Integrative analyses of hub genes and their association with immune infiltration in adipose tissue, liver tissue and skeletal muscle of obese patients after bariatric surgery.

Bariatric surgery (BS) is an effective treatment for obesity. Adipose tissue, liver tissue and skeletal muscle are important metabolic tissues. This study investigated hub genes and their association with immune infiltration in these metabolic tissues of obese patients after BS by bioinformatic analysis with Gene Expression Omnibus datasets. Differentially expressed genes (DEGs) were identified, and a protein-protein interaction network was constructed to identify hub genes. As a result, 121 common DEGs were identified and mainly enriched in cytokine-cytokine receptor interactions, chemokine signaling pathway, neutrophil activation and immune responses. Immune cell infiltration analysis showed that the abundance of M1 macrophages was significantly lower in adipose and liver tissue after BS (p<0.05). Ten hub genes (TYROBP, TLR8, FGR, NCF2, HCK, CCL2, LAPTM5, MNDA and S100A9) that were all downregulated after BS were also associated with immune cells. Consistently, results in the validated dataset showed that the expression levels of these hub genes were increased in obese patients and mice, and decreased after BS. In conclusion, this study analysed the potential immune and inflammatory mechanisms of BS in three key metabolic tissues of obese patients, and revealed hub genes associated with immune cell infiltration, thus providing potential targets for obesity treatment.

Sex Differences in the Immune System Become Evident in the Perinatal Period in the Four Core Genotypes Mouse.

We have used the four core genotypes (FCG) mouse model, which allows a distinction between effects of gonadal secretions and chromosomal complement, to determine when sex differences in the immune system first appear and what influences their development. Using splenic T cell number as a measure that could be applied to neonates with as yet immature immune responses, we found no differences among the four genotypes at postnatal day 1, but by day 7, clear sex differences were observed. These sex differences were unexpectedly independent of chromosomal complement and similar in degree to gonadectomized FCG adults: both neonatal and gonadectomized adult females (XX and XY) showed 2-fold the number of CD4+ and 7-fold the number of CD8+ T cells versus their male (XX and XY) counterparts. Appearance of this long-lived sex difference between days 1 and 7 suggested a role for the male-specific perinatal surge of testicular testosterone. Interference with the testosterone surge significantly de-masculinized the male CD4+, but not CD8+ splenic profile. Treatment of neonates demonstrated elevated testosterone limited mature cell egress from the thymus, whereas estradiol reduced splenic T cell seeding in females. Neonatal male splenic epithelium/stroma expressed aromatase mRNA, suggesting capacity for splenic conversion of perinatal testosterone into estradiol in males, which, similar to administration of estradiol in females, would result in reduced splenic T cell seeding. These sex steroid effects affected both CD4+ and CD8+ cells and yet interference with the testosterone surge only significantly de-masculinized the splenic content of CD4+ cells. For CD8+ cells, male cells in the thymus were also found to express one third the density of sphingosine-1-phosphate thymic egress receptors per cell compared to female, a male characteristic most likely an indirect result of Sry expression. Interestingly, the data also support a previously unrecognized role for non-gonadal estradiol in the promotion of intra-thymic cell proliferation in neonates of both sexes. Microarray analysis suggested the thymic epithelium/stroma as the source of this hormone. We conclude that some immune sex differences appear long before puberty and more than one mechanism contributes to differential numbers and distribution of T cells.

Whole-Exome Sequencing, Proteome Landscape, and Immune Cell Migration Patterns in a Clinical Context of Menkes Disease.

Menkes disease (MD) is a rare and often lethal X-linked recessive syndrome, characterized by generalized alterations in copper transport and metabolism, linked to mutations in the ATPase copper transporting α (ATP7A) gene. Our objective was to identify genomic alterations and circulating proteomic profiles related to MD assessing their potential roles in the clinical features of the disease. We describe the case of a male patient of 8 months of age with silvery hair, tan skin color, hypotonia, alterations in neurodevelopment, presence of seizures, and low values of plasma ceruloplasmin. Trio-whole-exome sequencing (Trio-WES) analysis, plasma proteome screening, and blood cell migration assays were carried out. Trio-WES revealed a hemizygous change c.4190C > T (p.S1397F) in exon 22 of the ATP7A gene. Compared with his parents and with child controls, 11 plasma proteins were upregulated and 59 downregulated in the patient. According to their biological processes, 42 (71.2%) of downregulated proteins had a participation in cellular transport. The immune system process was represented by 35 (59.3%) downregulated proteins (p = 9.44 × 10-11). Additional studies are necessary to validate these findings as hallmarks of MD.

