Cytokinesis in bloodstream stage Trypanosoma brucei requires a family of katanins and spastin

Microtubule severing enzymes regulate microtubule dynamics in a wide range of organisms and are implicated in important cell cycle processes such as mitotic spindle assembly and disassembly, chromosome movement and cytokinesis. Here we explore the function of several microtubule severing enzyme homologues, the katanins (KAT80, KAT60a, KAT60b and KAT60c), spastin (SPA) and fidgetin (FID) in the bloodstream stage of the African trypanosome parasite, Trypanosoma brucei. The trypanosome cytoskeleton is microtubule based and remains assembled throughout the cell cycle, necessitating its remodelling during cytokinesis. Using RNA interference to deplete individual proteins, we show that the trypanosome katanin and spastin homologues are non-redundant and essential for bloodstream form proliferation. Further, cell cycle analysis revealed that these proteins play essential but discrete roles in cytokinesis. The KAT60 proteins each appear to be important during the early stages of cytokinesis, while downregulation of KAT80 specifically inhibited furrow ingression and SPA depletion prevented completion of abscission. In contrast, RNA interference of FID did not result in any discernible effects. We propose that the stable microtubule cytoskeleton of T. brucei necessitates the coordinated action of a family of katanins and spastin to bring about the cytoskeletal remodelling necessary to complete cell divisio

Omalizumab efficacy in cases of chronic spontaneous urticaria is not explained by the inhibition of sera activity in effector cells

Omalizumab (OmAb) is a humanized anti-IgE antibody approved for the treatment of chronic spontaneous urticaria (CSU). OmAb's mechanism of action is known to include actions on free IgE and on pre-bound IgE. However, OmAb is equally and rapidly effective against autoimmune and non-autoimmune urticaria where IgE involvement is not clear, suggesting the involvement of additional mechanisms of action. In this study, we sought to investigate the ability of OmAb to inhibit mast cell and basophil degranulation induced by sera from CSU patients. For this purpose, we performed a comparison between the in vitro incubation of sera from CSU patients treated with OmAb and the in vivo administration of OmAb in a clinical trial. We found that OmAb added in vitro to sera from CSU patients did not modify the ability of the sera to induce cell degranulation. Similarly, the sera from patients treated with OmAb in the context of the clinical trial who had a good clinical outcome maintained the capacity to activate mast cells and basophils. Thus, we conclude that the beneficial activity of OmAb does not correlate with the ability of patient sera to induce cell degranulation

Decreased Striatal RGS2 Expression Is Neuroprotective in Huntington's Disease (HD) and Exemplifies a Compensatory Aspect of HD-Induced Gene Regulation

The molecular phenotype of Huntington's disease (HD) is known to comprise highly reproducible changes in gene expression involving striatal signaling genes. Here we test whether individual changes in striatal gene expression are capable of mitigating HD-related neurotoxicity.We used protein-encoding and shRNA-expressing lentiviral vectors to evaluate the effects of RGS2, RASD2, STEP and NNAT downregulation in HD. Of these four genes, only RGS2 and RASD2 modified mutant htt fragment toxicity in cultured rat primary striatal neurons. In both cases, disease modulation was in the opposite of the predicted direction: whereas decreased expression of RGS2 and RASD2 was associated with the HD condition, restoring expression enhanced degeneration of striatal cells. Conversely, silencing of RGS2 or RASD2 enhanced disease-related changes in gene expression and resulted in significant neuroprotection. These results indicate that RGS2 and RASD2 downregulation comprises a compensatory response that allows neurons to better tolerate huntingtin toxicity. Assessment of the possible mechanism of RGS2-mediated neuroprotection showed that RGS2 downregulation enhanced ERK activation. These results establish a novel link between the inhibition of RGS2 and neuroprotective modulation of ERK activity.Our findings both identify RGS2 downregulation as a novel compensatory response in HD neurons and suggest that RGS2 inhibition might be considered as an innovative target for neuroprotective drug development

Evidence for Top Quark Production in Nucleus-Nucleus Collisions

Peer reviewe

Search for dark matter produced in association with a single top quark or a top quark pair in proton-proton collisions at s=13 TeV

A search has been performed for heavy resonances decaying to ZZ or ZW in 2l2q final states, with two charged leptons (l = e, mu) produced by the decay of a Z boson, and two quarks produced by the decay of a W or Z boson. The analysis is sensitive to resonances with masses in the range from 400 to 4500 GeV. Two categories are defined based on the merged or resolved reconstruction of the hadronically decaying vector boson, optimized for high- and low-mass resonances, respectively. The search is based on data collected during 2016 by the CMS experiment at the LHC in proton-proton collisions with a center-of-mass energy of root s = 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). No excess is observed in the data above the standard model background expectation. Upper limits on the production cross section of heavy, narrow spin-1 and spin-2 resonances are derived as a function of the resonance mass, and exclusion limits on the production of W' bosons and bulk graviton particles are calculated in the framework of the heavy vector triplet model and warped extra dimensions, respectively.A search has been performed for heavy resonances decaying to ZZ or ZW in 2l2q final states, with two charged leptons (l = e, mu) produced by the decay of a Z boson, and two quarks produced by the decay of a W or Z boson. The analysis is sensitive to resonances with masses in the range from 400 to 4500 GeV. Two categories are defined based on the merged or resolved reconstruction of the hadronically decaying vector boson, optimized for high- and low-mass resonances, respectively. The search is based on data collected during 2016 by the CMS experiment at the LHC in proton-proton collisions with a center-of-mass energy of root s = 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). No excess is observed in the data above the standard model background expectation. Upper limits on the production cross section of heavy, narrow spin-1 and spin-2 resonances are derived as a function of the resonance mass, and exclusion limits on the production of W' bosons and bulk graviton particles are calculated in the framework of the heavy vector triplet model and warped extra dimensions, respectively.A search for dark matter produced in association with top quarks in proton-proton collisions at a center-of-mass energy of 13 TeV is presented. The data set used corresponds to an integrated luminosity of 35.9 fb(-1) recorded with the CMS detector at the LHC. Whereas previous searches for neutral scalar or pseudoscalar mediators considered dark matter production in association with a top quark pair only, this analysis also includes production modes with a single top quark. The results are derived from the combination of multiple selection categories that are defined to target either the single top quark or the top quark pair signature. No significant deviations with respect to the standard model predictions are observed. The results are interpreted in the context of a simplified model in which a scalar or pseudoscalar mediator particle couples to a top quark and subsequently decays into dark matter particles. Scalar and pseudoscalar mediator particles with masses below 290 and 300 GeV, respectively, are excluded at 95% confidence level, assuming a dark matter particle mass of 1 GeV and mediator couplings to fermions and dark matter particles equal to unity.Peer reviewe

