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Abstract Background Staphylococcus aureus can cause serious infections by secreting many superantigen exotoxins in “carrier” or “pathogenic” states. HLA DQ and HLA DR humanized mice have been used as a small animal model to study the role of two molecules during S. aureus infection. However, the contribution of HLA DP to S. aureus infection is unknown yet. Methods In this study, we have produced HLA DP401 and HLA DRA0101 humanized mice by microinjection of C57BL/6J zygotes. Neo‐floxed IAβ+/− mice were crossbred with Ella‐Cre and further crossbred with HLA DP401 or HLA‐DRA0101 humanized mice. After several rounds of traditional crossbreeding, we finally obtained HLA DP401‐IAβ−/− and HLA DRA‐IAβ−/− humanized mice, in which human DP401 or DRA0101 molecule was introduced into IAβ−/− mice deficient in endogenous murine MHC class II molecules. A transnasal infection murine model of S. aureus pneumonia was induced in the humanized mice by administering 2 × 108 CFU of S. aureus Newman dropwise into the nasal cavity. The immune responses and histopathology changes were further assessed in lungs in these infected mice. Results We evaluated the local and systemic effects of S. aureus delivered intranasally in HLA DP401‐IAβ−/− and HLA DRA‐IAβ−/− transgenic mice. S. aureus Newman infection significantly increased the mRNA level of IL 12p40 in lungs in humanized mice. An increase in IFN‐γ and IL‐6 protein was observed in HLA DRA‐IAβ−/− mice. We observed a declining trend in the percentage of F4/80+ macrophages in lungs in HLA DP401‐IAβ−/− mice and a decreasing ratio of CD4+ to CD8+ T cells in lungs in IAβ−/− mice and HLA DP401‐IAβ−/− mice. A decreasing ratio of Vβ3+ to Vβ8+ T cells was also found in the lymph node of IAβ−/− mice and HLA DP401‐IAβ−/− mice. S. aureus Newman infection resulted in a weaker pathological injury in lungs in IAβ−/− genetic background mice. Conclusion These humanized mice will be an invaluable mouse model to resolve the pathological mechanism of S. aureus pneumonia and study what role DP molecule plays in S. aureus infection.

BACKGROUND: The abnormal expression of HLA-DR gene is related to the progression and prognosis of various tumors. The research on editing the HLA-DRA gene of endometrial cancer using CRISPR/Cas9 technology has not been reported at home and abroad. OBJECTIVE: The HLA-DRA gene of HEC-1-A cells was targeted knocked out by CRISPR/Cas9 genome engineering technology, and the function of HLA-DRA was preliminarily explored. METHODS: According to the HLA-DRA gene sequence, sgRNA was designed for HLA-DRA exons, and sg RNA, CRISPR/Cas9, enhanced green fluorescent protein and puromycin were cloned into YKO vector, respectively. The plasmid expressing sgRNA was transfected into HEC-1-A cells by liposome. After evaluating the knockout efficiency of sgRNA according to fluorescence expression, the plasmid expressing sgRNA was transfected and screened with the best concentration of puromycin to obtain stable green fluorescent protein positive cells, which were verified and analyzed by PCR, gene sequencing, and transcriptome sequencing. RESULTS AND CONCLUSION: After transfection and puromycin screening, HEC-1-A cells stably expressing green fluorescent protein were obtained. Sanger sequencing showed that the HLA-DRA exon gene in HEC-1-A cells was targeted knockout. The transcriptome sequencing results were screened for differential genes. According to the 686 differentially expressed genes screened, GO enrichment analysis and KEGG enrichment analysis were carried out, and the protein interaction network was constructed. Through the analysis of differential genes related to tumor proliferation and differentiation, it was found that the expression of COL3A1, BCL2A1, TACSTD2 and CXCR2 genes was up-regulated, and the expression of GNG11, BMP7, IL1RN, PLEK2 and CDH6 genes was down regulated. It is concluded that the HLA-DRA gene is involved in the functional regulation of a variety of organs, tissues, and cells. In addition, HLA-DRA genes may regulate the proliferation, differentiation, migration, and invasion of endometrial adenocarcinoma cells through two pathways (upregulation/ downregulation). To establish a single plasmid gene knockout method using CRISPR/Cas9 technology combined with liposome transfection, HLA-DRA was knocked out for the first time, which laid the experimental foundation for the study of endometrial cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Infertility is a common condition affecting approximately 10–20% of the reproductive age population. Idiopathic infertility cases are thought to have a genetic basis, but the underlying causes are largely unknown. However, the genetic basis underlying male infertility in humans is only partially understood. The Purpose of the study is to understand the current state of research on the genetics of male infertility and its association with significant biological mechanisms. Results: We performed an Identify Candidate Causal SNPs and Pathway (ICSN Pathway) analysis using a genome-wide association study (GWAS) dataset, and NCBI-PubMed search which included 632 SNPs in GWAS and 451 SNPs from the PubMed server, respectively. The ICSN Pathway analysis produced three hypothetical biological mechanisms associated with male infertility: (1) rs8084 and rs7192→HLA-DRA→inflammatory pathways and cell adhesion; rs7550231 and rs2234167→TNFRSF14→TNF Receptor Superfamily Member 14→T lymphocyte proliferation and activation; rs1105879 and rs2070959→UGT1A6→UDP glucuronosyltransferase family 1 member A6→Metabolism of Xenobiotics, androgen, estrogen, retinol, and carbohydrates. Conclusions: We believe that our results may be helpful to study the genetic mechanisms of male infertility. Pathway-based methods have been applied to male infertility GWAS datasets to investigate the biological mechanisms and reported some novel male infertility risk pathways. This pathway analysis using GWAS dataset suggests that the biological process related to inflammation and metabolism might contribute to male infertility susceptibility. Our analysis suggests that genetic contribution to male infertility operates through multiple genes affecting common inflammatory diseases interacting in functional pathways.

