Somatic MED12 Nonsense Mutation Escapes mRNA Decay and Reveals a Motif Required for Nuclear Entry

MED12 is a key component of the transcription-regulating Mediator complex. Specific missense and in-frame insertion/deletion mutations in exons 1 and 2 have been identified in uterine leiomyomas, breast tumors, and chronic lymphocytic leukemia. Here, we characterize the first MED12 5 end nonsense mutation (c.97G > T, p.E33X) identified in acute lymphoblastic leukemia and show that it escapes nonsense-mediated mRNA decay (NMD) by using an alternative translation initiation site. The resulting N-terminally truncated protein is unable to enter the nucleus due to the lack of identified nuclear localization signal (NLS). The absence of NLS prevents the mutant MED12 protein to be recognized by importin- and subsequent loading into the nuclear pore complex. Due to this mislocalization, all interactions between the MED12 mutant and other Mediator components are lost. Our findings provide new mechanistic insights into the MED12 functions and indicate that somatic nonsense mutations in early exons may avoid NMD. (C) 2017 Wiley Periodicals, Inc.Peer reviewe

MITS: the Multi-Imaging Transient Spectrograph for SOXS

The Son Of X-Shooter (SOXS) is a medium resolution spectrograph R~4500 proposed for the ESO 3.6 m NTT. We present the optical design of the UV-VIS arm of SOXS which employs high efficiency ion-etched gratings used in first order (m=1) as the main dispersers. The spectral band is split into four channels which are directed to individual gratings, and imaged simultaneously by a single three-element catadioptric camera. The expected throughput of our design is >60% including contingency. The SOXS collaboration expects first light in early 2021. This paper is one of several papers presented in these proceedings describing the full SOXS instrument

Optical design of the SOXS spectrograph for ESO NTT

An overview of the optical design for the SOXS spectrograph is presented. SOXS (Son Of X-Shooter) is the new wideband, medium resolution (R>4500) spectrograph for the ESO 3.58m NTT telescope expected to start observations in 2021 at La Silla. The spectroscopic capabilities of SOXS are assured by two different arms. The UV-VIS (350-850 nm) arm is based on a novel concept that adopts the use of 4 ion-etched high efficiency transmission gratings. The NIR (800- 2000 nm) arm adopts the '4C' design (Collimator Correction of Camera Chromatism) successfully applied in X-Shooter. Other optical sub-systems are the imaging Acquisition Camera, the Calibration Unit and a pre-slit Common Path. We describe the optical design of the five sub-systems and report their performance in terms of spectral format, throughput and optical quality. This work is part of a series of contributions describing the SOXS design and properties as it is about to face the Final Design Review.Comment: 9 pages, 9 figures, published in SPIE Proceedings 1070

The VIS detector system of SOXS

SOXS will be a unique spectroscopic facility for the ESO NTT telescope able to cover the optical and NIR bands thanks to two different arms: the UV-VIS (350-850 nm), and the NIR (800-1800 nm). In this article, we describe the design of the visible camera cryostat and the architecture of the acquisition system. The UV-VIS detector system is based on a e2v CCD 44-82, a custom detector head coupled with the ESO continuous ow cryostats (CFC) cooling system and the NGC CCD controller developed by ESO. This paper outlines the status of the system and describes the design of the different parts that made up the UV-VIS arm and is accompanied by a series of contributions describing the SOXS design solutions.Comment: 9 pages, 13 figures, to be published in SPIE Proceedings 1070

The Acquisition Camera System for SOXS at NTT

SOXS (Son of X-Shooter) will be the new medium resolution (R$\sim$4500 for a 1 arcsec slit), high-efficiency, wide band spectrograph for the ESO-NTT telescope on La Silla. It will be able to cover simultaneously optical and NIR bands (350-2000nm) using two different arms and a pre-slit Common Path feeding system. SOXS will provide an unique facility to follow up any kind of transient event with the best possible response time in addition to high efficiency and availability. Furthermore, a Calibration Unit and an Acquisition Camera System with all the necessary relay optics will be connected to the Common Path sub-system. The Acquisition Camera, working in optical regime, will be primarily focused on target acquisition and secondary guiding, but will also provide an imaging mode for scientific photometry. In this work we give an overview of the Acquisition Camera System for SOXS with all the different functionalities. The optical and mechanical design of the system are also presented together with the preliminary performances in terms of optical quality, throughput, magnitude limits and photometric properties.Comment: 9 pages, 7 figures, SPIE conferenc

WNT2 activation through proximal germline deletion predisposes to small intestinal neuroendocrine tumors and intestinal adenocarcinomas

Many hereditary cancer syndromes are associated with an increased risk of small and large intestinal adenocarcinomas. However, conditions bearing a high risk to both adenocarcinomas and neuroendocrine tumors are yet to be described.We studied a family with 16 individuals in four generations affected by a wide spectrum of intestinal tumors, including hyperplastic polyps, adenomas, small intestinal neuroendocrine tumors, and colorectal and small intestinal adenocarcinomas.To assess the genetic susceptibility and understand the novel phenotype, we utilized multiple molecular methods, including whole genome sequencing, RNA sequencing, single cell sequencing, RNA in situ hybridization and organoid culture.We detected a heterozygous deletion at the cystic fibrosis locus (7q31.2) perfectly segregating with the intestinal tumor predisposition in the family. The deletion removes a topologically associating domain border between CFTR and WNT2, aberrantly activating WNT2 in the intestinal epithelium. These consequences suggest that the deletion predisposes to small intestinal neuroendocrine tumors and small and large intestinal adenocarcinomas, and reveals the broad tumorigenic effects of aberrant WNT activation in the human intestine.Peer reviewe

