Glycosylation, one of the ancient post-translational modifications, is often associated with extracellular glycocalyx or intracellular endoplasmic reticulum or the Golgi apparatus. Recently, an emerging intracellular glycosylation has caught our attention: O-linked β-N-acetylglucosamine(O-GlcNAc). As the only form of glycosylation that occurs in the cytosol and nucleus, O-GlcNAc was discovered in the 1980 s and has captured the interests of biologists and chemists alike. Mechanistically, it modifies the Ser and Thr residues of proteins, so it forms a yin-yang relationship with phosphorylation. Although vital for the signal transduction process, its innate low stoichiometry and high lability has impeded in-depth analysis of its modification site and function. In this review, we will provide a historical perspective on O-GlcNAc, and summarize how the recent development of chemical biology tools has sparked the glycosylation field, with a particular emphasis on its function in cell cycle control and epigenetics. As we take on a more inter-disciplinary approach with more advanced mass spectrometry technologies, we are bound to embrace a sweet future where O-GlcNAc studies will bloom and blossom.

Three dimensional genomics is an emerging field, which focuses on chromatin conformation of eukaryotic genome and related transcriptional regulation. As a hot topic in post-genomic era, it could unveil the correlation between chromatin conformation and gene regulation. With the cuttingedge 3D genomic technologies, researchers would further explore complex biological processes, such as genome folding, chromatin conformation, mechanism of transcriptional regulation, complicated biological traits, signal transduction pathways and genome maintaining, which could provide theoretical basis for life encyclopedia and precision biology. Here, we review the technologies, current situation, progress, challenges, future and effects on precision biology in the field. Hopefully, it would show the route from chromatin conformation to gene function study and how to precisely determine different spatial-template expression pattern with gene regulation network via series 3D genomics achievements.

Chromatin accessibility is one of the important indicators to evaluate the stability of chromatin structure, which is used to evaluate the binding ability of chromatin binding factors to chromosome DNA. It plays an important role in different nuclear processes, including gene transcription regulation and DNA damage repair. Abnormal regulation of chromatin accessibility is closely related to the occurrence and development of a variety of diseases, including tumors and neurodegenerative diseases. Therefore, exploration of this attribute has become a hot spot in the field of life science and disease. More and more new technologies came into being, such as chromatin conformation capture, high-throughput sequencing, and the combination of these two technologies. With the progress of technology, more and more factors involved in the regulation of chromosome accessibility have been found and summarized, including nucleosome occupation, histone modification and non-coding RNA. A number of large-scale genomic data have drawn the chromatin accessibility map of a variety of diseases, which provides data support for revealing the relationship between the occurrence and development of diseases and chromatin accessibility. Meanwhile, with the development of single-cell chromatin accessibility sequencing technology, the investigation for division of cell types at chromatin level was achieved, which makes up for the deficiency of solely relying on gene expression for cell type division. This review will explain the development and prospect of the research about chromatin accessibility from the aspects of chromatin composition and accessibility, factors affecting chromatin accessibility, detection methods of chromatin accessibility, and its roles in cancer, briefly.

Migrasomes are newly discovered cellular organelles generated during cell migration. The process to generate migrasomes is named migracytosis. Migracytosis and migrasomes function in long term intracellular communications and are shown to be essential in zebrafish embryonic development. In this review, we summarized the current research progress on migrasome, including the molecular mechanisms involved in migrasome biogenesis and its physiological significance. We also reviewed the established protocols and tools for migrasome studies, which may help setting up standard in migrasome field. In addition, we proposed the unsolved questions and potential directions of this emerging field, hoping more scientists from other field to be interested and to work on migrasomes.

Hydrogen gas (H₂) is a novel gaseous signaling molecule. Since 2007, more attention has been paid to the physiological functions and signal transduction pathways of H2. Thus, a new discipline, called hydrogen biology, has been gradually developed to elucidate the biological functions and corresponding molecular mechanisms of H2. Hydrogen biology can be divided into hydrogen medicine and hydrogen agronomy, according to its actual scope of application. In medicine, the anti-oxidative, anti-inflammatory, and anti-apoptotic effects of H₂ have been discovered based on studies in multiple animal models and thereafter some clinical trials. In fact, H₂ has ideal positive effects on ischemia/reperfusion, inflammatory-based acute tissue ischemic diseases and chronic degenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, and atherosclerosis. In plants and agronomy, it was found that H₂ could enhance plant tolerance against abiotic stress in alfalfa, rice and Arabidopsis, regulate growth, development, and nutritional values of cucumber, tomato, kiwifruit, sprouting vegetable, black barley and edible fungi. It is also demonstrated that H₂ could extend the vase life of lisianthus, rose and lily cut flowers, and improve the resistance of livestock against pathogens. In this paper, the history of hydrogen biology is described firstly, and it is proposed that electrolyzed water might be the first source of hydrogen medicine. The determination approaches of H₂, the synthetic pathway(s) of endogenous H₂, and the progresses of molecular mechanism and corresponding signal transduction of hydrogen biology were reviewed. Subsequently, the application status of hydrogen medicine and hydrogen agronomy was introduced from the perspectives of delivery, biological effects and safety of H₂. It is very interesting that the selective antioxidant mechanism of molecular hydrogen can not fully explain the existing biological effects of H₂, reflecting the complexity and diversity of this discipline. Finally, some important scientific and practical issues of hydrogen biology are proposed. Importantly, we pointed out that further development in hydrogen medicine depends on a large number of clinical trials with high reliability. Meanwhile, hydrogen agriculture also relies on large-scale field trials with multi-year and multi-site experiments in the future.

As the first-line antimalarial drugs in the world, artemisinin and its bioactive derivatives are considered high and fast effectiveness, low toxicity and safety. In the last three decades, accumulating evidences have revealed that artemisinins possess potent antiinflammatory and immunoregulatory properties, and most of these studies are focused on the autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, asthma and allergic diseases. Recent researches, however, have made an intriguing role of artemisinins in preventing obesity by inducing browning of white fat and enhancing brown fat function. Adipose tissue undergoes significant changes in terms of immune cell and inflammatory state during the progress of obesity. The potential function of artemisinins in obesity related immune regulation needs more experimental exploration. Here we provide a comprehensive summary on the reports of artemisinin and its derivatives affecting inflammation and immune response and get a promising perspective of the potential application of artemisinins in ameliorating obesity induced metabolic inflammation.