Abstract Background Immune checkpoint blockade (ICB) only works well for a certain subset of patients with non-small cell lung cancer (NSCLC). Therefore, biomarkers for patient stratification are desired, which can suggest the most beneficial treatment. Methods In this study, three datasets (GSE126044, GSE135222, and GSE136961) of immunotherapy from the Gene Expression Omnibus (GEO) database were analyzed, and seven intersected candidates were extracted as potential biomarkers for ICB followed by validation with The Cancer Genome Atlas (TCGA) dataset and the in-house cohort data. Results Among these candidates, we found that human leukocyte antigen-DR alpha (HLA-DRA) was downregulated in NSCLC tissues and both tumor and immune cells expressed HLA-DRA. In addition, HLA-DRA was associated with an inflamed tumor microenvironment (TME) and could predict the response to ICB in NSCLC. Moreover, we validated the predictive value of HLA-DRA in immunotherapy using an in-house cohort. Furthermore, HLA-DRA was related to the features of inflamed TME in not only NSCLC but also in most cancer types. Conclusion Overall, HLA-DRA could be a promising biomarker for guiding ICB in NSCLC.

Abstract Background Low-grade gliomas (LGG) are WHO grade II tumors presenting as the most common primary malignant brain tumors in adults. Currently, LGG treatment involves either or a combination of surgery, radiation therapy, and chemotherapy. Despite the knowledge of constitutive genetic risk factors contributing to gliomas, the role of single genes as diagnostic and prognostic biomarkers is limited. The aim of the current study is to discover the predictive and prognostic genetic markers for LGG. Methods Transcriptome data and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. We first performed the tumor microenvironment (TME) survival analysis using the Kaplan-Meier method. An analysis was undertaken to screen for differentially expressed genes. The function of these genes was studied by Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Following which a protein-protein interaction network (PPI) was constructed and visualized. Univariate and multivariate COX analyses were performed to obtain the probable prognostic genes. The key genes were selected by an intersection of core and prognostic genes. A clinical correlation analysis of single-gene expression was undertaken. GSEA enrichment analysis was performed to identify the function of key genes. Finally, a single gene-related correlation analysis was performed to identify the core immune cells involved in the development of LGG. Results A total of 529 transcriptome data and 515 clinical samples were obtained from the TCGA. Immune cells and stromal cells were found to be significantly increased in the LGG microenvironment. The top five core genes intersected with the top 38 prognostically relevant genes and two key genes were identified. Our analysis revealed that a high expression of HLA-DRA was associated with a poor prognosis of LGG. Correlation analysis of immune cells showed that HLA-DRA expression level was related to immune infiltration, positively related to macrophage M1 phenotype, and negatively related to activation of NK cells. Conclusions HLA-DRA may be an independent prognostic indicator and an important biomarker for diagnosing and predicting survival in LGG patients. It may also be associated with the immune infiltration phenotype in LGG.

Summary: Background: Mass vaccination has dramatically reduced the incidence of severe COVID-19, with most cases now presenting as self-limiting upper respiratory tract infections. However, those with co-morbidities, the elderly and immunocompromised, as well as the unvaccinated, remain disproportionately vulnerable to severe COVID-19 and its sequelae. Furthermore, as the effectiveness of vaccination wanes with time, immune escape SARS-CoV-2 variants could emerge to cause severe COVID-19. Reliable prognostic biomarkers for severe disease could be used as early indicator of re-emergence of severe COVID-19 as well as for triaging of patients for antiviral therapy. Methods: We performed a systematic review and re-analysis of 7 publicly available datasets, analysing a total of 140 severe and 181 mild COVID-19 patients, to determine the most consistent differentially regulated genes in peripheral blood of severe COVID-19 patients. In addition, we included an independent cohort where blood transcriptomics of COVID-19 patients were prospectively and longitudinally monitored previously, to track the time in which these gene expression changes occur before nadir of respiratory function. Single cell RNA-sequencing of peripheral blood mononuclear cells from publicly available datasets was then used to determine the immune cell subsets involved. Findings: The most consistent differentially regulated genes in peripheral blood of severe COVID-19 patients were MCEMP1, HLA-DRA and ETS1 across the 7 transcriptomics datasets. Moreover, we found significantly heightened MCEMP1 and reduced HLA-DRA expression as early as four days before the nadir of respiratory function, and the differential expression of MCEMP1 and HLA-DRA occurred predominantly in CD14+ cells. The online platform which we developed is publicly available at https://kuanrongchan-covid19-severity-app-t7l38g.streamlitapp.com/, for users to query gene expression differences between severe and mild COVID-19 patients in these datasets. Interpretation: Elevated MCEMP1 and reduced HLA-DRA gene expression in CD14+ cells during the early phase of disease are prognostic of severe COVID-19. Funding: K.R.C is funded by the National Medical Research Council (NMRC) of Singapore under the Open Fund Individual Research Grant (MOH-000610). E.E.O. is funded by the NMRC Senior Clinician-Scientist Award (MOH-000135-00). J.G.H.L. is funded by the NMRC under the Clinician-Scientist Award (NMRC/CSAINV/013/2016-01). S.K. is funded by the NMRC under the Transition Award. This study was sponsored in part by a generous gift from The Hour Glass.

Background: Hepatitis is an inflammation of the liver that has several potential causes; however, the genetic association has recently begun to be studied. Objectives: Human leukocyte antigen (HLA) is an essential component of the immune response, and in this study, we conducted a correlation analysis to determine whether genetic polymorphisms of HLA and drinking habits affect hepatitis development. Methods: Genetic polymorphisms of HLA were investigated using Korean genomic and epidemiological data. A gene association study was performed using PLINK version 1.07. Other statistical analyses and multivariate logistic regression analyses were performed using PASW Statistics version 18.0. Results: Thirteen single nucleotide polymorphisms (SNPs) in HLA-DRA showed significant statistical correlations with hepatitis. In particular, rs9268645 showed the highest statistical association with hepatitis (P = 3.97 × 10–5, odds ratio [OR] = 0.72, 95% confidence interval [CI] = 0.61–0.84). In multivariate logistic regression analysis, when considering only genetic factors, the A allele of rs9268644 showed a reduced hepatitis OR of approximately 0.52-fold. However, the group carrying the minor A allele (AA + AC) with alcohol consumption had an approximately 1.58-fold OR of hepatitis compared to that of the group carrying the same allele with no alcohol consumption. This implies that the A allele of rs9268644 has a protective effect on hepatitis by genetic factors and shows sensitivity to alcohol. Conclusions: Our results showed that hepatitis is influenced by both genetic and external factors (drinking habits), which can provide new guidelines for the prevention or treatment of hepatitis. [ABSTRACT FROM AUTHOR]

