Functional characterisation of novel NR5A1 variants reveals multiple complex roles in Disorders of Sex Development

Variants in the NR5A1 gene encoding SF1 have been described in a diverse spectrum of disorders of sex development (DSD). Recently, we reported the use of a targeted gene panel for DSD where we identified 15 individuals with a variant in NR5A1, nine of which are novel. Here, we examine the functional effect of these changes in relation to the patient phenotype. All novel variants tested had reduced trans-activational activity, while several had altered protein level, localization, or conformation. In addition, we found evidence of new roles for SF1 protein domains including a region within the ligand binding domain that appears to contribute to SF1 regulation of Mu¨llerian development. There was little correlation between the severity of the phenotype and the nature of the NR5A1 variant. We report two familial cases of NR5A1 deficiency with evidence of variable expressivity; we also report on individuals with oligogenic inheritance. Finally, we found that the nature of the NR5A1 variant does not inform patient outcomes (including pubertal androgenization and malignancy risk). This study adds nine novel pathogenic NR5A1 variants to the pool of diagnostic variants. It highlights a greater need for understanding the complexity of SF1 function and the additional factors that contribute

Time-integrated luminosity recorded by the BABAR detector at the PEP-II e+e- collider

This article is the Preprint version of the final published artcile which can be accessed at the link below.We describe a measurement of the time-integrated luminosity of the data collected by the BABAR experiment at the PEP-II asymmetric-energy e+e- collider at the ϒ(4S), ϒ(3S), and ϒ(2S) resonances and in a continuum region below each resonance. We measure the time-integrated luminosity by counting e+e-→e+e- and (for the ϒ(4S) only) e+e-→μ+μ- candidate events, allowing additional photons in the final state. We use data-corrected simulation to determine the cross-sections and reconstruction efficiencies for these processes, as well as the major backgrounds. Due to the large cross-sections of e+e-→e+e- and e+e-→μ+μ-, the statistical uncertainties of the measurement are substantially smaller than the systematic uncertainties. The dominant systematic uncertainties are due to observed differences between data and simulation, as well as uncertainties on the cross-sections. For data collected on the ϒ(3S) and ϒ(2S) resonances, an additional uncertainty arises due to ϒ→e+e-X background. For data collected off the ϒ resonances, we estimate an additional uncertainty due to time dependent efficiency variations, which can affect the short off-resonance runs. The relative uncertainties on the luminosities of the on-resonance (off-resonance) samples are 0.43% (0.43%) for the ϒ(4S), 0.58% (0.72%) for the ϒ(3S), and 0.68% (0.88%) for the ϒ(2S).This work is supported by the US Department of Energy and National Science Foundation, the Natural Sciences and Engineering Research Council (Canada), the Commissariat à l’Energie Atomique and Institut National de Physique Nucléaire et de Physiquedes Particules (France), the Bundesministerium für Bildung und Forschung and Deutsche Forschungsgemeinschaft (Germany), the Istituto Nazionale di Fisica Nucleare (Italy), the Foundation for Fundamental Research on Matter (The Netherlands), the Research Council of Norway, the Ministry of Education and Science of the Russian Federation, Ministerio de Ciencia e Innovación (Spain), and the Science and Technology Facilities Council (United Kingdom). Individuals have received support from the Marie-Curie IEF program (European Union) and the A.P. Sloan Foundation (USA)

Observation of the baryonic decay B \uaf 0 \u2192 \u39bc+ p \uaf K-K+

We report the observation of the baryonic decay B\uaf0\u2192\u39bc+p\uafK-K+ using a data sample of 471 7106 BB\uaf pairs produced in e+e- annihilations at s=10.58GeV. This data sample was recorded with the BABAR detector at the PEP-II storage ring at SLAC. We find B(B\uaf0\u2192\u39bc+p\uafK-K+)=(2.5\ub10.4(stat)\ub10.2(syst)\ub10.6B(\u39bc+)) 710-5, where the uncertainties are statistical, systematic, and due to the uncertainty of the \u39bc+\u2192pK-\u3c0+ branching fraction, respectively. The result has a significance corresponding to 5.0 standard deviations, including all uncertainties. For the resonant decay B\uaf0\u2192\u39bc+p\uaf\u3c6, we determine the upper limit B(B\uaf0\u2192\u39bc+p\uaf\u3c6)<1.2 710-5 at 90% confidence level