Distinct placental molecular processes associated with early-onset and late-onset preeclampsia.

Background: Patients with preeclampsia display a spectrum of onset time and severity of clinical presentation, yet the underlying molecular bases for the early-onset and late-onset clinical subtypes are not known. Although several transcriptome studies have been done on placentae from PE patients, only a small number of differentially expressed genes have been identified due to very small sample sizes and no distinguishing of clinical subtypes. Methods: We carried out RNA-seq on 65 high-quality placenta samples, including 33 from 30 patients and 32 from 30 control subjects, to search for dysregulated genes and the molecular network and pathways they are involved in. Results: We identified two functionally distinct sets of dysregulated genes in the two major subtypes: 2,977 differentially expressed genes in early-onset severe preeclampsia, which are enriched with metabolism-related pathways, notably transporter functions; and 375 differentially expressed genes in late-onset severe preeclampsia, which are enriched with immune-related pathways. We also identified some key transcription factors, which may drive the widespread gene dysregulation in both early-onset and late-onset patients. Conclusion: These results suggest that early-onset and late-onset severe preeclampsia have different molecular mechanisms, whereas the late-onset mild preeclampsia may have no placenta-specific causal factors. A few regulators may be the key drivers of the dysregulated molecular pathways.

Immune cell infiltration landscape and immune marker molecular typing in preeclampsia.

Preeclampsia (PE) is an important topic in obstetrics. In this study, we used weighted gene co-expression network analysis (WGCNA) to screen the key modules related to immune cell infiltration and to identify the hub genes for the molecular subtyping of PE. We first downloaded a set of PE transcriptional data (GSE75010; 157 samples: 80 PE and 77 non-PE) from the GEO database. We then analyzed the PE samples and non-PE samples for immune cell infiltration and screened cells with differences in such infiltration. Next, we downloaded the immune-related genes from an immune-related database to screen the expression profile of the immune-related genes. Then, we obtained a candidate gene set by screening the immune-related genes differentially expressed between the two groups. We used WGCNA to construct a weighted co-expression network for these candidate genes, mined co-expression modules, and then calculated the correlation between each module and immune cells with differential infiltration. We screened the modules related to infiltrating immune cells, identified the key modules' hub genes, and determined the key module genes that interacted with each other. Finally, we obtained the hub genes related to the infiltrating immune cells. We classified the preeclampsia patients by unsupervised cluster molecular typing, determined the difference of immune cell infiltration among the different PE subtypes, and calculated the expression of hub genes in these different subtypes. In conclusion, we found 41 hub genes that may be closely related to the molecular typing of PE.

Association of novel rare coding variants with juvenile idiopathic arthritis.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is the most common type of arthritis among children, but a few studies have investigated the contribution of rare variants to JIA. In this study, we aimed to identify rare coding variants associated with JIA for the genome-wide landscape. METHODS: We established a rare variant calling and filtering pipeline and performed rare coding variant and gene-based association analyses on three RNA-seq datasets composed of 228 JIA patients in the Gene Expression Omnibus against different sets of controls, and further conducted replication in our whole-exome sequencing (WES) data of 56 JIA patients. Then we conducted differential gene expression analysis and assessed the impact of recurrent functional coding variants on gene expression and signalling pathway. RESULTS: By the RNA-seq data, we identified variants in two genes reported in literature as JIA causal variants, as well as additional 63 recurrent rare coding variants seen only in JIA patients. Among the 44 recurrent rare variants found in polyarticular patients, 10 were replicated by our WES of patients with the same JIA subtype. Several genes with recurrent functional rare coding variants have also common variants associated with autoimmune diseases. We observed immune pathways enriched for the genes with rare coding variants and differentially expressed genes. CONCLUSION: This study elucidated a novel landscape of recurrent rare coding variants in JIA patients and uncovered significant associations with JIA at the gene pathway level. The convergence of common variants and rare variants for autoimmune diseases is also highlighted in this study.

Long noncoding RNAs in cancer immunity: a new avenue in drug discovery.

