Loss of the Orphan Nuclear Receptor SHP Is More Pronounced in Fibrolamellar Carcinoma than in Typical Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains a major problem in oncology. The molecular mechanisms which underlie its pathogenesis are poorly understood. Recently the Small Heterodimer Partner (SHP), an orphan nuclear receptor, was suggested to be involved as a tumor suppressor in hepatocellular carcinoma development. To date, there are no such studies regarding fibrolamellar carcinoma, a less common variant of HCC, which usually affects young people and displays distinct morphological features. The aim of our project was to evaluate the SHP levels in typical and fibrolamellar hepatocellular carcinoma with respect to the levels of one of the cell cycle regulators, cyclin D1. We assessed the immunoreactivity levels of SHP and cyclin D1 in 48 typical hepatocellular carcinomas, 9 tumors representing the fibrolamellar variant, 29 non malignant liver tissues and 7 macroregenerative nodules. We detected significantly lower SHP immunoreactivity in hepatocellular carcinoma when compared to non malignant liver tissue. Moreover, we found that SHP immunoreactivity is reduced in fibrolamellar carcinoma when compared to typical hepatocellular carcinoma. We also found that SHP is more commonly lost in HCC which arises in the liver with steatosis. The comparison between the cyclin D1 and SHP expression revealed the negative correlation between these proteins in the high grade HCC. Our results indicate that the impact of loss of SHP protein may be even more pronounced in fibrolamellar carcinoma than in a typical form of HCC. Further investigation of mechanisms through which the loss of SHP function may influence HCC formation may provide important information in order to design more effective HCC therapy

Milk exosomes: beyond dietary microRNAs

Extracellular vesicles deliver a variety of cargos to recipient cells, including the delivery of cargos in dietary vesicles from bovine milk to non-bovine species. The rate of discovery in this important line of research is slowed by a controversy whether the delivery and bioactivity of a single class of vesicle cargos, microRNAs, are real or not. This opinion paper argues that the evidence in support of the bioavailability of microRNAs encapsulated in dietary exosomes outweighs the evidence produced by scholars doubting that phenomenon is real. Importantly, this paper posits that the time is ripe to look beyond microRNA cargos and pursue innovative pathways through which dietary exosomes alter metabolism. Here, we highlight potentially fruitful lines of exploration

Structural and Histone Binding Ability Characterizations of Human PWWP Domains

The PWWP domain was first identified as a structural motif of 100-130 amino acids in the WHSC1 protein and predicted to be a protein-protein interaction domain. It belongs to the Tudor domain 'Royal Family', which consists of Tudor, chromodomain, MBT and PWWP domains. While Tudor, chromodomain and MBT domains have long been known to bind methylated histones, PWWP was shown to exhibit histone binding ability only until recently.The PWWP domain has been shown to be a DNA binding domain, but sequence analysis and previous structural studies show that the PWWP domain exhibits significant similarity to other 'Royal Family' members, implying that the PWWP domain has the potential to bind histones. In order to further explore the function of the PWWP domain, we used the protein family approach to determine the crystal structures of the PWWP domains from seven different human proteins. Our fluorescence polarization binding studies show that PWWP domains have weak histone binding ability, which is also confirmed by our NMR titration experiments. Furthermore, we determined the crystal structures of the BRPF1 PWWP domain in complex with H3K36me3, and HDGF2 PWWP domain in complex with H3K79me3 and H4K20me3.PWWP proteins constitute a new family of methyl lysine histone binders. The PWWP domain consists of three motifs: a canonical β-barrel core, an insertion motif between the second and third β-strands and a C-terminal α-helix bundle. Both the canonical β-barrel core and the insertion motif are directly involved in histone binding. The PWWP domain has been previously shown to be a DNA binding domain. Therefore, the PWWP domain exhibits dual functions: binding both DNA and methyllysine histones.This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1

Structure-Function Analysis of Barley NLR Immune Receptor MLA10 Reveals Its Cell Compartment Specific Activity in Cell Death and Disease Resistance