Measurement of the CP-Violating Asymmetry Amplitude sin2β\beta

We present results on time-dependent CP-violating asymmetries in neutral B decays to several CP eigenstates. The measurements use a data sample of about 88 million Y(4S) --> B Bbar decays collected between 1999 and 2002 with the BABAR detector at the PEP-II asymmetric-energy B Factory at SLAC. We study events in which one neutral B meson is fully reconstructed in a final state containing a charmonium meson and the other B meson is determined to be either a B0 or B0bar from its decay products. The amplitude of the CP-violating asymmetry, which in the Standard Model is proportional to sin2beta, is derived from the decay-time distributions in such events. We measure sin2beta = 0.741 +/- 0.067 (stat) +/- 0.033 (syst) and |lambda| = 0.948 +/- 0.051 (stat) +/- 0.017 (syst). The magnitude of lambda is consistent with unity, in agreement with the Standard Model expectation of no direct CP violation in these modes

Decreased occurrence of ketoacidosis and preservation of beta cell function in relatives screened and monitored for type 1 diabetes in Australia and New Zealand

Published December 2022Aims: Islet autoantibody screening of infants and young children in the Northern Hemisphere, together with semi-annual metabolic monitoring, is associated with a lower risk of ketoacidosis (DKA) and improved glucose control after diagnosis of clinical (stage 3) type 1 diabetes (T1D). We aimed to determine if similar benefits applied to older Australians and New Zealanders monitored less rigorously. Methods: DKA occurrence and metabolic control were compared between T1D relatives screened and monitored for T1D and unscreened individuals diagnosed in the general population, ascertained from the Australasian Diabetes Data Network. Results: Between 2005 and 2019, 17,105 relatives (mean (SD) age 15.7 (10.8) years; 52% female) were screened for autoantibodies against insulin, glutamic acid decarboxylase, and insulinoma-associated protein 2. Of these, 652 screened positive to a single and 306 to multiple autoantibody specificities, of whom 201 and 215, respectively, underwent metabolic monitoring. Of 178 relatives diagnosed with stage 3 T1D, 9 (5%) had DKA, 7 of whom had not undertaken metabolic monitoring. The frequency of DKA in the general population was 31%. After correction for age, sex and T1D family history, the frequency of DKA in screened relatives was >80% lower than in the general population. HbA1c and insulin requirements following diagnosis were also lower in screened relatives, consistent with greater beta cell reserve. Conclusions: T1D autoantibody screening and metabolic monitoring of older children and young adults in Australia and New Zealand, by enabling pre-clinical diagnosis when beta cell reserve is greater, confers protection from DKA. These clinical benefits support ongoing efforts to increase screening activity in the region and should facilitate the application of emerging immunotherapies.John M. Wentworth, Helena Oakey, Maria E. Craig, Jennifer J. Couper, Fergus J. Cameron, Elizabeth A. Davis, Antony R. Lafferty, Mark Harris, Benjamin J. Wheeler, Craig Jefferies, Peter G. Colman, Leonard C. Harriso

Requirements for improving health and well-being of children with Prader-Willi syndrome and their families

Prader-Willi syndrome (PWS) is a rare genetic condition with multi-system involvement. The literature was reviewed to describe neurodevelopment and the behavioural phenotype, endocrine and metabolic disorders and respiratory and sleep functioning. Implications for child and family quality of life were explored. Challenging behaviours contribute to poorer well-being and quality of life for both the child and caregiver. Recent evidence indicates healthy outcomes of weight and height can be achieved with growth hormone therapy and dietary restriction and should be the current target for all individuals with PWS. Gaps in the literature included therapies to manage challenging behaviours, as well as understanding the effects of growth hormone on respiratory and sleep function. New knowledge regarding the transition of children and families from schooling and paediatric health services to employment, accommodation and adult health services is also needed. Developing a national population-based registry could address these knowledge gaps and inform advocacy for support services that improve the well-being of individuals with PWS and their families

