Proteomic Profiling in the Brain of CLN1 Disease Model Reveals Affected Functional Modules.

PubMed

Tikka, Saara; Monogioudi, Evanthia; Gotsopoulos, Athanasios; Soliymani, Rabah; Pezzini, Francesco; Scifo, Enzo; Uusi-Rauva, Kristiina; Tyynelä, Jaana; Baumann, Marc; Jalanko, Anu; Simonati, Alessandro; Lalowski, Maciej

2016-03-01

Neuronal ceroid lipofuscinoses (NCL) are the most commonly inherited progressive encephalopathies of childhood. Pathologically, they are characterized by endolysosomal storage with different ultrastructural features and biochemical compositions. The molecular mechanisms causing progressive neurodegeneration and common molecular pathways linking expression of different NCL genes are largely unknown. We analyzed proteome alterations in the brains of a mouse model of human infantile CLN1 disease-palmitoyl-protein thioesterase 1 (Ppt1) gene knockout and its wild-type age-matched counterpart at different stages: pre-symptomatic, symptomatic and advanced. For this purpose, we utilized a combination of laser capture microdissection-based quantitative liquid chromatography tandem mass spectrometry (MS) and matrix-assisted laser desorption/ionization time-of-flight MS imaging to quantify/visualize the changes in protein expression in disease-affected brain thalamus and cerebral cortex tissue slices, respectively. Proteomic profiling of the pre-symptomatic stage thalamus revealed alterations mostly in metabolic processes and inhibition of various neuronal functions, i.e., neuritogenesis. Down-regulation in dynamics associated with growth of plasma projections and cellular protrusions was further corroborated by findings from RNA sequencing of CLN1 patients' fibroblasts. Changes detected at the symptomatic stage included: mitochondrial functions, synaptic vesicle transport, myelin proteome and signaling cascades, such as RhoA signaling. Considerable dysregulation of processes related to mitochondrial cell death, RhoA/Huntington's disease signaling and myelin sheath breakdown were observed at the advanced stage of the disease. The identified changes in protein levels were further substantiated by bioinformatics and network approaches, immunohistochemistry on brain tissues and literature knowledge, thus identifying various functional modules affected in the CLN1 childhood

Cln6 mutants associated with neuronal ceroid lipofuscinosis are degraded in a proteasome-dependent manner.

PubMed

Oresic, Kristina; Mueller, Britta; Tortorella, Domenico

2009-06-01

NCLs (neuronal ceroid lipofuscinoses), a group of inherited neurodegenerative lysosomal storage diseases that predominantly affect children, are the result of autosomal recessive mutations within one of the nine cln genes. The wild-type cln gene products are composed of membrane and soluble proteins that localize to the lysosome or the ER (endoplasmic reticulum). However, the destiny of the Cln variants has not been fully characterized. To explore a possible link between ER quality control and processing of Cln mutants, we investigated the fate of two NCL-related Cln6 mutants found in patient samples (Cln6(G123D) and Cln6(M241T)) in neuronal-derived human cells. The point mutations are predicted to be in the putative transmembrane domains and most probably generate misfolded membrane proteins that are subjected to ER quality control. Consistent with this paradigm, both mutants underwent rapid proteasome-mediated degradation and complexed with components of the ER extraction apparatus, Derlin-1 and p97. In addition, knockdown of SEL1L [sel-1 suppressor of lin-12-like (Caenorhabditis elegans)], a member of an E3 ubiquitin ligase complex involved in ER protein extraction, rescued significant amounts of Cln6(G123D) and Cln6(M241T) polypeptides. The results implicate ER quality control in the instability of the Cln variants that probably contributes to the development of NCL.

Distinguished Astronomer Awarded Jansky Lectureship

NASA Astrophysics Data System (ADS)

2008-05-01

Associated Universities, Inc. (AUI), and the National Radio Astronomy Observatory (NRAO) have awarded the 2008 Karl G. Jansky Lectureship to Dr. Arthur M. Wolfe of the University of California, San Diego (UCSD). The Jansky Lectureship is an honor established by the trustees of AUI to recognize outstanding contributions to the advancement of radio astronomy. Dr. Arthur M. Wolfe Dr. Arthur M. Wolfe CREDIT: UCSD Click on image for high-resolution file Dr. Wolfe has made major contributions in several areas of astronomy. Along with Rainer Sachs, he predicted the Sachs-Wolfe Effect, a phenomenon which forms the basis for modern precision cosmology using the background radio emission left over from the Big Bang. In the 1970s, he discovered that light emitted by very distant galaxies is absorbed by hydrogen atoms in previously-undetected intervening gas clouds. From the 1980s until the present, he used optical light emitted by distant quasars to show that these clouds are the progenitors of stars found in modern galaxies. This phenomenon has since been used extensively to study the production of heavy elements and history of star formation in the Universe. He also did landmark research on whether the fundamental constants of nature, such as the charge of the electron and the masses of elementary particles, do, in fact, remain constant through cosmological time. Dr. Wolfe was the Director of the Center for Astrophysics and Space Sciences at UCSD from 1997 to 2007. He joined UCSD as a Professor of Physics and Astronomy in 1989, leaving the University of Pittsburgh, where he had taught since 1973. He holds the Chancellor's Associates Chair of Physics at UCSD. Dr. Wolfe received his Ph.D from the University of Texas at Austin. He is a Fellow of the American Academy of Arts and Sciences, and received the Sackler Fellowship of the Institute of Astronomy at the University of Cambridge, UK, in 2004. As Jansky Lecturer, Wolfe will give a presentation entitled, Finding the Gas that

A mutation in canine CLN5 causes neuronal ceroid lipofuscinosis in Border collie dogs.

PubMed

Melville, Scott A; Wilson, Carmen L; Chiang, Chiu S; Studdert, Virginia P; Lingaas, Frode; Wilton, Alan N

2005-09-01

Neuronal ceroid lipofuscinosis (NCL) is a neurodegenerative disease found in Border collie dogs, humans, and other animals. Disease gene studies in humans and animals provided candidates for the NCL gene in Border collies. A combination of linkage analysis and comparative genomics localized the gene to CFA22 in an area syntenic to HSA13q that contains the CLN5 gene responsible for the Finnish variant of human late infantile NCL. Sequencing of CLN5 revealed a nonsense mutation (Q206X) within exon 4 that correlated with NCL in Border collies. This truncation mutation should result in a protein product of a size similar to that of some mutations identified in human CLN5 and therefore the Border collie may make a good model for human NCL. A simple test was developed to enable screening of the Border collie population for carriers so the disease can be eliminated as a problem in the breed.

Progressive thalamocortical neuron loss in Cln5 deficient mice: distinct effects in Finnish variant late infantile NCL

PubMed Central

von Schantz, Carina; Kielar, Catherine; Hansen, Stine N; Pontikis, Charlie C; Alexander, Noreen A; Kopra, Outi; Jalanko, Anu; Cooper, Jonathan D

2009-01-01

Finnish variant LINCL (vLINCLFin) is the result of mutations in the CLN5 gene. To gain insights into the pathological staging of this fatal pediatric disorder, we have undertaken a stereological analysis of the CNS of Cln5 deficient mice (Cln5-/-) at different stages of disease progression. Consistent with human vLINCLFin, these Cln5-/- mice displayed a relatively late onset regional atrophy and generalized cortical thinning and synaptic pathology, preceded by early and localized glial responses within the thalamocortical system. However, in marked contrast to other forms of NCL, neuron loss in Cln5-/- mice began in the cortex and only subsequently occurred within thalamic relay nuclei. Nevertheless, as in other NCL mouse models, this progressive thalamocortical neuron loss was still most pronounced within the visual system. These data provide unexpected evidence for a distinctive sequence of neuron loss in the thalamocortical system of Cln5-/- mice, diametrically opposed to that seen in other forms of NCL. PMID:19385065

Progressive thalamocortical neuron loss in Cln5 deficient mice: Distinct effects in Finnish variant late infantile NCL.

PubMed

von Schantz, Carina; Kielar, Catherine; Hansen, Stine N; Pontikis, Charlie C; Alexander, Noreen A; Kopra, Outi; Jalanko, Anu; Cooper, Jonathan D

2009-05-01

Finnish variant LINCL (vLINCL(Fin)) is the result of mutations in the CLN5 gene. To gain insights into the pathological staging of this fatal pediatric disorder, we have undertaken a stereological analysis of the CNS of Cln5 deficient mice (Cln5-/-) at different stages of disease progression. Consistent with human vLINCL(Fin), these Cln5-/- mice displayed a relatively late onset regional atrophy and generalized cortical thinning and synaptic pathology, preceded by early and localized glial responses within the thalamocortical system. However, in marked contrast to other forms of NCL, neuron loss in Cln5-/- mice began in the cortex and only subsequently occurred within thalamic relay nuclei. Nevertheless, as in other NCL mouse models, this progressive thalamocortical neuron loss was still most pronounced within the visual system. These data provide unexpected evidence for a distinctive sequence of neuron loss in the thalamocortical system of Cln5-/- mice, diametrically opposed to that seen in other forms of NCL.

Identification of CLN6 as a molecular entity of endoplasmic reticulum-driven anti-aggregate activity.

PubMed

Yamashita, Arisa; Hiraki, Yuri; Yamazaki, Tetsuo

2017-06-10

αB-crystallin (αBC) is a small heat shock protein. Mutations in the αBC gene are linked to α-crystallinopathy, a hereditary myopathy histologically characterized by intracellular accumulation of protein aggregates. The disease-causing R120G αBC mutant, harboring an arginine-to-glycine replacement at position 120, is an aggregate-prone protein. We previously showed that the R120G mutant's aggregation in HeLa cells was prevented by enforced expression of αBC on the endoplasmic reticulum (ER). To elucidate the molecular nature of the preventive effect on the R120G mutant, we isolated proteins binding to ER-anchored αBC (TMαBC). The ER transmembrane CLN6 protein was identified as a TMαBC's binder. CLN6 knockdown in HeLa cells attenuated TMαBC's anti-aggregate activity against the R120G mutant. Conversely, CLN6 overexpression enhanced the activity, indicating that CLN6 operates as a downstream effector of TMαBC. CLN6 physically interacted with the R120G mutant, and repressed its aggregation in HeLa cells even when TMαBC was not co-expressed. Furthermore, CLN6's antagonizing effect on the R120G mutant was compromised upon treatment with a lysosomal inhibitor, suggesting CLN6 requires the intact autophagy-lysosome system to prevent the R120G mutant from aggregating. We hence conclude that CLN6 is not only a molecular entity of the anti-aggregate activity conferred by the ER manipulation using TMαBC, but also serves as a potential target of therapeutic interventions. Copyright © 2017 Elsevier Inc. All rights reserved.

Characterization of endopeptidase activity of tripeptidyl peptidase-I/CLN2 protein which is deficient in classical late infantile neuronal ceroid lipofuscinosis.

PubMed

Ezaki, J; Takeda-Ezaki, M; Oda, K; Kominami, E

2000-02-24

Endopeptidase activities of the CLN2 gene product (Cln2p)/tripeptidyl peptidase I (TPP-I), purified from rat spleen, were studied using the synthetic fluorogenic substrates. We designed and constructed decapeptides, based on the known sequence cleavage specificities of bacterial pepstatin-insensitive carboxyl proteases (BPICP). MOCAc-Gly-Lys-Pro-Ile-Pro-Phe-Phe-Arg-Leu-Lys(Dnp)r-NH(2) is readily hydrolyzed by Cln2p/TPP-I (K(cat)/K(m) = 7.8 s(-1) mM(-1)). The enzyme had a maximal activity at pH 3.0 for an endopeptidase substrate, but at pH 4.5 with respect to tripeptidyl peptidase activity. Both endopeptidase and tripeptidyl peptidase activities were strongly inhibited by Ala-Ala-Phe-CH(2)Cl, but not inhibited by tyrostatin, an inhibitor of bacterial pepstatin-insensitive carboxyl proteases, pepstatin, or inhibitors of serine proteases. Fibroblasts from classical late infantile neuronal ceroid lipofuscinosis patients have less than 5% of the normal tripeptidyl peptidase activity and pepstatin-insensitive endopeptidase activity. Cln2p/TPP-I is a unique enzyme with both tripeptidyl peptidase and endopeptidase activities for certain substrate specificity. Copyright 2000 Academic Press.

Thalamocortical neuron loss and localized astrocytosis in the Cln3Deltaex7/8 knock-in mouse model of Batten disease.

PubMed

Pontikis, Charlie C; Cotman, Susan L; MacDonald, Marcy E; Cooper, Jonathan D

2005-12-01

Juvenile neuronal ceroid lipofuscinosis (JNCL) is the result of mutations in the Cln3 gene. The Cln3 knock-in mouse (Cln3Deltaex7/8) reproduces the most common Cln3 mutation and we have now characterized the CNS of these mice at 12 months of age. With the exception of the thalamus, Cln3Deltaex7/8 homozygotes displayed no significant regional atrophy, but a range of changes in individual laminar thickness that resulted in variable cortical thinning across subfields. Stereological analysis revealed a pronounced loss of neurons within individual laminae of somatosensory cortex of affected mice and the novel finding of a loss of sensory relay thalamic neurons. These affected mice also exhibited profound astrocytic reactions that were most pronounced in the neocortex and thalamus, but diminished in other brain regions. These data provide the first direct evidence for neurodegenerative and reactive changes in the thalamocortical system in JNCL and emphasize the localized nature of these events.

An unusual clinical severity of 16p11.2 deletion syndrome caused by unmasked recessive mutation of CLN3.

PubMed

Pebrel-Richard, Céline; Debost-Legrand, Anne; Eymard-Pierre, Eléonore; Greze, Victoria; Kemeny, Stéphan; Gay-Bellile, Mathilde; Gouas, Laetitia; Tchirkov, Andreï; Vago, Philippe; Goumy, Carole; Francannet, Christine

2014-03-01

With the introduction of array comparative genomic hybridization (aCGH) techniques in the diagnostic setting of patients with developmental delay and congenital malformations, many new microdeletion syndromes have been recognized. One of these recently recognized microdeletion syndromes is the 16p11.2 deletion syndrome, associated with variable clinical outcomes including developmental delay, autism spectrum disorder, epilepsy, and obesity, but also apparently normal phenotype. We report on a 16-year-old patient with developmental delay, exhibiting retinis pigmentosa with progressive visual failure from the age of 9 years, ataxia, and peripheral neuropathy. Chromosomal microarray analysis identified a 1.7-Mb 16p11.2 deletion encompassing the 593-kb common deletion (∼29.5 to ∼30.1 Mb; Hg18) and the 220-kb distal deletion (∼28.74 to ∼28.95 Mb; Hg18) that partially included the CLN3 gene. As the patient's clinical findings were different from usual 16p11.2 microdeletion phenotypes and showed some features reminiscent of juvenile neuronal ceroid-lipofuscinosis (JNCL, Batten disease, OMIM 204200), we suspected and confirmed a mutation of the remaining CLN3 allele. This case further illustrates that unmasking of hemizygous recessive mutations by chromosomal deletion represents one explanation for the phenotypic variability observed in chromosomal deletion disorders.

An unusual clinical severity of 16p11.2 deletion syndrome caused by unmasked recessive mutation of CLN3

PubMed Central

Pebrel-Richard, Céline; Debost-Legrand, Anne; Eymard-Pierre, Eléonore; Greze, Victoria; Kemeny, Stéphan; Gay-Bellile, Mathilde; Gouas, Laetitia; Tchirkov, Andreï; Vago, Philippe; Goumy, Carole; Francannet, Christine

2014-01-01

With the introduction of array comparative genomic hybridization (aCGH) techniques in the diagnostic setting of patients with developmental delay and congenital malformations, many new microdeletion syndromes have been recognized. One of these recently recognized microdeletion syndromes is the 16p11.2 deletion syndrome, associated with variable clinical outcomes including developmental delay, autism spectrum disorder, epilepsy, and obesity, but also apparently normal phenotype. We report on a 16-year-old patient with developmental delay, exhibiting retinis pigmentosa with progressive visual failure from the age of 9 years, ataxia, and peripheral neuropathy. Chromosomal microarray analysis identified a 1.7-Mb 16p11.2 deletion encompassing the 593-kb common deletion (∼29.5 to ∼30.1 Mb; Hg18) and the 220-kb distal deletion (∼28.74 to ∼28.95 Mb; Hg18) that partially included the CLN3 gene. As the patient's clinical findings were different from usual 16p11.2 microdeletion phenotypes and showed some features reminiscent of juvenile neuronal ceroid-lipofuscinosis (JNCL, Batten disease, OMIM 204200), we suspected and confirmed a mutation of the remaining CLN3 allele. This case further illustrates that unmasking of hemizygous recessive mutations by chromosomal deletion represents one explanation for the phenotypic variability observed in chromosomal deletion disorders. PMID:23860047

German Astronomer Karl Menten Is 2007 Jansky Awardee

NASA Astrophysics Data System (ADS)

2007-06-01

Associated Universities, Inc., (AUI) and the National Radio Astronomy Observatory (NRAO) have awarded the 2007 Karl G. Jansky Lectureship to Professor Karl M. Menten of the Max-Planck-Institute for Radioastronomy in Bonn, Germany. The Jansky Lectureship is an honor established by the trustees of AUI to recognize outstanding contributions to the advancement of astronomy. Karl M. Menten Professor Karl M. Menten CREDIT: NRAO/AUI Click on image for high-resolution file (433 KB) Professor Menten is an extraordinarily productive scientist whose research has improved our fundamental understanding in a number of areas of astronomy. He has studied the chemistry of molecular clouds from which new stars are formed, the process of star formation in our own Milky Way Galaxy and in the early Universe, and the outer atmospheres of stars nearing the end of their "normal" lives. In 1991, Menten used NRAO's 140-foot Telescope at Green Bank, West Virginia, to discover strong radio emission from methanol masers in star-forming regions. These masers amplify, or strengthen, radio emission the same way a laser amplifies visible-light emission. Menten developed the observation of these methanol masers into a powerful tool for studying the formation of stars much more massive than our Sun, because the strong maser emission points astronomers to the stellar birthplaces. In addition, Menten pioneered the use of ultra-high-resolution observations with NRAO's Very Long Baseline Array to observe masers to make precision determinations of the structure, size and dynamics of the Milky Way. Menten received his doctoral degree in 1987 from the University of Bonn, Germany. He then joined the Harvard-Smithsonian Center for Astrophysics, working there until 1996, when he became the Director for Millimeter and Submillimeter Astronomy at the Max-Planck-Institute for Radioastronomy. In addition to that position, he also has been a Professor for Experimental Astrophysics at the University of Bonn since

Photoreceptor phagosome processing defects and disturbed autophagy in retinal pigment epithelium of Cln3Δex1-6 mice modelling juvenile neuronal ceroid lipofuscinosis (Batten disease)

PubMed Central

Wavre-Shapton, Silène T.; Calvi, Alessandra A.; Turmaine, Mark; Seabra, Miguel C.; Cutler, Daniel F.; Futter, Clare E.; Mitchison, Hannah M.

2015-01-01

Retinal degeneration and visual impairment are the first signs of juvenile neuronal ceroid lipofuscinosis caused by CLN3 mutations, followed by inevitable progression to blindness. We investigated retinal degeneration in Cln3Δex1-6 null mice, revealing classic ‘fingerprint’ lysosomal storage in the retinal pigment epithelium (RPE), replicating the human disease. The lysosomes contain mitochondrial F0-ATP synthase subunit c along with undigested membranes, indicating a reduced degradative capacity. Mature autophagosomes and basal phagolysosomes, the terminal degradative compartments of autophagy and phagocytosis, are also increased in Cln3Δex1-6 RPE, reflecting disruption to these key pathways that underpin the daily phagocytic turnover of photoreceptor outer segments (POS) required for maintenance of vision. The accumulated autophagosomes have post-lysosome fusion morphology, with undigested internal contents visible, while accumulated phagosomes are frequently docked to cathepsin D-positive lysosomes, without mixing of phagosomal and lysosomal contents. This suggests lysosome-processing defects affect both autophagy and phagocytosis, supported by evidence that phagosomes induced in Cln3Δex1-6-derived mouse embryonic fibroblasts have visibly disorganized membranes, unprocessed internal vesicles and membrane contents, in addition to reduced LAMP1 membrane recruitment. We propose that defective lysosomes in Cln3Δex1-6 RPE have a reduced degradative capacity that impairs the final steps of the intimately connected autophagic and phagocytic pathways that are responsible for degradation of POS. A build-up of degradative organellar by-products and decreased recycling of cellular materials is likely to disrupt processes vital to maintenance of vision by the RPE. PMID:26450516

Partial Correction of the CNS Lysosomal Storage Defect in a Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis by Neonatal CNS Administration of an Adeno-Associated Virus Serotype rh.10 Vector Expressing the Human CLN3 Gene

PubMed Central

Sondhi, Dolan; Scott, Emma C.; Chen, Alvin; Hackett, Neil R.; Wong, Andrew M.S.; Kubiak, Agnieszka; Nelvagal, Hemanth R.; Pearse, Yewande; Cotman, Susan L.; Cooper, Jonathan D.

2014-01-01

Abstract Juvenile neuronal ceroid lipofuscinosis (JNCL or CLN3 disease) is an autosomal recessive lysosomal storage disease resulting from mutations in the CLN3 gene that encodes a lysosomal membrane protein. The disease primarily affects the brain with widespread intralysosomal accumulation of autofluorescent material and fibrillary gliosis, as well as the loss of specific neuronal populations. As an experimental treatment for the CNS manifestations of JNCL, we have developed a serotype rh.10 adeno-associated virus vector expressing the human CLN3 cDNA (AAVrh.10hCLN3). We hypothesized that administration of AAVrh.10hCLN3 to the Cln3Δex7/8 knock-in mouse model of JNCL would reverse the lysosomal storage defect, as well as have a therapeutic effect on gliosis and neuron loss. Newborn Cln3Δex7/8 mice were administered 3×1010 genome copies of AAVrh.10hCLN3 to the brain, with control groups including untreated Cln3Δex7/8 mice and wild-type littermate mice. After 18 months, CLN3 transgene expression was detected in various locations throughout the brain, particularly in the hippocampus and deep anterior cortical regions. Changes in the CNS neuronal lysosomal accumulation of storage material were assessed by immunodetection of subunit C of ATP synthase, luxol fast blue staining, and periodic acid-Schiff staining. For all parameters, Cln3Δex7/8 mice exhibited abnormal lysosomal accumulation, but AAVrh.10hCLN3 administration resulted in significant reductions in storage material burden. There was also a significant decrease in gliosis in AAVrh.10hCLN3-treated Cln3Δex7/8 mice, and a trend toward improved neuron counts, compared with their untreated counterparts. These data demonstrate that AAVrh.10 delivery of a wild-type cDNA to the CNS is not harmful and instead provides a partial correction of the neurological lysosomal storage defect of a disease caused by a lysosomal membrane protein, indicating that this may be an effective therapeutic strategy for JNCL and

Neuronal ceroid lipofuscinosis type CLN2: A new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America

PubMed Central

Kohan, Romina; Noelia Carabelos, María; Xin, Winnie; Sims, Katherine; Guelbert, Norberto; Adriana Cismondi, Inés; Pons, Patricia; Alonso, Graciela Irene; Troncoso, Mónica; Witting, Scarlet; Pearce, David A.; de Kremer, Raquel Dodelson; Oller-Ramírez, Ana María; de Halac, Inés Noher

2013-01-01

Tripeptidyl-peptidase 1 (TPP1) null or residual activity occurs in neuronal ceroid lipofuscinosis (NCL) with underlying TPP1/CLN2 mutations. A survey of 25 South American CLN2 affected individuals enabled the differentiation of two phenotypes: classical late-infantile and variant juvenile, each in approximately 50% of patients, with residual TPP1 activity occurring in approximately 32%. Each individual was assigned to one of three subgroups: (I) n=11, null TPP1 activity in leukocytes; (II) n=8, residual TPP1 activity of 0.60–15.85 nmol/h/mg (nr 110–476); (III) n=6, activity not measured in leukocytes. Curvilinear bodies (CB) appeared in almost all studied CLN2 subjects; the only exceptions occurred in cases of subgroup II: two individuals had combined CBs/fingerprints (FPs), and one case had pure FPs. There were 15 mutations (4 first published in this paper, 3 previously observed in South America by our group, and 8 previously observed by others). In subgroup I, mutations were either missense or nonsense; in subgroups II and III, mutations prevailed at the non-conserved intronic site, c.887-10A>G (intron 7), and to a lesser extent at c.89+5G>C (intron 2), in heterozygous combinations. Grouping phenotypically and genetically known individuals on the basis of TPP1 activity supported the concept that residual enzyme activity underlies a protracted disease course. The prevalence of intronic mutations at nonconserved sites in subgroup II individuals indicates that some alternative splicing might allow some residual TPP1 activity. PMID:23266810

Jansky and Reber: Two Remarkable Stories in Early Radio Astronomy

NASA Astrophysics Data System (ADS)

Sullivan, W. T., III

1996-05-01

Extraterrestrial radio waves were first detected in 1931-32 by Karl Jansky at the Bell Telephone Labs in New Jersey while he was investigating sources of interference to recently opened, trans-Atlantic shortwave (20 MHz) radiotelephone circuits. At this time Jansky was only a few years beyond his physics degree from the University of Wisconsin, where his father was a professor of engineering. Jansky studied this "star noise" off and on until 1935, establishing that the emission came from the direction of the Milky Way and the galactic center, but did not pursue it in any further detail. The only other person to make a significant contribution to the nascent subject before World War II was Grote Reber, an electrical engineer who worked for several different radio firms in Chicago. After reading Jansky's articles, in 1937 Reber decided to build a 30-ft diameter dish antenna in the backyard of his suburban home in Wheaton, Illinois. By 1939 he had detected the Jansky radiation, which he called "cosmic noise", at 160 MHz and he comenced a long term program of mapping it in detail (with a 12 degree beam). Reber became a well-known figure to the astronomers at the University of Chicago and Yerkes Observatory (Struve, Greenstein, Kuiper, Henyey, Keenan) as he sought to learn astronomy and convince the staff that this cosmic noise was of importance. Struve, editor of the "Astrophysical Journal", was finally persuaded to publish Reber's articles. During and just after the war Reber extended his work to 480 MHz. He then sought funds to move his dish to a quieter locale and to build a second, much larger dish, but neither of these plans came to fruition. It is ironic that the remarkable contributions of these two pioneers to the field that would eventually become known as "radio astronomy" (a term only introduced in the late 1940s) had little influence on the spectacular growth of the field in the decade after World War II. The great bulk of the important work was done in

Translational neurophysiology in sheep: measuring sleep and neurological dysfunction in CLN5 Batten disease affected sheep

PubMed Central

Perentos, Nicholas; Martins, Amadeu Q.; Watson, Thomas C.; Bartsch, Ullrich; Mitchell, Nadia L.; Palmer, David N.; Jones, Matthew W.

2015-01-01

Creating valid mouse models of slowly progressing human neurological diseases is challenging, not least because the short lifespan of rodents confounds realistic modelling of disease time course. With their large brains and long lives, sheep offer significant advantages for translational studies of human disease. Here we used normal and CLN5 Batten disease affected sheep to demonstrate the use of the species for studying neurological function in a model of human disease. We show that electroencephalography can be used in sheep, and that longitudinal recordings spanning many months are possible. This is the first time such an electroencephalography study has been performed in sheep. We characterized sleep in sheep, quantifying characteristic vigilance states and neurophysiological hallmarks such as sleep spindles. Mild sleep abnormalities and abnormal epileptiform waveforms were found in the electroencephalographies of Batten disease affected sheep. These abnormalities resemble the epileptiform activity seen in children with Batten disease and demonstrate the translational relevance of both the technique and the model. Given that both spontaneous and engineered sheep models of human neurodegenerative diseases already exist, sheep constitute a powerful species in which longitudinal in vivo studies can be conducted. This will advance our understanding of normal brain function and improve our capacity for translational research into neurological disorders. PMID:25724202

Atypical CLN2 with later onset and prolonged course: a neuropathologic study showing different sensitivity of neuronal subpopulations to TPP1 deficiency

PubMed Central

Dvořáková, Lenka; Stolnaja, Larisa; Vlášková, Hana; Hůlková, Helena; Druga, Rastislav; Poupětová, Helena; Košťálová, Eva; Mikuláštík, Josef

2008-01-01

This is the first neuropathology report of a male patient (born 1960–died 1975) with an extremely rare, atypical variant of CLN2 that has been diagnosed only in five families so far. The clinical history started during his preschool years with relatively mild motor and psychological difficulties, but with normal intellect and vision. Since age six there were progressive cerebellar and extrapyramidal symptomatology, amaurosis, and mental deterioration. Epileptic seizures were absent. The child died aged 15 years in extreme cachexy. Neuropathology revealed neurolysosomal storage of autofluorescent, curvilinear and subunit c of mitochondrial ATP synthase (SCMAS) rich material. The neuronal storage led to laminar neuronal depopulation in the cerebral cortex and to a practically total eradication of the cerebellar cortical neurons. The other areas of the central nervous system including hippocampus, which are usually heavily affected in classical forms of CLN2, displayed either a lesser degree or absence of neuronal storage, or storage without significant neuronal loss. Transformation of the stored material to the spheroid like perikaryal inclusions was rudimentary. The follow-up, after 30 years, showed heterozygous values of TPP1 (tripeptidylpeptidase 1) activity in the white blood cells of both parents and the sister. DNA analysis of CLN2 gene identified a paternal frequent null mutation c.622C > T (p.Arg208 X) in the 6th exon and a maternal novel mutation c.1439 T > G in exon 12 (p.Val480Gly). TPP1 immunohistochemistry using a specific antibody gave negative results in the brain and other organs. Our report supports the notion that the spectrum of CLN2 phenotypes may be surprisingly broad. The study revealed variable sensitivities in neuronal subpopulations to the metabolic defect which may be responsible for the variant’s serious course. PMID:18283468

Neuronal ceroid lipofuscinosis (NCL) is caused by the entire deletion of CLN8 in the Alpenländische Dachsbracke dog.

PubMed

Hirz, M; Drögemüller, M; Schänzer, A; Jagannathan, V; Dietschi, E; Goebel, H H; Hecht, W; Laubner, S; Schmidt, M J; Steffen, F; Hilbe, M; Köhler, K; Drögemüller, C; Herden, C

2017-03-01

Neuronal ceroid lipofuscinoses (NCLs) are inherited lysosomal storage diseases that have been described in a variety of dog breeds, where they are caused by different mutations in different genes. However, the causative gene defect in the breed Alpenländische Dachsbracke remained unknown so far. Here we present two confirmed cases of NCL in Alpenländische Dachsbracke dogs from different litters of the same sire with a different dam harboring the same underlying novel mutation in the CLN8 gene. Case 1, a 2-year-old male Alpenländische Dachsbracke was presented with neurological signs including disorientation, character changes including anxiety states and aggressiveness, sudden blindness and reduction of food intake. Magnetic resonance imaging (MRI) scans showed cerebral atrophy with dilation of all cerebral ventricles, thinning of the intermediate mass of the thalamus and widening of the cerebral sulci. Postmortem examination of the central nervous system (CNS) showed neuronal loss in the cerebral cortex, cerebellum and spinal cord with massive intracellular deposits of ceroid pigment. Additional ceroid-lipofuscin deposits were observed in the enteric nervous system and in macrophages within spleen, lymph nodes and lung. Ultrastructural analyses confirmed NCL with the presence of osmiophilic membrane bounded lamellar-like structures. Case 2, a 1,5-year old female Alpenländische Dachsbracke was presented with progressive generalized forebrain disease including mental changes such as fearful reactions to various kinds of external stimuli and disorientation. The dog also displayed seizures, absence of menace reactions and negative cotton-ball test with normal pupillary light reactions. The clinical and post mortem examination yielded similar results in the brain as in Case 1. Whole genome sequencing of Case 1 and PCR results of both cases revealed a homozygous deletion encompassing the entire CLN8 gene as the most likely causative mutation for the NCL form

Lysosomal membrane permeability stimulates protein aggregate formation in neurons of a lysosomal disease.

PubMed

Micsenyi, Matthew C; Sikora, Jakub; Stephney, Gloria; Dobrenis, Kostantin; Walkley, Steven U

2013-06-26

Protein aggregates are a common pathological feature of neurodegenerative diseases and several lysosomal diseases, but it is currently unclear what aggregates represent for pathogenesis. Here we report the accumulation of intraneuronal aggregates containing the macroautophagy adapter proteins p62 and NBR1 in the neurodegenerative lysosomal disease late-infantile neuronal ceroid lipofuscinosis (CLN2 disease). CLN2 disease is caused by a deficiency in the lysosomal enzyme tripeptidyl peptidase I, which results in aberrant lysosomal storage of catabolites, including the subunit c of mitochondrial ATP synthase (SCMAS). In an effort to define the role of aggregates in CLN2, we evaluated p62 and NBR1 accumulation in the CNS of Cln2(-/-) mice. Although increases in p62 and NBR1 often suggest compromised degradative mechanisms, we found normal ubiquitin-proteasome system function and only modest inefficiency in macroautophagy late in disease. Importantly, we identified that SCMAS colocalizes with p62 in extra-lysosomal aggregates in Cln2(-/-) neurons in vivo. This finding is consistent with SCMAS being released from lysosomes, an event known as lysosomal membrane permeability (LMP). We predicted that LMP and storage release from lysosomes results in the sequestration of this material as cytosolic aggregates by p62 and NBR1. Notably, LMP induction in primary neuronal cultures generates p62-positive aggregates and promotes p62 localization to lysosomal membranes, supporting our in vivo findings. We conclude that LMP is a previously unrecognized pathogenic event in CLN2 disease that stimulates cytosolic aggregate formation. Furthermore, we offer a novel role for p62 in response to LMP that may be relevant for other diseases exhibiting p62 accumulation.

Lysosomal Membrane Permeability Stimulates Protein Aggregate Formation in Neurons of a Lysosomal Disease

PubMed Central

Micsenyi, Matthew C.; Sikora, Jakub; Stephney, Gloria; Dobrenis, Kostantin

2013-01-01

Protein aggregates are a common pathological feature of neurodegenerative diseases and several lysosomal diseases, but it is currently unclear what aggregates represent for pathogenesis. Here we report the accumulation of intraneuronal aggregates containing the macroautophagy adapter proteins p62 and NBR1 in the neurodegenerative lysosomal disease late-infantile neuronal ceroid lipofuscinosis (CLN2 disease). CLN2 disease is caused by a deficiency in the lysosomal enzyme tripeptidyl peptidase I, which results in aberrant lysosomal storage of catabolites, including the subunit c of mitochondrial ATP synthase (SCMAS). In an effort to define the role of aggregates in CLN2, we evaluated p62 and NBR1 accumulation in the CNS of Cln2−/− mice. Although increases in p62 and NBR1 often suggest compromised degradative mechanisms, we found normal ubiquitin–proteasome system function and only modest inefficiency in macroautophagy late in disease. Importantly, we identified that SCMAS colocalizes with p62 in extra-lysosomal aggregates in Cln2−/− neurons in vivo. This finding is consistent with SCMAS being released from lysosomes, an event known as lysosomal membrane permeability (LMP). We predicted that LMP and storage release from lysosomes results in the sequestration of this material as cytosolic aggregates by p62 and NBR1. Notably, LMP induction in primary neuronal cultures generates p62-positive aggregates and promotes p62 localization to lysosomal membranes, supporting our in vivo findings. We conclude that LMP is a previously unrecognized pathogenic event in CLN2 disease that stimulates cytosolic aggregate formation. Furthermore, we offer a novel role for p62 in response to LMP that may be relevant for other diseases exhibiting p62 accumulation. PMID:23804102

Production of a conjugated fatty acid by Bifidobacterium breve LMC520 from α-linolenic acid: conjugated linolenic acid (CLnA).

PubMed

Park, Hui Gyu; Cho, Hyung Taek; Song, Myoung-Chong; Kim, Sang Bum; Kwon, Eung Gi; Choi, Nag Jin; Kim, Young Jun

2012-03-28

This study was performed to characterize natural CLnA isomer production by Bifidobacterium breve LMC520 of human origin in comparison to conjugated linoleic acid (CLA) production. B. breve LMC520 was found to be highly active in terms of CLnA production, of which the major portion was identified as cis-9,trans-11,cis-15 CLnA isomer by GC-MS and NMR analysis. B. breve LMC520 was incubated for 48 h using MRS medium (containing 0.05% L-cysteine · HCl) under different environmental conditions such as atmosphere, pH, and substrate concentration. The high conversion rate of α-linolenic acid (α-LNA) to CLnA (99%) was retained up to 2 mM α-LNA, and the production was proportionally increased nearly 7-fold with 8 mM by the 6 h of incubation under anaerobic conditions at a wide range of pH values (between 5 and 9). When α-LNA was compared with linoleic acid (LA) as a substrate for isomerization by B. breve LMC520, the conversion of α-LNA was higher than that of LA. These results demonstrated that specific CLnA isomer could be produced through active bacterial conversion at an optimized condition. Because many conjugated octadecatrienoic acids in nature are shown to play many positive roles, the noble isomer found in this study has potential as a functional source.

Modeling the mechanism of CLN025 beta-hairpin formation

NASA Astrophysics Data System (ADS)

McKiernan, Keri A.; Husic, Brooke E.; Pande, Vijay S.

2017-09-01

Beta-hairpins are substructures found in proteins that can lend insight into more complex systems. Furthermore, the folding of beta-hairpins is a valuable test case for benchmarking experimental and theoretical methods. Here, we simulate the folding of CLN025, a miniprotein with a beta-hairpin structure, at its experimental melting temperature using a range of state-of-the-art protein force fields. We construct Markov state models in order to examine the thermodynamics, kinetics, mechanism, and rate-determining step of folding. Mechanistically, we find the folding process is rate-limited by the formation of the turn region hydrogen bonds, which occurs following the downhill hydrophobic collapse of the extended denatured protein. These results are presented in the context of established and contradictory theories of the beta-hairpin folding process. Furthermore, our analysis suggests that the AMBER-FB15 force field, at this temperature, best describes the characteristics of the full experimental CLN025 conformational ensemble, while the AMBER ff99SB-ILDN and CHARMM22* force fields display a tendency to overstabilize the native state.

Computer-based simulation of the Bielschowsky head-tilt test using the SEE++ software system.

PubMed

Kaltofen, Thomas; Buchberger, Michael; Priglinger, Siegfried

2008-01-01

Latest measurements of the vestibulo-ocular reflex (VOR) allowed the integration of the simulation of the Bielschowsky head-tilt test (BHTT) into the SEE++ software system. SEE++ realizes a biomechanical model of the human eye in order to simulate eye motility disorders and strabismus surgeries. With the addition of the BHTT it can now also be used for differential-diagnostic simulations of complex disorders (e.g., superior oblique palsies). In order to simulate the BHTT in SEE++, the user can freely choose the desired head-tilt angle from -45 degrees to +45 degrees. The chosen angle is shown in the 3D view with a human body model and is also used in the calculation of the Hess-Lancaster test. The integration of the BHTT offers an additional improvement of the possibilities for simulating eye motility disorders. Moreover, SEE++ allows the creation of a video of the "virtual patient" while tilting the head from one side to the other, which shows dynamic changes in the simulated Hess-diagrams. Comparisons of simulation results with patient-measured data showed a good correlation between the simulated and the measured data. Further comparisons with patient data are planned.

Optimization of Process Parameters in Preparation of Nanoemulsions of CLnA Rich Oil by Response Surface Methodology

NASA Astrophysics Data System (ADS)

Sengupta, Avery; Gupta, Surashree Sen; Ghosh, Mahua

2013-03-01

The purpose of the present study was to obtain optimal processing for preparation of uniform-sized nanoemulsion of conjugated linolenic acid (CLnA) rich oil to increase the oxidative stability of CLnA by using a high-speed disperser (HSD) and ultrasonication. The emulsifiers used were egg phospholipid and soya protein isolate. The effects of oil concentration [0.05 to 1.25 % (w/w)], emulsifier ratio [0.1:0.9 to 0.9:0.1 (phospholipid:protein)], speed of the HSD (2,000 to 12,000 rpm) and times of HSD and sonication treatments (10 to 50 min) were observed. Optimization was performed with and without response surface methodology (RSM). The optimum compositional variables i.e. concentration of oil was 1 % and phospholipid:protein molar ratio was 0.5:0.5. Maximum size reduction occurred at 10,000 rpm speed of HSD. HSD should be administered for 40 min followed by 40 min ultrasonication. The range of the size of the droplets in the nanoemulsion was between 173 ± 1.20 and 183 ± 0.94 nm. Nanoemulsion is a size reduction technique where the oil present in the emulsion can be easily stabilized which increases the shelf-life of the oil. The present study derived the reaction parameters were optimized using RSM to produce nanoemulsion of CLnA rich oils of minimum size to obtain maximum stability.

The Jansky VLA: Rebuilt for 21st Century Astronomy

NASA Astrophysics Data System (ADS)

Hallinan, Gregg

2016-01-01

At the start of this decade, the Very Large Array underwent a transformative upgrade. While retaining its original 27 antennas, the signal transmission and processing systems, originally developed and built in the 1970s, have been replaced with state of the art wideband receivers and a new data transmission system, as well as one of the most powerful correlators yet built. With a ten-fold increase in continuum sensitivity, up to 4 million frequency channels and complete frequency coverage from 1-50 GHz, the resulting increase in capability and versatility is analogous to the transition from photographic plate to CCD technology that revolutionized optical astronomy in the 1980s. Post upgrade, the Jansky VLA will be the most sensitive radio interferometer in the world for this decade, probing the sub-uJy radio sky for the first time, and will remain the most versatile, frequency-agile radio telescope for the foreseeable future. Underscoring this versatility, is the VLA's capability to trace both thermal and non-thermal emission over a wide range of spatial, time and velocity resolution. At the highest frequencies, this includes imaging cool gas in high redshift galaxies and dusty disks in nearby protoplanetary systems, while at the lowest frequencies tracing AGN activity and star formation back to the epoch of reionization. In the time domain, the VLA can respond to external triggers within 15 minutes to provide an instantaneous broadband radio spectrum of explosive events. I will review some of the exciting science emerging from the Jansky VLA as well as the range of science-ready data products that will make the VLA increasingly accessible to the wider astronomical community. Finally, I will briefly introduce the new VLA Sky Survey (VLASS), a community-driven project to image 80% of the sky over multiple epochs with the VLA, reaching a depth of ~70 uJy and detecting ~10 million radio sources at high spatial and spectral resolution with full polarization information.

Cln1 gene disruption in mice reveals a common pathogenic link between two of the most lethal childhood neurodegenerative lysosomal storage disorders.

PubMed

Chandra, Goutam; Bagh, Maria B; Peng, Shiyong; Saha, Arjun; Sarkar, Chinmoy; Moralle, Matthew; Zhang, Zhongjian; Mukherjee, Anil B

2015-10-01

Neurodegeneration is a devastating manifestation in the majority of >50 lysosomal storage disorders (LSDs). Neuronal ceroid lipofuscinoses (NCLs) are the most common childhood neurodegenerative LSDs. Mutations in 13 different genes (called CLNs) underlie various types of NCLs, of which the infantile NCL (INCL) and congenital NCL (CNCL) are the most lethal. Although inactivating mutations in the CLN1 gene encoding palmitoyl-protein thioesterase-1 (PPT1) cause INCL, those in the CLN10 gene encoding cathepsin D (CD) underlie CNCL. PPT1 is a lysosomal thioesterase that cleaves the thioester linkage in S-acylated proteins required for their degradation by lysosomal hydrolases like CD. Thus, PPT1 deficiency causes lysosomal accumulation of these lipidated proteins (major constituents of ceroid) leading to INCL. We sought to determine whether there is a common pathogenic link between INCL and CNCL. Using biochemical, histological and confocal microscopic analyses of brain tissues and cells from Cln1(-/-) mice that mimic INCL, we uncovered that Cln10/CD is overexpressed. Although synthesized in the endoplasmic reticulum, the CD-precursor protein (pro-CD) is transported through endosome to the lysosome where it is proteolytically processed to enzymatically active-CD. We found that despite Cln10 overexpression, the maturation of pro-CD to enzymatically active-CD in lysosome was disrupted. This defect impaired lysosomal degradative function causing accumulation of undegraded cargo in lysosome leading to INCL. Notably, treatment of intact Cln1(-/-) mice as well as cultured brain cells derived from these animals with a thioesterase-mimetic small molecule, N-tert-butyl-hydroxylamine, ameliorated the CD-processing defect. Our findings are significant in that they define a pathway in which Cln1 mutations disrupt the maturation of a major degradative enzyme in lysosome contributing to neuropathology in INCL and suggest that lysosomal CD deficiency is a common pathogenic link

A novel histochemical method of simultaneous detection by a single- or double-immunofluorescence and Bielschowsky's silver staining in teased rat sciatic nerves.

PubMed

Segura-Anaya, Edith; Flores-Miranda, Rommel; Martínez-Gómez, Alejandro; Dent, Myrna A R

2018-07-01

The Golgi silver method has been widely used in neuroscience for the study of normal and pathological morphology of neurons. The method has been steadily improved and Bielschowsky's silver staining method (BSSM) is widely used in various pathological conditions, like Alzheimer's disease. In this work, teased sciatic nerves were silver impregnated using BSSM. We also developed simultaneous staining by silver impregnation and single- or double-immunofluorescence of the same section in teased nerve preparations. We immunostained against non-myelinating Schwann cells and different myelinating Schwann cell domains. BSSM teased nerves show a strong staining of axons (black) and a gold-brown staining of myelinating and non-myelinating Schwann cells. We were also able to stain by immunofluorescence these BSSM teased nerves with specific molecular markers against non-myelinating Schwann cells, also against non-compact myelin such as the Schmidt-Lanterman incisures or paranodal regions and compact myelin, but not axons. In peripheral nerves, several silver impregnation methods have been used to stain nerves in paraffin sections, but not in teased nerves to enable the assessment of isolated nerve fibers. In conclusion, BSSM gives accurate information of nerve morphology and combining the procedure with immunofluorescence it would be very useful to study the molecular nerve domain organization of the nerve fibers, and to study the molecular pathology of axon degeneration, or myelin disorders, or of any peripheral neuropathy, also to study demyelination diseases in the central nervous system. Copyright © 2018. Published by Elsevier B.V.

Generation of an induced pluripotent stem cell line from a patient with non-syndromic CLN3-associated retinal degeneration and a coisogenic control line.

PubMed

Zhang, Xiao; Zhang, Dan; Chen, Shang-Chih; Lamey, Tina; Thompson, Jennifer A; McLaren, Terri; De Roach, John N; Chen, Fred K; McLenachan, Samuel

2018-05-01

We report the generation of the human iPSC line LEIi004-A from a patient with late-onset non-syndromic retinitis pigmentosa caused by compound heterozygous mutations in the CLN3 gene. Reprogramming of primary dermal fibroblasts was performed using episomal plasmids containing OCT4, SOX2, KLF4, L-MYC, LIN28, shRNA for p53 and mir302/367 microRNA. To create a coisogenic control line, one CLN3 variant was corrected in the patient-iPSC using CRISPR/Cas9 gene editing to generate the iPSC line LEIi004-A-1. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Modulating membrane fluidity corrects Batten disease phenotypes in vitro and in vivo.

PubMed

Schultz, Mark L; Tecedor, Luis; Lysenko, Elena; Ramachandran, Shyam; Stein, Colleen S; Davidson, Beverly L

2018-07-01

The neuronal ceroid lipofuscinoses are a class of inherited neurodegenerative diseases characterized by the accumulation of autofluorescent storage material. The most common neuronal ceroid lipofuscinosis has juvenile onset with rapid onset blindness and progressive degeneration of cognitive processes. The juvenile form is caused by mutations in the CLN3 gene, which encodes the protein CLN3. While mouse models of Cln3 deficiency show mild disease phenotypes, it is apparent from patient tissue- and cell-based studies that its loss impacts many cellular processes. Using Cln3 deficient mice, we previously described defects in mouse brain endothelial cells and blood-brain barrier (BBB) permeability. Here we expand on this to other components of the BBB and show that Cln3 deficient mice have increased astrocyte endfeet area. Interestingly, this phenotype is corrected by treatment with a commonly used GAP junction inhibitor, carbenoxolone (CBX). In addition to its action on GAP junctions, CBX has also been proposed to alter lipid microdomains. In this work, we show that CBX modifies lipid microdomains and corrects membrane fluidity alterations in Cln3 deficient endothelial cells, which in turn improves defects in endocytosis, caveolin-1 distribution at the plasma membrane, and Cdc42 activity. In further work using the NIH Library of Integrated Network-based Cellular Signatures (LINCS), we discovered other small molecules whose impact was similar to CBX in that they improved Cln3-deficient cell phenotypes. Moreover, Cln3 deficient mice treated orally with CBX exhibited recovery of impaired BBB responses and reduced autofluorescence. CBX and the compounds identified by LINCS, many of which have been used in humans or approved for other indications, may find therapeutic benefit in children suffering from CLN3 deficiency through mechanisms independent of their original intended use. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Late onset neurodegeneration in the Cln3-/- mouse model of juvenile neuronal ceroid lipofuscinosis is preceded by low level glial activation.

PubMed

Pontikis, Charlie C; Cella, Claire V; Parihar, Nisha; Lim, Ming J; Chakrabarti, Shubhodeep; Mitchison, Hannah M; Mobley, William C; Rezaie, Payam; Pearce, David A; Cooper, Jonathan D

2004-10-15

Mouse models of neuronal ceroid lipofuscinosis (NCL) exhibit many features of the human disorder, with widespread regional atrophy and significant loss of GABAergic interneurons in the hippocampus and neocortex. Reactive gliosis is a characteristic of all forms of NCL, but it is unclear whether glial activation precedes or is triggered by neuronal loss. To explore this issue we undertook detailed morphological characterization of the Cln3 null mutant (Cln3(-/-)) mouse model of juvenile NCL (JNCL) that revealed a delayed onset neurodegenerative phenotype with no significant regional atrophy, but with widespread loss of hippocampal interneurons that was first evident at 14 months of age. Quantitative image analysis demonstrated upregulation of markers of astrocytic and microglial activation in presymptomatic Cln3(-/-) mice at 5 months of age, many months before significant neuronal loss occurs. These data provide evidence for subtle glial responses early in JNCL pathogenesis.

New Surveys of the Universe with the Jansky Very Large Array (VLA) and the Very Long Baseline Array (VLBA)

NASA Astrophysics Data System (ADS)

Myers, Steven T.

2013-01-01

The Jansky Very Large Array is a recently completed upgrade to the VLA that has significantly expanded its capabilities through replacement of the receivers, electronics, signal paths, and correlator with cutting-edge technology. This enhancement provides significantly increased continuum sensitivity and spectral survey speeds (by factors of 100 or more in select cases) from 1-50 GHz and in key bands below 1 GHz. Concurrently, we are greatly enhancing the sensitivity of the Very Long Baseline Array. A suite of ever more ambitious radio sky survey programs undertaken with these new instruments address science goals central to answering the questions posed by Astro2010, and will undoubtedly incite new inquiries. The science themes of the Jansky VLA and the VLBA are: illuminating the obscured, probing the magnetic, sounding the transient, and charting the evolving Universe. New observations will allow us to image young stars in massive black holes in dust enshrouded environments, measure the strength and topology of the cosmic magnetic field, follow the rapid evolution of energetic phenomena, and to study the formation and evolution of stars, galaxies, AGN, and the Universe itself. We can follow the evolution of gas and galaxies and particles and fields through cosmic time to bridge the eras from cosmic dawn to the dawn of new worlds. I will describe the salient features of the Jansky VLA and the VLBA for cosmological survey work, and summarize the multi-wavelength aspects in regard to those with ALMA and next generation optical, infrared, X-ray and Gamma-ray telescopes. Example data taken from Janksy VLA and upgraded VLBA commissioning tests and early science will illustrate these features. I also describe evolution of the VLA and VLBA and their capabilities for future surveys that will lead towards the next decade, into the era of the LSST and the SKA.

Genetics Home Reference: CLN2 disease

MedlinePlus

... Z, Mole SE, Noher de Halac I, Pearce DA, Poupetova H, Schulz A, Specchio N, Xin W, ... Jul 25. Citation on PubMed Getty AL, Pearce DA. Interactions of the proteins of neuronal ceroid lipofuscinosis: ...

Genetics Home Reference: CLN10 disease

MedlinePlus

... Foundation CLIMB: Children Living with Inherited Metabolic Diseases March of Dimes: Neonatal Death The ... Sources for This Page Anderson GW, Goebel HH, Simonati A. Human pathology in NCL. Biochim Biophys Acta. 2013 Nov;1832( ...

Jansky Very Large Array: technology advancing science

NASA Astrophysics Data System (ADS)

Carilli, Christopher

2015-08-01

Over the last decade, the NRAO has completed on time, and on budget, a major reconstruction of the Very Large Array. Building on existing infrastructure to maximize efficiency, the entire VLA electronics system, including correlator, receivers, data transmission, and monitor and control, have been replaced with state of the art systems. This complete rebuild establishes the new Jansky VLA, operating between 75MHz and 50GHz, as the most powerful radio telescope in the world for the coming decade.I will review the technical improvements of the array, including:- Correlator: Increased bandwidth from 100MHz to 8GHz, with thousands of spectral channels.- Receivers: replaced the previous narrow bands with receivers covering the full frequency range from 1 GHz to 50GHz. New systems are also being tested to cover from 50MHz to 400MHz.- Data transmission: 8GHz over optical fiber out to 30km.I will then highlight some of the science enabled by these improvements, including:- Large cosmic volume searches for atomic and molecular gas, from the nearby Universe to the most distant galaxies, plus kpc-scale imaging of the cool gas in distant starburst galaxies.- High resolution studies of star and planet formation.- Innovative interferometric searches for transient phenomena.- The first radio continuum deep fields with sensitivities < 1uJy, with full polarization for Faraday tomography.- Imaging radio-mode feedback in galaxies and clusters, and delineating the complex plasma physical processes involved on scales from a few kpc to hundreds of kpc.I will conclude with a few words about the major challenges facing such a new instrument. These challenges are all on the critical path toward any successful development of future facilities, such as the next generation VLA and SKA:- Big data: data volumes and post-processing are currently major bottlenecks in the turn-over from observation to science publication. NRAO is developing calibration and imaging pipelines to provide science

The neuronal ceroid lipofuscinoses program: A translational research experience in Argentina.

PubMed

Kohan, Romina; Pesaola, Favio; Guelbert, Norberto; Pons, Patricia; Oller-Ramírez, Ana María; Rautenberg, Gisela; Becerra, Adriana; Sims, Katherine; Xin, Winnie; Cismondi, Inés Adriana; Noher de Halac, Inés

2015-10-01

The Argentinean program was initiated more than a decade ago as the first experience of systematic translational research focused on NCL in Latin America. The aim was to overcome misdiagnoses and underdiagnoses in the region. 216 NCL suspected individuals from 8 different countries and their direct family members. Clinical assessment, enzyme testing, electron microscopy, and DNA screening. 1) The study confirmed NCL disease in 122 subjects. Phenotypic studies comprised epileptic seizures and movement disorders, ophthalmology, neurophysiology, image analysis, rating scales, enzyme testing, and electron microscopy, carried out under a consensus algorithm; 2) DNA screening and validation of mutations in genes PPT1 (CLN1), TPP1 (CLN2), CLN3, CLN5, CLN6, MFSD8 (CLN7), and CLN8: characterization of variant types, novel/known mutations and polymorphisms; 3) Progress of the epidemiological picture in Latin America; and 4) NCL-like pathology studies in progress. The Translational Research Program was highly efficient in addressing the misdiagnosis/underdiagnosis in the NCL disorders. The study of "orphan diseases" in a public administrated hospital should be adopted by the health systems, as it positively impacts upon the family's quality of life, the collection of epidemiological data, and triggers research advances. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)". Copyright © 2015 Elsevier B.V. All rights reserved.

Human pathology in NCL.

PubMed

Anderson, Glenn W; Goebel, Hans H; Simonati, Alessandro

2013-11-01

In childhood the neuronal ceroid lipofuscinoses (NCL) are the most frequent lysosomal diseases and the most frequent neurodegenerative diseases but, in adulthood, they represent a small fraction among the neurodegenerative diseases. Their morphology is marked by: (i) loss of neurons, foremost in the cerebral and cerebellar cortices resulting in cerebral and cerebellar atrophy; (ii) an almost ubiquitous accumulation of lipopigments in nerve cells, but also in extracerebral tissues. Loss of cortical neurons is selective, indiscriminate depletion in early childhood forms occurring only at an advanced stage, whereas loss of neurons in subcortical grey-matter regions has not been quantitatively documented. Among the fourteen different forms of NCL described to date, CLN1 and CLN10 are marked by granular lipopigments, CLN2 by curvilinear profiles (CVPs), CLN3 by fingerprint profiles (FPPs), and other forms by a combination of these features. Among extracerebral tissues, lymphocytes, skin, rectum, skeletal muscle and, occasionally, conjunctiva are possible guiding targets for diagnostic identification, the precise type of NCL then requiring molecular analysis within the clinical and morphological context. Autosomal-recessive adult NCL has been linked molecularly to different childhood forms, i.e. CLN1, CLN5, and CLN6, whilst autosomal-dominant adult NCL, now designated as CLN4, is caused by a newly identified separate gene, DNAJC5. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease. Copyright © 2012 Elsevier B.V. All rights reserved.

Comparative Evaluation of Partial α2 -Adrenoceptor Agonist and Pure α2 -Adrenoceptor Antagonist on the Behavioural Symptoms of Withdrawal after Chronic Alcohol Administration in Mice.

