Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma

Multiple myeloma (MM), an incurable plasma cell malignancy, requires localisation within the bone marrow. This microenvironment facilitates crucial interactions between the cancer cells and stromal cell types that permit the tumour to survival and proliferate. There is increasing evidence that the bone marrow mesenchymal stem cell (BMMSC) is stably altered in patients with MM – a phenotype also postulated to exist in patients with monoclonal gammopathy of undetermined significance (MGUS) a benign condition that precedes MM. In this study, we describe a mechanism by which increased expression of peptidyl arginine deiminase 2 (PADI2) by BMMSCs in patients with MGUS and MM directly alters malignant plasma cell phenotype. We identify PADI2 as one of the most highly upregulated transcripts in BMMSCs from both MGUS and MM patients, and that through its enzymatic deimination of histone H3 arginine 26, PADI2 activity directly induces the upregulation of interleukin-6 (IL-6) expression. This leads to the acquisition of resistance to the chemotherapeutic agent, bortezomib, by malignant plasma cells. We therefore describe a novel mechanism by which BMMSC dysfunction in patients with MGUS and MM directly leads to pro-malignancy signalling through the citrullination of histone H3R26

Estimating trace deposition time with circadian biomarkers: a prospective and versatile tool for crime scene reconstruction

Linking biological samples found at a crime scene with the actual crime event represents the most important aspect of forensic investigation, together with the identification of the sample donor. While DNA profiling is well established for donor identification, no reliable methods exist for timing forensic samples. Here, we provide for the first time a biochemical approach for determining deposition time of human traces. Using commercial enzyme-linked immunosorbent assays we showed that the characteristic 24-h profiles of two circadian hormones, melatonin (concentration peak at late night) and cortisol (peak in the morning) can be reproduced from small samples of whole blood and saliva. We further demonstrated by analyzing small stains dried and stored up to 4 weeks the in vitro stability of melatonin, whereas for cortisol a statistically significant decay with storage time was observed, although the hormone was still reliably detectable in 4-week-old samples. Finally, we showed that the total protein concentration, also assessed using a commercial assay, can be used for normalization of hormone signals in blood, but less so in saliva. Our data thus demonstrate that estimating normalized concentrations of melatonin and cortisol represents a prospective approach for determining deposition time of biological trace samples, at least from blood, with promising expectations for forensic applications. In the broader context, our study opens up a new field of circadian biomarkers for deposition timing of forensic traces; future studies using other circadian biomarkers may reveal if the time range offered by the two hormones studied here can be specified more exactly

Measurement of melatonin in body fluids: Standards, protocols and procedures

Abstract: The circadian rhythm of melatonin in saliva or plasma, or of the melatonin metabolite 6‐ sulphatoxymelatonin in urine, is a defining feature of suprachiasmatic nucleus function, the endogenous oscillatory pacemaker. These measurements are useful to evaluate problems related to the onset or offset of sleep and for assessing phase delays or advances of rhythms in entrained individuals. Additionally, they have become an important tool for psychiatric diagnosis, its use being recommended for phase typing in patients suffering from sleep and mood disorders. Thus, the development of sensitive and selective methods for the precise detection of melatonin in tissues and fluids of animals emerges as necessary. Due to its low concentration and the co‐existence of many other endogenous compounds in blood, the determination of melatonin has been an analytical challenge. This review discusses current methodologies employed for detection and quantification of melatonin in biological fluids and tissues

Observation of the Bc+_\mathrm{c}^+ Meson in Pb-Pb and pp Collisions at sNN\sqrt{s_{\mathrm{NN}}} = 5.02 TeV and Measurement of its Nuclear Modification Factor

The B$_\mathrm{c}^+$ meson is observed for the first time in heavy ion collisions. Data from the CMS detector are used to study the production of the B$_\mathrm{c}^+$ meson in lead-lead (Pb-Pb) and proton-proton (pp) collisions at a center-of-mass energy per nucleon pair of $\sqrt{s_{\mathrm{NN}}}$ = 5.02 TeV , via the B$_\mathrm{c}^+$ → (J/ψ → μ$^+$μ$^−$)μ$^+$ν$_μ$ decay. The B$_\mathrm{c}^+$ nuclear modification factor, derived from the PbPb-to-pp ratio of production cross sections, is measured in two bins of the trimuon transverse momentum and of the PbPb collision centrality. The B$_\mathrm{c}^+$meson is shown to be less suppressed than quarkonia and most of the open heavy-flavor mesons, suggesting that effects of the hot and dense nuclear matter created in heavy ion collisions contribute to its production. This measurement sets forth a promising new probe of the interplay of suppression and enhancement mechanisms in the production of heavy-flavor mesons in the quark-gluon plasma

