data allows a finer binning in the high-x region of the neutral current cross section and leads to a measurement with much improved precision compared to a similar earlier analysis. The measurements are compared to Standard Model expectations based on a variety of recent parton distribution functions.Comment: 39 pages, 9 figure

Measurement of (anti)deuteron and (anti)proton production in DIS at HERA

The first observation of (anti)deuterons in deep inelastic scattering at HERA has been made with the ZEUS detector at a centre-of-mass energy of 300--318 GeV using an integrated luminosity of 120 pb-1. The measurement was performed in the central rapidity region for transverse momentum per unit of mass in the range 0.3<p_T/M<0.7. The particle rates have been extracted and interpreted in terms of the coalescence model. The (anti)deuteron production yield is smaller than the (anti)proton yield by approximately three orders of magnitude, consistent with the world measurements.Comment: 26 pages, 9 figures, 5 tables, submitted to Nucl. Phys.