 Autophagy is an evolutionally conserved cell process, which degrades cellular contents to generate biomolecules depending on lysosome (or vacuole). The proper operation of autophagy has been shown to be tightly related to human health and diseases. 50 years ago, Christian de Duve discovered lysosome and proposed the idea of "autophagy". Nowadays, the Japanese molecular and cell biologist Yoshinori Ohsumi was given the Nobel Prize in Physiology or Medicine in 2016 because of his great breakthrough in discovery of autophagy essential genes. This review will summarize the brief history of autophagy researches and propose some unanswered questions which are worth studying in the future.

Recent technical breakthroughs in cryoelectron microscopy (cryo-EM) revolutionized structural biology, which led to the 2017 Nobel Prize in chemistry award to three scientists Jacques Dubochet, Joachim Frank and Richard Henderson, who had groundbreaking contribution to the development of cryo-EM. In this review, I will give a comprehensive review on the development history of cryo-EM, the technical aspects of the breakthroughs in cryo-EM leading to structural biology revolution, including electron microscope, image recording device and image processing algorithm, and major scientific achievements by Chinese scientists employing cryo-EM, covering protein complexes involved in or related to gene expression and regulation, protein synthesis and degradation, membrane proteins, immunity and viruses. Finally, I will give a perspective outlook on the development of cryo-EM in the future.

Dynamic functions of proteins regulate and determine the physiological and pathological processes of cells. They are not only regulated by protein’s intrinsic biochemical characteristics, but also by complex biomechanical microenvironments in vivo. The biomechanical cues often couple with biochemical cues to cooperatively modulate dynamics of protein-protein interactions, protein conformations and subsequent signal transduction. Recently, in order to investigate how biomechanical cues regulate protein dynamics, single-molecule force spectroscopy (SMFS) has been developed to successfully break the limits of traditional biochemical assays, effectively revealing protein dynamics and their regulation mechanisms. In this review, we mainly introduce four representative SMFS techniques (atomic force microscopy, optical tweezers, biomembrane force probe and magnetic tweezers) in details, and focus on their typical applications in investigating most important aspects of protein dynamics. Additionally, we also introduce commonly used force-spectroscopy assays that have been extensively applied along with above SMFS techniques, to precisely quantify the kinetics of protein-protein interactions (especially protein dissociations under biomechanical force) and conformational changes. Finally, we briefly envision future direction of the development of SMFS techniques, especially discussing how to integrate other functional assays with SMFS to study the dynamic functions of proteins in a more comprehensive way. We hope this review provide new concepts and tools for the field of biochemistry to help more biochemists to study protein dynamic functions in a more comprehensive way.

The nuclear genetic code is universal in the vast majority of living organisms. Rare non-canonical genetic codes have been described in eukaryotic nuclear genomes. Most non-canonical genetic codes reassign one or two stop codons as sense ones, and have at least one codon encoding the translation terminal signal. However, a recent study revealed that in two ciliates all three stop codons encode amino acids as well as signal for translation ermination. Furthermore, a transcriptome-based analysis revealed that Euplotes exhibit widespread programmed ribosomal frameshifting at in-frame stop codons. These findings imply that there is more than one way to read stop codons and that translation termination depends on molecular factors that we do not entirely understand. In this review, we examine evidence for ambiguous stop codon usage in ciliates, with a focus on the possible molecular mechanisms that differentiate true stop codons from “sense” stop codons. The results obtained by studying these amazing phenomena will provide insights into translation termination and gene regulation in all eukaryotes.

Dynamic ubiquitination in eukaryotes either enters proteins into the 26S proteasome degradation pathway or functions in signal transduction, and therefore regulates protein stability, localization and activity, thus participates in transcription, cell cycle, inflammation, tumor, immunity and other functions. Ubiquitination modification is a reversible process, which is regulated by ubiquitin ligases (E3s) and deubiquitylases (DUBs). DUBs mediate the deubiquitination of substrate proteins, regulate protein functions, and participate in various cellular processes. The protein abundance, localization and catalytic activity of deubiquitylases are strictly regulated. During the occurrence and development of tumors, many important tumor-related proteins are regulated by deubiquitylases, and dysfunction of deubiquitylases also affect DNA damage repair, apoptosis, autophagy, molecular signaling pathways and chromatin remodeling, which modulate the process of cell growth, invasion and metastasis in tumors. Therefore, DUB is an important protein family involved in tumorigenesis, and is potential drug targets. Many small molecule inhibitors have been used in the research of anti-tumor treatments. This article mainly summarizes the regulation mechanism of ubiquitin molecules, ubiquitin chain specificity, and deubiquitinating enzyme system in tumors, and provides basis for the design of clinical drug targets and diagnostic indicators.

The matrix remodeling associated genes family (MXRAs) was brought forward in 2002 to represent eight less-defined genes found to co-express with about three dozen well-characterized matrix remodeling-related genes in human cDNA libraries. Later studies discovered functions or biological features of most MXRAs members, but MXRA7 remained unaddressed until recently. MXRA7 was first proposed to be involved in pathogenesis of inflammatory neovascularization or fungal infection models in murine corneas, and to act as an inflammation mediator in the carbon tetrachlorideinduced acute liver injury model in mice. In the immunitymediated disease psoriasis, both public Gene Expression Omnibus(GEO) datasets obtained with human samples and our own data obtained in experimental animal model suggested that MXRA7 acted like a brake for disease development. On the other side, tibia shortening was the only anatomic phenotype observed in genetic MXRA7 deficient (MXRA7-/-) mice, implying a role of MXRA7 in osteogenesis. Lastly, public data in platforms like NCBI and Ensembl demonstrated that MXRA7 gene was conservative among vertebrate species and, at least in human and murine system, MXRA7 gene produced multiple proteincoding transcripts to generate multiple isoforms. High throughput datasets like those in GEO or publications in Pubmed revealed more clues to MXRA7 biology. In short, MXRA7 potentially plays roles during embryonic development or cell differentiation, in cellular metabolism, or in physiological or pathological processes in neural or ocular system, cardiovascular system, skeletal system, or in solid tumors, leukemia, immune diseases or infections. In conclusion, current data strongly suggested that MXRA7 proteins are novel constituents of extracellular and intracellular matrixes and might play significant roles in health or diseases, thus deserve more investigation.

