tbuckley/cabot-search huggingface dataset:
Definition of a discontinuous immunodominant epitope at the NH2 terminus of the La/SS-B ribonucleoprotein autoantigen.
Authors: L J McNeilage, K Umapathysivam, E Macmillan, A Guidolin, S Whittingham, T Gordon
Journal: Journal of Clinical Investigation (1992)

High-titer IgG autoantibodies to the La/SS-B ribonucleoprotein (RNP) are a hallmark of patients with primary Sjogren's syndrome. Anti-La/SS-B-positive human sera bind to multiple epitopes on recombinant La/SS-B, although the initial response is against an immunodominant epitope within the first 107 NH2-terminal amino acids (aa). Sequence analysis has identified a striking homology between aa 88-101 in this NH2-terminal region of La/SS-B and a feline retroviral gag polypeptide suggesting the anti-La/SS-B response may be initiated by cross-reactivity with an exogenous agent. In the present study, detailed mapping of this NH2-terminal epitope, using recombinant La/SS-B purified from the expression of overlapping DNA fragments spanning aa 1-107, has shown that this immunodominant epitope is a complex conformational or discontinuous epitope dependent upon both aa 12-28 and 82-99 for expression, even though these regions share no homology with each other. This requirement questions the significance of the homology between La/SS-B and a retroviral gag polypeptide in the generation of the B cell response to La/SS-B and is in accord with the general concept that B cells recognize conformational epitopes on antigens rather than small linear peptide sequences. The finding also reinforces the notion that native autoantigen could be the initiator of the autoimmune response.
Pneumonia in the acquired immune deficiency syndrome.
Authors: N M Johnson
Journal: BMJ (1985)

may be ingeniously overcome by coating the resin with an indigestible material which is degradable by bacteria so that the resin is dispersed only where it is needed, in the colon.On p 1315 Einar Krag's group in Copenhagen shows that such tablets work well and are free ofthe undesired effects.Should tablets of this type be marketed they will provide a useful alternative to standard antidiarrhoeal drugs in some patients with "functional diarrhoea."
Abstract 8840: P21-Activated Kinase Improves Myocardial Performance through Modulation of Troponin-T and Myosin Light Chain 2 during Global Myocardial Ischemia and Reperfusion Injury
Authors: Michelle M Monasky, Domenico M Taglieri, Bindiya G Patel, Jonathan Chernoff, Beata M Wolska, Yunbo Ke, R. J Solaro
Journal: Circulation (2011)

Emerging evidence indicates a role for p21-activated kinase (Pak1) in ischemia/reperfusion (I/R), but it is not clear whether Pak1 activation during ischemia reduces or increases injury. We hypothesize that activation of the Pak1 signaling pathway activates NADPH oxidase and induces post-translational modifications in myofilament proteins, which promote cardioprotective mechanisms that prevent or reverse the detrimental effects of ischemic injury in mouse cardiac tissue. We subjected ex vivo hearts from WT (wild type, n=9) and Pak1-KO (knock-out, n=16) mice to 20 minutes of global ischemia followed by 30 minutes of reperfusion. Percent recovery of the left ventricular developed pressure (LVDP) after I/R injury (LVDP after I/R divided by the LVDP before ischemia) in Pak1-KO hearts was significantly reduced (37.6 ± 4.9%) compared to WT (49.9 ± 2.2%). End systolic pressure was significantly reduced after I/R injury in both WT (85.6 ± 1.7 before I/R to 69.8 ± 1.8 mmHg after I/R) and Pak1-KO hearts (90.8 ± 3.7 to 68.8 ± 3.2 mmHg after I/R), but was not significantly different between WT and Pak1-KO hearts. However, ANOVA revealed end diastolic pressure was significantly increased in Pak1-KO hearts during reperfusion, compared to WT controls. ProQ analysis showed TnT phosphorylation was increased at baseline in Pak1-KO hearts compared to WT, and increased in WT after I/R, but did not increase in Pak1-KO hearts after I/R. MLC2 phosphorylation was significantly decreased in Pak1-KO hearts compared to WT after I/R injury. The current study has advanced the field by demonstrating for the first time that Pak1 and p47 phox establish a protein-protein interaction in left ventricular cardiac tissue as assessed by co-immunoprecipitation, and that Pak1 co-localizes with p47 phox and p22 phox in the adult mouse cardiac myocyte, as assessed by immunofluorescence. Additionally, Pak1 signaling acts upon myofilament proteins and is beneficial during I/R injury, in that Pak1 reduces end diastolic pressure and increases left ventricular developed pressure after I/R injury. Thus, the current study provides a novel pathway including the targets Pak1, p47 phox , TnT, and MLC2 for development of pharmaceutical interventions for use in the clinic for patients with ischemic events.
Circuit- and Diagnosis-Specific DNA Methylation Changes at γ-Aminobutyric Acid–Related Genes in Postmortem Human Hippocampus in Schizophrenia and Bipolar Disorder
Authors: W. Brad Ruzicka, Sivan Subburaju, Francine M. Benes
Journal: JAMA Psychiatry (2015)

