Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome

A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related (ATR) gene was previously reported in two related families displaying Seckel Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome patient with mutations in ATRIP, the gene encoding ATR-Interacting Protein (ATRIP), the partner protein of ATR required for ATR stability and recruitment to the site of DNA damage. The patient has compound heterozygous mutations in ATRIP resulting in reduced ATRIP and ATR expression. A nonsense mutational change in one ATRIP allele results in a C-terminal truncated protein, which impairs ATR-ATRIP interaction; the other allele is abnormally spliced. We additionally describe two further unrelated patients native to the UK with the same novel, heterozygous mutations in ATR, which cause dramatically reduced ATR expression. All patient-derived cells showed defective DNA damage responses that can be attributed to impaired ATR-ATRIP function. Seckel Syndrome is characterised by microcephaly and growth delay, features also displayed by several related disorders including Majewski (microcephalic) osteodysplastic primordial dwarfism (MOPD) type II and Meier-Gorlin Syndrome (MGS). The identification of an ATRIP-deficient patient provides a novel genetic defect for Seckel Syndrome. Coupled with the identification of further ATR-deficient patients, our findings allow a spectrum of clinical features that can be ascribed to the ATR-ATRIP deficient sub-class of Seckel Syndrome. ATR-ATRIP patients are characterised by extremely severe microcephaly and growth delay, microtia (small ears), micrognathia (small and receding chin), and dental crowding. While aberrant bone development was mild in the original ATR-SS patient, some of the patients described here display skeletal abnormalities including, in one patient, small patellae, a feature characteristically observed in Meier-Gorlin Syndrome. Collectively, our analysis exposes an overlapping clinical manifestation between the disorders but allows an expanded spectrum of clinical features for ATR-ATRIP Seckel Syndrome to be define

Deficiency in origin licensing proteins impairs cilia formation: implications for the aetiology of meier-gorlin syndrome

Mutations in ORC1, ORC4, ORC6, CDT1, and CDC6, which encode proteins required for DNA replication origin licensing, cause Meier-Gorlin syndrome (MGS), a disorder conferring microcephaly, primordial dwarfism, underdeveloped ears, and skeletal abnormalities. Mutations in ATR, which also functions during replication, can cause Seckel syndrome, a clinically related disorder. These findings suggest that impaired DNA replication could underlie the developmental defects characteristic of these disorders. Here, we show that although origin licensing capacity is impaired in all patient cells with mutations in origin licensing component proteins, this does not correlate with the rate of progression through S phase. Thus, the replicative capacity in MGS patient cells does not correlate with clinical manifestation. However, ORC1-deficient cells from MGS patients and siRNA-mediated depletion of origin licensing proteins also have impaired centrosome and centriole copy number. As a novel and unexpected finding, we show that they also display a striking defect in the rate of formation of primary cilia. We demonstrate that this impacts sonic hedgehog signalling in ORC1-deficient primary fibroblasts. Additionally, reduced growth factor-dependent signaling via primary cilia affects the kinetics of cell cycle progression following cell cycle exit and re-entry, highlighting an unexpected mechanism whereby origin licensing components can influence cell cycle progression. Finally, using a cell-based model, we show that defects in cilia function impair chondroinduction. Our findings raise the possibility that a reduced efficiency in forming cilia could contribute to the clinical features of MGS, particularly the bone development abnormalities, and could provide a new dimension for considering developmental impacts of licensing deficiency

Courtship Initiation Is Stimulated by Acoustic Signals in Drosophila melanogaster

Finding a mating partner is a critical task for many organisms. It is in the interest of males to employ multiple sensory modalities to search for females. In Drosophila melanogaster, vision is thought to be the most important courtship stimulating cue at long distance, while chemosensory cues are used at relatively short distance. In this report, we show that when visual cues are not available, sounds produced by the female allow the male to detect her presence in a large arena. When the target female was artificially immobilized, the male spent a prolonged time searching before starting courtship. This delay in courtship initiation was completely rescued by playing either white noise or recorded fly movement sounds to the male, indicating that the acoustic and/or seismic stimulus produced by movement stimulates courtship initiation, most likely by increasing the general arousal state of the male. Mutant males expressing tetanus toxin (TNT) under the control of Gr68a-GAL4 had a defect in finding active females and a delay in courtship initiation in a large arena, but not in a small arena. Gr68a-GAL4 was found to be expressed pleiotropically not only in putative gustatory pheromone receptor neurons but also in mechanosensory neurons, suggesting that Gr68a-positive mechanosensory neurons, not gustatory neurons, provide motion detection necessary for courtship initiation. TNT/Gr68a males were capable of discriminating the copulation status and age of target females in courtship conditioning, indicating that female discrimination and formation of olfactory courtship memory are independent of the Gr68a-expressing neurons that subserve gustation and mechanosensation. This study suggests for the first time that mechanical signals generated by a female fly have a prominent effect on males' courtship in the dark and leads the way to studying how multimodal sensory information and arousal are integrated in behavioral decision making

