Expression In Blood Leukocytes Research Articles

Prenatal alcohol exposure dysregulates spinal and circulating immune cell circular RNA expression in adult female rats with chronic sciatic neuropathy.

Alcohol consumption during pregnancy is associated with Fetal Alcohol Spectrum Disorders (FASD) that results in a continuum of central nervous system (CNS) deficits. Emerging evidence from both preclinical and clinical studies indicate that the biological vulnerability to chronic CNS disease in FASD populations is driven by aberrant neuroimmune actions. Our prior studies suggest that, following minor nerve injury, prenatal alcohol exposure (PAE) is a risk factor for developing adult-onset chronic pathological touch sensitivity or allodynia. Allodynia in PAE rats occurs concurrently with heightened proinflammatory peripheral and spinal glial-immune activation. However, minor nerve-injured control rats remain non-allodynic, and corresponding proinflammatory factors are unaltered. A comprehensive molecular understanding of the mechanism(s) that underlie PAE-induced proinflammatory bias during adulthood remains elusive. Non-coding circular RNAs (circRNAs) are emerging as novel modulators of gene expression. Here, we hypothesized that PAE induces dysregulation of circRNAs that are linked to immune function under basal and nerve-injured conditions during adulthood. Utilizing a microarray platform, we carried out the first systematic profiling of circRNAs in adult PAE rats, prior to and after minor nerve injury. The results demonstrate a unique circRNA profile in adult PAE rats without injury; 18 circRNAs in blood and 32 spinal circRNAs were differentially regulated. Following minor nerve injury, more than 100 differentially regulated spinal circRNAs were observed in allodynic PAE rats. Bioinformatic analysis identified that the parental genes of these circRNAs are linked to the NF-κB complex, a central transcription factor for pain-relevant proinflammatory cytokines. Quantitative real-time PCR was employed to measure levels of selected circRNAs and linear mRNA isoforms. We have validated that circVopp1 was significantly downregulated in blood leukocytes in PAE rats, concurrent with downregulation of Vopp1 mRNA levels. Spinal circVopp1 levels were upregulated in PAE rats, regardless of nerve injury. Additionally, PAE downregulated levels of circItch and circRps6ka3, which are linked to immune regulation. These results demonstrate that PAE exerts long-lasting dysregulation of circRNA expression in blood leukocytes and the spinal cord. Moreover, the spinal circRNA expression profile following peripheral nerve injury is differentially modulated by PAE, potentially contributing to PAE-induced neuroimmune dysregulation.

TREML4 polymorphisms increase the mRNA in blood leukocytes in the progression of atherosclerosis

TREML4 and other members of the triggering receptor expressed in the myeloid cell family are associated with a risk of atherosclerosis and progression in coronary artery disease, acute coronary syndrome, and coronary artery calcification. Herein, the relationship between TREML4 expression and its polymorphisms (rs2803495 and rs280396) was evaluated in patients with subclinical atherosclerosis (n = 340) and heart failure post-acute myocardial infarction (MI) (n = 68) for the first time. TREML4 variants rs2803495 (A > G) and rs2803496 (T > C) and leukocyte mRNA expression was analyzed by qRT–PCR. The rs2803495 G allele was associated with TREML4 expression (OR 8.01, CI 3.78–16.99, p < 0.001). Patients carrying the rs2803496 C minor allele (TC/CC genotypes) were more likely to express TREML4 than those without the C allele (OR 10.42, CI 4.76–22.78, p < 0.001), as well as having higher levels of TREML4 expression (OR 4.88, CI 2.35–10.12, p < 0.001). Thus, we report for the first time that TREML4 is not associated with the early stages of atherosclerotic plaque formation and later stages after MI. In conclusion, TREML4 mRNA expression in blood leukocytes is influenced by minor alleles (G and C) and may regulate differently during the atherosclerosis progression stages, but not in asymptomatic atherosclerosis disease and post-MI.