Background: Infertility is a common condition affecting approximately 10–20% of the reproductive age population. Idiopathic infertility cases are thought to have a genetic basis, but the underlying causes are largely unknown. However, the genetic basis underlying male infertility in humans is only partially understood. The Purpose of the study is to understand the current state of research on the genetics of male infertility and its association with significant biological mechanisms. Results: We performed an Identify Candidate Causal SNPs and Pathway (ICSN Pathway) analysis using a genome-wide association study (GWAS) dataset, and NCBI-PubMed search which included 632 SNPs in GWAS and 451 SNPs from the PubMed server, respectively. The ICSN Pathway analysis produced three hypothetical biological mechanisms associated with male infertility: (1) rs8084 and rs7192→HLA-DRA→inflammatory pathways and cell adhesion; rs7550231 and rs2234167→TNFRSF14→TNF Receptor Superfamily Member 14→T lymphocyte proliferation and activation; rs1105879 and rs2070959→UGT1A6→UDP glucuronosyltransferase family 1 member A6→Metabolism of Xenobiotics, androgen, estrogen, retinol, and carbohydrates. Conclusions: We believe that our results may be helpful to study the genetic mechanisms of male infertility. Pathway-based methods have been applied to male infertility GWAS datasets to investigate the biological mechanisms and reported some novel male infertility risk pathways. This pathway analysis using GWAS dataset suggests that the biological process related to inflammation and metabolism might contribute to male infertility susceptibility. Our analysis suggests that genetic contribution to male infertility operates through multiple genes affecting common inflammatory diseases interacting in functional pathways. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint blockade (ICB) only works well for a certain subset of patients with non-small cell lung cancer (NSCLC). Therefore, biomarkers for patient stratification are desired, which can suggest the most beneficial treatment.Methods: In this study, three datasets (GSE126044, GSE135222, and GSE136961) of immunotherapy from the Gene Expression Omnibus (GEO) database were analyzed, and seven intersected candidates were extracted as potential biomarkers for ICB followed by validation with The Cancer Genome Atlas (TCGA) dataset and the in-house cohort data.Results: Among these candidates, we found that human leukocyte antigen-DR alpha (HLA-DRA) was downregulated in NSCLC tissues and both tumor and immune cells expressed HLA-DRA. In addition, HLA-DRA was associated with an inflamed tumor microenvironment (TME) and could predict the response to ICB in NSCLC. Moreover, we validated the predictive value of HLA-DRA in immunotherapy using an in-house cohort. Furthermore, HLA-DRA was related to the features of inflamed TME in not only NSCLC but also in most cancer types.Conclusion: Overall, HLA-DRA could be a promising biomarker for guiding ICB in NSCLC. [ABSTRACT FROM AUTHOR]

Purpose: Reliable biomarkers to predict the outcome and treatment response of estrogen receptor (ER)-negative breast cancer (BC) are urgently needed. Since immune-related signaling plays an important role in the tumorigenesis of ER-negative BC, we asked whether Notch genes, alone or in combination with other immune genes, can be used to predict the clinical outcome and immune checkpoint blockade (ICB) for this type of cancer. Methods: We analyzed transcriptome data of 6918 BC samples from five independent cohorts, 81 xenograft triple-negative BC tumors that respond differently to ICB treatment and 754 samples of different cancer types from patients treated with ICB agents. Results: We found that among four Notch genes, the expression levels of NOTCH1 and NOTCH4 were positively associated with recurrence of ER-negative BC, and that combined expression of these two genes (named Notch14) further enhanced this association, which was comparable with that of the Notch pathway signature. Analysis of 1182 immune-related genes revealed that the expression levels of most HLA genes, particularly HLA-DMA and -DRA, were reversely associated with recurrence in ER-negative BC with low, but not high Notch14 expression. A combined expression signature of NOTCH1, NOTCH4, HLA-DMA and HLA-DRA was more prognostic for ER-negative and triple-negative BCs than previously reported immune-related signatures. Furthermore, we found that the expression levels of these four genes were also synergistically associated with T cell exclusion score, infiltration of specific T cells and ICB efficacy in ER-negative BC, thereby providing a potential molecular mechanism for the synergistic effect of these genes on BC. Conclusions: Our data indicate that a gene signature composed of NOTCH1, NOTCH4, HLA-DMA and HLA-DRA may serve as a potential promising biomarker for predicting ICB therapy efficacy and recurrence in ER-negative/triple-negative BCs. [ABSTRACT FROM AUTHOR]

Background: Low-grade gliomas (LGG) are WHO grade II tumors presenting as the most common primary malignant brain tumors in adults. Currently, LGG treatment involves either or a combination of surgery, radiation therapy, and chemotherapy. Despite the knowledge of constitutive genetic risk factors contributing to gliomas, the role of single genes as diagnostic and prognostic biomarkers is limited. The aim of the current study is to discover the predictive and prognostic genetic markers for LGG. Methods: Transcriptome data and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. We first performed the tumor microenvironment (TME) survival analysis using the Kaplan-Meier method. An analysis was undertaken to screen for differentially expressed genes. The function of these genes was studied by Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Following which a protein-protein interaction network (PPI) was constructed and visualized. Univariate and multivariate COX analyses were performed to obtain the probable prognostic genes. The key genes were selected by an intersection of core and prognostic genes. A clinical correlation analysis of single-gene expression was undertaken. GSEA enrichment analysis was performed to identify the function of key genes. Finally, a single gene-related correlation analysis was performed to identify the core immune cells involved in the development of LGG. Results: A total of 529 transcriptome data and 515 clinical samples were obtained from the TCGA. Immune cells and stromal cells were found to be significantly increased in the LGG microenvironment. The top five core genes intersected with the top 38 prognostically relevant genes and two key genes were identified. Our analysis revealed that a high expression of HLA-DRA was associated with a poor prognosis of LGG. Correlation analysis of immune cells showed that HLA-DRA expression level was related to immune infiltration, positively related to macrophage M1 phenotype, and negatively related to activation of NK cells. Conclusions: HLA-DRA may be an independent prognostic indicator and an important biomarker for diagnosing and predicting survival in LGG patients. It may also be associated with the immune infiltration phenotype in LGG. [ABSTRACT FROM AUTHOR]

