The T-Cell Antigen Receptor: A Logical Response to an Unknown Ligand

The immune system can be roughly divided into innate and adaptive compartments. The adaptive compartment includes the B and T lymphocytes, whose antigen receptors are generated by recombination of gene segments. The consequence is that the creation of self-reactive lymphocytes is unavoidable. For the host to remain viable, the immune system has evolved a strategy for removing autoimmune lymphocytes during development. This review discusses how T lymphocytes are generated, how they recognize antigens, and how their antigen receptor directs the removal of self-reactive T cells.     

The Influence of Sequence Microvariation Among HLA-DR3 Alleles on their Structure and Complexes Formation with Presentation Peptides

The three-dimensional structure of human leukocyte antigens HLA-DR*0301 and HLA-DR*0302 have been calculated using the homology modeling approach. General structural features of our models are similar to those of related HLA molecules. The typical layout of segments of the secondary structure is well preserved. However polypeptide chains are less tightly bound, which causes slightly broader opening of the binding groove. It also results in the modified layout of pockets in the binding groove. Amino acids defining the restricted sequence diversity of studied proteins are easily available for interactions with ligands.A set of docking simulations was performed using modeled structures of both HLA molecules and various specific peptide ligands. The control docking of influenza hemagglutinin peptide into HLA-DR*0101 molecule gives the complex structure which is in good agreement with that from crystallographic studies. The extensive analysis of the structure of modeled complexes of HLA-DR*0301 and HLA-DR*0302 with various ligands indicates that sequence microvariation of both alleles is not directly controlling the binding specificity. Preferences for binding of specific ligands, as evaluated from interactions in modeled complexes, agree qualitatively with experimental observations. Thus the computer aided docking simulations can be successfully used to calculate the three-dimensional structure of HLA-ligand complexes. However detailed explanation of binding specificity can not be achieved using presently available modeling procedures.Electronic Supplementary Material available.     

乳腺癌磁共振成像影像表现与糖类抗原153、癌胚抗原、铁蛋白的相关性研究

摘要 目的：探讨乳腺癌患者磁共振成像（MRI）影像表现与糖类抗原153（CA153）、癌胚抗原（CEA）、铁蛋白的相关性。方法：收集2018年1月-2022年3月于中国人民解放军联勤保障部队第九〇一医院经手术病理证实为乳腺癌的患者48例作为研究组,其中临床分期I期15例,II期19例,III期6例,IV期8例。另选取同时期经手术确诊为乳腺良性病变的患者36例作为对照组。分析比较研究组和对照组血清CA153、CEA、铁蛋白含量及不同临床分期乳腺癌患者血清CA153、CEA、铁蛋白含量的差异。采用Pearson分析乳腺癌患者MRI影像学表现与血清CA153、CEA、铁蛋白含量的相关性。结果：研究组血清CA153、CEA、铁蛋白含量均显著高于对照组,差异有统计学意义（P＜0.001）;III-IV期乳腺癌患者血清CA153、CEA、铁蛋白含量均显著高于I-II期,差异有统计学意义（P＜0.001）。经Pearson相关性分析显示,肿瘤直径越大和有淋巴结转移时,血清CA153、CEA、铁蛋白含量越高,即乳腺癌患者肿瘤直径和淋巴结转移与血清CA153、CEA、铁蛋白含量呈正相关性（P＜0.05）;而乳腺癌患者病灶类型、肿瘤形态、肿瘤边缘、强化特征和时间-信号强度曲线与血清CA153、CEA、铁蛋白含量无相关性（P＞0.05）。结论：乳腺癌患者血清CA153、CEA、铁蛋白的含量与临床分期相关,同时与MRI影像检查发现的肿瘤直径和淋巴结转移具有一定相关性。     

Correlation between simulated physicochemical properties and hemolycity of protegrin-like antimicrobial peptides: predicting experimental toxicity

