Immunological Reviews最新文献

{"title":"Allosteric Changes Underlie the Outside-In Transmission of Activatory Signals in the TCR","authors":"Balbino Alarcon,&nbsp;Wolfgang W. Schamel","doi":"10.1111/imr.13438","DOIUrl":"10.1111/imr.13438","url":null,"abstract":"<div>\u0000 \u0000 <p>Rather than being contained in a single polypeptide, and unlike receptor tyrosine kinases, the T cell receptor (TCR) divides its signaling functions among its subunits: TCRα/β bind the extracellular ligand, an antigenic peptide–MHC complex (pMHC), and the CD3 subunits (CD3γ, CD3δ, CD3ε, and CD3ζ) transmit this information to the cytoplasm. How information about the quality of pMHC binding outside is transmitted to the cytoplasm remains a matter of debate. In this review, we compile data generated using a wide variety of experimental systems indicating that TCR engagement by an appropriate pMHC triggers allosteric changes transmitted from the ligand-binding loops in the TCRα and TCRβ subunits to the cytoplasmic tails of the CD3 subunits. We summarize how pMHC and stimulatory antibody binding to TCR ectodomains induces the exposure of a polyproline sequence in the CD3ε cytoplasmic tail for binding to the Nck adapter, the exposure of the RK motif in CD3ε for recruiting the Lck tyrosine kinase, and the induced exposure and phosphorylation of tyrosine residues in all the CD3 cytoplasmic tails. We also review the yet incipient data that help elucidate the structural basis of the Active and Resting conformations of the TCR.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"329 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MAP Kinase Signaling at the Crossroads of Inflammasome Activation","authors":"Alex Vervaeke,&nbsp;Mohamed Lamkanfi","doi":"10.1111/imr.13436","DOIUrl":"10.1111/imr.13436","url":null,"abstract":"<div>\u0000 \u0000 <p>Inflammasomes are crucial mediators of both antimicrobial host defense and inflammatory pathology, requiring stringent regulation at multiple levels. This review explores the pivotal role of mitogen-activated protein kinase (MAPK) signaling in modulating inflammasome activation through various regulatory mechanisms. We detail recent advances in understanding MAPK-mediated regulation of NLRP3 inflammasome priming, licensing and activation, with emphasis on MAPK-induced activator protein-1 (AP-1) signaling in NLRP3 priming, ERK1 and JNK in NLRP3 licensing, and TAK1 in connecting death receptor signaling to NLRP3 inflammasome activation. Furthermore, we discuss novel insights into MAPK signaling in human NLRP1 inflammasome activation, focusing on the MAP3K member ZAKα as a key kinase linking ribosomal stress to inflammasome activation. Lastly, we review recent work elucidating how <i>Bacillus anthracis</i> lethal toxin (LeTx) manipulates host MAPK signaling to induce macrophage apoptosis as an immune evasion strategy, and the counteraction of this effect through genotype-specific Nlrp1b inflammasome activation in certain rodent strains.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"329 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HLA-E: Immune Receptor Functional Mechanisms Revealed by Structural Studies","authors":"Geraldine M. Gillespie,&nbsp;Max N. Quastel,&nbsp;Andrew J. McMichael","doi":"10.1111/imr.13434","DOIUrl":"10.1111/imr.13434","url":null,"abstract":"<p>HLA-E is a nonclassical, nonpolymorphic, class Ib HLA molecule. Its primary function is to present a conserved nonamer peptide, termed VL9, derived from the signal sequence of classical MHC molecules to the NKG2x-CD94 receptors on NK cells and a subset of T lymphocytes. These receptors regulate the function of NK cells, and the importance of this role, which is conserved across mammalian species, probably accounts for the lack of genetic polymorphism. A second minor function is to present other, weaker binding, pathogen-derived peptides to T lymphocytes. Most of these peptides bind suboptimally to HLA-E, but this binding appears to be enabled by the relative stability of peptide-free, but receptive, HLA-E-β2m complexes. This, in turn, may favor nonclassical antigen processing that may be associated with bacteria infected cells. This review explores how the structure of HLA-E, bound to different peptides and then to NKG2-CD94 or T-cell receptors, relates to HLA-E cell biology and immunology. A detailed understanding of this molecule could open up opportunities for development of universal T-cell and NK-cell-based immunotherapies.