Plant intracellular immune receptors comprise a large number of multi-domain proteins resembling animal NOD-like receptors (NLRs). Plant NLRs typically recognize isolate-specific pathogen-derived effectors, encoded by avirulence (AVR) genes, and trigger defense responses often associated with localized host cell death. The barley MLA gene is polymorphic in nature and encodes NLRs of the coiled-coil (CC)-NB-LRR type that each detects a cognate isolate-specific effector of the barley powdery mildew fungus. We report the systematic analyses of MLA10 activity in disease resistance and cell death signaling in barley and Nicotiana benthamiana. MLA10 CC domain-triggered cell death is regulated by highly conserved motifs in the CC and the NB-ARC domains and by the C-terminal LRR of the receptor. Enforced MLA10 subcellular localization, by tagging with a nuclear localization sequence (NLS) or a nuclear export sequence (NES), shows that MLA10 activity in cell death signaling is suppressed in the nucleus but enhanced in the cytoplasm. By contrast, nuclear localized MLA10 is sufficient to mediate disease resistance against powdery mildew fungus. MLA10 retention in the cytoplasm was achieved through attachment of a glucocorticoid receptor hormone-binding domain (GR), by which we reinforced the role of cytoplasmic MLA10 in cell death signaling. Together with our data showing an essential and sufficient nuclear MLA10 activity in disease resistance, this suggests a bifurcation of MLA10-triggered cell death and disease resistance signaling in a compartment-dependent manner

Measurement of the inclusive and differential Higgs boson production cross sections in the decay mode to a pair of τ Leptons in pp collisions at sqrt[s]=13 TeV

Measurements of the inclusive and differential fiducial cross sections of the Higgs boson are presented, using the τ lepton decay channel. The differential cross sections are measured as functions of the Higgs boson transverse momentum, jet multiplicity, and transverse momentum of the leading jet in the event, if any. The analysis is performed using proton-proton collision data collected with the CMS detector at the LHC at a center-of-mass energy of 13  TeV and corresponding to an integrated luminosity of 138  fb^{-1}. These are the first differential measurements of the Higgs boson cross section in the final state of two τ leptons. In final states with a large jet multiplicity or with a Lorentz-boosted Higgs boson, these measurements constitute a significant improvement over measurements performed in other final states

Search for Higgs boson decays to a Z boson and a photon in proton-proton collisions at s \sqrt{s} = 13 TeV

A preprint version of the article is available at arXiv:2204.12945v2 [hep-ex], https://arxiv.org/abs/2204.12945v2 . Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/HIG-19-014 (CMS Public Pages). Report number: CMS-HIG-19-014, CERN-EP-2022-019.Results are presented from a search for the Higgs boson decay H → Zγ, where Z → ℓ+ℓ− with ℓ = e or μ. The search is performed using a sample of proton-proton (pp) collision data at a center-of-mass energy of 13 TeV, recorded by the CMS experiment at the LHC, corresponding to an integrated luminosity of 138 fb^{−1}. Events are assigned to mutually exclusive categories, which exploit differences in both event topology and kinematics of distinct Higgs production mechanisms to enhance signal sensitivity. The signal strength μ, defined as the product of the cross section and the branching fraction [σ(pp → H)B(H → Zγ)] relative to the standard model prediction, is extracted from a simultaneous fit to the ℓ+ℓ−γ invariant mass distributions in all categories and is found to be μ = 2.4 ± 0.9 for a Higgs boson mass of 125.38 GeV. The statistical significance of the observed excess of events is 2.7 standard deviations. This measurement corresponds to σ(pp → H)B(H → Zγ) = 0.21 ± 0.08 pb. The observed (expected) upper limit at 95% confidence level on μ is 4.1 (1.8). The ratio of branching fractions B(H → Zγ)/B(H → γγ) is measured to be 1.5 +0.7−0.6, which agrees with the standard model prediction of 0.69 ± 0.04 at the 1.5 standard deviation level.SCOAP3

Search for electroweak production of charginos and neutralinos at s\sqrt{s} = 13 TeV in final states containing hadronic decays of WW, WZ, or WH and missing transverse momentum

Data availability: Release and preservation of data used by the CMS Collaboration as the basis for publications is guided by the CMS policy as stated in “CMS data preservation, re-use and open access policy”.A preprint version of this article is archived at: arXiv:2205.09597v2 [hep-ex], https://arxiv.org/abs/2205.09597v2 . Comments: Replaced with the published version. Added the journal reference. All the figures and tables, including additional supplementary figures and tables, can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/SUS-21-002 (CMS Public Pages). Report number: CMS-SUS-21-002, CERN-EP-2022-031This Letter presents a search for direct production of charginos and neutralinos via electroweak interactions. The results are based on data from proton-proton collisions at a center-of-mass energy of 13 TeV collected with the CMS detector at the LHC, corresponding to an integrated luminosity of 137 fb^{-1}. The search considers final states with large missing transverse momentum and pairs of hadronically decaying bosons WW, WZ, and WH, where H is the Higgs boson. These bosons are identified using novel algorithms. No significant excess of events is observed relative to the expectations from the standard model. Limits at the 95% confidence level are placed on the cross section for production of mass-degenerate wino-like supersymmetric particles χ~±1 and χ~02, and mass-degenerate higgsino-like supersymmetric particles χ~±1, χ~02, and χ~03. In the limit of a nearly-massless lightest supersymmetric particle χ~01, wino-like particles with masses up to 870 and 960 GeV are excluded in the cases of χ~02 → Zχ~01 and χ~02 → Hχ~01, respectively, and higgsino-like particles are excluded between 300 and 650 GeV.SCOAP3