Dysfunction related to γ-aminobutyric acid (GABA)-ergic neurotransmission in the pathophysiology of major psychosis has been well established by the work of multiple groups across several decades, including the widely replicated downregulation of GAD1. Prior gene expression and network analyses within the human hippocampus implicate a broader network of genes, termed the GAD1 regulatory network, in regulation of GAD1 expression. Several genes within this GAD1 regulatory network show diagnosis- and sector-specific expression changes within the circuitry of the hippocampus, influencing abnormal GAD1 expression in schizophrenia and bipolar disorder.To investigate the hypothesis that aberrant DNA methylation contributes to circuit- and diagnosis-specific abnormal expression of GAD1 regulatory network genes in psychotic illness.This epigenetic association study targeting GAD1 regulatory network genes was conducted between July 1, 2012, and June 30, 2014. Postmortem human hippocampus tissue samples were obtained from 8 patients with schizophrenia, 8 patients with bipolar disorder, and 8 healthy control participants matched for age, sex, postmortem interval, and other potential confounds from the Harvard Brain Tissue Resource Center, McLean Hospital, Belmont, Massachusetts. We extracted DNA from laser-microdissected stratum oriens tissue of cornu ammonis 2/3 (CA2/3) and CA1 postmortem human hippocampus, bisulfite modified it, and assessed it with the Infinium HumanMethylation450 BeadChip (Illumina, Inc). The subset of CpG loci associated with GAD1 regulatory network genes was analyzed in R version 3.1.0 software (R Foundation) using the minfi package. Findings were validated using bisulfite pyrosequencing.Methylation levels at 1308 GAD1 regulatory network-associated CpG loci were assessed both as individual sites to identify differentially methylated positions and by sharing information among colocalized probes to identify differentially methylated regions.A total of 146 differentially methylated positions with a false detection rate lower than 0.05 were identified across all 6 groups (2 circuit locations in each of 3 diagnostic categories), and 54 differentially methylated regions with P < .01 were identified in single-group comparisons. Methylation changes were enriched in MSX1, CCND2, and DAXX at specific loci within the hippocampus of patients with schizophrenia and bipolar disorder.This work demonstrates diagnosis- and circuit-specific DNA methylation changes at a subset of GAD1 regulatory network genes in the human hippocampus in schizophrenia and bipolar disorder. These genes participate in chromatin regulation and cell cycle control, supporting the concept that the established GABAergic dysfunction in these disorders is related to disruption of GABAergic interneuron physiology at specific circuit locations within the human hippocampus.
Serial Magnetic Resonance Spectroscopy Reveals a Direct Metabolic Effect of Cediranib in Glioblastoma
Authors: Heisoog Kim, Ciprian Catana, Eva-Maria Ratai, Ovidiu C. Andronesi, Dominique L. Jennings, Tracy T. Batchelor, Rakesh K. Jain, A. Gregory Sorensen
Journal: Cancer Research (2011)

Abstract Proton magnetic resonance spectroscopy is increasingly used in clinical studies of brain tumor to provide information about tissue metabolic profiles. In this study, we evaluated changes in the levels of metabolites predominant in recurrent glioblastoma multiforme (rGBM) to characterize the response of rGBM to antiangiogenic therapy. We examined 31 rGBM patients treated with daily doses of cediranib, acquiring serial chemical shift imaging data at specific time points during the treatment regimen. We defined spectra from three regions of interest (ROI)—enhancing tumor (ET), peritumoral tissue, and normal tissue on the contralateral side (cNT)—in post-contrast T1-weighted images, and normalized the concentrations of N-acetylaspartate (NAA) and choline (Cho) in each ROI to the concentration of creatine in cNT (norCre). We analyzed the ratios of these normalized metabolites (i.e., NAA/Cho, NAA/norCre, and Cho/norCre) by averaging all patients and categorizing two different survival groups. Relative to pretreatment values, NAA/Cho in ET was unchanged through day 28. However, after day 28, NAA/Cho significantly increased in relation to a significant increase in NAA/norCre and a decrease in Cho/norCre; interestingly, the observed trend was reversed after day 56, consistent with the clinical course of GBM recurrence. Notably, receiver operating characteristic analysis indicated that NAA/Cho in tumor shows a high prediction to 6-month overall survival. These metabolic changes in these rGBM patients strongly suggest a direct metabolic effect of cediranib and might also reflect an antitumor response to antiangiogenic treatment during the first 2 months of treatment. Further study is needed to confirm these findings. Cancer Res; 71(11); 3745–52. ©2011 AACR.
Point-Counterpoint of Sphingosine 1-Phosphate Metabolism
Authors: Julie D. Saba, Timothy Hla
Journal: Circulation Research (2004)