PubMed

Arora, Shivani; Vohora, Divya

2016-08-01

As an addictive drug, alcohol produces withdrawal symptoms if discontinued abruptly after chronic use. Clonidine (CLN), a partial α2 -adrenergic agonist, and mirtazapine (MRT), an antagonist of α2 -adrenoceptor, both clinically aid alcohol withdrawal. Considering different mechanisms of action of the two drugs, this study was designed to see how far these two mechanistically different drugs differ in their ability to decrease the severity of ethanol withdrawal syndrome. The effect of CLN and MRT on ethanol withdrawal-induced anxiety, depression and memory impairment was analysed using EPM, FST and PAR tests, respectively. Animals received distilled water, ethanol and/or either of the drugs (CLN and MRT) in different doses. Relapse to alcohol use was analysed by CPP test. Animals received ethanol as a conditioning drug and distilled water, CLN or MRT as test drug. CLN and MRT both alleviated anxiety in a dose-dependent manner. MRT (4 mg/kg) was more effective than CLN (0.1 mg/kg) in ameliorating the anxiogenic effect of alcohol withdrawal. However, CLN treatment increased depression. It significantly decreased swimming time and increased immobility time, whereas MRT treatment decreased immobility time and increased climbing and swimming time during abstinence. The effect was dose dependent for both drugs. The results of PAR test show that CLN treatment worsens working memory. Significant increase in SDE and TSZ and decrease in SDL were observed in CLN-treated animals. MRT treatment, on the other hand, improved working memory at both doses. Further, both CLN and MRT alleviated craving. A significant decrease in time spent in the ethanol-paired chamber was seen. MRT treatment at both doses showed better effect than CLN in preventing the development of preference in CPP test. These findings indicate a potential therapeutic use and better profile of mirtazapine over clonidine in improving memory, as well as in alleviating depression, anxiety and craving associated

Neural stem cells for disease modeling and evaluation of therapeutics for infantile (CLN1/PPT1) and late infantile (CLN2/TPP1) neuronal ceroid lipofuscinoses.

PubMed

Sima, Ni; Li, Rong; Huang, Wei; Xu, Miao; Beers, Jeanette; Zou, Jizhong; Titus, Steven; Ottinger, Elizabeth A; Marugan, Juan J; Xie, Xing; Zheng, Wei

2018-04-10

Infantile and late infantile neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage diseases affecting the central nervous system (CNS). The infantile NCL (INCL) is caused by mutations in the PPT1 gene and late-infantile NCL (LINCL) is due to mutations in the TPP1 gene. Deficiency in PPT1 or TPP1 enzyme function results in lysosomal accumulation of pathological lipofuscin-like material in the patient cells. There is currently no small-molecular drug treatment for NCLs. We have generated induced pluripotent stem cells (iPSC) from three patient dermal fibroblast lines and further differentiated them into neural stem cells (NSCs). Using these new disease models, we evaluated the effect of δ-tocopherol (DT) and hydroxypropyl-β-cyclodextrin (HPBCD) with the enzyme replacement therapy as the control. Treatment with the relevant recombinant enzyme or DT significantly ameliorated the lipid accumulation and lysosomal enlargement in the disease cells. A combination therapy of δ-tocopherol and HPBCD further improved the effect compared to that of either drug used as a single therapy. The results demonstrate that these patient iPSC derived NCL NSCs are valid cell- based disease models with characteristic disease phenotypes that can be used for study of disease pathophysiology and drug development.

Jansky Array mapping of Gravitational Bursts as Afterglows in Radio (JAGWAR): The VLA Large Program and Initial Results

NASA Astrophysics Data System (ADS)

Mooley, Kunal; Hallinan, Gregg; Hotokezaka, Kenta; Frail, Dale; Myers, Steven T.; Horesh, Assaf; Kasliwal, Mansi; Kulkarni, Shri; Pound Singer, Leo; nissanke, Samaya; Rana, Javed

2018-01-01

The era of gravitational waves and multi-messenger astronomy has begun. Telescopes around the globe are now in hot pursuit of electromagnetic counterparts (EM) to aLIGO/VIRGO sources, especially double-neutron star (NS-NS) and neutron star-black hole mergers (NS-BH). The EM counterparts are crucial for 1) providing arcsecond localization and identifying the precise host galaxy and merger redshift, 2) understanding the energetics and physics of the merger, 3) mapping their environments and pre-merger mass ejection processes, and 4) confirming the validity of the GW signals at low signal-to-noise ratios. Radio wavelengths provide one of the best diagnostics of both the dynamical sub-relativistic ejecta and any ultra-relativistic jet launched, as well as the possible interaction of these two components. In this talk I will introduce the Jansky Array mapping of Gravitational Bursts as Afterglows in Radio (JAGWAR) program, running on the VLA, aimed at maximizing the discoveries of the radio afterglows of NS-NS and NS-BH mergers. I will also present the JAGWAR results from the aLIGO/VIRGO observing run O2, which concluded in August 2017.

Computational study of the free energy landscape of the miniprotein CLN025 in explicit and implicit solvent.

PubMed

Rodriguez, Alex; Mokoema, Pol; Corcho, Francesc; Bisetty, Khrisna; Perez, Juan J

2011-02-17

The prediction capabilities of atomistic simulations of peptides are hampered by different difficulties, including the reliability of force fields, the treatment of the solvent or the adequate sampling of the conformational space. In this work, we have studied the conformational profile of the 10 residue miniprotein CLN025 known to exhibit a β-hairpin in its native state to understand the limitations of implicit methods to describe solvent effects and how these may be compensated by using different force fields. For this purpose, we carried out a thorough sampling of the conformational space of CLN025 in explicit solvent using the replica exchange molecular dynamics method as a sampling technique and compared the results with simulations of the system modeled using the analytical linearized Poisson-Boltzmann (ALPB) method with three different AMBER force fields: parm94, parm96, and parm99SB. The results show the peptide to exhibit a funnel-like free energy landscape with two minima in explicit solvent. In contrast, the higher minimum nearly disappears from the energy surface when the system is studied with an implicit representation of the solvent. Moreover, the different force fields used in combination with the ALPB method do not describe the system in the same manner. The results of this work suggest that the balance between intra- and intermolecular interactions is the cause of the differences between implicit and explicit solvent simulations in this system, stressing the role of the environment to define properly the conformational profile of a peptide in solution.

Using the social amoeba Dictyostelium to study the functions of proteins linked to neuronal ceroid lipofuscinosis.

PubMed

Huber, Robert J

2016-11-24

Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a debilitating neurological disorder that affects both children and adults. Thirteen genetically distinct genes have been identified that when mutated, result in abnormal lysosomal function and an excessive accumulation of ceroid lipofuscin in neurons, as well as other cell types outside of the central nervous system. The NCL family of proteins is comprised of lysosomal enzymes (PPT1/CLN1, TPP1/CLN2, CTSD/CLN10, CTSF/CLN13), proteins that peripherally associate with membranes (DNAJC5/CLN4, KCTD7/CLN14), a soluble lysosomal protein (CLN5), a protein present in the secretory pathway (PGRN/CLN11), and several proteins that display different subcellular localizations (CLN3, CLN6, MFSD8/CLN7, CLN8, ATP13A2/CLN12). Unfortunately, the precise functions of many of the NCL proteins are still unclear, which has made targeted therapy development challenging. The social amoeba Dictyostelium discoideum has emerged as an excellent model system for studying the normal functions of proteins linked to human neurological disorders. Intriguingly, the genome of this eukaryotic soil microbe encodes homologs of 11 of the 13 known genes linked to NCL. The genetic tractability of the organism, combined with its unique life cycle, makes Dictyostelium an attractive model system for studying the functions of NCL proteins. Moreover, the ability of human NCL proteins to rescue gene-deficiency phenotypes in Dictyostelium suggests that the biological pathways regulating NCL protein function are likely conserved from Dictyostelium to human. In this review, I will discuss each of the NCL homologs in Dictyostelium in turn and describe how future studies can exploit the advantages of the system by testing new hypotheses that may ultimately lead to effective therapy options for this devastating and currently untreatable neurological disorder.

COLDz: KARL G. JANSKY VERY LARGE ARRAY DISCOVERY OF A GAS-RICH GALAXY IN COSMOS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lentati, L.; Wagg, J.; Carilli, C. L.

2015-02-10

The broad spectral bandwidth at millimeter and centimeter wavelengths provided by the recent upgrades to the Karl G. Jansky Very Large Array (VLA) has made it possible to conduct unbiased searches for molecular CO line emission at redshifts, z > 1.31. We present the discovery of a gas-rich, star-forming galaxy at z = 2.48 through the detection of CO J = 1-0 line emission in the COLDz survey and through a sensitive, Ka-band (31-39 GHz) VLA survey of a 6.5 arcmin{sup 2} region of the COSMOS field. We argue that the broad line (FWHM ∼ 570 ± 80 km s{supmore » –1}) is most likely to be CO J = 1-0 at z = 2.48, as the integrated emission is spatially coincident with an infrared-detected galaxy with a photometric redshift estimate of z {sub phot} = 3.2 ± 0.4. The CO J = 1-0 line luminosity is L{sub CO}{sup ′}=(2.2±0.3)×10{sup 10} K km s{sup –1} pc{sup 2}, suggesting a cold molecular gas mass of M {sub gas} ∼ (2-8) × 10{sup 10} M {sub ☉} depending on the assumed value of the molecular gas mass to CO luminosity ratio α{sub CO}. The estimated infrared luminosity from the (rest-frame) far-infrared spectral energy distribution (SED) is L {sub IR} = 2.5 × 10{sup 12} L {sub ☉} and the star formation rate is ∼250 M {sub ☉} yr{sup –1}, with the SED shape indicating substantial dust obscuration of the stellar light. The infrared to CO line luminosity ratio is ∼114 ± 19 L {sub ☉}/(K km s{sup –1} pc{sup 2}), similar to galaxies with similar SFRs selected at UV/optical to radio wavelengths. This discovery confirms the potential for molecular emission line surveys as a route to study populations of gas-rich galaxies in the future.« less

Foreground Characterization for the Murchison Widefield Array Using the Jansky Very Large Array

NASA Astrophysics Data System (ADS)

Busch, Michael P.; Bowman, Judd D.; Kittiwisit, Piyanat; Jacobs, Danny

2016-01-01

One of the most compelling questions in astrophysics today is how the process of galaxy formation unfolded during the Epoch of Reionization (EoR). A new generation of radio telescopes, including the Murchison Widefield Array (MWA) and others, are attempting to capture the redshifted 21cm signal from neutral hydrogen during the EoR. Mapping the reionization of the intergalactic medium (IGM) is one of the core objectives of 21 cm observatories. A pressing concern of these observations is the bright foreground sources in the telescope's sidelobes outside the primary beam of the MWA. These sources, including AGN, radio galaxies and local Galactic sources, are numerous and difficult to deal with. These foreground contaminants are five orders of magnitude brighter than the redshifted 21 cm emission expected from the IGM during the EoR. The Jansky Very Large Array (JVLA) in New Mexico can provide sensitive characterization of these sources in the MWA's northern sidelobe. We observed 100 bright radio sources using the JVLA in P-band and characterized these sources by extracting the spectral fits and fluxes for each source. By creating a foreground model for these data, the MWA will be able to better subtract these sources from future EoR measurements. We report the current status of the creation of the foreground model.

Intramolecular chalcogen-tin interactions in [(o-MeE-C6H4)CH2]2SnPh2-nCln; E = S, O, CH2, n = 0, 1, 2 and intermolecular chlorine-tin interactions in the meta and para-methoxy isomers

PubMed Central

Vargas-Pineda, Diana Gabriela; Guardado, Tanya; Cervantes-Lee, Francisco; Metta-Magana, Alejandro J.

2010-01-01

Organotin(IV) compounds of the type [(o-MeE-C6H4)CH2]2SnPh2-nCln were synthesized, E = O, n = 0 (1), n = 1 (2), n = 2 (3), E = S, n = 0 (4), n = 1 (5), n = 2 (6) and E = CH2, n = 0 (7), n = 1 (8), n = 2 (9). The dichloro compounds 3 and 6 have been investigated by single crystal X-ray diffraction and exhibit bi-capped tetrahedral geometry at the tin atom as a consequence of significant intramolecular Sn⋯O (3) and Sn⋯S (6) secondary bonding, in monomolecular units. Compound 3 when crystallized from a hexane/thf solvent mixture shows two different conformers, 3′ and 3″, in the crystal structure, 3′ has two equivalent Sn⋯O interactions, while 3″ has two non-equivalent Sn⋯O interactions. Upon recrystallization of 3 from hexane only a single structural form is observed, 3′. The Sn⋯E distances in 3′, 3″, and 6 are 71.3; 73.5, 72.9; and 76.3% of the ΣvdW radii, respectively. The meta and para-substituted isomers of 3 (10, 11) exhibit a distortion at the tin atom due to self-association via intermolecular Sn⋯Cl interactions resulting in polymeric structures. 119Sn NMR spectroscopy suggests that the intramolecular Sn⋯E interactions persist in solution for the dichloride compounds 3 and 6. PMID:20047301

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hellsten, E.; Vesa, J.; Peltonen, L.

Infantile neuronal ceroid lipofuscinosis, INCL, CLN1, is an autosomally inherited progressive neuro-generative disorder. The disease results in the massive death of cortical neurons, suggesting an essential role for the CLN1 gene product in the normal neuronal maturation during the first years of life. Identification of new multiallelic markers has now made possible the construction of a refined genetic map encompassing the CLN1 locus at 1p32. Strong allelic association was detected with a new, highly polymorphic HY-TM1 marker. The authors incorporated this observed linkage disequilibrium into multipoint linkage analysis, which significantly increased the informativeness of the limited family material and facilitatedmore » refined assignment of the CLN1 locus. 23 refs., 2 figs., 4 tabs.« less

Cerebellar defects in a mouse model of juvenile neuronal ceroid lipofuscinosis.

PubMed

Weimer, Jill M; Benedict, Jared W; Getty, Amanda L; Pontikis, Charlie C; Lim, Ming J; Cooper, Jonathan D; Pearce, David A

2009-04-17

Juvenile neuronal ceroid lipofuscinosis (JNCL), or Batten disease, is a neurodegenerative disease resulting from a mutation in CLN3, which presents clinically with visual deterioration, seizures, motor impairments, cognitive decline, hallucinations, loss of circadian rhythm, and premature death in the late-twenties to early-thirties. Using a Cln3 null (Cln3(-/-)) mouse, we report here several deficits in the cerebellum in the absence of Cln3, including cell loss and early onset motor deficits. Surprisingly, early onset glial activation and selective neuronal loss within the mature fastigial pathway of the deep cerebellar nuclei (DCN), a region critical for balance and coordination, are seen in many regions of the Cln3(-/-) cerebellum. Additionally, there is a loss of Purkinje cells (PC) in regions of robust Bergmann glia activation in Cln3(-/-) mice and human JNCL post-mortem cerebellum. Moreover, the Cln3(-/-) cerebellum had a mis-regulation in granule cell proliferation and maintenance of PC dendritic arborization and spine density. Overall, this study defines a novel multi-faceted, early-onset cerebellar disruption in the Cln3 null brain, including glial activation, cell loss, and aberrant cell proliferation and differentiation. These early alterations in the maturation of the cerebellum could underlie some of the motor deficits and pathological changes seen in JNCL patients.

Exome Sequencing Is an Efficient Tool for Variant Late-Infantile Neuronal Ceroid Lipofuscinosis Molecular Diagnosis

PubMed Central

Ortega-Recalde, Oscar; Nallathambi, Jeyabalan; Anandula, Venkata Ramana; Renukaradhya, Umashankar; Laissue, Paul

2014-01-01

The neuronal ceroid-lipofuscinoses (NCL) is a group of neurodegenerative disorders characterized by epilepsy, visual failure, progressive mental and motor deterioration, myoclonus, dementia and reduced life expectancy. Classically, NCL-affected individuals have been classified into six categories, which have been mainly defined regarding the clinical onset of symptoms. However, some patients cannot be easily included in a specific group because of significant variation in the age of onset and disease progression. Molecular genetics has emerged in recent years as a useful tool for enhancing NCL subtype classification. Fourteen NCL genetic forms (CLN1 to CLN14) have been described to date. The variant late-infantile form of the disease has been linked to CLN5, CLN6, CLN7 (MFSD8) and CLN8 mutations. Despite advances in the diagnosis of neurodegenerative disorders mutations in these genes may cause similar phenotypes, which rends difficult accurate candidate gene selection for direct sequencing. Three siblings who were affected by variant late-infantile NCL are reported in the present study. We used whole-exome sequencing, direct sequencing and in silico approaches to identify the molecular basis of the disease. We identified the novel c.1219T>C (p.Trp407Arg) and c.1361T>C (p.Met454Thr) MFSD8 pathogenic mutations. Our results highlighted next generation sequencing as a novel and powerful methodological approach for the rapid determination of the molecular diagnosis of NCL. They also provide information regarding the phenotypic and molecular spectrum of CLN7 disease. PMID:25333361

Exome sequencing is an efficient tool for variant late-infantile neuronal ceroid lipofuscinosis molecular diagnosis.

PubMed

Patiño, Liliana Catherine; Battu, Rajani; Ortega-Recalde, Oscar; Nallathambi, Jeyabalan; Anandula, Venkata Ramana; Renukaradhya, Umashankar; Laissue, Paul

2014-01-01

The neuronal ceroid-lipofuscinoses (NCL) is a group of neurodegenerative disorders characterized by epilepsy, visual failure, progressive mental and motor deterioration, myoclonus, dementia and reduced life expectancy. Classically, NCL-affected individuals have been classified into six categories, which have been mainly defined regarding the clinical onset of symptoms. However, some patients cannot be easily included in a specific group because of significant variation in the age of onset and disease progression. Molecular genetics has emerged in recent years as a useful tool for enhancing NCL subtype classification. Fourteen NCL genetic forms (CLN1 to CLN14) have been described to date. The variant late-infantile form of the disease has been linked to CLN5, CLN6, CLN7 (MFSD8) and CLN8 mutations. Despite advances in the diagnosis of neurodegenerative disorders mutations in these genes may cause similar phenotypes, which rends difficult accurate candidate gene selection for direct sequencing. Three siblings who were affected by variant late-infantile NCL are reported in the present study. We used whole-exome sequencing, direct sequencing and in silico approaches to identify the molecular basis of the disease. We identified the novel c.1219T>C (p.Trp407Arg) and c.1361T>C (p.Met454Thr) MFSD8 pathogenic mutations. Our results highlighted next generation sequencing as a novel and powerful methodological approach for the rapid determination of the molecular diagnosis of NCL. They also provide information regarding the phenotypic and molecular spectrum of CLN7 disease.

Cerebellar defects in a mouse model of juvenile neuronal ceroid lipofuscinosis

PubMed Central

Weimer, Jill M.; Benedict, Jared W.; Getty, Amanda L.; Pontikis, Charlie C.; Lim, Ming J.; Cooper, Jonathan D.; Pearce, David A.

2013-01-01

Juvenile neuronal ceroid lipofuscinosis (JNCL), or Batten disease, is a neurodegenerative disease resulting from a mutation in CLN3, which presents clinically with visual deterioration, seizures, motor impairments, cognitive decline, hallucinations, loss of circadian rhythm, and premature death in the late-twenties to early-thirties. Using a Cln3 null (Cln3−/−) mouse, we report here several deficits in the cerebellum in the absence of Cln3, including cell loss and early onset motor deficits. Surprisingly, early onset glial activation and selective neuronal loss within the mature fastigial pathway of the deep cerebellar nuclei (DCN), a region critical for balance and coordination, are seen in many regions of the Cln3−/− cerebellum. Additionally, there is a loss of Purkinje cells (PC) in regions of robust Bergmann glia activation in Cln3−/− mice and human JNCL post-mortem cerebellum. Moreover, the Cln3−/− cerebellum had a mis-regulation in granule cell proliferation and maintenance of PC dendritic arborization and spine density. Overall, this study defines a novel multi-faceted, early-onset cerebellar disruption in the Cln3 null brain, including glial activation, cell loss, and aberrant cell proliferation and differentiation. These early alterations in the maturation of the cerebellum could underlie some of the motor deficits and pathological changes seen in JNCL patients. PMID:19230832

[Evaluation of central lymph node dissection for papillary thyroid carcinoma in cN0 T1/T2].

PubMed

Zhao, S Y; Ma, Y H; Yin, Z; Zhan, X X; Cheng, R C; Qian, J

2018-02-07

Objective: To evaluate the application of the central lymph node dissection (CLND) for papillary thyroid carcinoma (PTC) in cN0 T1/T2. Methods: Retrospective analysis of 532 cases with PTC in cN0 T1/T2 who underwent CLND between October 2014 and September 2016 in the Department of Thyroid Surgery, the First Affiliated Hospital of the Kunming Medical University. The incidence of central lymph node (CLN) metastasis and risk factors were analyzed. Results: CLN metastasis rates: 41.2% (42/102) in males vs 34.9% (150/430) in females, P =0.252; 33.9% (116/342) in single focal carcinoma vs 40.4% (74/183) in multifocal carcinoma, P =0.157; 44.0% (125/284) in patients with 45 years old or less vs 27.0% (67/248) in patients more than 45 years old, P =0.000; 30.3% (113/373) in microcarcinoma vs 50.9% (81/159) in non-microcarcinoma, P =0.000.In unilateral lesions, ipsilateral CLN metastasis was correlated with the tumor diameter ( P =0.012), but not with the number of lesions ( P =0.653). also contralateral CLN metastasis was correlated with the tumor diameter ( P =0.000), but not with the number of lesions ( P =0.815). For the left or right unilateral single focal lesion, the tumor diameter was not correlated with the metastasis of the posterior to right recurrent laryngeal nerve central lymph nodes (LN-prRLN-CLN) ( P =0.652, P =0.088). But in bilateral multifocal carcinoma the tumor diameter was correlated with metastasis of LN-prRLN-CLN ( P =0.039). Conclusions: Prophylactic CLND is reasonable for PTC in cN0 T1/T2. A bilateral CLND should be conducted for patients with bilateral multi-focus cancer and unilateral or bilateral non-microcarcinoma, especially in patients more than 45 years old. For unilateral single focal microcarcinoma on the right, the content of CLND should be from laryngeal nerve on right center to posterior branche; for unilateral single focal microcarcinoma on the left side, the left CLND should be conducted. An ipsilateral CLND can be considered in

Aberrant adhesion impacts early development in a Dictyostelium model for juvenile neuronal ceroid lipofuscinosis

PubMed Central

Huber, Robert J.; Myre, Michael A.; Cotman, Susan L.

2017-01-01

ABSTRACT Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, refers to a group of severe neurodegenerative disorders that primarily affect children. The most common subtype of the disease is caused by loss-of-function mutations in CLN3, which is conserved across model species from yeast to human. The precise function of the CLN3 protein is not known, which has made targeted therapy development challenging. In the social amoeba Dictyostelium discoideum, loss of Cln3 causes aberrant mid-to-late stage multicellular development. In this study, we show that Cln3-deficiency causes aberrant adhesion and aggregation during the early stages of Dictyostelium development. cln3− cells form ∼30% more multicellular aggregates that are comparatively smaller than those formed by wild-type cells. Loss of Cln3 delays aggregation, but has no significant effect on cell speed or cAMP-mediated chemotaxis. The aberrant aggregation of cln3− cells cannot be corrected by manually pulsing cells with cAMP. Moreover, there are no significant differences between wild-type and cln3− cells in the expression of genes linked to cAMP chemotaxis (e.g., adenylyl cyclase, acaA; the cAMP receptor, carA; cAMP phosphodiesterase, pdsA; g-protein α 9 subunit, gpaI). However, during this time in development, cln3− cells show reduced cell-substrate and cell-cell adhesion, which correlate with changes in the levels of the cell adhesion proteins CadA and CsaA. Specifically, loss of Cln3 decreases the intracellular level of CsaA and increases the amount of soluble CadA in conditioned media. Together, these results suggest that the aberrant aggregation of cln3− cells is due to reduced adhesion during the early stages of development. Revealing the molecular basis underlying this phenotype may provide fresh new insight into CLN3 function. PMID:27669405

First detection of thermal radio emission from solar-type stars with the Karl G. Jansky very large array

DOE Office of Scientific and Technical Information (OSTI.GOV)

Villadsen, Jackie; Hallinan, Gregg; Bourke, Stephen

2014-06-20

We present the first detections of thermal radio emission from the atmospheres of solar-type stars τ Cet, η Cas A, and 40 Eri A. These stars all resemble the Sun in age and level of magnetic activity, as indicated by X-ray luminosity and chromospheric emission in Ca II H and K lines. We observed these stars with the Karl G. Jansky Very Large Array with sensitivities of a few μJy at combinations of 10.0, 15.0, and 34.5 GHz. τ Cet, η Cas A, and 40 Eri A are all detected at 34.5 GHz with signal-to-noise ratios of 6.5, 5.2, andmore » 4.5, respectively. 15.0 GHz upper limits imply a rising spectral index greater than 1.0 for τ Cet and 1.6 for η Cas A, at the 95% confidence level. The measured 34.5 GHz flux densities correspond to stellar disk-averaged brightness temperatures of roughly 10,000 K, similar to the solar brightness temperature at the same frequency. We explain this emission as optically thick thermal free-free emission from the chromosphere, with possible contributions from coronal gyroresonance emission above active regions and coronal free-free emission. These and similar quality data on other nearby solar-type stars, when combined with Atacama Large Millimeter/Submillimeter Array observations, will enable the construction of temperature profiles of their chromospheres and lower transition regions.« less

Diagnostic effectiveness of quantitative [18F]flutemetamol PET imaging for detection of fibrillar amyloid β using cortical biopsy histopathology as the standard of truth in subjects with idiopathic normal pressure hydrocephalus

PubMed Central

2014-01-01

Introduction PET imaging of amyloid-β (Aβ) in vivo holds promise for aiding in earlier diagnosis and intervention in Alzheimer’s disease (AD) and mild cognitive impairment. AD-like Aβ pathology is a common comorbidity in patients with idiopathic normal pressure hydrocephalus (iNPH). Fifty patients with iNPH needing ventriculo-peritoneal shunting or intracranial pressure monitoring underwent [18F]flutemetamol PET before (N = 28) or after (N = 22) surgery. Cortical uptake of [18F]flutemetamol was assessed visually by blinded reviewers, and also quantitatively via standard uptake value ratio (SUVR) in specific neocortical regions in relation to either cerebellum or pons reference region: the cerebral cortex of (prospective studies) or surrounding (retrospective studies) the biopsy site, the contralateral homolog, and a calculated composite brain measure. Aβ pathology in the biopsy specimen (standard of truth [SoT]) was measured using Bielschowsky silver and thioflavin S plaque scores, percentage area of grey matter positive for monoclonal antibody to Aβ (4G8), and overall pathology impression. We set out to find (1) which pair(s) of PET SUVR and pathology SoT endpoints matched best, (2) whether quantitative measures of [18F]flutemetamol PET were better for predicting the pathology outcome than blinded image examination (BIE), and (3) whether there was a better match between PET image findings in retrospective vs. prospective studies. Results Of the 24 possible endpoint/SoT combinations, the one with composite-cerebellum SUVR and SoT based on overall pathology had the highest Youden index (1.000), receiver operating characteristic area under the curve (1.000), sensitivity (1.000), specificity (1.000), and sum of sensitivity and specificity for the pooled data as well as for the retrospective and prospective studies separately (2.00, for all 3). The BIE sum of sensitivity and specificity, comparable to that for quantitation, was highest using Bielschowsky

N-acetylcysteine normalizes the urea cycle and DNA repair in cells from patients with Batten disease.

PubMed

Kim, June-Bum; Lim, Nary; Kim, Sung-Jo; Heo, Tae-Hwe

2012-12-01

Batten disease is an inherited disorder characterized by early onset neurodegeneration due to the mutation of the CLN3 gene. The function of the CLN3 protein is not clear, but an association with oxidative stress has been proposed. Oxidative stress and DNA damage play critical roles in the pathogenesis of neurodegenerative diseases. Antioxidants are of interest because of their therapeutic potential for treating neurodegenerative diseases. We tested whether N-acetylcysteine (NAC), a well-known antioxidant, improves the pathology of cells from patients with Batten disease. At first, the expression levels of urea cycle components and DNA repair enzymes were compared between Batten disease cells and normal cells. We used both mRNA expression levels and Western blot analysis. We found that carbamoyl phosphate synthetase 1, an enzyme involved in the urea cycle, 8-oxoguanine DNA glycosylase 1 and DNA polymerase beta, enzymes involved in DNA repair, were expressed at higher levels in Batten disease cells than in normal cells. The treatment of Batten disease cells with NAC for 48 h attenuated activities of the urea cycle and of DNA repair, as indicated by the substantially decreased expression levels of carbamoyl phosphate synthetase 1, 8-oxoguanine DNA glycosylase 1 and DNA polymerase beta proteins compared with untreated Batten cells. NAC may serve in alleviating the burden of urea cycle and DNA repair processes in Batten disease cells. We propose that NAC may have beneficial effects in patients with Batten disease. Copyright © 2012 John Wiley & Sons, Ltd.

The lysosomal degradation of neuromedin B is dependent on tripeptidyl peptidase-I: evidence for the impairment of neuropeptide degradation in late-infantile neuronal ceroid lipofuscinosis.

PubMed

Kopan, Sharmila; Sivasubramaniam, Uthayatharsini; Warburton, Michael J

2004-06-18

Late-infantile neuronal ceroid lipofuscinosis (CLN2), previously known as the late-infantile form of Batten disease, is a lysosomal storage disease which results from mutations in the gene that codes for tripeptidyl peptidase-I (TPP-I). This disease is characterised by progressive neurodegeneration in young children although the molecular mechanisms responsible for neuronal cell death are unclear. TPP-I is an exopeptidase which removes N-terminal tripeptides from small peptides, including several peptide hormones. We report that the degradation of the neuropeptide, neuromedin B, by mouse brain cells is restricted to lysosomes and that the pattern of degradation products is consistent with a predominant role for TPP-I. Neuromedin B is degraded by a similar pathway in a mouse neuronal cell line and also in cultured human fibroblasts. A specific inhibitor of TPP-I is able to abolish neuromedin B degradation in a variety of cell types. Fibroblasts from CLN2 patients, which are deficient in TPP-I activity, are unable to degrade neuromedin B. These observations suggest that TPP-I is the predominant proteolytic enzyme responsible for the intracellular degradation of neuromedin B. The inability of cells from CLN2 patients to degrade neuromedin B and other neuropeptides may contribute to the pathogenesis of the disease.

CHILES Con Pol: Probing galaxy evolution, the dark Universe, and cosmic magnetism with a deep 1000 hour Jansky VLA survey

NASA Astrophysics Data System (ADS)

Hales, Christopher A.; Chiles Con Pol Collaboration

2014-04-01

We recently started a 1000 hour campaign to observe 0.2 square degrees of the COSMOS field in full polarization continuum at 1.4 GHz with the Jansky VLA, as part of a joint program with the spectral line COSMOS HI Large Extragalactic Survey (CHILES). When complete, we expect our CHILES Continuum Polarization (CHILES Con Pol) survey to reach an unprecedented SKA-era sensitivity of 0.7 uJy per 4 arcsecond FWHM beam. Here we present the key goals of CHILES Con Pol, which are to (i) produce a source catalog of legacy value to the astronomical community, (ii) measure differential source counts in total intensity, linear polarization, and circular polarization in order to constrain the redshift and luminosity distributions of source populations, (iii) perform a novel weak lensing study using radio polarization as an indicator of intrinsic alignment to better study dark energy and dark matter, and (iv) probe the unknown origin of cosmic magnetism by measuring the strength and structure of intergalactic magnetic fields in the filaments of large scale structure. The CHILES Con Pol source catalog will be a useful resource for upcoming wide-field surveys by acting as a training set for machine learning algorithms, which can then be used to identify and classify radio sources in regions lacking deep multiwavelength coverage.

The GOODS-N Jansky VLA 10 GHz Pilot Survey: Sizes of Star-forming μJY Radio Sources

NASA Astrophysics Data System (ADS)

Murphy, Eric J.; Momjian, Emmanuel; Condon, James J.; Chary, Ranga-Ram; Dickinson, Mark; Inami, Hanae; Taylor, Andrew R.; Weiner, Benjamin J.

2017-04-01

Our sensitive ({σ }{{n}}≈ 572 {nJy} {{beam}}-1), high-resolution (FWHM {θ }1/2=0\\buildrel{\\prime\\prime}\\over{.} 22≈ 2 {kpc} {at} z≳ 1), 10 GHz image covering a single Karl G. Jansky Very Large Array (VLA) primary beam (FWHM {{{\\Theta }}}1/2≈ 4\\buildrel{ \\prime}\\over{.} 25) in the GOODS-N field contains 32 sources with {S}{{p}}≳ 2 μ {Jy} {{beam}}-1 and optical and/or near-infrared (OIR) counterparts. Most are about as large as the star-forming regions that power them. Their median FWHM major axis is < {θ }{{M}}> =167+/- 32 {mas}≈ 1.2+/- 0.28 {kpc}, with rms scatter ≈ 91 {mas}≈ 0.79 {kpc}. In units of the effective radius {r}{{e}} that encloses half their flux, these radio sizes are < {r}{{e}}> ≈ 69+/- 13 {mas}≈ 509+/- 114 {pc}, with rms scatter ≈ 38 {mas}≈ 324 {pc}. These sizes are smaller than those measured at lower radio frequencies, but agree with dust emission sizes measured at mm/sub-mm wavelengths and extinction-corrected Hα sizes. We made a low-resolution ({θ }1/2=1\\buildrel{\\prime\\prime}\\over{.} 0) image with ≈ 10× better brightness sensitivity, in order to detect extended sources and measure matched-resolution spectral indices {α }1.4 {GHz}10 {GHz}. It contains six new sources with {S}{{p}}≳ 3.9 μ {Jy} {{beam}}-1 and OIR counterparts. The median redshift of all 38 sources is < z> =1.24+/- 0.15. The 19 sources with 1.4 GHz counterparts have a median spectral index of < {α }1.4 {GHz}10 {GHz}> =-0.74+/- 0.10, with rms scatter ≈ 0.35. Including upper limits on α for sources not detected at 1.4 GHz flattens the median to < {α }1.4 {GHz}10 {GHz}> ≳ -0.61, suggesting that the μJy radio sources at higher redshifts—and hence those selected at higher rest-frame frequencies—may have flatter spectra. If the non-thermal spectral index is {α }{NT}≈ -0.85, the median thermal fraction of sources selected at median rest-frame frequency ≈ 20 {GHz} is ≳48%.

Complete identification of the Parkes half-Jansky sample of GHz peaked spectrum radio galaxies

NASA Astrophysics Data System (ADS)

de Vries, N.; Snellen, I. A. G.; Schilizzi, R. T.; Lehnert, M. D.; Bremer, M. N.

2007-03-01

Context: Gigahertz Peaked Spectrum (GPS) radio galaxies are generally thought to be the young counterparts of classical extended radio sources. Statistically complete samples of GPS sources are vital for studying the early evolution of radio-loud AGN and the trigger of their nuclear activity. The "Parkes half-Jansky" sample of GPS radio galaxies is such a sample, representing the southern counterpart of the 1998 Stanghellini sample of bright GPS sources. Aims: As a first step of the investigation of the sample, the host galaxies need to be identified and their redshifts determined. Methods: Deep R-band VLT-FORS1 and ESO 3.6 m EFOSC II images and long slit spectra have been taken for the unidentified sources in the sample. Results: We have identified all twelve previously unknown host galaxies of the radio sources in the sample. Eleven have host galaxies in the range 21.0 < RC < 23.0, while one object, PKS J0210+0419, is identified in the near infrared with a galaxy with Ks = 18.3. The redshifts of 21 host galaxies have been determined in the range 0.474 < z < 1.539, bringing the total number of redshifts to 39 (80%). Analysis of the absolute magnitudes of the GPS host galaxies show that at z>1 they are on average a magnitude fainter than classical 3C radio galaxies, as found in earlier studies. However their restframe UV luminosities indicate that there is an extra light contribution from the AGN, or from a population of young stars. Based on observations collected at the European Southern Observatory Very Large Telescope, Paranal, Chile (ESO prog. ID No. 073.B-0289(B)) and the European Southern Observatory 3.6 m Telescope, La Silla, Chile (prog. ID No. 073.B-0289(A)). Appendices are only available in electronic form at http://www.aanda.org

Ibuprofen and lipoic acid conjugate neuroprotective activity is mediated by Ngb/Akt intracellular signaling pathway in Alzheimer's disease rat model.

PubMed

Zara, Susi; De Colli, Marianna; Rapino, Monica; Pacella, Stephanie; Nasuti, Cinzia; Sozio, Piera; Di Stefano, Antonio; Cataldi, Amelia

2013-01-01

Alzheimer's disease (AD) is a frequent form of senile dementia. Neuroglobin (Ngb) has a neuroprotective role and decreases Aβ peptide levels. Ngb, promoting Akt phosphorylation, activates cell survival involving cyclic-nucleotide response element-binding protein (CREB). A new molecule (IBU-LA) was synthetized and administered to an AD rat model to counteract AD progression. The aim of this study was to investigate the IBU-LA-mediated induction of Ngb neuroprotective and antiapoptotic activities. Brain morphology was analyzed through Bielschowsky staining, Aβ(1-40) and Ngb expression by immunohistochemistry. Akt, p-Akt, CREB and p-CREB expression was evaluated by Western blot, apoptosis through cytochrome C/Apaf 1 immunocomplex formation, and TUNEL analysis. Bielschowsky staining and Aβ(1-40) expression show few nerve connections and Aβ(1-40) expression in an Aβ sample, preserved neuronal cells and Aβ(1-40) expression lowering in an IBU sample, mostly in IBU-LA. The Ngb level decreases in Aβ samples, compared to control and IBU-LA samples. p-Akt/Akt and p-CREB/CREB ratios reveal a reduction in Aβ sample, going back to the basal level in control and IBU-LA samples. Cytochrome C/Apaf 1 co-immunoprecipitate occurs and TUNEL-positive nuclei percentage decreases in Aβ sample. Probe test performance shows an increased spatial reference memory in the IBU-LA compared to the Aβ sample; no significant differences were seen between the IBU-LA and IBU samples. This evidence reveals that IBU-LA administration has the capability to maintain a high Ngb level allowing Ngb to perform a neuroprotective and antiapoptotic role, representing a valid tool in the therapeutic strategy of AD progression. Copyright © 2013 S. Karger AG, Basel.

Alterations in ROS Activity and Lysosomal pH Account for Distinct Patterns of Macroautophagy in LINCL and JNCL Fibroblasts

PubMed Central

Casanova, Bonaventura; Aguado, Carmen; Knecht, Erwin

2013-01-01

Neuronal Ceroid Lipofuscinoses (NCL) are lysosomal storage disorders characterized by the accumulation of lipofuscin within lysosomes. Late infantile (LINCL) and juvenile (JNCL) are their most common forms and are caused by loss-of-function mutations in tripeptidyl peptidase 1 (TPP1), a lysosomal endopeptidase, and CLN3 protein (CLN3p), whose location and function is still controversial. LINCL patients suffer more severely from NCL consequences than JNCL patients, in spite of having in common an abnormal accumulation of material with a similar composition in the lysosomes. To identify distinctive characteristics that could explain the differences in the severity of LINCL and JNCL pathologies, we compared the protein degradation mechanisms in patientś fibroblasts. Pulse-chase experiments show a significant decrease in protein degradation by macroautophagy in fibroblasts bearing TPP1 (CLN2) and CLN3p (CLN3) mutations. In CLN2 fibroblasts, LC3-II levels and other procedures indicate an impaired formation of autophagosomes, which confirms the pulse-chase experiments. This defect is linked to an accumulation of Reactive Oxygen Species (ROS), an upregulation of the Akt-mTOR signalling pathway and increased activities of the p38α and ERK1/2 MAPKs. In CLN3 fibroblasts, LC3-II analysis indicates impairment in autophagosome maturation and there is also a defect in fluid phase endocytosis, two alterations that can be related to an observed increase of 0.5 units in lysosomal pH. CLN3 fibroblasts also accumulate ROS but to a lower extent than CLN2. TPP1 activity is completely abrogated in CLN2 and partially diminished in CLN3 fibroblasts. TPP1 cleaves small hydrophobic proteins like subunit c of mitochondrial ATP synthase and the lack or a lower activity of this enzyme can contribute to lipofuscin accumulation. These alterations in TPP1 activity lead to an increased ROS production, especially in CLN2 in which it is aggravated by a decrease in catalase activity. This could

Survival Advantage of Neonatal CNS Gene Transfer for Late Infantile Neuronal Ceroid Lipofuscinosis

PubMed Central

Sondhi, Dolan; Peterson, Daniel A.; Edelstein, Andrew M.; del Fierro, Katrina; Hackett, Neil R.; Crystal, Ronald G.

2009-01-01

Summary Late infantile neuronal ceroid lipofuscinosis (LINCL), a fatal autosomal recessive neurodegenerative lysosomal storage disorder of childhood, is caused by mutations in the CLN2 gene, resulting in deficiency of the protein tripeptidyl peptidase I (TPP-I). We have previously shown that direct CNS administration of AAVrh.10hCLN2 to adult CLN2 knockout mice, a serotype rh.10 adeno-associated virus expressing the wild type CLN2 cDNA, will partially improve neurological function and survival. In this study, we explore the hypothesis that administration of AAVrh.10hCLN2 to the neonatal brain will significantly improve the results of AAVrh.10hCLN2 therapy. To assess this concept, AAVrh.10hCLN2 vector was administered directly to the CNS of CLN2 knockout mice at 2 days, 3 wk and 7 wk of age. While all treatment groups show a marked increase in total TPP-I activity over wild-type mice, neonatally treated mice displayed high levels of TPP-I activity in the CNS 1 yr after administration which was spread throughout the brain. Using behavioral markers, 2 day treated mice demonstrate marked improvement over 3 wk, 7 wk or untreated mice. Finally, neonatal administration of AAVrh.10hCLN2 was associated with markedly enhanced survival, with a median time of death 376 days for neonatal treated mice, 277 days for 3 wk treated mice, 168 days for 7 wk treated mice, and 121 days for untreated mice. These data suggest that neonatal treatment offers many unique advantages, and that early detection and treatment may be essential for maximal gene therapy for childhood lysosomal storage disorders affecting the CNS. PMID:18639872

Genetics Home Reference: CLN7 disease

MedlinePlus

... unknown. The MFSD8 protein is embedded in the membrane of cell compartments called lysosomes , which digest and recycle different types of molecules. Based on the structure of the protein, MFSD8 probably transports molecules across the lysosomal membrane, but the specific molecules it moves have not ...

Genetics Home Reference: CLN1 disease

MedlinePlus

... 10.1172/JCI33482. Citation on PubMed or Free article on PubMed Central Kollmann K, Uusi-Rauva K, Scifo E, Tyynelä J, Jalanko A, Braulke T. Cell biology and function of neuronal ceroid lipofuscinosis-related proteins. ...

Genetics Home Reference: CLN4 disease

MedlinePlus

... with each other. Specifically, CSPα is involved in recycling certain proteins that are involved in nerve impulse ... protein cannot perform its function, which reduces protein recycling, causing a shortage (deficiency) of functional proteins needed ...

Gemfibrozil, food and drug administration-approved lipid-lowering drug, increases longevity in mouse model of late infantile neuronal ceroid lipofuscinosis.

PubMed

Ghosh, Arunava; Rangasamy, Suresh Babu; Modi, Khushbu K; Pahan, Kalipada

2017-05-01

Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL) is a rare neurodegenerative disease caused by mutations in the Cln2 gene that leads to deficiency or loss of function of the tripeptidyl peptidase 1 (TPP1) enzyme. TPP1 deficiency is known to cause the accumulation of autofluoroscent lipid-protein pigments in brain. Similar to other neurodegenerative disorders, LINCL is also associated with neuroinflammation and neuronal damage. Despite investigations, no effective therapy is currently available for LINCL. Therefore, we administered gemfibrozil (gem), an food and drug administration (FDA)-approved lipid-lowering drug, which has been shown to stimulate lysosomal biogenesis and induce anti-inflammation, orally, at a dose of 7.5 mg/kg body wt/day to Cln2 (-/-) mice. We observed that gem-fed Cln2 (-/-) mice lived longer by more than 10 weeks and had better motor activity compared to vehicle (0.1% Methyl cellulose) treatment. Gem treatment lowered the burden of storage materials, increased anti-inflammatory factors like SOCS3 and IL-1Ra, up-regulated anti-apoptotic molecule like phospho-Bad, and reduced neuronal apoptosis in the brain of Cln2 (-/-) mice. Collectively, this study reinforces a neuroprotective role of gem that may be of therapeutic interest in improving the quality of life in LINCL patients. © 2017 International Society for Neurochemistry.

Cervical Lymph Nodes as a Selective Niche for Brucella during Oral Infections

PubMed Central

von Bargen, Kristine; Gagnaire, Aurélie; Arce-Gorvel, Vilma; de Bovis, Béatrice; Baudimont, Fannie; Chasson, Lionel; Bosilkovski, Mile; Papadopoulos, Alexia; Martirosyan, Anna; Henri, Sandrine; Mège, Jean-Louis; Malissen, Bernard; Gorvel, Jean-Pierre

2015-01-01

Cervical lymph nodes (CLN) are the first lymph nodes encountered by material taking the oral route. To study their role in orally acquired infections, we analyzed 307 patients of up to 14 years treated in the university clinic of Skopje, Macedonia, for brucellosis, a zoonotic bacterial disease frequently acquired by ingestion of contaminated dairy products. From these children, 36% had lymphadenopathy. Among orally infected children, lymphadenopathy with CLN being the only lymph nodes affected was significantly more frequent as compared to those infected by contact with animals (83% vs. 63%), suggesting a possible involvement of CLN during orally acquired human brucellosis. Using a murine model where bacteria are delivered into the oral cavity, we show that Brucella quickly and selectively colonize the CLN where they proliferate and persist over long periods of time for up to 50 days post-infection. A similar efficient though less specific drainage to CLN was found for Brucella, Salmonella typhimurium and fluorescent microspheres delivered by gavage, a pathway likely representing a mixed infection mode of intragastric and oral infection, suggesting a central pathway of drained material. Microspheres as well as bacteria drained to CLN predominately reside in cells expressing CD68 and no or low levels of CD11c. Even though no systemic response could be detected, Brucella induced a locally restricted inflammatory reaction with increased expression levels of interferon γ, interleukin (IL)-6, IL-12, granzyme B and a delayed induction of Nos2. Inflammation led to pronounced lymphadenopathy, infiltration of macrophages/monocytes expressing high levels of major histocompatibility complex II and to formation of epitheloid granulomas. Together, these results highlight the role of CLN in oral infections as both, an initial and efficient trap for bacterial invaders and as possible reservoir for chronic pathogens. They likewise cast a new light on the significance of oral

Large-Scale Phenotyping of an Accurate Genetic Mouse Model of JNCL Identifies Novel Early Pathology Outside the Central Nervous System

PubMed Central

Staropoli, John F.; Haliw, Larissa; Biswas, Sunita; Garrett, Lillian; Hölter, Sabine M.; Becker, Lore; Skosyrski, Sergej; Da Silva-Buttkus, Patricia; Calzada-Wack, Julia; Neff, Frauke; Rathkolb, Birgit; Rozman, Jan; Schrewe, Anja; Adler, Thure; Puk, Oliver; Sun, Minxuan; Favor, Jack; Racz, Ildikó; Bekeredjian, Raffi; Busch, Dirk H.; Graw, Jochen; Klingenspor, Martin; Klopstock, Thomas; Wolf, Eckhard; Wurst, Wolfgang; Zimmer, Andreas; Lopez, Edith; Harati, Hayat; Hill, Eric; Krause, Daniela S.; Guide, Jolene; Dragileva, Ella; Gale, Evan; Wheeler, Vanessa C.; Boustany, Rose-Mary; Brown, Diane E.; Breton, Sylvie; Ruether, Klaus; Gailus-Durner, Valérie; Fuchs, Helmut; de Angelis, Martin Hrabě; Cotman, Susan L.

2012-01-01

Cln3Δex7/8 mice harbor the most common genetic defect causing juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive disease involving seizures, visual, motor and cognitive decline, and premature death. Here, to more thoroughly investigate the manifestations of the common JNCL mutation, we performed a broad phenotyping study of Cln3Δex7/8 mice. Homozygous Cln3Δex7/8 mice, congenic on a C57BL/6N background, displayed subtle deficits in sensory and motor tasks at 10–14 weeks of age. Homozygous Cln3Δex7/8 mice also displayed electroretinographic changes reflecting cone function deficits past 5 months of age and a progressive decline of retinal post-receptoral function. Metabolic analysis revealed increases in rectal body temperature and minimum oxygen consumption in 12–13 week old homozygous Cln3Δex7/8mice, which were also seen to a lesser extent in heterozygous Cln3Δex7/8 mice. Heart weight was slightly increased at 20 weeks of age, but no significant differences were observed in cardiac function in young adults. In a comprehensive blood analysis at 15–16 weeks of age, serum ferritin concentrations, mean corpuscular volume of red blood cells (MCV), and reticulocyte counts were reproducibly increased in homozygous Cln3 Δ ex7/8 mice, and male homozygotes had a relative T-cell deficiency, suggesting alterations in hematopoiesis. Finally, consistent with findings in JNCL patients, vacuolated peripheral blood lymphocytes were observed in homozygous Cln3 Δ ex7/8 neonates, and to a greater extent in older animals. Early onset, severe vacuolation in clear cells of the epididymis of male homozygous Cln3 Δ ex7/8 mice was also observed. These data highlight additional organ systems in which to study CLN3 function, and early phenotypes have been established in homozygous Cln3 Δ ex7/8 mice that merit further study for JNCL biomarker development. PMID:22701626

Visual deficits in a mouse model of Batten disease are the result of optic nerve degeneration and loss of dorsal lateral geniculate thalamic neurons

PubMed Central

Weimer, Jill M.; Custer, Andrew W.; Benedict, Jared W.; Alexander, Noreen A.; Kingsley, Evan; Federoff, Howard J.; Cooper, Jonathan D.; Pearce, David A.

2013-01-01

Juvenile neuronal ceroid lipofuscinosis (JNCL) is an autosomal recessive disorder of childhood caused by mutations in CLN3. Although visual deterioration is typically the first clinical sign to manifest in affected children, loss of Cln3 in a mouse model of JNCL does not recapitulate this retinal deterioration. This suggests that either the loss of CLN3 does not directly affect retinal cell survival or that nuclei involved in visual processing are affected prior to retinal degeneration. Having previously demonstrated that Cln3−/− mice have decreased optic nerve axonal density, we now demonstrate a decrease in nerve conduction. Examination of retino-recipient regions revealed a decreased number of neurons within the dorsal lateral geniculate nucleus (LGNd). We demonstrate decreased transport of amino acids from the retina to the LGN, suggesting an impediment in communication between the retina and projection nuclei. This study defines a novel path of degeneration within the LGNd, providing a mechanism for causation of JNCL visual deficits. PMID:16412658

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, D.; Worster, T.; Boustany, R.M.

The neuronal lipofuscinoses (NCLs) are a group of disorders characterized by cognitive decline, blindness, seizures, and death. Pathologically, it is characterized by accumulation of lipofuscin deposits, generally in easily identifiable `curvilinear bodies`. It is inherited as an autosomal recessive disorder, with the exception of the adult onset form, which may be inherited as an autosomal dominant trait. The loci for the juvenile (CLN3), infantile (CLN1), and very recently, Finnish late-infantile (CLN5) NCLs have been mapped by genetic linkage analysis to chromosome 16p, 1p, and 13q, respectively. The classical late-infantile (LNCL) defect (CLN2) has not yet been mapped. Previous analysis withmore » tightly linked markers excluded CLN2 from the CLN1 and CLN3 regions. We have initiated a genome-wide screen for CLN2, taking advantage of the large collection of highly polymorphic markers that has been developed through the Human Genome Initiative. The high degree of heterozygosity of these markers makes it feasible to carry out successful linkage analysis in small nuclear families, such as found in LNCL. Our current collection of LNCL pedigrees includes 19 U.S. families and 11 Costa Rican families. Simulation studies have shown that we can detect linkage using a subset of 6 LNCL families, a 10 cM sieve, and a lod score criterion of 0.50 for follow-up. A linked region spanned by two markers has over a 95% chance of generating such a lod score, while an unlinked marker has less than a 5% chance of doing so. Follow-up will consist of genotyping the additional families and two additional markers in this region. To date, we have completed typing with 65 markers on chromosomes 1, 2, 9, 13, 16, 18, 19, 20, 21, and 22. The results of this analysis formally exclude about 25% of the human genome as the location of CLN2, including the region of chromosome 13 where CLN5 has been mapped. Updated results will be presented.« less

Development of nanoemulsion for efficient brain parenteral delivery of cefuroxime: designs, characterizations, and pharmacokinetics

PubMed Central

Harun, Siti Norhawani; Nordin, Syafinaz Amin; Gani, Siti Salwa Abd; Shamsuddin, Ahmad Fuad; Basri, Mahiran; Basri, Hamidon Bin

2018-01-01

Background and aim Drugs that are effective against diseases in the central nervous system and reach the brain via blood must pass through the blood–brain barrier (BBB), a unique interface that protects against potential harmful molecules. This presents a major challenge in neuro-drug delivery. This study attempts to fabricate the cefuroxime-loaded nanoemulsion (CLN) to increase drug penetration into the brain when parenterally administered. Methods The nanoemulsions were formulated using a high-pressure homogenization technique and were characterized for their physicochemical properties. Results The characterizations revealed a particle size of 100.32±0.75 nm, polydispersity index of 0.18±0.01, zeta potential of −46.9±1.39 mV, viscosity of 1.24±0.34 cps, and osmolality of 285.33±0.58 mOsm/kg, indicating that the nanoemulsion has compatibility for parenteral application. CLN was physicochemically stable within 6 months of storage at 4°C, and the transmission electron microscopy revealed that the CLN droplets were almost spherical in shape. The in vitro release of CLN profile followed a sustained release pattern. The pharmacokinetic profile of CLN showed a significantly higher Cmax, area under the curve (AUC)0–t, prolonged half-life, and lower total plasma clearance, indicating that the systemic concentration of cefuroxime was higher in CLN-treated rats as compared to cefuroxime-free treated rats. A similar profile was obtained for the biodistribution of cefuroxime in the brain, in which CLN showed a significantly higher Cmax, AUC0–t, prolonged half-life, and lower clearance as compared to free cefuroxime solution. Conclusion Overall, CLN showed excellent physicochemical properties, fulfilled the requirements for parenteral administration, and presented improved in vivo pharmacokinetic profile, which reflected its practical approach to enhance cefuroxime delivery to the brain. PMID:29731632

Application of chromosome 16 markers in the differential diagnosis of neuronal ceroid-lipofuscinosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taschner, P.E.M.; Vos, N. de; Breuning, M.H.

Accurate diagnosis of neuronal ceroid lipofuscinosis (NCL) is important for a correct prognosis of the disease and for genetic counseling. Up to now, no direct diagnostic test has been available for NCL. The clinical diagnosis is made on the basis of symptoms, neurophysiological, neuroradiological, and specific lipopigment pattern data. Recent advances in the genetics of NCL have enabled us to use polymorphic DNA markers linked to the CLN1 and CLN3 loci as a tool in the differential diagnosis of NCL. We have applied genetic analysis with polymorphic DNA markers flanking the CLN3 gene on chromosome 16 to two consanguineous familiesmore » in which NCL occurs. In the first family, which is of Turkish extraction, two patients suffering from a protracted form of juvenile NCL previously had been diagnosed with juvenile NCL. Haplotypes from this family indicate that the patients and their healthy sibling are haplo-identical, suggesting that this protracted form of juvenile NCL is not linked to the CLN3 locus. In the second family, which is Moroccan origin, one patient suffers from the early juvenile variant of NCL (Lake-Cavanagh). In this family, the patient and one of the healthy siblings have identical haplotypes, excluding linkage of early juvenile NCL to the CLN3 locus on 16p12.1-11.2. Therefore, these cases from different populations demonstrate that haplotype analysis can be used as an additional method to exclude the diagnosis of juvenile NCL. 21 refs., 4 figs., 1 tab.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sharp, J.; Wheeler, R.B.; Jaervelae, I.

The neuronal ceroid-lipofuscinoses (NCL) are a group of neurodegenerative disorders with an autosomal-recessive pattern of inheritance. There are 3 main categories of childhood NCL, namely, infantile, late-infantile, and juvenile NCL. These can be distinguished on the basis of age of onset, clinical course, and histopathology. A number of variant forms of NCL have also been mapped to chromosome areas 1p32 and 16p12, respectively. The gene for late-infantile NCL (LINCL), CLN2, has been excluded from both these loci, but its location is as yet unknown. Recently, CLN5, the gene for the Finnish variant form of LINCL, was mapped to 13q21.1-32. Usingmore » the 3 microsatellite markers which were most tightly linked to CLN5, we have excluded CLN2 from this region using a subset of 17 families. Thus, CLN2 represents a fourth distinct genetic locus involved in the pathogenesis of NCL. 6 refs., 1 fig., 1 tab.« less

Karl G. Jansky very large array observations of cold dust and molecular gas in starbursting quasar host galaxies at z ∼ 4.5

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wagg, J.; Carilli, C. L.; Lentati, L.

2014-03-10

We present Karl G. Jansky Very Large Array (VLA) observations of 44 GHz continuum and CO J = 2-1 line emission in BRI 1202–0725 at z = 4.7 (a starburst galaxy and quasar pair) and BRI 1335–0417 at z = 4.4 (also hosting a quasar). With the full 8 GHz bandwidth capabilities of the upgraded VLA, we study the (rest-frame) 250 GHz thermal dust continuum emission for the first time along with the cold molecular gas traced by the low-J CO line emission. The measured CO J = 2-1 line luminosities of BRI 1202–0725 are L{sub CO}{sup ′}=(8.7±0.8)×10{sup 10} Kmore » km s{sup –1} pc{sup 2} and L{sub CO}{sup ′}=(6.0 ± 0.5)×10{sup 10} K km s{sup –1} pc{sup 2} for the submillimeter galaxy (SMG) and quasar, respectively, which are equal to previous measurements of the CO J = 5-4 line luminosities implying thermalized line emission, and we estimate a combined cold molecular gas mass of ∼9×10{sup 10} M {sub ☉}. In BRI 1335–0417 we measure L{sub CO}{sup ′}=(7.3±0.6)×10{sup 10} K km s{sup –1} pc{sup 2}. We detect continuum emission in the SMG BRI 1202–0725 North (S {sub 44} {sub GHz} = 51 ± 6 μJy), while the quasar is detected with S {sub 44} {sub GHz} = 24 ± 6 μJy and in BRI 1335–0417 we measure S {sub 44} {sub GHz} = 40 ± 7 μJy. Combining our continuum observations with previous data at (rest-frame) far-infrared and centimeter wavelengths, we fit three-component models in order to estimate the star formation rates. This spectral energy distribution fitting suggests that the dominant contribution to the observed 44 GHz continuum is thermal dust emission, while either thermal free-free or synchrotron emission contributes less than 30%.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Andermann, F.; Andermann, E.; Carpenter, S.

