242 research outputs found
Cholesterol-modifying drugs in COVID-19
Infection with severe acute respiratory syndrom coronavirus 2 (SARS-CoV-2) is more likely to lead to poor outcomes in the elderly and those with cardiovascular disease, obesity or metabolic syndrome. Here, we consider mechanisms by which dyslipidaemia and the use of cholesterol-modifying drugs could influence the virus–host relationship. Cholesterol is essential for the assembly, replication and infectivity of enveloped virus particles; we highlight several cholesterol-modifying drugs with the potential to alter the SARS-CoV-2 life cycle that could be tested in in vitro and in vivo models. Although cholesterol is an essential component of immune cell membranes, excess levels can dysregulate protective immunity and promote exaggerated pulmonary and systemic inflammatory responses. Statins block the production of multiple sterols, oxysterols and isoprenoids, resulting in a pleiotropic range of context-dependent effects on virus infectivity, immunity and inflammation. We highlight antiviral, immunomodulatory and anti-inflammatory effects of cholesterol-modifying drugs that merit further consideration in the management of SARS-CoV-2 infection
Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint
Determining divergent metabolic requirements of T cells, and the viruses and tumours they fail to combat, could provide new therapeutic checkpoints. Inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) has direct anti-carcinogenic activity. Here, we show that ACAT inhibition has antiviral activity against hepatitis B (HBV), as well as boosting protective anti-HBV and anti-hepatocellular carcinoma (HCC) T cells. ACAT inhibition reduces CD8+ T cell neutral lipid droplets and promotes lipid microdomains, enhancing TCR signalling and TCR-independent bioenergetics. Dysfunctional HBV- and HCC-specific T cells are rescued by ACAT inhibitors directly ex vivo from human liver and tumour tissue respectively, including tissue-resident responses. ACAT inhibition enhances in vitro responsiveness of HBV-specific CD8+ T cells to PD-1 blockade and increases the functional avidity of TCR-gene-modified T cells. Finally, ACAT regulates HBV particle genesis in vitro, with inhibitors reducing both virions and subviral particles. Thus, ACAT inhibition provides a paradigm of a metabolic checkpoint able to constrain tumours and viruses but rescue exhausted T cells, rendering it an attractive therapeutic target for the functional cure of HBV and HBV-related HCC
Jet production in charged current deep inelastic e⁺p scatteringat HERA
The production rates and substructure of jets have been studied in charged current deep inelastic e⁺p scattering for Q² > 200 GeV² with the ZEUS detector at HERA using an integrated luminosity of 110.5 pb⁻¹. Inclusive jet cross sections are presented for jets with transverse energies E_{T}^{jet} > 5 GeV. Measurements of the mean subjet multiplicity, 〈n_{sbj}〉, of the inclusive jet sample are presented. Predictions based on parton-shower Monte Carlo models and next-to-leading-order QCD calculations are compared to the measurements. The value of α_{s} (M_{z}), determined from 〈n_{sbj}〉 at y_{cut} = 10⁻² for jets with 25 < E_{T}^{jet} < 119 GeV, is α_{s} (M_{z}) = 0.1202 ± 0.0052 (stat.)_{-0.0019}^{+0.0060} (syst.)_{-0.0053}^{+0.0065} (th.). The mean subjet multiplicity as a function of Q² is found to be consistent with that measured in NC DIS
Search for lepton-flavor violation at HERA
A search for lepton-flavor-violating interactions and has been performed with the ZEUS detector using the entire HERA I
data sample, corresponding to an integrated luminosity of 130 pb^{-1}. The data
were taken at center-of-mass energies, , of 300 and 318 GeV. No
evidence of lepton-flavor violation was found, and constraints were derived on
leptoquarks (LQs) that could mediate such interactions. For LQ masses below
, limits were set on , where
is the coupling of the LQ to an electron and a
first-generation quark , and is the branching ratio of
the LQ to the final-state lepton ( or ) and a quark . For
LQ masses much larger than , limits were set on the four-fermion
interaction term for LQs that couple to an electron and a quark
and to a lepton and a quark , where and are
quark generation indices. Some of the limits are also applicable to
lepton-flavor-violating processes mediated by squarks in -Parity-violating
supersymmetric models. In some cases, especially when a higher-generation quark
is involved and for the process , the ZEUS limits are the most
stringent to date.Comment: 37 pages, 10 figures, Accepted by EPJC. References and 1 figure (Fig.
6) adde
The dependence of dijet production on photon virtuality in ep collisions at HERA
The dependence of dijet production on the virtuality of the exchanged photon,
Q^2, has been studied by measuring dijet cross sections in the range 0 < Q^2 <
2000 GeV^2 with the ZEUS detector at HERA using an integrated luminosity of
38.6 pb^-1.
