RETRACTED ARTICLE: Age-dependent Increase in Desmosterol Restores DRM Formation and Membrane-related Functions in Cholesterol-free DHCR24−/− Mice

Cholesterol is a prominent modulator of the integrity and functional activity of physiological membranes and the most abundant sterol in the mammalian brain. DHCR24-knock-out mice lack cholesterol and accumulate desmosterol with age. Here we demonstrate that brain cholesterol deficiency in 3-week-old DHCR24−/− mice was associated with altered membrane composition including disrupted detergent-resistant membrane domain (DRM) structure. Furthermore, membrane-related functions differed extensively in the brains of these mice, resulting in lower plasmin activity, decreased β-secretase activity and diminished Aβ generation. Age-dependent accumulation and integration of desmosterol in brain membranes of 16-week-old DHCR24−/− mice led to the formation of desmosterol-containing DRMs and rescued the observed membrane-related functional deficits. Our data provide evidence that an alternate sterol, desmosterol, can facilitate processes that are normally cholesterol-dependent including formation of DRMs from mouse brain extracts, membrane receptor ligand binding and activation, and regulation of membrane protein proteolytic activity. These data indicate that desmosterol can replace cholesterol in membrane-related functions in the DHCR24−/− mouse

Measurements of Higgs boson production cross sections and couplings in the diphoton decay channel at root s=13 TeV

Measurements of Higgs boson production cross sections and couplings in events where the Higgs boson decays into a pair of photons are reported. Events are selected from a sample of proton-proton collisions at root s = 13TeV collected by the CMS detector at the LHC from 2016 to 2018, corresponding to an integrated luminosity of 137 fb(-1). Analysis categories enriched in Higgs boson events produced via gluon fusion, vector boson fusion, vector boson associated production, and production associated with top quarks are constructed. The total Higgs boson signal strength, relative to the standard model (SM) prediction, is measured to be 1.12 +/- 0.09. Other properties of the Higgs boson are measured, including SM signal strength modifiers, production cross sections, and its couplings to other particles. These include the most precise measurements of gluon fusion and vector boson fusion Higgs boson production in several different kinematic regions, the first measurement of Higgs boson production in association with a top quark pair in five regions of the Higgs boson transverse momentum, and an upper limit on the rate of Higgs boson production in association with a single top quark. All results are found to be in agreement with the SM expectations.Peer reviewe

Measurements of the Electroweak Diboson Production Cross Sections in Proton-Proton Collisions at root s=5.02 TeV Using Leptonic Decays

The first measurements of diboson production cross sections in proton-proton interactions at a center-of-mass energy of 5.02 TeV are reported. They are based on data collected with the CMS detector at the LHC, corresponding to an integrated luminosity of 302 pb(-1). Events with two, three, or four charged light leptons (electrons or muons) in the final state are analyzed. The WW, WZ, and ZZ total cross sections are measured as sigma(WW) = 37:0(-5.2)(+5.5) (stat)(-2.6)(+2.7) (syst) pb, sigma(WZ) = 6.4(-2.1)(+2.5) (stat)(-0.3)(+0.5)(syst) pb, and sigma(ZZ) = 5.3(-2.1)(+2.5)(stat)(-0.4)(+0.5) (syst) pb. All measurements are in good agreement with theoretical calculations at combined next-to-next-to-leading order quantum chromodynamics and next-to-leading order electroweak accuracy

Search for lepton-flavor violating decays of the Higgs boson in the mu tau and e tau final states in proton-proton collisions at root s=13 TeV

A search is presented for lepton-flavor violating decays of the Higgs boson to mu t and et. The dataset corresponds to an integrated luminosity of 137 fb(-1) collected at the LHC in proton-proton collisions at a center-of-mass energy of 13 TeV. No significant excess has been found, and the results are interpreted in terms of upper limits on lepton-flavor violating branching fractions of the Higgs boson. The observed (expected) upper limits on the branching fractions are, respectively, B(H -> mu t) e tau) < 0.22(0.16)% at 95% confidence level.Peer reviewe

Search for a heavy Higgs boson decaying into two lighter Higgs bosons in the tau tau bb final state at 13 TeV