Most forms of neuronal ceroid lipofuscinosis (NCL) are autosomal recessive, and three genes have already been mapped: the infantile form (CLN 1); the juvenile form (CLN 3); and the early juvenile variant (CLN 5) on chromosomes 1, 16 and 13, respectively. Kufs` disease or adolescent-adult onset NCL is usually inherited as an autosomal recessive trait, and presents as three distinct clinical syndromes: progressive myoclonus epilepsy (PME) with onset in the early teens or around age 30; and onset of dementia with motor disability in the 30s. We have studied three families originating from different parts of the USA manifesting dominantlymore » inherited Kufs` disease. Granular osmophilic deposits (GROD) were found in brain, but storage in skin was not an obligatory feature. Six dominantly inherited PME families have been ascertained from three different regions of Spain. No storage was found in skin or muscle in any of these families. The mean age of onset in the American families is earlier, the clinical manifestations more severe, and the progression much more rapid that in the Spanish families. These findings would suggest the possibility of genetic heterogeneity involving two or more loci, or different mutations at the same gene locus. Genetic linkage studies have been carried out in a six-generation New Jersey family in an attempt to characterize the gene(s) responsible for this disorder. The infantile NCL locus on chromosome 1p (CLN1) and the juvenile NCL locus on chromosome 16p (CLN 3) have been excluded in this family. Further clinical, pathological and molecular genetic studies should lead to the clarification of the diagnostic approaches in this disorder.« less

3-(4-Chloro­phen­yl)-7-methyl-4-(4-methyl­phen­yl)-1-oxa-2,7-diaza­spiro­[4.5]dec-2-en-10-one

PubMed Central

Gayathri, D.; Velmurugan, D.; Ranjith Kumar, R.; Perumal, S.; Ravikumar, K.

2008-01-01

In the title compound, C21H21ClN2O2, the dihydro­isoxazole ring adopts an envelope conformation and the piperidinone ring is in a chair conformation. The dihedral angle between the two benzene rings is 84.2 (1)°. The crystal used was an inversion twin. PMID:21201426

Gemfibrozil and fenofibrate, Food and Drug Administration-approved lipid-lowering drugs, up-regulate tripeptidyl-peptidase 1 in brain cells via peroxisome proliferator-activated receptor α: implications for late infantile Batten disease therapy.

PubMed

Ghosh, Arunava; Corbett, Grant T; Gonzalez, Frank J; Pahan, Kalipada

2012-11-09

The classical late infantile neuronal ceroid lipofuscinosis (LINCLs) is an autosomal recessive disease, where the defective gene is Cln2, encoding tripeptidyl-peptidase I (TPP1). At the molecular level, LINCL is caused by accumulation of autofluorescent storage materials in neurons and other cell types. Currently, there is no established treatment for this fatal disease. This study reveals a novel use of gemfibrozil and fenofibrate, Food and Drug Administration-approved lipid-lowering drugs, in up-regulating TPP1 in brain cells. Both gemfibrozil and fenofibrate up-regulated mRNA, protein, and enzymatic activity of TPP1 in primary mouse neurons and astrocytes as well as human astrocytes and neuronal cells. Because gemfibrozil and fenofibrate are known to activate peroxisome proliferator-activated receptor-α (PPARα), the role of PPARα in gemfibrozil- and fenofibrate-mediated up-regulation of TPP1 was investigated revealing that both drugs up-regulated TPP1 mRNA, protein, and enzymatic activity both in vitro and in vivo in wild type (WT) and PPARβ(-/-), but not PPARα(-/-), mice. In an attempt to delineate the mechanism of TPP1 up-regulation, it was found that the effects of the fibrate drugs were abrogated in the absence of retinoid X receptor-α (RXRα), a molecule known to form a heterodimer with PPARα. Accordingly, all-trans-retinoic acid, alone or together with gemfibrozil, up-regulated TPP1. Co-immunoprecipitation and ChIP studies revealed the formation of a PPARα/RXRα heterodimer and binding of the heterodimer to an RXR-binding site on the Cln2 promoter. Together, this study demonstrates a unique mechanism for the up-regulation of TPP1 by fibrate drugs via PPARα/RXRα pathway.

Altered Expression of Ganglioside Metabolizing Enzymes Results in GM3 Ganglioside Accumulation in Cerebellar Cells of a Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis.

PubMed

Somogyi, Aleksandra; Petcherski, Anton; Beckert, Benedikt; Huebecker, Mylene; Priestman, David A; Banning, Antje; Cotman, Susan L; Platt, Frances M; Ruonala, Mika O; Tikkanen, Ritva

2018-02-22

Juvenile neuronal ceroid lipofuscinosis (JNCL) is caused by mutations in the CLN3 gene. Most JNCL patients exhibit a 1.02 kb genomic deletion removing exons 7 and 8 of this gene, which results in a truncated CLN3 protein carrying an aberrant C-terminus. A genetically accurate mouse model ( Cln3 Δex7/8 mice) for this deletion has been generated. Using cerebellar precursor cell lines generated from wildtype and Cln3 Δex7/8 mice, we have here analyzed the consequences of the CLN3 deletion on levels of cellular gangliosides, particularly GM3, GM2, GM1a and GD1a. The levels of GM1a and GD1a were found to be significantly reduced by both biochemical and cytochemical methods. However, quantitative high-performance liquid chromatography analysis revealed a highly significant increase in GM3, suggesting a metabolic blockade in the conversion of GM3 to more complex gangliosides. Quantitative real-time PCR analysis revealed a significant reduction in the transcripts of the interconverting enzymes, especially of β-1,4- N -acetyl-galactosaminyl transferase 1 (GM2 synthase), which is the enzyme converting GM3 to GM2. Thus, our data suggest that the complex a-series gangliosides are reduced in Cln3 Δex7/8 mouse cerebellar precursor cells due to impaired transcription of the genes responsible for their synthesis.

Clobazam and Its Active Metabolite N-desmethylclobazam Display Significantly Greater Affinities for α2- versus α1-GABAA–Receptor Complexes

PubMed Central

Jensen, Henrik Sindal; Nichol, Kathryn; Lee, Deborah; Ebert, Bjarke

2014-01-01

Clobazam (CLB), a 1,5-benzodiazepine (BZD), was FDA-approved in October 2011 for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years and older. BZDs exert various CNS effects through allosteric modulation of GABAA receptors. The structurally distinct, 1,4-BZD clonazepam (CLN) is also approved to treat LGS. The precise mechanisms of action and clinical efficacy of both are unknown. Data show that the GABAA α1-subunit–selective compound zolpidem [ZOL] exhibits hypnotic/sedative effects. Conversely, data from knock-in mice carrying BZD binding site mutations suggest that the α2 subunit mediates anticonvulsant effects, without sedative actions. Hence, the specific pattern of interactions across the GABAA receptor complexes of BZDs might be reflected in their clinical efficacies and adverse effect profiles. In this study, GABAA-receptor binding affinities of CLB, N-desmethylclobazam (N-CLB, the major metabolite of CLB), CLN, and ZOL were characterized with native receptors from rat-brain homogenates and on cloned receptors from HEK293 cells transfected with combinations of α (α1, α2, α3, or α5), β2, and γ2 subtypes. Our results demonstrate that CLB and N-CLB have significantly greater binding affinities for α2- vs. α1-receptor complexes, a difference not observed for CLN, for which no distinction between α2 and α1 receptors was observed. Our experiments with ZOL confirmed the high preference for α1 receptors. These results provide potential clues to a new understanding of the pharmacologic modes of action of CLB and N-CLB. PMID:24533090

2-[2-(3-Chloro­phen­yl)hydrazinyl­idene]-1,3-diphenyl­propane-1,3-dione

PubMed Central

Bustos, Carlos; Alvarez-Thon, Luis; Cárcamo, Juan-Guillermo; Ibañez, Andrés; Sánchez, Christian

2011-01-01

The mol­ecular structure of the title compound, C21H15ClN2O2, features one strong intra­molecular N—H⋯O resonance-assisted hydrogen bond (RAHB). In the crystal, mol­ecules form inversion-related dimers via pairs of weak inter­molecular N—H⋯O contacts. These dimers are further stabilized via three weak C—H⋯O contacts, developing the three-dimensional structure. PMID:21754825

Altered Expression of Ganglioside Metabolizing Enzymes Results in GM3 Ganglioside Accumulation in Cerebellar Cells of a Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis

PubMed Central

Somogyi, Aleksandra; Petcherski, Anton; Beckert, Benedikt; Huebecker, Mylene; Priestman, David A.; Banning, Antje; Cotman, Susan L.; Platt, Frances M.; Ruonala, Mika O.

2018-01-01

Juvenile neuronal ceroid lipofuscinosis (JNCL) is caused by mutations in the CLN3 gene. Most JNCL patients exhibit a 1.02 kb genomic deletion removing exons 7 and 8 of this gene, which results in a truncated CLN3 protein carrying an aberrant C-terminus. A genetically accurate mouse model (Cln3Δex7/8 mice) for this deletion has been generated. Using cerebellar precursor cell lines generated from wildtype and Cln3Δex7/8 mice, we have here analyzed the consequences of the CLN3 deletion on levels of cellular gangliosides, particularly GM3, GM2, GM1a and GD1a. The levels of GM1a and GD1a were found to be significantly reduced by both biochemical and cytochemical methods. However, quantitative high-performance liquid chromatography analysis revealed a highly significant increase in GM3, suggesting a metabolic blockade in the conversion of GM3 to more complex gangliosides. Quantitative real-time PCR analysis revealed a significant reduction in the transcripts of the interconverting enzymes, especially of β-1,4-N-acetyl-galactosaminyl transferase 1 (GM2 synthase), which is the enzyme converting GM3 to GM2. Thus, our data suggest that the complex a-series gangliosides are reduced in Cln3Δex7/8 mouse cerebellar precursor cells due to impaired transcription of the genes responsible for their synthesis. PMID:29470438

Neck dissection after chemoradiotherapy for oropharyngeal and hypopharyngeal cancer: the correlation between cervical lymph node metastasis and prognosis.

PubMed

Hanai, Nobuhiro; Kawakita, Daisuke; Ozawa, Taijiro; Hirakawa, Hitoshi; Kodaira, Takeshi; Hasegawa, Yasuhisa

2014-02-01

Recently, the role of chemoradiotherapy (CRT) for preserving organs in the treatment of head and neck cancer has been increasing. However, the indication for post-CRT neck dissection (ND) and its surgical extent is still controversial. The purpose of this study was to discuss the indications for post-CRT ND and the proper extent of the surgical procedure. We performed a retrospective analysis on N2-3 oropharyngeal and hypopharyngeal squamous cell carcinoma (OHSCC) patients treated with CRT in our institute from 1995 to 2008, and determined the prognostic impact of post-CRT ND and the distribution of cervical lymph node (CLN) metastasis based on the pathological results of ND. The patients without pathological CLN metastases had good prognoses, whereas patients with pathological CLN metastases exhibited a significantly high recurrence rate (P = 0.033). Based on the pathological results of ND, performing selective ND at levels II-IV can contain 88 and 85 % of CLN metastasis of the oropharynx and hypopharynx, respectively. In all cases, when pathological CLN metastases were found at level V in ND following CRT, distant metastases developed. The presence of pathological CLN metastasis affects prognosis, but also a diffuse distribution of CLN metastasis worsens prognosis; that is, the presence of CLN metastasis at level V after CRT appears to be an indicator of distant metastasis. Post-CRT ND may not make sense as a salvage intervention for improving the prognosis in such situations. We concluded that the proper extent of post-CRT ND of OHSCC is selective ND including levels II-IV.

A novel peptide, colivelin, prevents alcohol-induced apoptosis in fetal brain of C57BL/6 mice: signaling pathway investigations

PubMed Central

Sari, Youssef; Chiba, Tomohiro; Yamada, Marina; Rebec, George V.; Aiso, Sadakazu

2009-01-01

Fetal alcohol exposure is known to induce cell death through apoptosis. We found that colivelin (CLN), a novel peptide with the sequence SALLRSIPAPAGASRLLLLTGEIDLP, prevents this apoptosis. Our initial experiment revealed that CLN enhanced the viability of primary cortical neurons exposed to alcohol. We then used a mouse model of fetal alcohol exposure to identify the intracellular mechanisms underlying these neuroprotective effects. On embryonic day 7 (E7), weight-matched pregnant females were assigned to the following groups: (1) ethanol liquid diet (ALC) 25% (4.49%, v/v) ethanol derived calories; (2) pair-fed control; (3) normal chow; (4) ALC combined with administration (i.p.) of CLN (20 μg/20 g body weight); and (5) pair-fed combined with administration (i.p.) of CLN (20 μg/20 g body weight). On E13, fetal brains were collected and assayed for TUNEL staining, caspase-3 colorimetric assay, ELISA, and MSD electrochemiluminescence. CLN blocked the alcohol-induced decline in brain weight and prevented alcohol-induced: apoptosis, activation of caspase-3 and increases of cytosolic cytochrome c, and decreases of mitochondrial cytochrome c. Analysis of proteins in the upstream signaling pathway revealed that CLN down-regulated the phosphorylation of the c-Jun N-terminal kinase. Moreover, CLN prevented alcohol-induced reduction in phosphorylation of BAD protein. Thus, CLN appears to act directly on upstream signaling proteins to prevent alcohol-induced apoptosis. Further assessment of these proteins and their signaling mechanisms is likely to enhance development of neuroprotective therapies. PMID:19782727

The Star Formation in Radio Survey: Jansky Very Large Array 33 GHz Observations of Nearby Galaxy Nuclei and Extranuclear Star-forming Regions

NASA Astrophysics Data System (ADS)

Murphy, E. J.; Dong, D.; Momjian, E.; Linden, S.; Kennicutt, R. C., Jr.; Meier, D. S.; Schinnerer, E.; Turner, J. L.

2018-02-01

We present 33 GHz imaging for 112 pointings toward galaxy nuclei and extranuclear star-forming regions at ≈2″ resolution using the Karl G. Jansky Very Large Array (VLA) as part of the Star Formation in Radio Survey. A comparison with 33 GHz Robert C. Byrd Green Bank Telescope single-dish observations indicates that the interferometric VLA observations recover 78% ± 4% of the total flux density over 25″ regions (≈kpc scales) among all fields. On these scales, the emission being resolved out is most likely diffuse non-thermal synchrotron emission. Consequently, on the ≈30–300 pc scales sampled by our VLA observations, the bulk of the 33 GHz emission is recovered and primarily powered by free–free emission from discrete H II regions, making it an excellent tracer of massive star formation. Of the 225 discrete regions used for aperture photometry, 162 are extranuclear (i.e., having galactocentric radii r G ≥ 250 pc) and detected at >3σ significance at 33 GHz and in Hα. Assuming a typical 33 GHz thermal fraction of 90%, the ratio of optically-thin 33 GHz to uncorrected Hα star formation rates indicates a median extinction value on ≈30–300 pc scales of A Hα ≈ 1.26 ± 0.09 mag, with an associated median absolute deviation of 0.87 mag. We find that 10% of these sources are “highly embedded” (i.e., A Hα ≳ 3.3 mag), suggesting that on average, H II regions remain embedded for ≲1 Myr. Finally, we find the median 33 GHz continuum-to-Hα line flux ratio to be statistically larger within r G < 250 pc relative to the outer disk regions by a factor of 1.82 ± 0.39, while the ratio of 33 GHz to 24 μm flux densities is lower by a factor of 0.45 ± 0.08, which may suggest increased extinction in the central regions.

Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS: Safety, pharmacokinetics, and distribution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vuillemenot, Brian R., E-mail: bvuillemenot@bmrn.com; Kennedy, Derek; Reed, Randall P.

CLN2 disease is caused by deficiency in tripeptidyl peptidase-1 (TPP1), leading to neurodegeneration and death. The safety, pharmacokinetics (PK), and CNS distribution of recombinant human TPP1 (rhTPP1) were characterized following a single intracerebroventricular (ICV) or intrathecal-lumbar (IT-L) infusion to cynomolgus monkeys. Animals received 0, 5, 14, or 20 mg rhTPP1, ICV, or 14 mg IT-L, in artificial cerebrospinal fluid (aCSF) vehicle. Plasma and CSF were collected for PK analysis. Necropsies occurred at 3, 7, and 14 days post-infusion. CNS tissues were sampled for rhTPP1 distribution. TPP1 infusion was well tolerated and without effect on clinical observations or ECG. A mildmore » increase in CSF white blood cells (WBCs) was detected transiently after ICV infusion. Isolated histological changes related to catheter placement and infusion were observed in ICV treated animals, including vehicle controls. The CSF and plasma exposure profiles were equivalent between animals that received an ICV or IT-L infusion. TPP1 levels peaked at the end of infusion, at which point the enzyme was present in plasma at 0.3% to 0.5% of CSF levels. TPP1 was detected in brain tissues with half-lives of 3–14 days. CNS distribution between ICV and IT-L administration was similar, although ICV resulted in distribution to deep brain structures including the thalamus, midbrain, and striatum. Direct CNS infusion of rhTPP1 was well tolerated with no drug related safety findings. The favorable nonclinical profile of ICV rhTPP1 supports the treatment of CLN2 by direct administration to the CNS. - Highlights: • TPP1 enzyme replacement therapy to the CNS is in development for CLN2 disease. • Toxicology, pharmacokinetics, and CNS distribution were assessed in monkeys. • TPP1 infusion directly to the brain did not result in any safety concerns. • A positive pharmacokinetic and distribution profile resulted from TPP1 infusion. • This study demonstrates the feasibility of ICV

Increased brain lysosomal pepstatin-insensitive proteinase activity in patients with neurodegenerative diseases.

PubMed

Junaid, M A; Pullarkat, R K

1999-04-02

A recent study has shown mutations in CLN2 gene, that encodes a novel lysosomal pepstatin-insensitive proteinase (LPIP), in the pathophysiology of late-infantile neuronal ceroid lipofuscinosis (LINCL). We have measured the LPIP activities in brains from various forms of human neuronal ceroid lipofuscinoses (NCL), canine ceroid lipofuscinosis and other neurodegenerative disorders with a highly sensitive assay using a tetrapeptide Gly-Phe-Phe-Leu-amino-trifluoromethyl coumarin (AFC) as substrate. Brain LPIP has a pH optimum of 3.5 and an apparent km of 100 microM for the crude enzyme. The enzyme activity is totally absent in LINCL patients. Pronounced increase in the LPIP activity was seen in patients suffering from infantile (INCL), juvenile (JNCL) and adult (ANCL) forms of neuronal ceroid lipofuscinoses. LPIP activity was also found to be increased about two-fold in Alzheimer's disease when compared with normal or age-matched controls, while in globoidal-cell leukodystrophy (Krabbe's disease) it was similar to the normal controls. Although mannose-6-phosphorylated LPIP is increased 13-fold in brains of patients with JNCL, this form of LPIP did not have any enzyme activity. The mechanism by which LPIP activities are increased in a wide range of neurodegenerative diseases is unknown, although neuronal loss, followed by gliosis are common characteristics of these diseases.

Supramolecular interactions in carboxylate and sulfonate salts of 2,6-diamino-4-chloropyrimidinium.

PubMed

Mohana, Marimuthu; Thomas Muthiah, Packianathan; Butcher, Ray J

2017-07-01

Two new salts, namely 2,6-diamino-4-chloropyrimidinium 2-carboxy-3-nitrobenzoate, C 4 H 6 ClN 4 + ·C 8 H 4 NO 6 - , (I), and 2,6-diamino-4-chloropyrimidinium p-toluenesulfonate monohydrate, C 4 H 6 ClN 4 + ·C 7 H 7 O 3 S - ·H 2 O, (II), have been synthesized and characterized by single-crystal X-ray diffraction. In both crystal structures, the N atom in the 1-position of the pyrimidine ring is protonated. In salt (I), the protonated N atom and the amino group of the pyrimidinium cation interact with the carboxylate group of the anion through N-H...O hydrogen bonds to form a heterosynthon with an R 2 2 (8) ring motif. In hydrated salt (II), the presence of the water molecule prevents the formation of the familiar R 2 2 (8) ring motif. Instead, an expanded ring [i.e. R 3 2 (8)] is formed involving the sulfonate group, the pyrimidinium cation and the water molecule. Both salts form a supramolecular homosynthon [R 2 2 (8) ring motif] through N-H...N hydrogen bonds. The molecular structures are further stabilized by π-π stacking, and C=O...π, C-H...O and C-H...Cl interactions.

Effect of dietary pomegranate seed oil on laying hen performance and physicochemical properties of eggs.

PubMed

Kostogrys, Renata B; Filipiak-Florkiewicz, Agnieszka; Dereń, Katarzyna; Drahun, Anna; Czyżyńska-Cichoń, Izabela; Cieślik, Ewa; Szymczyk, Beata; Franczyk-Żarów, Magdalena

2017-04-15

The objective of the study was to determine the effects of pomegranate seed oil, used as a source of punicic acid (CLnA) in the diets of laying hens, on the physicochemical properties of eggs. Forty Isa Brown laying hens (26weeks old) were equally subjected to 4 dietary treatments (n=10) and fed a commercial layer diet supplying 2.5% sunflower oil (control) or three levels (0.5, 1.0 and 1.5%) of punicic acid in the diets. After 12weeks of feeding the hens, eggs collection began. Sixty eggs - randomly selected from each group - were analysed for physicochemical properties. Eggs naturally enriched with CLnA preserve their composition and conventional properties in most of the analysed parameters (including chemical composition, physical as well as organoleptic properties). Dietary CLnA had positive impact on the colour of the eggs' yolk, whereas the hardness of hard-boiled egg yolks was not affected. Additionally, increasing dietary CLnA led to an increase not only the CLnA concentrations, but also CLA in egg-yolk lipids. Copyright © 2016. Published by Elsevier Ltd.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wenliang Yan; Ozelius, L.; Breakefield, X.O.

The neuronal ceroid lipofuscinoses (NCL) are a group of progressive neurodegenerative disorders characterized by the deposition of autofluorescent proteinaceous fingerprint or curvilinear bodies. The authors have found that CLN3, the gene underlying the juvenile form of NCL, is very tightly linked to the dinucleotide repeat marker D16S285 on chromosome 16. Integration of D16S285 into the genetic map of chromosome 16 by using the Centre d'Etude du Polymorphisme Humain panel of reference pedigrees yielded a favored marker order in the CLN3 region of qtel-D16S150-.08-D16S285-.04-D16S148-.02-D16S67-ptel. The most likely location of the disease gene, near D16S285 in the D16S150-D16S148 interval, was favored bymore » odds of greater than 10[sup 4]:1 over the adjacent D16S148-D16S67 interval, which was recently reported as the minimum candidate region. Analysis of D16S285 in pedigrees with late-infantile NCL virtually excluded the CLN3 region, suggesting that these two forms of NCL are genetically distinct. 23 refs., 3 figs., 2 tabs.« less

Comparative study of hypocholesterolemic and hypolipidemic effects of conjugated linolenic acid isomers against induced biochemical perturbations and aberration in erythrocyte membrane fluidity.

PubMed

Saha, Siddhartha S; Chakraborty, Anirban; Ghosh, Santinath; Ghosh, Mahua

2012-06-01

The purpose of the study was to evaluate hypolipidemic and hypocholesterolemic activities of conjugated linolenic acid (CLnA) isomers, present in bitter gourd and snake gourd seed, in terms of amelioration of plasma lipid profile, lipoprotein oxidation and erythrocyte membrane fluidity after oral administration. Male albino rats were divided into six groups. Group 1 was control, and others were induced with oxidative stress by oral gavage of sodium arsenite (Sa). Group 2 was kept as treated control, and groups 3-6 were further treated with different oral doses of seed oils to maintaining definite concentration of CLnA isomers (0.5 and 1.0% of total lipid for each CLnA isomer). CLnA isomers normalized cholesterol, LDL-cholesterol, HDL-cholesterol and triglyceride contents in plasma and body weight of experimental rats and decreased cholesterol synthesis by reducing hepatic HMG-CoA reductase activity. Administration of Sa caused alteration in erythrocyte membrane fluidity due to increase in cholesterol and decrease in phospholipid content. Tissue cholesterol and lipid contents were also increased by Sa administration. These altered parameters were reversed by experimental oil administration. Protective effect of CLnA isomers on erythrocyte morphology was observed by atomic force microscopy (AFM). Fatty acid composition of erythrocyte membrane showed decrease in polyunsaturated fatty acid (PUFA) and increase in arachidonic acid content after Sa administration, which was normalized with the treatment of these oils. Supplementation of CLnA isomers restored erythrocyte membrane (EM) lipid peroxidation and lipoprotein oxidation. CLnA isomers, present in vegetable oils, showed potent hypolipidemic and hypocholesterolemic activities against biochemical perturbations.

Phosphorylation of Bem2p and Bem3p may contribute to local activation of Cdc42p at bud emergence

PubMed Central

Knaus, Michèle; Pelli-Gulli, Marie-Pierre; van Drogen, Frank; Springer, Sander; Jaquenoud, Malika; Peter, Matthias

2007-01-01

Site-specific activation of the Rho-type GTPase Cdc42p is critical for the establishment of cell polarity. Here we investigated the role and regulation of the GTPase-activating enzymes (GAPs) Bem2p and Bem3p for Cdc42p activation and actin polarization at bud emergence in Saccharomyces cerevisiae. Bem2p and Bem3p are localized throughout the cytoplasm and the cell cortex in unbudded G1 cells, but accumulate at sites of polarization after bud emergence. Inactivation of Bem2p results in hyperactivation of Cdc42p and polarization toward multiple sites. Bem2p and Bem3p are hyperphosphorylated at bud emergence most likely by the Cdc28p-Cln2p kinase. This phosphorylation appears to inhibit their GAP activity in vivo, as non-phosphorylatable Bem3p mutants are hyperactive and interfere with Cdc42p activation. Taken together, our results indicate that Bem2p and Bem3p may function as global inhibitors of Cdc42p activation during G1, and their inactivation by the Cdc28p/Cln kinase contributes to site-specific activation of Cdc42p at bud emergence. PMID:17914457

(E)-N′-(4-Chloro­benzyl­idene)-1-benzofuran-2-carbohydrazide monohydrate

PubMed Central

Fun, Hoong-Kun; Quah, Ching Kheng; Nitinchandra; Kalluraya, Balakrishna; Babu, M.

2012-01-01

The title compound, C16H11ClN2O2·H2O, exists in an E conformation with respect to the N=C bond. The benzofuran ring system forms a dihedral angle of 1.26 (4)° with the benzene ring. In the crystal, mol­ecules are linked via (N,C)—H⋯O bifurcated acceptor hydrogen bonds and (O,O,C)—H⋯O trifurcated acceptor hydrogen bonds, forming layers parallel to the bc plane. PMID:22798835

1-[(6-Chloro-3-pyrid­yl)meth­yl]-5-eth­oxy-8-nitro-1,2,3,5,6,7-hexa­hydro­imidazo[1,2-a]pyridine

PubMed Central

Tian, Zhongzhen; Li, Dongmei; Li, Zhong

2009-01-01

In the title compound, C15H19ClN4O3, an active agrochemical possessing insecticidal activity, the dihedral angle between the mean planes passing through the pyridine ring and the five-membered ring is 87.3 (2)°. The fused pyridine ring adopts a twisted sofa conformation. The mol­ecular structure features close intra­molecular C—H⋯N and C—H⋯O hydrogen bonding. PMID:21577964

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pang, Yuan-Ping, E-mail: pang@mayo.edu

Highlights: • Reducing atomic masses by 10-fold vastly improves sampling in MD simulations. • CLN025 folded in 4 of 10 × 0.5-μs MD simulations when masses were reduced by 10-fold. • CLN025 folded as early as 96.2 ns in 1 of the 4 simulations that captured folding. • CLN025 did not fold in 10 × 0.5-μs MD simulations when standard masses were used. • Low-mass MD simulation is a simple and generic sampling enhancement technique. - Abstract: CLN025 is one of the smallest fast-folding proteins. Until now it has not been reported that CLN025 can autonomously fold to its nativemore » conformation in a classical, all-atom, and isothermal–isobaric molecular dynamics (MD) simulation. This article reports the autonomous and repeated folding of CLN025 from a fully extended backbone conformation to its native conformation in explicit solvent in multiple 500-ns MD simulations at 277 K and 1 atm with the first folding event occurring as early as 66.1 ns. These simulations were accomplished by using AMBER forcefield derivatives with atomic masses reduced by 10-fold on Apple Mac Pros. By contrast, no folding event was observed when the simulations were repeated using the original AMBER forcefields of FF12SB and FF14SB. The results demonstrate that low-mass MD simulation is a simple and generic technique to enhance configurational sampling. This technique may propel autonomous folding of a wide range of miniature proteins in classical, all-atom, and isothermal–isobaric MD simulations performed on commodity computers—an important step forward in quantitative biology.« less

Daughter-Specific Transcription Factors Regulate Cell Size Control in Budding Yeast

PubMed Central

Di Talia, Stefano; Wang, Hongyin; Skotheim, Jan M.; Rosebrock, Adam P.; Futcher, Bruce; Cross, Frederick R.

2009-01-01

In budding yeast, asymmetric cell division yields a larger mother and a smaller daughter cell, which transcribe different genes due to the daughter-specific transcription factors Ace2 and Ash1. Cell size control at the Start checkpoint has long been considered to be a main regulator of the length of the G1 phase of the cell cycle, resulting in longer G1 in the smaller daughter cells. Our recent data confirmed this concept using quantitative time-lapse microscopy. However, it has been proposed that daughter-specific, Ace2-dependent repression of expression of the G1 cyclin CLN3 had a dominant role in delaying daughters in G1. We wanted to reconcile these two divergent perspectives on the origin of long daughter G1 times. We quantified size control using single-cell time-lapse imaging of fluorescently labeled budding yeast, in the presence or absence of the daughter-specific transcriptional regulators Ace2 and Ash1. Ace2 and Ash1 are not required for efficient size control, but they shift the domain of efficient size control to larger cell size, thus increasing cell size requirement for Start in daughters. Microarray and chromatin immunoprecipitation experiments show that Ace2 and Ash1 are direct transcriptional regulators of the G1 cyclin gene CLN3. Quantification of cell size control in cells expressing titrated levels of Cln3 from ectopic promoters, and from cells with mutated Ace2 and Ash1 sites in the CLN3 promoter, showed that regulation of CLN3 expression by Ace2 and Ash1 can account for the differential regulation of Start in response to cell size in mothers and daughters. We show how daughter-specific transcriptional programs can interact with intrinsic cell size control to differentially regulate Start in mother and daughter cells. This work demonstrates mechanistically how asymmetric localization of cell fate determinants results in cell-type-specific regulation of the cell cycle. PMID:19841732

Alterations in striatal dopamine catabolism precede loss of substantia nigra neurons in a mouse model of Juvenile Neuronal Ceroid Lipofuscinosis

PubMed Central

Weimer, Jill M.; Benedict, Jared W.; Elshatory, Yasser M.; Short, Douglas W.; Ramirez-Montealegre, Denia; Ryan, Deborah A.; Alexander, Noreen A.; Federoff, Howard J.; Cooper, Jonathan D.; Pearce, David A.

2016-01-01

Batten disease, or juvenile neuronal ceroid lipofuscinosis (JNCL), results from mutations in the CLN3 gene. This disorder presents clinically around the age of five years with visual deficits progressing to include seizures, cognitive impairment, motor deterioration, hallucinations, and premature death by the third to forth decade of life. The motor deficits include coordination and gait abnormalities, myoclonic jerks, inability to initiate movements, and spasticity. Previous work from our laboratory has identified an early reduction in catechol-O-methyltransferase (COMT), an enzyme responsible for the efficient degradation of dopamine. Alterations in the kinetics of dopamine metabolism could cause the accumulation of undegraded or unsequestered dopamine leading to the formation of toxic dopamine intermediates. We report an imbalance in the catabolism of dopamine in three month Cln3-/- mice persisting through nine months of age that may be causal to oxidative damage within the striatum at nine months of age. Combined with the previously reported inflammatory changes and loss of post-synaptic D1α receptors, this could facilitate cell loss in striatal projection regions and underlie a general locomotion deficit that becomes apparent at twelve months of age in Cln3-/- mice. This study provides evidence for early changes in the kinetics of COMT in the Cln3-/- mouse striatum, affecting the turnover of dopamine, likely leading to neuron loss and motor deficits. These data provide novel insights into the basis of motor deficits in JNCL and how alterations in dopamine catabolism may result in oxidative damage and localized neuronal loss in this disorder. PMID:17617387

N-(2-Chloro­eth­yl)morpholine-4-carbox­amide

PubMed Central

Ujam, Oguejiofo T.; Asegbeloyin, Jonnie N.; Nicholson, Brian K.; Ukoha, Pius O.; Ukwueze, Nkechi N.

2014-01-01

The title compound, C7H13ClN2O2, synthesized by the reaction of 2-chloro­ethyl iso­cyanate and morpholine, crystallizes with four molecules in the asymmetric unit, which have similar conformations and comprise two pairs each related by approximate non-crystallographic inversion centres. Two of them have a modest orientational disorder of the 2-chloro­ethyl fragments [occupancy ratio of 0.778 (4):0.222 (4)]. In the crystal, mol­ecules are linked by N—H⋯O=C hydrogen bonds, forming three crystallographically different kinds of infinite hydrogen-bonded chains extending along [001]. PMID:24826162

6-Chloro-3-phenethyl-2-thioxo-2,3-di­hydro­quinazolin-4(1H)-one

PubMed Central

Hashim, Norhafizah Mohd; Osman, Hasnah; Rahim, Afidah Abdul; Yeap, Chin Sing; Fun, Hoong-Kun

2010-01-01

The asymmetric unit of the title quinazolinone compound, C16H13ClN2OS, consists of two crystallographically independent mol­ecules, A and B. The dihedral angles between the quinazoline and benzene rings are 16.88 (6) and 32.34 (6)° for mol­ecules A and B, respectively. In the crystal structure, mol­ecules A and B are linked by two bifurcated inter­molecular N—H⋯S and C—H⋯S hydrogen bonds. Pairs of mol­ecules are further linked by C—H⋯O and C—H⋯Cl hydrogen bonds into a chain aligned approximately along [110]. PMID:21580754

A novel core-shell lipid nanoparticle for improving oral administration of water soluble chemotherapeutic agents: inhibited intestinal hydrolysis and enhanced lymphatic absorption.

PubMed

Wang, Tao; Shen, Liao; Zhang, Zhen; Li, Haiyan; Huang, Ri; Zhang, Yadan; Quan, Dongqin

2017-11-01

The oral administration of water-soluble chemotherapeutical agents is limited by their serious gastrointestinal side effects, instability at intestinal pH, and poor absorption. Aiming to solve these problems, we chose topotecan (TPT) as a model drug and developed a novel lipid formulation containing core-shell lipid nanoparticle (CLN) that makes the water-soluble drug to 'dissolve' in oil. TPT molecules can be encapsulated into nanoparticles surrounded by oil barrier while avoiding the direct contact with intestinal environment, thus easing the intestinal hydrolytic degradation and gastrointestinal (GI) irritation. Microstructure and mean particle size of TPT-CLN were characterized by Transmission Electron Microscope (TEM) and Dynamic Light Scattering (DLS), respectively. The average size of nanoparticles was approximately 60 nm with a homogeneous distribution in shapes of spheres or ellipsoid. According to in vitro stability studies, more initial form of TPT was observed in presence of lipid nanoparticle compared with free topotecan solution in artificial intestinal juice (pH 6.5). After oral administration of TPT-CLN in rats, AUC and C max of TPT were all increased compared with free TPT, indicating significant enhancement of oral absorption. Intestinal lymphatic transport was confirmed as the major way for CLN to enhance oral absorption of TPT by the treatment of blocking chylomicron flow. Lower GI irritation of TPT-CLN was observed in the gastrointestinal damage studies. The in vivo antitumor activity of TPT-CLN showed an improved antitumor efficacy by oral treatment of TPT-CLN compared to free TPT. From the obtained data, the systems appear an attractive progress in oral administration of topotecan.

Transfected Babesia bovis Expressing a Tick GST as a Live Vector Vaccine

PubMed Central

Oldiges, Daiane P.; Laughery, Jacob M.; Tagliari, Nelson Junior; Leite Filho, Ronaldo Viana; Davis, William C.; da Silva Vaz, Itabajara; Termignoni, Carlos; Knowles, Donald P.; Suarez, Carlos E.

2016-01-01

The Rhipicephalus microplus tick is a notorious blood-feeding ectoparasite of livestock, especially cattle, responsible for massive losses in animal production. It is the main vector for transmission of pathogenic bacteria and parasites, including Babesia bovis, an intraerythrocytic apicomplexan protozoan parasite responsible for bovine Babesiosis. This study describes the development and testing of a live B. bovis vaccine expressing the protective tick antigen glutathione-S-transferase from Haemaphysalis longicornis (HlGST). The B. bovis S74-T3B parasites were electroporated with a plasmid containing the bidirectional Ef-1α (elongation factor 1 alpha) promoter of B. bovis controlling expression of two independent genes, the selectable marker GFP-BSD (green fluorescent protein–blasticidin deaminase), and HlGST fused to the MSA-1 (merozoite surface antigen 1) signal peptide from B. bovis. Electroporation followed by blasticidin selection resulted in the emergence of a mixed B. bovis transfected line (termed HlGST) in in vitro cultures, containing parasites with distinct patterns of insertion of both exogenous genes, either in or outside the Ef-1α locus. A B. bovis clonal line termed HlGST-Cln expressing intracellular GFP and HlGST in the surface of merozoites was then derived from the mixed parasite line HlGST using a fluorescent activated cell sorter. Two independent calf immunization trials were performed via intravenous inoculation of the HlGST-Cln and a previously described control consisting of an irrelevant transfected clonal line of B. bovis designated GFP-Cln. The control GFP-Cln line contains a copy of the GFP-BSD gene inserted into the Ef-1α locus of B. bovis in an identical fashion as the HIGST-Cln parasites. All animals inoculated with the HlGST-Cln and GFP-Cln transfected parasites developed mild babesiosis. Tick egg fertility and fully engorged female tick weight was reduced significantly in R. microplus feeding on HlGST-Cln-immunized calves

Different patterns of supramolecular assembly in constitutionally similar 6-arylimidazo[2,1-b][1,3,4]thiadiazoles.

PubMed

Praveen, Aletti S; Yathirajan, Hemmige S; Kaur, Manpreet; Narayana, Badiadka; Hosten, Eric C; Betz, Richard; Glidewell, Christopher

2014-09-01

Four imidazo[2,1-b][1,3,4]thiadiazoles containing a simply-substituted 6-aryl group have been synthesized by reaction of 2-amino-1,3,4-thiadiazoles with bromoacetylarenes using microwave irradiation and brief reaction times. 6-(2-Chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazole, C(10)H(6)ClN(3)S, (I), 6-(2-chlorophenyl)-2-methylimidazo[2,1-b][1,3,4]thiadiazole, C(11)H(8)ClN(3)S, (II), 6-(3,4-dichlorophenyl)imidazo[2,1-b][1,3,4]thiadiazole, C(10)H(5)Cl(2)N(3)S, (III), and 6-(4-fluoro-3-methoxyphenyl)-2-methylimidazo[2,1-b][1,3,4]thiadiazole, C(12)H(10)FN(3)OS, (IV), crystallize with Z' values of 2, 1, 1 and 2 respectively. The molecular skeletons are all nearly planar and the dihedral angles between the imidazole and aryl rings are 1.51 (8) and 7.28 (8)° in (I), 9.65 (7)° in (II), 10.44 (8)° in (III), and 1.05 (8) and 7.21 (8)° in (IV). The molecules in (I) are linked by three independent C-H...N hydrogen bonds to form ribbons containing alternating R2(2)(8) and R4(4)(18) rings, and these ribbons are linked into a three-dimensional array by three independent π-stacking interactions. Both (II) and (III) contain centrosymmetric dimers formed by π-stacking interactions but hydrogen bonds are absent, and the molecules of (IV) are linked into centrosymmetric R2(2)(8) dimers by C-H...N hydrogen bonds. Comparisons are made with a number of related compounds.

The Climate Literacy Network: Leveraging a Diverse Community to Broaden the Reach of Your Climate Literacy Efforts

NASA Astrophysics Data System (ADS)

Ledley, T. S.; Carley, S.; Niepold, F.; Duggan-Haas, D. A.; Hollweg, K.; McCaffrey, M. S.

2012-12-01

There are a wide range of programs, activities, and projects focused on improving the understanding of climate science by citizens in a multitude of contexts. While most of these are necessarily customized for the particular audiences, communities, or regions they address, they can learn a lot from each other by sharing their experiences, expertise, and materials. The Climate Literacy Network (CLN, http://cleanet.org/cln), established in 2008 to facilitate the implementation of the Climate Literacy Essential Principles of Climate Science, is a diverse group of over 370 stakeholders with a wide range of expertise in, for example, science, policy, media, arts, economics, psychology, education, and social sciences. The CLN meets virtually weekly to share information about ongoing activities and new resources, discuss controversial public issues and ways to address them, get input from this diverse community on directions individual efforts might take, organize climate literacy sessions at professional meetings, provide input on documents relevant to climate literacy, and address common needs of the individual members. The weekly CLN teleconferences are also a venue for presentations from climate change education efforts to extend their reach and potential impact. The teleconferences are supported by an active listserv that is archived on the CLN website along with recordings of past teleconference and the schedule of upcoming teleconferences (http://cleanet.org/clean/community/cln/telecon_schedule.html). In this presentation we will describe the details of these various activities, give examples of how discussions within the CLN has led to funded efforts and expanded partnerships, and identify ways you can participate in and leverage this very active community.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haines, J.L.; Worster, T.; Ter-Minassian, M.

The loci for juvenile (CLN3) and infantile (CLN1) neuronal ceroid lipofuscinosis (NCL) types have been mapped by genetic linkage analysis to chromosome arms 16p and 1p, respectively. The late-infantile defect CLN2 has not yet been mapped, although linkage analysis with tightly linked markers excludes it from both the JNCL and INCL loci. We have initiated a genome-wide search for the LNCL gene, taking advantage of the large collection of highly polymorphic markers that has been developed through the Human Genome Initiative. The high degree of heterozygosity of these markers makes it possible to carry out successful linkage analysis in smallmore » nuclear families, such as found in LNCL. Our current collection of LNCL pedigrees includes 19 US families and 11 Costa Rican families. To date, we have completed typing with over 50 markers on chromosomes 2, 9, 13, and 18-22. The results of this analysis formally exclude about 10% of the human genome as the location of the LNCL gene. 14 refs., 3 tabs.« less

Neuropathological changes in brain cortex and hippocampus in a rat model of Alzheimer's disease.

PubMed

Nobakht, Maliheh; Hoseini, Seyed Mohammad; Mortazavi, Pejman; Sohrabi, Iraj; Esmailzade, Banafshe; Rahbar Rooshandel, Nahid; Omidzahir, Shila

2011-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder with progressive loss of cognitive abilities and memory loss. The aim of this study was to compare neuropathological changes in hippocampus and brain cortex in a rat model of AD. Adult male Albino Wistar rats (weighing 250-300 g) were used for behavioral and histopathological studies. The rats were randomly assigned to three groups: control, sham and Beta amyloid (ABeta) injection. For behavioral analysis, Y-maze and shuttle box were used, respectively at 14 and 16 days post-lesion. For histological studies, Nissl, modified Bielschowsky and modified Congo red staining were performed. The lesion was induced by injection of 4 muL of ABeta (1-40) into the hippocampal fissure. In the present study, ABeta (1-40) injection into hippocampus could decrease the behavioral indexes and the number of CA1 neurons in hippocampus. ABeta injection CA1 caused ABeta deposition in the hippocampus and less than in cortex. We observed the loss of neurons in the hippocampus and cerebral cortex and certain subcortical regions. Y-maze test and single-trial passive avoidance test showed reduced memory retention in AD group. We found a significant decreased acquisition of passive avoidance and alternation behavior responses in AD group compared to control and sham group (P<0.0001). Compacted amyloid cores were present in the cerebral cortex, hippocampus and white matter, whereas, scattered amyloid cores were seen in cortex and hippocampus of AD group. Also, reduced neuronal density was indicated in AD group.

[Vitamin K2 influences several diseases].

PubMed

Hey, Henrik; Brasen, Claus Lohman

2015-08-03

In this paper we discuss the evidence of vitamin K2 deficiency which is a factor in several chronic diseases like diabetes, osteoporosis, cancer, inflammatory and cardiovascular diseases. This deficiency is very common in the mentioned diseases although it is rarely treated by clinicians. Randomized clinical trials have shown that patients with osteoporosis, cardiovascular diseases and cancer can benefit from vitamin K2 supplement. Further studies are needed to ascertain the effect of vitamin K2 supplement in patients with diabetes and inflammatory bowel diseases.

TREM2 Variants in Alzheimer's Disease

PubMed Central

Guerreiro, Rita; Wojtas, Aleksandra; Bras, Jose; Carrasquillo, Minerva; Rogaeva, Ekaterina; Majounie, Elisa; Cruchaga, Carlos; Sassi, Celeste; Kauwe, John S.K.; Younkin, Steven; Hazrati, Lilinaz; Collinge, John; Pocock, Jennifer; Lashley, Tammaryn; Williams, Julie; Lambert, Jean-Charles; Amouyel, Philippe; Goate, Alison; Rademakers, Rosa; Morgan, Kevin; Powell, John; St. George-Hyslop, Peter; Singleton, Andrew; Hardy, John

2013-01-01

BACKGROUND Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P = 0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P = 0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. CONCLUSIONS Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.) PMID:23150934

Patterning of silver nanoparticles on visible light-sensitive Mn-doped lithium niobate photogalvanic crystals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu Xiaoyan; Ohuchi, Fumio; Hatano, Hideki

2011-08-01

Visible light-induced polarization-dependent photochemical deposition of silver nanoparticles (AgNPs) has been demonstrated using Mn-doped congruent LiNbO{sub 3} (CLN) single crystals. Mn-doped CLN has a strong absorption over a wide region of the visible spectrum that allowed effective visible light irradiation for photochemical deposition. The AgNPs deposition on Mn-doped CLN was compared with that on non-doped congruent LiNbO{sub 3}, and together these further confirmed that the photochemical deposition on LiNbO{sub 3} is caused by the strong photogalvanic effect.

2-Amino-5-chloro-pyrimidin-1-ium hydrogen maleate.

PubMed

Fun, Hoong-Kun; Hemamalini, Madhukar; Rajakannan, Venkatachalam

2012-01-01

In the title salt, C(4)H(5)ClN(3) (+)·C(4)H(3)O(4) (-), the 2-amino-5-chloro-pyrimidinium cation is protonated at one of its pyrimidine N atoms. In the roughly planar (r.m.s. deviation = 0.026 Å) hydrogen malate anion, an intra-molecular O-H⋯O hydrogen bond generates an S(7) ring. In the crystal, the protonated N atom and the 2-amino group of the cation are hydrogen bonded to the carboxyl-ate O atoms of the anion via a pair of N-H⋯O hydrogen bonds, forming an R(2) (2)(8) ring motif. The ion pairs are connected via further N-H⋯O hydrogen bonds and a short C-H⋯O inter-action, forming layers lying parallel to the bc plane.

Neuropathological Changes in Brain Cortex and Hippocampus in a Rat Model of Alzheimer’s Disease

PubMed Central

Nobakht, Maliheh; Hoseini, Seyed Mohammad; Mortazavi, Pejman; Sohrabi, Iraj; Esmailzade, Banafshe; Roosh, Nahid Rahbar; Omidzahir, Shila

2011-01-01

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder with progressive loss of cognitive abilities and memory loss. The aim of this study was to compare neuropathological changes in hippocampus and brain cortex in a rat model of AD. Methods: Adult male Albino Wistar rats (weighing 250-300 g) were used for behavioral and histopathological studies. The rats were randomly assigned to three groups: control, sham and β-amyloid (Aβ) injection. For behavioral analysis, Y-maze and shuttle box were used, respectively at 14 and 16 days post-lesion. For histological studies, Nissl, modified Bielschowsky and modified Congo red staining were performed. The lesion was induced by injection of 4 µL of Aβ (1-40) into the hippocampal fissure. Results: In the present study, Aβ (1-40) injection into hippocampus could decrease the behavioral indexes and the number of CA1 neurons in hippocampus. Aβ injection CA1 caused Aβ deposition in the hippocampus and less than in cortex. We observed the loss of neurons in the hippocampus and cerebral cortex and certain subcortical regions. Y-maze test and single-trial passive avoidance test showed reduced memory retention in AD group. Conclusion: We found a significant decreased acquisition of passive avoidance and alternation behavior responses in AD group compared to control and sham group (P<0.0001). Compacted amyloid cores were present in the cerebral cortex, hippocampus and white matter, whereas, scattered amyloid cores were seen in cortex and hippocampus of AD group. Also, reduced neuronal density was indicated in AD group. PMID:21725500

Three Gravitationally Lensed Supernovae Behind Clash Galaxy Clusters

NASA Technical Reports Server (NTRS)

Patel, Brandon; McCully, Curtis; Jha, Saurbh W.; Rodney, Steven A.; Jones, David O.; Graur, Or; Merten, Julian; Zitrin, Adi; Riess, Adam G.; Matheson, Thomas;

ACE2 alterations in kidney disease.

PubMed

Soler, María José; Wysocki, Jan; Batlle, Daniel

2013-11-01

Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that degrades angiotensin (Ang) II to Ang-(1-7). ACE2 is highly expressed within the kidneys, it is largely localized in tubular epithelial cells and less prominently in glomerular epithelial cells and in the renal vasculature. ACE2 activity has been shown to be altered in diabetic kidney disease, hypertensive renal disease and in different models of kidney injury. There is often a dissociation between tubular and glomerular ACE2 expression, particularly in diabetic kidney disease where ACE2 expression is increased at the tubular level but decreased at the glomerular level. In this review, we will discuss alterations in circulating and renal ACE2 recently described in different renal pathologies and disease models as well as their possible significance.

ACE2 alterations in kidney disease

PubMed Central

Soler, María José; Wysocki, Jan; Batlle, Daniel

2013-01-01

Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that degrades angiotensin (Ang) II to Ang-(1–7). ACE2 is highly expressed within the kidneys, it is largely localized in tubular epithelial cells and less prominently in glomerular epithelial cells and in the renal vasculature. ACE2 activity has been shown to be altered in diabetic kidney disease, hypertensive renal disease and in different models of kidney injury. There is often a dissociation between tubular and glomerular ACE2 expression, particularly in diabetic kidney disease where ACE2 expression is increased at the tubular level but decreased at the glomerular level. In this review, we will discuss alterations in circulating and renal ACE2 recently described in different renal pathologies and disease models as well as their possible significance. PMID:23956234

Lysosomal degradation of cholecystokinin-(29-33)-amide in mouse brain is dependent on tripeptidyl peptidase-I: implications for the degradation and storage of peptides in classical late-infantile neuronal ceroid lipofuscinosis.

PubMed Central

Bernardini, Francesca; Warburton, Michael J

2002-01-01

Tripeptidyl peptidase-I (TPP-I) is a lysosomal exopeptidase which removes tripeptides from the N-terminus of small peptides. Mutations in the TPP-I gene result in a lethal neurodegenerative disease, classical late-infantile neuronal ceroid lipofuscinosis (CLN2). This disease is characterized by the accumulation of proteinaceous and autofluorescent material within the lysosomes of neurons, which undergo massive cell death during the course of the disease. The absence of TPP-I may result in the lysosomal accumulation of small peptides and proteins, which eventually compromises lysosomal functions critical to the survival of neurons. To investigate the metabolism of small peptides, we have studied the degradation of cholecystokinin-(29-33)-amide (GWMDF-NH2; cholecystokinin C-terminal pentapeptide) by lysosomal fractions isolated from mouse brain and several other tissues. GWMDF-NH2 is cleaved at only one peptide bond by brain lysosomes, to produce GWM and DF-NH2. Inhibitor studies demonstrate that this reaction is catalysed by TPP-I. In contrast, lysosomal fractions from other mouse tissues additionally cleave a second peptide bond to produce GW and MDF-NH2. Inhibitor studies indicate that this reaction is catalysed by dipeptidyl peptidase-I (DPP-I; cathepsin C). Inhibitors of TPP-I are sufficient to completely block the degradation of GWMDF-NH2 by brain, but inhibitors of both TPP-I and DPP-I are required to completely inhibit the degradation of GWMDF-NH2 by other mouse tissues. Enzyme assays confirm the low activity of DPP-I in brain. An unrelated neuropeptide, neuromedin B, is degraded by a pathway that is partially dependent on TPP-I. These results indicate that TPP-I is required for the partial or complete digestion of certain neuropeptides by brain lysosomes. In the absence of TPP-I, neuropeptides or their degradation products will accumulate in brain lysosomes and may contribute to the pathogenesis of CLN2. Other tissues are spared because they express another

Lysosomal degradation of cholecystokinin-(29-33)-amide in mouse brain is dependent on tripeptidyl peptidase-I: implications for the degradation and storage of peptides in classical late-infantile neuronal ceroid lipofuscinosis.

PubMed

Bernardini, Francesca; Warburton, Michael J

2002-09-01

Tripeptidyl peptidase-I (TPP-I) is a lysosomal exopeptidase which removes tripeptides from the N-terminus of small peptides. Mutations in the TPP-I gene result in a lethal neurodegenerative disease, classical late-infantile neuronal ceroid lipofuscinosis (CLN2). This disease is characterized by the accumulation of proteinaceous and autofluorescent material within the lysosomes of neurons, which undergo massive cell death during the course of the disease. The absence of TPP-I may result in the lysosomal accumulation of small peptides and proteins, which eventually compromises lysosomal functions critical to the survival of neurons. To investigate the metabolism of small peptides, we have studied the degradation of cholecystokinin-(29-33)-amide (GWMDF-NH2; cholecystokinin C-terminal pentapeptide) by lysosomal fractions isolated from mouse brain and several other tissues. GWMDF-NH2 is cleaved at only one peptide bond by brain lysosomes, to produce GWM and DF-NH2. Inhibitor studies demonstrate that this reaction is catalysed by TPP-I. In contrast, lysosomal fractions from other mouse tissues additionally cleave a second peptide bond to produce GW and MDF-NH2. Inhibitor studies indicate that this reaction is catalysed by dipeptidyl peptidase-I (DPP-I; cathepsin C). Inhibitors of TPP-I are sufficient to completely block the degradation of GWMDF-NH2 by brain, but inhibitors of both TPP-I and DPP-I are required to completely inhibit the degradation of GWMDF-NH2 by other mouse tissues. Enzyme assays confirm the low activity of DPP-I in brain. An unrelated neuropeptide, neuromedin B, is degraded by a pathway that is partially dependent on TPP-I. These results indicate that TPP-I is required for the partial or complete digestion of certain neuropeptides by brain lysosomes. In the absence of TPP-I, neuropeptides or their degradation products will accumulate in brain lysosomes and may contribute to the pathogenesis of CLN2. Other tissues are spared because they express another

N-(2-Allyl-4-chloro-2H-indazol-5-yl)-4-meth-oxy-benzene-sulfonamide hemi-hydrate.

PubMed

Chicha, Hakima; Kouakou, Assoman; Rakib, El Mostapha; Saadi, Mohamed; El Ammari, Lahcen

2013-01-01

The fused five- and six-membered rings in the title compound, C17H16ClN3O3S·0.5H2O, are practically coplanar, with the maximum deviation from the mean plane being 0.057 (3) Å for the C atom bound to the exocyclic N atom. The indazole system makes a dihedral angle of 66.18 (12)° with the plane through the benzene ring, and it is nearly perpendicular to the allyl group, as indicated by the N-N-C-C torsion angle of 79.2 (3)°. In the crystal, the water mol-ecule, lying on a twofold axis, forms O-H⋯N and accepts N-H⋯O hydrogen bonds. Additional C-H⋯O hydrogen bonds contribute to the formation of a chain along the b-axis direction.

2-tert-Butylamino-4-chloro-6-ethylamino-1,3,5-triazine: a structure with Z' = 4 containing two different molecular conformations and two independent chains of hydrogen-bonded R(2)2(8) rings.

PubMed

Quesada, Antonio; Fontecha, Maria A; López, Maria V; Low, John N; Glidewell, Christopher

2008-08-01

The title compound (trivial name terbutylazine), C(9)H(16)ClN(5), (I), crystallizes with Z' = 4 in the space group Pca2(1), and equal numbers of molecules adopt two different conformations for the ethylamine groups. The four independent molecules form two approximately enantiomorphic pairs. Eight independent N-H...N hydrogen bonds link the molecules into two independent chains of R(2)(2)(8) rings, in which the arrangement of the alkylamine substituents in the independent molecules precludes any further crystallographic symmetry. The significance of this study lies in its finding of two distinct molecular conformations within the structure and two distinct ways in which the molecules are organized into hydrogen-bonded chains, and in its comparison of the hydrogen-bonded structure of (I) with those of analogous 1,3,5-triazines and pyrimidines.

Characterizing brain structures and remodeling after TBI based on information content, diffusion entropy.