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"329 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11698700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The β Common Cytokine Receptor Family Reveals New Functional Paradigms From Structural Complexities","authors":"Winnie L. Kan,&nbsp;Claire M. Weekley,&nbsp;Tracy L. Nero,&nbsp;Timothy R. Hercus,&nbsp;Kwok Ho Yip,&nbsp;Damon J. Tumes,&nbsp;Joanna M. Woodcock,&nbsp;David M. Ross,&nbsp;Daniel Thomas,&nbsp;David Terán,&nbsp;Catherine M. Owczarek,&nbsp;Nora W. Liu,&nbsp;Luciano G. Martelotto,&nbsp;Jose M. Polo,&nbsp;Harshita Pant,&nbsp;Denis Tvorogov,&nbsp;Angel F. Lopez,&nbsp;Michael W. Parker","doi":"10.1111/imr.13430","DOIUrl":"10.1111/imr.13430","url":null,"abstract":"<div>\u0000 \u0000 <p>Cytokines are small proteins that are critical for controlling the growth and activity of hematopoietic cells by binding to cell surface receptors and transmitting signals across membranes. The β common (βc) cytokine receptor family, consisting of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 cytokine receptors, is an architype of the heterodimeric cytokine receptor systems. We now know that signaling by cytokine receptors is not always an “all or none” phenomenon. Subtle alterations of the cytokine:receptor complex can result in differential or selective signaling and underpin a variety of diseases including chronic inflammatory conditions and cancers. Structural biology techniques, such as X-ray crystallography and cryo-electron microscopy alongside cell biology studies, are providing detailed insights into cytokine receptor signaling. Recently, we found that the IL-3 receptor ternary complex forms higher-order assemblies, like those found earlier for the GM-CSF receptor, and demonstrated that functionally distinct biological signals arise from different IL-3 receptor oligomeric assemblies. As we enhance our understanding of the structural nuances of cytokine–receptor interactions, we foresee a new era of theranostics whereby structurally guided mechanism-based manipulation of cytokine signaling through rational/targeted protein engineering will harness the full potential of cytokine biology for precision medicine.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"329 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142918830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recognition of Self and Viral Ligands by NK Cell Receptors","authors":"Roy A. Mariuzza,&nbsp;Pragya Singh,&nbsp;Sharanbasappa S. Karade,&nbsp;Salman Shahid,&nbsp;Vijay Kumar Sharma","doi":"10.1111/imr.13435","DOIUrl":"10.1111/imr.13435","url":null,"abstract":"<p>Natural killer (NK) cells are essential elements of the innate immune response against tumors and viral infections. NK cell activation is governed by NK cell receptors that recognize both cellular (self) and viral (non-self) ligands, including MHC, MHC-related, and non-MHC molecules. These diverse receptors belong to two distinct structural families, the C-type lectin superfamily and the immunoglobulin superfamily. NK receptors include Ly49s, KIRs, LILRs, and NKG2A/CD94, which bind MHC class I (MHC-I) molecules, and NKG2D, which binds MHC-I paralogs such MICA and ULBP. Other NK receptors recognize tumor-associated antigens (NKp30, NKp44, NKp46), cell–cell adhesion proteins (KLRG1, CD96), or genetically coupled C-type lectin-like ligands (NKp65, NKR-P1). Additionally, cytomegaloviruses have evolved various immunoevasins, such as m157, m12, and UL18, which bind NK receptors and act as decoys to enable virus-infected cells to escape NK cell-mediated lysis. We review the remarkable progress made in the past 25 years in determining structures of representatives of most known NK receptors bound to MHC, MHC-like, and non-MHC ligands. Together, these structures reveal the multiplicity of solutions NK receptors have developed to recognize these molecules, and thereby mediate crucial interactions for regulating NK cytolytic activity by self and viral ligands.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"329 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695704/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142918829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Z-Nucleic Acid Sensing and Activation of ZBP1 in Cellular Physiology and Disease Pathogenesis","authors":"Sanchita Mishra,&nbsp;Ayushi Amin Dey,&nbsp;Sannula Kesavardhana","doi":"10.1111/imr.13437","DOIUrl":"10.1111/imr.13437","url":null,"abstract":"<div>\u0000 \u0000 <p>Z-nucleic acid binding protein 1 (ZBP1) is an innate immune sensor recognizing nucleic acids in Z-conformation. Upon Z-nucleic acid sensing, ZBP1 triggers innate immune activation, inflammation, and programmed cell death during viral infections, mice development, and inflammation-associated diseases. The Zα domains of ZBP1 sense Z-nucleic acids and promote RIP-homotypic interaction motif (RHIM)-dependent signaling complex assembly to mount cell death and inflammation. The studies on ZBP1 spurred an understanding of the role of Z-form RNA and DNA in cellular and physiological functions. In particular, short viral genomic segments, endogenous retroviral elements, and 3′UTR regions are likely sources of Z-RNAs that orchestrate ZBP1 functions. Recent seminal studies identify an intriguing association of ZBP1 with adenosine deaminase acting on RNA-1 (ADAR1), and cyclic GMP-AMP synthase (cGAS) in regulating aberrant nucleic acid sensing, chronic inflammation, and cancer. Thus, ZBP1 is an attractive target to aid the development of specific therapeutic regimes for disease biology. Here, we discuss the role of ZBP1 in Z-RNA sensing, activation of programmed cell death, and inflammation. Also, we discuss how ZBP1 coordinates intracellular perturbations in homeostasis, and Z-nucleic acid formation to regulate chronic diseases and cancer.