Long noncoding RNA GSEC promotes neutrophil inflammatory activation by supporting PFKFB3-involved glycolytic metabolism in sepsis

Metabolic reprogramming is a hallmark of neutrophil activation in sepsis. LncRNAs play important roles in manipulating cell metabolism; however, their specific involvement in neutrophil activation in sepsis remains unclear. Here we found that 11 lncRNAs and 105 mRNAs were differentially expressed in three transcriptome datasets (GSE13904, GSE28750, and GSE64457) of gene expression in blood leukocytes and neutrophils of septic patients and healthy volunteers. After Gene Ontology biological process analysis and lncRNA–mRNA pathway network construction, we noticed that GSEC lncRNA and PFKFB3 were co-expressed and associated with enhanced glycolytic metabolism. Our clinical observations confirmed the expression patterns of GSEC lncRNA and PFKFB3 genes in neutrophils in septic patients. Performing in vitro experiments, we found that the expression of GSEC lncRNA and PFKFB3 was increased when neutrophils were treated with inflammatory stimuli. Knockdown and overexpression experiments showed that GSEC lncRNA was essential for mediating PFKFB3 mRNA expression and stability in neutrophil-like dHL-60 cells. In addition, we found that GSEC lncRNA-induced PFKFB3 expression was essential for mediating dHL-60 cell inflammatory cytokine expression. Performing mechanistic experiments, we found that glycolytic metabolism with PFKFB3 involvement supported inflammatory cytokine expression. In summary, our study uncovers a mechanism by which GSEC lncRNA promotes neutrophil inflammatory activation in sepsis by supporting glycolytic metabolism with PFKFB3.

Effect of maternal separation and transportation stress on the bovine upper respiratory tract microbiome and the immune response to resident opportunistic pathogens

BackgroundThe bovine upper respiratory tract (URT) microbiome includes opportunistic pathogens that cause respiratory disease and stress associated with maternal separation and transportation contributes to the severity of this respiratory disease. Stress is known to alter the gut microbiome but little is known regarding the effect of stress on the URT microbiota. This study used six-month old suckling beef calves to investigate whether maternal separation (weaned), by itself or combined with transportation (weaned + transport), altered the URT microbiome and host immune responses to resident opportunistic pathogens.ResultsTaxonomic and functional composition of the URT microbiome in suckling and weaned beef calves did not change significantly when serially sampled over a one-month period. Subtle temporal changes in the URT microbiome composition were observed in weaned + transport calves. Total bacterial density was lower (p < 0.05) on day 4 post-weaning in both the weaned and weaned + transport groups when compared to suckling calves. In addition, significant (p < 0.05) temporal changes in the density of the opportunistic pathogens, M. haemolytica and P. multocida, were observed independent of treatment but these changes did not correlate with significantly increased (p < 0.05) serum antibody responses to both of these bacteria in the weaned and weaned + transport groups. Serum antibody responses to My. bovis, another opportunistic pathogen, remained unchanged in all treatment groups. Weaning, by itself and in combination with transportation, also had significant (p < 0.05) short- (2 to 8 days post-weaning) and long-term (28 days post-weaning) effects on the expression of adrenergic receptor genes in blood leukocytes when compared to age-matched suckling beef calves.ConclusionsMaternal separation (weaning) and transportation has minor effects on the taxonomic and functional composition of the URT microbiome and temporal changes in the density of opportunistic pathogen residing in the URT did not correlate with significant changes in immune responses to these bacteria. Significant changes in adrenergic receptor expression in blood leukocytes following weaning, with or without transportation, suggests altered neuroimmune regulation should be further investigated as a mechanism by which stress can alter host-microbiome interactions for some opportunistic respiratory pathogens that reside in the URT.

HERV-W envelope expression in blood leukocytes as a marker of disease severity of COVID-19

We are currently in the midst of a pandemic, caused by SARS-CoV-2, that has shaken the entire social and economic fabric of society. Within less than a year it spread across the entire globe and has spared no country, society, race or age group. Even several world leaders have been infected. While we have made great progress towards developing effective vaccines, to date we do not have any effective anti-viral agents. This desperate situation has called for desperate measures. For example, hydroxychloroquine was initially used for treating the infection based on minimal in vitro data, resulting in world-wide shortages of the drug, only for subsequent clinical trials to show that it was ineffective in treating the infection.

Neuroinflammatory Gene Expression Pattern Is Similar between Allergic Rhinitis and Atopic Dermatitis but Distinct from Atopic Asthma.