PubMed

Fozouni, Niloufar; Chopp, Michael; Nejad-Davarani, Siamak P; Zhang, Zheng Gang; Lehman, Norman L; Gu, Steven; Ueno, Yuji; Lu, Mei; Ding, Guangliang; Li, Lian; Hu, Jiani; Bagher-Ebadian, Hassan; Hearshen, David; Jiang, Quan

2013-01-01

To overcome the limitations of conventional diffusion tensor magnetic resonance imaging resulting from the assumption of a Gaussian diffusion model for characterizing voxels containing multiple axonal orientations, Shannon's entropy was employed to evaluate white matter structure in human brain and in brain remodeling after traumatic brain injury (TBI) in a rat. Thirteen healthy subjects were investigated using a Q-ball based DTI data sampling scheme. FA and entropy values were measured in white matter bundles, white matter fiber crossing areas, different gray matter (GM) regions and cerebrospinal fluid (CSF). Axonal densities' from the same regions of interest (ROIs) were evaluated in Bielschowsky and Luxol fast blue stained autopsy (n = 30) brain sections by light microscopy. As a case demonstration, a Wistar rat subjected to TBI and treated with bone marrow stromal cells (MSC) 1 week after TBI was employed to illustrate the superior ability of entropy over FA in detecting reorganized crossing axonal bundles as confirmed by histological analysis with Bielschowsky and Luxol fast blue staining. Unlike FA, entropy was less affected by axonal orientation and more affected by axonal density. A significant agreement (r = 0.91) was detected between entropy values from in vivo human brain and histologically measured axonal density from post mortum from the same brain structures. The MSC treated TBI rat demonstrated that the entropy approach is superior to FA in detecting axonal remodeling after injury. Compared with FA, entropy detected new axonal remodeling regions with crossing axons, confirmed with immunohistological staining. Entropy measurement is more effective in distinguishing axonal remodeling after injury, when compared with FA. Entropy is also more sensitive to axonal density than axonal orientation, and thus may provide a more accurate reflection of axonal changes that occur in neurological injury and disease.

Characterizing Brain Structures and Remodeling after TBI Based on Information Content, Diffusion Entropy

PubMed Central

Fozouni, Niloufar; Chopp, Michael; Nejad-Davarani, Siamak P.; Zhang, Zheng Gang; Lehman, Norman L.; Gu, Steven; Ueno, Yuji; Lu, Mei; Ding, Guangliang; Li, Lian; Hu, Jiani; Bagher-Ebadian, Hassan; Hearshen, David; Jiang, Quan

2013-01-01

Background To overcome the limitations of conventional diffusion tensor magnetic resonance imaging resulting from the assumption of a Gaussian diffusion model for characterizing voxels containing multiple axonal orientations, Shannon's entropy was employed to evaluate white matter structure in human brain and in brain remodeling after traumatic brain injury (TBI) in a rat. Methods Thirteen healthy subjects were investigated using a Q-ball based DTI data sampling scheme. FA and entropy values were measured in white matter bundles, white matter fiber crossing areas, different gray matter (GM) regions and cerebrospinal fluid (CSF). Axonal densities' from the same regions of interest (ROIs) were evaluated in Bielschowsky and Luxol fast blue stained autopsy (n = 30) brain sections by light microscopy. As a case demonstration, a Wistar rat subjected to TBI and treated with bone marrow stromal cells (MSC) 1 week after TBI was employed to illustrate the superior ability of entropy over FA in detecting reorganized crossing axonal bundles as confirmed by histological analysis with Bielschowsky and Luxol fast blue staining. Results Unlike FA, entropy was less affected by axonal orientation and more affected by axonal density. A significant agreement (r = 0.91) was detected between entropy values from in vivo human brain and histologically measured axonal density from post mortum from the same brain structures. The MSC treated TBI rat demonstrated that the entropy approach is superior to FA in detecting axonal remodeling after injury. Compared with FA, entropy detected new axonal remodeling regions with crossing axons, confirmed with immunohistological staining. Conclusions Entropy measurement is more effective in distinguishing axonal remodeling after injury, when compared with FA. Entropy is also more sensitive to axonal density than axonal orientation, and thus may provide a more accurate reflection of axonal changes that occur in neurological injury and disease

Supra­molecular inter­actions in 2,6-di­amino-4-chloro­pyrimidin-1-ium 5-chloro­salicylate and bis­(2,6-di­amino-4-chloro­pyrimidin-1-ium) naphthalene-1,5-di­sulfonate

PubMed Central

Swinton Darious, Robert; Thomas Muthiah, Packianathan

2018-01-01

The crystals of two new salts, 2,6-di­amino-4-chloro­pyrimidin-1-ium 5-chloro­salicylate, C4H6ClN4 +·C7H4ClO3 −, (I), and bis­(2,6-di­amino-4-chloro­pyrimidin-1-ium) naphthalene-1,5-di-sulfonate, 2C4H6ClN4 +·C10H6O6S2 2−, (II), have been synthesized and characterized by single-crystal X-ray diffraction. In both compounds, the N atom of the pyrimidine group in between the amino substituents is protonated and the pyrimidinium cation forms a pair of N—H⋯O hydrogen bonds with the carboxyl­ate/sulfonate ion, leading to a robust R 2 2(8) motif (supra­molecular heterosynthon). In compound (I), a self-complementary base pairing involving the other pyrimidinium ring nitro­gen atom and one of the amino groups via a pair of N—H⋯N hydrogen bonds [R 2 2(8) homosynthon] is also present. In compound (II), the crystallographic inversion centre coincides with the inversion centre of the naphthalene-1,5-di­sulfonate ion and all the sulfonate O atoms are hydrogen-bond acceptors, generating fused-ring motifs and a quadruple DDAA array. A halogen-bond (Cl⋯Cl) inter­action is present in (I) with a distance and angle of 3.3505 (12) Å and 151.37 (10)°, respectively. In addition, a C—Cl⋯π inter­action and a π–π inter­action in (I) and a π–π inter­action in (II) further stabilize these crystal structures. PMID:29850062

Outcome of childhood lupus nephritis in Saudi children.

PubMed

Al-Mayouf, Sulaiman Mohammed; AlAmeer, Ali; Alfattani, Areej; Alsonbul, Abdullah

2017-01-01

Our aim in this study is to report the long-term renal outcome of a cohort of Saudi children with systemic lupus erythematosus (SLE). All patients with childhood lupus nephritis (cLN) proved by renal biopsy seen between January 2000 and June 2015 were reviewed. The renal outcome was assessed according to serum creatinine level, protein/creatinine ratio at the last follow-up visit, and/or evidence of renal impairment during follow-up period and end-stage renal disease (ESRD). Additional outcome measures include accrual damage measured by pediatric adaptation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (pSDI), and death related to SLE was determined. A total of 84 (72 females) cLN patients with follow-up duration of 9.3 years (±5.2) were included in this study. The mean current age was 19.4 years (±5.5) and mean age at onset was 9.2 years (±2.4). The most frequent histopathological class was proliferative glomerulonephritis (64.3%) followed by membranous nephritis (27.4%). The mean activity and chronicity indices were 5.9 (±3.9) and 2.9 (±2.2), respectively. Renal microthrombosis was found in 9 (10.7%) patients. All patients treated with immunosuppressive medications; cyclophosphamide used in 64 followed by mycophenolate mofetil in 42, then azathioprine in 19 patients, while rituximab used in 24 patients. At the last follow-up visit, the mean serum creatinine was 147 umol/L (±197) and the mean protein/ creatinine ratio was 0.8 (± 1.1) while the mean total pSDI was 1.9 (±1.9) and mean renal SDI was 0.7 (±1.1). Sixteen (19%) patients had ESRD and eight of them had class IV nephritis. However, there was no significant difference in ESRD by histological class. The overall survival rates were five years: 94% and 10 years: 87%. Infection was the leading cause of mortality. Our patients had severe cLN and required intensive treatment. Despite the survival rate is comparable to other studies, ESRD is more

The structural and spectroscopic investigation of 2-chloro-3-methylquinoline by DFT method and UV-Vis, NMR and vibrational spectral techniques combined with molecular docking analysis

NASA Astrophysics Data System (ADS)

Kose, Etem; Atac, Ahmet; Bardak, Fehmi

2018-07-01

This study comprises the structural and spectroscopic evaluation of a quinoline derivative, 2-chloro-3-methylquinoline (2Cl3MQ), via UV-Vis, 1H and 13C NMR, FT-IR and FT-Raman techniques experimentally, theoretically with DFT and TD-DFT quantum chemical calculations at B3LYP/6-311++G (d, p) level of theory, and investigation of the in silico pharmaceutical potent of 2Cl3MQ in comparison to 2ClnMQ (n = 3,4,7,8,9,10) substituted quinolines. The experimental measurements were recorded as follows; UV-vis spectra were obtained in the range of 200-400 nm in the water and ethanol solvents. 1H and 13C NMR spectra were recorded in CDCl3. Vibrational spectra were obtained in the region of 4000-400 cm-1 and 3500-10 cm-1 for FT-IR and FT-Raman spectra, respectively. Structural and spectroscopic features obtained through theoretical evaluations include: electrostatic features, atomic charges and molecular electrostatic potential surface, the frontier molecular orbital characteristics, the density of states and their overlapping nature, the electronic transition properties, thermodynamical and nonlinear optical characteristics, and predicted UV-Vis, 1H and 13C NMR, FT-IR and FT-Raman spectra. Ligand-enzyme interactions of 2ClnMQ (n = 3,4,7,8,9,10) substituted quinolines with Malate Synthase from Mycobacterium Tuberculosis (MtbMS) were investigated via molecular docking. The role of position of methyl substitution on the inhibitor character of the ligands was discussed on the basis of noncovalent interaction profiles.

The Fire Learning Network: A promising conservation strategy for forestry

Treesearch

Bruce E. Goldstein; William H. Butler; R. Bruce Hull

2010-01-01

Conservation Learning Networks (CLN) are an emerging conservation strategy for addressing complex resource management challenges that face the forestry profession. The US Fire Learning Network (FLN) is a successful example of a CLN that operates on a national scale. Developed in 2001 as a partnership between The Nature Conservancy, the US Forest Service, and land-...

N-(2-Allyl-4-chloro-2H-indazol-5-yl)-4-meth­oxy­benzene­sulfonamide hemi­hydrate

PubMed Central

Chicha, Hakima; Kouakou, Assoman; Rakib, El Mostapha; Saadi, Mohamed; El Ammari, Lahcen

2013-01-01

The fused five- and six-membered rings in the title compound, C17H16ClN3O3S·0.5H2O, are practically coplanar, with the maximum deviation from the mean plane being 0.057 (3) Å for the C atom bound to the exocyclic N atom. The indazole system makes a dihedral angle of 66.18 (12)° with the plane through the benzene ring, and it is nearly perpendicular to the allyl group, as indicated by the N—N—C—C torsion angle of 79.2 (3)°. In the crystal, the water mol­ecule, lying on a twofold axis, forms O—H⋯N and accepts N—H⋯O hydrogen bonds. Additional C—H⋯O hydrogen bonds contribute to the formation of a chain along the b-axis direction. PMID:24109418

Three gravitationally lensed supernovae behind clash galaxy clusters

DOE Office of Scientific and Technical Information (OSTI.GOV)

Patel, Brandon; McCully, Curtis; Jha, Saurabh W.

2014-05-01

We report observations of three gravitationally lensed supernovae (SNe) in the Cluster Lensing And Supernova survey with Hubble (CLASH) Multi-Cycle Treasury program. These objects, SN CLO12Car (z = 1.28), SN CLN12Did (z = 0.85), and SN CLA11Tib (z = 1.14), are located behind three different clusters, MACSJ1720.2+3536 (z = 0.391), RXJ1532.9+3021 (z = 0.345), and A383 (z = 0.187), respectively. Each SN was detected in Hubble Space Telescope optical and infrared images. Based on photometric classification, we find that SNe CLO12Car and CLN12Did are likely to be Type Ia supernovae (SNe Ia), while the classification of SN CLA11Tib is inconclusive.more » Using multi-color light-curve fits to determine a standardized SN Ia luminosity distance, we infer that SN CLO12Car was ∼1.0 ± 0.2 mag brighter than field SNe Ia at a similar redshift and ascribe this to gravitational lens magnification. Similarly, SN CLN12Did is ∼0.2 ± 0.2 mag brighter than field SNe Ia. We derive independent estimates of the predicted magnification from CLASH strong+weak-lensing maps of the clusters (in magnitude units, 2.5 log{sub 10}μ): 0.83 ± 0.16 mag for SN CLO12Car, 0.28 ± 0.08 mag for SN CLN12Did, and 0.43 ± 0.11 mag for SN CLA11Tib. The two SNe Ia provide a new test of the cluster lens model predictions: we find that the magnifications based on the SN Ia brightness and those predicted by the lens maps are consistent. Our results herald the promise of future observations of samples of cluster-lensed SNe Ia (from the ground or space) to help illuminate the dark-matter distribution in clusters of galaxies, through the direct determination of absolute magnifications.« less

Lyso-GM2 ganglioside: a possible biomarker of Tay-Sachs disease and Sandhoff disease.

PubMed

Kodama, Takashi; Togawa, Tadayasu; Tsukimura, Takahiro; Kawashima, Ikuo; Matsuoka, Kazuhiko; Kitakaze, Keisuke; Tsuji, Daisuke; Itoh, Kohji; Ishida, Yo-Ichi; Suzuki, Minoru; Suzuki, Toshihiro; Sakuraba, Hitoshi

2011-01-01

To find a new biomarker of Tay-Sachs disease and Sandhoff disease. The lyso-GM2 ganglioside (lyso-GM2) levels in the brain and plasma in Sandhoff mice were measured by means of high performance liquid chromatography and the effect of a modified hexosaminidase (Hex) B exhibiting Hex A-like activity was examined. Then, the lyso-GM2 concentrations in human plasma samples were determined. The lyso-GM2 levels in the brain and plasma in Sandhoff mice were apparently increased compared with those in wild-type mice, and they decreased on intracerebroventricular administration of the modified Hex B. The lyso-GM2 levels in plasma of patients with Tay-Sachs disease and Sandhoff disease were increased, and the increase in lyso-GM2 was associated with a decrease in Hex A activity. Lyso-GM2 is expected to be a potential biomarker of Tay-Sachs disease and Sandhoff disease.

A multicentre, randomized, single-blind, parallel-group study comparing the efficacy and tolerability of benzoyl peroxide 3%/clindamycin 1% with azelaic acid 20% in the topical treatment of mild-to-moderate acne vulgaris.

PubMed

Schaller, M; Sebastian, M; Ress, C; Seidel, D; Hennig, M

2016-06-01

Mild-to-moderate acne vulgaris is treated with a range of mono- and combination therapies; however, clinical evidence is still required to optimize treatment recommendations. To compare the efficacy, tolerability and safety of a combination of benzoyl peroxide 3% and clindamycin 1% (BPO + CLN) with azelaic acid 20% (AzA) for the topical treatment of mild-to-moderate acne vulgaris. This was a randomized, assessor-blinded, parallel-group, multicentre study conducted in Germany. Patients with a confirmed diagnosis of acne vulgaris, aged 12-45 years, were randomized 1 : 1 to once-daily BPO + CLN gel or twice-daily AzA cream for up to 12 weeks. The primary endpoint was the percentage change in inflammatory lesions from baseline at Week 4. Secondary endpoints included total and inflammatory lesion counts and tolerability assessments. For selected secondary endpoints, inductive statistical analysis was performed post hoc. Patient safety was assessed by adverse event (AE) monitoring. Efficacy was assessed in the modified intent-to-treat (mITT) population [patients using ≥1 dose of study medication (ITT), plus baseline and ≥1 post-baseline lesion count (n = 215)]. There was a statistically significant difference in the primary endpoint, with a median decrease of -52.6% for BPO + CLN (n = 107) vs.-38.8% for AzA (n = 108; P = 0.0004). There was also a greater difference in secondary lesion endpoints at Week 12, with a median decrease in inflammatory lesions of -78.8% and -65.3% and total lesions of -69.0% and -53.9% with BPO + CLN and AzA, respectively (both P < 0.0001). Tolerability was acceptable for both treatments. Overall, 55.6% (BPO + CLN) and 69.7% (AzA) of patients reported treatment-emergent AEs, and 15.7% and 35.8% of patients experienced application site reactions with BPO + CLN (24 events; 17 patients) and AzA (60 events; 39 patients) treatment, respectively (ITT population). BPO + CLN demonstrated greater efficacy than AzA in the treatment of mild

Group 2 innate lymphoid cells in disease

PubMed Central

2016-01-01

Abstract Group 2 innate lymphoid cells (ILC2) are now recognized as an important innate source of type-2 effector cytokines. Although initially associated with mucosal tissues, it is clear that ILC2 are present in diverse anatomical locations. The function of ILC2 at these sites is equally varied, and although ILC2 represent a relatively minor population, they are fundamentally important regulators of innate and adaptive immune processes. As such, there is much interest to understand the role of ILC2 in diseases with a type-2 inflammatory component. This review explores the known roles of ILC2 in disease, and the diseases that show associations or other strong evidence for the involvement of ILC2. PMID:26306498

Lyso-GM2 Ganglioside: A Possible Biomarker of Tay-Sachs Disease and Sandhoff Disease

PubMed Central

Kodama, Takashi; Togawa, Tadayasu; Tsukimura, Takahiro; Kawashima, Ikuo; Matsuoka, Kazuhiko; Kitakaze, Keisuke; Tsuji, Daisuke; Itoh, Kohji; Ishida, Yo-ichi; Suzuki, Minoru; Suzuki, Toshihiro; Sakuraba, Hitoshi

2011-01-01

To find a new biomarker of Tay-Sachs disease and Sandhoff disease. The lyso-GM2 ganglioside (lyso-GM2) levels in the brain and plasma in Sandhoff mice were measured by means of high performance liquid chromatography and the effect of a modified hexosaminidase (Hex) B exhibiting Hex A-like activity was examined. Then, the lyso-GM2 concentrations in human plasma samples were determined. The lyso-GM2 levels in the brain and plasma in Sandhoff mice were apparently increased compared with those in wild-type mice, and they decreased on intracerebroventricular administration of the modified Hex B. The lyso-GM2 levels in plasma of patients with Tay-Sachs disease and Sandhoff disease were increased, and the increase in lyso-GM2 was associated with a decrease in Hex A activity. Lyso-GM2 is expected to be a potential biomarker of Tay-Sachs disease and Sandhoff disease. PMID:22205997

δ-Tocopherol Reduces Lipid Accumulation in Niemann-Pick Type C1 and Wolman Cholesterol Storage Disorders*

PubMed Central

Xu, Miao; Liu, Ke; Swaroop, Manju; Porter, Forbes D.; Sidhu, Rohini; Finkes, Sally; Ory, Daniel S.; Marugan, Juan J.; Xiao, Jingbo; Southall, Noel; Pavan, William J.; Davidson, Cristin; Walkley, Steven U.; Remaley, Alan T.; Baxa, Ulrich; Sun, Wei; McKew, John C.; Austin, Christopher P.; Zheng, Wei

2012-01-01

Niemann-Pick disease type C (NPC) and Wolman disease are two members of a family of storage disorders caused by mutations of genes encoding lysosomal proteins. Deficiency in function of either the NPC1 or NPC2 protein in NPC disease or lysosomal acid lipase in Wolman disease results in defective cellular cholesterol trafficking. Lysosomal accumulation of cholesterol and enlarged lysosomes are shared phenotypic characteristics of both NPC and Wolman cells. Utilizing a phenotypic screen of an approved drug collection, we found that δ-tocopherol effectively reduced lysosomal cholesterol accumulation, decreased lysosomal volume, increased cholesterol efflux, and alleviated pathological phenotypes in both NPC1 and Wolman fibroblasts. Reduction of these abnormalities may be mediated by a δ-tocopherol-induced intracellular Ca2+ response and subsequent enhancement of lysosomal exocytosis. Consistent with a general mechanism for reduction of lysosomal lipid accumulation, we also found that δ-tocopherol reduces pathological phenotypes in patient fibroblasts from other lysosomal storage diseases, including NPC2, Batten (ceroid lipofuscinosis, neuronal 2, CLN2), Fabry, Farber, Niemann-Pick disease type A, Sanfilippo type B (mucopolysaccharidosis type IIIB, MPSIIIB), and Tay-Sachs. Our data suggest that regulated exocytosis may represent a potential therapeutic target for reduction of lysosomal storage in this class of diseases. PMID:23035117

Targeting TRPM2 in ROS-Coupled Diseases.

PubMed

Yamamoto, Shinichiro; Shimizu, Shunichi

2016-09-07

Under pathological conditions such as inflammation and ischemia-reperfusion injury large amounts of reactive oxygen species (ROS) are generated which, in return, contribute to the development and exacerbation of disease. The second member of the transient receptor potential (TRP) melastatin subfamily, TRPM2, is a Ca(2+)-permeable non-selective cation channel, activated by ROS in an ADP-ribose mediated fashion. In other words, TRPM2 functions as a transducer that converts oxidative stress into Ca(2+) signaling. There is good evidence that TRPM2 plays an important role in ROS-coupled diseases. For example, in monocytes the influx of Ca(2+) through TRPM2 activated by ROS contributes to the aggravation of inflammation via chemokine production. In this review, the focus is on TRPM2 as a molecular linker between ROS and Ca(2+) signaling in ROS-coupled diseases.

4-{2-[2-(4-Chloro­benzyl­idene)hydrazinyl­idene]-3,6-dihydro-2H-1,3,4-thia­diazin-5-yl}-3-phenyl­sydnone

PubMed Central

Fun, Hoong-Kun; Loh, Wan-Sin; Nithinchandra; Kalluraya, Balakrishna

2011-01-01

The title compound, C18H13ClN6O2S, exists in trans and cis configurations with respect to the acyclic C=N bonds [C=N = 1.2837 (15) and 1.3000 (14) Å, respectively]. The 3,6-dihydro-2H-1,3,4-thia­diazine ring adopts a half-boat conformation. The sydnone ring is approximately planar [maximum deviation = 0.002 (1) Å] and forms dihedral angles of 50.45 (7) and 61.21 (6)° with the aromatic rings. In the crystal, inter­molecular N—H⋯N, C—H⋯Cl and C—H⋯S hydrogen bonds link the mol­ecules into layers parallel to ab plane. The crystal packing is stabilized by C—H⋯π inter­actions and further consolidated by π–π inter­actions involving the phenyl rings [centroid–centroid distance = 3.6306 (7) Å]. PMID:21754481

2-(3-Chloro­phen­yl)-4,5-dihydro-1H-imidazole

PubMed Central

Kia, Reza; Fun, Hoong-Kun; Kargar, Hadi

2009-01-01

In the title compound, C9H9ClN2, a substituted imidazoline, the six- and five-membered rings are twisted from each other, making a dihedral angle of 17.07 (5)°. In the crystal structure, a short Cl⋯Cl [3.3540 (3) Å] inter­action is observed. Neighbouring mol­ecules are linked together by inter­molecular N—H⋯N hydrogen bonds into a one-dimensional infinite chain along the [101] direction and short Cl⋯Cl contacts link the chains into a three-dimensional network. There is also a significant π-stacking inter­action between the planar sections of the six- and five-membered rings. PMID:21581940

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hellsten, E.; Vesa, J.; Peltonen, L.

Infantile neuronal ceroid lipofuscinosis (INCL, CLN1) is a neurodegenerative disorder in which the biochemical defect is unknown. We earlier assigned the disease locus to chromosome 1p32 in the immediate vicinity of the highly informative HY-TM1 marker by linkage and linkage disequilibrium analysis. Here we report the construction of PFGE maps on the CLN1 region covering a total of 4 Mb of this relatively poorly mapped chromosomal region. We established the order of loci at 1p32 as tel-D1S57-L-myc-HY-TM1-rlf-COL9A2-D1S193-D1S62-D1S211-cen by combining data obtained from analysis of a chromosome 1 somatic cell hybrid panel, PFGE, and interphase FISH. We isolated YACs and constructedmore » two separate YAC contigs, the loci L-myc, HY-TM1, rlf, and COL9A2 being present on a 1000-kb contig and the markers D1S193, D1S62, and D1S211 on a YAC contig spanning a maximum of 860 kb. Within the 1000-kb contig we were able to identify five CpG islands in addition to those associated with the earlier cloned genes. The YAC contigs as well as the physical map provide us with tools for the identification of the INCL gene. 36 refs., 4 figs., 3 tabs.« less

Crystal structure and X-ray photoemission spectroscopic study of A{sub 2}LaMO{sub 6} [A=Ba, Ca; M=Nb, Ta

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dutta, Alo, E-mail: alo_dutta@yahoo.com; Saha, Sujoy; Kumari, Premlata

2015-09-15

The X-ray photoemission spectroscopic (XPS) study of the double perovskite oxides A{sub 2}LaMO{sub 6} [A=Ba, Ca; M=Nb, Ta] synthesized by the solid-state reaction technique has been carried out to investigate the nature of the chemical state of the constituent ions and the bonding between them. The Rietveld refinement of the X-ray diffraction patterns suggests the monoclinic crystal structure of all the materials at room temperature. The negative and positive chemical shifts of the core level XPS spectrum of O-1s and Nb-3d{sub 3/2}/Ta-4f{sub 5/2} respectively suggest the covalent bonding between Nb/Ta cations and O ion. The change of the bonding strengthmore » between the anion and the cations from one material to another has been analyzed. The vibrational property of the materials is investigated using the room temperature Raman spectra. A large covalency of Ta-based compound than Nb compound is confirmed from the relative shifting of the Raman modes of the materials. - Graphical abstract: Crystal structure of two perovskite oxides CLN and CLT is investigated. XPS study confirms the two different co-ordination environments of Ca and covalent bonding between B-site cations and O-ion. - Highlights: • Ordered perovskite structure obtained by Rietveld refinement of XRD patterns. • Study of nature of chemical bonding by X-ray photoemission spectroscopy. • Opposite chemical shift of d-states of Nb/Ta with respect to O. • Covalent bonding between d-states of Nb/Ta and O. • Relative Raman shifts of CLN and CLT substantiate the more covalent character of Ta than Nb.« less

5-Chloro-5''-[4-(di-methyl-amino)-benzyl-idene]-4'-[4-(di-methyl-amino)-phen-yl]-1',1''-di-methyl-dispiro-[indoline-3,2'-pyrrolidine-3',3''-piperidine]-2,4''-dione.

PubMed

Farag, I S Ahmed; Girgis, Adel S; Ramadan, A A; Moustafa, A M; Tiekink, Edward R T

2014-01-01

The title compound, C34H38ClN5O2, has spiro links connecting the pyrrolidine ring and indole residue, as well as the piperidine and pyrrolidine rings. A half-chair conformation is found for the piperidine ring with the C atom connected to the spiro-C atom lying 0.738 (4) Å out of the plane of the remaining five atoms (r.m.s. deviation = 0.0407 Å). The methyl-ene C atom is the flap in the envelope conformation for the pyrrolidine ring. In the crystal, supra-molecular chains are sustained by alternating eight-membered {⋯HNCO}2 and 14-membered {⋯HC5O}2 synthons. Chains are connected into a three-dimensional network by (pyrrolidine-bound phenyl-meth-yl)C-H⋯π(pyrrolidine-bound phen-yl) edge-to-face inter-actions.

Homozygous PPT1 Splice Donor Mutation in a Cane Corso Dog With Neuronal Ceroid Lipofuscinosis.

PubMed

Kolicheski, A; Barnes Heller, H L; Arnold, S; Schnabel, R D; Taylor, J F; Knox, C A; Mhlanga-Mutangadura, T; O'Brien, D P; Johnson, G S; Dreyfus, J; Katz, M L

2017-01-01

A 10-month-old spayed female Cane Corso dog was evaluated after a 2-month history of progressive blindness, ataxia, and lethargy. Neurologic examination abnormalities indicated a multifocal lesion with primarily cerebral and cerebellar signs. Clinical worsening resulted in humane euthanasia. On necropsy, there was marked astrogliosis throughout white matter tracts of the cerebrum, most prominently in the corpus callosum. In the cerebral cortex and midbrain, most neurons contained large amounts of autofluorescent storage material in the perinuclear area of the cells. Cerebellar storage material was present in the Purkinje cells, granular cell layer, and perinuclear regions of neurons in the deep nuclei. Neuronal ceroid lipofuscinosis (NCL) was diagnosed. Whole genome sequencing identified a PPT1c.124 + 1G>A splice donor mutation. This nonreference assembly allele was homozygous in the affected dog, has not previously been reported in dbSNP, and was absent from the whole genome sequences of 45 control dogs and 31 unaffected Cane Corsos. Our findings indicate a novel mutation causing the CLN1 form of NCL in a previously unreported dog breed. A canine model for CLN1 disease could provide an opportunity for therapeutic advancement, benefiting both humans and dogs with this disorder. Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Presence of DQ2.2 Associated with DQ2.5 Increases the Risk for Celiac Disease

PubMed Central

Almeida, Lucas Malta; Gandolfi, Lenora; Pratesi, Riccardo; Uenishi, Rosa Harumi; de Almeida, Fernanda Coutinho; Selleski, Nicole

2016-01-01

Background. Celiac disease (CD) is a genetically determined immune-mediated disorder in which gluten immunogenic peptides are presented to CD4 T cells by HLA-DQ2.5, DQ8, DQ2.2, and their combinations. Our aim is to establish a risk gradient for celiac disease based on HLA-DQ profile in a brazilian representative population and the relevance of DQ2.2 in celiac disease development. Materials and Methods. 237 celiac patients and 237 controls (both groups with 164 females and 73 males) were included. All samples were tested for the presence of predisposing HLA-DQ alleles using the PCR-SSP method. Results were considered significant when p < 0.05. Disease risk was expressed as 1 : N for each HLA-DQ category described at this study. Results. DQ2.5 and/or DQ8 were detected in 224 celiac patients (94.5%) and 84 controls (35.4%). Eight celiac patients (3.4%) and 38 controls (16%) disclosed only DQ2.2. Even though DQ2.2 (β2/β2 or β2/x) showed a low CD risk of 1 : 251 and 1 : 550, respectively, the genotype DQ2.5/DQ2.2 (β2/β2) showed high CD risk of 1 : 10 (p < 0.0001). The disease risk gradient ranged from 1 : 3014 to 1 : 7. Conclusion. Our study allowed the determination of a risk gradient for celiac disease development in at-risk population, showing that DQ2.2 variant was relevant when associated with DQ2.5. PMID:28042478

7-Chloro-5-(2-ethoxy­phen­yl)-1-methyl-3-propyl-2,6-dihydro-1H-pyrazolo[4,3-d]pyrimidine

PubMed Central

Zhou, Ming-Qiu; Zhu, Kai; Lv, Xiao-Ping; Han, Ping-Fang; Wei, Ping

2009-01-01

In the title compound, C17H21ClN4O, the benzene ring is oriented at dihedral angles of 1.59 (3) and 1.27 (3)° with respect to the pyrimidine and pyrazole rings, while the dihedral angle between the pyrimidine and pyrazole rings is 0.83 (3)°. An intra­molecular N—H⋯O hydrogen bond results in the formation of a planar (r.m.s. deviation 0.004 Å) six-membered ring. PMID:21577789

Uncoupling Protein 2 and Metabolic Diseases

PubMed Central

Sreedhar, Annapoorna; Zhao, Yunfeng

2017-01-01

Mitochondria are fascinating organelles involved in various cellular-metabolic activities that are integral for mammalian development. Although they perform diverse, yet interconnected functions, mitochondria are remarkably regulated by complex signaling networks. Therefore, it is not surprising that mitochondrial dysfunction is involved in plethora of diseases, including neurodegenerative and metabolic disorders. One of the many factors that lead to mitochondrial-associated metabolic diseases is the uncoupling protein-2, a family of mitochondrial anion proteins present in the inner mitochondrial membrane. Since their discovery, uncoupling proteins have attracted considerable attention due to their involvement in mitochondrial-mediated oxidative stress and energy metabolism. This review attempts to provide a summary of recent developments in the field of uncoupling protein 2 relating to mitochondrial associated metabolic diseases. PMID:28351676

A lysosomal pepstatin-insensitive proteinase as a novel biomarker for breast carcinoma.

PubMed

Junaid, M A; Clark, G M; Pullarkat, R K

2000-01-01

Lysosomal proteinases play an important role in the turnover of intracellular proteins, and acidic proteinases such as cathepsin D are known to be increased in breast carcinoma. In the present study the activity of a newly discovered acidic lysosomal pepstatin-insensitive proteinase (CLN2p) was measured in breast tissues by the most sensitive and highly specific assay that we had developed for the diagnosis of late-infantile neuronal ceroid lipofuscinosis (LINCL) (2). Samples from eight normal subjects undergoing reductive mammoplasty and 200 patients with primary breast carcinoma were analyzed. The results suggest a two- to seventeen-fold higher CLN2p activity in tumors, which was significantly and positively correlated with already known breast cancer biomarkers such as levels of cathepsin D, estrogen receptor and progesterone receptor. These results suggest a diagnostic and prognostic potential for this novel acid proteinase in breast cancer.

Gemfibrozil and Fenofibrate, Food and Drug Administration-approved Lipid-lowering Drugs, Up-regulate Tripeptidyl-peptidase 1 in Brain Cells via Peroxisome Proliferator-activated Receptor α

PubMed Central

Ghosh, Arunava; Corbett, Grant T.; Gonzalez, Frank J.; Pahan, Kalipada

2012-01-01

The classical late infantile neuronal ceroid lipofuscinosis (LINCLs) is an autosomal recessive disease, where the defective gene is Cln2, encoding tripeptidyl-peptidase I (TPP1). At the molecular level, LINCL is caused by accumulation of autofluorescent storage materials in neurons and other cell types. Currently, there is no established treatment for this fatal disease. This study reveals a novel use of gemfibrozil and fenofibrate, Food and Drug Administration-approved lipid-lowering drugs, in up-regulating TPP1 in brain cells. Both gemfibrozil and fenofibrate up-regulated mRNA, protein, and enzymatic activity of TPP1 in primary mouse neurons and astrocytes as well as human astrocytes and neuronal cells. Because gemfibrozil and fenofibrate are known to activate peroxisome proliferator-activated receptor-α (PPARα), the role of PPARα in gemfibrozil- and fenofibrate-mediated up-regulation of TPP1 was investigated revealing that both drugs up-regulated TPP1 mRNA, protein, and enzymatic activity both in vitro and in vivo in wild type (WT) and PPARβ−/−, but not PPARα−/−, mice. In an attempt to delineate the mechanism of TPP1 up-regulation, it was found that the effects of the fibrate drugs were abrogated in the absence of retinoid X receptor-α (RXRα), a molecule known to form a heterodimer with PPARα. Accordingly, all-trans-retinoic acid, alone or together with gemfibrozil, up-regulated TPP1. Co-immunoprecipitation and ChIP studies revealed the formation of a PPARα/RXRα heterodimer and binding of the heterodimer to an RXR-binding site on the Cln2 promoter. Together, this study demonstrates a unique mechanism for the up-regulation of TPP1 by fibrate drugs via PPARα/RXRα pathway. PMID:22989886

Guidelines for incorporating scientific knowledge and practice on rare diseases into higher education: neuronal ceroid lipofuscinoses as a model disorder.

PubMed

Cismondi, Inés Adriana; Kohan, Romina; Adams, Heather; Bond, Mike; Brown, Rachel; Cooper, Jonathan D; de Hidalgo, Perla K; Holthaus, Sophia-Martha Kleine; Mole, Sara E; Mugnaini, Julia; de Ramirez, Ana María Oller; Pesaola, Favio; Rautenberg, Gisela; Platt, Frances M; Noher de Halac, Inés

2015-10-01

This article addresses the educational issues associated with rare diseases (RD) and in particular the Neuronal Ceroid Lipofuscinoses (NCLs, or CLN diseases) in the curricula of Health Sciences and Professional's Training Programs. Our aim is to develop guidelines for improving scientific knowledge and practice in higher education and continuous learning programs. Rare diseases (RD) are collectively common in the general population with 1 in 17 people affected by a RD in their lifetime. Inherited defects in genes involved in metabolism are the commonest group of RD with over 8000 known inborn errors of metabolism. The majority of these diseases are neurodegenerative including the NCLs. Any professional training program on NCL must take into account the medical, social and economic burdens related to RDs. To address these challenges and find solutions to them it is necessary that individuals in the government and administrative authorities, academia, teaching hospitals and medical schools, the pharmaceutical industry, investment community and patient advocacy groups all work together to achieve these goals. The logistical issues of including RD lectures in university curricula and in continuing medical education should reflect its complex nature. To evaluate the state of education in the RD field, a summary should be periodically up dated in order to assess the progress achieved in each country that signed up to the international conventions addressing RD issues in society. It is anticipated that auditing current practice will lead to higher standards and provide a framework for those educators involved in establishing RD teaching programs world-wide. Copyright © 2015 Elsevier B.V. All rights reserved.

Porcine circovirus type 2 (PCV2) enteric disease: an independent condition or part of the systemic disease?

PubMed

Baró, J; Segalés, J; Martínez, J

2015-03-23

Intestinal disorders in growing and finishing pigs have been associated with several infectious agents, including Porcine circovirus type 2 (PCV2). This virus has been mainly related with PCV2-systemic disease (PCV2-SD); nevertheless, some authors have suggested a possible restricted intestinal infection of this virus associated with enteric clinical signs. This condition has been referred as PCV2-enteric disease (PCV2-ED). The present study analysed retrospectively, from a pathological point of view, the relation between intestinal disorders and PCV2 infection in nursery and growing-finishing pigs. Among the 96 selected pigs suffering from enteric disease and submitted for necropsy between 1998 and 2011, the most prevalent enteric lesions were catarrhal enteritis/colitis (77.1%), followed by fibrinous lesions (11.5%), granulomatous inflammation (4.2%) and other lesions such as haemorrhages or ulceration (4.2%). Seventy-two pigs (75%) were positive for PCV2 by in situ hybridization (ISH). Among positive pigs for PCV2 ISH, 39 animals suffered from PCV2-SD and 33 had no lymphoid lesions but low amount of viral nucleic acid in several lymphoid tissues, therefore, these animals did not qualify for PCVD-ED. In conclusion, all animals with enteric disorders that were positive to PCV2 by ISH had evidence of viral systemic infection. These results suggest that PCV2-ED is probably a negligible condition and PCV2 mainly contributes to enteric clinical disorders in relation to PCV2-SD occurrence. Copyright © 2015 Elsevier B.V. All rights reserved.

Synthesis and structural study of 4-(2-chlorophenyl)-2-ethoxy-5,6,7,8,9,10-hexahydrocycloocta[B]pyridine-3-carbonitrile

NASA Astrophysics Data System (ADS)

Fathima, K. Saiadali; Vasumathi, M.; Anitha, K.

2016-05-01

The novel organic material C20H21ClN2O was synthesized by One-Pot synthesis method and the single crystals were grown by slow evaporation solution growth technique. The crystal structure was elucidated by subjecting the grown crystals to the single crystal x-ray diffraction analysis and was refined by full matrix least-squares method to R=0.039 for 2746 reflections. Crystal system of the grown crystal was found to be monoclinic with the space group P21/a and a=9.196(4) Å, b=13.449(4) Å, c=14.818(4) Å, β= 101.542(3)°, V=1795.6(11) Å3 and Z=4. In this crystal structure, cyclooctanone prefers to reside in a chair-boat conformation. The structure is stabilized by attractive molecular force such as CH/π interaction called hydrophobic interaction.

Synthetic Approaches to (smif)2Ti (smif = 1,3-di-(2-pyridyl)-2-azaallyl) Reveal Redox Non-Innocence and C-C Bond-Formation

PubMed Central

Frazier, Brenda A.; Wolczanski, Peter T.; Keresztes, Ivan; DeBeer, Serena; Lobkovsky, Emil B.; Pierpont, Aaron W.; Cundari, Thomas R.

2012-01-01

Attempted syntheses of (smif)2Ti (smif = 1,3-di-(2-pyridyl)-2-azaallyl) based on metatheses of TiClnLm (n = 2–4) with M(smif) (M = Li, Na), in the presence of a reducing agent (Na/Hg) when necessary, failed, but several apparent Ti(II) species were identified by X-ray crystallography and multidimensional NMR spectroscopy: (smif){Li(smif-smif)}Ti (1, X-ray), [(smif)Ti]2(μ-κ3,κ3-N,N(py)2-smif,smif) (2), (smif)Ti(κ3-N,N(py)2-smif,(smif)H) (3), and (smif)Ti(dpma) (4). NMR spectroscopy and K-edge XAS showed that each compound possesses ligands that are redox non-innnocent, such that d1 Ti(III) centers AF-couple to ligand radicals: (smif){Li(smif-smif)2−}TiIII (1), [(smif2−)TiIII]2(μ-κ3,κ3-N,N(py)2-smif,smif) (2), [(smif2−)TiIII](κ3-N,N(py)2-smif,(smif)H) (3), and (smif2−)TiIII(dpma) (4). The instability of the (smif)2Ti relative to its C-C coupled dimer, 2, is rationalized via the complementary nature of the amide and smif radical anion ligands, which are also common to 3 and 4. Calculations support this contention. PMID:22830452

GATA2 Deficiency and Epstein-Barr Virus Disease.

PubMed

Cohen, Jeffrey I

2017-01-01

GATA2 is a transcription factor that binds to the promoter of hematopoietic genes. Mutations in one copy of the gene are associated with haploinsufficiency and reduced levels of protein. This results in reduced numbers of several cell types important for immune surveillance including dendritic cells, monocytes, CD4, and NK cells, as well as impaired NK cell function. Recently, GATA2 has been associated with several different presentations of severe Epstein-Barr virus (EBV) disease including primary infection requiring repeated hospitalizations, chronic active EBV disease, EBV-associated hydroa vacciniforme with hemophagocytosis, and EBV-positive smooth muscle tumors. EBV was found predominantly in B cells in each of the cases in which it was studied, unlike most cases of chronic active EBV disease in which the virus is usually present in T or NK cells. The variety of EBV-associated diseases seen in patients with GATA2 deficiency suggest that additional forms of severe EBV disease may be found in patients with GATA2 deficiency in the future.

Chemical Complexity in Local Diffuse and Translucent Clouds: Ubiquitous Linear C3H and CH3CN, a Detection of HC3N and an Upper Limit on the Abundance of CH2CN

NASA Astrophysics Data System (ADS)

Liszt, Harvey; Gerin, Maryvonne; Beasley, Anthony; Pety, Jerome

2018-04-01

We present Jansky Very Large Array observations of 20–37 GHz absorption lines from nearby Galactic diffuse molecular gas seen against four cosmologically distant compact radio continuum sources. The main new observational results are that l-C3H and CH3CN are ubiqitous in the local diffuse molecular interstellar medium at {\\text{}}{A}{{V}} ≲ 1, while HC3N was seen only toward B0415 at {\\text{}}{A}{{V}} > 4 mag. The linear/cyclic ratio is much larger in C3H than in C3H2 and the ratio CH3CN/HCN is enhanced compared to TMC-1, although not as much as toward the Horsehead Nebula. More consequentially, this work completes a long-term program assessing the abundances of small hydrocarbons (CH, C2H, linear and cyclic C3H and C3 {{{H}}}2, and C4H and C4H‑) and the CN-bearing species (CN, HCN, HNC, HC3N, HC5N, and CH3CN): their systematics in diffuse molecular gas are presented in detail here. We also observed but did not strongly constrain the abundances of a few oxygen-bearing species, most prominently HNCO. We set limits on the column density of CH2CN, such that the anion CH2CN‑ is only viable as a carrier of diffuse interstellar bands if the N(CH2CN)/N(CH2CN‑) abundance ratio is much smaller in this species than in any others for which the anion has been observed. We argue that complex organic molecules (COMS) are not present in clouds meeting a reasonable definition of diffuse molecular gas, i.e., {\\text{}}{A}{{V}} ≲ 1 mag. Based on observations obtained with the NRAO Jansky Very Large Array (VLA).

mNos2 deletion and human NOS2 replacement in Alzheimer disease models.

PubMed

Colton, Carol A; Wilson, Joan G; Everhart, Angela; Wilcock, Donna M; Puoliväli, Jukka; Heikkinen, Taneli; Oksman, Juho; Jääskeläinen, Olli; Lehtimäki, Kimmo; Laitinen, Teemu; Vartiainen, Nina; Vitek, Michael P

2014-08-01

Understanding the pathophysiologic mechanisms underlying Alzheimer disease relies on knowledge of disease onset and the sequence of development of brain pathologies. We present a comprehensive analysis of early and progressive changes in a mouse model that demonstrates a full spectrum of characteristic Alzheimer disease-like pathologies. This model demonstrates an altered immune redox state reminiscent of the human disease and capitalizes on data indicating critical differences between human and mouse immune responses, particularly in nitric oxide levels produced by immune activation of the NOS2 gene. Using the APPSwDI(+)/(+)mNos2(-/-) (CVN-AD) mouse strain, we show a sequence of pathologic events leading to neurodegeneration,which include pathologically hyperphosphorylated tau in the perforant pathway at 6 weeks of age progressing to insoluble tau, early appearance of β-amyloid peptides in perivascular deposits around blood vessels in brain regions known to be vulnerable to Alzheimer disease, and progression to damage and overt loss in select vulnerable neuronal populations in these regions. The role of species differences between hNOS2 and mNos2 was supported by generating mice in which the human NOS2 gene replaced mNos2. When crossed with CVN-AD mice, pathologic characteristics of this new strain (APPSwDI(+)/(-)/HuNOS2(tg+)/(+)/mNos2(-/-)) mimicked the pathologic phenotypes found in the CVN-AD strain.

TRPM2, calcium and neurodegenerative diseases

PubMed Central

Xie, Yu-Feng; MacDonald, John F; Jackson, Michael F

2010-01-01

NMDA receptor overactivation triggers intracellular Ca2+ dysregulation, which has long been thought to be critical for initiating excitotoxic cell death cascades associated with stroke and neurodegenerative disease. The inability of NMDA receptor antagonists to afford neuroprotection in clinical stroke trials has led to a re-evaluation of excitotoxic models of cell death and has focused research efforts towards identifying additional Ca2+ influx pathways. Recent studies indicate that TRPM2, a member of the TRPM subfamily of Ca2+-permeant, non-selective cation channel, plays an important role in mediating cellular responses to a wide range of stimuli that, under certain situations, can induce cell death. These include reactive oxygen and nitrogen species, tumour necrosis factor as well as soluble oli-gomers of amyloid beta. However, the molecular basis of TRPM2 channel involvement in these processes is not fully understood. In this review, we summarize recent studies about the regulation of TRPM2, its interaction with calcium and the possible implications for neurodegenerative diseases. PMID:21383889

Survival of macrovascular disease, chronic kidney disease, chronic respiratory disease, cancer and smoking in patients with type 2 diabetes: BioBank Japan cohort.

PubMed

Yokomichi, Hiroshi; Nagai, Akiko; Hirata, Makoto; Kiyohara, Yutaka; Muto, Kaori; Ninomiya, Toshiharu; Matsuda, Koichi; Kamatani, Yoichiro; Tamakoshi, Akiko; Kubo, Michiaki; Nakamura, Yusuke; Yamagata, Zentaro

2017-03-01

The number of patients with diabetes is increasing worldwide. Macrovascular disease, chronic kidney disease, chronic respiratory disease, cancer and smoking frequently accompany type 2 diabetes. Few data are available related to mortality of Asians with diabetes associated with these serious comorbidities. The present study aimed to quantify the excess mortality risks of type 2 diabetic patients with comorbidities. We analysed the available records of 30,834 Japanese patients with type 2 diabetes from the BioBank Japan Project between 2003 and 2007. Men and women were followed up for median 8.03 and 8.30 years, respectively. We applied Cox proportional hazard model and Kaplan-Meier estimates for survival curves to evaluate mortality in diabetic patients with or without macrovascular disease, chronic respiratory disease, chronic kidney disease, cancer and smoking. Adjusted hazard ratios (HRs) for mortality were 1.39 (95% CI, 1.09-1.78) for male sex, 2.01 (95% CI, 1.78-2.26) per 10-year increment of age. Adjusted HRs of primary interest were 1.77 (95% CI, 1.42-2.22), macrovascular disease; 1.58 (95% CI, 1.08-2.31), chronic respiratory disease; 2.03 (95% CI, 1.67-2.47), chronic kidney disease; 1.16 (95% CI, 0.86-1.56), cancer; and 1.74 (95% CI, 1.30-2.31), current smoking. Diabetic patients with a past or current history of chronic kidney, macrovascular or respiratory diseases or smoking habit have exhibited the highest risk of mortality. Data were limited to those of survivors of comorbidities but we propose the need to improve comorbidities and terminate cigarette smoking for better prognosis in patients with diabetes. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Leptin, cardiovascular diseases and type 2 diabetes mellitus.

PubMed

Katsiki, Niki; Mikhailidis, Dimitri P; Banach, Maciej

2018-06-07

Leptin, an adipokine that is implicated in the control of food intake via appetite suppression, may also stimulate oxidative stress, inflammation, thrombosis, arterial stiffness, angiogenesis and atherogenesis. These leptin-induced effects may predispose to the development of cardiovascular diseases. In the present review we discuss the evidence linking leptin levels with the presence, severity and/or prognosis of both coronary artery disease and non-cardiac vascular diseases such as stroke, carotid artery disease, peripheral artery disease (PAD) and abdominal aortic aneurysms (AAA) as well as with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). Leptin levels have been positively associated with the presence, severity, extent and lesion complexity of coronary atherosclerosis as well as with the presence, severity and poor clinical outcomes of both ischemic and hemorrhagic strokes. But conflicting results also exist. Furthermore, leptin was reported to independently predict common carotid intima-media thickness and carotid plaque instability. A link between hyperleptinemia and PAD has been reported, whereas limited data were available on the potential association between leptin and AAA. Elevated leptin concentrations have also been related to CKD incidence and progression as well as with insulin resistance, T2DM, micro- and macrovascular diabetic complications. Statins and antidiabetic drugs (including sitagliptin, metformin, pioglitazone, liraglutide and empagliflozin) may affect leptin levels. Further research is needed to establish the potential use (if any) of leptin as a therapeutic target in these diseases.

Ethyl 2-{N-[N-(4-chloro-6-methoxy­pyrimidin-2-yl)carbamo­yl]sulfamo­yl}benzoate

PubMed Central

Lu, Chui; Li, Fang-Shi; Yu, Da-Sheng; Yao, Wei; Liu, Yin-Hong

2008-01-01

The asymmetric unit of the title compound, C15H15ClN4O6S, contains two independent mol­ecules, in which the pyrimidine and benzene rings are oriented at dihedral angles of 75.21 (3) and 86.00 (3)°. Intra­molecular N—H⋯N and C—H⋯O hydrogen bonds result in the formation of two five- and two six-membered rings. The six-membered rings have flattened-boat conformations, while the five-membered rings adopt envelope conformations. In the crystal structure, inter­molecular N—H⋯O hydrogen bonds link the mol­ecules. PMID:21202882

The linear interplay of intrinsic and extrinsic noises ensures a high accuracy of cell fate selection in budding yeast

PubMed Central

Li, Yongkai; Yi, Ming; Zou, Xiufen

2014-01-01

To gain insights into the mechanisms of cell fate decision in a noisy environment, the effects of intrinsic and extrinsic noises on cell fate are explored at the single cell level. Specifically, we theoretically define the impulse of Cln1/2 as an indication of cell fates. The strong dependence between the impulse of Cln1/2 and cell fates is exhibited. Based on the simulation results, we illustrate that increasing intrinsic fluctuations causes the parallel shift of the separation ratio of Whi5P but that increasing extrinsic fluctuations leads to the mixture of different cell fates. Our quantitative study also suggests that the strengths of intrinsic and extrinsic noises around an approximate linear model can ensure a high accuracy of cell fate selection. Furthermore, this study demonstrates that the selection of cell fates is an entropy-decreasing process. In addition, we reveal that cell fates are significantly correlated with the range of entropy decreases. PMID:25042292

Nrf2 Is an Attractive Therapeutic Target for Retinal Diseases

PubMed Central

2016-01-01

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes encoding many antioxidant enzymes and phase II detoxifying enzymes. Activation of Nrf2 functions is one of the critical defensive mechanisms against oxidative stress in many species. The retina is constantly exposed to reactive oxygen species, and oxidative stress is a major contributor to age-related macular diseases. Moreover, the resulting inflammation and neuronal degeneration are also related to other retinal diseases. The well-known Nrf2 activators, bardoxolone methyl and its derivatives, have been the subject of a number of clinical trials, including those aimed at treating chronic kidney disease, pulmonary arterial hypertension, and mitochondrial myopathies. Recent studies suggest that Nrf2 activation protects the retina from retinal diseases. In particular, this is supported by the finding that Nrf2 knockout mice display age-related retinal degeneration. Moreover, the concept has been validated by the efficacy of Nrf2 activators in a number of retinal pathological models. We have also recently succeeded in generating a novel Nrf2 activator, RS9, using a biotransformation technique. This review discusses current links between retinal diseases and Nrf2 and the possibility of treating retinal diseases by activating the Nrf2 signaling pathway. PMID:27818722

[Porcine circovirus type 2 and PCV2-systemic disease--a review].

PubMed

Gu, Jinyan; Xing, Gang; Lei, Jing; Liu, Fei; Zhou, Jiyong

2015-06-01

Porcine circovirus type 2 (PCV2) can cause immunosuppression on herds. PCV2, as an essential pathogen of PCV2-systemic disease (PCV2-SD), has caused considerable economic losses in pig industry worldwide. Here we review and address the evolution, viral protein and immunolesion of PCV2 and preventive techniques of PCV2-SD.

The value of metaphorical reasoning in bioethics: An empirical-ethical study.

PubMed

Olsman, Erik; Veneberg, Bert; van Alfen, Claudia; Touwen, Dorothea

2017-01-01

Metaphors are often used within the context of ethics and healthcare but have hardly been explored in relation to moral reasoning. To describe a central set of metaphors in one case and to explore their contribution to moral reasoning. Semi-structured interviews were conducted with 16 parents of a child suffering from the neurodegenerative disease CLN3. The interviews were recorded, transcribed, and metaphors were analyzed. The researchers wrote memos and discussed about their analyses until they reached consensus. Ethical considerations: Participants gave oral and written consent and their confidentiality and anonymity were respected. A central set of metaphors referred to the semantic field of the hands and arms and consisted of two central metaphors that existed in a dialectical relationship: grasping versus letting go. Participants used these metaphors to describe their child's experiences, who had to "let go" of abilities, while "clinging" to structures and the relationship with their parent(s). They also used it to describe their own experiences: participants tried to "grab" the good moments with their child and had to "let go" of their child when (s)he approached death. Participants, in addition, "held" onto caring for their child while being confronted with the necessity to "let go" of this care, leaving it to professional caregivers. The ethical analysis of the findings shows that thinking in terms of the dialectical relationship between "grasping" and "letting go" helps professional caregivers to critically think about images of good care for children with CLN3. It also helps them to bear witness to the vulnerable, dependent, and embodied nature of the moral self of children with CLN3 and their parents. Metaphorical reasoning may support the inclusion of marginalized perspectives in moral reasoning. Future studies should further explore the contribution of metaphorical reasoning to moral reasoning in other cases.

Crystal structure of 6-chloro-5-iso-propyl-pyrimidine-2,4(1H,3H)-dione.

PubMed

Haress, Nadia G; Ghabbour, Hazem A; El-Emam, Ali A; Chidan Kumar, C S; Fun, Hoong-Kun

2014-11-01

In the mol-ecule of the title compound, C7H9ClN2O2, the conformation is determined by intra-molecular C-H⋯O and C-H⋯Cl hydrogen bonds, which generate S(6) and S(5) ring motifs. The isopropyl group is almost perpendicular to the pyrimidine ring with torsion angles of -70.8 (3) and 56.0 (3)°. In the crystal, two inversion-related mol-ecules are linked via a pair of N-H⋯O hydrogen bonds into R 2 (2)(8) dimers; these dimers are connected into chains extending along the bc plane via an additional N-H⋯O hydrogen bond and weaker C-H⋯O hydrogen bonds. The crystal structure is further stabilized by a weak π-π inter-action [3.6465 (10) Å] between adjacent pyrimidine-dione rings arranged in a head-to-tail fashion, producing a three-dimensional network.

Cyclooxygenase-2 polymorphisms in Parkinson's disease.

PubMed

Håkansson, Anna; Bergman, Olle; Chrapkowska, Cecilia; Westberg, Lars; Belin, Andrea Carmine; Sydow, Olof; Johnels, Bo; Olson, Lars; Holmberg, Björn; Nissbrandt, Hans

2007-04-05

Accumulating evidence indicate that cyclooxygenase-2 (COX-2) is of pathophysiological importance for the neurodegeneration in Parkinson's disease (PD). For example, in a large epidemiological study, use of NSAIDs was associated with a lower risk of PD. Genetic variants of the COX-2 gene might therefore influence the risk of developing the disease. The genotype distribution of four common single nucleotide polymorphisms (SNPs) in the COX-2 gene (rs689466:A496G, rs20417:G926C, rs5277:G3050C, rs5275:C8473T) was analyzed in PD patients and control subjects in a Swedish population. No differences could be seen between the PD-patient and controls regarding the A496G, G926C, and G3050C SNPs, but the allele frequency of the C8473T SNP was found to differ when male patients were compared to controls (P = 0.007). In females no difference could be seen between PD-patients and controls. In conclusion, the results suggest a possible influence of the COX-2 C8473T SNP in PD, although it only seems to be of importance in men. (c) 2006 Wiley-Liss, Inc.

Connecting Ca2+ and lysosomes to Parkinson disease

PubMed Central

Kilpatrick, Bethan S.

2017-01-01

The neurodegenerative movement disorder Parkinson disease (PD) is prevalent in the aged population. However, the underlying mechanisms that trigger disease are unclear. Increasing work implicates both impaired Ca2+ signalling and lysosomal dysfunction in neuronal demise. Here I aim to connect these distinct processes by exploring the evidence that lysosomal Ca2+ signalling is disrupted in PD. In particular, I highlight defects in lysosomal Ca2+ content and signalling through NAADP-regulated two-pore channels in patient fibroblasts harbouring mutations in the PD-linked genes, GBA1 and LRRK2. As an emerging contributor to PD pathogenesis, the lysosomal Ca2+ signalling apparatus could represent a novel therapeutic target. PMID:28529829

SeqSIMLA2_exact: simulate multiple disease sites in large pedigrees with given disease status for diseases with low prevalence.

