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Artemisinins have revolutionized the treatment ofPlasmodium falciparummalaria; however, resistance threatens to undermine global control efforts. To broadly explore artemisinin susceptibility in apicomplexan parasites, we employ genome-scale CRISPR screens recently developed forToxoplasma gondiito discover sensitizing and desensitizing mutations. Using a sublethal concentration of dihydroartemisinin (DHA), we uncover the putative transporter Tmem14c whose disruption increases DHA susceptibility. Screens performed under high doses of DHA provide evidence that mitochondrial metabolism can modulate resistance. We show that disrupting a top candidate from the screens, the mitochondrial protease DegP2, lowers porphyrin levels and decreases DHA susceptibility, without significantly altering parasite fitness in culture. Deletingmore »the homologous gene inP. falciparum, PfDegP, similarly lowers heme levels and DHA susceptibility. These results expose the vulnerability of heme metabolism to genetic perturbations that can lead to increased survival in the presence of DHA.

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A bstract A search is presented for new particles produced at the LHC in proton-proton collisions at $$ \sqrt{s} $$ s = 13 TeV, using events with energetic jets and large missing transverse momentum. The analysis is based on a data sample corresponding to an integrated luminosity of 101 fb − 1 , collected in 2017–2018 with the CMS detector. Machine learning techniques are used to define separate categories for events with narrow jets from initial-state radiation and events with large-radius jets consistent with a hadronic decay of a W or Z boson. A statistical combination is made with anmore »earlier search based on a data sample of 36 fb − 1 , collected in 2016. No significant excess of events is observed with respect to the standard model background expectation determined from control samples in data. The results are interpreted in terms of limits on the branching fraction of an invisible decay of the Higgs boson, as well as constraints on simplified models of dark matter, on first-generation scalar leptoquarks decaying to quarks and neutrinos, and on models with large extra dimensions. Several of the new limits, specifically for spin-1 dark matter mediators, pseudoscalar mediators, colored mediators, and leptoquarks, are the most restrictive to date.« less

Abstract Production cross sections of the Higgs boson are measured in the $${\mathrm{H}} \rightarrow {\mathrm{Z}} {\mathrm{Z}} \rightarrow 4\ell $$ H → Z Z → 4 ℓ ( $$\ell ={\mathrm{e}},{{{\upmu }}_{\mathrm{}}^{\mathrm{}}} $$ ℓ = e , μ ) decay channel. A data sample of proton–proton collisions at a center-of-mass energy of 13 $$\,\text {Te}\text {V}$$ Te , collected by the CMS detector at the LHC and corresponding to an integrated luminosity of 137 $$\,\text {fb}^{-1}$$ fb - 1 is used. The signal strength modifier $$\mu $$ μ , defined as the ratio of the Higgs boson production rate in the $$4\ellmore »$$ 4 ℓ channel to the standard model (SM) expectation, is measured to be $$\mu =0.94 \pm 0.07 \,\text {(stat)} ^{+0.09}_{-0.08} \,\text {(syst)} $$ μ = 0.94 ± 0.07 (stat) - 0.08 + 0.09 (syst) at a fixed value of $$m_{{\mathrm{H}}} = 125.38\,\text {Ge}\text {V} $$ m H = 125.38 Ge . The signal strength modifiers for the individual Higgs boson production modes are also reported. The inclusive fiducial cross section for the $${\mathrm{H}} \rightarrow 4\ell $$ H → 4 ℓ process is measured to be $$2.84^{+0.23}_{-0.22} \,\text {(stat)} ^{+0.26}_{-0.21} \,\text {(syst)} \,\text {fb} $$ 2 . 84 - 0.22 + 0.23 (stat) - 0.21 + 0.26 (syst) fb , which is compatible with the SM prediction of $$2.84 \pm 0.15 \,\text {fb} $$ 2.84 ± 0.15 fb for the same fiducial region. Differential cross sections as a function of the transverse momentum and rapidity of the Higgs boson, the number of associated jets, and the transverse momentum of the leading associated jet are measured. A new set of cross section measurements in mutually exclusive categories targeted to identify production mechanisms and kinematical features of the events is presented. The results are in agreement with the SM predictions.« less

A bstract Jet production in lead-lead (PbPb) and proton-proton (pp) collisions at a nucleon-nucleon center-of-mass energy of 5.02 TeV is studied with the CMS detector at the LHC, using PbPb and pp data samples corresponding to integrated luminosities of 404 μ b − 1 and 27.4 pb − 1 , respectively. Jets with different areas are reconstructed using the anti- k T algorithm by varying the distance parameter R . The measurements are performed using jets with transverse momenta ( p T ) greater than 200 GeV and in a pseudorapidity range of |η| < 2. To reveal the mediummore »modification of the jet spectra in PbPb collisions, the properly normalized ratio of spectra from PbPb and pp data is used to extract jet nuclear modification factors as functions of the PbPb collision centrality, p T and, for the first time, as a function of R up to 1.0. For the most central collisions, a strong suppression is observed for high- p T jets reconstructed with all distance parameters, implying that a significant amount of jet energy is scattered to large angles. The dependence of jet suppression on R is expected to be sensitive to both the jet energy loss mechanism and the medium response, and so the data are compared to several modern event generators and analytic calculations. The models considered do not fully reproduce the data.« less