Dijet cross sections were measured for jets with transverse energy E_T^jet >
7.5 and 6.5 GeV and pseudorapidities in the photon-proton centre-of-mass frame
in the range -3 < eta^jet <0. The variable xg^obs, a measure of the photon
momentum entering the hard process, was used to enhance the sensitivity of the
measurement to the photon structure. The Q^2 dependence of the ratio of low- to
high-xg^obs events was measured.
Next-to-leading-order QCD predictions were found to generally underestimate
the low-xg^obs contribution relative to that at high xg^obs. Monte Carlo models
based on leading-logarithmic parton-showers, using a partonic structure for the
photon which falls smoothly with increasing Q^2, provide a qualitative
description of the data.Comment: 35 pages, 6 eps figures, submitted to Eur.Phys.J.
Multijet production in neutral current deep inelastic scattering at HERA and determination of alpha_s
Multijet production rates in neutral current deep inelastic scattering have
been measured in the range of exchanged boson virtualities 10 < Q2 < 5000 GeV2.
The data were taken at the ep collider HERA with centre-of-mass energy sqrt(s)
= 318 GeV using the ZEUS detector and correspond to an integrated luminosity of
82.2 pb-1. Jets were identified in the Breit frame using the k_T cluster
algorithm in the longitudinally invariant inclusive mode. Measurements of
differential dijet and trijet cross sections are presented as functions of jet
transverse energy E_{T,B}{jet}, pseudorapidity eta_{LAB}{jet} and Q2 with
E_{T,B}{jet} > 5 GeV and -1 < eta_{LAB}{jet} < 2.5. Next-to-leading-order QCD
calculations describe the data well. The value of the strong coupling constant
alpha_s(M_Z), determined from the ratio of the trijet to dijet cross sections,
is alpha_s(M_Z) = 0.1179 pm 0.0013(stat.) {+0.0028}_{-0.0046}(exp.)
{+0.0064}_{-0.0046}(th.)Comment: 22 pages, 5 figure
Beauty photoproduction measured using decays into muons in dijet events in ep collisions at =318 GeV
The photoproduction of beauty quarks in events with two jets and a muon has
been measured with the ZEUS detector at HERA using an integrated luminosity of
110 pb. The fraction of jets containing b quarks was extracted from the
transverse momentum distribution of the muon relative to the closest jet.
Differential cross sections for beauty production as a function of the
transverse momentum and pseudorapidity of the muon, of the associated jet and
of , the fraction of the photon's momentum participating in
the hard process, are compared with MC models and QCD predictions made at
next-to-leading order. The latter give a good description of the data.Comment: 32 pages, 6 tables, 7 figures Table 6 and Figure 7 revised September
200
Photoproduction of mesons associated with a leading neutron
The photoproduction of mesons associated with a leading
neutron has been observed with the ZEUS detector in collisions at HERA
using an integrated luminosity of 80 pb. The neutron carries a large
fraction, {}, of the incoming proton beam energy and is detected at
very small production angles, { mrad}, an indication of
peripheral scattering. The meson is centrally produced with
pseudorapidity {
GeV}, which is large compared to the average transverse momentum of the neutron
of 0.22 GeV. The ratio of neutron-tagged to inclusive production is
in the photon-proton
center-of-mass energy range { GeV}. The data suggest that the
presence of a hard scale enhances the fraction of events with a leading neutron
in the final state.Comment: 28 pages, 4 figures, 2 table
Measurement of the open-charm contribution to the diffractive proton structure function
Production of D*+/-(2010) mesons in diffractive deep inelastic scattering has
been measured with the ZEUS detector at HERA using an integrated luminosity of
82 pb^{-1}. Diffractive events were identified by the presence of a large
rapidity gap in the final state. Differential cross sections have been measured
in the kinematic region 1.5 < Q^2 < 200 GeV^2, 0.02 < y < 0.7, x_{IP} < 0.035,
beta 1.5 GeV and |\eta(D*+/-)| < 1.5. The measured cross
sections are compared to theoretical predictions. The results are presented in
terms of the open-charm contribution to the diffractive proton structure
function. The data demonstrate a strong sensitivity to the diffractive parton
densities.Comment: 35 pages, 11 figures, 6 table
Measurement of beauty production in deep inelastic scattering at HERA
The beauty production cross section for deep inelastic scattering events with
at least one hard jet in the Breit frame together with a muon has been
measured, for photon virtualities Q^2 > 2 GeV^2, with the ZEUS detector at HERA
using integrated luminosity of 72 pb^-1. The total visible cross section is
sigma_b-bbar (ep -> e jet mu X) = 40.9 +- 5.7 (stat.) +6.0 -4.4 (syst.) pb. The
next-to-leading order QCD prediction lies about 2.5 standard deviations below
the data. The differential cross sections are in general consistent with the
NLO QCD predictions; however at low values of Q^2, Bjorken x, and muon
transverse momentum, and high values of jet transverse energy and muon
pseudorapidity, the prediction is about two standard deviations below the data.Comment: 18 pages, 4 figure
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