Methods In the study, we included 86 children diagnosed with atopic asthma (n = 25), allergic rhinitis (n = 20), and atopic dermatitis (n = 20) and healthy control subjects (n = 21) of Caucasian origin from the Polish population. The blood leukocyte expression of 31 genes involved in neuroinflammatory response (neurotrophins, their receptors, neuropeptides, and histamine signaling pathway) was analysed using TaqMan low-density arrays. The relative expression of selected proteins from plasma was done using TaqMan Protein Assays. Statistical analysis was done using Statistica. Results Blood expression of 31 genes related to neuroimmune interactions showed significant increase in both allergic diseases, allergic rhinitis and atopic dermatitis, in comparison to the control group. We found 12 genes significantly increased in allergic rhinitis and 9 genes in which the expression was elevated in atopic dermatitis. Moreover, 9 genes with changed expression in atopic dermatitis overlapped with those in allergic rhinitis. Atopic asthma showed 5 genes with altered expression. The peripheral expression of neuroinflammatory genes in the human study was verified in target tissues (nasal epithelium and skin) in a rat model of allergic inflammation. Conclusions A common pattern of neuroinflammatory gene expression between allergic rhinitis and atopic dermatitis may reflect similar changes in sensory nerve function during chronic allergic inflammation.

TREML4 mRNA Expression and Polymorphisms in Blood Leukocytes are Associated with Atherosclerotic Lesion Extension in Coronary Artery Disease

Members of the triggering receptor expressed on myeloid cells (TREM) family are associated with atherosclerosis risk and progression. TREML4 is upregulated in the early phase of acute coronary syndrome. We investigated the relationship between the mRNA expression of 13 genes in blood leukocytes, TREML4 polymorphisms, and coronary artery lesion extension (Friesinger index) in patients with coronary artery disease (CAD) (n = 137). TREML4 rs2803495 (A > G) and rs2803496 (T > C) variants and leukocyte mRNA expression were analysed by qRT-PCR. TREML4 expression was higher in patients with major coronary artery lesions than in subjects without or with low and intermediate lesions (p < 0.05). However, TREML4 polymorphisms were not associated with coronary lesion extent. Presence of the rs2803495 G allele was not associated with increased TREML4 mRNA expression. Patients carrying the rs2803496 C allele (TC/CC genotypes) were more likely to express TREML4 mRNA than non-C allele carriers (allele C: OR 7.3, and 95% CI 1.9–27.5, p = 0.03). In conclusion, increased TREML4 mRNA expression in blood leukocytes is influenced by gene polymorphisms and is associated with more severe coronary artery lesions, suggesting its potential as a biomarker of the extent of coronary lesions in patients with CAD.

Tobacco exposure-related alterations in DNA methylation and gene expression in human monocytes: the Multi-Ethnic Study of Atherosclerosis (MESA)

ABSTRACTAlterations in DNA methylation and gene expression in blood leukocytes are potential biomarkers of harm and mediators of the deleterious effects of tobacco exposure. However, methodological issues, including the use of self-reported smoking status and mixed cell types have made previously identified alterations in DNA methylation and gene expression difficult to interpret. In this study, we examined associations of tobacco exposure with DNA methylation and gene expression, utilizing a biomarker of tobacco exposure (urine cotinine) and CD14+ purified monocyte samples from 934 participants of the community-based Multi-Ethnic Study of Atherosclerosis (MESA). Urine cotinine levels were measured using an immunoassay. DNA methylation and gene expression were measured with microarrays. Multivariate linear regression was used to test for associations adjusting for age, sex, race/ethnicity, education, and study site. Urine cotinine levels were associated with methylation of 176 CpGs [false discovery rate (FDR)<0.01]. Four CpGs not previously identified by studies of non-purified blood samples nominally replicated (P value<0.05) with plasma cotinine-associated methylation in 128 independent monocyte samples. Urine cotinine levels associated with expression of 12 genes (FDR<0.01), including increased expression of P2RY6 (Beta ± standard error = 0.078 ± 0.008, P = 1.99 × 10−22), a gene previously identified to be involved in the release of pro-inflammatory cytokines. No cotinine-associated (FDR<0.01) methylation profiles significantly (FDR<0.01) correlated with cotinine-associated (FDR<0.01) gene expression profiles. In conclusion, our findings i) identify potential monocyte-specific smoking-associated methylation patterns and ii) suggest that alterations in methylation may not be a main mechanism regulating gene expression in monocytes in response to cigarette smoking.