Hydrogen sulfide (H₂S), the third gasotransmitter, was first known as poisonous and its physiological function has been uncovered increasingly in living organism. In less than a decade, significant research progresses on the H₂S signal in plants were achieved. H₂S synthetases, which are located in various subcellular fractions such as cytoplasm, mitochondria and chloroplast, are more abundant in plants than in animals and show a spatio-temporal expression pattern. Pharmaceutical method is the primary way to study H₂S function at present and genetic evidences are growing constantly. In addition, tools for studying endogenous H₂S is changing from indirect method such as methylene blue measurement to direct gas/liquid chromatography, fluorescent probe or active electrode monitoring. Recent studies for the physiological effects of H2S in plants are mainly focused on the alleviating effects and mechanisms of abiotic stresses such as drought or heavy metal. There are also reports focused on studying the effects of H₂S on the regulation of plant growth and development. It is found that H₂S displays physiological effects either through interactions with phytohormone, other gasotransmitters and reactive oxygen, or through sulfhydrylation modification of proteins and so on. Though the specificity of plant gasotransmitter makes it difficult to study, the extensive and peculiar physiological functions of H₂S signal always own the scientific significance and the application prospect now and into the future.

DNA double-strand breaks (DSBs) is the most deleterious DNA lesion that threatens genomic integrity and cell survival. Homologous recombination (HR) and non-homologous end joining (NHEJ) are the two major repair pathways. The repair of DSBs involves both concentration of DNA repair proteins at the site of damage and alterations of chromatin structure. Dynamic changes of chromatin architecture surrounding the DSBs are spatially and temporally regulated, so as to elaborately regulate DSB repair. Specific chromatin modifications develop a repair permissive chromatin state, which directly contributes to the access and assembly of DSB repair machinery, channels repair pathway choice and controls DNA damage checkpoints. Notably, repair pathway choice is critical to genome stability. Inappropriate repair or repair failure will lead to genome instability and even contribute to tumorigenesis. In this review, we summarize the important roles of chromatin structure and dynamic changes of chromatin modifications in DSB repair. Also, we highlight the concept of targeting chromatin regulators in response to genotoxic stress for cancer treatment, and how this can provide significant opportunities for DNA damage-based therapies in the future.

The 2017 Nobel Prize in Chemistry was awarded to Jacques Dubochet, Joachim Frank and Richard Henderson for their development of cryo-electron microscopy (cryo-EM), which revolutionized structural biology. In this survey review, I will first introduce cryo-EM and review the history of its development and the contributions of three Nobel Prize laureates in the development of cryo-EM, and give a personal opinion on the reason for the Nobel Prize award, and finally, give a personal view on the enlightenment to Chinese scientists of the Nobel Prize award.

The discovery of integrator complex (INT) expanded our understanding of noncoding U-rich small nuclear RNA (U snRNA) maturation and transcriptional regulation, and has revived the research boom in related fields. This complex consists of at least 14 subunits, weighting over 1.4 MD. On one hand, it functions by the cleavage of transcripts; on the other hand, it interacts with protein phosphatase 2A (PP2A) and dephosphorylates the C-terminal repeat sequence of RNA polymerase Ⅱ (PolⅡ), thus regulating the transcriptional activity of RNA PolⅡ, and functions in the production of various RNAs (messenger RNA, small nuclear RNA, enhancer RNA, etc.). INT is recruited to the CTD during transcriptional initiation stage and moves along the U small nuclear RNA (snRNA) gene during transcription. Upon the recognition of 3′ maturation sequence element, its cleavage activity is triggered and the matured transcripts are released. Besides, it is also involved in many other processes, including protein-coding gene transcription pause-release, transcriptional elongation, regulation of enhancer RNA transcription, and DNA and RNA metabolism etc. Meanwhile, the significance of INT complex or its components in tumorigenesis, pathogenesis, and ontogeny has being gradually highlighted. Nevertheless, the structural and compositional studies just took a new breakthrough recently. The 14 subunits that make up the complex are characterized by a large number of α-helices, which are further assembled into a huge transcription regulation machine based on the formation of functional modules. This article will mainly discuss about the composition, structural characteristics, functional studies, disease-association, and problem outlook of the integrator complex.

10月1日，2018年度诺贝尔生理学或医学奖揭晓。鉴于他们在肿瘤免疫治疗领域的开拓性工作，来自美国MD安德森癌症研究中心的James Allison和日本京都大学的Tasuku Honjo摘得桂冠。......

Genomic DNA is the genetic carrier, and it encodes the information needed to guide the multiplying of all living species, and the growth, development and metabolic activation of organisms. DNA damage occurs momently even under the environmental stress or normal living status. As a principal cellular intrinsic mechanism, DNA repair plays an irreplaceable role in maintaining genomic stability and decreasing the risk of cancer and some other critical human diseases. 2015 Nobel Chemistry Prize has awarded to T Lindahl, A Sancar and P Modrich for their outstanding contributions on DNA repair mechanisms studies. This review focused on three Nobel Prize laureates and their main contributions on the discovery and mechanism delineating of DNA repair pathways. The related three fundamental DNA repair pathways, base excision repair, nucleotide excision repair and mismatch repair were discussed. These three repair pathways are mainly responsible for repairing the DNA damage induced by UV radiation and genotoxic chemicals, such as base damage, pyrimidine dimer, chemical adduct, and the mismatch of base-pair produced during DNA replication. It was also reviewed that the two gainers of 2015 Albert Lasker Basic Medical Research Award and their contributions on discovering how the DNA-damage response protects cells against DNA damage. At last, a brief outlook was made on the development of DNA repair research teams and status in China.

Protein production by the ribosome is an essential process that accounts for nearly 50% of the energy demand in rapidly dividing cells. This complex process is not perfect and can be perturbed by various factors such as defects on the mRNA or the ribosome, starvation, stress, and others. If protein synthesis stops before the ribosome reaches a stop codon, the cell needs to employ a network of quality control factors that release the stalled ribosome, degrade the mRNA and the partially synthesized polypeptide. In eukaryotes this surveillance system is collectively called Ribosome Quality Control (RQC), and in this review we will focus on the function, targets, and evolution of RQC from yeast to human.

