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2021 ◽  
Vol 12 ◽  
Author(s):  
Soumya Mukherjee ◽  
Alvaro Sanchez-Bernabeu ◽  
Laura C. Demmers ◽  
Wei Wu ◽  
Albert J. R. Heck

Mass-spectrometry based immunopeptidomics has provided unprecedented insights into antigen presentation, not only charting an enormous ligandome of self-antigens, but also cancer neoantigens and peptide antigens harbouring post-translational modifications. Here we concentrate on the latter, focusing on the small subset of HLA Class I peptides (less than 1%) that has been observed to be post-translationally modified (PTM) by a O-linked N-acetylglucosamine (GlcNAc). Just like neoantigens these modified antigens may have specific immunomodulatory functions. Here we compiled from literature, and a new dataset originating from the JY B cell lymphoblastoid cell line, a concise albeit comprehensive list of O-GlcNAcylated HLA class I peptides. This cumulative list of O-GlcNAcylated HLA peptides were derived from normal and cancerous origin, as well as tissue specimen. Remarkably, the overlap in detected O-GlcNAcylated HLA peptides as well as their source proteins is strikingly high. Most of the O-GlcNAcylated HLA peptides originate from nuclear proteins, notably transcription factors. From this list, we extract that O-GlcNAcylated HLA Class I peptides are preferentially presented by the HLA-B*07:02 allele. This allele loads peptides with a Proline residue anchor at position 2, and features a binding groove that can accommodate well the recently proposed consensus sequence for O-GlcNAcylation, P(V/A/T/S)g(S/T), essentially explaining why HLA-B*07:02 is a favoured binding allele. The observations drawn from the compiled list, may assist in the prediction of novel O-GlcNAcylated HLA antigens, which will be best presented by patients harbouring HLA-B*07:02 or related alleles that use Proline as anchoring residue.


2021 ◽  
Vol 12 ◽  
Author(s):  
Xuelun Zou ◽  
Leiyun Wang ◽  
Linxiao Xiao ◽  
Zihao Xu ◽  
Tianxing Yao ◽  
...  

BackgroundTo investigate the relationship between different classes of obesity and stroke, we conducted a stratified Mendelian randomization (MR) study.MethodsThe body mass index (BMI) data of 263,407 Europeans with three classes of obesity (obesity class I, 30 kg/m2 ≤ BMI < 35 kg/m2; obesity class II, 35 kg/m2 ≤ BMI < 40 kg/m2; obesity class III, 40 kg/m2 ≤ BMI) were extracted from the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Summary-level data of stroke and its subtypes [ischemic stroke (IS) and intracerebral hemorrhage (ICH)] were obtained from the genome-wide association study (GWAS) meta-analysis, which was performed by the MEGASTROKE consortium. MR methods were used to identify the causal relationships.ResultsThe MR analysis revealed that both obesity class I [odds ratio (OR) = 1.08, 95% CI: 1.05–1.12, p = 1.0 × 10-5] and obesity class II (OR = 1.06, 95% CI: 1.03–1.09, p = 1 × 10-4) were significantly positively related to IS, while obesity class III was not (OR = 1.01, 95% CI: 0.96–1.06, p = 0.65). In contrast to IS, there was no class of obesity associated with ICH risk. Further examination of the relationship between obesity classification and IS subtypes revealed that certain degrees of obesity were related to large artery stroke (LAS) (OR = 1.14, 95% CI: 1.04–1.24, p = 2.8 × 10-3 for class I; OR = 1.08, 95% CI: 1.01–1.16, p = 0.002 for class II) and cardioembolic stroke (CES) (OR = 1.11, 95% CI: 1.02–1.20, p = 0.02 for class I; OR = 1.08, 95% CI: 1.02–1.15, p = 0.007 for class II).ConclusionsA higher risk of IS, but not ICH, could be linked to obesity classes I and II. A strong association between LAS and CES and obesity was observed among all IS subtypes in the obese population.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bénédicte Pérignon ◽  
Octave Nadile Bandiaky ◽  
Caroline Fromont-Colson ◽  
Stéphane Renaudin ◽  
Morgane Peré ◽  
...  

