An outbreak of 2019‐nCoV infection has spread across the world. No specific antiviral drugs have been approved for the treatment of COVID‐2019. In addition to the recommended antiviral drugs, such as ...interferon‐ɑ, lopinavir/ritonavir, ribavirin, and chloroquine phosphate, some clinical trials focusing on virus RNA‐dependent RNA polymerase (RdRp) inhibitors have been registered and initiated. Favipiravir, a purine nucleic acid analog and potent RdRp inhibitor approved for use in influenza, is also considered in several clinical trials. Herein, we summarized the pharmacokinetic characteristics of favipiravir and possible drug–drug interactions from the view of drug metabolism. We hope this will be helpful for the design of clinical trials for favipiravir in COVID‐2019, as data regarding in vitro virus inhibition and efficacy in preclinical animal studies are still not available.
The methyltransferase like 3 （METTL3）-containing methyltransferase complex catalyzes the N6-methyladenosine （m6A） formation, a novel epitranscriptomic marker; however, the nature of this complex ...remains largely unknown. Here we report two new components of the human m6A methyltransferase complex, Wilms＇ tumor 1-associating protein （WTAP） and methyltransferase like 14 （METTL14）. WTAP interacts with METTL3 and METTL14, and is required for their localization into nuclear speckles enriched with pre-mRNA processing factors and for catalytic ac- tivity of the m6A methyltransferase in vivo. The majority of RNAs bound by WTAP and METTL3 in vivo represent mRNAs containing the consensus m6A motif. In the absence of WTAP, the RNA-binding capability of METTL3 is strongly reduced, suggesting that WTAP may function to regulate recruitment of the m6A methyltransferase complex to mRNA targets. Furthermore, transcriptomic analyses in combination with photoactivatable-ribonucleoside-en- hanced crosslinking and immunoprecipitation （PAR-CLIP） illustrate that WTAP and METTL3 regulate expression and alternative splicing of genes involved in transcription and RNA processing. Morpholino-mediated knockdown targeting WTAP and/or METTL3 in zebrafish embryos caused tissue differentiation defects and increased apoptosis. These findings provide strong evidence that WTAP may function as a regulatory subunit in the m6A methyltransferase complex and play a critical role in epitranscriptomic regulation of RNA metabolism.
Defining a sound shift operator for graph signals, similar to the shift operator in classical signal processing, is a crucial problem in graph signal processing (GSP), since almost all operations, ...such as filtering, transformation, prediction, are directly related to the graph shift operator. We define a set of energy-preserving shift operators that satisfy many properties similar to their counterparts in classical signal processing, but are different from the shift operators defined in the literature, such as the graph adjacency matrix and Laplacian matrix based shift operators, which modify the energy of a graph signal. We decouple the graph structure represented by eigengraphs and the eigenvalues of the adjacency matrix or the Laplacian matrix. We show that the adjacency matrix of a graph is indeed a linear shift invariant (LSI) graph filter with respect to the defined shift operator. We further define autocorrelation and cross-correlation functions of signals on the graph, enabling us to obtain the solution to the optimal filtering on graphs, i.e., the corresponding Wiener filtering on graphs and the efficient spectra analysis and frequency domain filtering in parallel with those in classical signal processing. This new shift operator based GSP framework enables the signal analysis along a correlation structure defined by a graph shift manifold as opposed to classical signal processing operating on the assumption of the correlation structure with a linear time shift manifold. Several illustrative simulations are presented to validate the performance of the designed optimal LSI filters.
In this paper, we present an end-to-end architecture for multi-exposure image fusion based on generative adversarial networks, termed as MEF-GAN. In our architecture, a generator network and a ...discriminator network are trained simultaneously to form an adversarial relationship. The generator is trained to generate a real-like fused image based on the given source images which is expected to fool the discriminator. Correspondingly, the discriminator is trained to distinguish the generated fused images from the ground truth. The adversarial relationship makes the fused image not limited to the restriction of the content loss. Therefore, the fused images are closer to the ground truth in terms of probability distribution, which can compensate for the insufficiency of single content loss. Moreover, aiming at the problem that the luminance of multi-exposure images varies greatly with spatial location, the self-attention mechanism is employed in our architecture to allow for attention-driven and long-range dependency. Thus, local distortion, confusing results, or inappropriate representation can be corrected in the fused image. Qualitative and quantitative experiments are performed on publicly available datasets, where the results demonstrate that MEF-GAN outperforms the state-of-the-art, in terms of both visual effect and objective evaluation metrics. Our code is publicly available at https://github.com/jiayi-ma/MEF-GAN .