The circadian clock is an evolved internal mechanism enables organisms to adapt to day-night environmental changes. Circadian clocks function widely in the regulation of physiological activities, so malfunction of the clock can result in severe health problems that can substantially decrease quality-of-life. In mammals, the suprachiasmatic nucleus (SCN)-a small region located in the hypothalamus-functions as the master clock in governing the whole
body’s oscillations and coordinates appropriate responses to exogenous environmental changes. From the 1980 s to the 1990 s, a number of genes controlling the clock were discovered through genetic mutation screens. In mammals and most other organisms, the circadian clock is composed of a so-called "transcription-translation negative feedback loop (TTFL)". Long-term recording methods have been greatly enabling in the circadian research field and have substantially deepened our understanding of clock mechanisms. For instance, genetic period mutants in Drosophila were discovered, and the causal gene was subsequently cloned by measuring eclosion and locomotor rhythms. mammalian Clock mutant was discovered and the causal gene was cloned by recording the autonomous activity (wheel-running) rhythm in mice. Furthermore, studies of circadian clock gene expression rhythms at the cellular and tissue levels were enabled by recording luminescent rhythms of PER2::LUC mice from ex vivo cultured tissues or cells in the presence of luciferin. Notably, in vivo circadian clock measurement, especially recordings in the brain, have had slower progress. Nevertheless, in recent years there have been substantial breakthroughs in the techniques that can be used for in vivo circadian recording studies. In this review, we summarize various circadian clock recoding systems and highlight a recent study from our laboratory in which we achieved the in vivo recording of circadian rhythms in freely moving mice.

Hepatitis B virus (HBV) is prevalent worldwide. More than 600 000 people die from liver cirrhosis, liver failure and hepatocellular carcinoma caused by HBV infection annually, making it a serious threaten to human life and health. Nucleos(t)ide analogs and interferons are two main antiviral agents used in clinical practice, but neither of them directly target or eliminate intrahepatic covalently closed circular (cccDNA), which is exactly why chronic hepatitis B (CHB) is difficult to be cured and it also contributes to viral rebound after secession of antiviral therapy. Therefore, quantification of intrahepatic cccDNA is of great significance in evaluating efficacy and estimating the endpoint of antiviral treatment. However, several limitations prevent the liver biopsy from being a routine clinical practice. Serum HBV RNA has been suggested as one of the ideal surrogates of cccDNA activity. This article summarizes the features of serum HBV RNA and its potentials to reflect the activity of intrahepatic cccDNA. Also, we discuss some clinical practice guidelines on the management of HBV infection and expert consensuses that accept HBV RNA as biomarkers. And finally, we expect its future use as an indicator to evaluate the antiviral activity of new therapeutic compounds.

   

     自2016年第1期，我刊开设特约综述栏目，精心邀选在某一专业或专题研究上有影响力的专家进行约稿，就其研究领域进行系统的总结和展望，反映国内外热点研究领域的最新进展，为目标学术领域的发展趋势提供指导和参考建议。
    至今已发表9篇特约综述，篇篇精品，有前沿与热点，如对当年诺奖及相关内容的解读；有对某一领域、专题全面的总结；也有对当今最新技术系统性的介绍。这些特约综述都是在编辑与专家的多次沟通和交流之后的成果，发表之后表现出更大的影响力，有更高的点击量、下载量和引用率。
    我刊重点打造特约综述栏目，头版头条、封面文章，并有编者按和作者简介。我们希望把特约综述栏目建设成学术交流的桥梁，一方面推广介绍特约专家个人及研究领域，一方面为本领域专家相互了解提供平台，特别是对于青年学者、研究生而言，通过对特约综述的阅读，可以快速掌握某一领域的知识框架，把握领域发展的方向。
    中文毕竟是我们的母语，中文特约综述为科研工作者认识、了解国际科学前沿、发展趋势提供最快捷的途径。我们希望特约综述成为广大读者喜爱的栏目，期待未来有更多的特约综述发表。
                   《中国生物化学与分子生物学报》编辑部 尚伟芬

So far, researchers have found more than one hundred different kinds of chemical modifications on RNA. Most of these modifications are distributed on high abundant non-coding RNAs and are important for maintaining the functions of these non-coding RNAs. In recent years, thanks to the application of highresolution mass spectrometry and the development of whole-transcriptome sequencing technologies, more and more modifications on mRNA have been discovered, and accurately mapped and localized, including N6-methyladenosine (m6A), N6,2-O-Dimethyladenosine (m6Am), 5-methylcytosine (m5C), inosine (I), pseudouridine (Ψ), N1-methyladenine (m1A), 2′-O-methylation (Nm), N4-acetylcytosine (ac4C) and N7-methylguanine (m7G), etc. Among them, m6A is the most abundant internal modification in eukaryotic mRNA. The identification of its modifying enzymes, recognition proteins, and the discovery of its extensive biological functions have set off an upsurge in the study of ost-transcriptional modifications on mRNA, thus promoting an emerging research field, i.e. Epitranscriptomics. Although our understanding of these reversible and dynamic chemical modifications has just begun to take shape, there is no doubt that a new era of research on genetic information regulation has arrived. This review focuses on the three types of epitranscriptome modifications, namely m6Am, m1A, and pseudouridine—that have been studied by our group. It provides an in-depth introduction to its distribution, function, and high-throughput detection technology, and aims to provide a better understanding of related fields and a window into the flourishing development of the epitranscriptomics.

Hypoxia-inducible factor (HIF) is a family of transcription factor regulated by oxygen. The α subunit, including HIF-1α, HIF-2α and HIF-3α, is oxygen-labile subunit which forms heterodimer with β subunit, to activate target gene expression in response to hypoxia. Moreover, HIF per se is under tight control, including regulation of protein level through transcription and posttranslational modification, to ensure cell response to hypoxia appropriately. Since immune response is often accompanied by local hypoxia, HIF plays a key role in innate and adaptive immune responses. For innate immunity system, HIF regulates the development, polarization and function of neutrophils, macrophages and dendritic cells, by activating metabolism-related gene expression and other mechanisms. For adaptive immunity, recent studies have established the crucial function of HIF in mediating CD4⁺ T cell differentiation and function. This review summarizes recent progress on the regulating mechanisms and functions of HIF in immune cells.

