Understanding the negative regulators of antiviral immune responses will be critical for advancing immune-modulated antiviral strategies. NLRX1, an NLR protein that negatively regulates innate ...immunity, was previously identified in an unbiased siRNA screen as required for HIV infection. We find that NLRX1 depletion results in impaired nuclear import of HIV-1 DNA in human monocytic cells. Additionally, NLRX1 was observed to reduce type-I interferon (IFN-I) and cytokines in response to HIV-1 reverse-transcribed DNA. NLRX1 sequesters the DNA-sensing adaptor STING from interaction with TANK-binding kinase 1 (TBK1), which is a requisite for IFN-1 induction in response to DNA. NLRX1-deficient cells generate an amplified STING-dependent host response to cytosolic DNA, c-di-GMP, cGAMP, HIV-1, and DNA viruses. Accordingly, Nlrx1−/− mice infected with DNA viruses exhibit enhanced innate immunity and reduced viral load. Thus, NLRX1 is a negative regulator of the host innate immune response to HIV-1 and DNA viruses.
Display omitted
•NLRX1 inhibits HIV-1 cDNA-induced innate immune response and enhances HIV-1 infection•NLRX1 interacts with the DNA-sensing adaptor STING to disrupt STING-TBK1 signaling•STING deficiency abrogates the enhancement of HIV-1 infection by NLRX1•Nlrx1−/− mice show enhanced innate immunity and are more resistant to DNA viruses
Negative regulation of innate immunity is critical to maintain homeostasis, but it can have negative consequences in an infection context. Guo et al. demonstrate that NLRX1 sequesters the DNA-sensing adaptor STING to disrupt STING-TBK1 signaling and inhibit innate immunity to HIV-1 and DNA viruses. Thus, NLRX1 facilitates virus infection.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A super stiff rock mechanics testing machine called Stiffman is introduced in this paper. This test facility uses composite loading frames and relay loading by two loading hydraulic actuators and ...overcomes the technical difficulties of conventional rock mechanics testing machines such as insufficient loading system stiffness, inability to use axial-strain-controlled loading in the post-peak deformation stage, limited straining amount to reach the residual deformation stage. To validate the reliability of the newly developed test machine, a benchmark study was carried out first. Then, systematic uniaxial and triaxial compression tests under axial-strain-controlled loading for three brittle hard rocks were conducted and the results are compared with those obtained using a conventional rock mechanics testing system called Rockman. The test results of Rockman show that under uniaxial compression and triaxial compression under axial-strain-controlled loading at low confining pressures, the rock specimens failed violently in the post-peak deformation stage and it was not possible to obtain complete stress–strain curves of the rocks. On the other hand, it was possible to load the rocks under axial-strain-controlled loading in a stable fashion using Stiffman and complete stress–strain curves of the rocks under uniaxial compression and triaxial compression at low confining pressures could be obtained. Stiffman-tested rock specimens showed signs of spalling but stayed mostly in one piece. Finally, peak and residual strength envelopes of the three brittle rocks are given based on the test results of Stiffman. The experiment results show that Stiffman can be used to capture complete post-peak stress–strain curves of brittle rocks reliably under axial-strain-controlled loading. It provides a new platform for studying post-peak deformation behaviors of brittle hard rocks reliably in a loading control mode that other conventional test machines cannot provide.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
There are many electronic and magnetic properties exhibited by complex oxides. Electronic phase separation (EPS) is one of those, the presence of which can be linked to exotic behaviours, such as ...colossal magnetoresistance, metal-insulator transition and high-temperature superconductivity. A variety of new and unusual electronic phases at the interfaces between complex oxides, in particular between two non-magnetic insulators LaAlO(3) and SrTiO(3), have stimulated the oxide community. However, no EPS has been observed in this system despite a theoretical prediction. Here, we report an EPS state at the LaAlO(3)/SrTiO(3) interface, where the interface charges are separated into regions of a quasi-two-dimensional electron gas, a ferromagnetic phase, which persists above room temperature, and a (superconductor like) diamagnetic/paramagnetic phase below 60 K. The EPS is due to the selective occupancy (in the form of 2D-nanoscopic metallic droplets) of interface sub-bands of the nearly degenerate Ti orbital in the SrTiO(3). The observation of this EPS demonstrates the electronic and magnetic phenomena that can emerge at the interface between complex oxides mediated by the Ti orbital.
