Human APOBEC3G (hA3G) is a cytidine deaminase that restricts replication of certain viruses. We have previously reported that hA3G was a host restriction factor against hepatitis C virus (HCV) ...replication, and hA3G stabilizers showed a significant inhibitory activity against HCV. However, the molecular mechanism of hA3G against HCV remains unknown. We show in this study that hA3G's C-terminal directly binds HCV non-structural protein NS3 at its C-terminus, which is responsible for NS3's helicase and NTPase activity. Binding of hA3G to the C-terminus of NS3 reduced helicase activity, and therefore inhibited HCV replication. The anti-HCV mechanism of hA3G appeared to be independent of its deamination activity. Although early stage HCV infection resulted in an increase in host hA3G as an intracellular response against HCV replication, hA3G was gradually diminished after a long-term incubation, suggesting an unknown mechanism(s) that protects HCV NS3 from inactivation by hA3G. The process represents, at least partially, a cellular defensive mechanism against HCV and the action is mediated through a direct interaction between host hA3G and HCV NS3. We believe that understanding of the antiviral mechanism of hA3G against HCV might open an interesting avenue to explore hA3G stabilizers as a new class of anti-HCV agents.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
DNA-demethylating agents have shown clinical anti-tumor efficacy via an unknown mechanism of action. Using a combination of experimental and bioinformatics analyses in colorectal cancer cells, we ...demonstrate that low-dose 5-AZA-CdR targets colorectal cancer-initiating cells (CICs) by inducing viral mimicry. This is associated with induction of dsRNAs derived at least in part from endogenous retroviral elements, activation of the MDA5/MAVS RNA recognition pathway, and downstream activation of IRF7. Indeed, disruption of virus recognition pathways, by individually knocking down MDA5, MAVS, or IRF7, inhibits the ability of 5-AZA-CdR to target colorectal CICs and significantly decreases 5-AZA-CdR long-term growth effects. Moreover, transfection of dsRNA into CICs can mimic the effects of 5-AZA-CdR. Together, our results represent a major shift in understanding the anti-tumor mechanisms of DNA-demethylating agents and highlight the MDA5/MAVS/IRF7 pathway as a potentially druggable target against CICs.
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•5-AZA-CdR induces formation of dsRNAs and activation of the MDA5/MAVS/IRF7 pathway•An anti-proliferative response to DNA demethylation is mediated by viral mimicry•5-AZA-CdR-mediated targeting of CICs is mainly mediated by viral mimicry•The MDA5/MAVS/IRF7 pathway is a potentially druggable target against colorectal cancer
Anti-tumor DNA-demethylating agents act by inducing transcription of endogenous dsRNAs that activate the viral recognition and interferon response pathway. This anti-viral response reduces proliferation of colorectal cancer-initiating cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In terrestrial ecosystems, plants take up phosphate predominantly via association with arbuscular mycorrhizal fungi (AMF). We identified loss of responsiveness to AMF in the rice (Oryza sativa) ...mutant hebiba, reflected by the absence of physical contact and of characteristic transcriptional responses to fungal signals. Among the 26 genes deleted in hebiba, DWARF 14 LIKE is, the one responsible for loss of symbiosis. It encodes an alpha/beta-fold hydrolase, that is a component of an intracellular receptor complex involved in the detection of the smoke compound karrikin. Our finding reveals an unexpected plant recognition strategy for AMF and a previously unknown signaling link between symbiosis and plant development.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
Climate change globally affects soil microbial community assembly across ecosystems. However, little is known about the impact of warming on the structure of soil microbial communities or underlying ...mechanisms that shape microbial community composition in subtropical forest ecosystems. To address this gap, we utilized natural variation in temperature via an altitudinal gradient to simulate ecosystem warming. After 6 years, microbial co‐occurrence network complexity increased with warming, and changes in their taxonomic composition were asynchronous, likely due to contrasting community assembly processes. We found that while stochastic processes were drivers of bacterial community composition, warming led to a shift from stochastic to deterministic drivers in dry season. Structural equation modelling highlighted that soil temperature and water content positively influenced soil microbial communities during dry season and negatively during wet season. These results facilitate our understanding of the response of soil microbial communities to climate warming and may improve predictions of ecosystem function of soil microbes in subtropical forests.
Climate change globally affects soil microbial community assembly across ecosystems. We utilized natural variation in temperature via an altitudinal gradient to simulate ecosystem warming. After 6 years of experiment, microbial co‐occurrence network complexity increased with warming, and changes in their taxonomic composition were asynchronous due to contrasting community assembly processes. Structural equation modelling highlighted that soil temperature and water content positively influenced soil microbial communities during dry season and negatively during wet season.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Context
. In the current multi-messenger astronomy era, it is important that information about joint gravitational wave (GW) and electromagnetic (EM) observations through short gamma-ray bursts ...(sGRBs) remains easily accessible to each member of the GW-EM community. The possibility for non-experts to execute quick computations of joint GW-sGRB detections should be facilitated.
Aims
. For this study, we constructed a model for sGRBs and added this to the framework of the previously built
Gravitational Wave Universe Toolbox
(
GWToolbox
or
Toolbox
). We provide expected joint GW-sGRB detection rates for different combinations of GW detectors and high-energy (HE) instruments.
Methods
. We employed and adapted a generic GRB model to create a computationally low-cost top-hat jet model suitable for the
GWToolbox
. With the
Toolbox
, we simulated a population of binary neutron stars (BNSs) observed by a user-specified GW detector such as LIGO, Virgo, the Einstein Telescope (ET), or the Cosmic Explorer (CE). Based on the characteristics of each binary, our model predicts the properties of a resulting sGRB, as well as its detectability for HE detectors such as
Fermi
/GBM,
Swift
/BAT, or GECAM.