Free editing of genomic DNA has long been a biologist’s dream, and with the discovery and application of a powerful gene-editing tool called CRISPR-Cas9, that dream is coming true. At first, several CRISPR-Cas systems such as Cas9, Cas12a and Cas12f were found to be used for eukaryotic DNA editing. Subsequently, RNA-targeting nucleases such as Cas13a, Cas13b and Cas13d were discovered successively. In addition, a variety of new CRISPR-Cas systems have been engineered with higher DNA-cutting activity, greater specificity and smaller sizes than the natural CRISPR system. These artificially engineered CRISPR-Cas systems form a powerful tool set for DNA sequence knockout, base replacement, epigenetic editing, and even activation and suppression of gene expression. CRISPR gene editing technology is not only a powerful tool for gene function research, but also shows great potential in the discovery of therapeutic targets for diseases, nucleic acid diagnosis of pathogens, clinical treatment of tumors and other diseases. Of course, many potential problems need to be solved in practical application of CRISPR, such as efficient delivery system in vivo, immunogenicity, off-target effect and so on. These issues will be discussed in this review. We believe that with the further improvement of CRISPR editing technology, it will play a greater role in the prevention and treatment of human diseases in a more perfect and precise manner.

Surf4 is a member of the Surfeit gene cluster. It is widely expressed and localized in endoplasmic reticulum. As a cargo receptor, Surf4 participates in the transport of proteins between the endoplasmic reticulum and Golgi apparatus. It is newly discovered that Surf4 participates in the transport of apolipoprotein B, thus affecting the transport of very low density lipoprotein precursors. It plays a regulatory role in VLDL secretion. Knockout of liver Surf4 can significantly reduce plasma total cholesterol and triglyceride levels without inducing liver lipid accumulation and pathological changes. These results suggest that Surf4 may be a potential drug target and has potential value in the diagnosis and treatment of cardiovascular diseases. In this paper, the main physiological functions of Surf4, especially the transport function of apolipoprotein B transport between endoplasmic reticulum and Golgi apparatus as a transport receptor, as well as the research progress of its involvement in the regulation of lipid metabolism and related diseases, are systematically expounded. This paper can also improve in-depth research of Surf4 and its potential application as a new method of lipid-lowering therapy for hyperlipidemia patients.

Protein ubiquitination, as one of the main protein post-translational modifications in eukaryotic cells, mediates the specific intracellular protein degradation through the ubiquitin - proteasome system (UPS), as well as broadly participates and regulates almost all living processes including gene transcription, signal transduction, DNA damage and repair, cell cycle, stress response, and immune response. The precise regulation of the UPS constitutes a stable and complex ubiquitination signal network, and the disorder of ubiquitination usually causes the occurrence and development of cancer, neurodegenerative diseases, metabolic diseases and other diseases. In recent years, proteomics based on mass spectrometry (MS) has gradually matured and greatly promoted the depth and breadth of ubiquitination modification research. Relying on ubiquitinated protein/peptide enrichment technology development and upgrading of high-throughput, high-coverage and high-sensitivity of mass spectrometry detection platform, the ubiquitinomics is rapidly developed and used to describe the protein ubiquitination map, which has been widely used in the research and mechanism exploration of ubiquitination proteome in human pathophysiology. In this paper, ubiquitinated protein/peptide enrichment methods, mass spectrometry identification techniques, quantitative labeling techniques and data processing methods, as well as existing problems and challenges in the research of ubiquitinomics are reviewed. Meanwhile, the applications of ubiquitinomics techniques in diseases research are reviewed, which provide a reference for the discovery and identification of ubiquitin modification proteins, and ideas for the screening of drug targets and therapeutics of related diseases.

The RNase A superfamily, also known as the vertebrate secreted ribonucleases superfamily, is the most extensively studied ribonuclease family in the fields of protein structure, enzymology and molecular evolution of the 20th century. Since the first member was isolated from the bovine pancreas in the early of last century, thousands of members have been identified from hundreds of vertebrates, including mammals, amphibians, reptiles, birds and fish. The early research on the members of this family has not only promoted the development of protein chemistry technology, but also set a foundation for the modern biological research. So far ithas been known that the human RNase A superfamily includes 8 canonical members (RNase 1 ~ RNase 8) and 5 non-canonical members (RNase 9 ~ RNase 13). In terms of their functions, it was once thought that the members of the family only degraded RNA. With the discovery of angiogenin (RNase 5), eosinophil-derived neurotoxin (EDN; RNase 2) and eosinophils cationic protein (ECP; RNase 3), it has been realized that other functions exist, which are either dependent or independent on their catalytic activity, including host defense, immunomodulation, angiogenesis, antitumor activity and so on. However, our understanding of the functions of these members remains incomplete. Herein, we review the research history of the RNase A superfamily and discuss the future direction with emphasis on their non-RNA degradation functions under both physiological and pathological conditions.

 

A series of compartments separating different biomolecules exist to ensure specificity and efficiency of biochemical reactions and regulation processes within living cells. Aside from membrane-bound organelles, membraneless organelles exist to condense proteins and nucleic acids in different granules so as to guarantee efficiency of biochemical reactions in specific spatiotemporal conditions. Mounting evidence indicates liquid-liquid phase separation (LLPS) as an important mechanism in mediating assembly of membraneless granules. This paper introduces the possible assembling mechanism of membraneless granules; then moves on to summarize the function of some membraneless granules and illustrates the role phase separation plays when they perform physiological functions. We also summarize some phase separation databases and the experimental evidences that they collected. This article expects to review the formation, biological function and data resources of membraneless compartments to inspire researchers and promote the application of high-throughput methods in this field.

Circadian clock is a mechanism that organisms evolved to adapt to the day-night alteration caused by the 24-hour-period of earth self-rotation. From photosynthesis and leaf opening-closing of plants to sleep-wake, feeding, metabolism, hormone secretion, and body temperature fluctuation of mammalians, are all under control of the circadian clock. Generally, endogenous rhythm is relatively stable and has the temperature compensation effects. Central clock is synchronized by external light conditions, and the rhythms of peripheral tissues are affected by the metabolism of the body’s own feedback. However, in certain extreme circumstances, such as the polar regions where constant darkness or light maintains for months, the plateaus where oxygen content is low and the temperature changes dramatically throughout the day, arid desert areas with a wide range of temperature variations between day and night, lightless deep-sea, and even the space far away from the Earth, other environmental factors besides light can also affect the circadian clock of the organisms. In this review, we discuss the molecular mechanisms by which light, hypoxia and temperature influence circadian clock, and summarize the effects of light, oxygen and temperature on circadian clock in the polar, plateau, desert, deep-sea, and space at individual and molecular level. These studies may help us to a better understanding on how organisms adapt to extreme environments, and provide more information for people who need to work in extreme environments to adjust their sleep and physical states.