Sphingosine 1-phosphate (S1P), an evolutionarily conserved bioactive lipid mediator, is now recognized as a potent modulator of cell regulation. In vertebrates, S1P interacts with cell surface G protein-coupled receptors of the EDG family and induces profound effects in a variety of organ systems. Indeed, an S1P receptor agonist is undergoing clinical trials to combat immune-mediated transplant rejection. Recent information on S1P receptor biology suggests potential utility in the control of cardiovascular processes, including angiogenesis, vascular permeability, arteriogenesis, and vasospasm. However, studies from diverse invertebrates, such as yeast, Dictyostelium, Drosophila, and Caenorhabditis elegans have shown that S1P is involved in important regulatory functions in the apparent absence of EDG S1P receptor homologues. Metabolic pathways of S1P synthesis, degradation, and release have recently been described at the molecular level. Genetic and biochemical studies of these enzymes have illuminated the importance of S1P signaling systems both inside and outside of cells. The revelation of receptor-dependent pathways, as well as novel metabolic/intracellular pathways has provided new biological insights and may ultimately pave the way for the development of novel therapeutic approaches for cardiovascular diseases.
Motion-Detecting Circuits in Flies: Coming into View
Authors: Marion Silies, Daryl M. Gohl, Thomas R. Clandinin
Journal: Annual Review of Neuroscience (2014)

Visual motion cues provide animals with critical information about their environment and guide a diverse array of behaviors. The neural circuits that carry out motion estimation provide a well-constrained model system for studying the logic of neural computation. Through a confluence of behavioral, physiological, and anatomical experiments, taking advantage of the powerful genetic tools available in the fruit fly Drosophila melanogaster, an outline of the neural pathways that compute visual motion has emerged. Here we describe these pathways, the evidence supporting them, and the challenges that remain in understanding the circuits and computations that link sensory inputs to behavior. Studies in flies and vertebrates have revealed a number of functional similarities between motion-processing pathways in different animals, despite profound differences in circuit anatomy and structure. The fact that different circuit mechanisms are used to achieve convergent computational outcomes sheds light on the evolution of the nervous system.
Long-term Benefit of Sustained-Delivery Fluocinolone Acetonide Vitreous Inserts for Diabetic Macular Edema
Authors: Peter A. Campochiaro, David M. Brown, Andrew Pearson, Thomas Ciulla, David Boyer, Frank G. Holz, Michael Tolentino, Amod Gupta, Lilianne Duarte, Steven Madreperla, John Gonder, Barry Kapik, Kathleen Billman, Frances E. Kane
Journal: Ophthalmology (2011)
Vibration therapy reduces plasma IL6 and muscle soreness after downhill running
Authors: S Broadbent, J J Rousseau, R M Thorp, S L Choate, F S Jackson, D S Rowlands
Journal: British Journal of Sports Medicine (2008)

Objective In this study, the effects of vibration therapy (VT) on delayed-onset muscle soreness (DOMS) and associated inflammatory markers after downhill running were determined. Methods 29 male recreational runners (33 (8) years; Vo 2 peak 57 (6) ml kg −1 min −1 ) completed a 40-min downhill run and were randomly allocated to a VT group or Control group. For 5 days post-run, the VT group underwent once-daily sessions of VT on the upper and lower legs. DOMS was assessed pre-run and for 5 days post-run by visual analogue scale. Immune cell subsets and plasma inflammatory markers were assessed pre-run, post-run, 24 and 120 h post-run by full differential cell count, and by ELISA and enzyme immunoassay, respectively. Data were analysed as per cent change from pre-run (ANOVA) and the magnitude of the treatment effect (Cohen's effect size statistics). Results VT significantly reduced calf pain 96 h post-run (−50% (40%), 90% confidence limits) and gluteal pain 96 h (−50% (40%)) and 120 h post-run (−30% (30%)); decreased interleukin 6 (IL6) 24 h (−46% (31%)) and 120 h post-run (−65% (30%)); substantially decreased histamine 24 h (−40% (50%)) and 120 h post-run (−37% (48%)); substantially increased neutrophils (8.6% (8.1%)) and significantly decreased lymphocytes (−17% (12%)) 24 h post-run. There were no clear substantial effects of VT on other leukocyte subsets and inflammatory markers. Conclusion VT reduces muscle soreness and IL6. It may stimulate lymphocyte and neutrophil responses and may be a useful modality in treating muscle inflammation.
Targeting Sirtuin 1 to Improve Metabolism: All You Need Is NAD<sup>+</sup>?
Authors: Carles Cantó, Johan Auwerx
Journal: Pharmacological Reviews (2011)

