Cholesterol 25-hydroxylase (CH25H) is an interferon (IFN)-stimulated gene that shows broad antiviral activities against a wide range of enveloped viruses. Here, using an IFN-stimulated gene screen ...against vesicular stomatitis virus (VSV)-SARS-CoV and VSV-SARS-CoV-2 chimeric viruses, we identified CH25H and its enzymatic product 25-hydroxycholesterol (25HC) as potent inhibitors of SARS-CoV-2 replication. Internalized 25HC accumulates in the late endosomes and potentially restricts SARS-CoV-2 spike protein catalyzed membrane fusion via blockade of cholesterol export. Our results highlight one of the possible antiviral mechanisms of 25HC and provide the molecular basis for its therapeutic development.
SARS-CoV-2 requires acidic pH to infect cells Kreutzberger, Alex J. B.; Sanyal, Anwesha; Saminathan, Anand ...
Proceedings of the National Academy of Sciences - PNAS,
09/2022, Letnik:
119, Številka:
38
Journal Article
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry starts with membrane attachment and ends with spike (S) protein–catalyzed membrane fusion depending on two cleavage steps, ...namely, one usually by furin in producing cells and the second by TMPRSS2 on target cells. Endosomal cathepsins can carry out both. Using real-time three-dimensional single-virion tracking, we show that fusion and genome penetration require virion exposure to an acidic milieu of pH 6.2 to 6.8, even when furin and TMPRSS2 cleavages have occurred. We detect the sequential steps of S1-fragment dissociation, fusion, and content release from the cell surface in TMPRRS2-overexpressing cells only when exposed to acidic pH. We define a key role of an acidic environment for successful infection, found in endosomal compartments and at the surface of TMPRSS2-expressing cells in the acidic milieu of the nasal cavity.
We report a quasidifferential upper limit on the extremely-high-energy (EHE) neutrino flux above 5×106 GeV based on an analysis of nine years of IceCube data. The astrophysical neutrino flux ...measured by IceCube extends to PeV energies, and it is a background flux when searching for an independent signal flux at higher energies, such as the cosmogenic neutrino signal. We have developed a new method to place robust limits on the EHE neutrino flux in the presence of an astrophysical background, whose spectrum has yet to be understood with high precision at PeV energies. A distinct event with a deposited energy above 106 GeV was found in the new two-year sample, in addition to the one event previously found in the seven-year EHE neutrino search. These two events represent a neutrino flux that is incompatible with predictions for a cosmogenic neutrino flux and are considered to be an astrophysical background in the current study. The obtained limit is the most stringent to date in the energy range between 5×106 and 2×1010 GeV. This result constrains neutrino models predicting a three-flavor neutrino flux of Eν2ϕνe+νμ+ντ≃2×10−8 GeV/cm2 sec sr at 109 GeV. A significant part of the parameter space for EHE neutrino production scenarios assuming a proton-dominated composition of ultra-high-energy cosmic rays is disfavored independently of uncertain models of the extragalactic background light which previous IceCube constraints partially relied on.
We report on measurements of the all-particle cosmic ray energy spectrum and composition in the PeV to EeV energy range using 3 years of data from the IceCube Neutrino Observatory. The IceTop ...detector measures cosmic ray induced air showers on the surface of the ice, from which the energy spectrum of cosmic rays is determined by making additional assumptions about the mass composition. A separate measurement is performed when IceTop data are analyzed in coincidence with the high-energy muon energy loss information from the deep in-ice IceCube detector. In this measurement, both the spectrum and the mass composition of the primary cosmic rays are simultaneously reconstructed using a neural network trained on observables from both detectors. The performance and relative advantages of these two distinct analyses are discussed, including the systematic uncertainties and the dependence on the hadronic interaction models, and both all-particle spectra as well as individual spectra for elemental groups are presented.