PubMed

Yao, Po-Ju; Chung, Ren-Hua

2016-02-15

It is difficult for current simulation tools to simulate sequence data in a pre-specified pedigree structure and pre-specified affection status. Previously, we developed a flexible tool, SeqSIMLA2, for simulating sequence data in either unrelated case-control or family samples with different disease and quantitative trait models. Here we extended the tool to efficiently simulate sequences with multiple disease sites in large pedigrees with a given disease status for each pedigree member, assuming that the disease prevalence is low. SeqSIMLA2_exact is implemented with C++ and is available at http://seqsimla.sourceforge.net. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Squamous Cell Carcinoma Antigen 2 (SCCA2, SERPINB4): An Emerging Biomarker for Skin Inflammatory Diseases.

PubMed

Izuhara, Kenji; Yamaguchi, Yukie; Ohta, Shoichiro; Nunomura, Satoshi; Nanri, Yasuhiro; Azuma, Yoshinori; Nomura, Noriko; Noguchi, Yasuhiko; Aihara, Michiko

2018-04-06

Squamous cell carcinoma antigens 1 and 2 (SCCA1 and 2, SERPIN B3 and B4), members of the ovalbumin serpin (ov-serpin)/clade B serpin family, were originally discovered as tumor-specific antigens and are used as tumor markers for various kinds of squamous cell carcinomas. Recently, our understanding of the underlying mechanisms of how SCCA1/2 enhance tumor growth has greatly increased. Moreover, it has been shown that SCCA1/2 are involved in the pathogenesis of several inflammatory diseases: asthma, psoriasis, and atopic dermatitis (AD). IL-22 and IL-17, signature cytokines of type 17 inflammation, as well as IL-4 and IL-13, signature cytokines of type 2 inflammation, both of which are positively correlated with the pathogenesis of psoriasis and allergic diseases, respectively, can induce expression of SCCA1/2 in airway epithelial cells and/or keratinocytes, leading to high expression of SCCA1/2 in these diseases. Based on these findings, several trials have been performed to examine the potential of applying SCCA1/2 to biomarkers for these diseases. The findings show that SCCA2 is useful to aid diagnosis, estimate clinical severity and disease type, and assess responses to treatment in psoriasis and AD. These results suggest that SCCA2 has emerged as a novel biomarker for skin inflammatory diseases.

1-(4-Chloro­benzyl­ideneamino)pyridinum iodide

PubMed Central

Cui, Yong-Tao; Wang, Jian-Qiang; Ji, Chun-Xiang; Wang, Hai-Bo; Cheng, Guo

2009-01-01

In the title compound, C12H10ClN2 +·I−, the aromatic rings are oriented at a dihedral angle of 54.55 (3)°. In the crystal structure, inter­molecular C—H⋯I and C—H⋯Cl hydrogen bonds link the mol­ecules. PMID:21581845

Possible Alzheimer’s Disease in an Apolipoprotein E2 Homozygote

PubMed Central

Ignatov, Ignat; Belden, Christine; Jacobson, Sandra; Connor, Donald; Sabbagh, Marwan N.

2010-01-01

The objective of this study was to describe a case of Alzheimer’s disease in an ApoE ε2/ε2 homozygote. ApoE ε2/ε2 is the rarest of the apolipoprotein E genotypes, representing only 1.4% of the population. There is only one case reported in the literature of a nonagenarian with minimal cognitive changes whose brain showed AD pathology on postmortem study. Here we report an 87-year-old ApoE ε2/ε2 female who meets clinical criteria for Alzheimer’s disease, with confirmation from neuropsychological testing and PET scan. Clinical course is typical for Alzheimer’s disease with decline on the Mini-Mental Status Examination from a score of 25 to 19 over 3.5 years. The patient is currently treated with donepezil and memantine. In conclusion, a clinically confirmed case of Alzheimer’s disease is rare in Apo E2 homozygotes but can occur. PMID:19158419

BioM2MetDisease: a manually curated database for associations between microRNAs, metabolites, small molecules and metabolic diseases

PubMed Central

Xu, Yanjun; Yang, Haixiu; Wu, Tan; Dong, Qun; Sun, Zeguo; Shang, Desi; Li, Feng; Xu, Yingqi; Su, Fei; Liu, Siyao

2017-01-01

Abstract BioM2MetDisease is a manually curated database that aims to provide a comprehensive and experimentally supported resource of associations between metabolic diseases and various biomolecules. Recently, metabolic diseases such as diabetes have become one of the leading threats to people’s health. Metabolic disease associated with alterations of multiple types of biomolecules such as miRNAs and metabolites. An integrated and high-quality data source that collection of metabolic disease associated biomolecules is essential for exploring the underlying molecular mechanisms and discovering novel therapeutics. Here, we developed the BioM2MetDisease database, which currently documents 2681 entries of relationships between 1147 biomolecules (miRNAs, metabolites and small molecules/drugs) and 78 metabolic diseases across 14 species. Each entry includes biomolecule category, species, biomolecule name, disease name, dysregulation pattern, experimental technique, a brief description of metabolic disease-biomolecule relationships, the reference, additional annotation information etc. BioM2MetDisease provides a user-friendly interface to explore and retrieve all data conveniently. A submission page was also offered for researchers to submit new associations between biomolecules and metabolic diseases. BioM2MetDisease provides a comprehensive resource for studying biology molecules act in metabolic diseases, and it is helpful for understanding the molecular mechanisms and developing novel therapeutics for metabolic diseases. Database URL: http://www.bio-bigdata.com/BioM2MetDisease/ PMID:28605773

Airway surface mycosis in chronic TH2-associated airway disease.

PubMed

Porter, Paul C; Lim, Dae Jun; Maskatia, Zahida Khan; Mak, Garbo; Tsai, Chu-Lin; Citardi, Martin J; Fakhri, Samer; Shaw, Joanne L; Fothergil, Annette; Kheradmand, Farrah; Corry, David B; Luong, Amber

2014-08-01

Environmental fungi have been linked to TH2 cell-related airway inflammation and the TH2-associated chronic airway diseases asthma, chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), and allergic fungal rhinosinusitis (AFRS), but whether these organisms participate directly or indirectly in disease pathology remains unknown. To determine the frequency of fungus isolation and fungus-specific immunity in patients with TH2-associated and non-TH2-associated airway disease. Sinus lavage fluid and blood were collected from sinus surgery patients (n = 118) including patients with CRSwNP, patients with CRS without nasal polyps, patients with AFRS, and non-CRS/nonasthmatic control patients. Asthma status was determined from medical history. Sinus lavage fluids were cultured and directly examined for evidence of viable fungi. PBMCs were restimulated with fungal antigens in an enzyme-linked immunocell spot assay to determine total memory fungus-specific IL-4-secreting cells. These data were compared with fungus-specific IgE levels measured from plasma by ELISA. Filamentous fungi were significantly more commonly cultured in patients with TH2-associated airway disease (asthma, CRSwNP, or AFRS: n = 68) than in control patients with non-TH2-associated disease (n = 31): 74% vs 16%, respectively (P < .001). Both fungus-specific IL-4 enzyme-linked immunocell spot (n = 48) and specific IgE (n = 70) data correlated with TH2-associated diseases (sensitivity 73% and specificity 100% vs 50% and 77%, respectively). The frequent isolation of fungi growing directly within the airways accompanied by specific immunity to these organisms only in patients with TH2-associated chronic airway diseases suggests that fungi participate directly in the pathogenesis of these conditions. Efforts to eradicate airway fungi from the airways should be considered in selected patients. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Risk factors and the preoperative assessment of right para-oesophageal lymph node metastasis in right lobe papillary thyroid carcinoma: A case series.

PubMed

Qu, You; Zhang, Hao; Zhang, Ping; Dong, Wenwu; He, Liang; Sun, Wei; Liu, Jinhao

2017-06-01

Right para-oesophageal lymph nodes (RPELN) are included among the right central compartment lymph nodes (rCLN) and located behind right recurrent laryngeal nerve (rRLN). However, due to the likelihood of increasing postoperative complications, and the extremely difficulties of RPELN dissection, the decision to perform RPELN dissection remains controversial. The aim of this study was to explore the risk factors of RPELN metastasis and evaluate RPELN metastasis by preoperative examination. We reviewed the medical records of 163 consecutive papillary thyroid carcinoma (PTC) patients (125 females and 38 males) who underwent right lobe plus isthmic resection (91 patients) or total thyroidectomy (72 patients) with right or bilateral central compartment lymph node dissection. The RPELN dissections were performed in all patients and were individually dissected and recorded intraoperatively. All patients underwent thyroid ultrasound and enhanced neck computed tomography (CT) routinely during preoperative examination. RPELN metastasis was detected in 20 patients (12.3%), among whom 6 (3.7%) had RPELN metastasis without rCLN metastasis. Total rCLN metastasis and lateral compartment lymph node metastasis were confirmed in 57 (35.0%) and 24 (14.7%) patients, respectively. The tumour diameter, number of metastatic rCLN and lateral compartment lymph nodes, RPELN visible on CT, and enhanced CT value of RPELN were confirmed significantly associated with RPELN metastasis by univariate analysis (P < 0.05). The area under the ROC curve of CT values was 0.77 (95% CI, 0.59-0.95; P = 0.003). The CT value of 132.0 was used as the cut-off point, and the specificity and sensitivity were 84.1% and 71.4%, respectively. PTC patients with a large tumour (>1 cm) in the right lobe or suspected rCLN metastasis were recommended to undergo prophylactic RPELN dissection, particularly in those with a high enhanced CT value (>132) of RPELN or those with the copresence of lateral compartment lymph

Electrochemical Degradation of Rhodamine B over Ti/SnO2-Sb Electrode.

PubMed

Maharana, Dusmant; Niu, Junfeng; Gao, Ding; Xu, Zesheng; Shi, Jianghong

2015-04-01

Electrochemical degradation of rhodamine B (C28H31ClN2O3) over Ti/SnO2-Sb anode was investigated in a rectangular cell. The degradation reaction follows pseudo-first-order kinetics. The degradation efficiency of rhodamine B attained >90.0% after 20 minutes of electrolysis at initial concentrations of 5 to 200 mg/L at a constant current density of 20 mA/cm2 with a 10 mmol/L Na2SO4 supporting electrolyte solution. Rhodamine B (50 mg/L) degradation and total organic carbon (TOC) removal ratio achieved 99.9 and 86.7%, respectively, at the optimal conditions after 30 minutes of electrolysis. The results showed that the energy efficiency of rhodamine B (50 mg/L) degradation at the optimal current densities from 2 to 30 mA/cm2 were 23.2 to 84.6 Wh/L, whereas the electrolysis time for 90% degradation of rhodamine B with Ti/SnO2-Sb anode was 36.6 and 7.3 minutes, respectively. The electrochemical method can be an advisable option for the treatment of dyes such as rhodamine B in wastewater.

Adenosine A2B receptor: from cell biology to human diseases

NASA Astrophysics Data System (ADS)

Sun, Ying; Huang, Pingbo

2016-08-01

Extracellular adenosine is a ubiquitous signaling molecule that modulates a wide array of biological processes. Recently, significant advances have been made in our understanding of A2B adenosine receptor (A2BAR). In this review, we first summarize some of the general characteristics of A2BAR, and then we describe the multiple binding partners of the receptor, such as newly identified α-actinin-1 and p105, and discuss how these associated proteins could modulate A2BAR’s functions, including certain seemingly paradoxical functions of the receptor. Growing evidence indicates a critical role of A2BAR in cancer, renal disease, and diabetes, in addition to its importance in the regulation of vascular diseases and lung disease. Here, we also discuss the role of A2BAR in cancer, renal disease, and diabetes and the potential of the receptor as a target for treating these three diseases.

BioM2MetDisease: a manually curated database for associations between microRNAs, metabolites, small molecules and metabolic diseases.

PubMed

Xu, Yanjun; Yang, Haixiu; Wu, Tan; Dong, Qun; Sun, Zeguo; Shang, Desi; Li, Feng; Xu, Yingqi; Su, Fei; Liu, Siyao; Zhang, Yunpeng; Li, Xia

2017-01-01

BioM2MetDisease is a manually curated database that aims to provide a comprehensive and experimentally supported resource of associations between metabolic diseases and various biomolecules. Recently, metabolic diseases such as diabetes have become one of the leading threats to people’s health. Metabolic disease associated with alterations of multiple types of biomolecules such as miRNAs and metabolites. An integrated and high-quality data source that collection of metabolic disease associated biomolecules is essential for exploring the underlying molecular mechanisms and discovering novel therapeutics. Here, we developed the BioM2MetDisease database, which currently documents 2681 entries of relationships between 1147 biomolecules (miRNAs, metabolites and small molecules/drugs) and 78 metabolic diseases across 14 species. Each entry includes biomolecule category, species, biomolecule name, disease name, dysregulation pattern, experimental technique, a brief description of metabolic disease-biomolecule relationships, the reference, additional annotation information etc. BioM2MetDisease provides a user-friendly interface to explore and retrieve all data conveniently. A submission page was also offered for researchers to submit new associations between biomolecules and metabolic diseases. BioM2MetDisease provides a comprehensive resource for studying biology molecules act in metabolic diseases, and it is helpful for understanding the molecular mechanisms and developing novel therapeutics for metabolic diseases. http://www.bio-bigdata.com/BioM2MetDisease/. © The Author(s) 2017. Published by Oxford University Press.

Early years of Radio Astronomy in the U.S.

NASA Astrophysics Data System (ADS)

Burke, B. F.

Radio Astronomy in the U.S. went through two distinct phases, the pioneering phase before the Second World War, when Karl Jansky and Grote Reber were the only two radio astronomers in the world, and the post-WWII era, when the subject blossomed throughout the world, especially in England and Australia, while U.S. radio astronomy languished at a relatively low level, until its resurgence a decade later. Here in Budapest we are celebrating the 70th anniversary of Jansky's discovery, and I shall start with a review of his work, and the subsequent work of Grote Reber, who died, regrettably, in December 2002. Two historical references will be cited frequently: Serendipitous Discoveries in Radio Astronomy (Kellermann & Sheets, eds. 1983, referred to as Paper 1) and the two historical collections edited by W.T. Sullivan, Classics in Radio Astronomy (1982, referred to as Paper 2) and The Early Years of Radio Astronomy (1984, Paper 3).

Diabetes and kidney disease: the role of sodium-glucose cotransporter-2 (SGLT-2) and SGLT-2 inhibitors in modifying disease outcomes.

PubMed

Mende, Christian W

2017-03-01

Patients with type 2 diabetes (T2D) often have coexisting chronic kidney disease (CKD). However, healthy renal function is crucial in maintaining glucose homeostasis, assuring that almost all of the filtered glucose is reabsorbed by the sodium glucose cotransporters (SGLTs) SGLT-1 and SGLT-2. In diabetes, an increased amount of glucose is filtered by the kidneys and SGLT-2 is upregulated, leading to increased glucose absorption and worsening hyperglycemia. Prolonged hyperglycemia contributes to the development of CKD by inducing metabolic and hemodynamic changes in the kidneys. Due to the importance of SGLT-2 in regulating glucose levels, investigation into SGLT-2 inhibitors was initiated as a glucose-dependent mechanism to control hyperglycemia, and there are three agents currently approved for use in the United States: dapagliflozin, canagliflozin, and empagliflozin. SGLT-2 inhibitors have been shown to reduce glycated hemoglobin (A1C), weight, and blood pressure, which not only affects glycemic control, but may also help slow the progression of renal disease by impacting the underlying mechanisms of kidney injury. In addition, SGLT-2 inhibitors have shown reductions in albuminuria, uric acid, and an increase in magnesium. Caution is advised when prescribing SGLT-2 inhibitors to patients with moderately impaired renal function and those at risk for volume depletion and hypotension. Published data on slowing of the development, as well as progression of CKD, is a hopeful indicator for the possible renal protection potential of this drug class. This narrative review provides an in-depth discussion of the interplay between diabetes, SGLT-2 inhibitors, and factors that affect kidney function.

Role of Type 2 Innate Lymphoid Cells in Allergic Diseases.

PubMed

Cosmi, Lorenzo; Liotta, Francesco; Maggi, Laura; Annunziato, Francesco

2017-09-11

The adaptive immune response orchestrated by type 2 T helper (Th2) lymphocytes, strictly cooperates with the innate response of group 2 innate lymphoid cells (ILC2), in the protection from helminths infection, as well as in the pathogenesis of allergic disease. The aim of this review is to explore the pathogenic role of ILC2 in different type 2-mediated disorders. Recent studies have shown that epithelial cell-derived cytokines and their responding cells, ILC2, play a pathogenic role in bronchial asthma, chronic rhinosinusitis, and atopic dermatitis. The growing evidences of the contribution of ILC2 in the induction and maintenance of allergic inflammation in such disease suggest the possibility to target them in therapy. Biological therapies blocking ILC2 activation or neutralizing their effector cytokines are currently under evaluation to be used in patients with type 2-dominated diseases.

Autocrine release of angiopoietin-2 mediates cerebrovascular disintegration in Moyamoya disease

PubMed Central

Blecharz, Kinga G; Frey, Dietmar; Schenkel, Tobias; Prinz, Vincent; Bedini, Gloria; Krug, Susanne M; Czabanka, Marcus; Wagner, Josephin; Fromm, Michael; Bersano, Anna

2016-01-01

Moyamoya disease is a rare steno-occlusive cerebrovascular disorder often resulting in hemorrhagic and ischemic strokes. Although sharing the same ischemic stimulus with atherosclerotic cerebrovascular disease, Moyamoya disease is characterized by a highly instable cerebrovascular system which is prone to rupture due to pathological neovascularization. To understand the molecular mechanisms underlying this instability, angiopoietin-2 gene expression was analyzed in middle cerebral artery lesions obtained from Moyamoya disease and atherosclerotic cerebrovascular disease patients. Angiopoietin-2 was significantly up-regulated in Moyamoya vessels, while serum concentrations of soluble angiopoietins were not changed. For further evaluations, cerebral endothelial cells incubated with serum from these patients in vitro were applied. In contrast to atherosclerotic cerebrovascular disease serum, Moyamoya disease serum induced an angiopoietin-2 overexpression and secretion, accompanied by loss of endothelial integrity. These effects were absent or inverse in endothelial cells of non-brain origin suggesting brain endothelium specificity. The destabilizing effects on brain endothelial cells to Moyamoya disease serum were partially suppressed by the inhibition of angiopoietin-2. Our findings define brain endothelial cells as the potential source of vessel-destabilizing factors inducing the high plasticity state and disintegration in Moyamoya disease in an autocrine manner. We also provide new insights into Moyamoya disease pathophysiology that may be helpful for preventive treatment strategies in future. PMID:27381827

Targeting key proximal drivers of type 2 inflammation in disease.

PubMed

Gandhi, Namita A; Bennett, Brandy L; Graham, Neil M H; Pirozzi, Gianluca; Stahl, Neil; Yancopoulos, George D

2016-01-01

Systemic type 2 inflammation encompassing T helper 2 (TH2)-type responses is emerging as a unifying feature of both classically defined allergic diseases, such as asthma, and a range of other inflammatory diseases. Rather than reducing inflammation with broad-acting immunosuppressants or narrowly targeting downstream products of the TH2 pathway, such as immunoglobulin E (IgE), efforts to target the key proximal type 2 cytokines - interleukin-4 (IL-4), IL-5 and IL-13 - represent a promising strategy to achieve therapeutic benefit across multiple diseases. After several initial disappointing clinical results with therapies targeting IL-4, IL-5 or IL-13 in asthma, applying a personalized approach achieved therapeutic benefit in an asthma subtype exhibiting an 'allergic' phenotype. More recently, efficacy was extended into a broad population of people with asthma. This argues that the Type 2 inflammation is broadly relevant across the severe asthma population if the key upstream drivers are properly blocked. Moreover, the simultaneous inhibition of IL-4 and IL-13 has shown significant clinical activity in diseases that are often co-morbid with asthma - atopic dermatitis and chronic sinusitis with nasal polyps - supporting the hypothesis that targeting a central 'driver pathway' could benefit multiple allergic diseases.

Thalidomide attenuates learning and memory deficits induced by intracerebroventricular administration of streptozotocin in rats.

PubMed

Elçioğlu, Hk; Kabasakal, L; Alan, S; Salva, E; Tufan, F; Karan, Ma

2013-05-01

Neuroinflammatory responses caused by amyloid β (Aβ) peptide deposits are involved in the pathogenesis of Alzheimer's disease (AD). Thalidomide has a significant anti-inflammatory effect by inhibiting TNF-α, which plays role in Aβ neurotoxicity. We investigated the effect of thalidomide on AD-like cognitive deficits caused by intracerebroventricular injection of streptozotocin (STZ). Intraperitoneal thalidomide was administered 1 h before the first dose of STZ and continued for 21 days. Learning and memory behavior was evaluated on days 17, 18 and 19, and the rats were sacrificed on day 21 to examine histopathological changes. STZ injection caused a significant decrease in the mean escape latency in passive avoidance and decreased improvement of performance in Morris water maze tests. Histopathological changes were examined using hematoxylin-eosin and Bielschowsky staining. Brain sections of STZ treated rats showed increased neurodegeneration and disturbed linear arrangement of cells in the cortical area compared to controls. Thalidomide treatment attenuated significantly STZ induced cognitive impairment and histopathological changes. Thalidomide appears to provide neuroprotection from the memory deficits and neuronal damage induced by STZ.

Mice heterozygous for cathepsin D deficiency exhibit mania-related behavior and stress-induced depression.

PubMed

Zhou, Rui; Lu, Yi; Han, Yong; Li, Xia; Lou, Huifang; Zhu, Liya; Zhen, Xuechu; Duan, Shumin

2015-12-03

Mutations in cathepsin D (CTSD), an aspartic protease in the endosomal-lysosomal system, underlie congenital neuronal ceroid-lipofuscinosis (cNCL, also known as CLN10), a devastating neurodegenerative disease. CLN10 patients die within the first few days of life, and in the few patients who live into adulthood psychopathological symptoms have not been reported. Extensive neuropathology and altered neurotransmission have been reported in CTSD-deficient mice; however signs of neuropsychiatric behavior in these mice are not well characterized due to the severe movement disorder and premature death of the animal. In the present study, we show that heterozygous CTSD-deficient (CTSD HET) mice display an overall behavioral profile that is similar to human mania, including hyperlocomotion, d-amphetamine-induced hyperactivity, sleep-disturbance, and reduced anxiety-like behavior. However, under stressful conditions CTSD HET mice manifest depressive-like behavior, including anhedonia, behavioral despair, and enhanced learned helplessness. Chronic administration of lithium chloride or valproic acid, two clinically effective mood stabilizers, reverses the majority of these behavioral abnormalities. In addition, CTSD HET mice display stress-induced hypersecretion of corticosterone. These findings suggest an important role for CTSD in the regulation of mood stabilization. Copyright © 2015 Elsevier Inc. All rights reserved.

Experimental study of the solubilities of pyrite in NaCl-bearing aqueous solutions at 250-350°C

NASA Astrophysics Data System (ADS)

Ohmoto, Hiroshi; Hayashi, Ken-Ichiro; Kajisa, Yukari

1994-05-01

A total of sixty-three silica capsule experiments were performed to determine the solubilities of pyrite in NaCl-bearing aqueous solutions (0, 0.1, 0.5, 1, 2, 3, and 4 m) at 250, 300, and 350°C at pressures of vapor/liquid coexistence. The starting materials in the capsules were H2O(1) + FeS2( s) + S ° ( s) ± NaCl ( s). After reaction times up to ~ 60 days, the quenched solutions were analyzed for ΣFe, σH2S, ΣSO42-, and pH; the ΣFe content, ranging 5-1,300 ppm, generally increased with increasing temperature and ΣCl content of solution. The calculated solution compositions at the experimental P-T conditions fall mostly in the following ranges: pH = 2.0 to 3.2, logaH2s = -1.9 to -1.0, logaHSO4- = -3.8 to -2.0, and logaH2( aq) = -7.0 to -5.0. Evaluation of the experimental data suggests that the various redox equilibria between solution and mineral were attained in most of the experimental solutions. The pH, aH2S( aq) , and aH2( aq) of the solutions were controlled by the sulfur hydrolysis reaction (48° + 4 H2O( l) = 3 H2S( aq) + HSO4- + H+) and the sulfide/sulfate reaction ( H2S( aq) + 4 H2O( l) = 4 H2( aq) + H+ + HSO4-). The pyrite solubility is controlled by a general reaction: FeS2( s) + nCl- + 2 H+ + H2( aq) = FeCln2- n + 2 H2S( aq). The equilibrium constants for this reaction, as well as those for association of ferrous chloride complexes ( Fe2+ + nCl- = FeCln2- n), were obtained at 250, 300, and 350°C; they were used also to compute the equilibrium constants for the reactions controlling the solubilities of pyrrhotite, magnetite, and hematite: FeS( s) + 2 H+ + nCl- = FeCln2- n + H2S( aq); Fe3O4( s) + 6 H+ + 3 nCl- + H2( aq) = 3 FeCln2- n + H2O( aq); Fe2O3( s) + 4 H+ + 2 nCl- + H2( aq) = 2 FeCln2- n + 3 H2O( aq). Our experimental data suggest that the dominant Fe-Cl complex is FeCl + in solutions of ΣCl ≤ 0.5 m at 250°C and ΣCl ≤ 0.1 m at 300 and 350°C; FeCl 20 is dominant in solutions of the higher ΣCl contents at each temperature. The

The emerging functions of UCP2 in health, disease, and therapeutics.

PubMed

Mattiasson, Gustav; Sullivan, Patrick G

2006-01-01

The uncoupling proteins (UCPs) are attracting an increased interest as potential therapeutic targets in a number of important diseases. UCP2 is expressed in several tissues, but its physiological functions as well as potential therapeutic applications are still unclear. Unlike UCP1, UCP2 does not seem to be important to thermogenesis or weight control, but appears to have an important role in the regulation of production of reactive oxygen species, inhibition of inflammation, and inhibition of cell death. These are central features in, for example, neurodegenerative and cardiovascular disease, and experimental evidence suggests that an increased expression and activity of UCP2 in models of these diseases has a beneficial effect on disease progression, implicating a potential therapeutic role for UCP2. UCP2 has an important role in the pathogenesis of type 2 diabetes by inhibiting insulin secretion in islet beta cells. At the same time, type 2 diabetes is associated with increased risk of cardiovascular disease and atherosclerosis where an increased expression of UCP2 appears to be beneficial. This illustrates that therapeutic applications involving UCP2 likely will have to regulate expression and activity in a tissue-specific manner.

Triggering receptor expressed on myeloid cells 2 (TREM2): a potential therapeutic target for Alzheimer disease?

PubMed

Deming, Yuetiva; Li, Zeran; Benitez, Bruno A; Cruchaga, Carlos

2018-06-20

There are currently no effective therapeutics for Alzheimer disease (AD). Clinical trials targeting amyloid beta thus far have shown very little benefit and only in the earliest stages of disease. These limitations have driven research to identify alternative therapeutic targets, one of the most promising is the triggering receptor expressed on myeloid cells 2 (TREM2). Areas covered: Here, we review the literature to-date and discuss the potentials and pitfalls for targeting TREM2 as a potential therapeutic for AD. We focus on research in animal and cell models for AD and central nervous system injury models which may help in understanding the role of TREM2 in disease. Expert opinion: Studies suggest TREM2 plays a key role in AD pathology; however, results have been conflicting about whether TREM2 is beneficial or harmful. More research is necessary before designing TREM2-targeting therapies. Successful therapeutics will most likely be administered early in disease.

PP2ARts1 is a master regulator of pathways that control cell size

PubMed Central

Zapata, Jessica; Dephoure, Noah; MacDonough, Tracy; Yu, Yaxin; Parnell, Emily J.; Mooring, Meghan; Gygi, Steven P.; Stillman, David J.

2014-01-01

Cell size checkpoints ensure that passage through G1 and mitosis occurs only when sufficient growth has occurred. The mechanisms by which these checkpoints work are largely unknown. PP2A associated with the Rts1 regulatory subunit (PP2ARts1) is required for cell size control in budding yeast, but the relevant targets are unknown. In this paper, we used quantitative proteome-wide mass spectrometry to identify proteins controlled by PP2ARts1. This revealed that PP2ARts1 controls the two key checkpoint pathways thought to regulate the cell cycle in response to cell growth. To investigate the role of PP2ARts1 in these pathways, we focused on the Ace2 transcription factor, which is thought to delay cell cycle entry by repressing transcription of the G1 cyclin CLN3. Diverse experiments suggest that PP2ARts1 promotes cell cycle entry by inhibiting the repressor functions of Ace2. We hypothesize that control of Ace2 by PP2ARts1 plays a role in mechanisms that link G1 cyclin accumulation to cell growth. PMID:24493588

Doping chloro boron subnaphthalocyanines and chloro boron subphthalocyanine in simple OLED architectures yields warm white incandescent-like emissions

NASA Astrophysics Data System (ADS)

Plint, Trevor G.; Lessard, Benoît H.; Bender, Timothy P.

2018-01-01

We have incorporated chloro boron subphthalocyanine (Cl-BsubPc) and chloro boron subnapthalocyanines (Cl-ClnBsubNcs) into organic light emitting diodes (OLEDs) that enabled an overall warm white emission with CIE coordinates close to that of a 60 W incandescent lightbulb. More specifically, we have shown that Cl-BsubPc and Cl-ClnBsubNcs can be used as dopant emitters in a simple host-dopant architecture, and we have compared the use of NPB and Alq3 as potential hosts for these materials. When doped into Alq3, Cl-BsubPc shows a strong orange emission, and Cl-ClnBsubNcs shows a moderately strong red emission. We have further demonstrated that Cl-BsubPc and Cl-ClnBsubNcs can be co-doped into the same layer giving combined orange and red emission peaks. A "cascade" energy transfer mechanism of sequential absorption and re-emission is proposed. Device performance characteristics such as luminance, current efficiency, photoluminescence efficiency, and external quantum efficiency are tabulated. Additionally, in view of ongoing research into white emitting OLEDs for indoor lighting purposes, the Colour Rendering Index (CRI), R9 values, and CIE co-ordinates for these devices are also discussed. We conclude from this study that the BsubNc chromophore has potential application as a red dopant in OLEDs including for indoor lighting. Additionally, given the scope for axial and peripheral derivatization of the BsubNc motif, we believe that this chromophore has many unexplored molecular design handles that will affect its ultimate performance and application in OLEDs and other opto-electronic devices.

Gas Phase Molecular Spectroscopy: Electronic Spectroscopy of Combustion Intermediates, Chlorine Azide kinetics, and Rovibrational Energy Transfer in Acetylene

NASA Astrophysics Data System (ADS)

Freel, Keith A.

This dissertation is composed of three sections. The first deals with the electronic spectroscopy of combustion intermediates that are related to the formation of polycyclic aromatic hydrocarbons. Absorption spectra for phenyl, phenoxy, benzyl, and phenyl peroxy radicals were recorded using the technique of cavity ring-down spectroscopy. When possible, molecular constants, vibrational frequencies, and excited state lifetimes for these radicals were derived from these data. The results were supported by theoretical predictions. The second section presents a study of electron attachment to chlorine azide (ClN3) using a flowing-afterglow Langmuir-probe apparatus. Electron attachment rates were measured to be 3.5x10-8 and 4.5x10-8 cm3s-1 at 298 and 400 K respectively. The reactions of ClN3 with eighteen cations and seventeen anions were characterized. Rate constants were measured using a selected ion flow tube. The ionization energy (>9.6eV), proton affinity (713+/-41 kJ mol-1), and electron affinity (2.48+/-0.2 eV) for ClN 3 were determined from these data. The third section demonstrates the use of double resonance spectroscopy to observe state-selected rovibrational energy transfer from the first overtone asymmetric stretch of acetylene. The total population removal rate constants from various rotational levels of the (1,0,1,00,00) vibrational state were determined to be in the range of (9-17) x 10 -10 cm3s-1. Rotational energy transfer accounted for approximately 90% of the total removal rate from each state. Therefore, the upper limit of vibrational energy transfer from the (1,0,1,0 0,00) state was 10%.

An i2b2-based, generalizable, open source, self-scaling chronic disease registry

PubMed Central

Quan, Justin; Ortiz, David M; Bousvaros, Athos; Ilowite, Norman T; Inman, Christi J; Marsolo, Keith; McMurry, Andrew J; Sandborg, Christy I; Schanberg, Laura E; Wallace, Carol A; Warren, Robert W; Weber, Griffin M; Mandl, Kenneth D

2013-01-01

Objective Registries are a well-established mechanism for obtaining high quality, disease-specific data, but are often highly project-specific in their design, implementation, and policies for data use. In contrast to the conventional model of centralized data contribution, warehousing, and control, we design a self-scaling registry technology for collaborative data sharing, based upon the widely adopted Integrating Biology & the Bedside (i2b2) data warehousing framework and the Shared Health Research Information Network (SHRINE) peer-to-peer networking software. Materials and methods Focusing our design around creation of a scalable solution for collaboration within multi-site disease registries, we leverage the i2b2 and SHRINE open source software to create a modular, ontology-based, federated infrastructure that provides research investigators full ownership and access to their contributed data while supporting permissioned yet robust data sharing. We accomplish these objectives via web services supporting peer-group overlays, group-aware data aggregation, and administrative functions. Results The 56-site Childhood Arthritis & Rheumatology Research Alliance (CARRA) Registry and 3-site Harvard Inflammatory Bowel Diseases Longitudinal Data Repository now utilize i2b2 self-scaling registry technology (i2b2-SSR). This platform, extensible to federation of multiple projects within and between research networks, encompasses >6000 subjects at sites throughout the USA. Discussion We utilize the i2b2-SSR platform to minimize technical barriers to collaboration while enabling fine-grained control over data sharing. Conclusions The implementation of i2b2-SSR for the multi-site, multi-stakeholder CARRA Registry has established a digital infrastructure for community-driven research data sharing in pediatric rheumatology in the USA. We envision i2b2-SSR as a scalable, reusable solution facilitating interdisciplinary research across diseases. PMID:22733975

An i2b2-based, generalizable, open source, self-scaling chronic disease registry.

PubMed

Natter, Marc D; Quan, Justin; Ortiz, David M; Bousvaros, Athos; Ilowite, Norman T; Inman, Christi J; Marsolo, Keith; McMurry, Andrew J; Sandborg, Christy I; Schanberg, Laura E; Wallace, Carol A; Warren, Robert W; Weber, Griffin M; Mandl, Kenneth D

2013-01-01

Registries are a well-established mechanism for obtaining high quality, disease-specific data, but are often highly project-specific in their design, implementation, and policies for data use. In contrast to the conventional model of centralized data contribution, warehousing, and control, we design a self-scaling registry technology for collaborative data sharing, based upon the widely adopted Integrating Biology & the Bedside (i2b2) data warehousing framework and the Shared Health Research Information Network (SHRINE) peer-to-peer networking software. Focusing our design around creation of a scalable solution for collaboration within multi-site disease registries, we leverage the i2b2 and SHRINE open source software to create a modular, ontology-based, federated infrastructure that provides research investigators full ownership and access to their contributed data while supporting permissioned yet robust data sharing. We accomplish these objectives via web services supporting peer-group overlays, group-aware data aggregation, and administrative functions. The 56-site Childhood Arthritis & Rheumatology Research Alliance (CARRA) Registry and 3-site Harvard Inflammatory Bowel Diseases Longitudinal Data Repository now utilize i2b2 self-scaling registry technology (i2b2-SSR). This platform, extensible to federation of multiple projects within and between research networks, encompasses >6000 subjects at sites throughout the USA. We utilize the i2b2-SSR platform to minimize technical barriers to collaboration while enabling fine-grained control over data sharing. The implementation of i2b2-SSR for the multi-site, multi-stakeholder CARRA Registry has established a digital infrastructure for community-driven research data sharing in pediatric rheumatology in the USA. We envision i2b2-SSR as a scalable, reusable solution facilitating interdisciplinary research across diseases.

Proteinase-activated receptor 2 and disease biomarkers in cerebrospinal fluid in cases with autopsy-confirmed prion diseases and other neurodegenerative diseases.

PubMed

Rohan, Zdenek; Smetakova, Magdalena; Kukal, Jaromir; Rusina, Robert; Matej, Radoslav

2015-03-31

Proteinase-activated receptor 2 (PAR-2) has been shown to promote both neurotoxic and neuroprotective effects. Similarly, other routinely used nonspecific markers of neuronal damage can be found in cerebrospinal fluid (CSF) and can be used as biomarkers for different neurodegenerative disorders. Using enzyme-linked immunosorbent assays and western blotting we assessed PAR-2, total-tau, phospho-tau, beta-amyloid levels, and protein 14-3-3 in the CSF of former patients who had undergone a neuropathological autopsy after death and who had been definitively diagnosed with a prion or other neurodegenerative disease. We did not find any significant correlation between levels of PAR-2 and other biomarkers, nor did we find any differences in PAR-2 levels between prion diseases and other neurodegenerative conditions. However, we confirmed that very high total-tau levels were significantly associated with definitive prion diagnoses and exhibited greater sensitivity and specificity than protein 14-3-3, which is routinely used as a marker. Our study showed that PAR-2, in CSF, was not specifically altered in prion diseases compared to other neurodegenerative conditions. Our results also confirmed that very high total-tau protein CSF levels were significantly associated with a definitive Creutzfeldt-Jakob disease (CJD) diagnosis and should be routinely tested as a diagnostic marker. Observed individual variability in CSF biomarkers provide invaluable feedback from neuropathological examinations even in "clinically certain" cases.

Molecular characterization of infants with type 2 Gaucher disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stubblefield, B.; Martin, B.M.; Ginns, E.I.

1994-09-01

Type 2 (acute neuronopathic) Gaucher disease was previously thought to be stereotypic in presentation with neurologic deterioration and death by age 2-3 years. However, the generation of a null allele knock-out Gaucher mouse led to the recognition of a subset of type 2 patients who die as neonates. To better understand this subgroup we studied DNA, RNA and residual enzyme activity in fibroblasts from neonatal type 2 Gaucher patients, {open_quotes}classic{close_quotes} type 2 patients, type 1 and type 3 patients and normal individuals. Mutational analysis revealed genotypic heterogeneity in each group. One patient with severe neonatal Gaucher disease and hydrops fetalismore » was homoallelic for a complex allele including mutations L44P, A456P and V460V, while others had different or unknown alleles. Northern blots demonstrated that transcription was intact even in the neonatal lethal patients. However, the more severe type 2 patients had virtually no protein on Western, indicating that the transcript is either not appropriately translated or results in an unstable protein. Thus type 2 Gaucher disease exhibits more phenotypic, genotypic and biochemical heterogeneity than previously appreciated.« less

N-((5-chloropyridin-2-yl)carbamothioyl)furan-2-carboxamide and its Co(II), Ni(II) and Cu(II) complexes: Synthesis, characterization, DFT computations, thermal decomposition, antioxidant and antitumor activity

NASA Astrophysics Data System (ADS)

Yeşilkaynak, Tuncay; Özpınar, Celal; Emen, Fatih Mehmet; Ateş, Burhan; Kaya, Kerem

2017-02-01

N-((5-chloropyridin-2-yl)carbamothioyl)furan-2-carboxamide (HL: C11H8ClN3O2S) and its Co(II), Ni(II) and Cu(II) complexes have been synthesized and characterized by elemental analysis, FT-IR,1H NMR and HR-MS methods. The HL was characterized by single crystal X-ray diffraction technique. It crystallizes in the monoclinic system. The HL has the space group P 1 21/c 1, Z = 4, and its unit cell parameters are a = 4.5437(5) Å, b = 22.4550(3) Å, c = 11.8947(14) Å. The ligand coordinates the metal ions as bidentate and thus essentially yields neutral complexes of the [ML2] type. ML2 complex structures were optimized using B97D/TZVP level. Molecular orbitals of both HL ligand were calculated at the same level. Thermal decomposition of the complexes has been investigated by thermogravimetry. The complexes were screened for their anticancer and antioxidant activities. Antioxidant activity of the complexes was determined by using the DPPH and ABTS assays. The anticancer activity of the complexes was studied by using MTT assay in MCF-7 breast cancer cells.

Parkinson's Disease: Leucine-Rich Repeat Kinase 2 and Autophagy, Intimate Enemies

PubMed Central

Bravo-San Pedro, José M.; Gómez-Sánchez, Rubén; Pizarro-Estrella, Elisa; Niso-Santano, Mireia; González-Polo, Rosa A.; Fuentes Rodríguez, José M.

2012-01-01

Parkinson's disease is the second common neurodegenerative disorder, after Alzheimer's disease. It is a clinical syndrome characterized by loss of dopamine-generating cells in the substancia nigra, a region of the midbrain. The etiology of Parkinson's disease has long been through to involve both genetic and environmental factors. Mutations in the leucine-rich repeat kinase 2 gene cause late-onset Parkinson's disease with a clinical appearance indistinguishable from Parkinson's disease idiopathic. Autophagy is an intracellular catabolic mechanism whereby a cell recycles or degrades damage proteins and cytoplasmic organelles. This degradative process has been associated with cellular dysfunction in neurodegenerative processes including Parkinson's disease. We discuss the role of leucine-rich repeat kinase 2 in autophagy, and how the deregulations of this degradative mechanism in cells can be implicated in the Parkinson's disease etiology. PMID:22970411

PREVALENCE OF CELIAC DISEASE PREDISPOSING GENOTYPES, INCLUDING HLA-DQ2.2 VARIANT, IN BRAZILIAN CHILDREN.

PubMed

Selleski, Nicole; Almeida, Lucas Malta; Almeida, Fernanda Coutinho de; Pratesi, Claudia Beatriz; Nóbrega, Yanna Karla de Medeiros; Gandolfi, Lenora

2018-01-01

Celiac disease is an autoimmune enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. Almost all celiac patients carry immune recognition genes coding for HLA-DQ2.5 and DQ8 heterodimers. Over the last few years, great importance has been given to HLA-DQ2.2 as probable predisposing variant, although controversies still exist regarding its relevance. The aim of our study was to determine the possible existence of an association between HLA-DQ2.2 and celiac disease in Brazilian children by analyzing the prevalence of the predisposing variants for celiac disease in a representative group of children of a population in which this determination is still missing. HLA-DQ typing was performed in samples from a group of celiac (n=100) and non-celiac children (n=110). All samples were tested for the presence of the following variants: DQA1*05-DQB1*02 (DQ2.5), DQA1*03-DQB1*03:02 (DQ8) and DQA1*02:01-DQB1*02:02 (DQ2.2). Fisher`s exact test was used for statistical analysis. In the group of 100 celiac children, 78 (78%) were positive for DQ2, 13 (13 %) were DQ2/DQ8 and 6 (6%) were DQ8 positives. The HLA-DQ pattern in the 110 non-celiac children was as follows: positive for DQ2 in 33 (29.9%) samples, in 2 (1.8 %) was positive for DQ2/DQ8 and in 15 (13.6%) was positive for DQ8. We found significant differences between the distribution of some but not all of the analyzed alleles when comparing celiac and non-celiac children. The genotyping of celiac disease HLA-DQ predisposing alleles showed similarities with HLA-DQ patterns found in both European and non-European populations, which may be a reflection of the miscegenation, which gave origin to the current Brazilian population. No significant association was found between DQ2.2 variant and celiac disease in the studied population.

PGE2, Kidney Disease, and Cardiovascular Risk: Beyond Hypertension and Diabetes

PubMed Central

Nasrallah, Rania; Hassouneh, Ramzi

2016-01-01

An important measure of cardiovascular health is obtained by evaluating the global cardiovascular risk, which comprises a number of factors, including hypertension and type 2 diabetes, the leading causes of illness and death in the world, as well as the metabolic syndrome. Altered immunity, inflammation, and oxidative stress underlie many of the changes associated with cardiovascular disease, diabetes, and the metabolic syndrome, and recent efforts have begun to elucidate the contribution of PGE2 in these events. This review summarizes the role of PGE2 in kidney disease outcomes that accelerate cardiovascular disease, highlights the role of cyclooxygenase-2/microsomal PGE synthase 1/PGE2 signaling in hypertension and diabetes, and outlines the contribution of PGE2 to other aspects of the metabolic syndrome, particularly abdominal adiposity, dyslipidemia, and atherogenesis. A clearer understanding of the role of PGE2 could lead to new avenues to improve therapeutic options and disease management strategies. PMID:26319242

CARDIO-i2b2: integrating arrhythmogenic disease data in i2b2.

PubMed

Segagni, Daniele; Tibollo, Valentina; Dagliati, Arianna; Napolitano, Carlo; G Priori, Silvia; Bellazzi, Riccardo

2012-01-01

The CARDIO-i2b2 project is an initiative to customize the i2b2 bioinformatics tool with the aim to integrate clinical and research data in order to support translational research in cardiology. In this work we describe the implementation and the customization of i2b2 to manage the data of arrhytmogenic disease patients collected at the Fondazione Salvatore Maugeri of Pavia in a joint project with the NYU Langone Medical Center (New York, USA). The i2b2 clinical research chart data warehouse is populated with the data obtained by the research database called TRIAD. The research infrastructure is extended by the development of new plug-ins for the i2b2 web client application able to properly select and export phenotypic data and to perform data analysis.

Clinical effects of CO2 laser on equine diseases

NASA Astrophysics Data System (ADS)

Lindholm, Arne; Svensson, Ulf; Collinder, Eje

2002-10-01

CO2 lasers has been used for five years at Malaren Equine Hospital, as an alternative treatment of some equine diseases. The application of CO2 laser has been studied for evaluation of its appropriateness for treatment of the equine diseases sarcoids, lameness in fetlock joints or pulmonary haemorrhage. During the last five years, above 100 equine sarcoids have been removed by laser surgery (CO2 laser) and so far resulting in significantly few recurrences compared with results from usual excision surgery. In one study, acute traumatic arthritis in fetlock joints was treated three times every second day with defocalised CO2 laser. The therapeutic effectiveness of CO2 laser in this study was better than that of the customary therapy with betamethasone plus hyaluronan. During one year, chronic pulmonary bleeders, namely exercise induced pulmonary haemorrhage, has been treated with defocalised CO2 laser. Six race horses have been treated once daily during five days. Until now, three of these horses have subsequently been successfully racing and no symptoms of pulmonary haemorrhage have been observed. These studies indicate that CO2 laser might be an appropriate therapy on sarcoids and traumatic arthritis, and probably also on exercise induced pulmonary haemorrhage. Other treatments for this pulmonary disease are few.

(S)-N-{1-[5-(4-Chloro-benzyl-sulfanyl)-1,3,4-oxadiazol-2-yl]eth-yl}-4-methyl-benzene-sulfonamide.

PubMed

Syed, Tayyaba; Hameed, Shahid; Jones, Peter G

2011-10-01

The title compound, C(18)H(18)ClN(3)O(3)S(2), adopts by folding the form of a distorted disc. Inter-planar angles are 29.51 (7) and 63.43 (7)° from the five-membered ring to the aromatic systems and 34.80 (6)° between these two latter rings. The absolute configuration was confirmed by determination of the Flack parameter. In the crystal, the mol-ecules are linked by four hydrogen bonds, one classical (N-H⋯N) and three 'weak' (C-H⋯O), forming layers parallel to the ac plane; these are in turn linked in the third dimension by Cl⋯N [3.1689 (16) Å] and Cl⋯O [3.3148 (13) Å] contacts to the heterocyclic ring.

Non-alcoholic fatty liver disease and type 2 diabetes mellitus: The liver disease of our age?

PubMed Central

Firneisz, Gábor

2014-01-01

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that might affect up to one-third of the adult population in industrialised countries. NAFLD incorporates histologically and clinically different non-alcoholic entities; fatty liver (NAFL, steatosis hepatis) and steatohepatitis (NASH-characterised by hepatocyte ballooning and lobular inflammation ± fibrosis) might progress to cirrhosis and rarely to hepatocellular cancer. NAFL increasingly affects children (paediatric prevalence is 4.2%-9.6%). Type 2 diabetes mellitus (T2DM), insulin resistance (IR), obesity, metabolic syndrome and NAFLD are particularly closely related. Increased hepatic lipid storage is an early abnormality in insulin resistant women with a history of gestational diabetes mellitus. The accumulation of triacylglycerols in hepatocytes is predominantly derived from the plasma nonesterified fatty acid pool supplied largely by the adipose tissue. A few NAFLD susceptibility gene variants are associated with progressive liver disease, IR, T2DM and a higher risk for hepatocellular carcinoma. Although not approved, pharmacological approaches might be considered in NASH patients. PMID:25083080

Non-alcoholic fatty liver disease and type 2 diabetes mellitus: the liver disease of our age?

PubMed

Firneisz, Gábor

2014-07-21

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that might affect up to one-third of the adult population in industrialised countries. NAFLD incorporates histologically and clinically different non-alcoholic entities; fatty liver (NAFL, steatosis hepatis) and steatohepatitis (NASH-characterised by hepatocyte ballooning and lobular inflammation ± fibrosis) might progress to cirrhosis and rarely to hepatocellular cancer. NAFL increasingly affects children (paediatric prevalence is 4.2%-9.6%). Type 2 diabetes mellitus (T2DM), insulin resistance (IR), obesity, metabolic syndrome and NAFLD are particularly closely related. Increased hepatic lipid storage is an early abnormality in insulin resistant women with a history of gestational diabetes mellitus. The accumulation of triacylglycerols in hepatocytes is predominantly derived from the plasma nonesterified fatty acid pool supplied largely by the adipose tissue. A few NAFLD susceptibility gene variants are associated with progressive liver disease, IR, T2DM and a higher risk for hepatocellular carcinoma. Although not approved, pharmacological approaches might be considered in NASH patients.

Shared Genetic Factors Involved in Celiac Disease, Type 2 Diabetes and Anorexia Nervosa Suggest Common Molecular Pathways for Chronic Diseases.

PubMed

Mostowy, Joanna; Montén, Caroline; Gudjonsdottir, Audur H; Arnell, Henrik; Browaldh, Lars; Nilsson, Staffan; Agardh, Daniel; Torinsson Naluai, Åsa

2016-01-01

Genome-wide association studies (GWAS) have identified several genetic regions involved in immune-regulatory mechanisms to be associated with celiac disease. Previous GWAS also revealed an over-representation of genes involved in type 2 diabetes and anorexia nervosa associated with celiac disease, suggesting involvement of common metabolic pathways for development of these chronic diseases. The aim of this study was to extend these previous analyses to study the gene expression in the gut from children with active celiac disease. Thirty six target genes involved in type 2 diabetes and four genes associated with anorexia nervosa were investigated for gene expression in small intestinal biopsies from 144 children with celiac disease at median (range) age of 7.4 years (1.6-17.8) and from 154 disease controls at a median (range) age 11.4.years (1.4-18.3). A total of eleven of genes were differently expressed in celiac patients compared with disease controls of which CD36, CD38, FOXP1, SELL, PPARA, PPARG, AGT previously associated with type 2 diabetes and AKAP6, NTNG1 with anorexia nervosa remained significant after correction for multiple testing. Shared genetic factors involved in celiac disease, type 2 diabetes and anorexia nervosa suggest common underlying molecular pathways for these diseases.

Long-acting beta 2-agonists in chronic obstructive pulmonary disease.

PubMed

Llewellyn-Jones, Carol

2002-01-01

Until recently, the use of long-acting beta 2-agonists in chronic obstructive pulmonary disease has been understated. There is now evidence that they may offer benefits beyond bronchodilation. This article reviews the management of chronic obstructive pulmonary disease and looks at the place of long-acting beta 2-agonists as a first-line treatment option.

Crystal structures of three indole derivatives: 3-ethnyl-2-methyl-1-phenyl­sulfonyl-1H-indole, 4-phenyl­sulfonyl-3H,4H-cyclo­penta­[b]indol-1(2H)-one and 1-{2-[(E)-2-(5-chloro-2-nitro­phen­yl)ethen­yl]-1-phenyl­sulfonyl-1H-indol-3-yl}ethan-1-one chloro­form monosolvate

PubMed Central

Gopinath, S.; Sethusankar, K.; Ramalingam, Bose Muthu; Mohanakrishnan, Arasambattu K.

2015-01-01

The title compounds, C17H13NO2S, (I), C17H13NO3S, (II), and C24H17ClN2O5S·CHCl3, (III), are indole derivatives. Compounds (I) and (II) crystalize with two independent mol­ecules in the asymmetric unit. The indole ring systems in all three structures deviate only slightly from planarity, with dihedral angles between the planes of the pyrrole and benzene rings spanning the tight range 0.20 (9)–1.65 (9)°. These indole ring systems, in turn, are almost orthogonal to the phenyl­sulfonyl rings [range of dihedral angles between mean planes = 77.21 (8)–89.26 (8)°]. In the three compounds, the mol­ecular structure is stabilized by intra­molecular C—H⋯O hydrogen bonds, generating S(6) ring motifs with the sulfone O atom. In compounds (I) and (II), the two independent mol­ecules are linked by C—H⋯O hydrogen bonds and C—H⋯π inter­actions, while in compound (III), the mol­ecules are linked by C—H⋯O hydrogen bonds, generating R 2 2(22) inversion dimers. PMID:26396842

[NOD2 gene mutation in Moroccan patients with Crohn's disease: prevalence, genotypic study and correlation of NOD2 gene mutation with the phenotype of Crohn's disease].

PubMed

Tamzaourte, Mouna; Errabih, Ikram; Krami, Hayat; Maha, Fadlouallah; Maria, Lahmiri; Benzzoubeir, Nadia; Ouazzani, Laaziza; Sefiani, Ahmed; Ouazzani, Houria

2017-01-01

The aim of this study was to determine the prevalence of NOD2/CARD15 gene mutations in a group of Moroccan patients with Crohn's disease and to study its correlation with genotype-phenotypic expression. We conducted a cross-sectional case-control study over a period of 16 months. 101 patients with Crohn's disease were enrolled between January 2012 and April 2013 as well as a control group of 107 patients. We performed a genetic analysis to identify 3 NOD2 gene variants: p.Arg702Trp, p.Gly908Arg and p.Leu1007fsins. Then we conducted a study of the correlation between genotype and phenotypic expression. The genetic analysis of patients with Crohn's disease highlighted the presence of NOD2 mutation in 14 patients (13.77%) versus 7 patients (6.53%) in the control group. The study of the frequency of different alleles showed p.Gly908Arg mutation in 6.43%, p.Leu1007fsins in 0.99% and p.Arg702Trp in 0.49% versus 2.80%, 0% and 0.46% in the control group respectively. The study of the correlation between genotype and phenotypic expression showed that CARD15 mutation is associated with ileocecal Crohn's disease, with fistulizing and stenosing behavior in Crohn's disease as well as with severe evolution and frequent recourse to surgery and immunosuppressants. The prevalence of NOD2/ CARD15 mutation in our case series is low. This mutation is correlated with severe Crohn's disease.

Mendelian randomisation in type 2 diabetes and coronary artery disease.

PubMed

Frayling, Timothy M; Stoneman, Charli E

2018-06-20

Type 2 diabetes, coronary artery disease and hypertension are associated with anthropometric and biomarker traits, including waist-to-hip-ratio, body mass index and altered glucose and insulin levels. Clinical trials, for example of weight-loss interventions, show these factors are causal, but lifelong impact of subtle changes in body mass index and body fat distribution are less clear. The use of human genetics can quantify the causal effects of long-term exposure to subtle changes of modifiable risk factors. Mendelian randomisation (MR) uses human genetic variants associated with the risk factor to quantify the relationship between risk factor and disease outcome. The last two years have seen an increase in the number of MR studies investigating the relationship between anthropometric traits and metabolic diseases. This review provides an overview of these recent MR studies in relation to type 2 diabetes, coronary artery disease and hypertension. MR provides evidence for causal associations of waist-to-hip-ratio, body mass index and altered glucose levels with type 2 diabetes, coronary artery disease and hypertension. Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.

Electrostatic properties of the pyrimethamine-2,4-dihydroxybenzoic acid cocrystal in methanol studied using transferred electron-density parameters.

PubMed

Faroque, Muhammad Umer; Noureen, Sajida; Ahmed, Maqsood; Tahir, Muhammad Nawaz

2018-01-01

The crystal structure of the cocrystal salt form of the antimalarial drug pyrimethamine with 2,4-dihydroxybenzoic acid in methanol [systematic name: 2,4-diamino-5-(4-chlorophenyl)-6-ethylpyrimidin-1-ium 2,4-dihydroxybenzoate methanol monosolvate, C 12 H 14 ClN 4 + ·C 7 H 5 O 4 - ·CH 3 OH] has been studied using X-ray diffraction data collected at room temperature. The crystal structure was refined using the classical Independent Atom Model (IAM) and the Multipolar Atom Model by transferring electron-density parameters from the ELMAM2 database. The Cl atom was refined anharmonically. The results of both refinement methods have been compared. The intermolecular interactions have been characterized on the basis of Hirshfeld surface analysis and topological analysis using Bader's theory of Atoms in Molecules. The results show that the molecular assembly is built primarily on the basis of charge transfer between 2,4-dihydroxybenzoic acid and pyrimethamine, which results in strong intermolecular hydrogen bonds. This fact is further validated by the calculation of the electrostatic potential based on transferred electron-density parameters.

Clobazam and its active metabolite N-desmethylclobazam display significantly greater affinities for α₂- versus α₁-GABA(A)-receptor complexes.