Search for invisible decays of the Higgs boson produced via vector boson fusion in proton-proton collisions at s\sqrt{s} = 13 TeV

A search for invisible decays of the Higgs boson produced via vector boson fusion (VBF) has been performed with 101  fb$^{-1}$ of proton-proton collisions delivered by the LHC at $\sqrt{s}$ =13  TeV and collected by the CMS detector in 2017 and 2018. The sensitivity to the VBF production mechanism is enhanced by constructing two analysis categories, one based on missing transverse momentum and a second based on the properties of jets. In addition to control regions with Z and W boson candidate events, a highly populated control region, based on the production of a photon in association with jets, is used to constrain the dominant irreducible background from the invisible decay of a Z boson produced in association with jets. The results of this search are combined with all previous measurements in the VBF topology, based on data collected in 2012 (at $\sqrt{s}$ =8  TeV), 2015, and 2016, corresponding to integrated luminosities of 19.7, 2.3, and 36.3  fb$^{-1}$, respectively. The observed (expected) upper limit on the invisible branching fraction of the Higgs boson is found to be 0.18 (0.10) at the 95% confidence level, assuming the standard model production cross section. The results are also interpreted in the context of Higgs-portal models

Search for flavor-changing neutral current interactions of the top quark and the Higgs boson decaying to a bottom quark-antiquark pair at s√ = 13 TeV

A search for flavor-changing neutral current interactions of the top quark (t) and the Higgs boson (H) is presented. The search is based on a data sample corresponding to an integrated luminosity of 137 fb−1 recorded by the CMS experiment at the LHC in proton-proton collisions at s√ = 13 TeV. Events containing exactly one lepton (muon or electron) and at least three jets, among which at least two are identified as originating from the hadronization of a bottom quark, are analyzed. A set of deep neural networks is used for kinematic event reconstruction, while boosted decision trees distinguish the signal from the background events. No significant excess over the background predictions is observed, and upper limits on the signal production cross sections are extracted. These limits are interpreted in terms of top quark decay branching fractions (B ) to the Higgs boson and an up (u) or a charm quark (c). Assuming one nonvanishing extra coupling at a time, the observed (expected) upper limits at 95% confidence level are B (t → Hu) < 0.079 (0.11)% and B (t → Hc) < 0.094 (0.086)%

Search for long-lived particles produced in association with a Z boson in proton-proton collisions at s \sqrt{s} = 13 TeV

A search for long-lived particles (LLPs) produced in association with a Z boson is presented. The study is performed using data from proton-proton collisions with a center-of-mass energy of 13 TeV recorded by the CMS experiment during 2016–2018, corresponding to an integrated luminosity of 117 fb−1. The LLPs are assumed to decay to a pair of standard model quarks that are identified as displaced jets within the CMS tracker system. Triggers and selections based on Z boson decays to electron or muon pairs improve the sensitivity to light LLPs (down to 15 GeV). This search provides sensitivity to beyond the standard model scenarios which predict LLPs produced in association with a Z boson. In particular, the results are interpreted in the context of exotic decays of the Higgs boson to a pair of scalar LLPs (H → SS). The Higgs boson decay branching fraction is constrained to values less than 6% for proper decay lengths of 10–100 mm and for LLP masses between 40 and 55 GeV. In the case of low-mass (≈ 15 GeV) scalar particles that subsequently decay to a pair of b quarks, the search is sensitive to branching fractions B(H → SS) < 20% for proper decay lengths of 10–50 mm. The use of associated production with a Z boson increases the sensitivity to low-mass LLPs of this analysis with respect to gluon fusion searches. In the case of 15 GeV scalar LLPs, the improvement corresponds to a factor of 2 at a proper decay length of 30 mm

Search for a right-handed W boson and a heavy neutrino in proton-proton collisions at s \sqrt{s} = 13 TeV

A search is presented for a right-handed W boson (WR) and a heavy neutrino (N), in a final state consisting of two same-flavor leptons (ee or μμ) and two quarks. The search is performed with the CMS experiment at the CERN LHC using a data sample of proton-proton collisions at a center-of-mass energy of 13 TeV corresponding to an integrated luminosity of 138 fb−1. The search covers two regions of phase space, one where the decay products of the heavy neutrino are merged into a single large-area jet, and one where the decay products are well separated. The expected signal is characterized by an excess in the invariant mass distribution of the final-state objects. No significant excess over the standard model background expectations is observed. The observations are interpreted as upper limits on the product of WR production cross sections and branching fractions assuming that couplings are identical to those of the standard model W boson. For N masses mN equal to half the WR mass mWR (mN = 0.2 TeV), mWR is excluded at 95% confidence level up to 4.7 (4.8) and 5.0 (5.4) TeV for the electron and muon channels, respectively. This analysis provides the most stringent limits on the WR mass to date