Peripheral Blood Leukocyte Expression of lncRNA MIAT and Its Diagnostic and Prognostic Value in Ischemic Stroke

Ischemic stroke (IS) is an extremely heterogeneous disease with variable pathogenesis. Due to the lack of early diagnostic markers, the mortality rate of IS remains high. Cumulative evidence shows that long noncoding RNAs among noncoding RNAs play important roles in cardiovascular diseases. In the present study, we focused on the expression pattern of myocardial infarction-associated transcript (MIAT) and its clinical significance in IS. Blood samples were obtained from IS patients (n = 189) and healthy controls (n = 189). The National Institutes of Health Stroke Scale (NIHSS) was measured at the time of admission. Short-term functional outcome was measured by the modified Rankin Scale (mRS) at 3 months after admission. Multivariate analyses were performed using logistic regression models. The receiver operating characteristic (ROC) curve was used to evaluate the accuracy of MIAT in the diagnosis and prognosis of IS. In IS patients, MIAT expression level was significantly upregulated and correlated with NIHSS scores (r = .421, P <.001), mRS (r = .339, P <.001), high-sensitivity C-reactive protein (r = .309, P <.001), and infarct volume (r = .318, P <.001). ROC curves indicated that MIAT could serve as a potential marker for discriminating IS patients from the controls with an area under the curve of .842 (95% confidence interval, .802-.881). The overall survival analysis showed that patients with higher MIAT expression had a relatively poor prognosis. Meanwhile, the multivariate analysis revealed that MIAT was an independent prognostic marker of functional outcome and death in patients with IS. Our data suggested that MIAT might be a potential diagnostic and prognostic indicator in IS.

Temporal Changes in Microrna Expression in Blood Leukocytes from Patients with the Acute Respiratory Distress Syndrome.

MicroRNA (miRNA) control gene transcription by binding to and repressing the translation of messenger RNA (mRNA). Their role in the acute respiratory distress syndrome (ARDS) is undefined. Blood leukocytes from 51 patients enrolled in a prior randomized trial of corticosteroids for ARDS were analyzed. After screening eight patients with microarrays for altered miRNA expression, 25 miRNAs were selected for further analysis using RT-PCR in all 51 patients. On day 0, the 51 patients had APACHE III score of 60.4 ± 17.7 and PaO2/FiO2 of 117 ± 49. 21 miRNA were expressed at increased levels in blood leukocytes at the onset of ARDS compared with healthy controls. These miRNA remained elevated at day 3 and increased further by day 7 (log2 fold change from 0.66 to 5.7 fold, P <0.05 compared to day 0). In a subgroup analysis (37 patients treated with corticosteroids and 14 treated with placebo), the interaction of miRNA expression over time and steroid administration was not significant suggesting that systemic corticosteroids had no effect on the miRNA detected in our study. In contrast, corticosteroids but not placebo decreased IL-6 and C-reactive protein at day 3 (P < 0.001) demonstrating an early systemic anti-inflammatory response whereas both treatment arms had decreased values by day 7 (P <0.001). Expression of miRNA is increased in blood leukocytes of patients with ARDS at day 0 and day 3 and rises further by day 7, when systemic inflammation is subsiding. These effects appear independent of the administration of steroids, suggesting different inflammatory modifying roles for each in the resolving phases of ARDS.

Safety, Phamacokinetics (PK), Pharmacodynamics (PD) and Preliminary Activity in Acute Leukemia of Ory-1001, a First-in-Class Inhibitor of Lysine-Specific Histone Demethylase 1A (LSD1/KDM1A): Initial Results from a First-in-Human Phase 1 Study