The central role of the nonprotein-coding portion of the genome, such as long noncoding (lnc)RNAs is emerging as a hidden player manipulating the immune system in cancer. lncRNAs, in association with their interacting partners, regulate the expression of various immune system genes, which are perturbed during cancer. The tissue-specific expression of lncRNAs and their importance in cellular proliferation, the tumor microenvironment (TME), epithelial-mesenchymal transition (EMT), and modulation of the cells of the innate and adaptive immune system have novel therapeutic implications in establishing lncRNAs as biomarkers and targets to overcome cancer-associated immunosuppression. In this review, we establish and strengthen the link between lncRNAs and cancer immunity.

Comparison of lncRNA and mRNA expression in mouse brains infected by a wild-type and a lab-attenuated Rabies lyssavirus.

Rabies is a lethal disease caused by Rabies lyssavirus, commonly known as rabies virus (RABV), and results in nearly 100 % death once clinical symptoms occur in human and animals. Long non-coding RNAs (lncRNAs) have been reported to be associated with viral infection. But the role of lncRNAs involved in RABV infection is still elusive. In this study, we performed global transcriptome analysis of both of lncRNA and mRNA expression profiles in wild-type (WT) and lab-attenuated RABV-infected mouse brains by using next-generation sequencing. The differentially expressed lncRNAs and mRNAs were analysed by using the edgeR package. We identified 1422 differentially expressed lncRNAs and 4475 differentially expressed mRNAs by comparing WT and lab-attenuated RABV-infected brains. Then we predicted the enriched biological pathways by the Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) database based on the differentially expressed lncRNAs and mRNAs. Our analysis revealed the relationships between lncRNAs and RABV-infection-associated immune response and ion transport-related pathways, which provide a fresh insight into the potential role of lncRNA in immune evasion and neuron injury induced by WT RABV.

Overexpression of TPX2 predicts poor clinical outcome and is associated with immune infiltration in hepatic cell cancer.

Targeting protein for Xenopus kinesin-like protein 2 (TPX2) has been identified as an oncogene in multiple cancers. However, the associations among TPX2 expression, prognosis, and tumor immunity in hepatic cell cancer (HCC) have not been explored. We analyzed TPX2 expression by multiple gene expression databases, including Oncomine, TIMER, and UALCAN. The prognosis effect of TPX2 was analyzed by Kaplan--Meier plotter. The coexpressed genes with TPX2 were analyzed using Linked Omics. The association among TPX2 and immune infiltrates and immune checkpoints was determined by TIMER. It was found that TPX2 expression was notably upregulated in multiple HCC tissues. Overexpression of TPX2 has associations with race, age, weight, clinical stage and tumor grade, as well as poor prognosis in overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), and disease-specific survival (DSS). In addition, TPX2 expression has a positive association with the infiltration of immune cells and the expression of immune checkpoint molecules. Coexpressed genes and functional network analysis suggested several potential mechanisms of TPX2 affecting HCC progression. The findings reveal that TPX2 has associations with prognosis and infiltration of immune cells in HCC patients, which has laid a basis for in-depth study of TPX2 role in HCC.

Immune-related gene signature in predicting prognosis of early-stage colorectal cancer patients.

AIM: Immune-related genes are associated with the prognosis of colorectal cancer (CRC) patients. The aim of this study was to evaluate the impact of an immune-related gene signature (IRGS) in predicting the prognosis of early-stage CRC patients. METHODS: In total, 309 CRC patients were selected for the identification of prognostic IRGS using the CIT/GSE39582 microarray dataset. Five independent datasets including 1587 CRC patients were divided into a training cohort (n = 566) and two validation cohorts (n = 624 in validation-1 and n = 397 in meta-validation). Prognostic analyses were performed to test the predictive value of IRGS. RESULTS: A prognostic IRGS that included 23 immune-related genes was constructed and significantly stratified patients into immune low-vs. high-risk groups in terms of disease-free survival using patients with early-stage disease (I or II) in the training cohort. Similarly, a higher IRGS was correlated with significantly worse prognosis of early-stage patients in validation-1 and meta-validation cohorts. Compared with Oncotype DX colon, we found that IRGS exhibited an improved survival correlation in the training cohort. After integration with clinical characteristics, IRGS remained as an independent prognostic factor in multivariate analysis. Furthermore, IRGS-stratified immune low-risk group patients gained less benefit from adjuvant chemotherapy in the validation-1 cohort. Several biological processes, including inflammatory response, were enriched among genes in identified the immune high-risk group. Consistent with this finding, the IRGS-identified immune high-risk group exhibited significantly increased immune and stromal cell infiltration. CONCLUSION: The proposed prognostic IRGS is a promising system for estimating DFS of colorectal cancer patients, especially those with early-stage disease.