Sirtuin 1 (SIRT1) is an evolutionarily conserved NAD(+)-dependent deacetylase that is at the pinnacle of metabolic control, all the way from yeast to humans. SIRT1 senses changes in intracellular NAD(+) levels, which reflect energy level, and uses this information to adapt the cellular energy output such that it matches cellular energy requirements. The changes induced by SIRT1 activation are generally (but not exclusively) transcriptional in nature and are related to an increase in mitochondrial metabolism and antioxidant protection. These attractive features have validated SIRT1 as a therapeutic target in the management of metabolic disease and prompted an intensive search to identify pharmacological SIRT1 activators. In this review, we first give an overview of the SIRT1 biology with a particular focus on its role in metabolic control. We then analyze the pros and cons of the current strategies used to activate SIRT1 and explore the emerging evidence indicating that modulation of NAD(+) levels could provide an effective way to achieve such goals.
Prostaglandin E2 suppresses the differentiation of retinoic acid–producing dendritic cells in mice and humans
Authors: Angus Stock, Sarah Booth, Vincenzo Cerundolo
Journal: The Journal of Experimental Medicine (2011)

The production of retinoic acid (RA) by dendritic cells (DCs) is critical for the induction of gut-tropic immune responses by driving the expression of intestinal-specific homing receptors, such as α4β7 and CCR9, upon T and B cell activation. However, how RA production is regulated during DC development remains unclear. We describe an unexpected role for prostaglandin E2 (PGE2) as a negative regulator of retinal dehydrogenases (RALDH), the enzymes responsible for RA synthesis. The presence of PGE2 during DC differentiation inhibited RALDH expression in mouse and human DCs, abrogating their ability to induce CCR9 expression upon T cell priming. Furthermore, blocking PGE2 signaling increased the frequency of RALDH(+) DCs in vitro, and reducing PGE2 synthesis in vivo promoted the systemic emergence of RA-producing DCs and the priming of CCR9(+) T cells in nonintestinal sites such as the spleen. Finally, we found that PGE2 stimulated the expression of the inducible cyclic AMP early repressor, which appears to directly inhibit RALDH expression in DCs, thus providing mechanistic insight into how PGE2 signaling down-modulates RALDH. Given the role of PGE2 in regulating the development of RA-producing DCs, modulating this pathway may prove a novel means to control the development of gut-tropic immune responses.
Growth stimulation by coexpression of transforming growth factor-alpha and epidermal growth factor-receptor in normal and adenomatous human colon epithelium.
Authors: S D Markowitz, K Molkentin, C Gerbic, J Jackson, T Stellato, J K Willson
Journal: Journal of Clinical Investigation (1990)

Autocrine stimulation of the epidermal growth factor receptor (EGF-R), by coexpression of transforming growth factor-alpha (TGF-alpha), causes malignant transformation of some fibroblast cell lines. TGF-alpha and EGF-R are both known to be expressed in colon carcinoma tissue and have been shown coexpressed in colon carcinoma cell lines. TGF-alpha autocrine activation of EGF-R has been suggested as a potential mechanism contributing to abnormal growth control in colon cancer. We now report coexpression of TGF-alpha and EGF-R transcripts in morphologically normal colonic epithelium from five individuals, in colonic adenomas from three individuals, and in a nontumorigenic colon adenoma cell line, VACO-330. Functional studies demonstrate VACO-330 growth is stimulated by exogenous TGF-alpha and is completely abolished by a blocking anti-EGF-R antibody. Autocrine stimulation of EGF-R by TGF-alpha is therefore required for growth of the adenoma cell line. Autocrine stimulation of EGF-R by TGF-alpha does not cause malignant transformation of the colonic epithelial cell. In normal and adenomatous human colon TGF-alpha, via either an autocrine or paracrine mechanism, is likely an important physiologic stimulant of epithelial proliferation.
The Prevalence and Management of Diabetes in Thai Adults
Authors: Wichai Aekplakorn, Ronald P. Stolk, Bruce Neal, Paibul Suriyawongpaisal, Virasakdi Chongsuvivatwong, Sayan Cheepudomwit, Mark Woodward
Journal: Diabetes Care (2003)