PubMed

Jensen, Henrik Sindal; Nichol, Kathryn; Lee, Deborah; Ebert, Bjarke

2014-01-01

Clobazam (CLB), a 1,5-benzodiazepine (BZD), was FDA-approved in October 2011 for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years and older. BZDs exert various CNS effects through allosteric modulation of GABAA receptors. The structurally distinct, 1,4-BZD clonazepam (CLN) is also approved to treat LGS. The precise mechanisms of action and clinical efficacy of both are unknown. Data show that the GABAA α₁-subunit-selective compound zolpidem [ZOL] exhibits hypnotic/sedative effects. Conversely, data from knock-in mice carrying BZD binding site mutations suggest that the α₂ subunit mediates anticonvulsant effects, without sedative actions. Hence, the specific pattern of interactions across the GABAA receptor complexes of BZDs might be reflected in their clinical efficacies and adverse effect profiles. In this study, GABAA-receptor binding affinities of CLB, N-desmethylclobazam (N-CLB, the major metabolite of CLB), CLN, and ZOL were characterized with native receptors from rat-brain homogenates and on cloned receptors from HEK293 cells transfected with combinations of α (α₁, α₂, α₃, or α₅), β₂, and γ₂ subtypes. Our results demonstrate that CLB and N-CLB have significantly greater binding affinities for α₂- vs. α₁-receptor complexes, a difference not observed for CLN, for which no distinction between α₂ and α₁ receptors was observed. Our experiments with ZOL confirmed the high preference for α₁ receptors. These results provide potential clues to a new understanding of the pharmacologic modes of action of CLB and N-CLB.

DR2DI: a powerful computational tool for predicting novel drug-disease associations

NASA Astrophysics Data System (ADS)

Lu, Lu; Yu, Hua

2018-05-01

Finding the new related candidate diseases for known drugs provides an effective method for fast-speed and low-risk drug development. However, experimental identification of drug-disease associations is expensive and time-consuming. This motivates the need for developing in silico computational methods that can infer true drug-disease pairs with high confidence. In this study, we presented a novel and powerful computational tool, DR2DI, for accurately uncovering the potential associations between drugs and diseases using high-dimensional and heterogeneous omics data as information sources. Based on a unified and extended similarity kernel framework, DR2DI inferred the unknown relationships between drugs and diseases using Regularized Kernel Classifier. Importantly, DR2DI employed a semi-supervised and global learning algorithm which can be applied to uncover the diseases (drugs) associated with known and novel drugs (diseases). In silico global validation experiments showed that DR2DI significantly outperforms recent two approaches for predicting drug-disease associations. Detailed case studies further demonstrated that the therapeutic indications and side effects of drugs predicted by DR2DI could be validated by existing database records and literature, suggesting that DR2DI can be served as a useful bioinformatic tool for identifying the potential drug-disease associations and guiding drug repositioning. Our software and comparison codes are freely available at https://github.com/huayu1111/DR2DI.

DR2DI: a powerful computational tool for predicting novel drug-disease associations

NASA Astrophysics Data System (ADS)

Lu, Lu; Yu, Hua

2018-04-01

Finding the new related candidate diseases for known drugs provides an effective method for fast-speed and low-risk drug development. However, experimental identification of drug-disease associations is expensive and time-consuming. This motivates the need for developing in silico computational methods that can infer true drug-disease pairs with high confidence. In this study, we presented a novel and powerful computational tool, DR2DI, for accurately uncovering the potential associations between drugs and diseases using high-dimensional and heterogeneous omics data as information sources. Based on a unified and extended similarity kernel framework, DR2DI inferred the unknown relationships between drugs and diseases using Regularized Kernel Classifier. Importantly, DR2DI employed a semi-supervised and global learning algorithm which can be applied to uncover the diseases (drugs) associated with known and novel drugs (diseases). In silico global validation experiments showed that DR2DI significantly outperforms recent two approaches for predicting drug-disease associations. Detailed case studies further demonstrated that the therapeutic indications and side effects of drugs predicted by DR2DI could be validated by existing database records and literature, suggesting that DR2DI can be served as a useful bioinformatic tool for identifying the potential drug-disease associations and guiding drug repositioning. Our software and comparison codes are freely available at https://github.com/huayu1111/DR2DI.

FOXL2 impairment in human disease.

PubMed

Verdin, Hannah; De Baere, Elfride

2012-01-01

FOXL2 encodes a forkhead transcription factor that plays important roles in the ovary during development and in post-natal, adult life. Here, we focus on the clinical consequences of FOXL2 impairment in human disease. In line with other forkhead transcription factors, its constitutional genetic defects and a somatic mutation lead to developmental disease and cancer, respectively. More than 100 unique constitutional mutations and regulatory defects have been found in blepharophimosis syndrome (BPES), a complex eyelid malformation associated (type I) or not (type II) with premature ovarian failure (POF). In agreement with the BPES phenotype, FOXL2 is expressed in the developing eyelids and in fetal and adult ovaries. Two knock-out mice and at least one natural animal model, the Polled Intersex Syndrome goat, are known. They recapitulate the BPES phenotype and have provided many insights into the ovarian pathology. Only a few constitutional mutations have been described in nonsyndromic POF. Moreover, a recurrent somatic mutation p.C134W was found to be specific for adult ovarian granulo-sa cell tumors. Functional studies investigating the consequences of FOXL2 mutations or regulatory defects have shed light on the molecular pathogenesis of the aforementioned conditions, and contributed considerably to genotype-phenotype correlations. Recently, a conditional knock-out of Foxl2 in the mouse induced somatic transdifferentiation of ovary into testis in adult mice, suggesting that Foxl2 has an anti-testis function in the adult ovary. This changed our view on the ovary and testis as terminally differentiated organs in adult mammals. Finally, this might have potential implications for the understanding and treatment of frequent conditions such as POF and polycystic ovary syndrome. Copyright © 2012 S. Karger AG, Basel.

Hsa-circRNA11783-2 in peripheral blood is correlated with coronary artery disease and type 2 diabetes mellitus.

PubMed

Li, Xuejie; Zhao, Zhenzhou; Jian, Dongdong; Li, Wentao; Tang, Haiyu; Li, Muwei

2017-11-01

The purpose of this study was to identify the expression characteristics of circular RNAs in the peripheral blood of coronary artery disease patients and type 2 diabetes mellitus patients. Circular RNA in the peripheral blood from 6 control individuals, 6 coronary artery disease patients, 6 type 2 diabetes mellitus patients and 6 coronary artery disease combined with type 2 diabetes mellitus patients was collected for microarray analysis, and a further independent cohort consisting of 20 normal individuals, 20 type 2 diabetes mellitus subjects and 20 coronary artery disease subjects was used to verify the expression of five circular RNAs chosen for further analysis. The findings were then tested in a third cohort using quantitative real-time polymerase chain reaction. In total, 40 circular RNAs differentially expressed between the three experimental groups and the control group were identified by microarray analysis: 13 were upregulated in the experimental groups, while 27 were downregulated. Of the five circular RNAs chosen for further analysis, three were significantly downregulated in the experimental groups. The crude odds ratios and adjusted odds ratios of hsa-circRNA11783-2 showed significant differences in both the coronary artery disease group and type 2 diabetes mellitus group. We then verified hsa-circRNA11783-2 in the third cohort, and it remained closely related to both coronary artery disease and type 2 diabetes mellitus. Hsa-circRNA11783-2 is closely related to both coronary artery disease and type 2 diabetes mellitus.

Tracing Evolution of Starbursts and AGNs using Ultra-deep Radio and mm/smm Surveys

NASA Astrophysics Data System (ADS)

Yun, Min S.; Gim, Hansung; Morrison, Glenn; Hales, Christopher A.; Momjian, Emmanuel; Owen, Frazer; Kellermann, Ken; Aretxaga, Itziar; Giavalisco, Mauro; Hughes, David; Lowenthal, James; Miller, Neal; Kawabe, Ryohei; Kohno, Kotaro

2015-08-01

There is growing evidence supporting a rapid build up of metals among massive galaxies during their rapid growth via an intense starburst in the early epochs. These star formation activities may be largely obscured in the UV and optical light, as in the local universe. If the growth of supermassive blackholes occurs at or nearly the same time, the accompanying AGN activity may also be heavily obscured. Ultra-deep surveys in the radio and far-infrared can offer extinction-free view of these systems, and the advent of new facilities such as the Jansky VLA, ALMA, and LMT now allows us to probe directly the population of starburst galaxies that are responsible for the bulk of the stellar mass build-up during the epoch of galaxy growth (SFR > 10-100 M⊙/yr at z≈2 or earlier). We will present our analysis of the properties of the micro-Jansky radio sources identified by new Jansky VLA surveys of the GOODS and COSMOS fields using the rich archival data already available (Herschel, Spitzer, Chandra, ALMA, LMT, etc.). Specifically, we find evidence for two populations of microJy radio sources with distinct spectral index distribution. We explore whether this reflects differences in the underlying powering mechanisms by examining their radio-FIR correlation and X-ray properties. We also find the previously reported apparent systematic change in the "q-value" with increasing redshift, and we examine the reality of this trend in some detail. Finally, we will also examine the spatial extent of activities for a subset of the sample where high angular resolution (better than 1") information is available.

Crystal structure of 3-(adamantan-1-yl)-4-(4-chloro-phen-yl)-1H-1,2,4-triazole-5(4H)-thione.

PubMed

Al-Wabli, Reem I; El-Emam, Ali A; Alroqi, Obaid S; Chidan Kumar, C S; Fun, Hoong-Kun

2015-02-01

The title compound, C18H20ClN3S, is a functionalized triazoline-3-thione derivative. The benzene ring is almost perpendic-ular to the planar 1,2,4-triazole ring [maximum deviation = 0.007 (1) Å] with a dihedral angle of 89.61 (5)° between them and there is an adamantane substituent at the 3-position of the triazole-thione ring. In the crystal, N-H⋯S hydrogen-bonding inter-actions link the mol-ecules into chains extending along the c-axis direction. The crystal packing is further stabilized by weak C-H⋯π inter-actions that link adjacent chains into a two-dimensional structure in the bc plane. The crystal studied was an inversion twin with a 0.50 (3):0.50 (3) domain ratio.

Niaspan increases axonal remodeling after stroke in type 1 diabetes rats✩

PubMed Central

Yan, Tao; Chopp, Michael; Ye, Xinchun; Liu, Zhongwu; Zacharek, Alex; Cui, Yisheng; Roberts, Cynthia; Buller, Ben; Chen, Jieli

2012-01-01

Background and objective We investigated axonal plasticity in the bilateral motor cortices and the long term therapeutic effect of Niaspan on axonal remodeling after stroke in type-1 diabetic (T1DM) rats. Experimental approaches T1DM was induced in young adult male Wistar rats via injection of streptozotocin. T1DM rats were subjected to 2 h transient middle cerebral artery occlusion (MCAo) and were treated with 40 mg/kg Niaspan or saline starting 24 h after MCAo and daily for 28 days. Anterograde tracing using biotinylated dextran amine (BDA) injected into the contralateral motor cortex was performed to assess axonal sprouting in the ipsilateral motor cortex area. Functional outcome, SMI-31 (a pan-axonal microfilament marker), Bielschowsky silver and synaptophysin expression were measured. In vitro studies using primary cortical neuron (PCN) cultures and in vivo BDA injection into the brain to anterogradely label axons and terminals were employed. Results Niaspan treatment of stroke in T1DM–MCAo rats significantly improved functional outcome after stroke and increased SMI-31, Bielschowsky silver and synaptophysin expression in the ischemic brain compared to saline treated T1DM–MCAo rats (p<0.05). Using BDA to anterograde label axons and terminals, Niaspan treatment significantly increased axonal density in ipsilateral motor cortex in T1DM–MCAo rats (p<0.05, n=7/group). Niacin treatment of PCN significantly increased Ang1 expression under high glucose condition. Niacin and Ang1 significantly increased neurite outgrowth, and anti-Ang1 antibody marginally attenuated Niacin induced neurite outgrowth (p=0.06, n=6/group) in cultured PCN under high glucose condition. Conclusion Niaspan treatment increased ischemic brain Ang1 expression and promoted axonal remodeling in the ischemic brain as well as improved functional outcome after stroke. Ang1 may partially contribute to Niaspan-induced axonal remodeling after stroke in T1DM-rats. PMID:22266016

N-[4-(9-Chloro­quino[3,2-b]benzo[1,4]thia­zin-6-yl)but­yl]acetamide1

PubMed Central

Jeleń, Małgorzata; Suwińska, Kinga; Pluta, Krystian; Morak-Młodawska, Beata

2012-01-01

In the title mol­ecule, C21H20ClN3OS, the tetra­cyclic system is close to planar [r.m.s. deviation = 0.110 (4) Å]. The dihedral angle between the quinoline ring system and the benzene ring is 178.3 (1)° and the angle between two (S—C=C—N) halves of the thia­zine ring is 173.4 (1)°. In the crystal, mol­ecules are arranged via π–π inter­actions [centroid–centroid distances = 3.603 (2)–3.739 (2) Å] into slipped stacks extending along [010]. Inter­molecular N—H⋯O hydrogen bonds link the amide groups of neighbouring mol­ecules along the stack, generating a C(4) motif. The title compound shows promising anti­proliferative and anti­cancer activity. PMID:23476166

Variant of TREM2 Associated with the Risk of Alzheimer’s Disease

PubMed Central

Jonsson, Thorlakur; Stefansson, Hreinn; Steinberg, Stacy; Jonsdottir, Ingileif; Jonsson, Palmi V.; Snaedal, Jon; Bjornsson, Sigurbjorn; Huttenlocher, Johanna; Levey, Allan I.; Lah, James J.; Rujescu, Dan; Hampel, Harald; Giegling, Ina; Andreassen, Ole A.; Engedal, Knut; Ulstein, Ingun; Djurovic, Srdjan; Ibrahim-Verbaas, Carla; Hofman, Albert; Ikram, M. Arfan; van Duijn, Cornelia M; Thorsteinsdottir, Unnur; Kong, Augustine; Stefansson, Kari

2013-01-01

BACKGROUND Sequence variants, including the ε4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer’s disease. Few rare variants affecting the risk of late-onset Alzheimer’s disease have been found. METHODS We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. We imputed these variants into the genomes of patients with Alzheimer’s disease and control participants and then tested for an association with Alzheimer’s disease. We performed replication tests using case–control series from the United States, Norway, the Netherlands, and Germany. We also tested for a genetic association with cognitive function in a population of unaffected elderly persons. RESULTS A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer’s disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P = 3.42×10−10). The mutation had a frequency of 0.46% in controls 85 years of age or older. We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P = 2.1×10−12 in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer’s disease had poorer cognitive function than noncarriers (P = 0.003). CONCLUSIONS Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer’s disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer’s disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.) PMID:23150908

Antigen-Specific Tolerance in Immunotherapy of Th2-Associated Allergic Diseases

PubMed Central

Smarr, Charles B.; Bryce, Paul J.; Miller, Stephen D.

2013-01-01

Allergic diseases are an increasing health concern, particularly in the developed world. The standard clinical approach to treatment of allergic disease focuses on allergen avoidance and symptom control but does little to address the underlying Th2 bias of disease. Specific immunotherapy (SIT) consisting of controlled administration of allergen, however, has been demonstrated to successfully induce desensitization and tolerance in an antigen-specific manner for a variety of Th2-mediated diseases. This review focuses on the mechanisms by which current SIT approaches induce tolerance as well as discussing attempts to modify the safety and efficacy of SIT. These refinements focus on three major aspects of SIT: the route of antigen administration, modification of the antigen to remove allergenic epitopes and reduce adverse events and choice of adjuvant used to induce tolerance and/or immune deviation from Th2 to Th1 and regulatory T cell (Treg) phenotypes. Synthesis of these recent developments in SIT provides considerable promise for more robust therapies with improved safety profiles to improve resolution of allergic disease and its associated costs. PMID:24099300

Using genes to triangulate the pathophysiology of granulomatous autoinflammatory disease: NOD2, PLCG2 and LACC1.

PubMed

Szymanski, Ann Marie; Ombrello, Michael J

2018-04-25

The intersection of granulomatosis and autoinflammatory disease is a rare occurrence that can be generally subdivided into purely granulomatous phenotypes and disease spectra that are inclusive of granulomatous features. NOD2 (nucleotide-binding oligomerization domain-containing protein 2)-related disease, which includes Blau syndrome and early-onset sarcoidosis, is the prototypic example of granulomatous inflammation in the context of monogenic autoinflammation. Granulomatous inflammation has also been observed in two related autoinflammatory diseases caused by mutations in PLCG2 (phospholipase Cγ2). More recently, mutations in LACC1 (laccase domain-containing protein 1) have been identified as the cause of a monogenic form of systemic juvenile idiopathic arthritis, which does not itself manifest granulomatous inflammation, but the same LACC1 mutations have also been shown to cause an early-onset, familial form of a well-known granulomatous condition, Crohn's disease (CD). Rare genetic variants of PLCG2 have also been shown to cause a monogenic form of CD, and moreover common variants of all three of these genes have been implicated in polygenic forms of CD. Additionally, common variants of NOD2 and LACC1 have been implicated in susceptibility to leprosy, a granulomatous infection. Although no specific mechanistic link exists between these three genes, they form an intriguing web of susceptibility to both monogenic and polygenic autoinflammatory and granulomatous phenotypes.

The purinergic receptor subtype P2Y2 mediates chemotaxis of neutrophils and fibroblasts in fibrotic lung disease

PubMed Central

Karmouty-Quintana, Harry; Cicko, Sanja; Ayata, Korcan; Zissel, Gernot; Goldmann, Torsten; Lungarella, Giuseppe; Ferrari, Davide; Di Virgilio, Francesco; Robaye, Bernard; Boeynaems, Jean-Marie; Blackburn, Michael R.; Idzko, Marco

2017-01-01

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with few available treatment options. Recently, the involvement of purinergic receptor subtypes in the pathogenesis of different lung diseases has been demonstrated. Here we investigated the role of the purinergic receptor subtype P2Y2 in the context of fibrotic lung diseases. The concentration of different nucleotides was measured in the broncho-alveolar lavage (BAL) fluid derived from IPF patients and animals with bleomycin-induced pulmonary fibrosis. In addition expression of P2Y2 receptors by different cell types was determined. To investigate the functional relevance of P2Y2 receptors for the pathogenesis of the disease the bleomycin model of pulmonary fibrosis was used. Finally, experiments were performed in pursuit of the involved mechanisms. Compared to healthy individuals or vehicle treated animals, extracellular nucleotide levels in the BAL fluid were increased in patients with IPF and in mice after bleomycin administration, paralleled by a functional up-regulation of P2Y2R expression. Both bleomycin-induced inflammation and fibrosis were reduced in P2Y2R-deficient compared to wild type animals. Mechanistic studies demonstrated that recruitment of neutrophils into the lungs, proliferation and migration of lung fibroblasts as well as IL6 production are key P2Y2R mediated processes. Our results clearly demonstrate the involvement of P2Y2R subtypes in the pathogenesis of fibrotic lung diseases in humans and mice and hence support the development of selective P2Y2R antagonists for the treatment of IPF. PMID:28415591

Kidney Disease and Youth Onset Type 2 Diabetes: Considerations for the General Practitioner

PubMed Central

Dart, Allison B.; Sellers, Elizabeth A.; Dean, Heather J.

2012-01-01

Youth onset type 2 diabetes (T2DM) continues to increase worldwide, concomitant with the rising obesity epidemic. There is evidence to suggest that youth with T2DM are affected by the same comorbidities and complications as adults diagnosed with T2DM. This review highlights specifically the kidney disease associated with youth onset T2DM, which is highly prevalent and associated with a high risk of end-stage kidney disease in early adulthood. A general understanding of this complex disease by primary care providers is critical, so that at-risk individuals are identified and managed early in the course of their disease, such that progression can be modified in this high-risk group of children and adolescents. A review of the pediatric literature will include a focus on the epidemiology, risk factors, pathology, screening, and treatment of kidney disease in youth onset T2DM. PMID:22315622

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease.

PubMed

Hui, Ken Y; Fernandez-Hernandez, Heriberto; Hu, Jianzhong; Schaffner, Adam; Pankratz, Nathan; Hsu, Nai-Yun; Chuang, Ling-Shiang; Carmi, Shai; Villaverde, Nicole; Li, Xianting; Rivas, Manual; Levine, Adam P; Bao, Xiuliang; Labrias, Philippe R; Haritunians, Talin; Ruane, Darren; Gettler, Kyle; Chen, Ernie; Li, Dalin; Schiff, Elena R; Pontikos, Nikolas; Barzilai, Nir; Brant, Steven R; Bressman, Susan; Cheifetz, Adam S; Clark, Lorraine N; Daly, Mark J; Desnick, Robert J; Duerr, Richard H; Katz, Seymour; Lencz, Todd; Myers, Richard H; Ostrer, Harry; Ozelius, Laurie; Payami, Haydeh; Peter, Yakov; Rioux, John D; Segal, Anthony W; Scott, William K; Silverberg, Mark S; Vance, Jeffery M; Ubarretxena-Belandia, Iban; Foroud, Tatiana; Atzmon, Gil; Pe'er, Itsik; Ioannou, Yiannis; McGovern, Dermot P B; Yue, Zhenyu; Schadt, Eric E; Cho, Judy H; Peter, Inga

2018-01-10

Crohn's disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of nonsynonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the LRRK2 gene that conferred risk for CD (N2081D variant, P = 9.5 × 10 -10 ) or protection from CD (N551K variant, tagging R1398H-associated haplotype, P = 3.3 × 10 -8 ). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated LRRK2 in CD pathogenesis. Analysis of the extended LRRK2 locus in 24,570 CD cases, patients with Parkinson's disease (PD), and healthy controls revealed extensive pleiotropy, with shared genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The LRRK2 N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant was associated with increased kinase activity, whereas neither N551K nor R1398H variants on the protective haplotype altered kinase activity. We also confirmed that R1398H, but not N551K, increased guanosine triphosphate binding and hydrolyzing enzyme (GTPase) activity, thereby deactivating LRRK2. The presence of shared LRRK2 alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and its association with cardiovascular disease.

PubMed

Vanjiappan, Sivabal; Hamide, Abdoul; Ananthakrishnan, Ramesh; Periyasamy, Senthilkumar Gandhipuram; Mehalingam, Vadivelan

2018-01-31

Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver disease that ranges from hepatic steatosis to non-alcoholic steatohepatitis. Obesity and diabetes mellitus are the prime risk factors for NAFLD. The aim of this study was to find out the prevalence of NAFLD among patients with type 2 diabetes mellitus and to detect the association of NAFLD with cardiovascular disease in them. Prospective observational study. The study was conducted on 300 patients with type 2 diabetes mellitus attending the outpatient department of a tertiary care teaching hospital. All patients underwent hepatic ultrasonography to look for hepatic steatosis. Among the 300 patients, 124 were divided into NAFLD and non-NAFLD groups based on the ultrasound findings. These patients were subjected to electrocardiogram, 2D echocardiogram, carotid intima media thickness (CIMT) measurement and ankle brachial pressure index measurement along with measurement of markers of oxidative stress. Hepatic steatosis was present in 61% of diabetic patients in this study. Cardiovascular disease was not found to be significantly associated in diabetic patients with NAFLD. However, cardiovascular risk factors like CIMT, high sensitivity c-reactive protein (hs-CRP) and malondialdehyde (MDA) were elevated in these patients. hs-CRP and MDA levels were found to be significantly associated with the severity of NAFLD. There is a high prevalence of NAFLD in type 2 diabetic patients. No correlation was detected between the presence of NAFLD and cardiovascular disease in them; although there was an association between cardiovascular risk factors and NAFLD. Copyright © 2018. Published by Elsevier Ltd.

Density functional theory studies of etoricoxib

NASA Astrophysics Data System (ADS)

Sachdeva, Ritika; Kaur, Prabhjot; Singh, V. P.; Saini, G. S. S.

2016-05-01

Etoricoxib is a COX-2 selective inhibitor drug with molecular formula C18H15ClN2O2S. It is primarily used for the treatment of arthritis(rheumatoid, psoriatic, osteoarthritis), ankylosing spondylitis, gout and chronic low back pain. Theoretical studies of the molecule including geometry optimization and vibrational frequency calculations were carried out with the help of density functional theory calculations using 6-311++ g (d, p) basis set and B3LYP functional.

Ab Initio Study of KCl and AgCl Clusters.

NASA Astrophysics Data System (ADS)

McKeough, James; Hira, Ajit; Cathey, Tommy; Valdez, Alexandra

This paper presents a theoretical study of molecular clusters that examines the chemical and physical properties of small KnCln and AgnCln clusters (n = 2 - 24). Due to combinations of attractive and repulsive long-range forces, such clusters exhibit structural and dynamical behavior different from that of homogeneous clusters. The potentially important role of these molecular species in biochemical and medicinal processes is widely known. This work applies the hybrid ab initio methods to derive the different alkali-halide (MnHn) geometries. Of particular interest is the competition between hexagonal ring geometries and rock salt structures. Electronic energies, rotational constants, dipole moments, and vibrational frequencies for these geometries are calculated. Magic numbers for cluster stability are identified and are related to the property of cluster compactness. Mapping of the singlet, triplet, and quintet, potential energy surfaces is performed. Calculations were performed to examine the interactions of these clusters with some atoms and molecules of biological interest, including O, O2, and Fe. Potential design of new medicinal drugs is explored. We will also investigate model and material dependence of the results. AMP program of the National Science Foundation.

Habitual coffee consumption and risk of type 2 diabetes, ischemic heart disease, depression and Alzheimer's disease: a Mendelian randomization study.

PubMed

Kwok, Man Ki; Leung, Gabriel M; Schooling, C Mary

2016-11-15

Observationally, coffee is inversely associated with type 2 diabetes mellitus (T2DM), depression and Alzheimer's disease, but not ischemic heart disease (IHD). Coffee features as possibly protective in the 2015 Dietary Guidelines for Americans. Short-term trials suggest coffee has neutral effect on most glycemic traits, but raises lipids and adiponectin. To clarify we compared T2DM, depression, Alzheimer's disease, and IHD and its risk factors by genetically predicted coffee consumption using two-sample Mendelian randomization applied to large extensively genotyped case-control and cross-sectional studies. Childhood cognition was used as a negative control outcome. Genetically predicted coffee consumption was not associated with T2DM (odds ratio (OR) 1.02, 95% confidence interval (CI) 0.76 to 1.36), depression (0.89, 95% CI 0.66 to 1.21), Alzheimer's disease (1.17, 95% CI 0.96 to 1.43), IHD (0.96, 95% CI 0.80 to 1.14), lipids, glycemic traits, adiposity or adiponectin. Coffee was unrelated to childhood cognition. Consistent with observational studies, coffee was unrelated to IHD, and, as expected, childhood cognition. However, contrary to observational findings, coffee may not have beneficial effects on T2DM, depression or Alzheimer's disease. These findings clarify the role of coffee with relevance to dietary guidelines and suggest interventions to prevent these complex chronic diseases should be sought elsewhere.

Diagnosis of diabetes diseases using an Artificial Immune Recognition System2 (AIRS2) with fuzzy K-nearest neighbor.

PubMed

Chikh, Mohamed Amine; Saidi, Meryem; Settouti, Nesma

2012-10-01

The use of expert systems and artificial intelligence techniques in disease diagnosis has been increasing gradually. Artificial Immune Recognition System (AIRS) is one of the methods used in medical classification problems. AIRS2 is a more efficient version of the AIRS algorithm. In this paper, we used a modified AIRS2 called MAIRS2 where we replace the K- nearest neighbors algorithm with the fuzzy K-nearest neighbors to improve the diagnostic accuracy of diabetes diseases. The diabetes disease dataset used in our work is retrieved from UCI machine learning repository. The performances of the AIRS2 and MAIRS2 are evaluated regarding classification accuracy, sensitivity and specificity values. The highest classification accuracy obtained when applying the AIRS2 and MAIRS2 using 10-fold cross-validation was, respectively 82.69% and 89.10%.

Primary Coenzyme Q Deficiency in Pdss2 Mutant Mice Causes Isolated Renal Disease

PubMed Central

Haase, Volker H.; King, Rhonda; Polyak, Erzsebet; Selak, Mary; Yudkoff, Marc; Hancock, Wayne W.; Meade, Ray; Saiki, Ryoichi; Lunceford, Adam L.; Clarke, Catherine F.; Gasser, David L.

2008-01-01

Coenzyme Q (CoQ) is an essential electron carrier in the respiratory chain whose deficiency has been implicated in a wide variety of human mitochondrial disease manifestations. Its multi-step biosynthesis involves production of polyisoprenoid diphosphate in a reaction that requires the enzymes be encoded by PDSS1 and PDSS2. Homozygous mutations in either of these genes, in humans, lead to severe neuromuscular disease, with nephrotic syndrome seen in PDSS2 deficiency. We now show that a presumed autoimmune kidney disease in mice with the missense Pdss2kd/kd genotype can be attributed to a mitochondrial CoQ biosynthetic defect. Levels of CoQ9 and CoQ10 in kidney homogenates from B6.Pdss2kd/kd mutants were significantly lower than those in B6 control mice. Disease manifestations originate specifically in glomerular podocytes, as renal disease is seen in Podocin/cre,Pdss2loxP/loxP knockout mice but not in conditional knockouts targeted to renal tubular epithelium, monocytes, or hepatocytes. Liver-conditional B6.Alb/cre,Pdss2loxP/loxP knockout mice have no overt disease despite demonstration that their livers have undetectable CoQ9 levels, impaired respiratory capacity, and significantly altered intermediary metabolism as evidenced by transcriptional profiling and amino acid quantitation. These data suggest that disease manifestations of CoQ deficiency relate to tissue-specific respiratory capacity thresholds, with glomerular podocytes displaying the greatest sensitivity to Pdss2 impairment. PMID:18437205

The progression rate of spinocerebellar ataxia type 2 changes with stage of disease.

PubMed

Monte, Thais Lampert; Reckziegel, Estela da Rosa; Augustin, Marina Coutinho; Locks-Coelho, Lucas D; Santos, Amanda Senna P; Furtado, Gabriel Vasata; de Mattos, Eduardo Preusser; Pedroso, José Luiz; Barsottini, Orlando Póvoas; Vargas, Fernando Regla; Saraiva-Pereira, Maria-Luiza; Camey, Suzi Alves; Leotti, Vanessa Bielefeldt; Jardim, Laura Bannach

2018-01-25

Spinocerebellar ataxia type 2 (SCA2) affects several neurological structures, giving rise to multiple symptoms. However, only the natural history of ataxia is well known, as measured during the study duration. We aimed to describe the progression rate of ataxia, by the Scale for the Assessment and Rating of Ataxia (SARA), as well as the progression rate of the overall neurological picture, by the Neurological Examination Score for Spinocerebellar Ataxias (NESSCA), and not only during the study duration but also in a disease duration model. Comparisons between these models might allow us to explore whether progression is linear during the disease duration in SCA2; and to look for potential modifiers. Eighty-eight evaluations were prospectively done on 49 symptomatic subjects; on average (SD), study duration and disease duration models covered 13 (2.16) months and 14 (6.66) years of individuals' life, respectively. SARA progressed 1.75 (CI 95%: 0.92-2.57) versus 0.79 (95% CI 0.45 to 1.14) points/year in the study duration and disease duration models. NESSCA progressed 1.45 (CI 95%: 0.74-2.16) versus 0.41 (95% CI 0.24 to 0.59) points/year in the same models. In order to explain these discrepancies, the progression rates of the study duration model were plotted against disease duration. Then an acceleration was detected after 10 years of disease duration: SARA scores progressed 0.35 before and 2.45 points/year after this deadline (p = 0.013). Age at onset, mutation severity, and presence of amyotrophy, parkinsonism, dystonic manifestations and cognitive decline at baseline did not influence the rate of disease progression. NESSCA and SARA progression rates were not constant during disease duration in SCA2: early phases of disease were associated with slower progressions. Modelling of future clinical trials on SCA2 should take this phenomenon into account, since disease duration might impact on inclusion criteria, sample size, and study duration. Our database is

A 2-d classification of diseases based on age-specific death rates

NASA Astrophysics Data System (ADS)

Richmond, Peter; Roehner, Bertrand M.

2018-02-01

Age specific mortality curves exhibit an age tc (about 10 years) which plays a crucial role in that the mortality curve decreases hyperbolically in the age interval A before tc and increases exponentially in the interval B following tc. For those familiar with reliability theory, region A is called the "burn in" phase and B is the "wear out" phase. Using the exponents of the hyperbolic and exponential phases, we introduce a new 2 dimensional map of diseases. This permits the classification of diseases into three broad classes: AS1, AS2 and S. Class AS1 includes all diseases arising from congenital malformations which dominate infant and child mortality; class AS2 includes degenerative diseases such as dementia and Alzheimer's which dominate old age mortality. In class S, which includes most infectious and metabolic diseases, the exponents from both aging phases contribute to positions on the map. Cancer is one of these mixed cases but is closer to class AS2 than AS1. A second line classification is needed to resolve S cases and to this end we introduce a 3rd dimension, namely (calendar) time. Using historical data we show that in their response to treatment (particularly vaccination), S diseases fall into three sub-classes. (i) Class E diseases (e.g. measles or meningococcal disease) which have been almost eliminated at all ages (ii) class C diseases (e.g. tuberculosis) which can be cured but whose cure becomes less effective at old age. (iii) Class U diseases for which radical cures are still unknown. Regarding the future, the fact that the wear-out process of numerous diseases already starts around the age of 25 means that a major extension of the human lifespan beyond 120 certainly also requires to uncover the secret of the "elixir of eternal youth" which has driven timeless human efforts and still seems unlikely in the foreseeable future.

VizieR Online Data Catalog: CNSS pilot survey (Mooley+, 2016)

NASA Astrophysics Data System (ADS)

Mooley, K. P.; Hallinan, G.; Bourke, S.; Horesh, A.; Myers, S. T.; Frail, D. A.; Kulkarni, S. R.; Levitan, D. B.; Kasliwal, M. M.; Cenko, S. B.; Cao, Y.; Bellm, E.; Laher, R. R.

2017-11-01

The radio observations were carried out across four epochs (E1-E4) with the Jansky VLA in B array configuration, and S band was chosen to maximize survey speed. The optical survey, designed to be contemporaneous with the radio survey, was carried out with the 1.2-m (48-inch) Samuel Oschin Telescope at the Palomar Observatory as part of the Palomar Transient Factory (PTF). (1 data file).

Genetic epidemiology of type 2 diabetes and cardiovascular diseases in Africa.

PubMed

Tekola-Ayele, Fasil; Adeyemo, Adebowale A; Rotimi, Charles N

2013-01-01

The burdens of type 2 diabetes (T2D) and cardiovascular diseases (CVD) are increasing in Africa. T2D and CVD are the result of the complex interaction between inherited characteristics, lifestyle, and environmental factors. The epidemic of obesity is largely behind the exploding global incidence of T2D. However, not all obese individuals develop diabetes and positive family history is a powerful risk factor for diabetes and CVD. Recent implementations of high throughput genotyping and sequencing approaches have advanced our understanding of the genetic basis of diabetes and CVD by identifying several genomic loci that were not previously linked to the pathobiology of these diseases. However, African populations have not been adequately represented in these global genomic efforts. Here, we summarize the state of knowledge of the genetic epidemiology of T2D and CVD in Africa and highlight new genomic initiatives that promise to inform disease etiology, public health and clinical medicine in Africa. © 2013.

Intra-Arterial Delivery of AAV Vectors to the Mouse Brain After Mannitol Mediated Blood Brain Barrier Disruption

PubMed Central

Santillan, Alejandro; Sondhi, Dolan; Dyke, Jonathan P.; Crystal, Ronald G.; Gobin, Y. Pierre; Ballon, Douglas J.

2014-01-01

The delivery of therapeutics to neural tissue is greatly hindered by the blood brain barrier (BBB). Direct local delivery via diffusive release from degradable implants or direct intra-cerebral injection can bypass the BBB and obtain high concentrations of the therapeutic in the targeted tissue, however the total volume of tissue that can be treated using these techniques is limited. One treatment modality that can potentially access large volumes of neural tissue in a single treatment is intra-arterial (IA) injection after osmotic blood brain barrier disruption. In this technique, the therapeutic of interest is injected directly into the arteries that feed the target tissue after the blood brain barrier has been disrupted by exposure to a hyperosmolar mannitol solution, permitting the transluminal transport of the therapy. In this work we used contrast enhanced magnetic resonance imaging (MRI) studies of IA injections in mice to establish parameters that allow for extensive and reproducible BBB disruption. We found that the volume but not the flow rate of the mannitol injection has a significant effect on the degree of disruption. To determine whether the degree of disruption we observed with this method was sufficient for delivery of nanoscale therapeutics, we performed IA injections of an adeno-associated viral vector containing the CLN2 gene (AAVrh.10CLN2), which is mutated in the lysosomal storage disorder Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL). We demonstrated that IA injection of AAVrh.10CLN2 after BBB disruption can achieve widespread transgene production in the mouse brain after a single administration. Further, we showed that there exists a minimum threshold of BBB disruption necessary to permit the AAV.rh10 vector to pass into the brain parenchyma from the vascular system. These results suggest that IA administration may be used to obtain widespread delivery of nanoscale therapeutics throughout the murine brain after a single

Extrahepatic Diseases and NAFLD: The Triangular Relationship between NAFLD, Type 2-Diabetes and Dysbiosis.

PubMed

Scorletti, Eleonora; Byrne, Christopher D

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver diseases from simple steatosis with hepatic lipid accumulation to end-stage liver disease with decompensated cirrhosis, liver failure and hepatocellular carcinoma. Recent data from the USA showed that in 2013, NAFLD was the second most frequent indication for liver transplantation behind hepatitis C. Since there are now effective treatments for hepatitis C and there is currently no licensed treatment for NAFLD, it has been predicted that over the next 10-15 years, NAFLD will replace hepatitis C as the most frequent indication for liver transplantation. Besides, increasing the risk of hepatocellular carcinoma and end-stage liver disease, it has recently become clear that NAFLD also increases risk of extrahepatic diseases such as type 2 diabetes mellitus (T2DM), cardiovascular disease, cardiac diseases and chronic kidney disease, to name but a few. Of each of these extrahepatic diseases, the evidence to date suggests that NAFLD is a strong risk factor for T2DM. When NAFLD occurs in combination with obesity and insulin resistance (as it frequently does), there is a marked increase in risk of incident T2DM with possible synergism occurring between liver fat accumulation, insulin resistance and obesity to further increase risk of development of T2DM. Thus, there is a reciprocal relationship between NAFLD as a risk factor for T2DM, and T2DM as a risk factor for liver disease progression in NAFLD. Moreover, recent evidence now points to the importance of perturbation of the intestinal microbiota (dysbiosis) in both T2DM and NAFLD. Consequently, there is a triangular relationship between dysbiosis and T2DM and NAFLD. This review will focus on T2DM as a key extrahepatic complication of NAFLD and will describe and discuss the triangular relationship between dysbiosis and T2DM and NAFLD and the factors and potential mechanisms underpinning this relationship. © 2016 S. Karger AG, Basel.

Hyaluronic Acid and Polyethylene Glycol Hybrid Hydrogel Encapsulating Nanogel with Hemostasis and Sustainable Antibacterial Property for Wound Healing.

PubMed

Zhu, Jie; Li, Faxue; Wang, Xueli; Yu, Jianyong; Wu, Dequn

2018-04-25

Immediate hemorrhage control and anti-infection play important roles in the wound management. Besides, a moist environment is also beneficial for wound healing. Hydrogels are promising materials in urgent hemostasis and drug release. However, hydrogels have the disadvantage of rapid release profiles, leading to the exposure to high drug concentrations. In this study, we constructed hybrid hydrogels with rapid hemostasis and sustainable antibacterial property combining aminoethyl methacrylate hyaluronic acid (HA-AEMA) and methacrylated methoxy polyethylene glycol (mPEG-MA) hybrid hydrogels and chlorhexidine diacetate (CHX)-loaded nanogels. The CHX-loaded nanogels (CLNs) were prepared by the enzyme degradation of CHX-loaded lysine-based hydrogels. The HA-AEMA and mPEG-MA hybrid hydrogel loaded with CLNs (labeled as Gel@CLN) displayed a three-dimensional microporous structure and exhibited excellent swelling, mechanical property, and low cytotoxicity. The Gel@CLN hydrogel showed a prolonged release period of CHX over 240 h and the antibacterial property over 10 days. The hemostasis and wound-healing properties were evaluated in vivo using a mouse model. The results showed that hydrogel had the rapid hemostasis capacity and accelerated wound healing. In summary, CLN-loaded hydrogels may be excellent candidates as hemostasis and anti-infection materials for the wound dressing application.

Lack of association of the two polymorphisms in alpha-2 macroglobulin with Alzheimer disease.

PubMed

Poduslo, S E; Shook, B; Drigalenko, E; Yin, X

2002-06-01

Alzheimer disease is a complex neurodegenerative disorder that is characterized by cognitive decline and distinct neuropathology. The gene for alpha-2 macroglobulin (A2M) on chromosome 12 has two polymorphisms that, in some cases, are associated with Alzheimer disease. We examined these two polymorphisms in our families in the DNA Bank (a collection of DNA samples from families with Alzheimer disease in Texas). Using both association studies and sib transmission/disequilibrium tests, we found no association of the two polymorphisms with the disease in our collection. In addition, we did not find an association of the disease with the two polymorphisms in A2M in a small subset of National Institute of Mental Health (NIMH) families. Thus, our studies do not support the A2M polymorphisms as a risk factor for Alzheimer disease. Copyright 2002 Wiley-Liss, Inc.

Is there a cluster in the massive star forming region IRAS 20126+4104?

NASA Astrophysics Data System (ADS)

Montes, V. A.; Hofner, Peter; Anderson, C.; Rosero, V.

2017-03-01

A Chandra X-ray Observatory ACIS-I observation and a 6 cm continuum radio observation with the Karl G. Jansky Very Large Array (VLA) together with a multiwavelength study in infrared (2MASS and Spitzer) and optical (USNO-B1.0) shows an increasing surface density of X-ray sources toward the massive protostar. There are at least 43 YSOs within 1.2 pc distance from the massive protostar. This number is consistent with typical B-type stars clusters (Lada & Lada 2003).

Emerging links between type 2 diabetes and Alzheimer’s disease

PubMed Central

Sridhar, Gumpeny R; Lakshmi, Gumpeny; Nagamani, Gumpeny

2015-01-01

Type 2 diabetes mellitus and Alzheimer’s disease are both associated with increasing age, and each increases the risk of development of the other. Epidemiological, clinical, biochemical and imaging studies have shown that elevated glucose levels and diabetes are associated with cognitive dysfunction, the most prevalent cause of which is Alzheimer’s disease. Cross sectional studies have clearly shown such an association, whereas longitudinal studies are equivocal, reflecting the many complex ways in which the two interact. Despite the dichotomy, common risk and etiological factors (obesity, dyslipidemia, insulin resistance, and sedentary habits) are recognized; correction of these by lifestyle changes and pharmacological agents can be expected to prevent or retard the progression of both diseases. Common pathogenic factors in both conditions span a broad sweep including chronic hyperglycemia per se, hyperinsulinemia, insulin resistance, acute hypoglycemic episodes, especially in the elderly, microvascular disease, fibrillar deposits (in brain in Alzheimer’s disease and in pancreas in type 2 diabetes), altered insulin processing, inflammation, obesity, dyslipidemia, altered levels of insulin like growth factor and occurrence of variant forms of the protein butyrylcholinesterase. Of interest not only do lifestyle measures have a protective effect against the development of cognitive impairment due to Alzheimer’s disease, but so do some of the pharmacological agents used in the treatment of diabetes such as insulin (especially when delivered intranasally), metformin, peroxisome proliferator-activated receptors γ agonists, glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes must be recognized as a risk for development of Alzheimer’s disease; clinicians must ensure preventive care be given to control and postpone both conditions, and to identify cognitive impairment early to manage it appropriately. PMID:26069723

Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease.

PubMed

West, Andrew B

2017-12-01

In the translation of discoveries from the laboratory to the clinic, the track record in developing disease-modifying therapies in neurodegenerative disease is poor. A carefully designed development pipeline built from discoveries in both pre-clinical models and patient populations is necessary to optimize the chances for success. Genetic variation in the leucine-rich repeat kinase two gene (LRRK2) is linked to Parkinson disease (PD) susceptibility. Pathogenic mutations, particularly those in the LRRK2 GTPase (Roc) and COR domains, increase LRRK2 kinase activities in cells and tissues. In some PD models, small molecule LRRK2 kinase inhibitors that block these activities also provide neuroprotection. Herein, the genetic and biochemical evidence that supports the involvement of LRRK2 kinase activity in PD susceptibility is reviewed. Issues related to the definition of a therapeutic window for LRRK2 inhibition and the safety of chronic dosing are discussed. Finally, recommendations are given for a biomarker-guided initial entry of LRRK2 kinase inhibitors in PD patients. Four key areas must be considered for achieving neuroprotection with LRRK2 kinase inhibitors in PD: 1) identification of patient populations most likely to benefit from LRRK2 kinase inhibitors, 2) prioritization of superior LRRK2 small molecule inhibitors based on open disclosures of drug performance, 3) incorporation of biomarkers and empirical measures of LRRK2 kinase inhibition in clinical trials, and 4) utilization of appropriate efficacy measures guided in part by rigorous pre-clinical modeling. Meticulous and rational development decisions can potentially prevent incredibly costly errors and provide the best chances for LRRK2 inhibitors to slow the progression of PD. Copyright © 2017 The Author. Published by Elsevier Inc. All rights reserved.

Periodontal disease in Hispanic Americans with type 2 diabetes.

PubMed

Novak, M John; Potter, Richard M; Blodgett, Janet; Ebersole, Jeffrey L

2008-04-01

Diabetes is a major risk factor for the development of periodontal disease in certain populations. The prevalence of type 2 diabetes is increased in Hispanic Americans, but its impact on the extent and severity of periodontal disease in this population has not been determined. Sixty-three Hispanic Americans, aged 33 to 72 years, from South Texas were grouped based on the presence or absence of type 2 diabetes. Past medical histories, including smoking, were obtained. Periodontal status was evaluated by measuring probing depth (PD), clinical attachment level (CAL), plaque, bleeding on probing, visual gingival inflammation, and calculus. Type 2 diabetes was associated frequently with major medical complications in this population. Diabetes was associated with significantly more calculus formation and tooth loss and an increased extent and severity of periodontitis. Subjects with diabetes had nearly three times the mean CAL and frequency of PD >6 mm than subjects without diabetes and nearly twice the frequency of moderate to advanced attachment loss (> or =3 mm). Smoking and diabetes had significant independent effects on mean CAL and the frequency of deep pockets. Diabetes and smoking combined were associated with a significantly higher frequency of sites with CAL > or =3 mm compared to healthy non-smokers, healthy smokers, and non-smokers with diabetes. Hispanic Americans with type 2 diabetes had more supra- and subgingival calculus, an increased extent and severity of periodontal destruction, and an increased frequency of tooth loss due to periodontitis. An additive/synergistic contribution of type 2 diabetes and smoking for increasing the extent of periodontal disease was observed.

Habitual coffee consumption and risk of type 2 diabetes, ischemic heart disease, depression and Alzheimer’s disease: a Mendelian randomization study

PubMed Central

Kwok, Man Ki; Leung, Gabriel M.; Schooling, C. Mary

2016-01-01

Observationally, coffee is inversely associated with type 2 diabetes mellitus (T2DM), depression and Alzheimer’s disease, but not ischemic heart disease (IHD). Coffee features as possibly protective in the 2015 Dietary Guidelines for Americans. Short-term trials suggest coffee has neutral effect on most glycemic traits, but raises lipids and adiponectin. To clarify we compared T2DM, depression, Alzheimer’s disease, and IHD and its risk factors by genetically predicted coffee consumption using two-sample Mendelian randomization applied to large extensively genotyped case-control and cross-sectional studies. Childhood cognition was used as a negative control outcome. Genetically predicted coffee consumption was not associated with T2DM (odds ratio (OR) 1.02, 95% confidence interval (CI) 0.76 to 1.36), depression (0.89, 95% CI 0.66 to 1.21), Alzheimer’s disease (1.17, 95% CI 0.96 to 1.43), IHD (0.96, 95% CI 0.80 to 1.14), lipids, glycemic traits, adiposity or adiponectin. Coffee was unrelated to childhood cognition. Consistent with observational studies, coffee was unrelated to IHD, and, as expected, childhood cognition. However, contrary to observational findings, coffee may not have beneficial effects on T2DM, depression or Alzheimer’s disease. These findings clarify the role of coffee with relevance to dietary guidelines and suggest interventions to prevent these complex chronic diseases should be sought elsewhere. PMID:27845333

Laser detection of CO2 concentration in human breath at various diseases

NASA Astrophysics Data System (ADS)

Ageev, Boris G.; Nikiforova, Olga Y.

2015-12-01

Absorption spectra of human breath in 10 μm region were recorded by the use of intracavity laser photo-acoustic gas analyzer based on tunable waveguide CO2 laser. Healthy persons and patients with various diseases were studied. For determination of CO2 concentration in exhalation samples gas analyzer was calibrated by reference gaseous mixture CO2-N2. It was obtained that CO2 concentration values in human breath of healthy persons are greater than that of patients with various diseases.

Origin of porcine circovirus type 2 (PCV2) from swine affected by PCV2-associated diseases in Croatia.

PubMed

Novosel, D; Tuboly, T; Csagola, A; Lorincz, M; Cubric-Curik, V; Jungic, A; Curik, I; Segalés, J; Cortey, M; Lipej, Z

2014-04-26

Porcine circovirus type 2 (PCV2) causes some of the most significant economic losses in pig production. Several multisystemic syndromes have been attributed to PCV2 infection, which are known as PCV2-associated diseases (PCVDs). This study investigated the origin and evolution of PCV2 sequences in domestic pigs and wild boars affected by PCVDs in Croatia. Viral sequences were recovered from three wild boars diagnosed with PCV2-systemic disease (PCV2-SD), 63 fetuses positive for PCV2 DNA as determined by PCR, 14 domestic pigs affected with PCV2-SD (displaying severe interstitial nephritis) and five domestic pigs with proliferative and necrotising pneumonia. Seventeen complete PCV2 genomes were recovered. Phylogenetic and evolutionary analyses based on median-joining phylogenetic networks, amino acid alignments and principal coordinate analysis were performed using complete genomes, as well as complete and partial ORF sequences for ORF1 and ORF2. Two of the 17 PCV2 sequences belonged to PCV2a, 14 to PCV2b and one was unclustered. PCV2b was the predominant genotype in Croatia and has been linked to international trade as a route of introduction. Correlation between particular viral strains with PCVDs is lacking.

CLC-2 single nucleotide polymorphisms (SNPs) as potential modifiers of cystic fibrosis disease severity

PubMed Central

Blaisdell, Carol J; Howard, Timothy D; Stern, Augustus; Bamford, Penelope; Bleecker, Eugene R; Stine, O Colin

2004-01-01

Background Cystic fibrosis (CF) lung disease manifest by impaired chloride secretion leads to eventual respiratory failure. Candidate genes that may modify CF lung disease severity include alternative chloride channels. The objectives of this study are to identify single nucleotide polymorphisms (SNPs) in the airway epithelial chloride channel, CLC-2, and correlate these polymorphisms with CF lung disease. Methods The CLC-2 promoter, intron 1 and exon 20 were examined for SNPs in adult CF dF508/dF508 homozygotes with mild and severe lung disease (forced expiratory volume at one second (FEV1) > 70% and < 40%). Results PCR amplification of genomic CLC-2 and sequence analysis revealed 1 polymorphism in the hClC -2 promoter, 4 in intron 1, and none in exon 20. Fisher's analysis within this data set, did not demonstrate a significant relationship between the severity of lung disease and SNPs in the CLC-2 gene. Conclusions CLC-2 is not a key modifier gene of CF lung phenotype. Further studies evaluating other phenotypes associated with CF may be useful in the future to assess the ability of CLC-2 to modify CF disease severity. PMID:15507145

Inducible CYP2J2 and its product 11,12-EET promotes bacterial phagocytosis: a role for CYP2J2 deficiency in the pathogenesis of Crohn's disease?

PubMed

Bystrom, Jonas; Thomson, Scott J; Johansson, Jörgen; Edin, Matthew L; Zeldin, Darryl C; Gilroy, Derek W; Smith, Andrew M; Bishop-Bailey, David

2013-01-01

The epoxygenase CYP2J2 has an emerging role in inflammation and vascular biology. The role of CYP2J2 in phagocytosis is not known and its regulation in human inflammatory diseases is poorly understood. Here we investigated the role of CYP2J2 in bacterial phagocytosis and its expression in monocytes from healthy controls and Crohns disease patients. CYP2J2 is anti-inflammatory in human peripheral blood monocytes. Bacterial LPS induced CYP2J2 mRNA and protein. The CYP2J2 arachidonic acid products 11,12-EET and 14,15-EET inhibited LPS induced TNFα release. THP-1 monocytes were transformed into macrophages by 48h incubation with phorbol 12-myristate 13-acetate. Epoxygenase inhibition using a non-selective inhibitor SKF525A or a selective CYP2J2 inhibitor Compound 4, inhibited E. coli particle phagocytosis, which could be specifically reversed by 11,12-EET. Moreover, epoxygenase inhibition reduced the expression of phagocytosis receptors CD11b and CD68. CD11b also mediates L. monocytogenes phagocytosis. Similar, to E. coli bioparticle phagocytosis, epoxygenase inhibition also reduced intracellular levels of L. monocytogenes, which could be reversed by co-incubation with 11,12-EET. Disrupted bacterial clearance is a hallmark of Crohn's disease. Unlike macrophages from control donors, macrophages from Crohn's disease patients showed no induction of CYP2J2 in response to E. coli. These results demonstrate that CYP2J2 mediates bacterial phagocytosis in macrophages, and implicates a defect in the CYP2J2 pathway may regulate bacterial clearance in Crohn's disease.

The Tie2 receptor antagonist angiopoietin-2 in systemic lupus erythematosus: its correlation with various disease activity parameters.

PubMed

Salama, Maysa K; Taha, Fatma M; Safwat, Miriam; Darweesh, Hanan E A; Basel, Mohamed El

2012-01-01

Systemic lupus erythematosus is one of the autoimmune diseases characterized by multisystem involvement associated with autoantibody and immune complex vasculitis along with endothelial cell damage. to study the possible role of Angiopoietin- 2 (Ang-2) as a recently highlighted inflammatory and angiogenic mediator in the pathogenesis of SLE and its correlation with the state of another inflammatory marker, P-Selectin, as well as with various markers of the disease activity. The present study included 3 main groups: active SLE patients (group I), inactive SLE patients (group II) and healthy normal control subjects (group III). Groups I and II were subjected to disease activity assessment using the SLEDAI scoring system and measurement of plasma Ang-2 and P-Selectin by ELISA in addition to various laboratory investigations to assess disease activity as: Complete blood count, ESR, serum creatinine, C3, C4 and 24-h urinary proteins. The mean level of Plasma Ang-2 and P-selectin showed a high significant increase in active group compared to inactive SLE patients and control subjects (p < 0.001).There was a significant positive correlation between Ang-2, P-Selectin, and each of SLEDAI score and 24-h urinary proteins in all SLE patients as well as in the active group, and Ang-2 was a significant independent marker for proteinuria. A significant negative correlation was found between Ang-2, P-Selectin and each of C3, C4. Ang-2 and P-Selectin showed a high sensitivity and specificity in the patients with SLE. Our study suggests that Ang-2 may be a more useful marker than P-Selectin, C3 and C4 in the assessment of disease activity.

Microfibril-associated glycoproteins MAGP-1 and MAGP-2 in disease.

PubMed

Craft, Clarissa S; Broekelmann, Thomas J; Mecham, Robert P

2018-03-07

Microfibril-associated glycoproteins 1 and 2 (MAGP-1, MAGP-2) are protein components of extracellular matrix microfibrils. These proteins interact with fibrillin, the core component of microfibrils, and impart unique biological properties that influence microfibril function in vertebrates. MAGPs bind active forms of TGFβ and BMPs and are capable of modulating Notch signaling. Mutations in MAGP-1 or MAGP-2 have been linked to thoracic aneurysms and metabolic disease in humans. MAGP-2 has also been shown to be an important biomarker in several human cancers. Mice lacking MAGP-1 or MAGP-2 have defects in multiple organ systems, which reflects the widespread distribution of microfibrils in vertebrate tissues. This review summarizes our current understanding of the function of the MAGPs and their relationship to human disease. Copyright © 2017 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.

Significance of the genetic polymorphism of CYP2D6 and NAT2 in patients with inflammatory bowel diseases.

PubMed

Dudarewicz, Michał; Rychlik-Sych, Mariola; Barańska, Małgorzata; Wojtczak, Anna; Trzciński, Radzisław; Dziki, Adam; Skrętkowicz, Jadwiga

2014-08-01

The main types of inflammatory bowel diseases (IBD) are ulcerative colitis (UC) and Crohn's disease (CD). There is evidence that, in addition to immunological and environmental factors, genetic factors also play an important role in the pathogenesis of IBD. Determination of polymorphism of CYP2D6 and NAT2 genes encoding I and II phase enzymes of xenobiotic biotransformation may have clinical value as an indicator of individual predisposition to diseases, and also contribute to effective and safe pharmacotherapy. The aim of this study was to investigate the association between genetic polymorphism of CYP2D6 and NAT2 and the incidence of IBD, including UC and CD, among inhabitants of central Poland. The study was performed in 258 individuals from central Poland (115 patients with IBD, including 65 patients with UC and 50 with CD; and in 143 healthy controls). The CYP2D6 genotypes of oxidation and NAT2 genotypes of acetylation were analyzed using the PCR-RFLP method. There were no statistically significant differences in the frequency of the CYP2D6 genotypes and alleles in patients with IBD, UC and CD in comparison with the control group. The relative risk (OR) of IBD, UC and CD was higher in carriers of the allele NAT2*7 and was OR=3.49 (p=0.0019), OR=3.86 (p=0.0019), and OR=3.02 (p=0.0247), respectively. Polymorphism of the gene encoding CYP2D6 does not affect the incidence of inflammatory bowel diseases. The carriers of the NAT2*7 allele which determines slow acetylation may be more predisposed to inflammatory bowel diseases, including ulcerative colitis and Crohn's disease. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Web 2.0 chronic disease self-management for older adults: a systematic review.

