COVID-19, caused by SARS-CoV-2, is a virulent pneumonia, with >4,000,000 confirmed cases worldwide and >290,000 deaths as of May 15, 2020. It is critical that vaccines and therapeutics be developed ...very rapidly. Mice, the ideal animal for assessing such interventions, are resistant to SARS-CoV-2. Here, we overcome this difficulty by exogenous delivery of human ACE2 with a replication-deficient adenovirus (Ad5-hACE2). Ad5-hACE2-sensitized mice developed pneumonia characterized by weight loss, severe pulmonary pathology, and high-titer virus replication in lungs. Type I interferon, T cells, and, most importantly, signal transducer and activator of transcription 1 (STAT1) are critical for virus clearance and disease resolution in these mice. Ad5-hACE2-transduced mice enabled rapid assessments of a vaccine candidate, of human convalescent plasma, and of two antiviral therapies (poly I:C and remdesivir). In summary, we describe a murine model of broad and immediate utility to investigate COVID-19 pathogenesis and to evaluate new therapies and vaccines.
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•Mice are sensitized for SARS-CoV-2 infection by Ad5-hACE2 transduction•Genetically deficient strains can be directly assessed without additional breeding•Mice useful for determining host factors necessary for optimal virus clearance•Useful for assessing efficacy of vaccines and therapies such as convalescent plasma
An adenoviral transduction-based mouse model that can be infected with SARS-CoV-2 provides a tool to understand host factors involved in viral infection and clearance as well as potential therapeutic modalities.
Mycobacterium tuberculosis is a hard-to-eradicate intracellular pathogen that infects one-third of the global population. It can live within macrophages owning to its ability to arrest phagolysosome ...biogenesis. Autophagy has recently been identified as an effective way to control the intracellular mycobacteria by enhancing phagosome maturation. In the present study, we demonstrate a novel role of miR-155 in regulating the autophagy-mediated anti-mycobacterial response. Both in vivo and in vitro studies showed that miR-155 expression was significantly enhanced after mycobacterial infection. Forced expression of miR-155 accelerated the autophagic response in macrophages, thus promoting the maturation of mycobacterial phagosomes and decreasing the survival rate of intracellular mycobacteria, while transfection with miR-155 inhibitor increased mycobacterial survival. However, macrophage-mediated mycobacterial phagocytosis was not affected after miR-155 overexpression or inhibition. Furthermore, blocking autophagy with specific inhibitor 3-methyladenine or silencing of autophagy related gene 7 (Atg7) reduced the ability of miR-155 to promote autophagy and mycobacterial elimination. More importantly, our study demonstrated that miR-155 bound to the 3'-untranslated region of Ras homologue enriched in brain (Rheb), a negative regulator of autophagy, accelerated the process of autophagy and sequential killing of intracellular mycobacteria by suppressing Rheb expression. Our results reveal a novel role of miR-155 in regulating autophagy-mediated mycobacterial elimination by targeting Rheb, and provide potential targets for clinical treatment.
It is experimentally demonstrated that even though the numerical aperture in the object space is fixed, the resolution of an imaging system still can be improved by adjusting the parameters in the ...image space. This strategy cannot be realized until the discovery of the violation of the Lagrange invariant in a kind of self-interference holography. With the violation, parameters in the image space can escape the constraint of the object space for resolution improvement. Experiments that directly confirm this new ability are implemented and results agree well with the theoretical prediction. Additionally, better performance on frequency recording and finer details beyond the diffraction limit have been recorded with this method.
The Lagrange invariant provides a basic description of an optical imaging system. Many important conclusions can be drawn from it. We discovered that the Lagrange invariant is violated in a ...self-interference holography system with particular characteristics. With a proof-of-principle system, we proved this violation both theoretically and experimentally. This finding enables future exciting possibilities in optical imaging.
Modal estimation of aberration can quantify the amount of aberration, which plays an important role in optical system optimization, aberration correction, and so on. Here, we propose a simple but ...effective method to find the modal wavefront of aberration. Once the aberrated wavefront has been detected, it will be automatically analyzed with a method based on one-dimensional standard polynomial fitting. According to the analysis, the modal wavefront and the property of aberration can be obtained for further studies. Here, for example, we show that it can be used to calculate the optimal correction wavefront. Experiments were implemented to testify the correctness and effectiveness of this method. This method provides users another option for aberration interpretation.
