Crystal Structure of the C-Terminal Cytoplasmic Domain of Non-Structural Protein 4 from Mouse Hepatitis Virus A59

BACKGROUND:The replication of coronaviruses takes place on cytoplasmic double membrane vesicles (DMVs) originating in the endoplasmic reticulum (ER). Three trans-membrane non-structural proteins, nsp3, nsp4 and nsp6, are understood to be membrane anchors of the coronavirus replication complex. Nsp4 is localized to the ER membrane when expressed alone but is recruited into the replication complex in infected cells. It is revealed to contain four trans-membrane regions and its N- and C-termini are exposed to the cytosol. METHODOLOGY/PRINCIPAL FINDINGS:We have determined the crystal structures of the C-terminal hydrophilic domain of nsp4 (nsp4C) from MHV strain A59 and a C425S site-directed mutant. The highly conserved 89 amino acid region from T408 to Q496 is shown to possess a new fold. The wild-type (WT) structure features two monomers linked by a Cys425-Cys425 disulfide bond in one asymmetric unit. The monomers are arranged with their N- and C-termini in opposite orientations to form an "open" conformation. Mutation of Cys425 to Ser did not affect the monomer structure, although the mutant dimer adopts strikingly different conformations by crystal packing, with the cross-linked C-termini and parallel N-termini of two monomers forming a "closed" conformation. The WT nsp4C exists as a dimer in solution and can dissociate easily into monomers in a reducing environment. CONCLUSIONS/SIGNIFICANCE:As nsp4C is exposed in the reducing cytosol, the monomer of nsp4C should be physiological. This structure may serve as a basis for further functional studies of nsp4

Shorter telomere length in children with autism spectrum disorder is associated with oxidative stress

ObjectiveAutism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder caused by a complex interaction between genetic and environmental risk factors. The balance between antioxidant capacity and oxidative stress (OS) induced free radicals may be crucial during the pathophysiological development of ASD.MethodsIn this study, 96 children with ASD who met the diagnostic and statistical manual of mental disorders were collected, and the number of children in the typical development (TD) group was matched by 1:1. Digital PCR (dPCR) for telomere length (TL) expression in ASD in peripheral blood leukocytes. Urine levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) content were measured by tandem triple quadrupole mass spectrometry and corrected by urinary creatinine levels. The levels of superoxide dismutase (SOD), catalase (CAT), and capacity (AOC) were detected by kits.ResultsThe TL of the ASD group was shorter than the TD group (p < 0.01) and had some accurate predictive significance for the identification of ASD (AUC = 0.632, 95% CI: 0.533–0.710, p = 0.002). Both 8-OHdG content and SOD activity in the ASD group were significantly higher than those in the TD group (p < 0.05). Shortened TL (Monofactor: 2.20 (1.22, 3.96), p = 0.009; Multifactor: 2.22 (1.22, 4.00), p = 0.008) and reduced CAT activity (Monofactor: 2.31 (1.28, 4.17), p = 0.006; Multifactor: 2.31 (1.28, 4.18), p = 0.006) are risk factors for the development of ASD, while reduced 8-OHdG content (Monofactor: 0.29 (0.14, 0.60), p = 0.001; Multifactor: 0.27 (0.13, 0.57), p = 0.001) and reduced SOD activity (Monofactor: 0.55 (0.31, 0.98), p = 0.042; Multifactor: 0.54 (0.30, 0.98), p = 0.042) are protective factors for the development of ASD.ConclusionIn this study, TL and OS were significantly different between the ASD group and the TD group. As guanine-rich telomere sequences were likely damaged by oxygen free radicals, creating OS, which is a factor in the incidence and progression of ASDs. In conclusion, oxidative damage occurs in the bodies of children with ASD, which may lead to sustained disease progression and severe clinical manifestations. We assume that timely supplementation of antioxidants is very likely to be a potential treatment for early intervention in children with ASD. Identification and detection of OS-related biomarkers may contribute to early diagnosis and timely interventions in young patients with ASD

Management of Abnormal Visual Developments

When human beings recognize the external world, more than 80% of the information come from visual function and visual system. Normal visual development and normal binocularity are the fundamental of good visual acuity and visual functions. Any abnormal visual experience would cause abnormality, such as refractive error, strabismus, amblyopia and other diseases. The patients with abnormal visual developments were reported to have abnormal, lonely, and other psycho problems. In this chapter, we will describe the normal developmental of visual function, summarize the abnormal developments and the correction or treatment

Prevalence and Prognostic Significance of HPV in Laryngeal Squamous Cell Carcinoma in Northeast China

Background/Aims: Human papillomavirus (HPV) is an etiological risk factor for a subset of head and neck squamous cell carcinomas. HPV has been proven to be a powerful prognostic biomarker for oropharyngeal cancer, but its role in the larynx has not been explored in depth. Here, we sought to evaluate the prevalence and genotype distribution of HPV in patients with laryngeal squamous cell carcinoma (LSCC) in northeast China. Methods: HPV DNA in specimens from 211 patients diagnosed with LSCC was analyzed by the polymerase chain reaction and in situ hybridization, and p16 overexpression was evaluated by immunohistochemistry. p16 expression was scored positive if strong and diffuse nuclear and cytoplasmic staining was present in > 75% of tumor cells. Results: In this study, infection with HPV and p16 expression were not absolutely consistent. Among all patients, 132 (62.6%) were positive for HPV DNA (HPV+), while 23 (10.9%) were inconsistent for HPV and p16. Multivariate analysis indicated that HPV, but not p16, is an independent prognostic factor for overall survival in LSCC. Overall survival was significantly improved in HPV+ LSCC patients compared with the HPV-negative group (hazard ratio, 0.395; 95% confidence interval, 0.185–0.843; p = 0.016). Among the 132 HPV+ patients, 28 (21.2%) were HPV-16 single infection. Conclusion: This study indicates that HPV DNA is a more reliable surrogate marker than p16 for the prediction of survival in patients with LSCC

