A Multi-Parameter Sensor Based on Cascaded Photonic Crystal Cavities Filled with Magnetic Fluid

A kind of photonic crystal (PC) micro-cavity sensor based on magnetic fluid (MF) filling is designed with simulation model. Generally, many sensors’ designs are based on a universal temperature in the whole structure. However, strong photothermal effect in high Q micro-cavities will lead to different temperatures between cavities and environment inevitably. In many theoretical PC sensor designs, researchers neglected the different temperature between environment and cavities. This simple hypothesis will probably lead to failure of sensor design and get wrong temperature. Moreover, few theoretical or experimental works have been done to study optical cavity’s heating process and temperature. We propose that researchers should take seriously about this point. Here, the designed cascaded micro-cavity structure has three spectral lines and a reversible sensitivity matrix, which can simultaneously detect magnetic field, ambient temperature and MF micro-cavity temperature. It can solve the magnetic field and temperature cross-sensitivity problem, and further, distinguish the different temperatures of environment and magnetic fluid cavities. The influence of hole radius and slab thickness on the depth and Q value of the resonant spectral line are also studied. Responses of three dips to magnetic field, ambient temperature and MF micro-cavity temperature are simulated, respectively, where dip 1 belongs to MF cavity 1, dip 2 and dip 3 belong to MF cavity 2. The obtained magnetic field sensitivities are 2.89 pm/Oe, 4.57 pm/Oe, and 5.14 pm/Oe, respectively;the ambient temperature sensitivities are 65.51 pm/K, 50.94 pm/K, and 58.98 pm/K, respectively;and the MF micro-cavity temperature sensitivities are −14.41 pm/K, −17.06 pm/K, and −18.81 pm/K, respectively.

Dynamic RNA methylation modifications and their regulatory role in mammalian development and diseases

Among over 170 different types of chemical modifications on RNA nucleobases identified so far,RNA methylation is the major type of epitranscriptomic modifications existing on almost all types of RNAs,and has been demonstrated to participate in the entire process of RNA metabolism,including transcription,pre-mRNA alternative splicing and maturation,mRNA nucleus export,mRNA degradation and stabilization,mRNA translation.Attributing to the development of high-throughput detection technologies and the identification of both dynamic regulators and recognition proteins,mechanisms of RNA methylation modification in regulating the normal development of the organism as well as various disease occurrence and developmental abnormalities upon RNA methylation dysregulation have become increasingly clear.Here,we particularly focus on three types of RNA methylations:N^(6)-methylcytosine(m^(6)A),5-methylcytosine(m^(5)C),and N^(7)-methyladenosine(m^(7)G).We summarize the elements related to their dynamic installment and removal,specific binding proteins,and the development of high-throughput detection technologies.Then,for a comprehensive understanding of their biological significance,we also overview the latest knowledge on the underlying mechanisms and key roles of these three mRNA methylation modifications in gametogenesis,embryonic development,immune system development,as well as disease and tumor progression.

Tubulointerstitial nephritis antigen-like 1 is a novel matricellular protein that promotes gastric bacterial colonization and gastritis in the setting of Helicobacter pylori infection

The interaction between the gastric epithelium and immune cells plays key roles in H. pylori-associated pathology. Here, we demonstrate a procolonization and proinflammatory role of tubulointerstitial nephritis antigen-like 1 (TINAGL1), a newly discovered matricellular protein, in H. pylori infection. Increased TINAGL1 production by gastric epithelial cells (GECs) in the infected gastric mucosa was synergistically induced by H. pylori and IL-1β via the ERK-SP1 pathway in a cagA-dependent manner. Elevated human gastric TINAGL1 correlated with H. pylori colonization and the severity of gastritis, and mouse TINAGL1 derived from non-bone marrow-derived cells promoted bacterial colonization and inflammation. Importantly, H. pylori colonization and inflammation were attenuated in Tinagl1−/− and Tinagl1ΔGEC mice and were increased in mice injected with mouse TINAGL1. Mechanistically, TINAGL1 suppressed CCL21 expression and promoted CCL2 production in GECs by directly binding to integrin α5β1 to inhibit ERK and activate the NF-κB pathway, respectively, which not only led to decreased gastric influx of moDCs via CCL21-CCR7-dependent migration and, as a direct consequence, reduced the bacterial clearance capacity of the H. pylori-specific Th1 response, thereby promoting H. pylori colonization, but also resulted in increased gastric influx of Ly6Chigh monocytes via CCL2-CCR2-dependent migration. In turn, TINAGL1 induced the production of the proinflammatory protein S100A11 by Ly6Chigh monocytes, promoting H. pylori-associated gastritis. In summary, we identified a model in which TINAGL1 collectively ensures H. pylori persistence and promotes gastritis.

Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide,such as the on-going outbreak of the novel coronavirus SARS-CoV-2.Herein,we identified two potent inhibitors of human DHODH,S312 and S416,with favorable drug-likeness and pharmacokinetic profiles,which all showed broad-spectrum antiviral effects against various RNA viruses,including influenza A virus,Zika virus,Ebola virus,and particularly against SARS-CoV-2.Notably,S416 is reported to be the most potent inhibitor so far with an EC5o of 17 nmol/L and an SI value of 10,505.88 in infec-ted cells.Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells.This work demonstrates that both S312/S416 and old drugs(Leflunomide/Teriflunomide)with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide,no matter such viruses are mutated or not.

Regulation of U6 Promoter Activity by Transcriptional Interference in Viral Vector-Based RNAi

The direct negative impact of the transcriptional activity of one component on the second one in c/s is referred to as transcriptional interference （TI）. U6 is a type III RNA polymerase III promoter commonly used for driving small hairpin RNA （shRNA） expression in vector-based RNAi. In the design and construction of viral vectors, multiple transcription units may be arranged in close proximity in a space-limited vector. Determining if U6 promoter activity can be affected by TI is critical for the expression of target shRNA in gene therapy or loss-of-function studies. In this research, we designed and implemented a modified retroviral system where shRNA and exogenous gene expressions were driven by two independent transcriptional units. We arranged U6 promoter driving .shRNA expression and UbiC promoter in two promoter arrangements. In primary macrophages, we found U6 promoter activity was inhibited by UbiC promoter when in the divergent arrangement but not in tandem. In contrast, PKG promoter had no such negative impact. Instead of enhancing U6 promoter activity, CMV enhancer had significant negative impact on U6 promoter activity in the presence of UbiC promoter. Our results indicate that U6 promoter activity can be affected by TI in a proximal promoter-specific and arrange- ment-dependent manner.

A Multifunctional Lentiviral-Based Gene Knockdown with Concurrent Rescue that Controls for Off-Target Effects of RNAi

The efficient, stable delivery of siRNA into cells, and the appropriate controls for non-specific off-target effects of siRNA are major limitations to functional studies using siRNA technology. To overcome these drawbacks, we have developed a single lentiviral vector that can concurrently deplete endogenous gene expression while expressing an epitope-tagged siRNA-resistant target gene in the same cell. To demonstrate the functional utility of this system, we performed RNAi-depleted α-actinin-1 （α-ACTN1） expression in human T cells. α-ACTN1 RNAi resulted in inhibited chemotaxis to SDF-1α, but it can be completely rescued by concurrent expression of RNAi-resistant α-ACTN1 （rr-α-ACTN1） in the same cell. The presence of a GFP tag on rr-α-ACTN1 allowed for detection of appropriate subcellular localization of rr-α-ACTN1. This system provides not only an internal control for RNAi off-target effects, but also the potential tool for rapid structure-function analyses and gene therapy.

An RNA-seq-based Gene Expression Profiling of Radiation-induced Tumorigenic Mammary Epithelial Cells

Immortality and tumorigenicity are two distinct characteristics of cancers. Immortalization has been suggested to precede tumorigenesis. To understand the molecular mechanisms of tumorigenicity and cancer progression in mammary epithelium, we established a tumori- genic cell model by means of heavy-ion radiation of an immortal cell model, which was created by overexpressing the human telomerase reverse transcriptase （hTERT） in normal human mammary epithelial cells. We examined the expression profile of this tumorigenic cell line （T hMEC） using the hTERT-overexpressing immortal cell line （IhMEC） as a control. In-depth RNA-seq data was generated by using the next-generation sequencing （NGS） platform （Life Technologies SOLID3）. We found that house-keeping （HK） and tissue-spe- cific （TS） genes were differentially regulated during the tumorigenic process. HK genes tended to be activated while TS genes tended to be repressed. In addition, the HK genes and TS genes tended to contribute differentially to the variation of gene expression at different RPKM （gene expression in reads per exon kilobase per million mapped sequence reads） levels. Based on transcriptome analysis of the two cell lines, we defined 7053 differentially-expressed genes （DEGs） between immortality and tumorigenicity. Differential expression of 20 manually-selected genes was further validated using qRT-PCR. Our observations may help to further our understanding of cellular mechanism（s） in the transition from immortalization to tumorigenesis.