A picosecond pulsed mid-infrared laser with multi-pulse operation is experimentally demonstrated. This mid-infrared laser was composed of a fiber laser pumped optical parametric oscillator (OPO). The ...pump source of this OPO was a master oscillator power amplification-structured picosecond fiber amplifier with pulse bunch output, which was further used to quasi-synchronously pump a periodically poled magnesium-oxide doped lithium niobate crystal based OPO to obtain 3.8-μm wavelength output with picosecond multi-pulse operation. The pump-idler conversion efficiency, the signal spectrum, and the signal pulse bunch are presented, respectively.
Abstract
Although microbial (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) can activate primate Vγ2Vδ2 T cells, molecular mechanisms by which HMBPP interacts with Vγ2Vδ2 T cells remain ...poorly characterized. Here, we developed soluble, tetrameric Vγ2Vδ2 TCR of rhesus macaques to define HMBPP/APC interaction with Vγ2Vδ2 TCR. While exogenous HMBPP was associated with APC membrane in an appreciable affinity, the membrane-associated HMBPP readily bound to the Vγ2Vδ2 TCR tetramer. The Vγ2Vδ2 TCR tetramer was shown to bind stably to HMBPP presented on membrane by various APC cell lines from humans and nonhuman primates but not those from mouse, rat, or pig. The Vγ2Vδ2 TCR tetramer also bound to the membrane-associated HMBPP on primary monocytes, B cells and T cells. Consistently, endogenous phosphoantigen produced in Mycobacterium-infected dendritic cells was transported and presented on membrane, and bound stably to the Vγ2Vδ2 TCR tetramer. The capability of APC to present HMBPP for recognition by Vγ2Vδ2 TCR was diminished after protease treatment of APC. Thus, our studies elucidated an affinity HMBPP-APC association conferring stable binding to the Vγ2Vδ2 TCR tetramer and the protease-sensitive nature of phosphoantigen presentation. The findings defined APC presentation of phosphoantigen HMBPP to Vγ2Vδ2 TCR.
4-Deoxybostrycin is a natural anthraquinone compound isolated from the Mangrove endophytic fungus Nigrospora sp. collected from the South China Sea. Nigrosporin is the deoxy-derivative of ...4-deoxybostrycin. They were tested against mycobacteria, especially Mycobacterium tuberculosis. In the Kirby-Bauer disk diffusion susceptibility test, they both had inhibition zone sizes of over 25 mm. The results of the absolute concentration susceptibility test suggested that they had inhibitory effects against mycobacteria. Moreover, 4-deoxybostrycin exhibited good inhibition which was even better than that of first line anti-tuberculosis (TB) drugs against some clinical multidrug-resistant (MDR) M. tuberculosis strains. The gene expression profile of M. tuberculosis H37Rv after treatment with 4-deoxybostrycin was compared with untreated bacteria. One hundred and nineteen out of 3,875 genes were significantly different in M. tuberculosis exposed to 4-deoxybostrycin from control. There were 46 functionally known genes which are involved in metabolism, information storage and processing and cellular processes. The differential expressions of six genes were further confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). The present study provides a useful experiment basis for exploitation of correlative new drugs against TB and for finding out new targets of anti-mycobacterial therapy.
A passively mode-locked Yb fiber laser using PbSe colloidal quantum dots (CQDs) as saturable absorber (SA) is experimentally demonstrated. An all-fiber experimental scheme was designed to understand ...the SA property of PbSe CQDs. The non-saturable loss, modulation depth, and saturable intensity of SA measured were 23%, 7%, and 12 MW/cm
, respectively. The PbSe CQDs were sandwiched in a fiber connector, which was further inserted into the Yb fiber laser for mode-locking. As the pump power up to 110 mW, the self-starting mode-locking pulses were observed. Under the pump power of 285 mW, a maximum average laser power with fundamental mode-locking operation was obtained to be 21.3 mW. In this situation, the pulse full width at half maximum (FWHM), pulse repetition rate, and spectral FWHM were measured to be 70 ps, 8.3 MHz, and 4.5 nm, respectively.
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