In preclinical studies, LSD1 inhibitors derived from tranylcypromine were active in acute myeloid leukemia models, particularly in the MLL-translocated subtype. We now report the safety, PK and PD properties of ORY-1001 (a potent and selective inhibitor of LSD1) in a multicenter phase I study (EUDRACT nº 2013-002447-29).The primary objective was to assess safety and tolerability in relapsed or refractory acute leukemia (RR-AL). Secondary objectives were to a) characterize PK, b) to monitor a panel of surrogate PD markers for target engagement and c) assess clinical response. Patients ≥16yr with RR-AL, ECOG PS ≤2 and life expectancy >8wk were eligible. ORY-1001 was administered orally once daily in a 28 day cycle (5d ON/2d OFF x4wk). Plasma ORY-1001 levels were analyzed by HPLC-MS/MS. Blood leukocyte expression of candidate differentiation PD biomarkers was determined by qRT-PCR.Twenty-seven subjects (mean age 66.5, range 40-81; gender 19 M/8F) were recruited into the dose escalation phase (26 - RR-AML; 1 - RR-ALL). Mean time since initial diagnosis was 12.6 months and since last treatment was 2.1 months. Twenty patients completed cycle 1, 9 started cycle 2 with 3 completions and 3 started and completed cycle 3. The most frequent ADR was thrombocytopenia (7 events, 5 subjects). Twenty-two subjects experienced 32 SAEs of which two (Cohort 8 - 220 µg/m2/d) were considered possibly related to ORY-1001: grade 5 lobar pneumonia and grade 3 febrile neutropenia (in combination with grade 2 fatigue and grade 2 erythema multiforme). These were considered dose limiting toxicities. Consequently the recommended dose for the extension phase was established at 140 μg/m2/d. At the end of the dose escalation phase, 358 treatment emergent AEs were reported. The most frequent were asthenia (16 events, 12 subjects), febrile neutropenia (15 events, 13 subjects), constipation (12 events, 9 subjects) and peripheral oedema (11 events, 8 subjects).ORY-1001 plasma concentration increased with dose across cohorts. At 140 µg/m2/d (recommended dose) on d1 mean±SD Cmax was 13.1±7.2 and mean±SD AUC (0-24h) was 181.7±61.3pg.hr/mL. On d5 mean±SD Cmax was 42.2±27 and mean±SD AUC (0-24h) 723.3±341.5pg.hr/mL.PD biomarker response varied due to differences in disease genetics and circulating blast percentages. Nevertheless select biomarkers demonstrated time and dose dependent response profiles in individual patients. For example, PI16 (peptidase inhibitor 16; or CRISP-9) levels were induced in cohort 7 (140 µg/m2/d). Maximum PI16 induction was seen at 18hr on d1, pre-dose levels remained high on d5 and were sustained through the OFF period until pre-dose on d8.An extension cohort of 14 patients (mean age 57; range 30-78, gender 8M/6F) with specific RR-AML subtypes predicted to be more sensitive based upon preclinical studies, was also enrolled (AML MLL-translocated n=10; acute erythroleukemia/M6 n=4). At data cut-off (31 July 2016), 131 AEs and 27 SAEs have been reported. Eight SAEs were considered related to treatment, including a differentiation syndrome in two patients. PK and PD analyses are ongoing. For response assessment, 14 patients were evaluable. Objective responses were seen in 5/14 patients (36%): two patients with t(9;11) exhibited stable disease and three a partial response (one MLL after 3 cycles, and two M6). Importantly, there was evidence of morphologic blast differentiation in blood and/or BM in 9/14 patients (5 MLL and 4 M6).In summary, ORY-1001 at the recommended dose is well tolerated and promotes blast cell differentiation in 64% of patients. This, together with the partial responses observed, suggest that LSD1 inhibition may be a possible therapy for some AML patients. DisclosuresSomervaille:Novartis: Consultancy, Honoraria; Imago Biosciences: Consultancy. Pigneux:Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria. Recher:Celgene, Sunesis, Amgen, Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene, Sunesis, Amgen, Novartis, Chugai: Research Funding. Molinero:Oryzon Genomics: Employment, Equity Ownership. Mascaro:Oryzon Genomics: Employment. Maes:Oryzon Genomics: Employment, Equity Ownership.

Thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients

AbstractPreclinical studies have suggested that platelets influence the host response during sepsis. We sought to assess the association of admission thrombocytopenia with the presentation, outcome, and host response in patients with sepsis. Nine hundred thirty-one consecutive sepsis patients were stratified according to platelet counts (very low <50 × 109/L, intermediate-low 50 × 109 to 99 × 109/L, low 100 × 109 to 149 × 109/L, or normal 150 × 109 to 399 × 109/L) on admission to the intensive care unit. Sepsis patients with platelet counts <50 × 109/L and 50 × 109 to 99 × 109/L presented with higher Acute Physiology and Chronic Health Evaluation scores and more shock. Both levels of thrombocytopenia were independently associated with increased 30-day mortality (hazard ratios with 95% confidence intervals 2.00 [1.32-3.05] and 1.72 [1.22-2.44], respectively). To account for baseline differences besides platelet counts, propensity matching was performed, after which the association between thrombocytopenia and the host response was tested, as evaluated by measuring 17 plasma biomarkers indicative of activation and/or dysregulation of pathways implicated in sepsis pathogenesis and by whole genome blood leukocyte expression profiling. In the propensity matched cohort, platelet counts < 50 × 109/L were associated with increased cytokine levels and enhanced endothelial cell activation. All thrombocytopenic groups showed evidence of impaired vascular integrity, whereas coagulation activation was similar between groups. Blood microarray analysis revealed a distinct gene expression pattern in sepsis patients with <50 × 109/L platelets, showing reduced signaling in leukocyte adhesion and diapedesis and increased complement signaling. These data show that admission thrombocytopenia is associated with enhanced mortality and a more disturbed host response during sepsis independent of disease severity, thereby providing clinical validity to animal studies on the role of platelets in severe infection.

Social threat exposure in juvenile mice promotes cocaine-seeking by altering blood clotting and brain vasculature.

Childhood maltreatment is associated with increased severity of substance use disorder and frequent relapse to drug use following abstinence. However, the molecular and neurobiological substrates that are engaged during early traumatic events and mediate the greater risk of relapse are poorly understood and knowledge of risk factors is to date extremely limited. In this study, we modeled childhood maltreatment by exposing juvenile mice to a threatening social experience (social stressed, S‐S). We showed that S‐S experience influenced the propensity to reinstate cocaine‐seeking after periods of withdrawal in adulthood. By exploring global gene expression in blood leukocytes we found that this behavioral phenotype was associated with greater blood coagulation. In parallel, impairments in brain microvasculature were observed in S‐S mice. Furthermore, treatment with an anticoagulant agent during withdrawal abolished the susceptibility to reinstate cocaine‐seeking in S‐S mice. These findings provide novel insights into a possible molecular mechanism by which childhood maltreatment heightens the risk for relapse in cocaine‐dependent individuals.

Gene Expression of Proresolving Lipid Mediator Pathways Is Associated With Clinical Outcomes in Trauma Patients.

Specialized proresolving lipid mediators have emerged as powerful modulators of inflammation and activators of resolution. Animal models show significant benefits of specialized proresolving lipid mediators on survival and wound healing after major burn trauma. To date, no studies have investigated specialized proresolving lipid mediators and their relation to other lipid mediator pathways in humans after trauma. Here we determine if patients with poor outcomes after trauma have dysregulated lipid mediator pathways. We studied blood leukocyte expression of 18 genes critical to the synthesis, signaling, and metabolism of specialized proresolving lipid mediators and proinflammatory lipid mediators, and we correlated these expression patterns with clinical outcomes in trauma patients from the Inflammation and the Host Response to Injury study. Seven U.S. medical trauma centers. Ninety-six patients enrolled in the Inflammation and Host Response to Injury study, after blunt trauma and unambiguously classified as having uncomplicated or complicated recoveries. Twenty-eight healthy volunteers were enrolled as controls. None. Within each patient, the 18 genes of interest were used to calculate scores for distinct families of lipid mediators, including resolvins, lipoxins, prostaglandins, and leukotrienes, as well as leukotriene to resolvin score ratios. Scores were built using a simple weighting scheme, taking into consideration both dependent and independent activities of enzymes and receptors responsible for lipid mediator biosynthesis and function. Individually, ALOX12, PTGS2, PTGES, PTGDS, ALOX5AP, LTA4H, FPR2, PTGER2, LTB4R, HPGD, PTGR1, and CYP4F3 were expressed differentially over 28 days posttrauma between patients with uncomplicated and complicated recoveries (p < 0.05). When all genes were combined into scores, patients with uncomplicated recoveries had differential and higher resolvin scores (p < 0.001) and lower leukotriene scores (p < 0.001). A final combined ratio was calculated for each patient, and posttrauma leukotriene score to resolvin score ratios were significantly lower in patients with uncomplicated clinical courses (p < 0.001). proresolving lipid mediator lipidomics and/or protein expression, and identifying associated therapeutic targets, may influence the clinical management of trauma patients.