The therapeutic, antibiotic potential of antimicrobial peptides can be prohibitively diminished because of the cytotoxicity and hemolytic profiles they exhibit. Quantifying and predicting antimicrobial peptide toxicity against host cells is thus an important goal of AMP related research. In this work, we present quantitative structure activity relationships for toxicity of protegrin-like antimicrobial peptides against human cells (epithelial and red blood cells) based on physicochemical properties, such as interaction energies and radius of gyration, calculated from molecular dynamics simulations of the peptides in aqueous solvent. The hypothesis is that physicochemical properties of peptides, as manifest by their structure and interactions in a solvent and as captured by atomistic simulations, are responsible for their toxicity against human cells. Protegrins are beta-hairpin peptides with high activity against a wide variety of microbial species, but in their native state are toxic to human cells. Sixty peptides with experimentally determined toxicities were used to develop the models. We test the resulting relationships to determine their ability to predict the toxicity of several protegrin-like peptides. The developed QSARs provide insight into the mechanism of cytotoxic action of antimicrobial peptides. In a subsequent blind test, the QSAR correctly ranked four of five protegrin analogues newly synthesized and tested for toxicity.     

Interaction between dihydropyridines and phospholipid bilayers: a molecular dynamics simulation

Interaction of the calcium-channel antagonist dihydropyridines (DHPs), lacidipine and nifedipine, with a phospholipid bilayer was studied using 600 ps molecular dynamic simulations. We have constructed a double layer membrane model composed of 42 dimirystoyl-phosphatidylcholine molecules. The DHP molecules locate at about 7 Å from the centre of the membrane, inducing an asymmetry in the bilayer. While lacidipine did not induce significant local perturbations as judged by the gauche-trans isomerisation rate, nifedipine significantly decreased this rate, probably by producing a local rigidity of the membrane in the vicinity of the DHP.     

综述: 细胞穿透肽及其结构改造在siRNA传递中的应用

小RNA药物应用于临床的主要技术瓶颈在于如何高效、低毒地将小RNA分子传递到它发挥功能的场所．基于细胞穿透肽在小RNA透皮给药的临床应用中所取得的进展,本文系统评述了近年来细胞穿透肽在小RNA的体内、体外传递方面的研究动态,分析了细胞穿透肽的结构改造对肽/小RNA复合物转染进入细胞发挥功能的影响,展望了细胞穿透肽作为小RNA的体内药物传递载体的发展方向．     

T-cell receptor-engineered T cells for cancer treatment: current status and future directions

T-cell receptor (TCR)-engineered T cells are a novel option for adoptive cell therapy used for the treatment of several advanced forms of cancer. Work using TCRengineered T cells began more than two decades ago, with numerous preclinical studies showing that such cells could mediate tumor lysis and eradication. The success of these trials provided the foundation for clinical trials, including recent clinical successes using TCRengineered T cells to target New York esophageal squamous cell carcinoma (NY-ESO-1). These successes demonstrate the potential of this approach to treat cancer. In this review, we provide a perspective on the current and future applications of TCR-engineered T cells for the treatment of cancer. Our summary focuses on TCR activation and both pre-clinical and clinical applications of TCR-engineered T cells. We also discuss how to enhance the function of TCR-engineered T cells and prolong their longevity in the tumor microenvironment.     

转录调控因子WRKY超级家族:起源、结构和功能

WRKY蛋白质是一个植物特有的超级转录调控因子家族,在拟南芥和水稻基因组中分别拥有至少74个和97个成员。最占老的WRKY转录调控因子拥有2个高度保守的WRKY结构域,可能起源于15～20亿年前的真核牛物。虽然所有WRKY蛋白质主要通过特异地结合靶基因启动子区域的W盒序列而调控其表达,但各家族成员基因的生物学功能存在着各自的特异性。本文详细总结了WRKY蛋白质在调控植物发育和逆境诱导反应的信号转导途径建立等方面的分子生物学功能。     