PubMed

Stellefson, Michael; Chaney, Beth; Barry, Adam E; Chavarria, Enmanuel; Tennant, Bethany; Walsh-Childers, Kim; Sriram, P S; Zagora, Justin

2013-02-14

Participatory Web 2.0 interventions promote collaboration to support chronic disease self-management. Growth in Web 2.0 interventions has led to the emergence of e-patient communication tools that enable older adults to (1) locate and share disease management information and (2) receive interactive healthcare advice. The evolution of older e-patients contributing to Web 2.0 health and medical forums has led to greater opportunities for achieving better chronic disease outcomes. To date, there are no review articles investigating the planning, implementation, and evaluation of Web 2.0 chronic disease self-management interventions for older adults. To review the planning, implementation, and overall effectiveness of Web 2.0 self-management interventions for older adults (mean age ≥ 50) with one or more chronic disease(s). A systematic literature search was conducted using six popular health science databases. The RE-AIM (Reach, Efficacy, Adoption, Implementation and Maintenance) model was used to organize findings and compute a study quality score (SQS) for 15 reviewed articles. Most interventions were adopted for delivery by multidisciplinary healthcare teams and tested among small samples of white females with diabetes. Studies indicated that Web 2.0 participants felt greater self-efficacy for managing their disease(s) and benefitted from communicating with health care providers and/or website moderators to receive feedback and social support. Participants noted asynchronous communication tools (eg, email, discussion boards) and progress tracking features (eg, graphical displays of uploaded personal data) as being particularly useful for self-management support. Despite high attrition being noted as problematic, this review suggests that greater Web 2.0 engagement may be associated with improvements in health behaviors (eg, physical activity) and health status (eg, HRQoL). However, few studies indicated statistically significant improvements in medication

Circulating angiotensin-converting enzyme 2 activity in patients with chronic kidney disease without previous history of cardiovascular disease.

PubMed

Anguiano, Lidia; Riera, Marta; Pascual, Julio; Valdivielso, José Manuel; Barrios, Clara; Betriu, Angels; Mojal, Sergi; Fernández, Elvira; Soler, María José

2015-07-01

Patients with cardiovascular (CV) disease have an increased circulating angiotensin-converting enzyme 2 (ACE2) activity, but there is little information about changes in ACE2 in chronic kidney disease (CKD) patients without history of CV disease. We examined circulating ACE2 activity in CKD patients at stages 3-5 (CKD3-5) and in dialysis (CKD5D) without any history of CV disease. Circulating ACE2 activity was measured in human ethylenediamine-tetraacetic acid (EDTA)-plasma samples from the NEFRONA study (n = 2572): control group (CONT) (n = 568), CKD3-5 (n = 1458) and CKD5D (n = 546). Different clinical and analytical variables such as gender; age; history of diabetes mellitus (DM), dyslipidemia and hypertension; glycaemic, renal, lipid and anaemia profiles; vitamin D analogues treatment and antihypertensive treatments (angiotensin-converting enzyme inhibitor and angiotensin receptor blockade) were analysed. Circulating ACE2 and ACE activities were measured using modified fluorimetric assay for EDTA-plasma samples, where zinc chloride was added to recover enzymatic activity. In CKD3-5 and CKD5D, significant decrease in circulating ACE2 activity was observed when compared with CONT, but no differences were found between CKD3-5 and CKD5 when performing paired case-control studies. By multivariate linear regression analysis, male gender and advanced age were identified as independent predictors of ACE2 activity in all groups. Diabetes was identified as independent predictor of ACE2 activity in CKD3-5. Significant increase in the activity of circulating ACE was found in CKD3-5 and CKD5D when compared with CONT and in CKD5D when compared with CKD3-5. By multiple regression analysis, female gender and younger age were identified as independent predictors of ACE activity in CONT and CKD3-5. Diabetes was also identified as an independent predictor of ACE activity in CKD3-5 patients. Circulating ACE2 and ACE activities can be measured in human EDTA-plasma samples with zinc

[Etiological analysis of 264 cases with chronic kidney disease stage 2 to 5 in children].

PubMed

Miao, Qianfan; Shen, Qian; Xu, Hong; Sun, Li; Tang, Xiaoshan; Fang, Xiaoyan; Liu, Haimei; Zhai, Yihui; Bi, Yunli; Wang, Xiang; Chen, Hong

2015-09-01

To study and summarize the etiology of children patients with chronic kidney disease (CKD) stage 2 to 5 seen in Children's Hospital of Fudan University from Jan. 2004 to Dec. 2013. By complying with the NKF-K/DOQI guidelines, we collected data of 264 cases of children patients with CKD stage 2-5 from Jan. 2004 to Dec. 2013 in the medical record system of Children's Hospital of Fudan University. And we retrospectively analyzed their age and CKD stage at first diagnosis, primary diseases, complications, etc. In the collected 264 cases, 52 cases (19.7%) were diagnosed at stage 2, 67 (25.4%) at stage 3, 52 (19.7%) at stage 4 and 93 (35.2%) at stage 5. For disease causes, 116 cases (43.9%) had congenital anomalies of the kidney and urinary tract (CAKUT), 61 cases (23.1%) had glomerular disease, 15 (5.7%) had hereditary kidney disease, 14 (5.3%) had other diseases and in 58 cases (22.0%) the causes of disease were unknown. In the group with age between 0 and 3.0 and 3.1 and 6.0 years, 57.1% (24 cases) and 60.0% (30 cases) had primary disease with CAKUT. In the group with age older than 10 years, 49.2% (30 cases) had primary disease with glomerular disease and 32.0% (32 cases) with unknown causes. The major cause of CKD stage 2-5 in children in our hospital during the last ten years was CAKUT (43.9%), followed by glomerular disease (23.1%). The primary diseases of CKD were significantly different between the 2 age groups. CAKUT was more common in infants and preschool children while for adolescents, glomerular disease was the major cause.

JUNCTOPHILIN 3 (JPH3) EXPANSION MUTATIONS CAUSING HUNTINGTON DISEASE LIKE 2 (HDL2) ARE COMMON IN SOUTH AFRICAN PATIENTS WITH AFRICAN ANCESTRY AND A HUNTINGTON DISEASE PHENOTYPE

PubMed Central

Krause, A; Mitchell, CL; Essop, F; Tager, S; Temlett, J; Stevanin, G; Ross, CA; Rudnicki, DD; Margolis, RL

2015-01-01

Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder, characterized by abnormal movements, cognitive decline and psychiatric symptoms, caused by a CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4p. A CAG/CTG repeat expansion in the junctophilin-3 (JPH3) gene on chromosome 16q24.2 causes a Huntington disease-like phenotype (HDL2). All patients to date with HDL2 have some African ancestry. The present study aimed to characterize the genetic basis of the Huntington disease phenotype in South Africans and to investigate the possible origin of the JPH3 mutation. In a sample of unrelated South African individuals referred for diagnostic HD testing, 62% (106/171) of white patients compared to only 36% (47/130) of black patients had an expansion in HTT. However, 15% (20/130) of black South African patients and no white patients (0/171) had an expansion in JPH3, confirming the diagnosis of Huntington disease like 2 (HDL2). Individuals with HDL2 share many clinical features with individuals with HD and are clinically indistinguishable in many cases, although the average age of onset and diagnosis in HDL2 is 5 years later than HD and individual clinical features may be more prominent. HDL2 mutations contribute significantly to the HD phenotype in South Africans with African ancestry. JPH3 haplotype studies in 31 families, mainly from South Africa and North America, provide evidence for a founder mutation and support a common African origin for all HDL2 patients. Molecular testing in individuals with an HD phenotype and African ancestry should include testing routinely for JPH3 mutations. PMID:26079385

Cardiovascular Disease, Cancer, and Mortality Among People With Type 2 Diabetes and Alcoholic or Nonalcoholic Fatty Liver Disease Hospital Admission.

PubMed

Wild, Sarah H; Walker, Jeremy J; Morling, Joanne R; McAllister, David A; Colhoun, Helen M; Farran, Bassam; McGurnaghan, Stuart; McCrimmon, Rory; Read, Stephanie H; Sattar, Naveed; Byrne, Christopher D

2018-02-01

To describe associations between alcoholic liver disease (ALD) or nonalcoholic fatty liver disease (NAFLD) hospital admission and cardiovascular disease (CVD), cancer, and mortality in people with type 2 diabetes mellitus (T2DM). We performed a retrospective cohort study by using linked population-based routine data from diabetes registry, hospital, cancer, and death records for people aged 40-89 years diagnosed with T2DM in Scotland between 2004 and 2013 who had one or more hospital admission records. Liver disease and outcomes were identified by using ICD-9 and ICD-10 codes. We estimated hazard ratios (HRs) from Cox proportional hazards regression models, adjusting for key risk factors. A total of 134,368 people with T2DM (1,707 with ALD and 1,452 with NAFLD) were studied, with a mean follow-up of 4.3 years for CVD and 4.7 years for mortality. Among those with ALD, NAFLD, or without liver disease hospital records 378, 320, and 21,873 CVD events; 268, 176, and 15,101 cancers; and 724, 221, and 16,203 deaths were reported, respectively. For ALD and NAFLD, respectively, adjusted HRs (95% CIs) compared with the group with no record of liver disease were 1.59 (1.43, 1.76) and 1.70 (1.52, 1.90) for CVD, 40.3 (28.8, 56.5) and 19.12 (11.71, 31.2) for hepatocellular carcinoma (HCC), 1.28 (1.12, 1.47) and 1.10 (0.94, 1.29) for non-HCC cancer, and 4.86 (4.50, 5.24) and 1.60 (1.40, 1.83) for all-cause mortality. Hospital records of ALD or NAFLD are associated to varying degrees with an increased risk of CVD, cancer, and mortality among people with T2DM. © 2017 by the American Diabetes Association.

Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease.

PubMed

Eriksson, D; Bianchi, M; Landegren, N; Nordin, J; Dalin, F; Mathioudaki, A; Eriksson, G N; Hultin-Rosenberg, L; Dahlqvist, J; Zetterqvist, H; Karlsson, Å; Hallgren, Å; Farias, F H G; Murén, E; Ahlgren, K M; Lobell, A; Andersson, G; Tandre, K; Dahlqvist, S R; Söderkvist, P; Rönnblom, L; Hulting, A-L; Wahlberg, J; Ekwall, O; Dahlqvist, P; Meadows, J R S; Bensing, S; Lindblad-Toh, K; Kämpe, O; Pielberg, G R

2016-12-01

Autoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology. To understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls. We identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 × 10 -15 , MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex. Whilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment. © 2016 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

Worse renal disease in postmenopausal F2[Dahl S x R]-intercross rats: detection of novel QTLs affecting hypertensive kidney disease.

PubMed

Herrera, Victoria L M; Pasion, Khristine A; Moran, Ann Marie; Ruiz-Opazo, Nelson

2013-01-01

The prevalence of hypertension increases after menopause with 75% of postmenopausal women developing hypertension in the United States, along with hypertensive end organ diseases. While human and animal model studies have indicated a protective role for estrogen against cardiovascular disease and glomerulosclerosis, clinical studies of hormone replacement therapy in postmenopausal women have shown polar results with some improvement in hypertension but worsening of hypertensive kidney disease, or no effect at all. These observations suggest that the pathogenesis of postmenopausal hypertension and its target organ complications is more complex than projected, and that loss of endogenous estrogens induces epigenetic changes that alter genetic susceptibility to end-organ complications per se resulting in pathogenetic mechanisms beyond correction by hormone replacement. We studied postmenopausal-induced changes in renal disease and performed a total genome scan for quantitative trait loci (QTLs) affecting kidney disease in postmenopausal 16m-old F2[Dahl S x R]-intercross female rats. We used glomerular injury score (GIS) as quantitative trait. We compared QTLs amongst premenopausal, ovariectomized and postmenopausal F2[Dahl S x R]-intercross rats using identical phenotype characterization. Postmenopausal F2[Dahl S x R]-intercross rats exhibited increased hypertensive glomerulosclerosis (P<0.01) and equivalent levels of kidney disease when compared to premenopausal and ovariectomized F2[Dahl S x R]-intercross rats respectively. We detected three significant to highly significant GIS-QTLs (GIS-pm1 on chromosome 4, LOD 3.54; GIS-pm2 on chromosome 3, LOD 2.72; GIS-pm3 on chromosome 5, LOD 2.37) and two suggestive GIS-QTLs (GIS-pm4 on chromosome 2, LOD 1.70; GIS-pm5 on chromosome 7, LOD 1.28), all of which were unique to this postmenopausal population. Detection of increased renal disease phenotype in postmenopausal and ovariectomized subjects suggests a protective role of

Worse Renal Disease in Postmenopausal F2[Dahl S x R]-Intercross Rats: Detection of Novel QTLs Affecting Hypertensive Kidney Disease

PubMed Central

Herrera, Victoria L. M.; Pasion, Khristine A.; Moran, Ann Marie; Ruiz-Opazo, Nelson

2013-01-01

The prevalence of hypertension increases after menopause with 75% of postmenopausal women developing hypertension in the United States, along with hypertensive end organ diseases. While human and animal model studies have indicated a protective role for estrogen against cardiovascular disease and glomerulosclerosis, clinical studies of hormone replacement therapy in postmenopausal women have shown polar results with some improvement in hypertension but worsening of hypertensive kidney disease, or no effect at all. These observations suggest that the pathogenesis of postmenopausal hypertension and its target organ complications is more complex than projected, and that loss of endogenous estrogens induces epigenetic changes that alter genetic susceptibility to end-organ complications per se resulting in pathogenetic mechanisms beyond correction by hormone replacement. We studied postmenopausal-induced changes in renal disease and performed a total genome scan for quantitative trait loci (QTLs) affecting kidney disease in postmenopausal 16m-old F2[Dahl S x R]-intercross female rats. We used glomerular injury score (GIS) as quantitative trait. We compared QTLs amongst premenopausal, ovariectomized and postmenopausal F2[Dahl S x R]-intercross rats using identical phenotype characterization. Postmenopausal F2[Dahl S x R]-intercross rats exhibited increased hypertensive glomerulosclerosis (P<0.01) and equivalent levels of kidney disease when compared to premenopausal and ovariectomized F2[Dahl S x R]-intercross rats respectively. We detected three significant to highly significant GIS-QTLs (GIS-pm1 on chromosome 4, LOD 3.54; GIS-pm2 on chromosome 3, LOD 2.72; GIS-pm3 on chromosome 5, LOD 2.37) and two suggestive GIS-QTLs (GIS-pm4 on chromosome 2, LOD 1.70; GIS-pm5 on chromosome 7, LOD 1.28), all of which were unique to this postmenopausal population. Detection of increased renal disease phenotype in postmenopausal and ovariectomized subjects suggests a protective role of

Pentraxin-2 suppresses c-Jun/AP-1 signaling to inhibit progressive fibrotic disease

PubMed Central

Nakagawa, Naoki; Gomez, Ivan G.; Johnson, Bryce G.; Kameoka, Sei; Jack, Richard M.; Lupher, Mark L.; Gharib, Sina A.; Duffield, Jeremy S.

2016-01-01

Pentraxin-2 (PTX-2), also known as serum amyloid P component (SAP/APCS), is a constitutive, antiinflammatory, innate immune plasma protein whose circulating level is decreased in chronic human fibrotic diseases. Here we show that recombinant human PTX-2 (rhPTX-2) retards progression of chronic kidney disease in Col4a3 mutant mice with Alport syndrome, reducing blood markers of kidney failure, enhancing lifespan by 20%, and improving histological signs of disease. Exogenously delivered rhPTX-2 was detected in macrophages but also in tubular epithelial cells, where it counteracted macrophage activation and was cytoprotective for the epithelium. Computational analysis of genes regulated by rhPTX-2 identified the transcriptional regulator c-Jun along with its activator protein–1 (AP-1) binding partners as a central target for the function of rhPTX-2. Accordingly, PTX-2 attenuates c-Jun and AP-1 activity, and reduces expression of AP-1–dependent inflammatory genes in both monocytes and epithelium. Our studies therefore identify rhPTX-2 as a potential therapy for chronic fibrotic disease of the kidney and an important inhibitor of pathological c-Jun signaling in this setting. PMID:27942582

MNDR v2.0: an updated resource of ncRNA–disease associations in mammals

PubMed Central

Cui, Tianyu; Zhang, Lin; Huang, Yan; Yi, Ying; Tan, Puwen; Zhao, Yue; Hu, Yongfei

2018-01-01

Abstract Accumulating evidence suggests that diverse non-coding RNAs (ncRNAs) are involved in the progression of a wide variety of diseases. In recent years, abundant ncRNA–disease associations have been found and predicted according to experiments and prediction algorithms. Diverse ncRNA–disease associations are scattered over many resources and mammals, whereas a global view of diverse ncRNA–disease associations is not available for any mammals. Hence, we have updated the MNDR v2.0 database (www.rna-society.org/mndr/) by integrating experimental and prediction associations from manual literature curation and other resources under one common framework. The new developments in MNDR v2.0 include (i) an over 220-fold increase in ncRNA–disease associations enhancement compared with the previous version (including lncRNA, miRNA, piRNA, snoRNA and more than 1400 diseases); (ii) integrating experimental and prediction evidence from 14 resources and prediction algorithms for each ncRNA–disease association; (iii) mapping disease names to the Disease Ontology and Medical Subject Headings (MeSH); (iv) providing a confidence score for each ncRNA–disease association and (v) an increase of species coverage to six mammals. Finally, MNDR v2.0 intends to provide the scientific community with a resource for efficient browsing and extraction of the associations between diverse ncRNAs and diseases, including >260 000 ncRNA–disease associations. PMID:29106639

Inducible CYP2J2 and Its Product 11,12-EET Promotes Bacterial Phagocytosis: A Role for CYP2J2 Deficiency in the Pathogenesis of Crohn’s Disease?

PubMed Central

Bystrom, Jonas; Thomson, Scott J.; Johansson, Jörgen; Edin, Matthew L.; Zeldin, Darryl C.; Gilroy, Derek W.; Smith, Andrew M.; Bishop-Bailey, David

2013-01-01

The epoxygenase CYP2J2 has an emerging role in inflammation and vascular biology. The role of CYP2J2 in phagocytosis is not known and its regulation in human inflammatory diseases is poorly understood. Here we investigated the role of CYP2J2 in bacterial phagocytosis and its expression in monocytes from healthy controls and Crohns disease patients. CYP2J2 is anti-inflammatory in human peripheral blood monocytes. Bacterial LPS induced CYP2J2 mRNA and protein. The CYP2J2 arachidonic acid products 11,12-EET and 14,15-EET inhibited LPS induced TNFα release. THP-1 monocytes were transformed into macrophages by 48h incubation with phorbol 12-myristate 13-acetate. Epoxygenase inhibition using a non-selective inhibitor SKF525A or a selective CYP2J2 inhibitor Compound 4, inhibited E. coli particle phagocytosis, which could be specifically reversed by 11,12-EET. Moreover, epoxygenase inhibition reduced the expression of phagocytosis receptors CD11b and CD68. CD11b also mediates L. monocytogenes phagocytosis. Similar, to E. coli bioparticle phagocytosis, epoxygenase inhibition also reduced intracellular levels of L. monocytogenes, which could be reversed by co-incubation with 11,12-EET. Disrupted bacterial clearance is a hallmark of Crohn’s disease. Unlike macrophages from control donors, macrophages from Crohn’s disease patients showed no induction of CYP2J2 in response to E. coli. These results demonstrate that CYP2J2 mediates bacterial phagocytosis in macrophages, and implicates a defect in the CYP2J2 pathway may regulate bacterial clearance in Crohn’s disease. PMID:24058654

Alzheimer's Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits

PubMed Central

Chatterjee, Shreyasi; Mudher, Amritpal

2018-01-01

Alzheimer's disease (AD) and Type 2 Diabetes Mellitus (T2DM) are two of the most prevalent diseases in the elderly population worldwide. A growing body of epidemiological studies suggest that people with T2DM are at a higher risk of developing AD. Likewise, AD brains are less capable of glucose uptake from the surroundings resembling a condition of brain insulin resistance. Pathologically AD is characterized by extracellular plaques of Aβ and intracellular neurofibrillary tangles of hyperphosphorylated tau. T2DM, on the other hand is a metabolic disorder characterized by hyperglycemia and insulin resistance. In this review we have discussed how Insulin resistance in T2DM directly exacerbates Aβ and tau pathologies and elucidated the pathophysiological traits of synaptic dysfunction, inflammation, and autophagic impairments that are common to both diseases and indirectly impact Aβ and tau functions in the neurons. Elucidation of the underlying pathways that connect these two diseases will be immensely valuable for designing novel drug targets for Alzheimer's disease. PMID:29950970

Web 2.0 Chronic Disease Self-Management for Older Adults: A Systematic Review

PubMed Central

Chaney, Beth; Barry, Adam E; Chavarria, Enmanuel; Tennant, Bethany; Walsh-Childers, Kim; Sriram, P.S; Zagora, Justin

2013-01-01

Background Participatory Web 2.0 interventions promote collaboration to support chronic disease self-management. Growth in Web 2.0 interventions has led to the emergence of e-patient communication tools that enable older adults to (1) locate and share disease management information and (2) receive interactive healthcare advice. The evolution of older e-patients contributing to Web 2.0 health and medical forums has led to greater opportunities for achieving better chronic disease outcomes. To date, there are no review articles investigating the planning, implementation, and evaluation of Web 2.0 chronic disease self-management interventions for older adults. Objective To review the planning, implementation, and overall effectiveness of Web 2.0 self-management interventions for older adults (mean age ≥ 50) with one or more chronic disease(s). Methods A systematic literature search was conducted using six popular health science databases. The RE-AIM (Reach, Efficacy, Adoption, Implementation and Maintenance) model was used to organize findings and compute a study quality score (SQS) for 15 reviewed articles. Results Most interventions were adopted for delivery by multidisciplinary healthcare teams and tested among small samples of white females with diabetes. Studies indicated that Web 2.0 participants felt greater self-efficacy for managing their disease(s) and benefitted from communicating with health care providers and/or website moderators to receive feedback and social support. Participants noted asynchronous communication tools (eg, email, discussion boards) and progress tracking features (eg, graphical displays of uploaded personal data) as being particularly useful for self-management support. Despite high attrition being noted as problematic, this review suggests that greater Web 2.0 engagement may be associated with improvements in health behaviors (eg, physical activity) and health status (eg, HRQoL). However, few studies indicated statistically

Roles of EphA2 in Development and Disease

PubMed Central

Park, Jeong Eun; Son, Alexander I.; Zhou, Renping

2013-01-01

The Eph family of receptor tyrosine kinases (RTKs) has been implicated in the regulation of many aspects of mammalian development. Recent analyses have revealed that the EphA2 receptor is a key modulator for a wide variety of cellular functions. This review focuses on the roles of EphA2 in both development and disease. PMID:24705208

Heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease.

PubMed

Wang, Wang; Patel, Vaibhav B; Parajuli, Nirmal; Fan, Dong; Basu, Ratnadeep; Wang, Zuocheng; Ramprasath, Tharmarajan; Kassiri, Zamaneh; Penninger, Josef M; Oudit, Gavin Y

2014-08-01

Angiotensin-converting enzyme 2 (ACE2) metabolizes Ang II into Ang 1-7 thereby negatively regulating the renin-angiotensin system. However, heart disease in humans and in animal models is associated with only a partial loss of ACE2. ACE2 is an X-linked gene; and as such, we tested the clinical relevance of a partial loss of ACE2 by using female ACE2(+/+) (wildtype) and ACE2(+/-) (heterozygote) mice. Pressure overload in ACE2(+/-) mice resulted in greater LV dilation and worsening systolic and diastolic dysfunction. These changes were associated with increased myocardial fibrosis, hypertrophy, and upregulation of pathological gene expression. In response to Ang II infusion, there was increased NADPH oxidase activity and myocardial fibrosis resulting in the worsening of Ang II-induced diastolic dysfunction with a preserved systolic function. Ang II-mediated cellular effects in cultured adult ACE2(+/-) cardiomyocytes and cardiofibroblasts were exacerbated. Ang II-mediated pathological signaling worsened in ACE2(+/-) hearts characterized by an increase in the phosphorylation of ERK1/2 and JNK1/2 and STAT-3 pathways. The ACE2(+/-) mice showed an exacerbated pressor response with increased vascular fibrosis and stiffness. Vascular superoxide and nitrotyrosine levels were increased in ACE2(+/-) vessels consistent with increased vascular oxidative stress. These changes occurred with increased renal fibrosis and superoxide production. Partial heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease secondary to pressure overload and Ang II infusion. Heart disease in humans with idiopathic dilated cardiomyopathy is associated with a partial loss of ACE2. Heterozygote female ACE2 mutant mice showed enhanced susceptibility to pressure overload-induced heart disease. Heterozygote female ACE2 mutant mice showed enhanced susceptibility to Ang II-induced heart and vascular diseases. Partial loss of ACE2 is sufficient to enhance the susceptibility to

Pesticides, Microglial NOX2, and Parkinson's disease

PubMed Central

Taetzsch, Thomas; Block, Michelle L.

2013-01-01

Accumulating evidence indicates that pesticide exposure is associated with an increased risk for developing Parkinson's disease (PD). Several pesticides known to damage dopaminergic (DA) neurons, such as paraquat, rotenone, lindane, and dieldrin also demonstrate the ability to activate microglia, the resident innate immune cell in the brain. While each of these environmental toxicants may impact microglia through unique mechanisms, they all appear to converge on a common final pathway of microglial activation: NADPH oxidase 2 (NOX2) activation. This review will detail the role of microglia in selective DA neurotoxicity, highlight what is currently known about the mechanism of microglial NOX2 activation in these key pesticides, and describe the importance for DA neuron survival and PD etiology. PMID:23349115

Human ETS2 gene on chromosome 21 is not rearranged in Alzheimer disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sacchi, N.; Nalbantoglu, J.; Sergovich, F.R.

1988-10-01

The human ETS2 gene, a member of the ETS gene family, with sequence homology with the retroviral ets sequence of the avian erythroblastosis retrovirus E26 is located on chromosome 21. Molecular genetic analysis of Down syndrome (DS) patients with partial trisomy 21 allowed us to reinforce the supposition that ETS2 may be a gene of the minimal DS genetic region. It was originally proposed that a duplication of a portion of the DS region represents the genetic basis of Alzheimer disease, a condition associated also with DS. No evidence of either rearrangements or duplications of ETS2 could be detected inmore » DNA from fibroblasts and brain tissue of Alzheimer disease patients with either the sporadic or the familiar form of the disease. Thus, an altered ETS2 gene dosage does not seem to be a genetic cause or component of Alzheimer disease.« less

The BTNL2 G16071A gene polymorphism increases granulomatous disease susceptibility

PubMed Central

Tong, Xiang; Ma, Yao; Niu, Xundong; Yan, Zhipeng; Liu, Sitong; Peng, Bo; Peng, Shifeng; Fan, Hong

2016-01-01

Abstract Objective: The butyrophilin-like 2 (BTNL2) G16071A gene polymorphism has been implicated in the susceptibility to granulomatous diseases, but the results were inconclusive. The objective of the current study was to precisely explore the relationship between BTNL2 G16071A gene polymorphism and granulomatous disease susceptibility by the meta-analysis including false-positive report probability (FPRP) test. Methods: A systematic literature search in the PubMed, Embase, and Wanfang databases, China National Knowledge Internet, and commercial Internet search engines was conducted to identify studies published up to April 1, 2016. The odds ratio (OR) with 95% confidence interval (CI) was used to assess the effect size. Statistical analysis was conducted using the STATA 12.0 software and FPRP test sheet. Results: In total, all 4324 cases and 4386 controls from 14 eligible studies were included in the current meta-analysis. By the overall meta-analysis, we found a significant association between BTNL2 G16071A gene polymorphism and granulomatous disease susceptibility (A vs G: OR = 1.25, 95% CI = 1.07–1.45, P = 0.005). The meta-regression analyses showed that a large proportion of the between-study heterogeneity was significantly attributed to the ethnicity (A vs G, P = 0.013) and the types of granulomatous diseases (A vs G, P = 0.002). By the subgroup meta-analysis, the BTNL2 G16071A gene polymorphism was associated with granulomatous disease susceptibility in Caucasians (A vs G: OR = 1.37, 95% CI = 1.18–1.58, P < 0.001). Moreover, a significant relationship between the BTNL2 G16071A gene polymorphism and sarcoidosis susceptibility (A vs G: OR = 1.52, 95% CI = 1.39–1.66, P < 0.001) was found. However, to avoid the “false-positive report,” we further investigated the significant associations observed in the present meta-analysis by the FPRP test. Interestingly, the results of FPRP test indicated that the BTNL2

Type 2 diabetes and cardiovascular disease: Have all risk factors the same strength?

PubMed Central

Martín-Timón, Iciar; Sevillano-Collantes, Cristina; Segura-Galindo, Amparo; del Cañizo-Gómez, Francisco Javier

2014-01-01

Diabetes mellitus is a chronic condition that occurs when the body cannot produce enough or effectively use of insulin. Compared with individuals without diabetes, patients with type 2 diabetes mellitus have a considerably higher risk of cardiovascular morbidity and mortality, and are disproportionately affected by cardiovascular disease. Most of this excess risk is it associated with an augmented prevalence of well-known risk factors such as hypertension, dyslipidaemia and obesity in these patients. However the improved cardiovascular disease in type 2 diabetes mellitus patients can not be attributed solely to the higher prevalence of traditional risk factors. Therefore other non-traditional risk factors may be important in people with type 2 diabetes mellitus. Cardiovascular disease is increased in type 2 diabetes mellitus subjects due to a complex combination of various traditional and non-traditional risk factors that have an important role to play in the beginning and the evolution of atherosclerosis over its long natural history from endothelial function to clinical events. Many of these risk factors could be common history for both diabetes mellitus and cardiovascular disease, reinforcing the postulate that both disorders come independently from “common soil”. The objective of this review is to highlight the weight of traditional and non-traditional risk factors for cardiovascular disease in the setting of type 2 diabetes mellitus and discuss their position in the pathogenesis of the excess cardiovascular disease mortality and morbidity in these patients. PMID:25126392

Novel therapy in Parkinson's disease: adenosine A(2A) receptor antagonists.

PubMed

Szabó, Nikoletta; Kincses, Zsigmond Tamás; Vécsei, László

2011-04-01

Parkinson's disease (PD) is a progressive neurodegenerative disorder. To date, most of the currently available therapies in PD target the dopaminergic system and none of these therapeutic approaches have been proven to modify the course of the disease. To various extents, these drugs can also cause motor and non-motor complications. A novel target, the adenosine A(2A) receptor (AA2AR), was recently identified, blockade of which may alleviate Parkinsonian symptoms, reduce motor fluctuations and potentially afford neuroprotection. This review is based on a PubMed search covering the relationship of the adenosine receptors and PD. The role of the AA2AR is reviewed and the results of preclinical investigations of antagonists are assessed. A synopsis of current drug development is provided, with a special focus on the pharmacokinetics and relevant clinical trials. The localization of the AA2AR in the central nervous system, the ultra structural localization and the molecular mechanism of its action reveal the potential importance of the AA2AR in movement disorders. The theoretical background and experimental data indicate that AA2AR antagonists may have a potential therapeutic effect in Parkinson's disease. More importantly, the putative neuroprotective effect needs further investigation.

Elevated galanin may predict the risk of type 2 diabetes mellitus for development of Alzheimer's disease.

PubMed

Zhang, Zhenwen; Fang, Penghua; Shi, Mingyi; Zhu, Yan; Bo, Ping

2015-09-01

Alzheimer's disease is the most common form of dementia among the elderly and is characterized by progressive loss of memory and cognition. Epidemiological and clinical studies demonstrated that type 2 diabetes mellitus is an important risk factor for the development of Alzheimer's disease, i.e., the patients with type 2 diabetes mellitus are frequently companied with Alzheimer's disease symptoms. Despite many studies recently probed into the comorbid state of both diseases, so far the precise mechanism for this association is poorly understood. Emerging evidences suggest that defects in galanin play a central role on type 2 diabetes mellitus and is considered to be a risk factor for Alzheimer's disease development. This review provides a new insight into the multivariate relationship among galanin, type 2 diabetes mellitus and Alzheimer's disease, highlighting the effect of galanin system on the cross-talk between both diseases in human and rodent models. The current data support that activating central GalR2 attenuates insulin resistance and Alzheimer's disease feature in animal models. These may help us better understanding the pathogenesis of both diseases and provide useful hints for the development of novel therapeutic approaches to treat type 2 diabetes mellitus and Alzheimer's disease. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Peripheral arterial disease, type 2 diabetes and postprandial lipidaemia: Is there a link?

PubMed Central

Valdivielso, Pedro; Ramírez-Bollero, José; Pérez-López, Carmen

2014-01-01

Peripheral arterial disease, manifested as intermittent claudication or critical ischaemia, or identified by an ankle/brachial index < 0.9, is present in at least one in every four patients with type 2 diabetes mellitus. Several reasons exist for peripheral arterial disease in diabetes. In addition to hyperglycaemia, smoking and hypertension, the dyslipidaemia that accompanies type 2 diabetes and is characterised by increased triglyceride levels and reduced high-density lipoprotein cholesterol concentrations also seems to contribute to this association. Recent years have witnessed an increased interest in postprandial lipidaemia, as a result of various prospective studies showing that non-fasting triglycerides predict the onset of arteriosclerotic cardiovascular disease better than fasting measurements do. Additionally, the use of certain specific postprandial particle markers, such as apolipoprotein B-48, makes it easier and more simple to approach the postprandial phenomenon. Despite this, only a few studies have evaluated the role of postprandial triglycerides in the development of peripheral arterial disease and type 2 diabetes. The purpose of this review is to examine the epidemiology and risk factors of peripheral arterial disease in type 2 diabetes, focusing on the role of postprandial triglycerides and particles. PMID:25317236

The P2X7 Receptor in Inflammatory Diseases: Angel or Demon?

PubMed Central

Savio, Luiz E. B.; de Andrade Mello, Paola; da Silva, Cleide Gonçalves; Coutinho-Silva, Robson

2018-01-01

Under physiological conditions, adenosine triphosphate (ATP) is present at low levels in the extracellular milieu, being massively released by stressed or dying cells. Once outside the cells, ATP and related nucleotides/nucleoside generated by ectonucleotidases mediate a high evolutionary conserved signaling system: the purinergic signaling, which is involved in a variety of pathological conditions, including inflammatory diseases. Extracellular ATP has been considered an endogenous adjuvant that can initiate inflammation by acting as a danger signal through the activation of purinergic type 2 receptors—P2 receptors (P2Y G-protein coupled receptors and P2X ligand-gated ion channels). Among the P2 receptors, the P2X7 receptor is the most extensively studied from an immunological perspective, being involved in both innate and adaptive immune responses. P2X7 receptor activation induces large-scale ATP release via its intrinsic ability to form a membrane pore or in association with pannexin hemichannels, boosting purinergic signaling. ATP acting via P2X7 receptor is the second signal to the inflammasome activation, inducing both maturation and release of pro-inflammatory cytokines, such as IL-1β and IL-18, and the production of reactive nitrogen and oxygen species. Furthermore, the P2X7 receptor is involved in caspases activation, as well as in apoptosis induction. During adaptive immune response, P2X7 receptor modulates the balance between the generation of T helper type 17 (Th17) and T regulatory (Treg) lymphocytes. Therefore, this receptor is involved in several inflammatory pathological conditions. In infectious diseases and cancer, P2X7 receptor can have different and contrasting effects, being an angel or a demon depending on its level of activation, cell studied, type of pathogen, and severity of infection. In neuroinflammatory and neurodegenerative diseases, P2X7 upregulation and function appears to contribute to disease progression. In this review, we

NRF2-regulation in brain health and disease: implication of cerebral inflammation

PubMed Central

Sandberg, Mats; Patil, Jaspal; D’Angelo, Barbara; Weber, Stephen G; Mallard, Carina

2014-01-01

The nuclear factor erythroid 2 related factor 2 (NRF2) is a key regulator of endogenous inducible defense systems in the body. Under physiological conditions NRF2 is mainly located in the cytoplasm. However, in response to oxidative stress, NRF2 translocates to the nucleus and binds to specific DNA sites termed “anti-oxidant response elements” or “electrophile response elements” to initiate transcription of cytoprotective genes. Acute oxidative stress to the brain, such as stroke and traumatic brain injury is increased in animals that are deficient in NRF2. Insufficient NRF2 activation in humans has been linked to chronic diseases such as Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis. New findings have also linked activation of the NRF2 system to anti-inflammatory effects via interactions with NF-κB. Here we review literature on cellular mechanisms of NRF2 regulation, how to maintain and restore NRF2 function and the relationship between NRF2 regulation and brain damage. We bring forward the hypothesis that inflammation via prolonged activation of key kinases (p38 and GSK-3β) and activation of histone deacetylases gives rise to dysregulation of the NRF2 system in the brain, which contributes to oxidative stress and injury. PMID:24262633

The Computerized Laboratory Notebook concept for genetic toxicology experimentation and testing.

PubMed

Strauss, G H; Stanford, W L; Berkowitz, S J

1989-03-01

We describe a microcomputer system utilizing the Computerized Laboratory Notebook (CLN) concept developed in our laboratory for the purpose of automating the Battery of Leukocyte Tests (BLT). The BLT was designed to evaluate blood specimens for toxic, immunotoxic, and genotoxic effects after in vivo exposure to putative mutagens. A system was developed with the advantages of low cost, limited spatial requirements, ease of use for personnel inexperienced with computers, and applicability to specific testing yet flexibility for experimentation. This system eliminates cumbersome record keeping and repetitive analysis inherent in genetic toxicology bioassays. Statistical analysis of the vast quantity of data produced by the BLT would not be feasible without a central database. Our central database is maintained by an integrated package which we have adapted to develop the CLN. The clonal assay of lymphocyte mutagenesis (CALM) section of the CLN is demonstrated. PC-Slaves expand the microcomputer to multiple workstations so that our computerized notebook can be used next to a hood while other work is done in an office and instrument room simultaneously. Communication with peripheral instruments is an indispensable part of many laboratory operations, and we present a representative program, written to acquire and analyze CALM data, for communicating with both a liquid scintillation counter and an ELISA plate reader. In conclusion we discuss how our computer system could easily be adapted to the needs of other laboratories.

Association between non-alcoholic fatty liver disease and peripheral artery disease in patients with type 2 diabetes.

PubMed

Zou, Yaowu; Li, Xinde; Wang, Can; Wang, Jing; Wang, Fei; Ma, Lidan; You, Wenjun; Li, Changgui

2017-10-01

Non-alcoholic fatty liver disease (NAFLD) is associated with the risk of coronary heart diseases; however, the relationship between NAFLD and peripheral artery disease (PAD) in patients with type 2 diabetes has not been investigated. To investigate the association between NAFLD and PAD in patients with type 2 diabetes. We carried out a cross-sectional study on 2646 type 2 diabetes patients ≥ 40 years. All patients provided fasting blood samples and underwent a liver ultrasonography and ankle-brachial index (ABI) test. PAD was defined as an ABI <0.9. Multiple logistic regression analyses were performed to investigate the odds ratio (OR) for PAD associated with NAFLD. Our analyses showed that patients with NAFLD had a significantly higher prevalence of PAD compared with those without NAFLD (12.8% vs 7.8%). NAFLD was associated with a 75% (OR 1.75, 95% confidence interval (CI) 1.35-2.28) increased risk of PAD after adjustment for demographic factors. Addition of various metabolic risk factors as confounders attenuated the association (OR 1.49, 95% CI 1.12-2.00). Further adjustment for C-reactive protein led the association to be marginally significant (OR 1.33, 95% CI 0.99-1.80). Analyses stratified by gender suggested the association was much stronger among women than among men. Type 2 diabetes patients with NAFLD had a higher prevalence of PAD, and this association was partly, but not entirely, explained by metabolic risk factors and inflammation. © 2017 Royal Australasian College of Physicians.

Cushing Disease in a patient with Multiple Endocrine Neoplasia type 2B.

PubMed

Kasturi, Kannan; Fernandes, Lucas; Quezado, Martha; Eid, Mary; Marcus, Leigh; Chittiboina, Prashant; Rappaport, Mark; Stratakis, Constantine A; Widemann, Brigitte; Lodish, Maya

2017-06-01

Multiple endocrine neoplasia type 2B (MEN2B) is a rare autosomal-dominant cancer syndrome characterized in part by metastatic medullary thyroid cancer (MTC) and pheochromocytoma. Cushing disease is a rare cause of endogenous hypercortisolism in children. We describe a 21-year-old African-American male who was diagnosed at age 10 with an ACTH-secreting pituitary microadenoma. At age 16 he developed medullary thyroid cancer and was found to have multiple endocrine neoplasia type 2B with the characteristic M918T mutation of the RET proto-oncogene. Following thyroidectomy, he was initiated on Vandetanib, a tyrosine kinase inhibitor, and has since had stable disease over the last 5 years. Our patient is the first individual with MEN2B to be described with Cushing disease. The RET oncogene may play a role in pituitary tumorigenesis; alternatively, the coexistence of these two entities may represent an extremely rare coincidence.

Emerging rabbit haemorrhagic disease virus 2 (RHDV2) at the gates of the African continent.

PubMed

Martin-Alonso, Aarón; Martin-Carrillo, Natalia; Garcia-Livia, Katherine; Valladares, Basilio; Foronda, Pilar

2016-10-01

Until the beginning of this decade, the genetic characterization of rabbit haemorrhagic disease virus (RHDV) from Iberian Peninsula had revealed the existence of two genogroups, G1 and sporadically G6. In 2010, the new emerging rabbit haemorrhagic disease variant, RHDV2 or RHDVb, was described in France, from where it has rapidly spread throughout Europe, including Iberian Peninsula countries. Nevertheless, although cases of rabbit haemorrhagic disease (RHD) have been reported in the Canary Islands, a Spanish archipelago located 100km off the coast of Morocco, no genetic characterization of RHDV had been carried out. Consequently, in order to identify the circulating RHDV strains in this archipelago, liver samples of six farm rabbits and fifteen wild rabbits were collected from several areas of the largest island, Tenerife, and analyzed for the presence of RHDV by antigen capture double antibody sandwich ELISA. In case of positive ELISA result, we amplified and sequenced two fragments of the vp60 gene, which were concatenated for phylogenetic purposes. The sequences analysis revealed the presence of RHDV2 in both farm and wild rabbits from several areas of Tenerife. This result constitutes the first finding of RHDV2 in the Canary Islands. These RHDV2 strains found in Tenerife shared two exclusive SNPs that have not been observed in the rest of RHDV2 strains. The identification of RHDV2 and the absence of classic RHDV strains in this study suggest that RHDV2 may be replacing classic strains in Tenerife, as has been also proposed in Iberian Peninsula, France and Azores. Given the proximity of the Canary Islands to the African continent, this result should raise awareness about a possible dispersal of RHDV2 from the Canary Islands to the North of Africa. Copyright © 2016 Elsevier B.V. All rights reserved.

Chlamydiosis in 2 biologists investigating disease occurrences in wild waterfowl

USGS Publications Warehouse

Wobeser, Gary; Brand, Christopher J.

1982-01-01

Chlamydiosis (ornithosis, psittacosis) is an infectious disease of birds that can be transmitted to humans. Human infections are probably acquired by inhalation of aerosols containing elementary bodies of the causative agent Chlamydia psittaci, from bird droppings, or from tissues. Infected birds do not have to be ill to transmit the organism (Schachter and Dawson 1978). The disease in humans is considered an occupational risk for people working with pet birds (particularly psittacine species) and poultry, but all avian species can be considered as potential reservoirs (Schachter and Dawson 1978). Burkhart and Page (1971) listed >130 species of wild birds as being infected.The purpose of this report is to draw the disease to the attention of those working with wild birds by describing 2 cases acquired from wild waterfowl and by reviewing other information on human infections associated with wild birds. We do this because the disease can be serious if not treated properly, and because the disease is not usually associated with wild birds the diagnosis may not be considered by physicians without some prompting from the patient.

Sulforaphane Protects against Cardiovascular Disease via Nrf2 Activation

PubMed Central

Bai, Yang; Wang, Xiaolu; Zhao, Song; Ma, Chunye; Cui, Jiuwei; Zheng, Yang

2015-01-01

Cardiovascular disease (CVD) causes an unparalleled proportion of the global burden of disease and will remain the main cause of mortality for the near future. Oxidative stress plays a major role in the pathophysiology of cardiac disorders. Several studies have highlighted the cardinal role played by the overproduction of reactive oxygen or nitrogen species in the pathogenesis of ischemic myocardial damage and consequent cardiac dysfunction. Isothiocyanates (ITC) are sulfur-containing compounds that are broadly distributed among cruciferous vegetables. Sulforaphane (SFN) is an ITC shown to possess anticancer activities by both in vivo and epidemiological studies. Recent data have indicated that the beneficial effects of SFN in CVD are due to its antioxidant and anti-inflammatory properties. SFN activates NF-E2-related factor 2 (Nrf2), a basic leucine zipper transcription factor that serves as a defense mechanism against oxidative stress and electrophilic toxicants by inducing more than a hundred cytoprotective proteins, including antioxidants and phase II detoxifying enzymes. This review will summarize the evidence from clinical studies and animal experiments relating to the potential mechanisms by which SFN modulates Nrf2 activation and protects against CVD. PMID:26583056

Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice

PubMed Central

Hartmann, Phillipp; Chen, Peng; Wang, Hui J.; Wang, Lirui; McCole, Declan F.; Brandl, Katharina; Stärkel, Peter; Belzer, Clara; Hellerbrand, Claus; Tsukamoto, Hidekazu; Ho, Samuel B.; Schnabl, Bernd

2013-01-01

The intestinal mucus layer protects the epithelium from noxious agents, viruses, and pathogenic bacteria present in the gastrointestinal tract. It is composed of mucins, predominantly mucin-2 (Muc2), secreted by goblet cells of the intestine. Experimental alcoholic liver disease requires translocation of bacterial products across the intestinal barrier into the systemic circulation, which induces an inflammatory response in the liver and contributes to steatohepatitis. We investigated the roles of the intestinal mucus layer, and in particular Muc2, in development of experimental alcohol-associated liver disease in mice. We studied experimental alcohol-induced liver disease, induced by the Tsukamoto-French method (which involves continuous intragastric feeding of an isocaloric diet or alcohol) in wild-type and Muc2−/− mice. Muc2−/− mice showed less alcohol-induced liver injury and steatosis that developed in wild-type mice. Most notably, Muc2−/− mice had significantly lower plasma levels of lipopolysaccharide than wild-type mice after alcohol feeding. In contrast to wild-type mice, Muc2−/− mice were protected from alcohol-associated microbiome changes that are dependent on intestinal mucins. The anti-microbial proteins Reg3b and Reg3g were expressed at significantly higher levels in the jejunum of Muc2−/− mice fed the isocaloric diet or alcohol, compared with wild-type mice. Consequently, Muc2−/− mice showed increased killing of commensal bacteria and prevented intestinal bacterial overgrowth. Conclusion: Muc2−/− mice are protected from intestinal bacterial overgrowth and dysbiosis in response to alcohol feeding. Subsequently, lower amounts of bacterial products such as endotoxin translocate into the systemic circulation, decreasing liver disease. PMID:23408358

Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease.

PubMed

Ross, Owen A; Wu, Yih-Ru; Lee, Mei-Ching; Funayama, Manabu; Chen, Meng-Ling; Soto, Alexandra I; Mata, Ignacio F; Lee-Chen, Guey-Jen; Chen, Chiung Mei; Tang, Michelle; Zhao, Yi; Hattori, Nobutaka; Farrer, Matthew J; Tan, Eng-King; Wu, Ruey-Meei

2008-07-01

Common genetic variants that increase the risk for Parkinson's disease may differentiate patient subgroups and influence future individualized therapeutic strategies. Herein we show evidence for leucine-rich repeat kinase 2 (LRRK2) c.4883G>C (R1628P) as a risk factor in ethnic Chinese populations. A study of 1,986 individuals from 3 independent centers in Taiwan and Singapore demonstrates that Lrrk2 R1628P increases risk for Parkinson's disease (odds ratio, 1.84; 95% confidence interval, 1.20-2.83; p = 0.006). Haplotype analysis suggests an ancestral founder for carriers approximately 2,500 years ago. These findings support the importance of LRRK2 variants in sporadic Parkinson's disease. Ann Neurol 2008.

Role of gut microbiota in obesity, type 2 diabetes and Alzheimer's disease.

PubMed

Naseer, Muhammad I; Bibi, Fehmida; Alqahtani, Mohammed H; Chaudhary, Adeel G; Azhar, Esam I; Kamal, Mohammad A; Yasir, Muhammad

2014-03-01

In recent years, there is a growing interest in research to investigate the importance of gut microbiome in health and diseases. This opens a new area of research for the role of microbial flora of the human gut in inflammation, energy homeostasis, pathogenesis of obesity and other associated disorders. Recent studies propose association of the gut microbiome with development of obesity and metabolic syndromes, such as type 2 diabetes mellitus (T2DM). The T2DM is a metabolic disease that is mainly caused by obesity-linked insulin resistance. The vascular effects of obesity appears to play a role in the development of Alzheimer's disease (AD) that is one of the rapidly growing diseases of a late stage of life all over the world. Studies from both humans and mice models have been demonstrated the engagement of gut microbial flora in the pathogenesis of obesity and host metabolism. The aim of this review is to discuss the current findings that may explain the cascade of gut microbial flora participation in the development of obesity, T2DM and further initiation of AD. In addition, the available data regarding the mechanisms that have been proposed to elucidate the role of gut microbiota in weight gain and possible cause of T2DM and AD have been examined.

Dietary patterns and the risk of obesity, type 2 diabetes mellitus, cardiovascular diseases, asthma, and neurodegenerative diseases.

PubMed

Medina-Remón, Alexander; Kirwan, Richard; Lamuela-Raventós, Rosa M; Estruch, Ramón

2018-01-22

Diet and lifestyle play a significant role in the development chronic diseases; however the full complexity of this relationship is not yet understood. Dietary pattern investigation, which reflects the complexity of dietary intake, has emerged as an alternative and complementary approach for examining the association between diet and chronic diseases. Literature on this association has largely focused on individual nutrients, with conflicting outcomes, but individuals consume a combination of foods from many groups that form dietary patterns. Our objective was to systematically review the current findings on the effects of dietary patterns on chronic diseases. In this review, we describe and discuss the relationships between dietary patterns, such as the Mediterranean, the Dietary Approach to Stop Hypertension, Prudent, Seventh-day Adventists, and Western, with risk of obesity, type-2 diabetes mellitus, cardiovascular diseases, asthma, and neurodegenearive diseases. Evidence is increasing from both observational and clinical studies that plant-based dietary patterns, which are rich in fruits, vegetables, and whole grains, are valuable in preventing various chronic diseases, whereas a diet high in red and processed meat, refined grains and added sugar seems to increase said risk. Dietary pattern analysis might be especially valuable to the development and evaluation of food-based dietary guidelines.

[The attitude of patients with types 1 and 2 diabetes mellitus towards having the disease].

PubMed

Sapozhnikova, I E; Zotina, E N

To analyze the types of attitude towards disease, their relationships to its course in patients with diabetes mellitus (DM). 418 patients with DM, including 318 with type 2 DM (T2DM) and 100 with Type 1 (T1DM), were examined. Clinical and laboratory examinations were performed; the types of attitude towards the disease were studied. The patients with T2DM were more frequently found to have anxious (12.9%) and hypochondriacal (10.7%) types of attitude towards the disease; those with T1DM had euphoric types. The paranoiac type of disease attitude, which was characterized by the presence of peculiar notions about the disease, was detected in 15.1% of the patients with T2DM and in 13% of those with T1DM. Hypernosognosia (overreaction to disease) was more often identified in T2DM (62.3% versus 39% in T1DM (χ2; p < 0.001). In the T2DM group, hypernosognosia was more frequently seen in women, unemployed persons, and obese patients. With the comparable awareness about the disease and degree of self-control, the patients with T2DM with no signs of hypernosognosia had a lower glycated hemoglobin level [7.35 (6.6; 8.6)%] than those with hypernosognosia [7.9 (7; 9.4)%] (p = 0.024). The revealed peculiarities of attitude towards the disease in patients with DM justify the need for increased attention to their psychological characteristics. The situation could be improved if the physicians are be informed, the time of outpatient care is prolonged, and psychotherapists and/or clinical psychologists are widely involved in the management of diabetic patients.

[Impact of PM2.5 on daily outpatient numbers for respiratory diseases in Shenzhen, China].

PubMed

Peng, C Q; Cai, J F; Yu, S Y; Cao, Z J; Liao, Y X; Liu, N; He, L; Zhang, L; Zheng, J; Shi, X M; Cheng, J Q

2016-10-06

Objective: To assess the association between the concentration of the air pollutant PM 2.5 and daily outpatient visits for respiratory disease. Methods: All records of daily outpatient visits to three hospitals in Shenzhen from January 1 to December 31, 2013 were collected. Daily air pollution monitoring and meteorology data from the same period were also collected in Shenzhen. The data were analyzed using a semiparametric generalized additive model with Poisson distribution of time series analysis controlling for long-term and seasonal trends, flu, DOW, public holidays, and meteorological factors. The excess risk( ER )of respiratory disease and its 95% CI value were calculated, along with the incremental increase of 10 μg/m 3 in PM 2.5 concentration. Results: Number of outpatient visits for respiratory diseases totaled 1 428 672(daily range: 1 790-5 228). The annual average PM 2.5 concentration was 40.2 μg/m 3 (daily range: 7.2-137.1 μg/m 3 ). The lag1 factor had the most significant impact on the lag effect. We estimated that a 10 μ g/m 3 increase in day-before PM 2.5 concentration was associated with a 1.809%(95% CI : 1.709%-1.909%) ER of visits for respiratory disease. After controlling for other pollutants(NO 2 , CO, and O 3 ), the effect remained stable. When NO 2 , CO, and O 3 were introduced separately, for every 10 μg/m 3 rise in PM 2.5 concentration, the excess risk of daily outpatient visits for respiratory disease was 1.814%(95% CI : 1.706%-1.923%), 2.780%(95% CI : 2.668%-2.892%), and 1.513%(95% CI : 1.403%-1.624%), respectively. With simultaneous control of NO 2 and O 3 , NO 2 and CO, and CO and O 3 , for every 10 μg/m 3 rise in PM 2.5 concentration, the excess risk of respiratory disease was 1.369%(95% CI : 1.242%-1.497%), 2.709%(95% CI : 2.590%-2.828%), and 2.577%(95% CI : 2.452%-2.702%), respectively. With simultaneous control of NO 2 , CO, and O 3 , for every 10 μg/m 3 rise in PM 2.5 concentration, the excess risk of respiratory disease was

Ethnic disparities in risk of cardiovascular disease, end-stage renal disease and all-cause mortality: a prospective study among Asian people with Type 2 diabetes.

PubMed

Liu, J J; Lim, S C; Yeoh, L Y; Su, C; Tai, B C; Low, S; Fun, S; Tavintharan, S; Chia, K S; Tai, E S; Sum, C F

2016-03-01

To study prospectively the ethnic-specific risks of cardiovascular disease, end-stage renal disease and all-cause mortality in patients with Type 2 diabetes mellitus among native Asian subpopulations. A total of 2337 subjects with Type 2 diabetes (70% Chinese, 17% Malay and 13% Asian Indian) were followed for a median of 4.0 years. Time-to-event analysis was used to study the association of ethnicity with adverse outcomes. Age- and gender-adjusted hazard ratios for cardiovascular disease in ethnic Malay and Asian Indian subjects were 2.01 (1.40-2.88; P<0.0001) and 1.60 (1.07-2.41; P=0.022) as compared with Chinese subjects. Adjustment for conventional cardiovascular disease risk factors, including HbA1c , blood pressure and lipid profile, slightly attenuated the hazards in Malay (1.82, 1.23-2.71; P=0.003) and Asian Indian subjects (1.47, 0.95-2.30; P=0.086); However, further adjustment for baseline renal function (estimated GFR) and albuminuria weakened the cardiovascular disease risks in Malay (1.48, 0.98-2.26; P=0.065) but strengthened that in Asian Indian subjects (1.81, 1.14-2.87; P=0.012). Competing-risk regression showed that the age- and gender-adjusted sub-distribution hazard ratio for end-stage renal disease was 1.87 (1.27-2.73; P=0.001) in Malay and 0.39 (0.18-0.83; P=0.015) in Asian Indian subjects. Notably, the difference in end-stage renal disease risk among the three ethnic groups was abolished after further adjustment for baseline estimated GFR and albuminuria. There was no significant difference in risk of all-cause mortality among the three ethnic groups. Risks of cardiovascular and end-stage renal diseases in native Asian subjects with Type 2 diabetes vary substantially among different ethnic groups. Differences in prevalence of diabetic kidney disease may partially explain the ethnic disparities. © 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.

X-Ray Line-Broadening Investigation of Deformation During Hot Rolling of Ti-6A1-4V with a Colony-Alpha Microstructure (PREPRINT)

DTIC Science & Technology

2006-07-01

was first studied by Krivoglaz and Ryaboshapka [1], Krivoglaz, et al . [2], and Wilkens [11, 20, 21]. More recently, Wu, et al . [22, 23] obtained the... al . [22] with an accuracy of 3 pct. over the range 0.1 _< M _< 10. The form of this function was: f(M) =aln(M+l)+bln2 (M+1)+cln3 (M+l)+dln4 (M+l), (2...Williams-Hall technique proposed by Ungdr, et al . [24]. Due to the limited number of peaks available for analysis, it was not possible to

Targeting IL-2: an unexpected effect in treating immunological diseases.