Search for Darkonium in e+e- Collisions

Collider searches for dark sectors, new particles interacting only feebly with ordinary matter, have largely focused on identifying signatures of new mediators, leaving much of dark sector structures unexplored. In particular, the existence of dark matter bound states (darkonia) remains to be investigated. This possibility could arise in a simple model in which a dark photon (A0 ) is light enough to generate an attractive force between dark fermions. We report herein a search for a JPC ¼ 1−− darkonium state, the ϒD, produced in the reaction eþe− → γϒD, ϒD → A0 A0 A0 , where the dark photons subsequently decay into pairs of leptons or pions, using 514 fb−1 of data collected with the BABAR detector. No significant signal is observed, and we set bounds on the γ − A0 kinetic mixing as a function of the dark sector coupling constant for 0.001 < mA0 < 3.16 GeV and 0.05 < mϒD < 9.5 GeV.publishedVersio

Measurement of the CKM angle γ in the B0→DK *0 channel using self-conjugate D→ KS0h+ h- decays

A model-independent study of CP violation in B-0 -&gt; DK (*0) decays is presented using data corresponding to an integrated luminosity of 9 fb(-1) collected by the LHCb experiment at centre-of-mass energies of v s = 7, 8 and 13TeV. The CKM angle. is determined by examining the distributions of signal decays in phase-space bins of the self-conjugate D. K(S)(0)h(+) h(-) decays, where h = p, K. Observables related to CP violation are measured and the angle. is determined to be. = (49+22 -19).. Measurements of the amplitude ratio and strong-phase difference between the favoured and suppressed B-0 decays are also presented

Study of the process e + e − → π + π − π0 using initial state radiation with BABAR

The process e+e− → π+π−π0γ is studied at a center-of-mass energy near the ϒ(4S) resonance using a data sample of 469 fb−1 collected with the BABAR detector at the PEP-II collider. We have performed a precise measurement of the e+e− → π+π−π0 cross section in the center-of-mass energy range from 0.62 to 3.5 GeV. In the energy regions of the ω and ϕ resonances, the cross section is measured with a systematic uncertainty of 1.3%. The leading-order hadronic contribution to the muon magnetic anomaly calculated using the measured e+e− → π+π−π0 cross section from threshold to 2.0 GeV is (45.86 ± 0.14 ± 0.58) × 10^−10. From the fit to the measured 3π mass spectrum we have determined the resonance parameters Γ(ω → e+e−)B(ω → π+π−π0) = (0.5698 ± 0.0031 ± 0.0082) keV, Γ(ϕ → e+e−)B(ϕ → π+π−π0) = (0.1841 ± 0.0021 ± 0.0080) keV, and B(ρ → 3π) = (0.88 ± 0.23 ± 0.30) × 10^−4. The significance of the ρ → 3π signal is greater than 6σ. For the J/ψ resonance we have measured the product Γ(J/ψ → e+e−)B(J/ψ → 3π) = (0.1248 ± 0.0019 ± 0.0026) keV

Study of the doubly charmed tetraquark T+cc

Quantum chromodynamics, the theory of the strong force, describes interactions of coloured quarks and gluons and the formation of hadronic matter. Conventional hadronic matter consists of baryons and mesons made of three quarks and quark-antiquark pairs, respectively. Particles with an alternative quark content are known as exotic states. Here a study is reported of an exotic narrow state in the D0D0π+ mass spectrum just below the D*+D0 mass threshold produced in proton-proton collisions collected with the LHCb detector at the Large Hadron Collider. The state is consistent with the ground isoscalar T+cc tetraquark with a quark content of ccu⎯⎯⎯d⎯⎯⎯ and spin-parity quantum numbers JP = 1+. Study of the DD mass spectra disfavours interpretation of the resonance as the isovector state. The decay structure via intermediate off-shell D*+ mesons is consistent with the observed D0π+ mass distribution. To analyse the mass of the resonance and its coupling to the D*D system, a dedicated model is developed under the assumption of an isoscalar axial-vector T+cc state decaying to the D*D channel. Using this model, resonance parameters including the pole position, scattering length, effective range and compositeness are determined to reveal important information about the nature of the T+cc state. In addition, an unexpected dependence of the production rate on track multiplicity is observed