AbstractThis prospective randomized clinical trial aimed to evaluate the effect of low-level laser therapy on tooth movement during Class II intermaxillary elastics treatment. Forty-two patients with Class II malocclusion were included, and their maxillary quadrants were allocated into two groups: treatment with an active diode laser and a placebo group. In each group, the time taken to obtain Class I occlusion after 6 months, rate of movement, total displacement of the maxillary canine to Class I occlusion and pain were recorded. The time to reach Class I occlusion in the active laser group (2.46 ± 2.1 months) was not significantly different from that in the placebo group (2.48 ± 2.0 months) (p = 0.938). Interestingly, the total distance of movement on the active laser side (2.27 ± 1.5 mm) was significantly greater than that on the placebo side (1.64 ± 1.3 mm) (p = 0.009). The pain levels on days 1, 2 and 3 were not significantly different between the laser and placebo sections. The rate of distance change toward Class I occlusion in the laser group (1.1 ± 0.7 mm/month) was significantly higher than that in the placebo group (0.74 ± 0.6 mm/month) (p = 0.037). Low-level laser therapy (970 nm) did not reduce the time needed to obtain Class I occlusion, but a significant acceleration in tooth movement was observed in the irradiated group.Trial registration: NCT02181439. Registered 04 July 2014—https://www.clinicaltrials.gov/ct2/results?term=cinelaser.


2021 ◽  
Author(s):  
Can Yue ◽  
Wangzhen Xiang ◽  
Xiaowen Huang ◽  
Yuan Sun ◽  
Jin Xiao ◽  
...  

African swine fever virus (ASFV) is the causative agent of African swine fever (ASF), which is a devastating pig disease threatening the global pork industry. However, currently no commercial vaccines are available. During the immune response, major histocompatibility complex (MHC) class I molecules select viral peptide epitopes and present them to host cytotoxic T lymphocytes, thereby playing critical roles in eliminating viral infections. Here we screened peptides derived from ASFV and determined the molecular basis of ASFV-derived peptides presented by the swine leukocyte antigen (SLA)-1*0101. We found that peptide binding in SLA-1*0101 differs from the traditional mammalian binding patterns. Unlike the typical B and F pockets used by the common MHC-I molecule, SLA-1*0101 uses the D and F pockets as major peptide anchor pockets. Furthermore, the conformationally stable Arg 114 residue located in the peptide-binding groove (PBG) was highly selective for the peptides. Arg 114 draws negatively charged residues at positions P5 to P7 of the peptides, which led to multiple bulged conformations of different peptides binding to SLA-1*0101 and creating diversity for T cells receptor docking. Thus, the solid Arg 114 residue acts as a “mooring stone” and pulls the peptides into the PBG of SLA-1*0101. Notably, the T cells recognition and activation of p72-derived peptides were verified by SLA-1*0101 tetramer-based flow cytometry in peripheral blood mononuclear cells (PBMCs) of the donor pigs. These results refresh our understanding of MHC I molecular anchor peptides, and provide new insights into vaccine development for the prevention and control of ASF. IMPORTANCE The spread of African swine fever virus (ASFV) has caused enormous losses to the pork industry worldwide. Here, a series of ASFV-derived peptides were identified, which could bind to swine leukocyte antigen SLA-1*0101, a prevalent SLA allele among Yorkshire pigs. The crystal structure of four ASFV-derived peptides and one foot-and-mouth disease virus (FMDV)-derived peptide complexed with SLA-1*0101 revealed an unusual peptide anchoring mode of SLA-1*0101 with D and F pockets as anchoring pockets. Negatively-charged residues are preferred within the middle portion of SLA-1*0101-binding peptides. Notably, we determined an unexpected role of Arg 114 of SLA-1*0101 as a “mooring stone” which pulls the peptide anchoring into the PBG in diverse “M” or “n” shaped conformation. Furthermore, T cells from donor pigs could activate through the recognition of ASFV-derived peptides. Our study sheds light on the uncommon presentation of ASFV peptides by swine MHC I and benefits the development of ASF vaccines.


2021 ◽  
Vol 12 ◽  
Author(s):  
Silvia D’Amico ◽  
Valerio D’Alicandro ◽  
Mirco Compagnone ◽  
Patrizia Tempora ◽  
Giusy Guida ◽  
...  