Peripheral blood leukocyte expression level of lncRNA steroid receptor RNA activator (SRA) and its association with polycystic ovary syndrome: a case control study

Polycystic ovary syndrome (PCOS) has been recognized as a common reproductive and endocrine disorder. Long noncoding RNA (lncRNA) steroid receptor RNA activator (SRA) affects multiple biological processes. However, it is not known whether lncRNA SRA is associated with PCOS. In the study, we measured the expression level of lncRNA SRA in PCOS patients, and analyzed the association between lncRNA SRA and multiple key endocrine parameters of PCOS. LncRNA SRA expression was significantly higher in the women with PCOS than that in the controls. There was a significant positive correlation between lncRNA SRA expression and BMI in PCOS group. Furthermore, obesity positively associates with the high expression of lncRNA SRA in PCOS women but without the association in control women. In conclusion, we found that the lncRNA SRA expression is potentially associated with PCOS and it has positive correlation with obesity in PCOS, thereby suggesting that elevated lncRNA SRA might be an important mediator in adiposity-related processes in PCOS for susceptible individuals.

ADRB2 and CHRM3 gene expression in blood leukocytes of patients with acute exacerbation of chronic obstructive pulmonary disease

This pilot study was aimed at evaluation of ADRB2 and CHRM3 gene expression in COPD. Methods. We evaluated ADRB2 and CHRM3 gene expression in blood leukocytes from 29 patients with acute exacerbation of COPD (GOLD stage II to III, Group D) before and after 2-week combined therapy including antimicrobials, tiotropium bromide, formoterol and an inhaled steroid. ADRB2- and CHRM3-specific mRNA content was determined in leukocytes using real-time PCR. Results. Mean gene expression levels did not differ before and after treatment. However, we found a significant correlation between changes in ADRB2 and CHRM3 gene expression, change in FEV1 and post-treatment C-reactive protein level. Conclusion. The results confirm a possibility to affect adrenoceptors using beta agonists and inhaled steroids and to inhibit M-cholinoreceptor expression with M3-cholinolytics and inhaled steroids.

A Better Understanding of Why Murine Models of Trauma Do Not Recapitulate the Human Syndrome*

Genomic analyses from blood leukocytes have concluded that mouse injury poorly reflects human trauma at the leukocyte transcriptome. Concerns have focused on the modest severity of murine injury models, differences in murine compared with human age, dissimilar circulating leukocyte populations between species, and whether similar signaling pathways are involved. We sought to examine whether the transcriptomic response to severe trauma in mice could be explained by these extrinsic factors, by utilizing an increasing severity of murine trauma and shock in young and aged mice over time, and by examining the response in isolated neutrophil populations. Preclinical controlled in vivo laboratory study and retrospective cohort study. Laboratory of Inflammation Biology and Surgical Science and multi-institution level 1 trauma centers. Six- to 10-week-old and 20- to 24-month-old C57BL/6 (B6) mice and two cohorts of 167 and 244 severely traumatized (Injury Severity Score > 15) adult (> 18 yr) patients. Mice underwent one of two severity polytrauma models of injury. Total blood leukocyte and neutrophil samples were collected. Fold expression changes in leukocyte and neutrophil genome-wide expression analyses between healthy and injured mice (p < 0.001) were compared with human total and enriched blood leukocyte expression analyses of severe trauma patients at 0.5, 1, 4, 7, 14, and 28 days after injury (Glue Grant trauma-related database). We found that increasing the severity of the murine trauma model only modestly improved the correlation in the transcriptomic response with humans, whereas the age of the mice did not. In addition, the genome-wide response to blood neutrophils (rather than total WBC) was also not well correlated between humans and mice. However, the expression of many individual gene families was much more strongly correlated after injury in mice and humans. Although overall transcriptomic association remained weak even after adjusting for the severity of injury, age of the animals, timing, and individual leukocyte populations, there were individual signaling pathways and ontogenies that were strongly correlated between mice and humans. These genes are involved in early inflammation and innate/adaptive immunity.

