Detection of a MicroRNA Signal in an In Vivo Expression Set of mRNAs

Background. microRNAs (miRNAs) are approximately 21 nucleotide non-coding transcripts capable of regulating gene expression. The most widely studied mechanism of regulation involves binding of a miRNA to the target mRNA. As a result, translation of the target mRNA is inhibited and the mRNA may be destabilized. The inhibitory effects of miRNAs have been linked to diverse cellular processes including malignant proliferation, apoptosis, development, differentiation, and metabolic processes. We asked whether endogenous fluctuations in a set of mRNA and miRNA profiles contain correlated changes that are statistically distinguishable from the many other fluctuations in the data set. Methodology/Principal Findings. RNA was extracted from 12 human primary brain tumor biopsies. These samples were used to determine genome-wide mRN

Keap1 loss promotes Kras-driven lung cancer and results in a dependence on glutaminolysis

Treating KRAS-mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein1. One approach to addressing this challenge is to define frequently co-occurring mutations with KRAS, which themselves may lead to therapeutic vulnerabilities in tumors. Approximately 20% of KRAS-mutant LUAD tumors carry loss-of-function (LOF) mutations in Kelch-like ECH-associated protein 1 (KEAP1)2-4, a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response5-10. The high frequency of mutations in KEAP1 suggests an important role for the oxidative stress response in lung tumorigenesis. Using a CRISPR/Cas9-based approach in a mouse model of Kras-driven LUAD we examined the effects of Keap1 loss in lung cancer progression. We show that loss of Keap1 hyper-activates Nrf2 and promotes Kras-driven LUAD. Combining CRISPR/Cas9-based genetic screening and metabolomic analyses, we show that Keap1/Nrf2-mutant cancers are dependent on increased glutaminolysis, and this property can be therapeutically exploited through the pharmacological inhibition of glutaminase. Finally, we provide a rationale for sub-stratification of human lung cancer patients with KRAS-KEAP1 or -NRF2-mutant tumors as likely to respond to glutaminase inhibition

Search for a high-mass dimuon resonance produced in association with b quark jets at s\sqrt{s}=13 TeV

International audienceA search for high-mass dimuon resonance production in association with one or more b quark jets is presented. The study uses proton-proton collision data collected with the CMS detector at the LHC corresponding to an integrated luminosity of 138 fb$^{-1}$ at a center-of-mass energy of 13 TeV. Model-independent limits are derived on the number of signal events with exactly one or more than one b quark jet. Results are also interpreted in a lepton-flavor-universal model with Z$'$ boson couplings to a bb quark pair ($g_\mathrm{b}$), an sb quark pair ($g_\mathrm{b}\delta_\mathrm{bs}$), and any same-flavor charged lepton ($g_\ell$) or neutrino pair ($g_\nu$), with $\left|g_{\nu}\right|=\left|g_\ell\right|$. For a Z$'$ boson with a mass $m_{\mathrm{Z}'}$ = 350 GeV (2 TeV) and $\left|\delta_\mathrm{bs}\right| \lt$ 0.25, the majority of the parameter space with 0.0057 $\lt \left|g_\ell\right| \lt$ 0.35 (0.25 $\lt \left|g_\ell\right| \lt$ 0.43) and 0.0079 $\lt \left|g_\mathrm{b}\right| \lt$ 0.46 (0.34 $\lt \left|g_\mathrm{b}\right| \lt$ 0.57) is excluded at 95% confidence level. Finally, constraints are set on a Z$'$ model with parameters consistent with low-energy b $\to$ s$\ell\ell$ measurements. In this scenario, most of the allowed parameter space is excluded for a Z$'$ boson with 350 $\lt m_{\mathrm{Z}'}\lt$ 500 GeV, while the constraints are less stringent for higher $m_{\mathrm{Z}'}$ hypotheses. This is the first dedicated search at the LHC for a high-mass dimuon resonance produced in association with multiple b quark jets, and the constraints obtained on models with this signature are the most stringent to date

Search for new physics in multijet events with at least one photon and large missing transverse momentum in proton-proton collisions at 13 TeV