The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cell lines perturbs the engagement of NK cell inhibitory receptors Ly49C/I and Killer-cell Immunoglobulin-like receptors (KIRs), respectively, by their specific ligands (MHC class I molecules), thus leading to NK cell killing. However, the effect of ERAP1 inhibition in tumor cells was highly variable, suggesting that its efficacy may depend on several factors, including MHC class I typing. To identify MHC class I alleles and KIRs that are more sensitive to ERAP1 depletion, we stably silenced ERAP1 expression in human HLA class I-negative B lymphoblastoid cell line 721.221 (referred to as 221) transfected with a panel of KIR ligands (i.e. HLA-B*51:01, -Cw3, -Cw4 and -Cw7), or HLA-A2 which does not bind any KIR, and tested their ability to induce NK cell degranulation and cytotoxicity. No change in HLA class I surface expression was detected in all 221 transfectant cells after ERAP1 depletion. In contrast, CD107a expression levels were significantly increased on NK cells stimulated with 221-B*51:01 cells lacking ERAP1, particularly in the KIR3DL1-positive NK cell subset. Consistently, genetic or pharmacological inhibition of ERAP1 impaired the recognition of HLA-B*51:01 by the YTS NK cell overexpressing KIR3DL1*001, suggesting that ERAP1 inhibition renders HLA-B*51:01 molecules less eligible for binding to KIR3DL1. Overall, these results identify HLA-B*51:01/KIR3DL1 as one of the most susceptible combinations for ERAP1 inhibition, suggesting that individuals carrying HLA-B*51:01-like antigens may be candidates for immunotherapy based on pharmacological inhibition of ERAP1.


2021 ◽  
Vol 10 (23) ◽  
pp. 5644
Author(s):  
Yu-Chuan Tseng ◽  
Shih-Wei Liang ◽  
Szu-Ting Chou ◽  
Shih-Chieh Chen ◽  
Chin-Yun Pan ◽  
...  

This study investigated the relationship between the thickness of the ramus and skeletal patterns using cone-beam computed tomography (CBCT) for sagittal split ramus osteotomy. Ninety participants were categorized into three skeletal patterns (Class I, Class II, and Class III). The first vertical slice (slice 0) was observed in the intact mandibular canal, and then moved forward to 40 mm (slice 21) with a 2 mm interval. The thickness of buccal bone marrow (B value) was measured. A B value of ≤0.8 mm was considered to be the major risk factor causing the occurrence of postoperative lower lip paresthesia. There were 461 sides with a B value of ≤0.8 mm. There was a significant difference in the skeletal patterns [Class III (198 sides: 15.7%) > Class I (159 sides: 12.6%) > Class II (104 sides: 8.3%)]. Class II participants had significantly larger B values (2.14 to 3.76 mm) and a lower occurrence rate (≤0.8 mm) than those of Class III participants (1.5 to 3 mm) in front of the mandibular foramen (from 6 mm to 20 mm). Class III participants had significantly shorter buccal bone marrow distance and a higher occurrence rate of B values (≤0.8 mm) than Class II.


2021 ◽  
Author(s):  
Xiaohui Liu ◽  
Fengwei Li ◽  
Tianjian Sun ◽  
Jiawei Guo ◽  
Xingwang Zhang ◽  
...  

Abstract Cytochrome P450 enzymes (P450s) are highly attractive biocatalysts due to their versatile catalytic activities. A vast majority of P450s require redox partner (RP) proteins to sequentially transfer two electrons for O2 activation and substrate oxidation. However, little information is available on cognate RPs for P450s, which greatly limits P450 function exploration and practical application. Thus, the stategy of building various hybrid P450 catalytic systems with surrogate RPs has often adopted to engineer P450 biocatalysts for different purposes. In this study, we comprehensively compare three pairs of frequently-used surrogate redox partners SelFdx1499/SelFdR0978, Adx/AdR and Pdx/PdR and in terms of their electron transfer properties. The three selected bacterial Class I P450s to accept electrons from RPs include PikC, P450sca-2 and CYP-sb21, which are responsible for production of macrolide antibiotics, the cholesterol-lowering drug pravastatin, and a hair-growth-stimulating agent. Both experimental studies and structural analysis show that SelFdx1499/SelFdR0978 is the most promising RP compared to Adx/AdR and Pdx/PdR. The results provide insights into the domination for P450-redox partner interactions in modulating the catalytic activity of P450s. This study not only produces a more active biocatalyst but also suggests a general chose for a universal reductase which would facilitate engineering of P450 catalyst.