Search for an exotic decay of the Higgs boson to a pair of light pseudoscalars in the final state with two bquarks and two tau leptons in proton-proton collisions at root s=13 TeV The CMS Collaboration

A search for an exotic decay of the Higgs boson to a pair of light pseudoscalar bosons is performed for the first time in the final state with two b quarks and two tau leptons. The search is motivated in the context of models of physics beyond the standard model (SM), such as two Higgs doublet models extended with a complex scalar singlet (2HDM + S), which include the next-to-minimal supersymmetric SM (NMSSM). The results are based on a data set of proton-proton collisions corresponding to an integrated luminosity of 35.9 fb(-1), accumulated by the CMS experiment at the LHC in 2016 at a center-of-mass energy of 13 TeV. Masses of the pseudoscalar boson between 15 and 60 GeVare probed, and no excess of events above the SM expectation is observed. Upper limits between 3 and 12% are set on the branching fraction B(h -> aa -> 2 tau 2b) assuming the SM production of the Higgs boson. Upper limits are also set on the branching fraction of the Higgs boson to two light pseudoscalar bosons in different 2HDM + S scenarios. Assuming the SM production cross section for the Higgs boson, the upper limit on this quantity is as low as 20% for a mass of the pseudoscalar of 40 GeV in the NMSSM. (C) 2018 The Author(s). Published by Elsevier B.V.Peer reviewe

Search for strongly interacting massive particles generating trackless jets in proton-proton collisions at s = 13 TeV

A search for dark matter in the form of strongly interacting massive particles (SIMPs) using the CMS detector at the LHC is presented. The SIMPs would be produced in pairs that manifest themselves as pairs of jets without tracks. The energy fraction of jets carried by charged particles is used as a key discriminator to suppress efficiently the large multijet background, and the remaining background is estimated directly from data. The search is performed using proton-proton collision data corresponding to an integrated luminosity of 16.1 fb - 1 , collected with the CMS detector in 2016. No significant excess of events is observed above the expected background. For the simplified dark matter model under consideration, SIMPs with masses up to 100 GeV are excluded and further sensitivity is explored towards higher masses

Search for the pair production of light top squarks in the e(+/-)mu(-/+) final state in proton-proton collisions at root s=13 TeV

A search for the production of a pair of top squarks at the LHC is presented. This search targets a region of parameter space where the kinematics of top squark pair production and top quark pair production are very similar, because of the mass difference between the top squark and the neutralino being close to the top quark mass. The search is performed with 35.9 fb(-1) of proton-proton collisions at a centre-of-mass energy of root s = 13 TeV, collected by the CMS detector in 2016, using events containing one electron-muon pair with opposite charge. The search is based on a precise estimate of the top quark pair background, and the use of the M-T2 variable, which combines the transverse mass of each lepton and the missing transverse momentum. No excess of events is found over the standard model predictions. Exclusion limits are placed at 95% confidence level on the production of top squarks up to masses of 208 GeV for models with a mass difference between the top squark and the lightest neutralino close to that of the top quark.Peer reviewe

Observation of the B-s(0) -> X(3872)phi Decay

Using a data sample of proton-proton collisions at root s = 13 TeV, corresponding to an integrated luminosity of 140 fb(-1) collected by the CMS experiment in 2016-2018, the B-s(0) -> X(3872)phi decay is observed. Decays into J/psi pi(+)pi(-) and K+K- are used to reconstruct, respectively, the X(3872) and phi. The ratio of the product of branching fractions B[B-s(0) -> X(3872)phi]B[X(3872) -> J/psi pi(+)pi(-)] to the product B[B-s(0) ->psi(2S)phi]B[psi(2S) -> J/psi pi(+)pi(-)] is measured to be [2.21 +/- 0.29(stat) +/- 0.17(syst)]%. The ratio B[B-s(0) -> X(3872)phi]/B[B-0 -> X(3872)K-0] is found to be consistent with one, while the ratio B[B-s(0) -> X(3872)phi]/B[B+-> X(3872)K+] is two times smaller. This suggests a difference in the production dynamics of the X(3872) in B-0 and B(0)s meson decays compared to B+. The reported observation may shed new light on the nature of the X(3872) particle.Peer reviewe