Innovation, R&D Investment and Productivity: Uruguayan Manufacturing Firms

Uruguays inability to sustain high levels of economic growth cannot be fully explained by external shocks, the prevailing institutional setting or the level of human capital accumulation. Instead, low investment in knowledge capital stands as a most likely explanation. This hypothesis is supported by empirical evidence analyzed in this study. Returns on innovation were found to be significant, promoting a non-negligible acceleration of labor productivity gains. However, the propensity to innovate and the intensity of the effort expended critically depend on the firms already having a high internal efficiency level. As firms behavior is differentiated depending on the type of innovation output pursued, the significantly higher frequency of processes relative to product-innovative firms is matched by the larger impact of novel processes with respect to products on labor productivity. However, the degree of novelty of process innovation is significantly inferior to that of product innovation. The research points to inadequate choices of input mixes as the underlying cause. Policy recommendations center on finding adequate channels to generate and disseminate information on the optimal input mixes depending on the type of innovation output sought

Differential branching fraction and angular analysis of the decay B0→K∗0μ+μ−

The angular distribution and differential branching fraction of the decay B 0→ K ∗0 μ + μ − are studied using a data sample, collected by the LHCb experiment in pp collisions at s√=7 TeV, corresponding to an integrated luminosity of 1.0 fb−1. Several angular observables are measured in bins of the dimuon invariant mass squared, q 2. A first measurement of the zero-crossing point of the forward-backward asymmetry of the dimuon system is also presented. The zero-crossing point is measured to be q20=4.9±0.9GeV2/c4 , where the uncertainty is the sum of statistical and systematic uncertainties. The results are consistent with the Standard Model predictions

Observation of the decay Bc→J/ψK+K−π+B_c \rightarrow J/\psi K^+ K^- \pi^+

The decay $B_c\rightarrow J/\psi K^+ K^- \pi^+$ is observed for the first time, using proton-proton collisions collected with the LHCb detector corresponding to an integrated luminosity of 3fb$^{-1}$. A signal yield of $78\pm14$ decays is reported with a significance of 6.2 standard deviations. The ratio of the branching fraction of \B_c \rightarrow J/\psi K^+ K^- \pi^+ decays to that of $B_c \rightarrow J/\psi \pi^+$ decays is measured to be $0.53\pm 0.10\pm0.05$, where the first uncertainty is statistical and the second is systematic.Comment: 18 pages, 2 figure

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

Measurement of the Bs0→J/ψηB_{s}^{0} \rightarrow J/\psi \eta lifetime

Using a data set corresponding to an integrated luminosity of $3 fb^{-1}$, collected by the LHCb experiment in $pp$ collisions at centre-of-mass energies of 7 and 8 TeV, the effective lifetime in the $B^0_s \rightarrow J/\psi \eta$ decay mode, $\tau_{\textrm{eff}}$, is measured to be $\tau_{\textrm{eff}} = 1.479 \pm 0.034~\textrm{(stat)} \pm 0.011 ~\textrm{(syst)}$ ps. Assuming $CP$ conservation, $\tau_{\textrm{eff}}$ corresponds to the lifetime of the light $B_s^0$ mass eigenstate. This is the first measurement of the effective lifetime in this decay mode.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-017.htm

Observation of associated production of a ZZ boson with a DD meson in the~forward region

A search for associated production of a $Z$ boson with an open charm meson is presented using a data sample, corresponding to an integrated luminosity of $1.0\,\mathrm{fb}^{-`}$ of proton--proton collisions at a centre-of-mass energy of 7\,TeV, collected by the LHCb experiment. %% Seven candidate events for associated production of a $Z$ boson with a $D^0$ meson and four candidate events for a $Z$ boson with a $D^+$ meson are observed with a combined significance of 5.1standard deviations. The production cross-sections in the forward region are measured to be $$\sigma_{Z\rightarrow\mu^+\mu^-\!,D^0} = 2.50\pm1.12\pm0.22pb$$ $$\sigma_{Z\rightarrow\mu^+\mu^-\!,D^+} = 0.44\pm0.23\pm0.03pb,$$ where the first uncertainty is statistical and the second systematic.Comment: 18 pages, 2 figure

Study of B0(s)→K0Sh+h′− decays with first observation of B0s→K0SK±π∓ and B0s→K0Sπ+π−

A search for charmless three-body decays of B 0 and B0s mesons with a K0S meson in the final state is performed using the pp collision data, corresponding to an integrated luminosity of 1.0 fb−1, collected at a centre-of-mass energy of 7 TeV recorded by the LHCb experiment. Branching fractions of the B0(s)→K0Sh+h′− decay modes (h (′) = π, K), relative to the well measured B0→K0Sπ+π− decay, are obtained. First observation of the decay modes B0s→K0SK±π∓ and B0s→K0Sπ+π− and confirmation of the decay B0→K0SK±π∓ are reported. The following relative branching fraction measurements or limits are obtained B(B0→K0SK±π∓)B(B0→K0Sπ+π−)=0.128±0.017(stat.)±0.009(syst.), B(B0→K0SK+K−)B(B0→K0Sπ+π−)=0.385±0.031(stat.)±0.023(syst.), B(B0s→K0Sπ+π−)B(B0→K0Sπ+π−)=0.29±0.06(stat.)±0.03(syst.)±0.02(fs/fd), B(B0s→K0SK±π∓)B(B0→K0Sπ+π−)=1.48±0.12(stat.)±0.08(syst.)±0.12(fs/fd)B(B0s→K0SK+K−)B(B0→K0Sπ+π−)∈[0.004;0.068]at90%CL