A search for a heavy Higgs boson H decaying into the observed Higgs boson h with a mass of 125 GeV and another Higgs boson h(S) is presented. The h and h(S) bosons are required to decay into a pair of tau leptons and a pair of b quarks, respectively. The search uses a sample of proton-proton collisions collected with the CMS detector at a center-of-mass energy of 13TeV, corresponding to an integrated luminosity of 137 fb(-1). Mass ranges of 240-3000 GeV for m(H) and 60-2800 GeV for m(hS) are explored in the search. No signal has been observed. Model independent 95% confidence level upper limits on the product of the production cross section and the branching fractions of the signal process are set with a sensitivity ranging from 125 fb (for m(H) = 240 GeV) to 2.7 fb (for m(H) = 1000 GeV). These limits are compared to maximally allowed products of the production cross section and the branching fractions of the signal process in the next-to-minimal supersymmetric extension of the standard model.Peer reviewe

Innate immunity regulates adaptive immune response: lessons learned from studying the interplay between NK and CD8+ T cells during MCMV infection

Natural killer (NK) cells play a crucial role in early immune response against cytomegalovirus infection. A large and mounting body of data indicate that these cells are involved in the regulation of the adaptive immune response as well. By using mouse cytomegalovirus (MCMV) as a model, several groups provided novel insights into the role of NK cells in the development and kinetics of antiviral CD8+ T cell response. Depending on infection conditions, virus strain and the genetic background of mice used, NK cells are either positive or negative regulators of the CD8+ T cell response. At present, there is no unique explanation for the observed differences between various experimental systems used. In this review we discuss the mechanisms involved in the interplay between NK and CD8+ T cells in the early control of MCMV infection

Human Epididymis Protein 4: A Novel Serum Inflammatory Biomarker in Cystic Fibrosis.

BACKGROUND: Increased expression of the human epididymis protein 4 (HE4) was previouslydescribed in lung biopsy samples from patients with cystic fibrosis (CF). It remains unknown,however, whether serum HE4 concentrations are elevated in CF.METHODS: Seventy-seven children with CF from six Hungarian CF centers and 57 adult patientswith CF from a Czech center were enrolled. In addition, 94 individuals with non-CF lung diseasesand 117 normal control subjects with no pulmonary disorders were analyzed. Serum HE4 levelswere measured by using an immunoassay, and their expression was further investigated via thequantification of HE4messengerRNAby using quantitative reverse transcription polymerase chainreaction in CF vs non-CF respiratory epithelium biopsy specimens. The expression of the potentialregulator miR-140-5p was analyzed by using an UPL-based quantitative reverse transcription polymerasechain reaction assay. HE4 was measured in the supernatants from unpolarized andpolarized cystic fibrosis bronchial epithelial cells expressing wild-type or F508del-CFTR.RESULTS: Median serum HE4 levels were significantly elevated in children with CF (99.5[73.1-128.9] pmol/L) compared with control subjects (36.3 [31.1-43.4] pmol/L; P<.0001). Thisobservation was replicated in adults with CF (115.7 [77.8-148.7] pmol/L; P<.0001). In contrast,abnormal but lower HE4 concentrations were found in cases of severe bronchitis, asthma,pneumonia, and bronchiectasis. In patients with CF, the concentrations of HE4 were positivelycorrelated with overall disease severity and C-reactive protein concentrations, whereas a significantinverse relationship was found between HE4 and the spirometric FEV1 value. RelativeHE4 mRNA levels were significantly upregulated (P ¼ .011) with a decreased miR-140-5pexpression (P ¼ .020) in the CF vs non-CF airway biopsy specimens. Twofold higher HE4concentrations were recorded in the supernatant of polarized F508del-CF transmembraneconductance regulator/bronchial epithelial cells compared with wild-type cells.CONCLUSIONS: HE4 serum levels positively correlate with the overall severity of CF and thedegree of pulmonary dysfunction. HE4 may thus be used as a novel inflammatory biomarkerand possibly also as a measure of treatment efficacy in CF lung disease

Original Paper Evaluating Structural Change in a Reference Terminology

Background: Clinical terminologies, like the domains they model, may change over time. Existing methods for identifying and characterizing terminology change, address individual concepts and their interrelationships rather than the overall structure of the terminology. Exposing high level terminology structure may improve developers ’ and users ’ ability to identify changes occurring over time. Objectives: To describe and demonstrate novel structural attributes for terminologies. Methods: We measured novel structural attributes of four successive versions of the National Drug File Reference Terminology Physiologic Effects hierarchy. Attributes included measures for overall size, dimension (ie, width, height, mass, depth), complexity (i.e., node recurrence, leafiness, branchiness) and balance (i.e., skew, variation, smoothness). Results: Among the four versions, the terminology size increased from 711 to 1638 concepts, increased in complexity, but did not improve in terms of symmetry. Conclusions: Visualizing and characterizing the structure of successive terminology versions revealed how the terminology changed at a high level, and where it may have been relatively over specified to meet modeling- or use-based needs