 

Obesity is a global health problem. One third of the adult population in the world is overweight or obese, and the proportion of obese children is also increasing year by year. In addition, overweight or obese people are vulnerable to serious chronic diseases, such as type II diabetes, hypertension, cardiovascular disease and asthma. Increasing evidence shows that chronic inflammation is an important feature of obesity, and persistent inflammation can lead to obesity or related metabolic diseases. Therefore, obesity is now considered as a low-grade chronic inflammatory disease associated with metabolic disorders. Understanding the relationship between immune cells and fat deposition may be of great significance for developing therapeutic strategies for obesity and related metabolic diseases. Macrophages are the most abundant immune cells in adipose tissues and play an important role in the induction and regression of inflammation. This review summarizes the response of macrophages in adipose tissues in obesity, and the regulatory mechanism of macrophages on adipocytes, which then affects the occurrence and development of obesity. We also summarize four main ways for macrophages for obesity regulation: macrophages reduce or increase fat deposition by interfering with the expression of PPARg or Nadk in adjacent adipocytes by secreting exosome; macrophage polarization between M1 and M2 types cause changes in fat deposition; macrophages regulate lipid deposition by secreting regulatory factors that cause changes of sympathetic nerve fibers in adipose tissues; macrophages regulate lipid deposition by capturing exogenous mitochondria. Thus, the change of macrophages in obesity is a key event and understanding its regulatory mechanism may be a new direction of obesity treatment in the future.

Organoid construction and culture technology opens a new frontier in biomedicine in recent years, which has been widely applied in the fields of tissue and organ development, disease pathogenesis, drug development and regenerative medicine. The core technique of organoid construction and culture is established according to the mechanistic studies about different tissue and organ development in vivo. A three-dimensional (3D) microenvironment consisting of extracellular matrix components and multiple cytokines is designed and constructed to support stem cell proliferation and differentiation. Based on the specific 3D microenvironment, stem cells and their differentiated cells can form self-organizing organoids resembling small units of the organ of origin in structure and function. Although the construction and culture technologies of various types of organoids have been widely used, there are still many technical challenges, such as the complexity of manipulation, the uncertainty of the yields of organoids, and structural and functional differences between organoids and real tissues. The development of advanced biofabrication technologies has promoted the improvement of organoid culture systems. In this review, we focus on the research progress of 3D microenvironment constructed by matrix components and cytokines and discuss the application of advanced biofabrication technologies in organoid construction and culture. Microwell-based cultural technology has been used to control organoid development and generate organoids in similar size and function. Micropatterning-based organoid platforms enable stem cells definitively proliferate and differentiate into functional cells in response to micropattern design and can accurately control organoid formation. 3D bioprinting technology can be used to build blocks in bioprinted 3D models reproducing the cellular variety and cytoarchitecture of real tissues. It remains a great challenge to improve the organoid culture systems and generate multiple organoids resembling the actual tissues or organs. The convergence of organoid culture and biofabrication technologies may help improve the utility of organoids in research and therapeutic applications.

Ubiquitination is a unique protein post-translational modification in eukaryotic cells. It regulates a variety of physiological processes, such as protein homeostasis, cell cycle, immune response, DNA repair, and vesicle transport. In view of the importance of ubiquitin in live cells, pathogens have derived a series of effector proteins targeting the host ubiquitin process in the long-term evolutionary process, aiming to regulate the ubiquitin process in the host and render an internal environment suitable for the growth and reproduction of pathogens. Legionella pneumophila is a gram-negative bacterium that is responsible for Legionella pneumoniae pneumonia, causing fever and lung infection with a fatality rate of 15%~30% in severe cases. The Dot/Icm type IV secretory system is the most important virulence system in the infection of Legionella pneumophila. In the process of infecting host cells, Legionella pneumophila uses this secretion system to secrete more than 330 effector proteins to assist bacterial survival, proliferation and escape in host cells. Several effector proteins of Legionella pneumophila regulate the host ubiquitination process directly or indirectly. Recent studies found that some effectors can mediate non-canonical ubiquitination of host proteins, which is different from the classical ubiquitination process. Here, we introduce the latest research progress of novel ubiquitination mediated by effecting proteins of Legionella pneumophila, providing a reference for understanding the important role of ubiquitination in the pathogenesis of Legionella pneumophila.

长久以来，我们“顾名思义”，“理所当然”地认为核糖核酸酶A的功能就是降解核糖核酸（RNA）。事实上，随着研究的深入，发现该家族不少成员不仅能降解RNA，而且能精准地在特定位点切割RNA产生功能性非编码RNA，甚至具有“非酶”功能！例如，我们课题组研究的核糖核酸酶A超家族成员5（ribonuclease 5，也称angiogenin，中文译为“血管生成素”）不仅以酶的形式参与RNA代谢（主要是rRNA、tRNA和miRNA），而且能以转录因子的方式促进rRNA转录、以细胞因子的方式调控细胞行为、作为细胞内分子机器的一个成员与蛋白质相互作用；不仅是一个应激响应蛋白质，而且在维持细胞/组织稳态中发挥重要作用。因此，在《中国生物化学与分子生物学报》编辑部的支持下，本专栏邀请了国内从事核糖核酸酶A研究的专家，结合自己的研究专长，分别从核糖核酸酶A超家族的研究历史、发挥多种生物学功能的结构基础、在肿瘤发生发展中的作用、抗微生物作用、活性检测方法等角度系统综述了该家族的研究进展，并在同一实验条件下系统评估了该家族在人体中的8个典型成员的抗菌活性。 首先，本课题组回顾了核糖核酸酶A超家族的研究历程，探讨了未来的研究方向，特别呼吁要系统研究该超家族成员除降解RNA外的其他生理病理功能；为吸引大家的关注，特别将文章题目定为“核糖核酸酶Ａ超家族：不仅仅是一组降解RNA的酶”。其次，为帮助读者更好地理解该家族成员发挥不同作用的原因，邀请从事人源核糖核酸酶A免疫调节研究的四川农业大学陆路副教授撰写“人核糖核酸酶Ａ家族生物学功能的结构基础”，概述了决定家族成员酶活性、抗微生物特征、免疫调节等生物学功能的结构基础。近年来，美国德州大学安德森癌症中心的洪明奇教授、塔夫茨大学的胡国富教授等团队相继报道了核糖核酸酶A超家族成员1、4、5、7等在不同肿瘤中的作用，引发了学术界的兴趣。为此，本专栏邀请在tiRNA等非编码RNA与肿瘤领域有深厚造诣的宁波大学郭俊明教授全面综述了“核糖核酸酶Ａ家族典型成员在肿瘤发生中的作用”。为深入理解该超家族成员对微生物的杀伤活性及内在机制，本专栏邀请长期从事微生物与宿主相互作用、最近专门研究家族成员1、2、5与先天免疫关系的哈尔滨医科大学张凤民教授撰写“人核糖核酸酶Ａ超家族抗微生物活性及其作用机制”，对各成员的抗微生物（包括病毒、细菌、真菌）和抗寄生虫活性及其作用机制进行系统综述，并展望了其作为抗微生物活性物质和天然免疫分子在治疗严重和耐药微生物感染中的应用前景。为帮助读者系统了解当前的核糖核酸酶A活性检测方法，邀请创新研发了多种新型检测技术的湖南大学刘斌教授撰写“RNase A活性检测及其在癌症靶向治疗中的应用”，不仅介绍了基于传统技术的酸溶法、凝胶电泳法、电化学法方法和液滴微流体法，而且全面总结了基于荧光探针技术的新型活性检测方法。最后，考虑到当前世界各实验室对该家族成员的抗菌活性报道不一致，安排浙江大学的盛静浩副教授组织队伍，在同一实验条件下以半致死浓度评估了人源8个典型成员对革兰氏阴性菌和革兰氏阳性菌的抗菌活性，为正确认识该家族的抗菌活性提供了参考。 希望通过本专栏的文章，让大家更全面地认识核糖核酸酶A超家族成员的功能及其在临床诊疗、甚至疾病预警预防的应用前景，吸引更多的研究者投入到相关领域的研究中，以期全面、深入地解析该家族成员的生理病理功能。