Main Immunogenic Region of Torpedo Electroplax and Human Muscle Acetylcholine Receptor: Localization and Microheterogeneity Revealed by the Use of Synthetic Peptides

Most anti-nicotinic acetylcholine receptor (AChR) antibodies in myasthenia gravis are directed against an immunodominant epitope or epitopes [main immunogenic region (MIR)] on the AChR alpha-subunit. Thirty-two synthetic peptides, corresponding to the complete Torpedo alpha-subunit sequence and to a segment of human muscle alpha-subunit, were used to map the epitopes for 11 monoclonal antibodies (mAbs) directed against the Torpedo and/or the human MIR and for a panel of anti-AChR mAbs directed against epitopes on the alpha-subunit other than the MIR. A main constituent loop of the MIR was localized within residues alpha 67-76. Residues 70 and 75, which are different in the Torpedo and human alpha-subunits, seem to be crucial in determining the binding profile for several mAbs whose binding to the peptides correlated very well with their binding pattern to native Torpedo and human AChRs. This strongly supports the identification of the peptide loop alpha 67-76 as the actual location of the MIR on the intact AChR molecule. Residues 75 and 76 were necessary for binding of some mAbs and irrelevant for others, in agreement with earlier suggestions that the MIR comprises overlapping epitopes. Structural predictions for the sequence segment alpha 67-76 indicate that this segment has a relatively high segmental mobility and a very strong turning potential centered around residues 68-71. The most stable structure predicted for this segment, in both the Torpedo and human alpha-subunits, is a hairpin loop, whose apex is a type I beta-turn and whose arms are beta-strands. This loop is highly hydrophilic, and its apex is negatively charged. All these structural properties have been proposed as characteristic of antibody binding sites. We also localized the epitopes for mAbs against non-MIR regions. Among these, the epitope for a monoclonal antibody (mAb 13) that noncompetitively inhibits channel function was localized within residues alpha 331-351.     

转录调控因子WRKY 超级家族: 起源、结构和功能*

WRKY 蛋白质是一个植物特有的超级转录调控因子家族, 在拟南芥和水稻基因组中分别拥有至少74 个和97 个成员。最古老的WRKY 转录调控因子拥有2 个高度保守的WRKY 结构域, 可能起源于15~ 20 亿年前的真核生物。虽然所有WRKY 蛋白质主要通过特异地结合靶基因启动子区域的W 盒序列而调控其表达, 但各家族成员基因的生物学功能存在着各自的特异性。本文详细总结了WRKY 蛋白质在调控植物发育和逆境诱导反应的信号转导途径建立等方面的分子生物学功能。     

Knowledge-based Homology Modeling and Experimental Determination of Amino Acid Side Chain Accessibility by the Laser Photo CIDNP (Chemically Induced Dynamic Nuclear Polarization) Approach in Solution: Lessons from the Small Sialidase of Clostridium perfringens

The success of knowledge-based homology modelling is critically dependent on the predictive potency of the program structure-based calculations, which attempt to translate homologous sequences into three-dimensional structures, and on the actual relevance of the crystal structure for the protein topology. As quality control, experimental data for selected parameters of the proteins conformation are required. Using the crystal structure of the sialidase of Salmonella typhimurium as framework for model building of the homologous enzyme from Clostridium perfringens, a set of energy-minimised conformers is derived. These proteins present e.g. Tyr, Trp and His residues with an assessable area on the surface, since the side chains of these amino acid residues are responsive to chemically induced dynamic nuclear polarization (CIDNP), monitored by NMR. Hence, as first lesson, a comparative analysis for model-derived and experimentally determined values can be performed. The second lesson of this study concerns the notable impact of single amino acid substitutions (Tyr/Phe, Cys/Ser) on the surface accessibility of the CIDNP-reactive amino acid side chains in mutant forms of the sialidase. Corroborating the predictions from the theoretical calculations, the spectra of the engineered mutants reveal marked and non-uniform alterations. Thus, the effect of apparently rather conservative amino acid substitutions on a distinct conformational aspect of this protein, even at distant sites, should not be underestimated.     