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Parkinson's disease (PD) is a common progressive neurodegenerative disorder. Up to now, several single-nucleotide polymorphisms (SNPs) located in virulence gene sites have been reported linked to PD. Candidate gene association studies and genome-wide association studies have identified rs3129882, rs4248166 in HLA-DRA and rs34372695 in SYT11 as risk factors for familial or sporadic PD. However, the association between variants of HLA-DRA, SYT11 and PD are still controversial, especially in the Central Chinese population. We here performed a case-control study to investigate whether HLA-DRA and SYT11 genes could predispose to sporadic PD in the Chinese population. We investigate 486 PD patients and 457 age- and sex-matched controls from Central China to assess this association. In the allele model, the odds ratio (OR) result of rs3129882 was 0.905 (p = 0.287). Moreover, no significant difference was observed in the association between rs424816 (OR = 0.864, p = 0.106) and rs34372695 (p = 1.0) with PD risk. Genotypic analysis in SNP rs3129882, rs4248166 and rs34372695 indicated no significant association with PD. Subgroup analysis of our data showed age-onset and gender were not associated with either genotype or minor allele frequencies of rs3129882 and rs4248166. Moreover, the negative results were also observed in a meta-analysis of studies of rs3129882 from mainland China and Taiwanese population. Our results reveal that rs3129882, rs4248166 and rs34372695 do not confer significant risks for sporadic PD in the Central Chinese population. [ABSTRACT FROM AUTHOR]

Objective. The development of obesity and its metabolic complications is associated with dysregulation of various intrinsic mechanisms, which control basic metabolic processes through changes in the expression of numerous regulatory genes.

North Borneo (NB) is home to more than 40 native populations. These natives are believed to have undergone local adaptation in response to environmental challenges such as the mosquito-abundant tropical rainforest. We attempted to trace the footprints of natural selection from the genomic data of NB native populations using a panel of ∼2.2 million genome-wide single nucleotide polymorphisms. As a result, an ∼13-kb haplotype in the Major Histocompatibility Complex Class II region encompassing candidate genes TSBP1–BTNL2–HLA-DRA was identified to be undergoing natural selection. This putative signature of positive selection is shared among the five NB populations and is estimated to have arisen ∼5.5 thousand years (∼220 generations) ago, which coincides with the period of Austronesian expansion. Owing to the long history of endemic malaria in NB, the putative signature of positive selection is postulated to be driven by Plasmodium parasite infection. The findings of this study imply that despite high levels of genetic differentiation, the NB populations might have experienced similar local genetic adaptation resulting from stresses of the shared environment. [ABSTRACT FROM AUTHOR]

Background and Objectives: Abnormal expressions of CD74 and human leukocyte antigen-DR alpha (HLA-DRA) have been reported in various cancers, though their roles in cervical cancer remain unclear. This study aimed to evaluate the gene and protein expressions of CD74 and HLA-DRA in the progression from normal cervix to precancerous cervical intraepithelial neoplasia (CIN) and finally to squamous cell carcinoma (SCC). Materials and Methods: The gene expression profiles of CD74 and HLA-DRA were determined in formalin-fixed paraffin-embedded tissues, with three samples each from normal cervixes, human papillomavirus type 16/18-positive, low-grade CIN (LGCIN), high-grade CIN (HGCIN), and squamous cell carcinoma (SCC) using Human Transcriptome Array 2.0. Immunohistochemical expression of the proteins was semi-quantitatively assessed in another cohort of tissue microarray samples comprising 7 normal cervix cases, 10 LGCIN, 10 HGCIN, and 95 SCC. Results: The transcriptomics profile and proteins’ expression demonstrated similar trends of upregulation of CD74 and HLA-DRA from normal cervix to CIN and highest in SCC. There was a significant difference in both proteins’ expression between the histological groups (p = 0.0001). CD74 and HLA-DRA expressions were significantly associated with CIN grade (p = 0.001 and p = 0.030, respectively) but not with the subjects’ age or SCC stage. Further analysis revealed a positive correlation between CD74 and HLA-DRA proteins. Conclusions: CD74 appears to promote cervical carcinogenesis via oncogenic signalling mechanisms and may serve as a potential antitumour target. Additionally, the upregulation of HLA-DRA, often associated with stronger immunogenicity, could be a promising biomarker for developing immunotherapies.

Three novel HLA‐DRA alleles, DRA*01:03, DRA*01:04, and DRA*01:05 alleles with unique amino acid sequences. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is a common demyelinating neurodegenerative disorder with significant heritability. Previous studies have associated genetic variants in human leukocyte antigen (HLA) complex, IL2RA, and HMGB1 genes with the pathophysiology of MS. Methods: In order to investigate the gene association in the Iranian population, we performed a genotyping study of 36 variants in the mentioned genes using Sanger sequencing in 102 MS patients and 113 healthy controls. Results: Our results identified significant associations as well as significant allele frequency differences in some of the studied single-nucleotide polymorphisms including rs4935356, rs3177928, and rs7197 from HLA-DRA gene, and rs12722489 and rs12722490 variants from IL2RA gene (p< 0.05). Moreover, the strong linkage disequilibrium of two common haplotypes was estimated from the HLA-DRA gene. Conclusions: This association study may suggest the role of these polymorphisms in the genetic susceptibility of MS in the Iranian population and would facilitate the recognition of causative variants in this disease. [ABSTRACT FROM AUTHOR]