Precision Methylome and In Vivo Methylation Kinetics Characterization of Klebsiella pneumoniae

Klebsiella pneumoniae(K.pneumoniae)is an important pathogen that can cause severe hospital-and community-acquired infections.To systematically investigate its methylation features,we determined the whole-genome sequences of 14 K.pneumoniae strains covering varying serotypes,multilocus sequence types,clonal groups,viscosity/virulence,and drug resistance.Their methylomes were further characterized using Pacific Biosciences single-molecule real-time and bisulfite technologies.We identified 15 methylation motifs[13 N6-methyladenine(6mA)and two 5-methylcytosine(5mC)motifs],among which eight were novel.Their corresponding DNA methyltransferases were also validated.Additionally,we analyzed the genomic distribution of GATC and CCWGG methylation motifs shared by all strains,and identified differential distribution patterns of some hemi-/un-methylated GATC motifs,which tend to be located within intergenic regions(IGRs).Specifically,we characterized the in vivo methylation kinetics at single-base resolution on a genome-wide scale by simulating the dynamic processes of replication-mediated passive demethylation and MTase-catalyzed re-methylation.The slow methylation of the GATC motifs in the replication origin(oriC)regions and IGRs implicates the epigenetic regulation of replication initiation and transcription.Our findings illustrate the first comprehensive dynamic methylome map of K.pneumoniae at single-base resolution,and provide a useful reference to better understand epigenetic regulation in this and other bacterial species.

Epitranscriptomic 5-Methylcytosine Profile in PM_(2.5)-induced Mouse Pulmonary Fibrosis

Exposure of airborne particulate matter(PM)with an aerodynamic diameter less than 2.5μm(PM2.5)is epidemiologically associated with lung dysfunction and respiratory symptoms,including pulmonary fibrosis.However,whether epigenetic mechanisms are involved in PM2.5-induced pulmonary fibrosis is currently poorly understood.Herein,using a PM2.5-induced pulmonary fibrosis mouse model,we found that PM2.5 exposure leads to aberrant mRNA5-methylcytosine(m5C)gain and loss in fibrotic lung tissues.Moreover,we showed the m5C-mediated regulatory map of gene functions in pulmonary fibrosis after PM2.5 exposure.Several genes act as m5C gain-upregulated factors,probably critical for the development of PM2.5-induced fibrosis in mouse lungs.These genes,including Lcn2,Mmp9,Chi3l1,Adipoq,Atp5j2,Atp5l,Atpif1,Ndufb6,Fgr,Slc11 a1,and Tyrobp,are highly related to oxidative stress response,inflammatory responses,and immune system processes.Our study illustrates the first epitranscriptomic RNA m5C profile in PM2.5-induced pulmonary fibrosis and will be valuable in identifying biomarkers for PM2.5 exposure-related lung pathogenesis with translational potential.

Fluorescence enhancement of Tb^(3+) complexes by adding silica-coated silver nanoparticles

Six kinds of terbium ternary complexes with halo-benzoic acids were synthesized. Their compositions were determined by C, H elemental analyzer and EDTA titration. The infrared spectra, ultraviolet absorption spectra, and fluorescence spectra were also measured to identify the complexes. Elemental analysis showed that the compositions of these complexes were Tb（p-BrBA）3- H20, Tb（p-CIBA）3- 2H20, Tb（p-FBA）3- H20, Tb（o-FBA）3·2H20, Tb（o-CIBA）3· H20, and Tb（o-BrBA）3. H20, respectively. The monodispersed Ag@SiO2 core-shell nanoparticles with silica thicknesses of 10, 15, and 25 nm were success- fully prepared and characterized by transmission-electron microscopy. Fluorescence intensities of the complexes were detected before and after Ag@SiO2core-shell nanoparticles were added; the enhancement times were related to the silica-shell thick- ness. The fluorescence enhancement times were largest when the thickness of the silica shell was 25 nm. The mechanism may be attributed to the localized surface-plasmon resonance. Furthermore, the enhancement effect of terbium fluoro-benzoate complexes was the strongest in these complexes. This result may be attributed to the hydrogen bond between the hydroxyl on the surface of the silica shell and the fluorine atom.