妊娠期阴道微生态失衡与胎膜早破相关性的Meta分析

目的分析妊娠期阴道微生态失衡与胎膜早破的关系,以期指导临床。方法从PubMed、Web of Science、Cochrane Library、中国知网、维普数据库、万方数据库获得妊娠期阴道微生态失衡与胎膜早破发生风险的相关文献,检索时限截止为2020年3月。根据特定的纳入和排除标准选择研究,所有研究的设计和质量都用NOS进行评估,计算具有95%置信区间(95% CI)的优势比(OR)。结果共纳入18篇文献,其中观察组2 939例,对照组4 526例。Meta分析结果显示与胎膜早破发生相关的因素有细菌性阴道病(BV)(OR=2.54,95% CI 2.11～3.05,P<0.05)、外阴阴道假丝酵母菌病(VVC)(OR=2.03,95% CI 1.65～2.49,P<0.05)、解脲支原体感染(UU)(OR=2.75,95% CI 2.27～3.34,P<0.05)、衣原体感染(CT)(OR=5.16,95% CI 3.38～7.88,P<0.05)、滴虫性阴道炎(TV)(OR=4.68,95% CI 2.42～9.06,P<0.05)。结论妊娠期间阴道微生态失衡与胎膜早破密切相关,其中BV、VVC、UU、CT和TV增加了胎膜早破发生的风险,因此应进行有效的诊断和治疗。     

Peptides and multiple antigen peptides from Schistosoma mansoni glyceraldehyde 3-phosphate dehydrogenase: preparation, immunogenicity and immunoprotective capacity in C57BL/6 mice.

Four monoepitopic MAPs (MAP A, B, C and E) and one bis-diepitopic MAP B-E derived fromthe primary sequence of Schistosoma mansoni glyceraldehyde 3-phosphate dehydrogenase, previously tested in BALB/c mice, were examined for their immunogenicity and protective capacity in C57BL/6 mice. Despite multimerization into MAPs, MAP Aand MAP C were poorly immunogenic. In contrast toBALB/c mice, MAP E was non-immunogenic in C57BL/6 mice. Peptide B in the form of MAP B orbis-diepitopic MAPB-E elicited immune responses in C57BL/6 mice that were associated with a significant decrease in worm burden. The MAPs were prepared by the stepwise solid-phase peptide synthesis using Boc/Bzl chemistry, successfully purified on the RP-HPLC column and characterized by RP-HPLC, HPCE and MALDI-TOF MS techniques. A general strategy for MAPs purification is discussed here and the purification of MAP Band MAP E is documented in detail.     

The Structure and Stability of the Monomorphic HLA-G Are Influenced by the Nature of the Bound Peptide

The highly polymorphic major histocompatibility complex class Ia (MHC-Ia) molecules present a broad array of peptides to the clonotypically diverse αβ T-cell receptors. In contrast, MHC-Ib molecules exhibit limited polymorphism and bind a more restricted peptide repertoire, in keeping with their major role in innate immunity. Nevertheless, some MHC-Ib molecules do play a role in adaptive immunity. While human leukocyte antigen E (HLA-E), the MHC-Ib molecule, binds a very restricted repertoire of peptides, the peptide binding preferences of HLA-G, the class Ib molecule, are less stringent, although the basis by which HLA-G can bind various peptides is unclear. To investigate how HLA-G can accommodate different peptides, we compared the structure of HLA-G bound to three naturally abundant self-peptides (RIIPRHLQL, KGPPAALTL and KLPQAFYIL) and their thermal stabilities. The conformation of HLA-G^KGPPAALTL was very similar to that of the HLA-G^RIIPRHLQL structure. However, the structure of HLA-G^KLPQAFYIL not only differed in the conformation of the bound peptide but also caused a small shift in the α2 helix of HLA-G. Furthermore, the relative stability of HLA-G was observed to be dependent on the nature of the bound peptide. These peptide-dependent effects on the substructure of the monomorphic HLA-G are likely to impact on its recognition by receptors of both innate and adaptive immune systems.     

