Serum anti-flagellin and anti-lipopolysaccharide immunoglobulins as predictors of linear growth faltering in Pakistani infants at risk for environmental enteric dysfunction

Background: Environmental Enteric Dysfunction (EED) in children from low-income countries has been linked to linear growth declines. There is a critical need to identify sensitive and early EED biomarkers.Objective: Determine whether levels of antibodies against bacterial components flagellin (flic) and lipopolysaccharide (LPS) predict poor growth.Design/Methods: In a prospective birth cohort of 380 children in rural Pakistan blood and stool samples were obtained at ages 6 and 9 months. Linear mixed effects models were used to examine longitudinal associations between quartiles of anti-flic and anti-LPS antibodies and changes in LAZ, WAZ and WLZ scores. Spearman\u27s correlations were measured between anti-flic and anti-LPS immunoglobulins with measures of systemic/enteric inflammation and intestinal regeneration.Results: Anti-LPS IgA correlated significantly with CRP, AGP and Reg1 serum at 6mo and with MPO at 9mo. In multivariate analysis at 6mo of age, higher anti-LPS IgA levels predicted greater declines in LAZ scores over subsequent 18mo (comparing highest to lowest quartile, β (SE) change in LAZ score/year = -0.313 (0.125), p-value = 0.013). Anti-flic Ig A in the two highest quartiles measured at 9mo of age had declines in LAZ of -0.269 (0.126), p = 0.033; and -0.306 (0.129), p = 0.018 respectively, during the subsequent 18mo of life, compared to those in the lowest quartile of anti-flic IgA.Conclusions and Relevance: Elevated anti-flic IgA and anti-LPS IgA antibodies at 6 and 9mo, predict declines in linear growth. Systemic and enteric inflammation correlated with anti-LPS IgA provides mechanistic considerations for potential future interventions

Presentation_1_Detection of Significant Association Between Variants in Cannabinoid Receptor 1 Gene (CNR1) and Personality in African–American Population.pdf

<p>Background: Several studies have revealed significant associations between single nucleotide polymorphisms (SNPs) in the cannabinoid receptor 1 (CNR1) gene and a broad spectrum of psychiatric disorders such as major depressive disorder (MDD), attention deficit hyperactivity disorder (ADHD), and schizophrenia. Personality traits that are highly related to susceptibility to these conditions have been associated with the CNR1 variants in subjects of Caucasian origin. However, there are no reported studies regarding the effects of CNR1 polymorphisms on personality traits in the African-American (AA) population.</p><p>Methods: We performed an imputation-based association analysis for 26 CNR1 variants with five dimensions of personality in 3,046 AAs.</p><p>Results: SNPs rs806372 and rs2180619 showed a significant association with extraversion after Bonferroni correction for multiple testing (p < 0.0019). Further, several extraversion-associated SNPs were significantly associated with conscientiousness, agreeableness, and openness. SNP priority score analysis indicated that SNPs rs806368, rs806371, and rs2180619 play a role in the modulation of personality and psychiatric conditions.</p><p>Conclusion:CNR1 is important in determining personality traits in the AA population.</p

Enriched biochemical pathways significantly altered in HIV-1Tg rats compared to F344 control rats in the PFC, HIP, and STR.

<p>These pathways were divided into three main groups directly related to immune responses (yellow bars), neurotransmission (blue bars), and neuroplasticity (white bars).</p

Transcriptome Sequencing of Gene Expression in the Brain of the HIV-1 Transgenic Rat

<div><p>The noninfectious HIV-1 transgenic (HIV-1Tg) rat was developed as a model of AIDs-related pathology and immune dysfunction by manipulation of a noninfectious HIV-1^gag-pol virus with a deleted 3-kb <i>Sph</i>I<i>-Msc</i>I fragment containing the 3′ -region of <i>gag</i> and the 5′ region of <i>pol</i> into F344 rats. Our previous studies revealed significant behavioral differences between HIV-1Tg and F344 control rats in their performance in the Morris water maze and responses to psychostimulants. However, the molecular mechanisms underlying these behavioral differences remain largely unknown. The primary goal of this study was to identify differentially expressed genes and enriched pathways affected by the <i>gag-pol</i>-deleted HIV-1 genome. Using RNA deep sequencing, we sequenced RNA transcripts in the prefrontal cortex, hippocampus, and striatum of HIV-1Tg and F344 rats. A total of 72 RNA samples were analyzed (i.e., 12 animals per group × 2 strains × 3 brain regions). Following deep-sequencing analysis of 50-bp paired-end reads of RNA-Seq, we used Bowtie/Tophat/Cufflinks suites to align these reads into transcripts based on the Rn4 rat reference genome and to measure the relative abundance of each transcript. Statistical analyses on each brain region in the two strains revealed that immune response- and neurotransmission-related pathways were altered in the HIV-1Tg rats, with brain region differences. Other neuronal survival-related pathways, including those encoding myelin proteins, growth factors, and translation regulators, were altered in the HIV-1Tg rats in a brain region-dependent manner. This study is the first deep-sequencing analysis of RNA transcripts associated the HIV-1Tg rat. Considering the functions of the pathways and brain regions examined in this study, our findings of abnormal gene expression patterns in HIV-1Tg rats suggest mechanisms underlying the deficits in learning and memory and vulnerability to drug addiction and other psychiatric disorders observed in HIV-positive patients.</p> </div

Detected interactions and clusters of enriched pathways in the HIP region in HIV-1 rats.