Search for supersymmetry in final states with two or three soft leptons and missing transverse momentum in proton-proton collisions at root s=13 TeV

ArXiv ePrint: 2111.06296 (https://arxiv.org/abs/2111.06296).Copyright © 2022 CERN, for the benefit of the CMS Collaboration. A search for supersymmetry in events with two or three low-momentum leptons and missing transverse momentum is performed. The search uses proton-proton collisions at s√ = 13 TeV collected in the three-year period 2016–2018 by the CMS experiment at the LHC and corresponding to an integrated luminosity of up to 137 fb−1. The data are found to be in agreement with expectations from standard model processes. The results are interpreted in terms of electroweakino and top squark pair production with a small mass difference between the produced supersymmetric particles and the lightest neutralino. For the electroweakino interpretation, two simplified models are used, a wino-bino model and a higgsino model. Exclusion limits at 95% confidence level are set on χ∼02/χ∼±1 masses up to 275 GeV for a mass difference of 10 GeV in the wino-bino case, and up to 205(150) GeV for a mass difference of 7.5 (3) GeV in the higgsino case. The results for the higgsino are further interpreted using a phenomenological minimal supersymmetric standard model, excluding the higgsino mass parameter μ up to 180 GeV with the bino mass parameter M1 at 800 GeV. In the top squark interpretation, exclusion limits are set at top squark masses up to 540 GeV for four-body top squark decays and up to 480 GeV for chargino-mediated decays with a mass difference of 30 GeV.SCOAP3

Search for a massive scalar resonance decaying to a light scalar and a Higgs boson in the four b quarks final state with boosted topology

Data availability: Release and preservation of data used by the CMS Collaboration as the basis for publications is guided by the CMS policy as stated in “CMS data preservation, re-use and open access policy”.Copyright © 2022 The Author(s). We search for new massive scalar particles X and Y through the resonant process X → YH → bb¯bb¯,, where H is the standard model Higgs boson. Data from CERN LHC proton-proton collisions are used, collected at a centre-of-mass energy of 13 TeV in 2016–2018 and corresponding to an integrated luminosity of 138 fb−1. The search is performed in mass ranges of 0.9–4 TeV for X and 60–600 GeV for Y, where both Y and H are reconstructed as Lorentz-boosted single large-area jets. The results are interpreted in the context of the next-to-minimal supersymmetric standard model and also in an extension of the standard model with two additional singlet scalar fields. The 95% confidence level upper limits for the production cross section vary between 0.1 and 150 fb depending on the X and Y masses, and represent a significant improvement over results from previous searches.SCOAP3

A new calibration method for charm jet identification validated with proton-proton collision events at √s = 13 TeV

ArXiv ePrint: 2111.03027Copyright © 2022 CERN for the benefit of the CMS collaboration. Many measurements at the LHC require efficient identification of heavy-flavour jets, i.e. jets originating from bottom (b) or charm (c) quarks. An overview of the algorithms used to identify c jets is described and a novel method to calibrate them is presented. This new method adjusts the entire distributions of the outputs obtained when the algorithms are applied to jets of different flavours. It is based on an iterative approach exploiting three distinct control regions that are enriched with either b jets, c jets, or light-flavour and gluon jets. Results are presented in the form of correction factors evaluated using proton-proton collision data with an integrated luminosity of 41.5 fb-1 at  √s = 13 TeV, collected by the CMS experiment in 2017. The closure of the method is tested by applying the measured correction factors on simulated data sets and checking the agreement between the adjusted simulation and collision data. Furthermore, a validation is performed by testing the method on pseudodata, which emulate various mismodelling conditions. The calibrated results enable the use of the full distributions of heavy-flavour identification algorithm outputs, e.g. as inputs to machine-learning models. Thus, they are expected to increase the sensitivity of future physics analyses.SCOAP