OBJECTIVE—The aim of this study was to determine in Thai adults aged ≥35 years the prevalence and management of diabetes and the associations of diabetes with cardiovascular risk factors. RESEARCH DESIGN AND METHODS—The International Collaborative Study of Cardiovascular Disease in Asia was a complex sample survey. Data from a structured questionnaire, brief physical examination, and blood sample were collected from 5,105 individuals aged ≥35 years (response rate 68%). Population estimates were calculated by applying sampling weights derived from the 2000 Thai census. RESULTS—The estimated national prevalence of diabetes in Thai adults was 9.6% (2.4 million people), which included 4.8% previously diagnosed and 4.8% newly diagnosed. The prevalence of impaired fasting glucose was 5.4% (1.4 million people). Diagnosed diabetes, undiagnosed diabetes, and impaired fasting glucose were associated with greater age, BMI, waist-to-hip ratio, systolic blood pressure, total cholesterol, and serum creatinine levels. The majority of individuals with diagnosed diabetes had received dietary or other behavioral advice, and 82% were taking oral hypoglycemic therapy. Blood pressure-lowering therapy was provided to 67% of diagnosed diabetic patients with concomitant hypertension. CONCLUSIONS—Diabetes is common in Thailand, but one-half of all cases are undiagnosed. Because diagnosed diabetes is likely to be treated with proven, low-cost, preventive therapies such as glucose lowering and blood pressure lowering, initiatives that increased diagnosis rates would be expected to produce substantial health benefits in Thailand.
CTLA-4 binding to the lipid kinase phosphatidylinositol 3-kinase in T cells.
Authors: H Schneider, K V Prasad, S E Shoelson, C E Rudd
Journal: The Journal of Experimental Medicine (1995)

CTLA-4 is a T cell antigen that is structurally related to CD28 and serves as a high affinity ligand for the B cell antigen B7-1/2. Unlike CD28, the function of CTLA-4 is unclear, although reports have implicated the antigen in the costimulation of T cells. Recently, phosphatidylinositol 3-kinase (PI 3-kinase) has been implicated in the costimulatory function of CD28 by virtue of its ability to bind to a pYMNM motif within the cytoplasmic tail of the antigen. In this study, we show that CTLA-4 can also associate with PI 3-kinase as detected by lipid kinase analysis and immunoblotting with anti-p85 antiserum. High pressure liquid chromatographic separation of deacylated lipids showed the presence of a peak corresponding to PI-3-P. Anti-CTLA-4 ligation of the receptor induced a significant increase in the levels of precipitable PI 3-kinase activity. Peptide binding studies revealed that the NH2- and COOH-terminal SH2 domains of p85 bind the CTLA-4 cytoplasmic pYVKM motif with an affinity (ID50: 0.6 and 0.04 microM), that is similar to CD28. CTLA-4 binding to PI 3-kinase provides further evidence that CTLA-4 is not an inert counterreceptor, but rather is coupled to an intracellular signaling molecule with the capacity to regulate cell growth.
Spindle assembly checkpoint and its regulators in meiosis
Authors: Shao-Chen Sun, Nam-Hyung Kim
Journal: Human Reproduction Update (2011)

Meiosis is a unique form of cell division in which cells divide twice but DNA is duplicated only once. Errors in chromosome segregation during meiosis will result in aneuploidy, followed by loss of the conceptus during pregnancy or birth defects. During mitosis, cells utilize a mechanism called the spindle assembly checkpoint (SAC) to ensure faithful chromosome segregation. A similar mechanism has been uncovered for meiosis in the last decade, especially in the past several years. For this review, we included data and relevant information obtained through a PubMed database search for all articles published in English from 1991 through 2011 which included the term 'meiosis', 'spindle assembly checkpoint', or 'SAC'. There are 91 studies included. Evidence for the existence of SAC functions in meiosis is provided by studies on the SAC proteins mitotic-arrest deficient-1 (Mad1), Mad2, budding uninhibited by benzimidazole-1 (Bub1), Bub3, BubR1 and Mps1; microtubule-kinetochore attachment regulators Ndc80 complex, chromosomal passenger complex, mitotic centromere-associated kinesin (MCAK), kinetochore null 1 (KNL1) and Mis12 complex and spindle stability regulators. SAC and its regulators exist and function in meiosis, and their malfunctions may cause germ cell aneuploidy. However, species and sexual differences exist. Moreover, interaction of SAC components with other regulators is still poorly understood, which needs further study.