Measurements of Innate Immune Function in C. elegans.

The microscopic nematode Caenorhabditis elegans has emerged as a powerful system to characterize evolutionarily ancient mechanisms of pathogen sensing, innate immune activation, and protective host responses. Experimentally, C. elegans can be infected with a wide variety of human pathogens, as well as with natural pathogens of worms that were isolated from wild-caught nematodes. Here, we focus on an experimental model of bacterial pathogenesis that utilizes the human opportunistic bacterial pathogen Pseudomonas aeruginosa and present an algorithm that can be used to study mechanisms of immune function in nematodes. An initial comparison of the susceptibility of a C. elegans mutant to P. aeruginosa infection with its normal lifespan permits an understanding of a mutant's effect on pathogen susceptibility in the context of potential pleotropic consequences on general worm fitness. Assessing the behavior of nematodes in the presence of P. aeruginosa can also help determine if a gene of interest modulates pathogen susceptibility by affecting the host's ability to avoid a pathogen. In addition, quantification of the pathogen load in the C. elegans intestine during infection, characterization of immune effector transcription that are regulated by host defense pathways and an initial assessment of tissue specificity of immune gene function can refine hypotheses about the mechanism of action of a gene of interest. Together, these protocols offer one approach to characterize novel host defense mechanisms in a simple metazoan host.

Roles of G protein-coupled receptors in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a complex disease with multiple pathogenic factors. Although the pathogenesis of IBD is still unclear, a current hypothesis suggests that genetic susceptibility, environmental factors, a dysfunctional immune system, the microbiome, and the interactions of these factors substantially contribute to the occurrence and development of IBD. Although existing and emerging drugs have been proven to be effective in treating IBD, none can cure IBD permanently. G protein-coupled receptors (GPCRs) are critical signaling molecules implicated in the immune response, cell proliferation, inflammation regulation and intestinal barrier maintenance. Breakthroughs in the understanding of the structures and functions of GPCRs have provided a driving force for exploring the roles of GPCRs in the pathogenesis of diseases, thereby leading to the development of GPCR-targeted medication. To date, a number of GPCRs have been shown to be associated with IBD, significantly advancing the drug discovery process for IBD. The associations between GPCRs and disease activity, disease severity, and disease phenotypes have also paved new avenues for the precise management of patients with IBD. In this review, we mainly focus on the roles of the most studied proton-sensing GPCRs, cannabinoid receptors, and estrogen-related GPCRs in the pathogenesis of IBD and their potential clinical values in IBD and some other diseases.

Prognostic Molecular Classification of Appendiceal Mucinous Neoplasms Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Appendiceal mucinous neoplasm (AMN) with peritoneal metastasis is a rare but deadly disease with few prognostic or therapy-predictive biomarkers to guide treatment decisions. Here, we investigated the prognostic and biological attributes of gene expression-based AMN molecular subtypes. METHODS: AMN specimens (n = 138) derived from a population-based subseries of patients treated at our institution with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) between 05/2000 and 05/2013 were analyzed for gene expression using a custom-designed NanoString 148-gene panel. Signed non-negative matrix factorization (sNMF) was used to define a gene signature capable of delineating robustly-classified AMN molecular subtypes. The sNMF class assignments were evaluated by topology learning, reverse-graph embedding and cross-cohort performance analysis. RESULTS: Three molecular subtypes of AMN were discerned by the expression patterns of 17 genes with roles in cancer progression or anti-tumor immunity. Tumor subtype assignments were confirmed by topology learning. AMN subtypes were termed immune-enriched (IE), oncogene-enriched (OE) and mixed (M) as evidenced by their gene expression patterns, and exhibited significantly different post-treatment survival outcomes. Genes with specialized immune functions, including markers of T-cells, natural killer cells, B-cells, and cytolytic activity showed increased expression in the low-risk IE subtype, while genes implicated in the promotion of cancer growth and progression were more highly expressed in the high-risk OE subtype. In multivariate analysis, the subtypes demonstrated independent prediction power for post-treatment survival. CONCLUSIONS: Our findings suggest a greater role for the immune system in AMN than previously recognized. AMN subtypes may have clinical utility for predicting CRS/HIPEC treatment outcomes.