HLA‐DRA encodes the alpha chain of the HLA‐DR protein, one of the classical HLA class II molecules. Reported polymorphism within HLA‐DRA is currently limited compared with other HLA genes, as only a single polymorphism encodes an amino acid difference in the translated protein. Since this SNP (rs7192, HLA00662.1:g.4276G>T p.Val217Leu) lies within exon 4, in the region encoding the cytoplasmic tail, the resulting protein is effectively monomorphic. For this reason, in‐depth studies on HLA‐DRA and its function have been limited. However, analysis of sequences from the 1000 Genomes Project and preliminary data from our lab reveals unrepresented polymorphism within HLA‐DRA, suggesting a more complex role within the MHC than previously assumed. This study focuses on elucidating the extent of HLA‐DRA polymorphism, and extending our understanding of the gene's role in HLA‐DR~HLA‐DQ haplotypes. Ninety‐eight samples were sequenced for full‐length HLA‐DRA, and from this analysis, we identified 20 novel SNP positions in the intronic sequences within the 5711 bp region represented in IPD‐IMGT/HLA. This polymorphism gives rise to at least 22 novel HLA‐DRA alleles, and the patterns of intronic and 3′ UTR polymorphism correspond to HLA‐DRA~HLA‐DRB345~HLA‐DRB1~HLA‐DQB1 haplotypes. The current understanding of the organization of the genes within the HLA‐DR region assumes a single lineage for the HLA‐DRA gene, as opposed to multiple gene lineages, such as in HLA‐DRB. This study suggests that the intron and 3′ UTR polymorphism of HLA‐DRA indicates different lineages, and represents the HLA‐DRA~HLA‐DRB345~HLA‐DRB1~HLA‐DQB1 haplotypes. [ABSTRACT FROM AUTHOR]

Background: Staphylococcus aureus can cause serious infections by secreting many superantigen exotoxins in "carrier" or "pathogenic" states. HLA DQ and HLA DR humanized mice have been used as a small animal model to study the role of two molecules during S. aureus infection. However, the contribution of HLA DP to S. aureus infection is unknown yet., Methods: In this study, we have produced HLA DP401 and HLA DRA0101 humanized mice by microinjection of C57BL/6J zygotes. Neo-floxed IAβ +/- mice were crossbred with Ella-Cre and further crossbred with HLA DP401 or HLA-DRA0101 humanized mice. After several rounds of traditional crossbreeding, we finally obtained HLA DP401-IAβ -/- and HLA DRA-IAβ -/- humanized mice, in which human DP401 or DRA0101 molecule was introduced into IAβ -/- mice deficient in endogenous murine MHC class II molecules. A transnasal infection murine model of S. aureus pneumonia was induced in the humanized mice by administering 2 × 10 8  CFU of S. aureus Newman dropwise into the nasal cavity. The immune responses and histopathology changes were further assessed in lungs in these infected mice., Results: We evaluated the local and systemic effects of S. aureus delivered intranasally in HLA DP401-IAβ -/- and HLA DRA-IAβ -/- transgenic mice. S. aureus Newman infection significantly increased the mRNA level of IL 12p40 in lungs in humanized mice. An increase in IFN-γ and IL-6 protein was observed in HLA DRA-IAβ -/- mice. We observed a declining trend in the percentage of F4/80 + macrophages in lungs in HLA DP401-IAβ -/- mice and a decreasing ratio of CD4 + to CD8 + T cells in lungs in IAβ -/- mice and HLA DP401-IAβ -/- mice. A decreasing ratio of Vβ3 + to Vβ8 + T cells was also found in the lymph node of IAβ -/- mice and HLA DP401-IAβ -/- mice. S. aureus Newman infection resulted in a weaker pathological injury in lungs in IAβ -/- genetic background mice., Conclusion: These humanized mice will be an invaluable mouse model to resolve the pathological mechanism of S. aureus pneumonia and study what role DP molecule plays in S. aureus infection., (© 2023 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Tuberculosis is a leading cause of death in India. To identify genetic variants associated with susceptibility or resistance to Mycobacterium tuberculosis infection, we have performed an exome-wide association study with 0.2 million exonic variants among 119 pairs of tuberculosis patients and their clinically asymptomatic household contacts. The strongest association was identified for rs61104666[A], a synonymous variant (p.E292E) of exon 5 of the gene SIGLEC15 (OR = 2.4, p = 1.49 × 10−5). We also found association of non-coding variants in the 3′UTR region of a gene encoding the class II human leukocyte antigens (HLAs), HLA-DRA. rs13209234[A] (minor allele frequency (MAF) = 13.8%) (OR = 0.35, P = 2.5 × 10−4) and rs3177928[A] (minor allele frequency (MAF) = 13.7%) (OR = 0.35, P = 3.3 × 10−4) were associated with protection from tuberculosis. These two SNPs, rs13209234 and rs3177928, are in complete linkage disequilibrium. These associations remained valid when additional data on freshly recruited individuals were jointly analyzed on 250 patient-control pairs. The identified gene, HLA-DRA , suggest involvement of immune regulation, indicating pathways associated with antigen presentation in tuberculosis infection. • This is a first exome-wide association study of tuberculosis among Indian population. • A case-household contacts association study is performed. • Novel polymorphisms in SIGLEC15 and HLA-DRA gene are associated with tuberculosis. [ABSTRACT FROM AUTHOR]

Objective: Endometriosis is a common gynaecological disease, associated with severe pelvic pain and reduced fertility; however, molecular mechanisms remain largely unknown. Genome-wide association studies (GWAS) are able to identify genetic loci, which can play significant role during endometriosis development.Aim: The study aimed at localisation of new genes and chromosomal loci, the nucleotide variants of which determine the level of susceptibility to endometriosis.Study Design: Blood samples from 171 patients with endometriosis were used as material for studies. The patients were recruited to the study at the Department of Operative Gynaecology of the Institute of the Polish Mother's Memorial Hospital in Lodz. A control group (n=2934) came from the POPULOUS collection registered at Biobank Lab, Department of Molecular Biophysics, University of Lodz. DNA of the patients with endometriosis was compared with DNA of women free from that disease, the comparison being supported by GWAS.Results: Genome-wide significant correlation was identified between one new, not previously described, single nucleotide polymorphism (SNP), rs10129516, localised on chromosome 14 in intergenic region between PARP1P2 and RHOJ genes (p=1.44×10-10, OR=3.104, 95% CI=2.329-4.136) and endometriosis. We have also identified significant association with endometriosis of 18 SNPs localised on chromosome 6 in position range 31883957 - 32681631 (C2 and HLA-DRA genes region) with the lowest observed p value for rs644045 in C2 gene (p=2.04×10-8, OR=1.955, 95% CI=1.541-2.480).Conclusion: Reported GWAS identified the novel loci associated with endometriosis in Polish women, not previously reported. The most interesting observation shown in our study are regions associated with susceptibility to endometriosis of loci located near C2, HLA-DRA and RHOJ genes.Results: of that study did not correspond to previously published data about polymorphism in that regions and further evaluations are necessary in groups with higher numbers of patients to explain whether the above-mentioned genetic variant may be the risk factor for pathogenesis of endometriosis. [ABSTRACT FROM AUTHOR]