Ambient Particulate Air Pollution and MicroRNAs in Elderly Men

Ambient particulate matter (PM) has been associated with mortality and morbidity for cardiovascular disease. MicroRNAs control gene expression at a posttranscriptional level. Altered microRNA expression has been reported in processes related to cardiovascular disease and PM exposure, such as systemic inflammation, endothelial dysfunction, and atherosclerosis. Polymorphisms in microRNA-related genes could influence response to PM. We investigated the association of exposure to ambient particles in several time windows (4-hour to 28-day moving averages) and blood leukocyte expression changes in 14 candidate microRNAs in 153 elderly males from the Normative Aging Study (examined 2005-2009). Potential effect modification by six single nucleotide polymorphisms (SNPs) in three microRNA-related genes was investigated. Fine PM (PM2.5), black carbon, organic carbon, and sulfates were measured at a stationary ambient monitoring site. Linear regression models, adjusted for potential confounders, were used to assess effects of particles and SNP-by-pollutant interaction. An in silico pathway analysis was performed on target genes of microRNAs associated with the pollutants. We found a negative association for pollutants in all moving averages and miR-1, -126, -135a, -146a, -155, -21, -222, and -9. The strongest associations were observed with the 7-day moving averages for PM2.5 and black carbon and with the 48-hour moving averages for organic carbon. The association with sulfates was stable across the moving averages. The in silico pathway analysis identified 18 pathways related to immune response shared by at least two microRNAs; in particular, the "high-mobility group protein B1/advanced glycosylation end product-specific receptor signaling pathway" was shared by miR-126, -146a, -155, -21, and -222. No important associations were observed for miR-125a-5p, -125b, -128, -147, -218, and -96. We found significant SNP-by-pollutant interactions for rs7813, rs910925, and rs1062923 in GEMIN4 and black carbon and PM2.5 for miR-1, -126, -146a, -222, and -9, and for rs1640299 in DGCR8 and SO4 for miR-1 and -135a. Exposure to ambient particles could cause a downregulation of microRNAs involved in processes related to PM exposure. Polymorphisms in GEMIN4 and DGCR8 could modify these associations.

Diurnal and seasonal changes in &lt;i&gt;IL-6&lt;/i&gt; and &lt;i&gt;IL-18&lt;/i&gt; gene expression in blood leukocytes of male chickens with experimental peritonitis: the impact of lighting conditions and melatonin

Diurnal and seasonal changes in &lt;i&gt;IL-6&lt;/i&gt; and &lt;i&gt;IL-18&lt;/i&gt; gene expression in blood leukocytes of male chickens with experimental peritonitis: the impact of lighting conditions and melatonin

Ig-like Transcript 7, but Not Bone Marrow Stromal Cell Antigen 2 (Also Known as HM1.24, Tetherin, or CD317), Modulates Plasmacytoid Dendritic Cell Function in Primary Human Blood Leukocytes

The Ig-like transcript (ILT) 7 is a surface molecule selectively expressed by human plasmacytoid dendritic cells (pDCs). ILT7 cross-linking suppresses pDC activation and type I IFN (IFN-I) secretion following TLR7/9 engagement. The bone marrow stromal cell Ag 2 (BST2, aka HM1.24, tetherin, or CD317) is expressed by different cell types upon exposure to IFN-I and is a natural ligand for ILT7. In this study, we show that ILT7 expression decreased spontaneously in pDCs upon in vitro culture, which correlates with pDC differentiation measured as increased side scatter properties and CCR7 expression. TLR7/9 ligands, as well as HIV, induced BST2 upregulation on all tested cell types except T cells, which required TCR stimulation to respond to TLR9L-induced IFN-I. IFN-γ, IL-4, IL-10, and TNF-α had only marginal effects on BST2 expression in blood leukocytes compared with TLR9L. Preincubation with ILT7 cross-linking Ab inhibited IFN-I production in PBMCs treated with TLR7/9L or HIV, whereas BST2 blockade did not affect IFN-I responses even when BST2 upregulation was further boosted with TCR agonists or immunoregulatory cytokines. Our data indicate that BST2-mediated ILT7 cross-linking may act as a homeostatic regulatory mechanism on immature circulating pDC, rather than a negative feedback for activated mature pDCs that have downregulated ILT7.