Optimization of cold-end system of thermal power plants based on entropy generation minimization

Cold-end systems are heat sinks of thermal power cycles,which have an essential effect on the overall performance of thermal power plants.To enhance the efficiency of thermal power plants,multi-pressure condensers have been applied in some large-capacity thermal power plants.However,little attention has been paid to the optimization of the cold-end system with multi-pressure condensers which have multiple parameters to be identified.Therefore,the design optimization methods of coldend systems with single-and multi-pressure condensers are developed based on the entropy generation rate,and the genetic algorithm(GA)is used to optimize multiple parameters.Multiple parameters,including heat transfer area of multi-pressure condensers,steam distribution in condensers,and cooling water mass flow rate,are optimized while considering detailed entropy generation rate of the cold-end systems.The results show that the entropy generation rate of the multi-pressure cold-end system is less than that of the single-pressure cold-end system when the total condenser area is constant.Moreover,the economic performance can be improved with the adoption of the multi-pressure cold-end system.When compared with the single-pressure cold-end system,the excess revenues gained by using dual-and quadruplepressure cold-end systems are 575 and 580 k$/a,respectively.

Correction to:Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

CORRECTION TO:PROTEIN CELL 2020,11(10):723–739 HTTPS://DOI.ORG/10.1007/S13238-020-00768-W In the original publication the author’s name‘Dimitri Lavillete’is published incorrectly.The correct author name should be spelt as‘Dimitri Lavillette’is provided in this correction.OPEN ACCESS This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use,sharing,adaptation,distribution and reproduction in any medium or format,as long as you give appropriate credit to the original author(s)and the source,provide a link to the Creative Commons licence,and indicate if changes were made.The images or other third party material in this article are included in the article's Creative Commons licence,unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use,you will need to obtain permission directly from the copyright holder.To view a copy of this licence,visit http://creativecommons.org/licenses/by/4.0/.

GPR54 deficiency reduces the Treg population and aggravates experimental autoimmune encephalomyelitis in mice

GPR54 is highly expressed in the central nervous system and plays a crucial role in pubertal development. However, GRP54 is also expressed in the immune system, implying possible immunoregulatory functions. Here we investigated the role of GPR54 in T cell and immune tolerance. GPR54 deficiency led to an enlarged thymus, an increased number of thymocytes, and altered thymic micro-architecture starting around puberty, indicating GPR54 function in T-cell development through its regulatory effect on the gonadal system. However, flow cytometry revealed a significant reduction in the peripheral regulatory T cell population and a moderate decrease in CD4 single-positive thymocytes in prepubertal Gpr54^(-/-) mice. These phenotypes were confirmed in chimeric mice with GPR54 deficient bone marrow-derived cells. In addition, we found elevated T cell activation in peripheral and thymic T cells in Gpr54^(-/-) mice. When intact mice were immunized with myelin oligodendrocyte glycoprotein, a more severe experimental autoimmune encephalomyelitis(EAE) developed in the Gpr54^(-/-) mice. Interestingly, aggravated EAE disease was also manifested in castrated and bone marrow chimeric Gpr54^(-/-) mice compared to the respective wild-type control,suggesting a defect in self-tolerance resulting from GPR54 deletion through a mechanism that bypassed sex hormones. These findings demonstrate a novel role for GPR54 in regulating self-tolerant immunity in a sex hormone independent manner.

Correction to: Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

Figure 1.Discovery of novel and potent DHODHi and their anti-influenza A virus activities.(A)The discovery and design of S312 and S416.The detailed descriptions of the discovery workflow are in Method.Binding analysis of S312(B)and S416(C).Thermodynamic analysis of the binding of S312 and S416 to DHODH was carried out at 25 C on a MicroCal iTC200 instrument.Kinetic analysis of the binding of S312 and S416 to DHODH was performed with a Biacore T200 instrument.