Measurements of production cross sections of polarized same-sign W boson pairs in association with two jets in proton-proton collisions at root s=13 TeV

The first measurements of production cross sections of polarized same-sign (WW +/-)-W-+/- boson pairs in proton-proton collisions are reported. The measurements are based on a data sample collected with the CMS detector at the LHC at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 137 fb(-1). Events are selected by requiring exactly two same-sign leptons, electrons or muons, moderate missing transverse momentum, and two jets with a large rapidity separation and a large dijet mass to enhance the contribution of same-sign (WW +/-)-W-+/- scattering events. An observed (expected) 95% confidence level upper limit of 1.17 (0.88) fbis set on the production cross section for longitudinally polarized same-sign W-+/- W-+/- boson pairs. The electroweak production of same-sign W-+/- W-+/- boson pairs with at least one of the W bosons longitudinally polarized is measured with an observed (expected) significance of 2.3 (3.1) standard deviations. (C) 2020 The Author(s). Published by Elsevier B.V.Peer reviewe

Measurement of the CP-violating phase phi(s) in the B-s(0) -> J/psi phi(1020) -> mu(+)mu-K+K- channel in proton-proton collisions at root s=13 TeV

The CP-violating weak phase ?s and the decay width difference ??s between the light and heavy B0s mass eigenstates are measured with the CMS detector at the LHC in a sample of 48 500 reconstructed B0s? J/I) d (1020) ?11+11? K+K? events. The measurement is based on a data sample corresponding to an integrated luminosity of 96.4 fb?1, collected in proton-proton collisions at ?s = 13 TeV in 2017?2018. To extract the values of ?s and ??s, a time-dependent and flavor-tagged angular analysis of the 11+11?K+K? final state is performed. The analysis employs a dedicated tagging trigger and a novel opposite-side muon flavor tagger based on machine learning techniques. The measurement yields ?s = ?11 ?50 (stat) ? 10 (syst) mrad and ??s = 0.114 ? 0.014 (stat)? 0.007 (syst) ps?1, in agreement with the standard model predictions. When combined with the previous CMS measurement at ?s = 8 TeV, the following values are obtained: ?s = ?21 ? 44 (stat) ? 10 (syst) mrad, ??s = 0.1032 ? 0.0095 (stat) ? 0.0048 (syst) ps?1, a significant improvement over the 8 TeV result. ? 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY licensePeer reviewe

Measurements of production cross sections of the Higgs boson in the four-lepton final state in proton-proton collisions at root s=13 TeV

Production cross sections of the Higgs boson are measured in the H -> ZZ -> 4l (l = e, mu) decay channel. A data sample of proton-proton collisions at a center-of-mass energy of 13 TeV, collected by the CMS detector at the LHC and corresponding to an integrated luminosity of 137 fb(-1) is used. The signal strength modifier mu, defined as the ratio of the Higgs boson production rate in the 4l channel to the standard model (SM) expectation, is measured to be mu = 0.94 +/- 0.07 (stat)(-0.08)(+0.09) (syst) at a fixed value of m(H) = 125.38 GeV. The signal strength modifiers for the individual Higgs boson production modes are also reported. The inclusive fiducial cross section for the H -> 4l process is measured to be 2.84(-0.22)(+0.23) (stat)(-0.21)(+0.26) (syst) fb, which is compatible with the SM prediction of 2.84 +/- 0.15 fb for the same fiducial region. Differential cross sections as a function of the transverse momentum and rapidity of the Higgs boson, the number of associated jets, and the transverse momentum of the leading associated jet are measured. A new set of cross section measurements in mutually exclusive categories targeted to identify production mechanisms and kinematical features of the events is presented. The results are in agreement with the SM predictions.Peer reviewe

Development and validation of HERWIG 7 tunes from CMS underlying-event measurements

This paper presents new sets of parameters ("tunes") for the underlying-event model of the herwig 7 event generator. These parameters control the description of multiple-parton interactions (MPI) and colour reconnection in herwig 7, and are obtained from a fit to minimum-bias data collected by the CMS experiment at v s = 0.9, 7, and 13 TeV. The tunes are based on the NNPDF3.1 next-to-nextto-leading-order parton distribution function (PDF) set for the parton shower, and either a leading-order or next-to-nextto-leading-order PDF set for the simulation of MPI and the beam remnants. Predictions utilizing the tunes are produced for event shape observables in electron-positron collisions, and forminimum-bias, inclusive jet, top quark pair, and Zand Wboson events in proton-proton collisions, and are compared with data. Each of the new tunes describes the data at a reasonable level, and the tunes using a leading-order PDF for the simulation of MPI provide the best description of the data.Peer reviewe