ABSTRACT To improve management of Staphylococcus aureus bacteremia (SAB), better understanding of host-pathogen interactions is needed. In vitro studies have shown that S. aureus bacteria induce dose-dependent immunosuppression that is evidenced by reduced expression of major histocompatibility complex (MHC) class II on antigen presenting cells. Thus, the aim of this study was to determine whether expression of the MHC class II-related genes HLA-DRA and CD74 is more greatly reduced in complicated SAB, with its probable higher loads of S. aureus, than in uncomplicated SAB. Adult patients with SAB were prospectively included and blood samples taken on the day of confirmation of SAB (Day 1) and on Days 2, 3, 5 and 7. HLA-DRA and CD74 mRNA expression was determined by quantitative reverse transcription PCR. Sepsis was defined according to the Sepsis-3 classification and SAB was categorized as complicated in patients with deep-seated infection and/or hematogenous seeding. Twenty patients with SAB were enrolled and samples obtained on all assessment days. HLA-DRA and CD74 expression did not differ significantly between patients with SAB and sepsis ( n = 13) and those without sepsis ( n = 7) on any assessment day. However, patients with complicated SAB ( n = 14) had significantly weaker HLA-DRA expression on all five assessment days than patients with uncomplicated SAB ( n = 6). Additionally, they tended to have weaker CD74 expressions. Neutrophil, monocyte and leukocyte counts did not differ significantly between complicated and uncomplicated SAB. In conclusion, patients with complicated SAB show weaker HLA-DRA expression than those with uncomplicated SAB during the first week of bacteremia. [ABSTRACT FROM AUTHOR]

Background: Mass vaccination has dramatically reduced the incidence of severe COVID-19, with most cases now presenting as self-limiting upper respiratory tract infections. However, those with co-morbidities, the elderly and immunocompromised, as well as the unvaccinated, remain disproportionately vulnerable to severe COVID-19 and its sequelae. Furthermore, as the effectiveness of vaccination wanes with time, immune escape SARS-CoV-2 variants could emerge to cause severe COVID-19. Reliable prognostic biomarkers for severe disease could be used as early indicator of re-emergence of severe COVID-19 as well as for triaging of patients for antiviral therapy., Methods: We performed a systematic review and re-analysis of 7 publicly available datasets, analysing a total of 140 severe and 181 mild COVID-19 patients, to determine the most consistent differentially regulated genes in peripheral blood of severe COVID-19 patients. In addition, we included an independent cohort where blood transcriptomics of COVID-19 patients were prospectively and longitudinally monitored previously, to track the time in which these gene expression changes occur before nadir of respiratory function. Single cell RNA-sequencing of peripheral blood mononuclear cells from publicly available datasets was then used to determine the immune cell subsets involved., Findings: The most consistent differentially regulated genes in peripheral blood of severe COVID-19 patients were MCEMP1, HLA-DRA and ETS1 across the 7 transcriptomics datasets. Moreover, we found significantly heightened MCEMP1 and reduced HLA-DRA expression as early as four days before the nadir of respiratory function, and the differential expression of MCEMP1 and HLA-DRA occurred predominantly in CD14+ cells. The online platform which we developed is publicly available at https://kuanrongchan-covid19-severity-app-t7l38g.streamlitapp.com/, for users to query gene expression differences between severe and mild COVID-19 patients in these datasets., Interpretation: Elevated MCEMP1 and reduced HLA-DRA gene expression in CD14+ cells during the early phase of disease are prognostic of severe COVID-19., Funding: K.R.C is funded by the National Medical Research Council (NMRC) of Singapore under the Open Fund Individual Research Grant (MOH-000610). E.E.O. is funded by the NMRC Senior Clinician-Scientist Award (MOH-000135-00). J.G.H.L. is funded by the NMRC under the Clinician-Scientist Award (NMRC/CSAINV/013/2016-01). S.K. is funded by the NMRC under the Transition Award. This study was sponsored in part by a generous gift from The Hour Glass., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: Human leukocyte antigen (HLA) class II antigens are expressed on antigen-presenting cells, that is, macrophages, dendritic cells, and B lymphocytes. Under the influence of IFN-γ, HLA class II molecules can also be expressed on T lymphocytes, epithelial and endothelial cells. In addition, HLA class II antigens can be expressed in a variety of malignancies; however, the link with prognosis and ultimately patient survival is controversial. Methods: The pattern of HLA-DRA expression in cervical carcinoma was studied using immunohistochemistry. In total, 124 cervical carcinomas were examined, of which 60 (48.4%) were squamous cell carcinomas and 64 (51.6%) were adenocarcinomas. Results: In squamous cell carcinoma, HLA-DRA was expressed in 41 (68.3%) of 60 tumors, whereas in adenocarcinoma, HLA-DRA was expressed in 60 (93.8%) of 64 tumors (P < 0.001). In adenocarcinoma, HLA-DRA expression was associated with an increased disease-free survival (211.0 ± 13.0 vs 53.3 ± 30.5 months; P = 0.004) and disease-specific survival (226.45 ± 11.5 vs 75.8 ± 27.6 months; P = 0.002). Conclusions: Upregulation of HLA-DRA is significantly related to an increased disease-free and disease-specific survival in cervical adenocarcinoma. These data warrant further analysis of the functional role of HLA-DRA in these tumors. [ABSTRACT FROM AUTHOR]