气体信号递质(gasotransmitters)又称气体信号分子,是一类细胞内源性小分子气体,参与细胞内诸多信号转导途径,在动植物代谢及其调控中发挥着不可替代的重要作用。经过二十多年的发展,科学家们已经逐步认识到除了一氧化氮(NO)、一氧化碳(CO)和硫化氢(H₂S)三种经典气体信号递质外,氢气(H₂)和甲烷(CH₄)等多种气体均可能是潜在的气体信号递质。
总体看,越来越多的研究成果展示出气体信号递质在医学和农业等领域所具有的理论意义和巨大应用潜力。气体递质的相关研究加深了我们对医学领域细胞信号转导过程的理解,同时也引起了植物领域研究者的广泛兴趣。本专栏以气体信号递质为主题,除了特邀长期从事相关研究领域的专家总结研究进展外,还收集了5篇气体信号递质方面的研究论文,以期为相关领域的研究者提供参考。
南京农业大学生命科学学院谢彦杰教授等在“硫化氢调节植物氧化应激响应的作用机制”一文中总结了植物中H₂S产生途径,以及H₂S、活性氧(reactive oxygen species, ROS)和活性氮(reactive nitrogen species, RNS)在调节植物氧化应激响应中的研究进展;山西大学生命科学学院的裴雁曦教授等在“硫化氢信号对大白菜FLCs时空表达模式的调控作用”研究论文中发现H₂S可能是通过调节大白菜中4个BrFLCs同源基因的表达影响植物开花;针对H₂S在植物能量代谢中扮演的角色,山西大学生命科学学院金竹萍教授等在“H₂S信号参与SDH调控能量和活性氧代谢过程的作用机制”研究论文中,初步揭示了H₂S信号与电子传递链之间的关系,并探索H₂S在能量代谢和ROS平衡过程中的相关调节机制;针对H₂S是否通过氧化应激调节动物衰老过程这一问题,厦门大学医学院李鸿珠教授在“硫化氢抗衰老作用的分子机制”一文中,从抑制氧化应激、抗炎、保护线粒体功能、维持蛋白质稳态和上调自噬方面总结了H₂S抗衰老的分子机制,讨论了目前研究存在的问题和未来研究方向,尝试为抗衰老和治疗衰老相关疾病提供新的思路。
与H₂S相类似,NO在农产品保鲜中也具有抗衰老作用。甘肃农业大学廖伟彪教授等在“一氧化氮在延缓农产品采后衰老中的作用机制”中针对NO延缓农产品采后衰老的作用机制,系统地总结了NO与褪黑素、乙烯(ETH)、H₂、H₂S、过氧化氢和钙离子等信号分子的互作,从而为利用NO以及衍生物延缓农产品衰老、提高储藏品质的理论研究,以及农产品采后保鲜剂的研发提供参考;华中农业大学植物科学技术学院吴洪洪教授团队在“CeO₂纳米颗粒调控活性氧稳态和一氧化氮水平提高水稻耐旱能力”研究论文中,从ROS和NO信号分子的角度,初步探索了氧化铈纳米颗粒提高水稻抗旱性的机制,从而丰富了纳米农业可持续发展的理论。
作物对重金属耐受和富集问题一直是现代农业生产实践中的重要命题。西北农林科技大学生命科学学院李积胜教授团队在“乙烯促进木质素合成减少镉吸收和积累提高番茄耐镉性”的论文中发现Cd²⁺胁迫提高了番茄幼苗ETH合成关键蛋白甲硫氨酸腺苷转移酶(methionine adenosyltransferase,MAT)活性,并提出MAT介导的ETH合成可能是番茄提高耐镉性的分子机制,从而为ETH在果蔬作物安全生产实践提供了初步的理论依据。
H₂是近来发现的一种潜在的气体信号递质。针对上述热点问题,河南师范大学生命科学学院段红英教授等在“氢气处理促进地黄生长发育及主要药用成分积累”一文中的研究结果表明纳米富氢水处理不仅可以促进地黄生长发育,还可以通过调控环烯醚萜苷合成通路关键酶基因,提高地黄药用成分积累,为H₂在中药材生产中的应用提供了新思路。
云南师范大学生命科学学院李忠光教授撰写的“气体递质:古老气体在植物响应温度胁迫中的新角色”一文,系统地总结了包括H₂S、NO、CO、ETH、H₂、CH₄等9种具备气体信号递质基本特征的分子在植物代谢和胁迫应答中的作用和最新研究进展,详细介绍了信号分子的特性、合成代谢、分解代谢及其相互作用,并从抗氧化系统、渗透调节系统、离子平衡系统、水平衡系统、热激蛋白、翻译后修饰和生物膜修复与重建的角度,综述了气体信号递质生物学作用的生物化学和分子生物学基础。
与已知的气体信号递质不同,氩气作为一种具有潜在生物学功能的气体,逐渐引起了科学家的注意。南京农业大学生命科学学院沈文飚教授团队在“方兴未艾的氩气生物学”一文中总结了氩气生物学效应及其潜在的分子机制,包括氩气的不同施用方式以及在动物神经保护、心血管疾病、炎症性疾病和器官移植等临床模型中的正面作用,并总结了其在农产品采后保鲜和植物耐逆性方面的研究进展,提出酶蛋白的磷酸化与脱磷酸化修饰可能是其生物学效应的重要分子机制。
总体看,气体信号递质调控的生理和病理代谢是一个极其复杂的调控过程,其相关研究已经逐步从动物扩大到植物,体现其生物学作用的广泛性。希望通过本专栏的文章,让读者进一步认识气体信号递质的功能及其在农业实践和临床诊疗中的潜在应用,吸引更多的研究者投入到相关领域的研究中,以期全面、深入地解析气体信号递质的生物学功能和作用机理。