In this paper, we proposed a new end-to-end model, termed as dual-discriminator conditional generative adversarial network (DDcGAN), for fusing infrared and visible images of different resolutions. ...Our method establishes an adversarial game between a generator and two discriminators. The generator aims to generate a real-like fused image based on a specifically designed content loss to fool the two discriminators, while the two discriminators aim to distinguish the structure differences between the fused image and two source images, respectively, in addition to the content loss. Consequently, the fused image is forced to simultaneously keep the thermal radiation in the infrared image and the texture details in the visible image. Moreover, to fuse source images of different resolutions, e.g., a low-resolution infrared image and a high-resolution visible image, our DDcGAN constrains the downsampled fused image to have similar property with the infrared image. This can avoid causing thermal radiation information blurring or visible texture detail loss, which typically happens in traditional methods. In addition, we also apply our DDcGAN to fusing multi-modality medical images of different resolutions, e.g., a low-resolution positron emission tomography image and a high-resolution magnetic resonance image. The qualitative and quantitative experiments on publicly available datasets demonstrate the superiority of our DDcGAN over the state-of-the-art, in terms of both visual effect and quantitative metrics.
Background and Aims
Wilson’s disease (WD) is a rare hereditary disorder due to ATP7B gene mutation, causing pathologic copper storage mainly in the liver and neurological systems. Hepatocyte ...transplantation showed therapeutic potential; however, this strategy is often hindered by a shortage of quality donor cells and by allogeneic immune rejection. In this study, we aimed to evaluate the function and efficacy of autologous reprogrammed, ATP7B gene‐restored hepatocytes using a mouse model of WD.
Approach and Results
Sufficient liver progenitor cells (LPCs) were harvested by reprogramming hepatocytes from ATP7B−/− mice with small molecules, which exhibited strong proliferation and hepatic differentiation capacity in vitro. After lentivirus‐mediated mini ATP7B gene transfection and redifferentiation, functional LPC‐ATP7B‐derived hepatocytes (LPC‐ATP7B‐Heps) were developed. RNA sequencing data showed that, compared with LPC–green fluorescent protein–Heps (LPC‐GFP‐Heps) with enrichment of genes that were mainly in pathways of oxidative stress and cell apoptosis, in LPC‐ATP7B‐Heps under high copper stress, copper ion binding and cell proliferation pathways were enriched. LPC‐ATP7B‐Heps transplantation into ATP7B−/− mice alleviated deposition of excess liver copper with its associated inflammation and fibrosis, comparable with those observed using normal primary hepatocytes at 4 months after transplantation.
Conclusions
We established a system of autologous reprogrammed WD hepatocytes and achieved ATP7B gene therapy in vitro. LPC‐ATP7B‐Heps transplantation demonstrated therapeutic efficacy on copper homeostasis in a mouse model of WD.
ATP7B gene therapy of autologous reprogrammed hepatocytes relieved liver copper accumulation in WD mice.
Tumour microenvironment (TME) is crucial to tumorigenesis. This study aimed to uncover the differences in immune phenotypes of TME in endometrial cancer (EC) using Uterine Corpus Endometrial ...Carcinoma (UCEC) cohort and explore the prognostic significance. We employed GVSA enrichment analysis to cluster The Cancer Genome Atlas (TCGA) EC samples into immune signature cluster modelling, evaluated immune cell profiling in UCEC cohort (n = 538) and defined four immune subtypes of EC. Next, we analysed the correlation between immune subtypes and clinical data including patient prognosis. Furthermore, we analysed the expression of immunomodulators and DNA methylation modification. The profiles of immune infiltration in TCGA UCEC cohort showed significant difference among four immune subtypes of EC. Among each immune subtype, natural killer T cells (NKT), dendritic cells (DCs) and CD8+T cells were significantly associated with EC patients survival. Each immune subtype exhibited specific molecular classification, immune cell characterization and immunomodulators expression. Moreover, the expression immunomodulators were significantly related to DNA methylation level. In conclusion, the identification of immune subtypes in EC tissues could reveal unique immune microenvironments in EC and predict the prognosis of EC patients.