Correlation between genetic diversity and environmental suitability: taking uncertainty from ecological niche models into account

The hindcast of shifts in the geographical ranges of species as estimated by ecological niche modelling (ENM) has been coupled with phylogeographical patterns, allowing the inference of past processes that drove population differentiation and genetic variability. However, more recently, some studies have suggested that maps of environmental suitability estimated by ENM may be correlated to species' abundance, raising the possibility of using environmental suitability to infer processes related to population demographic dynamics and genetic variability. In both cases, one of the main problems is that there is a wide variation in ENM development methods and climatic models. In this study, we analyse the relationship between heterozygosity (He) and environmental suitability from multiple ENMs for 25 population estimates for Dipteryx alata, a widely distributed, endemic tree species of the Cerrado region of central Brazil. We propose a new approach for generating a statistical distribution of correlations under randomly generated ENM. The confidence intervals from these distributions indicate how model selection with different properties affects the ability to detect a correlation of interest (e.g. the correlation between He and suitability). Additionally, our approach allows us to explore which particular ensemble of ENMs produces the better result for finding an association between environmental suitability and He. Caution is necessary when choosing a method or a climatic data set for modelling geographical distributions, but the new approach proposed here provides a conservative way to evaluate the ability of ensembles to detect patterns of interest.     

Structure and Function of the Vacuolar H+-ATPase: Moving from Low-Resolution Models to High-Resolution Structures

In the absence of a high-resolution structure for the vacuolar H⁺-ATPase, a number of approaches can yield valuable information about structure/function relationships in the enzyme. Electron microscopy can provide not only a representation of the overall architecture of the complex, but also a low-resolution map onto which structures solved for individually expressed subunits can be fitted. Here we review the possibilities for electron microscopy of the Saccharomyces V-ATPase and examine the suitability of V-ATPase subunits for expression in high yield prokaryotic systems, a key step towards high-resolution structural studies. We also review the role of experimentally-derived structural models in understanding structure/function relationships in the V-ATPase, with particular reference to the complex of proton-translocating 16 kDa proteolipids in the membrane domain of the V-ATPase. This model in turn makes testable predictions about the sites of binding of bafilomycins and the functional interactions between the proteolipid and the single-copy membrane subunit Vph1p, with implications for the constitution of the proton translocation pathway.     

The influence of the nitrogen substitution in three cytisine derivatives as ligands for the neuronal nAChRs: a structural and theoretical study

Three cytisine derivatives, (-)-(7R,9S)-1-phenyl-3-(cytisin-12-yl)propan-1-one (1), (-)-(7R,9S)-1-phenyl-2-(cytisin-12-yl)ethane (2), and (-)-(7R,9S)-1,2-bis(cytisin-12-yl)ethane (3), with different electronic and steric features have been characterized by X-ray analysis and theoretical calculations in order to evaluate how structural modulations affect the intrinsic binding affinity at the neuronal nicotinic receptors (nAChRs). The crystal structures of 1 and 2, which display comparable affinities, are characterized by the same conformation of the cytisine moiety with different orientations of the substituent at N2. In 3, two independent molecules have the pyridinone rings diversely oriented. This compound has a lower affinity with respect to 1 and 2, but it increases the expression of neuronal nAChRs. Compounds 1, 2, and 3 retain the key prerequisite of the classical pharmacophoric models, with sp(3)-N-atom--HBA distances close to the expected value, both in solid state and in solution (theoretical calculations), where, in contrast with the extended in the crystal state, a curled-up conformation has been found, though maintaining the N-substituent in equatorial position.