Inelasticity, the fraction of a neutrino’s energy transferred to hadrons, is a quantity of interest in the study of astrophysical and atmospheric neutrino interactions at multi-TeV energies with ...IceCube. In this work, a sample of contained neutrino interactions in IceCube is obtained from five years of data and classified as 2650 tracks and 965 cascades. Tracks arise predominantly from charged-current νμ interactions, and we demonstrate that we can reconstruct their energy and inelasticity. The inelasticity distribution is found to be consistent with the calculation of Cooper-Sarkar et al. across the energy range from ∼1 to ∼100 TeV. Along with cascades from neutrinos of all flavors, we also perform a fit over the energy, zenith angle, and inelasticity distribution to characterize the flux of astrophysical and atmospheric neutrinos. The energy spectrum of diffuse astrophysical neutrinos is described well by a power law in both track and cascade samples, and a best-fit index γ=2.62±0.07 is found in the energy range from 3.5 TeV to 2.6 PeV. Limits are set on the astrophysical flavor composition and are compatible with a ratio of (13∶13∶13)⊕. Exploiting the distinct inelasticity distribution of νμ and ν¯μ interactions, the atmospheric νμ to ν¯μ flux ratio in the energy range from 770 GeV to 21 TeV is found to be 0.77−0.25+0.44 times the calculation by Honda et al. Lastly, the inelasticity distribution is also sensitive to neutrino charged-current charm production. The data are consistent with a leading-order calculation, with zero charm production excluded at 91% confidence level. Future analyses of inelasticity distributions may probe new physics that affects neutrino interactions both in and beyond the Standard Model.
The influence of biochar (5%) on the loss, partitioning and bioaccessibility of 14C-isoproturon (14C-IPU) was evaluated. Results indicated that biochar had a dramatic effect upon 14C-IPU ...partitioning: 14C-IPU extractability (0.01 M CaCl2) in biochar-amended treatments was reduced to <2% while, 14C-IPU extractability in biochar free treatments decreased with ageing from 90% to 40%. A partitioning model was constructed to derive an effective partition coefficient for biochar:water (KBW of 7.82 × 104 L kg−1). This was two orders of magnitude greater than the apparent Kfoc value of the soil organic carbon:water (631 L kg−1). 14C-radiorespirometry assays indicated high competence of microorganisms to mineralise 14C-IPU in the absence of biochar (40.3 ± 0.9%). Where biochar was present 14C-IPU mineralisation never exceeded 2%. These results indicate reduced herbicide bioaccessibility. Increasing IPU application to ×10 its recommended dose was ineffective at redressing IPU sequestration and its low bioaccessibility.
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•Biochar had a dramatic effect on IPU partitioning.•IPU extractability was reduced to <2% in biochar treatments.•Effective partition coefficient for biochar:water (KBW) was 7.82 × 104 L kg−1.•KBW was 124 times greater than the apparent Kfoc value of the control.•Biochar precluded microbial bioaccessibility – no catabolic response was observed.
Biochar dramatically reduced 14C-IPU extractability (<2%) with KBW being ×123 greater than the apparent Kfoc. Correspondingly, microbial bioaccessibility of IPU was negligible.
The role of microglia in tau accumulation is currently unclear but could provide an important insight into the mechanisms underlying Alzheimer's disease (AD)
. Here, we measured the microglial marker ...soluble TREM2 and the disease-associated microglial activation stage 2 markers AXL, MERTK, GAS6, LPL, CST7, SPP1 and CSF1 in nondemented individuals from the Swedish BioFINDER-2 cohort who underwent longitudinal tau-positron emission tomography (PET), amyloid-PET and global cognitive assessment. To assess whether baseline microglial markers had an effect on AD-related changes, we studied three sub-groups of individuals: 121 with evidence of amyloid-PET pathology (A
), 64 with additional evidence of tau-PET pathology (A
T
) and 159 without amyloid- or tau-PET pathology (A
T
). Our results showed that increased levels of TREM2 were associated with slower amyloid accumulation in A
individuals in addition to slower tau deposition and cognitive decline in A
T
subjects. Similarly, higher levels of AXL, MERTK, GAS6, LPL, CST7 and CSF1 predicted slower tau accumulation and/or cognitive decline in the A
T
group. These findings have important implications for future therapeutic strategies aiming to boost microglial protective functions in AD.
We describe a search underway for periodic gravitational waves from the central compact object in the supernova remnant Cassiopeia A. The object is the youngest likely neutron star in the Galaxy. Its ...position is well known, but the object does not pulse in any electromagnetic radiation band and thus presents a challenge in searching the parameter space of frequency and frequency derivatives. We estimate that a fully coherent search can, with a reasonable amount of time on a computing cluster, achieve a sensitivity at which it is theoretically possible (though not likely) to observe a signal even with the initial LIGO noise spectrum. Cassiopeia A is only the second object after the Crab pulsar for which this is true. The search method described here can also obtain interesting results for similar objects with current LIGO sensitivity.
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