2021 ◽  
Vol 12 (2) ◽  
pp. 549-550
Author(s):  
Ahmed Ali Mhawesh ◽  
Reem Naeem Ibraheem ◽  
Tamara Husham Zedan

The opportunistic pathogen, E. Cloacae has been reported to carry carbapenemas genes worldwide. Our objective was assessing the association of antibiotic resistance, integron class I and carbapenemase genes among E. Cloacae. Herein, 200 E. Cloacae were collected and identified. The antibiotic resistance of them was evaluated using Kirby Bauer method. The existence of class I integron, carbapenemase genes was investigated using polymerase chain reaction (PCR). Of the 200 E. Cloacae isolates collected, 120 isolates (60%) were from male and 80 isolates (40%) were from females. Of them, 110 isolates (55%) showed a pattern of MDR phenotype. Of these, 18 isolates (9%) showed resistance to imipenem. Based on PCR test, 134 isolates (67%) had class I integrons. Also, out of 110 MDR isolates, 52 isolates (72%) were positive in terms of the presence of class I integrons. Isolates with integrons were mostly from urinary (61%) and blood (44%) and from ICU settings (46%) and inpatients (38%). A significant relationship was observed between the presence of integron and resistance to ciprofloxacin, imipenem, meropenem, and norfloxacin antibiotics. The prevalence of blaIMP, blaOXA-48 were 18% and 4%, respectively, but none of other carbapenemase genes were detected. The existence of class I integron was high among E. Cloacae from Baghdad city. The carriage of genes resistance to carbapenems were significantly associated to the class I integrin.


PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0260748
Author(s):  
Ibrahim Al-Sumaih ◽  
Michael Donnelly ◽  
Ciaran O’Neill

Background Recorded serum 25(OH)D in survey data varies with observed and unobserved respondent characteristics. The aim of this study was to expose latent population sub-groups and examine variation across groups regarding relationships between serum 25(OH)D and observable characteristics. Methods This study explored the role of unobserved heterogeneity on associations between surveyed 25(OH)D and various factors using a sample (n = 2,641) extracted from the Saudi Health Interview Survey (2013). Linear regression and finite mixture models (FMM) were estimated and compared. The number of latent classes in the FMM was chosen based on BIC score. Result Three latent classes were identified. Class I (39.82%), class II (41.03%), and class III (19.15%) with mean 25(OH)D levels of 22.79, 34.88, and 57.45 ng/ml respectively. Distinct patterns of associations with nutrition, behaviour and socio-demographic variables were recorded across classes that were not revealed in pooled linear regression. Conclusion FMM has the potential to provide additional insights on the relationship between 25(OH)D levels and observable characteristics. It should be more widely considered as a method of investigation in this area.


Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2388
Author(s):  
Brendan Russ ◽  
Friedhelm Pfeiffer ◽  
Mike Dyall-Smith

Halovirus HF2 was the first member of the Haloferacalesvirus genus to have its genome fully sequenced, which revealed two classes of intergenic repeat (IR) sequences: class I repeats of 58 bp in length, and class II repeats of 29 bp in length. Both classes of repeat contain AT-rich motifs that were conjectured to represent promoters. In the present study, nine IRs were cloned upstream of the bgaH reporter gene, and all displayed promoter activity, providing experimental evidence for the previous conjecture. Comparative genomics showed that IR sequences and their relative genomic positions were strongly conserved among other members of the same virus genus. The transcription of HF2 was also examined by the reverse-transcriptase-PCR (RT-PCR) method, which demonstrated very long transcripts were produced that together covered most of the genome, and from both strands. The presence of long counter transcripts suggests a regulatory role or possibly unrecognized coding potential.


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