Glass formation and its relation to the dendritic and eutectic growth has been investigated for the La100−xAl0.412(Cu,Ni)0.588x (x=30–56.3) and La86−yAl14(Cu,Ni)y (y=16–29) alloy systems. The ...experimental results show that in the La-rich pseudo ternary La–Al–(Cu,Ni) system, optimum glass formation actually occurs at an off-eutectic composition. A nearly fully amorphous rod with 12 mm in diameter can be obtained at an off-eutectic composition near La62Al15.7(Cu,Ni)22.3, while only a 1.5 mm diameter rod can be obtained fully amorphous for the eutectic alloy La66Al14(Cu,Ni)20. A strong dependence of GFA on the composition is observed for these alloys. In addition, formation of a composite (i.e. αLa dendrite reinforced glass matrix) in 12 mm diameter cast rods is observed over a wide range of composition, including the eutectic composition. It has been found that the GFA does not correlate well with the extent of the undercooled liquid region (ΔTx) and is not even closely related to the reduced glass transition temperature (Trg). These unusual observations in glass formation and its relation to the skewed eutectic coupled zone have been explained in terms of the competition between the growth of crystalline phases (i.e. eutectic and dendritic phases) and the formation of the amorphous phase.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Proteolytic processing of amyloid precursor protein (APP) C-terminal fragments (CTFs) by γ-secretase underlies the pathogenesis of Alzheimer’s disease (AD). An RNA interference screen using APP-CTF ...99-residue CTF (C99)- and Notch-specific γ-secretase interaction assays identified a unique ErbB2-centered signaling network that was predicted to preferentially govern the proteostasis of APP-C99. Consistently, significantly elevated levels of ErbB2 were confirmed in the hippocampus of human AD brains. We then found that ErbB2 effectively suppressed autophagic flux by physically dissociating Beclin-1 from the Vps34–Vps15 complex independent of its kinase activity. Down-regulation of ErbB2 by CL-387,785 decreased the levels of C99 and secreted amyloid-β in cellular, zebrafish, and mouse models of AD, through the activation of autophagy. Oral administration of an ErbB2-targeted CL-387,785 for 3 wk significantly improves the cognitive functions of APP/presenilin-1 (PS1) transgenic mice. This work unveils a noncanonical function of ErbB2 in modulating autophagy and establishes ErbB2 as a therapeutic target for AD.
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Past studies have shown that amplified insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1-R) signalling has an important role in colorectal cancer (CRC) development, progression and resistance ...to treatment. In this report, we demonstrate that downregulation of microRNA-497 (miR-497) as a result of DNA copy number reduction is involved in upregulation of IGF1-R in CRC cells. MiR-497 and miR-195 of the miR-15/16/195/424/497 family that share the same 3' untranslated region (3'UTR) binding seed sequence and are predicted to target IGF1-R were concurrently downregulated in the majority of CRC tissues relative to paired adjacent normal mucosa. However, only overexpression of miR-497 led to suppression of the IGF1-R 3'UTR activity and downregulation of the endogenous IGF1-R protein in CRC cells. This was associated with inhibition of cell survival, proliferation and invasion, and increased sensitivity to apoptosis induced by various stimuli including the chemotherapeutic drugs cisplatin and 5-fluorouracil, and the death ligand tumour necrosis factor-related apoptosis-inducing ligand. The biological effect of miR-497 on CRC cells was largely mediated by inhibition of phosphatidylinositol 3-kinase/Akt signalling, as overexpression of an active form of Akt reversed its impact on cell survival and proliferation, recapitulating the effect of overexpression of IGF1-R. Downregulation of miR-497 and miR-195 appeared to associate with copy number loss of a segment of chromosome 17p13.1, where these miRs are located at proximity. Similarly to miR-195, the members of the same miR family, miR-424 that was upregulated, and miR-15a, miR-15b and miR-16 that were unaltered in expression in CRC tissues compared with paired adjacent normal mucosa, did not appear to have a role in regulating the expression of IGF1-R. Taken together, these results identify downregulation of miR-497 as an important mechanism of upregulation of IGF1-R in CRC cells that contributes to malignancy of CRC.
Full text
Available for:
DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We designed and fabricated a new type of superconducting quantum interference device (SQUID) susceptometers for magnetic imaging of quantum materials. The 2-junction SQUID sensors employ 3D Nb ...nano-bridges fabricated using electron-beam lithography. The two counter-wound balanced pickup loops of the SQUID enable gradiometric measurement and they are surrounded by a one-turn field coil for susceptibility measurements. The smallest pickup loop of the SQUIDs were 1 m in diameter and the flux noise was around 1 0/ Hz at 100 Hz. We demonstrate scanning magnetometry, susceptometry and current magnetometry on some test samples using these nano-SQUIDs.
PDF