A biomarker is a measurable change associated with the biological process (including continuously from the healthy stage to the disease stage). According to the theory of homeostasis, urine accumulates all kinds of early changes of the body, so we can find subtle changes at the very beginning of the disease development. As urine is the better source of the next-generation biomarkers, urine biomarker studies are expected to greatly promote the development of medical technologies such as human disease diagnosis, prevention, treatment, or prognosis. However, the components found in clinical samples of urine are not only related to the disease, but also associated with many other confounding factors. Using animal models, we can eliminate interfering factors caused by medicine and other lifestyle factors and we can also study early biomarkers even before the earliest clinical symptoms appear. In biomarker studies of human samples, the effects of confounding factors such as therapeutic drugs must be considered. To discover small early changes in disease, pre-and-post control of the same person can minimize most interfering factors. The combined method of urine proteomics and one-to-many analysis can be applied to the exploration of any unknown disease. One-to-many analysis means a comparative analysis of one sample to many controls. In this way, changes in urinary proteins before, during and after disease and/or treatment can be found, which can provide useful information for early detection and evaluation of the disease condition and treatment effect. To sum up, the recognition of urinary biomarkers will require the support of the policy and ethical principles, the cooperation of more doctors and patients and the participation of more foundations and companies. This review focuses on the concepts, theoretical ideas, research status, methods and technologies, and prospects of urine biomarkers and urine proteomics.

The RNase A family members are involved in various physiological and pathological processes such as cell proliferation, survival, development, differentiation, migration, and invasion. Because the RNase A activity and protein expression levels in humans are closely related to the development of pancreatic, ovarian, bladder, and thyroid cancers, therefore accurate monitoring of RNase A levels can help to elucidate the molecular mechanism of tumor pathogenesis, drug screening, clinical diagnosis, and prognosis assessment. In addition, the RNase A family can specifically hydrolyze cytosine (C) or uracil (U) residues of RNA, which can effectively kill tumor cells and inhibit HIV-1 virus replication, thus RNase A has the function of killing tumor cells by lysing intracellular RNA molecules and inducing apoptosis, which is a promising class of anti-tumor protein drugs. Nanotechnology-based delivery of RNase A with therapeutic functions to specific target sites of cells to achieve the anti-tumor function of protein-targeted therapy has shown good application prospects. This paper focuses on the existing activity assays of RNase A and its application in targeted therapeutic-related diseases, aiming to provide a reference for utilization of RNase A in clinical applications and targeted drug screenings.

山东第一医科大学动脉粥样硬化研究所和第二附属医院的秦树存受邀撰写的“新的脂代谢调控基因-货运受体Surf4”一文，系统介绍了Surf4蛋白作为货运受体如何参与载脂蛋白在内质网与高尔基体之间的转运，进而影响肝细胞极低密度脂蛋白和小肠上皮细胞乳糜微粒分泌。希望深化人们对Surf4的认知，为其潜在的应用转化提供新的思路。血浆脂蛋白的组成和水平反映了机体内脂质代谢状态，临床检测已经把血浆脂蛋白检测作为常规指标，如何利用脂蛋白水平评价代谢性疾病患病风险、发展状况和治疗效果是临床医生普遍关心的问题。深圳大学化学与环境工程学院食品营养与安全实验室的何庆华围绕这些问题进行了“脂蛋白及其亚类在机体中的功能”的综述和展望。脂肪组织是体内脂代谢的重要场所，近年来对脂肪组织中巨噬细胞在脂代谢过程中的作用有了新的认识。西北农林科技大学的庞卫军在“脂肪组织中巨噬细胞在肥胖过程中的作用及其调控机制”一文中总结出巨噬细胞参与肥胖调控的4条主要途径，值得读者仔细阅读和学习。此外，质膜磷脂的脂质过氧化是诱发细胞铁死亡的关键因素，华中科技大学同济医学院的袁萍将肿瘤细胞抑制脂质过氧化和抵抗铁死亡的研究进展呈现在“癌症中与脂质过氧化相关的铁死亡抑制机制”一文中。脂代谢的表观遗传调控机制是本领域的新兴热点研究主题，尤其是对众多长非编码RNA以及环状RNA是否对脂代谢具有调控作用还不知晓。延安大学生命科学学院王晓涧在“长非编码RNA CASC15影响肝细胞SREBP1a表达及定位”的研究论文中揭示CASC15通过促进SREBP1a前体蛋白质表达以及向核内转位的方式影响肝细胞脂肪酸合成。山西农业大学动物科学学院的李步高发现猪环状RNA分子circECH1具有抑制前体脂肪细胞增殖功能，相关研究成果在“CircECH1 inhibits proliferation of porcine preadipocyte by sponging miR-365-5p”论文中展示。

脂代谢的生理和病理性改变是复杂的调控过程。希望通过本专栏的文章，让读者对血浆脂蛋白代谢、某些疾病状态下脂代谢过程的改变有更加深入的认识，并以此为基础在脂代谢领域做出突破性研究成果，为治疗脂代谢紊乱相关性疾病提供更多更好的干预靶点。