Immune gene expression in head and neck squamous cell carcinoma patients.

BACKGROUND: Nivolumab and pembrolizumab targeting programmed cell death protein 1 (PD-1) have recently been approved among patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) who failed platinum therapy. We aimed to evaluate the prognostic value of selected immune gene expression in HNSCC. PATIENTS AND METHODS: We retrospectively assessed the expression of 46 immune-related genes and immune-cell subpopulation genes including immune checkpoints by real-time polymerase chain reaction among 96 patients with HNSCC who underwent primary surgery at Institut Curie between 1990 and 2006. Univariate and multivariate analyses were performed to assess the prognostic value of dysregulated genes. RESULTS: The Median age of the population was 56 years [range: 35-78]. Primary tumour location was oral cavity (45%), oropharynx (21%), larynx (18%) and hypopharynx (17%). Twelve patients (13%) had an oropharyngeal human papillomavirus-positive tumour. Most significantly overexpressed immune-related genes were TNFRSF9/4-1BB (77%), IDO1 (75%), TNFSF4/OX40L (74%) and TNFRSF18/GITR (74%), and immune-cell subpopulation gene was FOXP3 (62%). Eighty-five percent of tumours analysed overexpressed actionable immunity genes, including PD-1/PD-L1, TIGIT, OX40/OX40L and/or CTLA4. Among the immune-related genes, high OX40L mRNA level (p = 0.0009) and low PD-1 mRNA level (p = 0.004) were associated with the highest risk of recurrence. Among the immune-cell subpopulation genes, patients with high PDGFRB mRNA level (p < 0.0001) and low CD3E (p = 0.0009) or CD8A mRNA levels (p = 0.004) were also at the highest risk of recurrence. CONCLUSIONS: OX40L and PDGFRB overexpression was associated with poor outcomes, whereas PD-1 overexpression was associated with good prognosis in patients with HNSCC treated with primary surgery, suggesting their relevance as potential prognostic biomarkers and major therapeutic targets.

Transcriptome Analysis of Immune Response of mIgM+ B Lymphocytes in Japanese Flounder (Paralichthys olivaceus) to Lactococcus lactis in vitro Revealed That IFN I-3 Could Enhance Their Phagocytosis.

B cells have recently been proven to have phagocytic activities, but few studies have explored the relevant regulation mechanisms. In this study, we showed that the Japanese flounder (Paralichthys olivaceus) membrane-bound (m)IgM+ B lymphocyte population could phagocytose inactivated Lactococcus lactis with a mean phagocytic rate of 25%. High-purity mIgM+ B lymphocytes were subsequently sorted to investigate the cellular response to L. lactis stimulation in vitro. Transcriptome analysis identified 1,375 differentially expressed genes (DEGs) after L. lactis stimulation, including 975 upregulated and 400 downregulated genes. Many of these DEGs were enriched in multiple pathways associated with phagocytosis such as focal adhesion, the phagosome, and actin cytoskeleton regulation. Moreover, many genes involved in phagolysosomal function and antigen presentation were also upregulated after stimulation, indicating that mIgM+ B lymphocytes may degrade the internalized bacteria and present processed antigenic peptides to other immune cells. Interestingly, the type I interferon 3 (IFN I-3) gene was upregulated after L. lactis stimulation, and further analysis showed that the recombinant (r)IFN I-3 significantly enhanced phagocytosis of L. lactis and Edwardsiella tarda by mIgM+ B lymphocytes. In addition, significantly higher intracellular reactive oxygen species (ROS) levels were detected in mIgM+ B lymphocytes following rIFN I-3 treatment. We also found that IFN I-3 significantly upregulated Stat1 expression in mIgM+ B lymphocytes, and the enhancing effect of IFN I-3 on mIgM+ B lymphocyte-mediated phagocytosis was suppressed by fludarabine treatment. Collectively, these results demonstrate that mIgM+ B cell-mediated phagocytosis in the Japanese flounder is effectively triggered by bacterial stimulation, and further enhanced by IFN I-3, which itself may be regulated by Stat1.