International audienceA search for new physics in final states consisting of at least one photon, multiple jets, and large missing transverse momentum is presented, using proton-proton collision events at a center-of-mass energy of 13 TeV. The data correspond to an integrated luminosity of 137 fb$^{-1}$, recorded by the CMS experiment at the CERN LHC from 2016 to 2018. The events are divided into mutually exclusive bins characterized by the missing transverse momentum, the number of jets, the number of b-tagged jets, and jets consistent with the presence of hadronically decaying W, Z, or Higgs bosons. The observed data are found to be consistent with the prediction from standard model processes. The results are interpreted in the context of simplified models of pair production of supersymmetric particles via strong and electroweak interactions. Depending on the details of the signal models, gluinos and squarks of masses up to 2.35 and 1.43 TeV, respectively, and electroweakinos of masses up to 1.23 TeV are excluded at 95% confidence level

Observation of the rare decay of the η\eta meson to four muons

A search for the rare $\eta$$\to$$\mu^+\mu^-\mu^+\mu^-$ double-Dalitz decay is performed using a sample of proton-proton collisions, collected by the CMS experiment at the CERN LHC with high-rate muon triggers in 2017-2018 and corresponding to an integrated luminosity of 101 fb$^{-1}$. A signal having a statistical significance well in excess of 5 standard deviations is observed. Using the \emm decay as normalization, the branching fraction $\mathcal{B}($η$\to \mu^+\mu^-\mu^+\mu^-)$ = ( 5.0 $\pm$ 0.8 (stat) $\pm$ 0.7 (syst) $\pm$ 0.7 $\mathcal{B}_{2\mu}$ ) $\times$ 10$^{-9}$ is measured, where the last term is the uncertainty in the normalization channel branching fraction. This is the first measurement of this branching fraction and is found to be in agreement with theoretical predictions

Development of the CMS detector for the CERN LHC Run 3

Since the initial data taking of the CERN LHC, the CMS experiment has undergone substantial upgrades and improvements. This paper discusses the CMS detector as it is configured for the third data-taking period of the CERN LHC, Run 3, which started in 2022. The entire silicon pixel tracking detector was replaced. A new powering system for the superconducting solenoid was installed. The electronics of the hadron calorimeter was upgraded. All the muon electronic systems were upgraded, and new muon detector stations were added, including a gas electron multiplier detector. The precision proton spectrometer was upgraded. The dedicated luminosity detectors and the beam loss monitor were refurbished. Substantial improvements to the trigger, data acquisition, software, and computing systems were also implemented, including a new hybrid CPU/GPU farm for the high-level trigger

Search for supersymmetry in final states with disappearing tracks in proton-proton collisions at s\sqrt{s} = 13 TeV

A search is presented for charged, long-lived supersymmetric particles in final states with one or more disappearing tracks. The search is based on data from proton-proton collisions at a center-of-mass energy of 13 TeV collected with the CMS detector at the CERN LHC between 2016 and 2018, corresponding to an integrated luminosity of 137 fb$^{-1}$. The search is performed over final states characterized by varying numbers of jets, b-tagged jets, electrons, and muons. The length of signal-candidate tracks in the plane perpendicular to the beam axis is used to characterize the lifetimes of wino- and higgsino-like charginos produced in the context of the minimal supersymmetric standard model. The d$E$/d$x$ energy loss of signal-candidate tracks is used to increase the sensitivity to charginos with a large mass and thus a small Lorentz boost. The observed results are found to be statistically consistent with the background-only hypothesis. Limits on the pair production cross section of gluinos and squarks are presented in the framework of simplified models of supersymmetric particle production and decay, and for electroweakino production based on models of wino and higgsino dark matter. The limits presented are the most stringent to date for scenarios with light third-generation squarks and a wino- or higgsino-like dark matter candidate capable of explaining the known dark matter relic density

Observation of the rare decay of the η\eta meson to four muons

A search for the rare $\eta$$\to$$\mu^+\mu^-\mu^+\mu^-$ double-Dalitz decay is performed using a sample of proton-proton collisions, collected by the CMS experiment at the CERN LHC with high-rate muon triggers in 2017-2018 and corresponding to an integrated luminosity of 101 fb$^{-1}$. A signal having a statistical significance well in excess of 5 standard deviations is observed. Using the \emm decay as normalization, the branching fraction $\mathcal{B}($η$\to \mu^+\mu^-\mu^+\mu^-)$ = ( 5.0 $\pm$ 0.8 (stat) $\pm$ 0.7 (syst) $\pm$ 0.7 $\mathcal{B}_{2\mu}$ ) $\times$ 10$^{-9}$ is measured, where the last term is the uncertainty in the normalization channel branching fraction. This is the first measurement of this branching fraction and is found to be in agreement with theoretical predictions