Increased expression of cathelicidin antimicrobial peptide (CAMP) is related to the pathogenesis of rosacea. CAMP plays a crucial role in antimicrobial defences, such as the killing of mycobacteria. CAMP gene expression is regulated by vitamin D-dependent (VDR) and vitamin D-independent (C/EBPα) transcription factors. VDR-dependent CAMP expression is sufficient during the summer months in Nordic countries, but insufficient during Nordic winters, due to low ultraviolet (UV) levels. Historically, the Celts may have overcome this geographical disadvantage of deficient CAMP production during the winter through an as-yet undefined acquired mutation that activates the alternative vitamin D-independent CAMP promoter C/EBPα. C/EBPα is the downstream transcription factor of Toll-like receptor (TLR)-mediated innate immune reactions and endoplasmic reticulum (ER) stress responses. At the molecular level, all clinical trigger factors for rosacea can be regarded as ER stressors. A mutation-based upregulation of ER stress responsiveness in rosacea may thus explain patients' reduced threshold for ER stressors. It is notable that ER stress upregulates the potent lipid-mediator sphingosine- 1-phosphate (S1P), which explains multiple pathological aberrations observed in rosacea skin. Enhanced ER stress/S1P signalling in rosacea appears to compensate for insufficient VDR-dependent CAMP expression, maintaining adequate CAMP levels during UV-deficient winter to combat life-threatening microbial infections, such as lupus vulgaris. Therefore, rosacea should not be considered as a disadvantage, but as evolution's blessing of the Celts which improved their survival. The concept presented here also explains the mechanism of Finsen's UV treatment of lupus vulgaris by UV- and ER stressmediated upregulation of CAMP expression. Rosacea could therefore be described as the Celts' "inborn Finsen lamp". [ABSTRACT FROM AUTHOR]

Purpose: Many studies have evaluated the association between the HLA-DRA rs3129882 A/G polymorphism and risk for Parkinson's disease (PD) in Chinese-based populations, however, published data remain inconclusive. Therefore, we performed a meta-analysis from all relevant studies to evaluate an association of HLA-DRA rs3129882 A/G polymorphism with susceptibility to PD. Methods: The summary odds ratio (OR) with its 95% confidence interval (CI) was calculated to evaluate the association. The Q statistic was used to evaluate homogeneity and funnel plots were used to assess publication bias. The minor A allele frequencies, additive, dominant as well as recessive genetic models were examined in the analyses. Results: Five case-control studies with a total of 2230 PD cases and 2262 controls from Mainland China, Taiwan, Singapore, and Malaysia were included in the final meta-analysis. Neither the minor A allele frequencies nor the genotypic distributions were significantly different between PD cases and controls when all studies were pooled into this meta-analysis. Conclusion: The results of this meta-analysis suggest that HLA-DRA rs3129882 A/G polymorphism was not responsible for PD in Chinese-based populations. [ABSTRACT FROM AUTHOR]

OBJECTIVE: As one of potential candidate genes for the risk of Parkinson's disease (PD), the HLA-DRA/PARK18 (rs3129882, A > G) gene has been studied extensively. However, direct evidence for the genetic association studies between PD and rs3129882 remains inconclusive. The aim of our meta-analysis was to determine a more reliable association between the rs3129882 and PD. MATERIALS AND METHODS: Comprehensive search strategy was used for electronic searches through PubMed, Elsevier, Springer Link, CNKI (Chinese National Knowledge Infrastructure) and WanFang (Chinese) databases to evaluate the association between rs3129882 and PD risk. Data were extracted and the odd ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Finally, we performed a meta-analysis of 13 appropriate papers by using a total of 11951 patients and 11902 controls. RESULTS: The meta-analysis showed no significant association between rs3129882 and PD risk in all four models (the allele model, dominant model, homozygote model and the recessive model). In allele model, the result was OR = 1.043 (95% CI = 0.978, 1.113). Moreover, this association remained no significant in the subgroup analysis stratified by ethnicity. CONCLUSIONS: In current meta-analysis, no significant association was found for rs3129882 and PD risk. And more well-designed primary researches will be needed to further evaluate the interaction of rs3129882 polymorphism and the susceptibility of PD. [ABSTRACT FROM AUTHOR]

Background and Objectives: Abnormal expressions of CD74 and human leukocyte antigen-DR alpha (HLA-DRA) have been reported in various cancers, though their roles in cervical cancer remain unclear. This study aimed to evaluate the gene and protein expressions of CD74 and HLA-DRA in the progression from normal cervix to precancerous cervical intraepithelial neoplasia (CIN) and finally to squamous cell carcinoma (SCC). Materials and Methods: The gene expression profiles of CD74 and HLA-DRA were determined in formalin-fixed paraffin-embedded tissues, with three samples each from normal cervixes, human papillomavirus type 16/18-positive, low-grade CIN (LGCIN), high-grade CIN (HGCIN), and squamous cell carcinoma (SCC) using Human Transcriptome Array 2.0. Immunohistochemical expression of the proteins was semi-quantitatively assessed in another cohort of tissue microarray samples comprising 7 normal cervix cases, 10 LGCIN, 10 HGCIN, and 95 SCC. Results: The transcriptomics profile and proteins' expression demonstrated similar trends of upregulation of CD74 and HLA-DRA from normal cervix to CIN and highest in SCC. There was a significant difference in both proteins' expression between the histological groups (p = 0.0001). CD74 and HLA-DRA expressions were significantly associated with CIN grade (p = 0.001 and p = 0.030, respectively) but not with the subjects' age or SCC stage. Further analysis revealed a positive correlation between CD74 and HLA-DRA proteins. Conclusions: CD74 appears to promote cervical carcinogenesis via oncogenic signalling mechanisms and may serve as a potential antitumour target. Additionally, the upregulation of HLA-DRA, often associated with stronger immunogenicity, could be a promising biomarker for developing immunotherapies. [ABSTRACT FROM AUTHOR]

HLA-DRA gene polymorphisms might play an important role in alcohol dependence (AD). We examined genetic associations of 29 single-nucleotide polymorphisms (SNPs) within the HLA-DRA gene with AD using two Caucasian samples-the Collaborative Study on the Genetics of Alcoholism (COGA) sample (660 AD cases and 400 controls) and the Study of Addiction: Genetics and Environment (SAGE) sample (623 cases and 1,016 controls). Logistic regression analysis using PLINK showed that 16 SNPs were associated with AD in the COGA sample and 13 SNPs were associated with AD in the SAGE sample ( p < 0.05). The best novel signal was SNP rs2239803 associated with AD in both samples ( p = 0.000817 for the COGA sample and p = 0.0026 for the SAGE sample, respectively) while one flanking SNP rs4935356 also showed strong association in both samples ( p = 0.00219 and 0.0026 for the COGA and SAGE samples, respectively). Furthermore, these two SNPs revealed stronger associations in meta-analysis of these two samples ( p = 8.97 × 10 and 2.02 × 10 for rs2239803 and rs4935356, respectively). In addition, the G-A haplotype from these two SNPs revealed a significant association with AD in both the COGA and SAGE samples ( p = 0.0007 and 0.0019, respectively). These findings highlight the novel associations with HLA-DRA that may play an important role in the etiology of AD. [ABSTRACT FROM AUTHOR]