Transcriptome Analyses of Heart and Liver Reveal Novel Pathways for Regulating Songbird Migration.

Many birds undertake long biannual voyages during the night. During these times of the year birds drastically reduce their amount of sleep, yet curiously perform as well on tests of physical and cognitive performance than during non-migrating times of the year. This inherent physiological protection disappears when birds are forced to stay awake at other times of the year; thus these protective changes are only associated with the nocturnal migratory state. The goal of the current study was to identify the physiological mechanisms that confer protection against the consequences of sleep loss while simultaneously allowing for the increased physical performance required for migration. We performed RNA-seq analyses of heart and liver collected from birds at different times of day under different migratory states and analyzed these data using differential expression, pathway analysis and WGCNA. We identified changes in gene expression networks implicating multiple systems and pathways. These pathways regulate many aspects of metabolism, immune function, wound repair, and protection of multiple organ systems. Consequently, the circannual program controlling the appearance of the migratory phenotype involves the complex regulation of diverse gene networks associated with the physical demands of migration.

In silico identification of critical proteins associated with learning process and immune system for Down syndrome.

Understanding expression levels of proteins and their interactions is a key factor to diagnose and explain the Down syndrome which can be considered as the most prevalent reason of intellectual disability in human beings. In the previous studies, the expression levels of 77 proteins obtained from normal genotype control mice and from trisomic Ts65Dn mice have been analyzed after training in contextual fear conditioning with and without injection of the memantine drug using statistical methods and machine learning techniques. Recent studies have also pointed out that there may be a linkage between the Down syndrome and the immune system. Thus, the research presented in this paper aim at in silico identification of proteins which are significant to the learning process and the immune system and to derive the most accurate model for classification of mice. In this paper, the features are selected by implementing forward feature selection method after preprocessing step of the dataset. Later, deep neural network, gradient boosting tree, support vector machine and random forest classification methods are implemented to identify the accuracy. It is observed that the selected feature subsets not only yield higher accuracy classification results but also are composed of protein responses which are important for the learning and memory process and the immune system.

Spatial Heterogeneity of Lung Strain and Aeration and Regional Inflammation During Early Lung Injury Assessed with PET/CT.

INTRODUCTION: Spatial heterogeneity of lung aeration and strain (change volume/resting volume) occurs at microscopic levels and contributes to lung injury. Yet, it is mostly assessed with histograms or large regions-of-interest. Spatial heterogeneity could also influence regional gene expression. We used positron emission tomography (PET)/computed tomography (CT) to assess the contribution of different length-scales to mechanical heterogeneity and to direct lung injury biological pathway identification. MATERIALS AND METHODS: Sheep exposed to mild (n = 5, supine and n = 3, prone) and moderate (n = 6, supine) systemic endotoxemia were protectively ventilated. At baseline, 6 hours and 20 hours length-scale analysis was applied to aeration in CT (mild groups) and PET transmission (moderate group) scans; and voxel-level strain derived from image registration of end-inspiratory and end-expiratory CTs (mild). 2-deoxy-2-[(18)F]fluoro-d-glucose (18F-FDG)-PET kinetics parameters in ventral and dorsal regions were correlated with tissue microarray gene expression (moderate). RESULTS: While aeration and strain heterogeneity were highest at 5-10 mm length-scales, larger length-scales contained a higher fraction of strain than aeration heterogeneity. Contributions of length-scales >5-10 mm to aeration and strain heterogeneity increased as lung injury progressed (p < 0.001) and were higher in supine than prone animals. Genes expressed with regional correlation to 18F-FDG-PET kinetics (|r| = 0.81 [0.78-0.85]) yielded pathways associated with immune system activation and fluid clearance. CONCLUSION: Normal spatial heterogeneity of aeration and strain suggest larger anatomical and functional determinants of lung strain than aeration heterogeneity. Lung injury and supine position increase the contribution of larger length-scales. 18F-FDG-PET-based categorization of gene expression results in known and novel biological pathways relevant to lung injury.

First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes.

OBJECTIVE: Latent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype. RESEARCH DESIGN AND METHODS: We performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10,396). RESULTS: The leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes. CONCLUSIONS: Our results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.