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"329 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142918831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biophysical and Structural Features of αβT-Cell Receptor Mechanosensing: A Paradigmatic Shift in Understanding T-Cell Activation","authors":"Robert J. Mallis,&nbsp;Kristine N. Brazin,&nbsp;Jonathan S. Duke-Cohan,&nbsp;Aoi Akitsu,&nbsp;Hanna M. Stephens,&nbsp;Ana C. Chang-Gonzalez,&nbsp;Daniel J. Masi,&nbsp;Evan H. Kirkpatrick,&nbsp;Elizabeth L. Holliday,&nbsp;Yinnian Feng,&nbsp;Katarzyna J. Zienkiewicz,&nbsp;Jonathan J. Lee,&nbsp;Vincenzo Cinella,&nbsp;Kaveri I. Uberoy,&nbsp;Kemin Tan,&nbsp;Gerhard Wagner,&nbsp;Haribabu Arthanari,&nbsp;Wonmuk Hwang,&nbsp;Matthew J. Lang,&nbsp;Ellis L. Reinherz","doi":"10.1111/imr.13432","DOIUrl":"10.1111/imr.13432","url":null,"abstract":"<p>αβT cells protect vertebrates against many diseases, optimizing surveillance using mechanical force to distinguish between pathophysiologic cellular alterations and normal self-constituents. The multi-subunit αβT-cell receptor (TCR) operates outside of thermal equilibrium, harvesting energy via physical forces generated by T-cell motility and actin-myosin machinery. When a peptide-bound major histocompatibility complex molecule (pMHC) on an antigen presenting cell is ligated, the αβTCR on the T cell leverages force to form a catch bond, prolonging bond lifetime, and enhancing antigen discrimination. Under load, the αβTCR undergoes reversible structural transitions involving partial unfolding of its clonotypic immunoglobulin-like (Ig) domains and coupled rearrangements of associated CD3 subunits and structural elements. We postulate that transitions provide critical energy to initiate the signaling cascade via induction of αβTCR quaternary structural rearrangements, associated membrane perturbations, exposure of CD3 ITAMs to phosphorylation by non-receptor tyrosine kinases, and phase separation of signaling molecules. Understanding force-mediated signaling by the αβTCR clarifies long-standing questions regarding αβTCR antigen recognition, specificity and affinity, providing a basis for continued investigation. Future directions include examining atomistic mechanisms of αβTCR signal initiation, performance quality, tissue compliance adaptability, and T-cell memory fate. The mechanotransduction paradigm will foster improved rational design of T-cell based vaccines, CAR-Ts, and adoptive therapies.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"329 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural Immunology of SARS-CoV-2","authors":"Meng Yuan,&nbsp;Ian A. Wilson","doi":"10.1111/imr.13431","DOIUrl":"10.1111/imr.13431","url":null,"abstract":"<p>The SARS-CoV-2 spike (S) protein has undergone significant evolution, enhancing both receptor binding and immune evasion. In this review, we summarize ongoing efforts to develop antibodies targeting various epitopes of the S protein, focusing on their neutralization potency, breadth, and escape mechanisms. Antibodies targeting the receptor-binding site (RBS) typically exhibit high neutralizing potency but are frequently evaded by mutations in SARS-CoV-2 variants. In contrast, antibodies targeting conserved regions, such as the S2 stem helix and fusion peptide, exhibit broader reactivity but generally lower neutralization potency. However, several broadly neutralizing antibodies have demonstrated exceptional efficacy against emerging variants, including the latest omicron subvariants, underscoring the potential of targeting vulnerable sites such as RBS-A and RBS-D/CR3022. We also highlight public classes of antibodies targeting different sites on the S protein. The vulnerable sites targeted by public antibodies present opportunities for germline-targeting vaccine strategies. Overall, developing escape-resistant, potent antibodies and broadly effective vaccines remains crucial for combating future variants. This review emphasizes the importance of identifying key epitopes and utilizing antibody affinity maturation to inform future therapeutic and vaccine design.