Metal‐organic cages (MOCs) are supramolecular coordination complexes that have internal cavities for hosting guest molecules and exhibiting various properties. However, the functions of MOCs are ...limited by the choice of the building blocks. Post‐synthetic modification (PSM) is a technique that can introduce new functional groups and replace existing ones on the MOCs without changing their geometry. Among many PSM methods, covalent PSM is a promising approach to modify MOCs with tailored structures and functions. Covalent PSM can be applied to either the internal cavity or the external surface of the MOCs, depending on the functionality expected to be customized. However, there are still some challenges and limitations in the field of covalent PSM of MOCs, such as the balance between the stability of MOCs and the harshness of organic reactions involved in covalent PSMs. This concept article introduces the organic reaction types involved in covalent PSM of MOCs, their new applications after modification, and summarizes and provides an outlook of this research field.
Covalent post‐synthetic modification (PSM) is a powerful research paradigm capable of constructing metal‐organic cages (MOCs) with customized structures and properties. A variety of efficient organic reactions have been developed for the functionalization of MOCs, and these new products have shown potential applications in multiple fields.
Substrate integrated waveguide (SIW) technology provides an attractive solution to the integration of planar and nonplanar circuits by using a planar circuit fabrication process. However, it is ...usually difficult to implement the negative coupling structure required for the design of compact canonical folded elliptic or quasi-elliptic cross-coupled bandpass filter on the basis of a single-layer SIW. In this paper, a special planar negative coupling scheme including a magnetic coupling post-wall iris and a balanced microstrip line with a pair of metallic via-holes is studied in detail. Two -band fourth-degree cross-coupled bandpass filters without and with source-load coupling using the negative coupling structures are then proposed and designed. The two novel SIW filters having the same center frequency of 20.5 GHz and respective passband width of 700 and 800 MHz are implemented on a single-layer Rogers RT/Duroid 5880 substrate with thickness of 0.508 mm. Measured results of those filters, which exhibit a high selectivity, and a minimum in-band insertion loss of approximately 0.9 and 1.0 dB, respectively, agree well with simulated results.
Medicines for the treatment of 2019-novel coronavirus (2019-nCoV) infections are urgently needed. However, drug screening using live 2019-nCoV requires high-level biosafety facilities, which imposes ...an obstacle for those institutions without such facilities or 2019-nCoV. This study aims to repurpose the clinically approved drugs for the treatment of coronavirus disease 2019 (COVID-19) in a 2019-nCoV-related coronavirus model.
A 2019-nCoV-related pangolin coronavirus GX_P2V/pangolin/2017/Guangxi was described. Whether GX_P2V uses angiotensin-converting enzyme 2 (ACE2) as the cell receptor was investigated by using small interfering RNA (siRNA)-mediated silencing of ACE2. The pangolin coronavirus model was used to identify drug candidates for treating 2019-nCoV infection. Two libraries of 2406 clinically approved drugs were screened for their ability to inhibit cytopathic effects on Vero E6 cells by GX_P2V infection. The anti-viral activities and anti-viral mechanisms of potential drugs were further investigated. Viral yields of RNAs and infectious particles were quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and plaque assay, respectively.
The spike protein of coronavirus GX_P2V shares 92.2% amino acid identity with that of 2019-nCoV isolate Wuhan-hu-1, and uses ACE2 as the receptor for infection just like 2019-nCoV. Three drugs, including cepharanthine (CEP), selamectin, and mefloquine hydrochloride, exhibited complete inhibition of cytopathic effects in cell culture at 10 μmol/L. CEP demonstrated the most potent inhibition of GX_P2V infection, with a concentration for 50% of maximal effect EC50 of 0.98 μmol/L. The viral RNA yield in cells treated with 10 μmol/L CEP was 15,393-fold lower than in cells without CEP treatment (6.48 ± 0.02 × 10vs. 1.00 ± 0.12, t = 150.38, P < 0.001) at 72 h post-infection (p.i.). Plaque assays found no production of live viruses in media containing 10 μmol/L CEP at 48 h p.i. Furthermore, we found CEP had potent anti-viral activities against both viral entry (0.46 ± 0.12, vs.1.00 ± 0.37, t = 2.42, P < 0.05) and viral replication (6.18 ± 0.95 × 10vs. 1.00 ± 0.43, t = 3.98, P < 0.05).
Our pangolin coronavirus GX_P2V is a workable model for 2019-nCoV research. CEP, selamectin, and mefloquine hydrochloride are potential drugs for treating 2019-nCoV infection. Our results strongly suggest that CEP is a wide-spectrum inhibitor of pan-betacoronavirus, and further study of CEP for treatment of 2019-nCoV infection is warranted.
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