Results
. We report predicted joint detection rates for combinations of GW detectors (LIGO and ET) with HE instruments (
Fermi
/GBM,
Swift
/BAT, and GECAM). Our findings stress the significance of the impact that ET will have on multi-messenger astronomy. While the LIGO sensitivity is currently the limiting factor regarding the number of joint detections, ET will observe BNSs at such a rate that the vast majority of detected sGRBs will have a GW counterpart observed by ET. These conclusions hold for CE as well. Additionally, since LIGO can only detect BNSs up to a redshift of ~0.1 where few sGRBs exist, a search for sub-threshold GW signals at higher redshifts using sGRB information from HE detectors has the potential to be very successful and significantly increase the number of joint detections. Equivalently, during the ET era, GW data can assist in finding sub-threshold sGRBs, potentially increasing, for example, the number of joint ET-
Fermi
/GBM observations by ~270%. Lastly, we find that our top-hat jet model underestimates the number of joint detections that include an off-axis sGRB. We corrected for this by introducing a second, wider and weaker jet component. We predict that the majority of joint detections during the LIGO/Virgo era will include an off-axis sGRB, making GRB170817A not as unlikely as one would think based on the simplest top-hat jet model. In the ET era, most joint detections will contain an on-axis sGRB.
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FMFMET, NUK, UL, UM, UPUK
Dijet, dihadron, hadron-jet angular correlations have been reckoned as important probes of the transverse momentum broadening effects in relativistic nuclear collisions. When a pair of high-energy ...jets created in hard collisions traverse the quark–gluon plasma produced in heavy-ion collisions, they become de-correlated due to the vacuum soft gluon radiation associated with the Sudakov logarithms and the medium-induced transverse momentum broadening. For the first time, we employ the systematical resummation formalism and establish a baseline calculation to describe the dihadron and hadron-jet angular correlation data in pp and peripheral AA collisions where the medium effect is negligible. We demonstrate that the medium-induced broadening 〈p⊥2〉 and the so-called jet quenching parameter qˆ can be extracted from the angular de-correlations observed in AA collisions. A global χ2 analysis of dihadron and hadron-jet angular correlation data renders 〈p⊥2〉∼13−4+5 GeV2 for a quark jet at RHIC top energy. Further experimental and theoretical efforts along the direction of this work shall significantly advance the quantitative understanding of transverse momentum broadening and help us acquire unprecedented knowledge of jet quenching parameter in relativistic heavy-ion collisions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The importance of the kynurenine pathway in normal immune system function has led to an appreciation of its possible contribution to autoimmune disorders such as rheumatoid arthritis. ...Indoleamine-2,3-dioxygenase (IDO) activity exerts a protective function, limiting the severity of experimental arthritis, whereas deletion or inhibition exacerbates the symptoms. Other chronic disorder with an inflammatory component, such as atherosclerosis, are also suppressed by IDO activity. It is suggested that this overall anti-inflammatory activity is mediated by a change in the relative production or activity of Th17 and regulatory T cell populations. Kynurenines may play an anti-inflammatory role also in CNS disorders such as Huntington's disease, Alzheimer's disease and multiple sclerosis, in which signs of inflammation and neurodegeneration are involved. The possibility is discussed that in Huntington's disease kynurenines interact with other anti-inflammatory molecules such as Human Lymphocyte Antigen-G which may be relevant in other disorders. Kynurenine involvement may account for the protection afforded to animals with cerebral malaria and trypanosomiasis when they are treated with an inhibitor of kynurenine-3-monoxygenase (KMO). There is some evidence that changes in IL-10 may contribute to this protection and the relationship between kynurenines and IL-10 in arthritis and other inflammatory conditions should be explored. In addition, metabolites of kynurenine downstream of KMO, such as anthranilic acid and 3-hydroxy-anthranilic acid can influence inflammation, and the ratio of these compounds is a valuable biomarker of inflammatory status although the underlying molecular mechanisms of the changes require clarification. Hence it is essential that more effort be expended to identify their sites of action as potential targets for drug development. Finally, we discuss increasing awareness of the epigenetic regulation of IDO, for example by DNA methylation, a phenomenon which may explain differences between individuals in their susceptibility to arthritis and other inflammatory disorders.
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•Manure application impacted the resistome in soil, earthworms and phyllosphere.•Manure with reduced antibiotic burden reduced the spread of the antibiotic resistome.•Shared ARGs and ...OTUs were founded within soil-earthworm-phyllosphere system.
The overuse of antibiotics in animal husbandry is widespread and believed to significantly contribute to the selection of antibiotic resistance genes (ARGs) in animals. Thus, there is a global drive to reduce antibiotic use in the agricultural sector. However, it has not been established whether a reduction in the use of antibiotics in livestock production would be effective in reducing the spread of ARGs. A microcosm approach was used to determine how the addition of manure with either reduced antibiotic levels or with typical antibiotic levels could affect the spread of antibiotic resistance genes between soil, earthworms and the phyllosphere. When compared to the control soil, earthworm and phyllosphere samples had the greater increase in ARG abundance in conventional manure treatments (P < 0.05). Reduced antibiotic manure also enriched the abundance of ARGs in the phyllosphere and soil but not earthworm guts when compared to the control (P < 0.05). In both soil and earthworm guts, the enrichment of ARGs was lower in reduced antibiotic manure than in conventional manure. This study has identified bacterial transfer through the soil-earthworm-phyllosphere system as a potential means to spread ARGs between habitats after fertilization with livestock derived manures.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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