<p>All pathways identified by IPA software, including both significant and insignificant pathways, are interrelated and can be divided into two functional groups, indicated by circles.</p

Comparison of the number of transcripts identified in the three brain regions in HIV-1Tg (A) and F344 (B) rats.

<p>Comparison of the number of transcripts identified in the three brain regions in HIV-1Tg (A) and F344 (B) rats.</p

Detected interactions and clusters of enriched pathways in the STR region in HIV-1Tg rats.

<p>All pathways identified by IPA software, including both significant and insignificant pathways, are interrelated and can be divided into three functional groups, indicated by circles.</p

Data_Sheet_1_Detection of Significant Association Between Variants in Cannabinoid Receptor 1 Gene (CNR1) and Personality in African–American Population.xlsx

<p>Background: Several studies have revealed significant associations between single nucleotide polymorphisms (SNPs) in the cannabinoid receptor 1 (CNR1) gene and a broad spectrum of psychiatric disorders such as major depressive disorder (MDD), attention deficit hyperactivity disorder (ADHD), and schizophrenia. Personality traits that are highly related to susceptibility to these conditions have been associated with the CNR1 variants in subjects of Caucasian origin. However, there are no reported studies regarding the effects of CNR1 polymorphisms on personality traits in the African-American (AA) population.</p><p>Methods: We performed an imputation-based association analysis for 26 CNR1 variants with five dimensions of personality in 3,046 AAs.</p><p>Results: SNPs rs806372 and rs2180619 showed a significant association with extraversion after Bonferroni correction for multiple testing (p < 0.0019). Further, several extraversion-associated SNPs were significantly associated with conscientiousness, agreeableness, and openness. SNP priority score analysis indicated that SNPs rs806368, rs806371, and rs2180619 play a role in the modulation of personality and psychiatric conditions.</p><p>Conclusion:CNR1 is important in determining personality traits in the AA population.</p

Summary of represented genes and enriched biochemical pathways related to neurobehavioral deficits in the HIV-1Tg rat.

<p>Red represents up-regulation, whereas green represents down-regulation in mRNA expression in the PFC¹, HIP², and STR³ of HIV-1Tg rats. Numbers with strikethroughs reflect marginal significance (0.005Table S1). Abbreviations: Aspa = aspartoacylase; Camk2b = calcium/calmodulin-dependent protein kinase II beta; Ccl2 =  chemokine ligand 2; Ccl6 =  chemokine ligand 6; Chrna4 =  neuronal acetylcholine receptor subunit alpha-4; Cldn = Claudin 1; Cnp = 2,3-cyclic-nucleotide 3-phosphodiesterase; Drd4 =  D(4) dopamine receptor; Ephb1 =  EPH receptor B1; Fgf9 =  fibroblast growth factor 9; Fgf13 =  fibroblast growth factor 13; Gabbr2, Gnal = guanine nucleotide binding protein, alpha activating activity polypeptide; Grid1 =  glutamate receptor, ionotropic, delta1; Grin2a = NMDA receptor subunit epsilon-1; HDGF = hepatoma-derived growth factor; Il1rap = interleukin 1 receptor accessory protein; Insr = insulin receptor; Irak4, interleukin-1 receptor-associated kinase 4; Irf5 =  interferon regulatory factor 5; Irf7 =  interferon regulatory factor 7; Mag = myelin-associated glycoprotein; Mbp = myelin-associated glycoprotein; Mog = myelin-oligodendrocyte glycoprotein; Mpz = myelin protein P0; Npm1 =  nucleophosmin; Opalin = oligodendrocytic myelin paranodal and inner loop protein; PDGFb = platelet-derived growth factor beta polypeptide; Ppm1l = protein phosphatase 1L; Ppp1r14a = protein phosphatase 1 regulatory subunit 14A; Ppp2ca = serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform; Rl39 =  ribosomal protein L39; Rpl13 =  ribosomal protein L13; Rpl35 =  ribosomal protein L35; Rpl37 =  ribosomal protein L37; Rps8 =  ribosomal protein S8; Rps19 =  ribosomal protein S19; Rps24 =  ribosomal protein S24; Rtp4 =  receptor transporter protein 4; Slc1a7 =  glutamate transporter, member 7; Wnt5a = wingless-type MMTV integration site family, 5A; Wnt5b = wingless-type MMTV integration site family, 5B.</p

Transcriptional changes in neurotranmission-related genes.

<p>Transcriptional changes in neurotranmission-related genes.</p