The Structure of Tumor Endothelial Marker 8 (TEM8) Extracellular Domain and Implications for Its Receptor Function for Recognizing Anthrax Toxin

Anthrax toxin, which is released from the Gram-positive bacterium Bacillus anthracis, is composed of three proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). PA binds a receptor on the surface of the target cell and further assembles into a homo-heptameric pore through which EF and LF translocate into the cytosol. Two distinct cellular receptors for anthrax toxin, TEM8/ANTXR1 and CMG2/ANTXR2, have been identified, and it is known that their extracellular domains bind PA with low and high affinities, respectively. Here, we report the crystal structure of the TEM8 extracellular vWA domain at 1.7 Å resolution. The overall structure has a typical integrin fold and is similar to that of the previously published CMG2 structure. In addition, using structure-based mutagenesis, we demonstrate that the putative interface region of TEM8 with PA (consisting of residues 56, 57, and 154–160) is responsible for the PA-binding affinity differences between the two receptors. In particular, Leu56 was shown to be a key factor for the lower affinity of TEM8 towards PA compared with CMG2. Because of its high affinity for PA and low expression in normal tissues, an isolated extracellular vWA domain of the L56A TEM8 variant may serve as a potent antitoxin and a potential therapeutic treatment for anthrax infection. Moreover, as TEM8 is often over-expressed in tumor cells, our TEM8 crystal structure may provide new insights into how to design PA mutants that preferentially target tumor cells

How Does Environmental Regulation Affect Industrial Transformation? A Study Based on the Methodology of Policy Simulation

The difference of factor input structure determines different response to environmental regulation. This paper constructs a theoretical model including environmental regulation, factor input structure, and industrial transformation and conducts a policy simulation based on the difference of influencing mechanism of environmental regulation considering industrial heterogeneity. The findings show that the impact of environmental regulation on industrial transformation presents comparison of distortion effect of resource allocation and technology effect. Environmental regulation will promote industrial transformation when technology effect of environmental regulation is stronger than distortion effect of resource allocation. Particularly, command-control environmental regulation has a significant incentive effect and spillover effect of technological innovation on cleaning industries, but these effects do not exist in pollution-intensive industries. Command-control environmental regulation promotes industrial transformation. The result of simulation showed that environmental regulation of market incentives is similar to that of command-control

Sketch Generation with Drawing Process Guided by Vector Flow and Grayscale

We propose a novel image-to-pencil translation method that could not only generate high-quality pencil sketches but also offer the drawing process. Existing pencil sketch algorithms are based on texture rendering rather than the direct imitation of strokes, making them unable to show the drawing process but only a final result. To address this challenge, we first establish a pencil stroke imitation mechanism. Next, we develop a framework with three branches to guide stroke drawing: the first branch guides the direction of the strokes, the second branch determines the shade of the strokes, and the third branch enhances the details further. Under this framework's guidance, we can produce a pencil sketch by drawing one stroke every time. Our method is fully interpretable. Comparison with existing pencil drawing algorithms shows that our method is superior to others in terms of texture quality, style, and user evaluation. Our code and supplementary material are now available at: https://github.com/TZYSJTU/Sketch-Generation-withDrawing-Process-Guided-by-Vector-Flow-and-Grayscal

Dynamic impacts of energy consumption on economic growth in China: Evidence from a non-parametric panel data model

To empirically gauge the efficacy of energy policies, we propose a non-parametric method to investigate the relationship between economic growth and energy consumption from both time and space perspectives. Specifically, we rely on the local linear dummy variable estimation (LLDVE) method to explore the time-varying province-specific trends, the common trend, and the coefficients based on panel data from 26 provinces in China from 1995 to 2017. We find that the promotion effect of energy consumption on economic growth changes over time, as evidenced by the inverted U shape of the relationship. Moreover, the non-parametric model captures such an effect better than the parametric model. With the dual goals of sustainable economic growth and carbon emissions reduction in mind, we classify the sample according to the degree of carbon intensity, which indicates that energy efficiency should be improved in high-carbon development areas, while more attention should be paid to investment and innovations in low-carbon development areas

Learning Continuous Depth Representation via Geometric Spatial Aggregator

Depth map super-resolution (DSR) has been a fundamental task for 3D computer vision. While arbitrary scale DSR is a more realistic setting in this scenario, previous approaches predominantly suffer from the issue of inefficient real-numbered scale upsampling. To explicitly address this issue, we propose a novel continuous depth representation for DSR. The heart of this representation is our proposed Geometric Spatial Aggregator (GSA), which exploits a distance field modulated by arbitrarily upsampled target gridding, through which the geometric information is explicitly introduced into feature aggregation and target generation. Furthermore, bricking with GSA, we present a transformer-style backbone named GeoDSR, which possesses a principled way to construct the functional mapping between local coordinates and the high-resolution output results, empowering our model with the advantage of arbitrary shape transformation ready to help diverse zooming demand. Extensive experimental results on standard depth map benchmarks, e.g., NYU v2, have demonstrated that the proposed framework achieves significant restoration gain in arbitrary scale depth map super-resolution compared with the prior art. Our codes are available at https://github.com/nana01219/GeoDSR