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"329 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11727448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Integrin Receptors: From Discovery to Structure to Medicines","authors":"M. Amin Arnaout","doi":"10.1111/imr.13433","DOIUrl":"10.1111/imr.13433","url":null,"abstract":"<div>\u0000 \u0000 <p>Innate immune cells perform vital tasks in detecting, seeking, and eliminating invading pathogens, thus ensuring host survival. However, loss of function of these cells or their overactive response to tissue injury often causes serious ailments. It is, therefore, crucial to understand at a basic level how these cells function in health and disease. A major step toward this goal came from studies I conducted in the late 1970s investigating the cause of life-threatening bacterial infections in a pediatric patient. This work led us to trace this disease to the inability of the patient's neutrophils to seek and clear infections due to an inherited deficiency in leukocyte adhesion caused by the loss of a plasma membrane glycoprotein complex now known as CD11/CD18 or β2 integrins. I followed this work by determining the 3-dimensional structures of integrins. These studies provided the foundation for understanding the unique properties of integrins in mediating bidirectional cell adhesion signaling and enabled a structure-guided design of compounds to dial down overactive integrins in common disorders, including thromboinflammatory and autoimmune diseases.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"329 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effector Functions of Antibodies","authors":"Marc Daëron","doi":"10.1111/imr.13428","DOIUrl":"10.1111/imr.13428","url":null,"abstract":"&lt;p&gt;“Antibody” is one of those specialists' words that became common language. Everyone knows that antibodies protect against infectious diseases, especially since the COVID-19 pandemic swept across the world. Everyone, or almost, even knows what antibodies look like. Their anthropomorphic Y shape has become an iconic symbol that most societies of immunology have included in their logo. What antibodies actually are, however, is not so clear in everyone's mind, as judged by media which often confuse serum with vaccine. What antibodies do and how they work is another question. Their well-known ability to recognize specific antigens with each of their two “arms” is often thought to be enough to protect; even by scientists, sometimes by immunologists. Whatever how, antibodies protect, and when they have pathogenic effects, these are viewed as the unfortunate consequences of targeting errors such as in allergic and autoimmune diseases, or collateral damages such as in inflammatory diseases.&lt;/p&gt;&lt;p&gt;Antibodies are also well known as tools. Due to their exquisite specificity, antibodies have proven unrivaled diagnostic tools and they are used in a variety of techniques adopted by all medical disciplines and beyond. Due to their powerful biological properties, antibodies have been increasingly used as therapeutic tools with amazing efficiencies. This is not new: antibodies saved thousands of children from diphtheria and many more wounded soldiers from tetanus at the beginning of the 20th century, when they were nothing but elusive substances in immune serum. They are well-known molecules now and, as serum therapy for deadly infectious diseases yesterday, humanized monoclonal antibodies have provided long-sought cures for cancers with a poor prognosis today. Not without side effects, though. But antibodies can be engineered genetically to enhance their expected effects and to decrease their unwanted effects.&lt;/p&gt;&lt;p&gt;Why, therefore, put together another series of review articles on such well-known molecules? As stated in its title, this volume of &lt;i&gt;Immunological Reviews&lt;/i&gt; is focused on the &lt;i&gt;effector functions&lt;/i&gt; of antibodies. Antibodies are bi-functional molecules: They can not only recognize antigens; they can also act on them. How they do so is poorly known by immunologists, except those who work specifically on the subject. Yet, antibodies are the main effectors of adaptive immunity, at least quantitatively: 10 mg/mL IgG and 2–3 mg/mL IgA circulate in the blood stream—and much more are present in tissues since 80% immunoglobulin-secreting plasma cells of the whole body produce mucosal IgA. How do these antibodies deal with pathogens and commensals? How can they both prevent infections and tolerate microbiotas without inducing devastating inflammatory reactions? How antibodies induced by vaccines exert their protective effects?&lt;/p&gt;&lt;p&gt;This volume deals with the effector functions of antibodies not only in health, but also in disease. If they protect aga","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"328 1","pages":"6-12"},"PeriodicalIF":7.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.13428","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}