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
Recenzirano
Odprti dostop
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.
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.
Display omitted
•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.
PDF