Abstract: The induction of the major histocompatibility (MHC), antigen-presenting class II molecules by interferon-gamma, in solid tumor cells, requires the retinoblastoma tumor suppressor protein (Rb). In the absence of Rb, a repressosome blocks the access of positive-acting, promoter binding proteins to the MHC class II promoter. However, a complete molecular linkage between Rb expression and the disassembly of the MHC class II repressosome has been lacking. By treating A549 lung carcinoma cells with a novel small molecule that prevents phosphorylation-mediated, Rb inactivation, we demonstrate that Rb represses the synthesis of an MHC class II repressosome component, YY1. The reduction in YY1 synthesis correlates with the advent of MHC class II inducibility; with loss of YY1 binding to the promoter of the HLA–DRA gene, the canonical human MHC class II gene; and with increased Rb binding to the YY1 promoter. These results support the concept that the Rb gene regulatory network (GRN) subcircuit that regulates cell proliferation is linked to a GRN subcircuit regulating a tumor cell immune function. [Copyright &y& Elsevier]

Generally speaking, inflammation as a key piece to the Parkinson's disease (PD) puzzle is a relatively new concept. Acceptance of this concept has gained ground as studies by various researchers have demonstrated the potential of mitigating nigral cell death by curtailing inflammation in animal models of PD. We propose that the significance of inflammation in PD pathology may extend beyond the nigrostriatal region. In the current review, we present an argument for this based on the Braak staging and discuss how inflammation might contribute to the development of non-motor PD symptoms. [ABSTRACT FROM AUTHOR]

Background: Nasal polyps, part of the aspirin triad symptoms, are edematous protrusions arising from the mucosa of the nasal sinuses. Although the causative factors and pathogenesis of the polyps are unknown, the significant effect of human leukocyte antigen-DR (HLA-DR) expression in nasal polyps and genetic associations of the major histocompatibility complex class II, DR alpha (HLA-DRA) with immune-mediated diseases have been revealed. Methods: To investigate the associations of HLA-DRA polymorphisms with nasal polyposis in asthmatic patients and in aspirin-hypersensitive subgroups, 22 single nucleotide polymorphisms (SNPs) were genotyped in a total of 467 asthmatic patients including 158 nasal polyp-positive and 309 polyp-negative subjects. Results: Statistical analysis showed that four SNPs (p = 0.0005-0.02; Pcorr = 0.009-0.033) and one haplotype (p = 0.002; Pcorr = 0.029) were significantly associated with the presence of nasal polyposis in asthmatic patients. In further analysis, although significant signals disappeared after corrections for multiple testing, two HLA-DRA polymorphisms (rs9268644C>A, rs3129878A>C) were found to be potential markers for nasal polyp development in aspirin-tolerant asthma (p = 0.005 and 0.007, respectively) compared with the aspirin-exacerbated respiratory disease (p > 0.05) subgroup. In silico analysis predicted major 'C' allele of rs14004C>A in 5′-untranslated region as a potential binding site for regulatory glucocorticoid receptor. In addition, sequence nearby rs1051336G>A is suspected to be a pyrimidine-rich element that affects mRNA stability. Conclusion: Despite the need for replication in larger cohorts and/or functional evaluations, our findings suggest that HLA-DRA polymorphisms might contribute to nasal polyposis susceptibility in patients with asthma. [ABSTRACT FROM AUTHOR]

The human HLA class II histocompatibility antigen, DR alpha chain ( HLA-DRA) is a member of the MHC class II gene family that activates T cells allowing secretion in various cytokines to immune responses. Thus, we explored whether the genetic variations in HLA-DRA gene can influence susceptibility for aspirin exacerbated respiratory disease (AERD). To carry out the investigation, 22 single nucleotide polymorphisms (SNPs) in HLA-DRA were genotyped in 592 Korean asthma patients. Logistic and regression analyseis wereas used to evaluate the P-values for associations of HLA-DRA polymorphisms with AERD and a relevant phenotype, the fall rate of forced expiratory volume in the 1 second (FEV). Logistic analyses revealed that two variants, rs6911777 and HLA_DRA_BL1_ht3 were initially associated with AERD via dominant and recessive models ( P = 0.05 and 0.01, respectively), however, the signals did not reach the threshold of significance after multiple corrections. Furthermore, we observed that fall rate of FEV1 by aspirin provocation was marginally different between AERD cases and aspirin-tolerant asthma (ATA) controls (mean = 24.63 vs 3.54, respectively). This study provides result of first association analysis between the variants of HLA-DRA and the risk of AERD, and conclusions derived from the study do not support significant roles of polymorphisms in HLA-DRA with AERD. [ABSTRACT FROM AUTHOR]

Background: There is an increasing demand for prognostic immune biomarkers of cancer. The prognostic significance of immune markers has been shown for various cancers, but biomarkers of bladder cancer (BCa) have not been fully evaluated. To clarify the role of human leukocyte antigen DR alpha chain (HLA-DRA) in BCa development, we examined expression of HLA-DRA mRNA in tissue samples of non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC).Materials and Methods: Tissues of 96 NMIBC, 43 MIBC and 59 controls comprising noncancerous BCa surrounding tissues were used to examine the expression of HLA-DRA gene by real-time polymerase chain reaction. The expression of up-stream genes regulating HLA-DRA were also measured to explain the role of HLA-DRA in BCa.Results: Patients with high grade NMIBC showed higher expression of HLA-DRA than those with low grade NMIBC (P < 0.05). In addition, NMIBC patients who progressed to MIBC showed high expression of HLA-DRA mRNA. Kaplan-Meier analysis showed that NMIBC patients with low expression of HLA-DRA had better progression-free survival than those with high expression (P = 0.004). Moreover, the expression of genes regulating HLA-DRA varied in NMIBC and MIBC, indicating a different immunoregulation effect of HLA-DRA in both cancers.Conclusions: High expression of HLA-DRA in NMIBC patients has implications for patient stratification strategies, as well as for BCa tumor immunology. [ABSTRACT FROM AUTHOR]