PubMed

Ye, Congxiu; Brand, David; Zheng, Song G

2018-01-01

Regulatory T cells (Treg) play a crucial role in maintaining immune homeostasis since Treg dysfunction in both animals and humans is associated with multi-organ autoimmune and inflammatory disease. While IL-2 is generally considered to promote T-cell proliferation and enhance effector T-cell function, recent studies have demonstrated that treatments that utilize low-dose IL-2 unexpectedly induce immune tolerance and promote Treg development resulting in the suppression of unwanted immune responses and eventually leading to treatment of some autoimmune disorders. In the present review, we discuss the biology of IL-2 and its signaling to help define the key role played by IL-2 in the development and function of Treg cells. We also summarize proof-of-concept clinical trials which have shown that low-dose IL-2 can control autoimmune diseases safely and effectively by specifically expanding and activating Treg. However, future studies will be needed to validate a better and safer dosing strategy for low-dose IL-2 treatments utilizing well-controlled clinical trials. More studies will also be needed to validate the appropriate dose of IL-2/anti-cytokine or IL-2/anti-IL-2 complex in the experimental animal models before moving to the clinic.

Association between TYK2 polymorphisms and susceptibility to autoimmune rheumatic diseases: a meta-analysis.

PubMed

Lee, Y H; Bae, S-C

2016-10-01

This study aimed to explore whether TYK2 polymorphisms are associated with susceptibility to autoimmune rheumatic diseases. We conducted a meta-analysis on the association between TYK2 polymorphisms and autoimmune rheumatic diseases. Twelve studies with a total of 16,335 patients and 30,065 controls were included in the meta-analysis. Meta-analysis revealed an association between rheumatic diseases and the 2 allele of the TYK2 rs2304256 (OR = 0.885, 95% CI = 0.802-0.978, p = 0.016). Furthermore, stratification by ethnicity identified a significant association between this polymorphism and rheumatic diseases in Caucasians (OR = 0.822, 95% CI = 0.706-0.889, p = 9.5 × 10(-7)), but not in Asians (OR = 1.127, 95% CI = 0.835-1.522, p = 0.434). Meta-analysis by rheumatic disease type revealed a significant association between the 2 allele of the TYK2 rs2304256 and SLE in Caucasians (OR = 0.737, 95% CI = 0.673-0.808, p < 1.0 × 10(-8)) but not in Asians (OR = 1.211, 95% CI = 0.813-1.804, p = 0.347). Meta-analysis revealed that the rs12720356 polymorphism was associated with susceptibility to rheumatic diseases in Caucasians (OR = 0.812, 95% CI = 0.661-0.997, p = 0.046) but not in Asians. Interestingly, the rs280519 polymorphism was significantly associated with susceptibility to SLE both in Caucasians and Asians. However, no associations were found between the rs12720270, rs280500, rs280523 and rs8108236 polymorphisms and susceptibility to rheumatic diseases. This meta-analysis demonstrates that the TYK2 rs2304256 and rs12720356 polymorphisms are associated with susceptibility to rheumatic diseases, rs2304256 polymorphism is associated with SLE in Caucasians, and rs280519 polymorphism is associated with SLE in Caucasians and Asians. © The Author(s) 2016.

Effects of feeding steers extruded flaxseed on its own before hay or mixed with hay on animal performance, carcass quality, and meat and hamburger fatty acid composition.

PubMed

Vahmani, P; Rolland, D C; McAllister, T A; Block, H C; Proctor, S D; Guan, L L; Prieto, N; López-Campos, Ó; Aalhus, J L; Dugan, M E R

2017-09-01

The objective of the present experiment was to determine if carcass quality and fatty acid profiles of longissimus thoracis (LT) and hamburger would be affected by feeding steers extruded flaxseed on its own followed by hay (non-TMR) compared to when hay and extruded flaxseed were fed together (TMR). Forty-eight steers in six pens were assigned to TMR or non-TMR for an average of 242days. Dry matter intake was lower for non-TMR versus TMR steers (10.56 vs. 11.42kg/d; P=0.02), but final live weight (610±0.50kg) and average daily gain (1.18±0.02kg/d) did not differ. Compared to TMR, feeding non-TMR enriched LT and hamburger with α-linolenic acid (ALA; 18:3n-3) by 14%, vaccenic acid (VA; t11-18:1) by 44%, rumenic acid (RA; c9,t11-18:2) by 40%, and conjugated linolenic acid (CLnA) by 58%. Overall, feeding extruded flaxseed separately from hay in a non-TMR was more effective at enhancing deposition of ALA, VA, RA and CLnA in beef. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

CSF Nrf2 and HSPA8 in Parkinson's disease patients with and without LRRK2 gene mutations.

PubMed

Loeffler, David A; Smith, Lynnae M; Coffey, Mary P; Aasly, Jan O; LeWitt, Peter A

2016-03-01

Leucine-rich repeat kinase 2 (LRRK2) gene mutations are the most common genetic cause of Parkinson's disease (PD). CSF specimens from LRRK2 + PD patients and healthy LRRK2 mutation carriers are, therefore, useful for biomarker studies. This study examined the hypothesis that differences are present between subjects with sporadic PD (sPD), PD carriers of LRRK2 mutations (LRRK2 + PD), healthy control subjects lacking LRRK2 mutations (CTL), and LRRK2 mutation-carrying healthy controls (LRRK2 + CTL) for CSF concentrations of six potential PD biomarkers. Two of these proteins, nuclear factor (erythroid-derived 2)-like 2 ("Nrf2") and heat shock 70 kDa protein 8 ("HSPA8"), were detected in preliminary ELISAs, then measured in a larger cohort (60 sPD, 10 LRRK2 + PD, 23 CTL, 31 LRRK2 + CTL). No statistically significant differences were found between the groups (Nrf2 p = 0.13, HSPA8 p = 0.21). Nrf2 concentrations in LRRK2 + PD subjects were strongly positively associated with Unified Parkinson's Disease Rating Scale (UPDRS) total and motor scores [Spearman rho = 0.77 (p = 0.012) and 0.83 (p = 0.005)] and negatively associated with Montreal Cognitive Assessment (MoCA) scores (rho = -0.57; p = 0.11). Partial correlation coefficient calculations indicated that disease duration contributed to the associations of Nrf2 levels with UPDRS scores and with MoCA scores in this group. While CSF Nrf2 and HSPA8 do not appear to offer diagnostic biomarkers for PD, the associations between Nrf2 levels and UPDRS scores in LRRK2 + PD patients merit further investigation.

The Triple Functions of D2 Silencing in Treatment of Periapical Disease.

PubMed

Pan, Jie; Wang, Jue; Hao, Liang; Zhu, Guochun; Nguyen, Diep N; Li, Qian; Liu, Yuehua; Zhao, Zhihe; Li, Yi-Ping; Chen, Wei

2017-02-01

Dental caries is the most widespread chronic infectious disease. Inflammation in pulp tissues caused by dental caries will lead to periapical granulomas, bone erosion, loss of the tooth, and severe pain. Despite numerous efforts in recent studies to develop effective treatments for dental caries, the need for a potent therapy is still urgent. In this study, we applied a gene-based therapy approach by administering recombinant adeno-associated virus (AAV)-mediated Atp6v0d2 (d2) RNA interference knockdown of d2 gene expression to prevent periapical bone loss and suppress periapical inflammation simultaneously. The results showed that d2 depletion is simultaneously capable of reducing bone resorption with 75% protection through reducing osteoclasts, enhancing bone formation by increasing osterix expression, and inhibiting inflammation by decreasing T-cell infiltration. Notably, AAV-mediated gene therapy of d2 knockdown significantly reduced proinflammatory cytokine expression, including tumor necrosis factor α, interferon-γ, interleukin-1α, and interleukin 6 levels in periapical diseases caused by bacterial infection. Quantitative real-time polymerase chain reaction revealed that d2 knockdown reduced osteoclast-specific functional genes (ie, Acp5 and Ctsk) and increased osteoblast marker genes (ie, Osx and Opg) in periapical tissues. Collectively, our results showed that AAV-mediated d2 depletion in the periapical lesion area can prevent the progression of endodontic disease and bone erosion while significantly reducing the inflammatory over-response. These findings show that the depletion of d2 simultaneously reduces bone resorption, enhances bone formation, and inhibits inflammation caused by periapical diseases and provide significant insights into the potential effectiveness of AAV-sh-d2-mediated d2 silencing gene therapy as a major endodontic treatment. Copyright © 2016. Published by Elsevier Inc.

The future of Canada's radio astronomy

NASA Astrophysics Data System (ADS)

Gaensler, Bryan M.

2017-11-01

Through involvement in CHIME, ALMA, the Jansky VLA and the Murchison Widefield Array, Canada is well placed in current radio astronomy facilities and the future looks even brighter, with strategic interest in the SKA and the Next Generation VLA.

Current Management of Patients With Diverticulosis and Diverticular Disease: A Survey From the 2nd International Symposium on Diverticular Disease.

PubMed

Tursi, Antonio; Picchio, Marcello; Elisei, Walter; Di Mario, Francesco; Scarpignato, Carmelo; Brandimarte, Giovanni

2016-10-01

Management of diverticular disease (DD) remains a point of debate. To investigate the current opinion of participants of the 2nd International Symposium on Diverticular Disease, on real-life management of patients with DD of the colon. Twelve questions were aimed at the diagnosis, treatment, and management options for diverticulosis and symptomatic DD. In total, 115 surveys from 8 European Countries were filled out. High fiber diet was widely prescribed in diverticulosis (59.1%). Probiotics (25%) were the most frequent prescribed drug, whereas 29.8% of participants did not prescribe any treatment in diverticulosis. Colonoscopy was frequently prescribed in symptomatic patients (69.3%), whereas 72.9% of participants did not prescribe any instrumental tool in their follow-up. Rifaximin, probiotics, and mesalazine were the most frequent prescribed drugs both in symptomatic patients (28.1, 14.9%, and 11.4%, respectively) and to prevent recurrence of the disease (42.5%, 12.4%, and 28.2%, respectively). With respect to laboratory exams, 57.9% of participants prescribed them during follow-up. The majority of participants (64.9%) managed suspected acute diverticulitis at home. Rifaximin, probiotics, and mesalazine were the most frequent prescribed drugs to prevent recurrence of the disease (32.2%, 13.2%, and 11.4%, respectively), whereas 25.4% of participants did not prescribe any drugs. Finally, no differences were found among gastroenterologists, surgeons, and general practitioners in managing this disease. This surveys shows that current management of DD is similar between different medical specialities, generally in line with current literature.

Cytokine and Lipid Mediator Regulation of Group 2 Innate Lymphoid Cells (ILC2s) in Human Allergic Airway Disease.

PubMed

Cavagnero, Kellen; Doherty, Taylor A

2017-08-01

The recent discovery of group 2 innate lymphoid cells (ILC2s) has caused a paradigm shift in the understanding of allergic airway disease pathogenesis. Prior to the discovery of ILC2s, Th2 cells were largely thought to be the primary source of type 2 cytokines; however, activated ILC2s have since been shown to contribute significantly, and in some cases, dominantly to type 2 cytokine production. Since the discovery of ILC2s in 2010, many mediators have been shown to regulate their effector functions. Initial studies identified the epithelial derived cytokines IL-25, IL-33, and TSLP as activators of ILC2s, and recent studies have identified many additional cytokine and lipid mediators that are involved in ILC2 regulation. ILC2s and their mediators represent novel therapeutic targets for allergic airway diseases and intensive investigation is underway to better understand ILC2 biology and upstream and downstream pathways that lead to ILC2-driven airway pathology. In this review, we will focus on the cytokine and lipid mediators that regulate ILC2s in human allergic airway disease, as well as highlight newly discovered mediators of mouse ILC2s that may eventually translate to humans.

Expression of Nrf2 in neurodegenerative diseases.

PubMed

Ramsey, Chenere P; Glass, Charles A; Montgomery, Marshall B; Lindl, Kathryn A; Ritson, Gillian P; Chia, Luis A; Hamilton, Ronald L; Chu, Charleen T; Jordan-Sciutto, Kelly L

2007-01-01

In response to oxidative stress, the nuclear factor E2-related factor 2 (Nrf2) transcription factor translocates from the cytoplasm into the nucleus and transactivates expression of genes with antioxidant activity. Despite this cellular mechanism, oxidative damage is abundant in Alzheimer and Parkinson disease (AD and PD). To investigate mechanisms by which Nrf2 activity may be aberrant or insufficient in neurodegenerative conditions, we assessed Nrf2 localization in affected brain regions of AD, Lewy body variant of AD (LBVAD), and PD. By immunohistochemistry, Nrf2 is expressed in both the nucleus and the cytoplasm of neurons in normal hippocampi with predominant expression in the nucleus. In AD and LBVAD, Nrf2 was predominantly cytoplasmic in hippocampal neurons and was not a major component of beta amyloid plaques or neurofibrillary tangles. By immunoblotting, we observed a significant decrease in nuclear Nrf2 levels in AD cases. In contrast, Nrf2 was strongly nuclear in PD nigral neurons but cytoplasmic in substantia nigra of normal, AD, and LBVAD cases. These findings suggest that Nrf2-mediated transcription is not induced in neurons in AD despite the presence of oxidative stress. In PD, nuclear localization of Nrf2 is strongly induced, but this response may be insufficient to protect neurons from degeneration.

Expression of Nrf2 in Neurodegenerative Diseases

PubMed Central

Ramsey, Chenere P.; Glass, Charles A.; Montgomery, Marshall B.; Lindl, Kathryn A.; Ritson, Gillian P.; Chia, Luis A.; Hamilton, Ronald L.; Chu, Charleen T.; Jordan-Sciutto, Kelly L.

2008-01-01

In response to oxidative stress, the nuclear factor E2-related factor 2 (Nrf2) transcription factor translocates from the cytoplasm into the nucleus and transactivates expression of genes with antioxidant activity. Despite this cellular mechanism, oxidative damage is abundant in Alzheimer and Parkinson disease (AD and PD). To investigate mechanisms by which Nrf2 activity may be aberrant or insufficient in neurodegenerative conditions, we assessed Nrf2 localization in affected brain regions of AD, Lewy body variant of AD (LBVAD), and PD. By immunohistochemistry, Nrf2 is expressed in both the nucleus and the cytoplasm of neurons in normal hippocampi with predominant expression in the nucleus. In AD and LBVAD, Nrf2 was predominantly cytoplasmic in hippocampal neurons and was not a major component of beta amyloid plaques or neurofibrillary tangles. By immunoblotting, we observed a significant decrease in nuclear Nrf2 levels in AD cases. In contrast, Nrf2 was strongly nuclear in PD nigral neurons but cytoplasmic in substantia nigra of normal, AD, and LBVAD cases. These findings suggest that Nrf2-mediated transcription is not induced in neurons in AD despite the presence of oxidative stress. In PD, nuclear localization of Nrf2 is strongly induced, but this response may be insufficient to protect neurons from degeneration. PMID:17204939

NOD2, an Intracellular Innate Immune Sensor Involved in Host Defense and Crohn's Disease

PubMed Central

Strober, Warren; Watanabe, Tomohiro

2013-01-01

Nucleotide binding oligomerization domain 2 (NOD2) is an intracellular sensor for small peptides derived from the bacterial cell wall component, peptidoglycan. Recent studies have uncovered unexpected functions of NOD2 in innate immune responses such as induction of type I IFN and facilitation of autophagy; moreover, they have disclosed extensive cross-talk between NOD2 and Toll-like receptors which plays an indispensable role both in host defense against microbial infection and in the development of autoimmunity. Of particular interest, polymorphisms of CARD15 encoding NOD2 are associated with Crohn's disease and other autoimmune states such as graft versus host disease. In this review, we summarize recent findings regarding normal functions of NOD2 and discuss the mechanisms by which NOD2 polymorphisms associated with Crohn's disease lead to intestinal inflammation. PMID:21750585

Disease expression in Usher syndrome caused by VLGR1 gene mutation (USH2C) and comparison with USH2A phenotype.

PubMed

Schwartz, Sharon B; Aleman, Tomas S; Cideciyan, Artur V; Windsor, Elizabeth A M; Sumaroka, Alexander; Roman, Alejandro J; Rane, Tej; Smilko, Elaine E; Bennett, Jean; Stone, Edwin M; Kimberling, William J; Liu, Xue-Zhong; Jacobson, Samuel G

2005-02-01

To investigate the retinal disease expression in USH2C, the subtype of Usher syndrome type 2 recently shown to be caused by mutation in the VLGR1 gene, and compare results with those from USH2A, a more common cause of Usher syndrome. Three siblings with USH2C and 14 patients with USH2A were studied. Visual function was measured by kinetic perimetry, static chromatic perimetry, and electroretinography (ERG). Central retinal microstructure was studied with optical coherence tomography (OCT). The siblings with VLGR1 mutation showed abnormal photoreceptor-mediated function in all retinal regions, and there was greater rod than cone dysfunction. USH2A had a wider spectrum of disease expression and included patients with normal function in some retinal regions. When abnormalities were detected, there was more rod than cone dysfunction. Retinal microstructure in both USH2C and USH2A shared the abnormality of loss of outer nuclear layer thickness. Central retinal structure in both genotypes was complicated by cystic macular lesions. A coincidental finding in an USH2C patient was that oral intake of antihistamines was associated with temporary resolution of the macular cystic change. USH2C and USH2A manifest photoreceptor disease with rod- and cone-mediated visual losses and thinning of the outer nuclear layer. An orderly progression through disease stages was estimated from cross-sectional and limited longitudinal data. Intrafamilial and interfamilial variation in retinal severity in USH2A, however, suggests that genetic or nongenetic modifiers may be involved in the disease expression.

Molecular Gas Excitation and the Evolutionary Connection Between Submillimeter Galaxies and AGN at z~2-3

NASA Astrophysics Data System (ADS)

Sharon, Chelsea; Riechers, Dominik Alexander; Carilli, Christopher; Hodge, Jacqueline; Walter, Fabian

2015-08-01

Theoretical work has suggested that active galactic nuclei (AGN) may play an important role in quenching star formation in massive galaxies. Due to sensitivity demands, direct evidence for AGN affecting the molecular ISM (the gas phase that fuels star formation) has so far been limited to detections of molecular outflows in low-redshift systems. Indirect evidence for an interplay between AGN and their host galaxies' cold gas phase may be provided by measurements of the gas excitation (and dynamics). At z~2-3, the peak epoch of star formation and AGN activity, previous observations of the CO(1-0) line revealed that submillimeter galaxies have substantial reservoirs of cold molecular gas. However, the molecular gas in AGN-host galaxies appears highly excited, potentially supporting an evolutionary connection between these two populations. We will present a new larger Karl G. Jansky Very Large Array sample that nearly doubles the number of CO(1-0) detections in z~2-3 submillimeter galaxies and AGN-host galaxies with existing CO(3-2) detections (from 13 to 23, plus four new upper limits) that allows us to better compare the low-excitation molecular gas properties of these systems and further investigate potential evidence for gas excitation due to active black holes.

Phenotype variability and allelic heterogeneity in KMT2B-Associated disease.

PubMed

Kawarai, Toshitaka; Miyamoto, Ryosuke; Nakagawa, Eiji; Koichihara, Reiko; Sakamoto, Takashi; Mure, Hideo; Morigaki, Ryoma; Koizumi, Hidetaka; Oki, Ryosuke; Montecchiani, Celeste; Caltagirone, Carlo; Orlacchio, Antonio; Hattori, Ayako; Mashimo, Hideaki; Izumi, Yuishin; Mezaki, Takahiro; Kumada, Satoko; Taniguchi, Makoto; Yokochi, Fusako; Saitoh, Shinji; Goto, Satoshi; Kaji, Ryuji

2018-04-05

Mutations in Lysine-Specific Histone Methyltransferase 2B gene (KMT2B) have been reported to be associated with complex early-onset dystonia. Almost all reported KMT2B mutations occurred de novo in the paternal germline or in the early development of the patient. We describe clinico-genetic features on four Japanese patients with novel de novo mutations and demonstrate the phenotypic spectrum of KMT2B mutations. We performed genetic studies, including trio-based whole exome sequencing (WES), in a cohort of Japanese patients with a seemingly sporadic early-onset generalized combined dystonia. Potential effects by the identified nucleotide variations were evaluated biologically. Genotype-phenotype correlations were also investigated. Four patients had de novo heterozygous mutations in KMT2B, c.309delG, c.1656dupC, c.3325_3326insC, and c.5636delG. Biological analysis of KMT2B mRNA levels showed a reduced expression of mutant transcript frame. All patients presented with motor milestone delay, microcephaly, mild psychomotor impairment, childhood-onset generalized dystonia and superimposed choreoathetosis or myoclonus. One patient cannot stand due to axial hypotonia associated with cerebellar dysfunction. Three patients had bilateral globus pallidal deep brain stimulation (DBS) with excellent or partial response. We further demonstrate the allelic heterogeneity and phenotypic variations of KMT2B-associated disease. Haploinsufficiency is one of molecular pathomechanisms underlying the disease. Cardinal clinical features include combined dystonia accompanying mild psychomotor disability. Cerebellum would be affected in KMT2B-associated disease. Copyright © 2018 Elsevier Ltd. All rights reserved.

Safety and potential efficacy of gemfibrozil as a supportive treatment for children with late infantile neuronal ceroid lipofuscinosis and other lipid storage disorders.

PubMed

Kim, Kyeongsoon; Kleinman, Hynda K; Lee, Hahn-Jun; Pahan, Kalipada

2017-06-17

Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is a group of genetically distinct lysosomal disorders that mainly affect the central nervous system, resulting in progressive motor and cognitive decline primarily in children. Multiple distinct genes involved in the metabolism of lipids have been identified to date with various mutations in this family of diseases. There is no cure for these diseases but some new therapeutic approaches have been tested that offer more hope than the standard palliative care. Many of the therapeutic advances require invasive procedures but some progress in slowing the disease has been found and more options can be expected in the future. We also review the literature on children with disease/conditions other than NCL for the non-invasive use, safety, and tolerability of a lipid-lowering drug, gemfibrozil, as a potential treatment for NCLs. Gemfibrozil has shown efficacy in an animal model of NCL known as CLN2 (late infantile classic juvenile) and has been shown to be safe for lowering lipids in children. Among the 200 non-NCL children found in the published literature who were treated with gemfibrozil for NCL-related problems, only 3 experienced adverse events, including 2 with muscle pain and 1 with localized linear IgA bullous dermatitis. We conclude that gemfibrozil is safe for long-term use in children, causes minimal adverse events, is well tolerated, and may delay the progression of NCLs. Gemfibrozil may potentially be an alternative to more invasive therapeutic approaches currently under investigation and has the potential to be used in combination with other therapeutic approaches.

Perceptions of risk of coronary heart disease among people living with type 2 diabetes mellitus.

PubMed

Ammouri, Ali Ahmad; Abu Raddaha, Ahmad H; Natarajan, Jansi; D'Souza, Melba Sheila

2018-02-01

Our aim is to assess perception of risk of developing coronary heart disease and to examine its associations with individuals' characteristics and health behaviours among Omani people with type 2 diabetes mellitus (T2DM). Evaluating perceptions of being at risk of developing a disease may give insight into health promotion behaviours. People with diabetes are at high risk of coronary heart disease. The management of diabetes mellitus should include prevention and control of coronary heart disease. A cross-sectional correlational study was conducted. A convenience sample of 160 adults with T2DM was invited to participate in this study between November 2014 and March 2015. Descriptive and regression analyses were performed to examine associations between study variables. Perception of risk of developing coronary heart disease was significantly associated with low educational level (β = 0.191, P < .05), low income (β = 0.201, P < .05), and high level of knowledge about diabetes mellitus (β = 0.200, P < .05). People with T2DM who perceived coronary heart disease as having few moderate known outcomes and consequences reported consuming healthy diet more frequently. Teaching people with T2DM about the risk of developing coronary heart disease is essential as it could motivate them to perform health promotion behaviours, which may assist in controlling and reducing coronary heart disease. © 2017 John Wiley & Sons Australia, Ltd.

Immunization with herpes simplex virus 2 (HSV-2) genes plus inactivated HSV-2 is highly protective against acute and recurrent HSV-2 disease.

PubMed

Morello, Christopher S; Levinson, Michael S; Kraynyak, Kimberly A; Spector, Deborah H

2011-04-01

To date, no vaccine that is safe and effective against herpes simplex virus 2 (HSV-2) disease has been licensed. In this study, we evaluated a DNA prime-formalin-inactivated-HSV-2 (FI-HSV2) boost vaccine approach in the guinea pig model of acute and recurrent HSV-2 genital disease. Five groups of guinea pigs were immunized and intravaginally challenged with HSV-2. Two groups were primed with plasmid DNAs encoding the secreted form of glycoprotein D2 (gD2t) together with two genes required for viral replication, either the helicase (UL5) and DNA polymerase (UL30) genes or the single-stranded DNA binding protein (UL29) and primase (UL52) genes. Both DNA-primed groups were boosted with FI-HSV2 formulated with monophosphoryl lipid A (MPL) and alum adjuvants. Two additional groups were primed with the empty backbone plasmid DNA (pVAX). These two groups were boosted with MPL and alum (MPL-alum) together with either formalin-inactivated mock HSV-2 (FI-Mock) or with FI-HSV2. The final group was immunized with gD2t protein in MPL-alum. After challenge, 0/9 animals in the group primed with UL5, UL30, and gD2t DNAs and all 10 animals in the mock-immunized control group (pVAX-FI-Mock) developed primary lesions. All mock controls developed recurrent lesions through day 100 postchallenge. Only 1 guinea pig in the group primed with pVAX DNA and boosted with FI-HSV2 (pVAX-FI-HSV2 group) and 2 guinea pigs in the group primed with UL5, UL30, and gD2t DNAs and boosted with FI-HSV2 (UL5, UL30, gD2t DNA-FI-HSV2 group) developed recurrent lesions. Strikingly, the UL5, UL30, gD2t DNA-FI-HSV2 group showed a 97% reduction in recurrent lesion days compared with the mock controls, had the highest reduction in days with recurrent disease, and contained the lowest mean HSV-2 DNA load in the dorsal root ganglia.

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach.

PubMed

Cuadrado, Antonio; Manda, Gina; Hassan, Ahmed; Alcaraz, María José; Barbas, Coral; Daiber, Andreas; Ghezzi, Pietro; León, Rafael; López, Manuela G; Oliva, Baldo; Pajares, Marta; Rojo, Ana I; Robledinos-Antón, Natalia; Valverde, Angela M; Guney, Emre; Schmidt, Harald H H W

2018-04-01

Systems medicine has a mechanism-based rather than a symptom- or organ-based approach to disease and identifies therapeutic targets in a nonhypothesis-driven manner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) by cross-validating its position in a protein-protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecular profiles suggests alterations of NRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome). This network joins apparently heterogeneous phenotypes such as autoimmune, respiratory, digestive, cardiovascular, metabolic, and neurodegenerative diseases, along with cancer. Importantly, this approach matches and confirms in silico several applications for NRF2-modulating drugs validated in vivo at different phases of clinical development. Pharmacologically, their profile is as diverse as electrophilic dimethyl fumarate, synthetic triterpenoids like bardoxolone methyl and sulforaphane, protein-protein or DNA-protein interaction inhibitors, and even registered drugs such as metformin and statins, which activate NRF2 and may be repurposed for indications within the NRF2 cluster of disease phenotypes. Thus, NRF2 represents one of the first targets fully embraced by classic and systems medicine approaches to facilitate both drug development and drug repurposing by focusing on a set of disease phenotypes that appear to be mechanistically linked. The resulting NRF2 drugome may therefore rapidly advance several surprising clinical options for this subset of chronic diseases. Copyright © 2018 by The Author(s).

A Chemokine Receptor CXCR2 Macromolecular Complex Regulates Neutrophil Functions in Inflammatory Diseases*

PubMed Central

Wu, Yanning; Wang, Shuo; Farooq, Shukkur M.; Castelvetere, Marcello P.; Hou, Yuning; Gao, Ji-Liang; Navarro, Javier V.; Oupicky, David; Sun, Fei; Li, Chunying

2012-01-01

Inflammation plays an important role in a wide range of human diseases such as ischemia-reperfusion injury, arteriosclerosis, cystic fibrosis, inflammatory bowel disease, etc. Neutrophilic accumulation in the inflamed tissues is an essential component of normal host defense against infection, but uncontrolled neutrophilic infiltration can cause progressive damage to the tissue epithelium. The CXC chemokine receptor CXCR2 and its specific ligands have been reported to play critical roles in the pathophysiology of various inflammatory diseases. However, it is unclear how CXCR2 is coupled specifically to its downstream signaling molecules and modulates cellular functions of neutrophils. Here we show that the PDZ scaffold protein NHERF1 couples CXCR2 to its downstream effector phospholipase C (PLC)-β2, forming a macromolecular complex, through a PDZ-based interaction. We assembled a macromolecular complex of CXCR2·NHERF1·PLC-β2 in vitro, and we also detected such a complex in neutrophils by co-immunoprecipitation. We further observed that the CXCR2-containing macromolecular complex is critical for the CXCR2-mediated intracellular calcium mobilization and the resultant migration and infiltration of neutrophils, as disrupting the complex with a cell permeant CXCR2-specific peptide (containing the PDZ motif) inhibited intracellular calcium mobilization, chemotaxis, and transepithelial migration of neutrophils. Taken together, our data demonstrate a critical role of the PDZ-dependent CXCR2 macromolecular signaling complex in regulating neutrophil functions and suggest that targeting the CXCR2 multiprotein complex may represent a novel therapeutic strategy for certain inflammatory diseases. PMID:22203670

Anderson's disease (chylomicron retention disease): a new mutation in the SARA2 gene associated with muscular and cardiac abnormalities.

PubMed

Silvain, M; Bligny, D; Aparicio, T; Laforêt, P; Grodet, A; Peretti, N; Ménard, D; Djouadi, F; Jardel, C; Bégué, J M; Walker, F; Schmitz, J; Lachaux, A; Aggerbeck, L P; Samson-Bouma, M E

2008-12-01

Anderson's disease (AD) or chylomicron retention disease (CMRD) is a rare hereditary lipid malabsorption syndrome linked to SARA2 gene mutations. We report in this study a novel mutation in two sisters for which the Sar1b protein is predicted to be truncated by 32 amino acids at its carboxyl-terminus. Because the SARA2 gene is also expressed in the muscle, heart, liver and placenta, extraintestinal clinical manifestations may exist. For the first time, we describe in this study in the two sisters muscular as well as cardiac abnormalities that could be related to the reported expression of SARA2 in these tissues. We also evaluated six other patients for potential manifestations of the SARA2 mutation. The creatine phosphokinase levels were increased in all patients [1.5-9.4 x normal (N)] and transaminases were moderately elevated in five of the eight patients (1.2-2.6 x N), probably related to muscle disease rather than to liver dysfunction. A decreased ejection fraction occurred in one patient (40%, N: 60%). The muscle, liver and placental tissues that were examined had no specific abnormalities and, in particular, no lipid accumulation. These results suggest that myolysis and other extraintestinal abnormalities can occur in AD/CMRD and that the clinical evaluation of patients should reflect this.

Novel mTORC1 and 2 Signaling Pathways in Polycystic Kidney Disease (PKD)

DTIC Science & Technology

2017-09-01

AWARD NUMBER: W81XWH-16-1-0172 TITLE: Novel mTORC1 and 2 Signaling Pathways in Polycystic Kidney Disease (PKD) PRINCIPAL INVESTIGATOR: Charles...TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-16-1-0172 Novel mTORC1 and 2 Signaling Pathways in Polycystic Kidney Disease (PKD) 5b. GRANT NUMBER 5c...investigate the effects of mTORC1 (Raptor) knockout, mTORC2 (Rictor) knockout or combined mTORC1 and 2 knockout on cyst growth and kidney function. The

Natural disease history of mouse models for limb girdle muscular dystrophy types 2D and 2F

PubMed Central

Putker, K.; Tanganyika-de Winter, C. L.; Boertje-van der Meulen, J. W.; van Vliet, L.; Overzier, M.; Plomp, J. J.; Aartsma-Rus, A.; van Putten, M.

2017-01-01

Limb-girdle muscular dystrophy types 2D and 2F (LGMD 2D and 2F) are autosomal recessive disorders caused by mutations in the alpha- and delta sarcoglycan genes, respectively, leading to severe muscle weakness and degeneration. The cause of the disease has been well characterized and a number of animal models are available for pre-clinical studies to test potential therapeutic interventions. To facilitate transition from drug discovery to clinical trials, standardized procedures and natural disease history data were collected for these mouse models. Implementing the TREAD-NMD standardized operating procedures, we here subjected LGMD2D (SGCA-null), LGMD2F (SGCD-null) and wild type (C57BL/6J) mice to five functional tests from the age of 4 to 32 weeks. To assess whether the functional test regime interfered with disease pathology, sedentary groups were taken along. Muscle physiology testing of tibialis anterior muscle was performed at the age of 34 weeks. Muscle histopathology and gene expression was analysed in skeletal muscles and heart. Muscle histopathology and gene expression was analysed in skeletal muscles and heart. Mice successfully accomplished the functional tests, which did not interfere with disease pathology. Muscle function of SGCA- and SGCD-null mice was impaired and declined over time. Interestingly, female SGCD-null mice outperformed males in the two and four limb hanging tests, which proved the most suitable non-invasive tests to assess muscle function. Muscle physiology testing of tibialis anterior muscle revealed lower specific force and higher susceptibility to eccentric-induced damage in LGMD mice. Analyzing muscle histopathology and gene expression, we identified the diaphragm as the most affected muscle in LGMD strains. Cardiac fibrosis was found in SGCD-null mice, being more severe in males than in females. Our study offers a comprehensive natural history dataset which will be useful to design standardized tests and future pre

Direct Evidence for Maser Emission from the 36.2 GHz Class I Transition of Methanol in NGC253

NASA Astrophysics Data System (ADS)

Chen, Xi; Ellingsen, Simon P.; Shen, Zhi-Qiang; McCarthy, Tiege P.; Zhong, Wei-Ye; Deng, Hui

2018-04-01

Observations made with the Jansky Very large Array (JVLA) at an angular resolution of ∼0.″1 have detected class I methanol maser emission from the 36.2 GHz transition toward the starburst galaxy NGC 253. The methanol emission is detected toward four sites which lie within the regions of extended methanol emission detected in previous lower angular resolution (a few arcseconds) observations. The peak flux densities of the detected compact components are in the range 3–9 mJy beam‑1. Combining the JVLA data with single-dish observations from the Shanghai Tianma Radio Telescope (TMRT) and previous interferometric observations with the Australia Telescope Compact Array (ATCA), we show that the 36.2 GHz class I methanol emission consists of both extended and compact structures, with typical scales of ∼6″ (0.1 kpc) and ∼0.″05 (1 pc), respectively. The strongest components have a brightness temperature of >103 K, much higher than the maximum kinetic temperature (∼100 K) of the thermal methanol emission from NGC 253. Therefore, these observations conclusively demonstrate for the first time the presence of maser emission from a class I methanol transition in an external galaxy.

The ACE2 gene: its potential as a functional candidate for cardiovascular disease.

PubMed

Burrell, Louise M; Harrap, Stephen B; Velkoska, Elena; Patel, Sheila K

2013-01-01

The RAS (renin-angiotensin system) plays an important role in the pathophysiology of CVD (cardiovascular disease), and RAS blockade is an important therapeutic strategy in the management of CVD. A new counterbalancing arm of the RAS is now known to exist in which ACE (angiotensin-converting enzyme) 2 degrades Ang (angiotensin) II, the main effector of the classic RAS, and generates Ang-(1-7). Altered ACE2 expression is associated with cardiac and vascular disease in experimental models of CVD, and ACE2 is increased in failing human hearts and atherosclerotic vessels. In man, circulating ACE2 activity increases with coronary heart disease, as well as heart failure, and a large proportion of the variation in plasma ACE2 levels has been attributed to hereditary factors. The ACE2 gene maps to chromosome Xp22 and this paper reviews the evidence associating ACE2 gene variation with CVD and considers clues to potential functional ACE2 variants that may alter gene expression or transcriptional activity. Studies to date have investigated ACE2 gene associations in hypertension, left ventricular hypertrophy and coronary artery disease, but the results have been inconsistent. The discrepancies may reflect the sample size of the studies, the gender or ethnicity of subjects, the cardiovascular phenotype or the ACE2 SNP investigated. The frequent observation of apparent sex-dependence might be of special importance, if confirmed. As yet, there are no studies to concurrently assess ACE2 gene polymorphisms and circulating ACE2 activity. Large-scale carefully conducted clinical studies are urgently needed to clarify more precisely the potential role of ACE2 in the CVD continuum.

Variation in GIGYF2 is not associated with Parkinson disease.

PubMed

Nichols, W C; Kissell, D K; Pankratz, N; Pauciulo, M W; Elsaesser, V E; Clark, K A; Halter, C A; Rudolph, A; Wojcieszek, J; Pfeiffer, R F; Foroud, T

2009-06-02

A recent study reported that mutations in a gene on chromosome 2q36-37, GIGYF2, result in Parkinson disease (PD). We have previously reported linkage to this chromosomal region in a sample of multiplex PD families, with the strongest evidence of linkage obtained using the subset of the sample having the strongest family history of disease and meeting the strictest diagnostic criteria. We have tested whether mutations in GIGYF2 may account for the previously observed linkage finding. We sequenced the GIGYF2 coding region in 96 unrelated patients with PD used in our original study that contributed to the chromosome 2q36-37 linkage signal. Subsequently, we genotyped the entire sample of 566 multiplex PD kindreds as well as 1,447 controls to test whether variants in GIGYF2 are causative or increase susceptibility for PD. We detected three novel variants as well as one of the previously reported seven variants in a total of five multiple PD families; however, there was no consistent evidence that these variants segregated with PD in these families. We also did not find a significant increase in risk for PD among those inheriting variants in GIGYF2 (p = 0.28). We believe that variation in a gene other than GIGYF2 accounts for the previously reported linkage finding on chromosome 2q36-37.

Multiple Roles of Pitx2 in Cardiac Development and Disease

PubMed Central

2017-01-01

Cardiac development is a complex morphogenetic process initiated as bilateral cardiogenic mesoderm is specified at both sides of the gastrulating embryo. Soon thereafter, these cardiogenic cells fuse at the embryonic midline configuring a symmetrical linear cardiac tube. Left/right bilateral asymmetry is first detected in the forming heart as the cardiac tube bends to the right, and subsequently, atrial and ventricular chambers develop. Molecular signals emanating from the node confer distinct left/right signalling pathways that ultimately lead to activation of the homeobox transcription factor Pitx2 in the left side of distinct embryonic organ anlagen, including the developing heart. Asymmetric expression of Pitx2 has therefore been reported during different cardiac developmental stages, and genetic deletion of Pitx2 provided evidence of key regulatory roles of this transcription factor during cardiogenesis and thus congenital heart diseases. More recently, impaired Pitx2 function has also been linked to arrhythmogenic processes, providing novel roles in the adult heart. In this manuscript, we provide a state-of-the-art review of the fundamental roles of Pitx2 during cardiogenesis, arrhythmogenesis and its contribution to congenital heart diseases. PMID:29367545

VizieR Online Data Catalog: Gould's Belt Very Large Array survey. IV. Taurus (Dzib+, 2015)

NASA Astrophysics Data System (ADS)

Dzib, S. A.; Loinard, L.; Rodriguez, L. F.; Mioduszewski, A. J.; Ortiz-Leon, G. N.; Kounkel, M. A.; Pech, G.; Rivera, J. L.; Torres, R. M.; Boden, A. F.; Hartmann, L.; Evans, N. J., II; Briceno, C.; Tobin, J.

2015-07-01

The observations were obtained with the Karl G. Jansky VLA of the National Radio Astronomy Observatory (NRAO). Two frequency sub-bands, each 1GHz wide, and centered at 4.5 and 7.5GHz, respectively, were recorded simultaneously. The observations were obtained on three different time periods (February 25/26/28 to March 6; April 12/17/20/25, and April 30 to May 1/5/14/22 in 2011) typically separated from one another by a month. (2 data files).

MND2: A new mouse model of inherited motor neuron disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jones, J.M.; Albin, R.L.; Feldman, E.L.

1993-06-01

The autosomal recessive mutation mnd2 results in early onset motor neuron disease with rapidly progressive paralysis, severe muscle wasting, regression of thymus and spleen, and death before 40 days of age. mnd2 has been mapped to mouse chromosome 6 with the gene order: centromere-Tcrb-Ly-2-Sftp-3-D6Mit4-mnd2-D6Mit6, D6Mit9-D6Rck132-Raf-1, D6Mit11-D6Mit12-D6Mit14. mnd2 is located within a conserved linkage group with homologs on human chromosome 2p12-p13. Spinal motor neurons of homozygous affected animals are swollen and stain weakly, and electromyography revealed spontaneous activity characteristic of muscle denervation. Myelin staining was normal throughout the neuraxis. The clinical observations are consistent with a primary abnormality of lower motormore » neuron function. This new animal model will be of value for identification of a genetic defect responsible for motor neuron disease and for evaluation of new therapies. 36 refs., 7 figs., 2 tabs.« less

Angiopoietin-2 serum levels correlate with severity, early onset and cardiovascular disease in patients with rheumatoid arthritis.

PubMed

López-Mejías, Raquel; Corrales, Alfonso; Genre, Fernanda; Hernández, José L; Ochoa, Rodrigo; Blanco, Ricardo; González-Juanatey, Carlos; Martín, Javier; Llorca, Javier; González-Gay, Miguel A

2013-01-01

Rheumatoid arthritis (RA) is an inflammatory disease associated with accelerated atherosclerosis and high risk of cardiovascular (CV) disease. Angiopoietin-2 (Angpt-2), a marker of endothelial cell activation, has been proposed as a mediator of angiogenesis, which might play an important role in the regulation of endothelial integrity and inflammation. Therefore, the aim of this study was to determine whether Angpt-2 is related to severity and CV disease in RA patients. Angpt-2 serum levels were measured by enzyme linked immunosorbent assay (ELISA) in 290 patients with RA. A control group of 100 individuals frequency matched by age and sex and classic CV risk factors and CV disease was also assessed. Eighty-four patients with RA (28.9%) had experienced CV events. Also, extra-articular manifestations were present in 41 (14%) of these patients. Although there were not significant differences between patients and controls, a correlation between age at the time of disease onset and Angpt-2 was observed in RA patients (r=-0.31; p=0.02). Angpt-2 serum levels also correlated positively with extra-articular disease (mean±standard deviation in RA patients with and without extra-articular manifestations were 2476±1716 pg/ml and 1897±1228 pg/ml, respectively; p=0.01). Moreover, after adjustment for sex, age at RA diagnosis and CV risk factors, Angpt-2 levels were higher in RA patients with CV disease than in RA patients without CV complications (2472±1826 pg/ml vs. 1875±1101 pg/ml; p=0.05). Angpt-2 serum levels remained significantly higher in RA patients with CV disease compared to those without CV disease after additional adjustment for extra-articular manifestations (p=0.04). Our results show that Angpt-2 serum levels correlate with disease severity, early onset and CV disease in RA patients.

Biochemical analysis of human POLG2 variants associated with mitochondrial disease

PubMed Central

Young, Matthew J.; Longley, Matthew J.; Li, Fang-Yuan; Kasiviswanathan, Rajesh; Wong, Lee-Jun; Copeland, William C.

2011-01-01

Defects in mitochondrial DNA (mtDNA) maintenance comprise an expanding repertoire of polymorphic diseases caused, in part, by mutations in the genes encoding the p140 mtDNA polymerase (POLG), its p55 accessory subunit (POLG2) or the mtDNA helicase (C10orf2). In an exploration of nuclear genes for mtDNA maintenance linked to mitochondrial disease, eight heterozygous mutations (six novel) in POLG2 were identified in one control and eight patients with POLG-related mitochondrial disease that lacked POLG mutations. Of these eight mutations, we biochemically characterized seven variants [c.307G>A (G103S); c.457C>G (L153V); c.614C>G (P205R); c.1105A>G (R369G); c.1158T>G (D386E); c.1268C>A (S423Y); c.1423_1424delTT (L475DfsX2)] that were previously uncharacterized along with the wild-type protein and the G451E pathogenic variant. These seven mutations encode amino acid substitutions that map throughout the protein, including the p55 dimer interface and the C-terminal domain that interacts with the catalytic subunit. Recombinant proteins harboring these alterations were assessed for stimulation of processive DNA synthesis, binding to the p140 catalytic subunit, binding to dsDNA and self-dimerization. Whereas the G103S, L153V, D386E and S423Y proteins displayed wild-type behavior, the P205R and R369G p55 variants had reduced stimulation of processivity and decreased affinity for the catalytic subunit. Additionally, the L475DfsX2 variant, which possesses a C-terminal truncation, was unable to bind the p140 catalytic subunit, unable to bind dsDNA and formed aberrant oligomeric complexes. Our biochemical analysis helps explain the pathogenesis of POLG2 mutations in mitochondrial disease and emphasizes the need to quantitatively characterize the biochemical consequences of newly discovered mutations before classifying them as pathogenic. PMID:21555342

External Validation of a Tool Predicting 7-Year Risk of Developing Cardiovascular Disease, Type 2 Diabetes or Chronic Kidney Disease.

PubMed

Rauh, Simone P; Rutters, Femke; van der Heijden, Amber A W A; Luimes, Thomas; Alssema, Marjan; Heymans, Martijn W; Magliano, Dianna J; Shaw, Jonathan E; Beulens, Joline W; Dekker, Jacqueline M

2018-02-01

Chronic cardiometabolic diseases, including cardiovascular disease (CVD), type 2 diabetes (T2D) and chronic kidney disease (CKD), share many modifiable risk factors and can be prevented using combined prevention programs. Valid risk prediction tools are needed to accurately identify individuals at risk. We aimed to validate a previously developed non-invasive risk prediction tool for predicting the combined 7-year-risk for chronic cardiometabolic diseases. The previously developed tool is stratified for sex and contains the predictors age, BMI, waist circumference, use of antihypertensives, smoking, family history of myocardial infarction/stroke, and family history of diabetes. This tool was externally validated, evaluating model performance using area under the receiver operating characteristic curve (AUC)-assessing discrimination-and Hosmer-Lemeshow goodness-of-fit (HL) statistics-assessing calibration. The intercept was recalibrated to improve calibration performance. The risk prediction tool was validated in 3544 participants from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab). Discrimination was acceptable, with an AUC of 0.78 (95% CI 0.75-0.81) in men and 0.78 (95% CI 0.74-0.81) in women. Calibration was poor (HL statistic: p < 0.001), but improved considerably after intercept recalibration. Examination of individual outcomes showed that in men, AUC was highest for CKD (0.85 [95% CI 0.78-0.91]) and lowest for T2D (0.69 [95% CI 0.65-0.74]). In women, AUC was highest for CVD (0.88 [95% CI 0.83-0.94)]) and lowest for T2D (0.71 [95% CI 0.66-0.75]). Validation of our previously developed tool showed robust discriminative performance across populations. Model recalibration is recommended to account for different disease rates. Our risk prediction tool can be useful in large-scale prevention programs for identifying those in need of further risk profiling because of their increased risk for chronic cardiometabolic diseases.

Hospital-based HIV/HSV-2 seroprevalence among male patients with anal disease in Korea: cross sectional study

PubMed Central

2014-01-01

Background This study aimed to identify the characteristics of HIV and herpes simplex virus (HSV)-2 seroprevalence in male patients with anal disease. Methods HIV seroprevalence was estimated for different age groups of male patients with anal disease who were treated at Songdo colorectal hospital in Korea between 2001 and 2011. HIV seroprevalence of patients with anal disease was compared with that of patients with nonanal disease for each year from 2007 to 2011. HSV-2 antibody tests were conducted on 2,038 HIV-tested male patients with anal disease in 2009. Results For 11 years from 2001, HIV seroprevalence differed significantly by age group (P < 0.001) and was highest in the group aged <20 years. From 2007 to 2011, HIV seroprevalence in patients with anal disease was 7.6/10,000–13.3/10,000 and that in patients with nonanal disease was 0–0.9/10,000. HSV-2 seroprevalence among patients with anal disease was 24.0%, and only one patient with HIV and HSV-2 was observed. Conclusions HIV seroprevalencein male patients with anal disease was significantly higher than that for other diseases. HSV-2 seroprevalence was similar to that in the general male population. Implementation of the current HIV surveillance system for male patients at colorectal hospitals is necessary to help prevent HIV transmission. PMID:24444046

Phenotypic and Genotypic Characterisation of Inflammatory Bowel Disease Presenting Before the Age of 2 years

PubMed Central

Dziubak, Robert; Pescarin, Matilde; Drury, Suzanne; Godwin, Heather; Reeve, Kate; Chadokufa, Sibongile; Huggett, Bonita; Sider, Sara; James, Chela; Acton, Nikki; Cernat, Elena; Gasparetto, Marco; Noble-Jamieson, Gabi; Kiparissi, Fevronia; Elawad, Mamoun; Beales, Phil L.; Sebire, Neil J.; Gilmour, Kimberly; Uhlig, Holm H.; Bacchelli, Chiara; Shah, Neil

2017-01-01

Abstract Objectives: Inflammatory bowel disease [IBD] presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of 2 years and establish phenotypic features associated with underlying monogenicity. Methods: Phenotype data of 62 children with disease onset before the age of 2 years presenting over the past 20 years were reviewed. Children without previously established genetic diagnosis were prospectively recruited for next-generation sequencing. Results: In all, 62 patients [55% male] were identified. The median disease onset was 3 months of age (interquartile range [IQR]: 1 to 11). Conventional IBD classification only applied to 15 patients with Crohn’s disease [CD]-like [24%] and three with ulcerative colitis [UC]-like [5%] phenotype; 44 patients [71%] were diagnosed with otherwise unclassifiable IBD. Patients frequently required parenteral nutrition [40%], extensive immunosuppression [31%], haematopoietic stem-cell transplantation [29%], and abdominal surgery [19%]. In 31% of patients, underlying monogenic diseases were established [EPCAM, IL10, IL10RA, IL10RB, FOXP3, LRBA, SKIV2L, TTC37, TTC7A]. Phenotypic features significantly more prevalent in monogenic IBD were: consanguinity, disease onset before the 6th month of life, stunting, extensive intestinal disease and histological evidence of epithelial abnormalities. Conclusions: IBD in children with disease onset before the age of 2 years is frequently unclassifiable into Crohn’s disease and ulcerative colitis, particularly treatment resistant, and can be indistinguishable from monogenic diseases with IBD-like phenotype. PMID:27302973

A novel mutation in PNPLA2 leading to neutral lipid storage disease with myopathy.

PubMed

Ash, Daniel B; Papadimitriou, Dimitra; Hays, Arthur P; Dimauro, Salvatore; Hirano, Michio

2012-09-01

Mutations in PNPLA2, a gene encoding adipose triglyceride lipase, lead to neutral lipid storage disease with myopathy. To report the clinical and molecular features of a case of neutral lipid storage disease with myopathy resulting from a novel mutation in PNPLA2. Case report. University hospital. A 65-year-old man with progressive muscle weakness and high serum creatine kinase levels. Direct sequencing of the PNPLA2 gene. Identification of a novel homozygous mutation in the patient's PNPLA2 gene confirmed the suspected diagnosis of neutral lipid storage disease with myopathy. Screening of the PNPLA2 gene should be considered for patients presenting with high levels of creatine kinase, progressive muscle weakness, and systemic lipid accumulation. The presence of Jordans anomaly can be a strong diagnostic clue.

Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases.

PubMed

Kumar, Hemant; Kim, In-Su; More, Sandeep Vasant; Kim, Byung-Wook; Choi, Dong-Kug

2014-01-01

Covering: 2000 to 2013. Oxidative stress is the central component of chronic diseases. The nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway is vital in the up-regulation of cytoprotective genes and enzymes in response to oxidative stress and treatment with certain dietary phytochemicals. Herein, we classify bioactive compounds derived from natural products that are Nrf2/ARE pathway activators and recapitulate the molecular mechanisms for inducing Nrf2 to provide favorable effects in experimental models of chronic diseases. Moreover, pharmacological inhibition of Nrf2 signalling has emerged as promising strategy against multi-drug resistance thereby improving the treatment efficacy. We have also enlisted natural product-derived inhibitors of Nrf2/ARE pathway.

NO2 inhalation promotes Alzheimer’s disease-like progression: cyclooxygenase-2-derived prostaglandin E2 modulation and monoacylglycerol lipase inhibition-targeted medication

NASA Astrophysics Data System (ADS)

Yan, Wei; Yun, Yang; Ku, Tingting; Li, Guangke; Sang, Nan

2016-03-01

Air pollution has been reported to be associated with increased risks of cognitive impairment and neurodegenerative diseases. Because NO2 is a typical primary air pollutant and an important contributor to secondary aerosols, NO2-induced neuronal functional abnormalities have attracted greater attention, but the available experimental evidence, modulating mechanisms, and targeting medications remain ambiguous. In this study, we exposed C57BL/6J and APP/PS1 mice to dynamic NO2 inhalation and found for the first time that NO2 inhalation caused deterioration of spatial learning and memory, aggravated amyloid β42 (Aβ42) accumulation, and promoted pathological abnormalities and cognitive defects related to Alzheimer’s disease (AD). The microarray and bioinformation data showed that the cyclooxygenase-2 (COX-2)-mediated arachidonic acid (AA) metabolism of prostaglandin E2 (PGE2) played a key role in modulating this aggravation. Furthermore, increasing endocannabinoid 2-arachidonoylglycerol (2-AG) by inhibiting monoacylglycerol lipase (MAGL) prevented PGE2 production, neuroinflammation-associated Aβ42 accumulation, and neurodegeneration, indicating a therapeutic target for relieving cognitive impairment caused by NO2 exposure.

Type 2 diabetes mellitus in the pathophysiology of Alzheimer's disease.

PubMed

de Nazareth, Aparecida Marcelino

2017-01-01

Both Alzheimer's disease (AD) and type 2 diabetes mellitus (DM) are two common forms of disease worldwide and many studies indicate that people with diabetes, especially DM, are at higher risk of developing AD. AD is characterized by progressive cognitive decline and accumulation of β-amyloid (Aβ) forming senile plaques. DM is a metabolic disorder characterized by hyperglycemia in the context of insulin resistance and relative lack of insulin. Both diseases also share common characteristics such as loss of cognitive function and inflammation. Inflammation resulting from Aβ further induces production of Aβ 1-42 peptides. Inflammation due to overnutrition induces insulin resistance and consequently DM. Memory deficit and a decrease in GLUT4 and hippocampal insulin signaling have been observed in animal models of insulin resistance. The objective of this review was to show the shared characteristics of AD and DM.

Application of L1/2 regularization logistic method in heart disease diagnosis.

PubMed

Zhang, Bowen; Chai, Hua; Yang, Ziyi; Liang, Yong; Chu, Gejin; Liu, Xiaoying

2014-01-01

Heart disease has become the number one killer of human health, and its diagnosis depends on many features, such as age, blood pressure, heart rate and other dozens of physiological indicators. Although there are so many risk factors, doctors usually diagnose the disease depending on their intuition and experience, which requires a lot of knowledge and experience for correct determination. To find the hidden medical information in the existing clinical data is a noticeable and powerful approach in the study of heart disease diagnosis. In this paper, sparse logistic regression method is introduced to detect the key risk factors using L(1/2) regularization on the real heart disease data. Experimental results show that the sparse logistic L(1/2) regularization method achieves fewer but informative key features than Lasso, SCAD, MCP and Elastic net regularization approaches. Simultaneously, the proposed method can cut down the computational complexity, save cost and time to undergo medical tests and checkups, reduce the number of attributes needed to be taken from patients.

Different molecular conformations co-exist in each of three 2-aryl-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)acetamides: hydrogen bonding in zero, one and two dimensions.

PubMed

Narayana, Badiadka; Yathirajan, Hemmige S; Rathore, Ravindranath S; Glidewell, Christopher

2016-09-01

4-Antipyrine [4-amino-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one] and its derivatives exhibit a range of biological activities, including analgesic, antibacterial and anti-inflammatory, and new examples are always of potential interest and value. 2-(4-Chlorophenyl)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)acetamide, C19H18ClN3O2, (I), crystallizes with Z' = 2 in the space group P\\overline{1}, whereas its positional isomer 2-(2-chlorophenyl)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)acetamide, (II), crystallizes with Z' = 1 in the space group C2/c; the molecules of (II) are disordered over two sets of atomic sites having occupancies of 0.6020 (18) and 0.3980 (18). The two independent molecules of (I) adopt different molecular conformations, as do the two disorder components in (II), where the 2-chlorophenyl substituents adopt different orientations. The molecules of (I) are linked by a combination of N-H...O and C-H...O hydrogen bonds to form centrosymmetric four-molecule aggregates, while those of (II) are linked by the same types of hydrogen bonds forming sheets. The related compound N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-(3-methoxyphenyl)acetamide, C20H21N3O3, (III), is isomorphous with (I) but not strictly isostructural; again the two independent molecules adopt different molecular conformations, and the molecules are linked by N-H...O and C-H...O hydrogen bonds to form ribbons. Comparisons are made with some related structures, indicating that a hydrogen-bonded R2(2)(10) ring is the common structural motif.

SERCA2 Haploinsufficiency in a Mouse Model of Darier Disease Causes a Selective Predisposition to Heart Failure.

PubMed

Prasad, Vikram; Lorenz, John N; Lasko, Valerie M; Nieman, Michelle L; Huang, Wei; Wang, Yigang; Wieczorek, David W; Shull, Gary E

2015-01-01

Null mutations in one copy of ATP2A2, the gene encoding sarco/endoplasmic reticulum Ca(2+)-ATPase isoform 2 (SERCA2), cause Darier disease in humans, a skin condition involving keratinocytes. Cardiac function appears to be unimpaired in Darier disease patients, with no evidence that SERCA2 haploinsufficiency itself causes heart disease. However, SERCA2 deficiency is widely considered a contributing factor in heart failure. We therefore analyzed Atp2a2 heterozygous mice to determine whether SERCA2 haploinsufficiency can exacerbate specific heart disease conditions. Despite reduced SERCA2a levels in heart, Atp2a2 heterozygous mice resembled humans in exhibiting normal cardiac physiology. When subjected to hypothyroidism or crossed with a transgenic model of reduced myofibrillar Ca(2+)-sensitivity, SERCA2 deficiency caused no enhancement of the disease state. However, when combined with a transgenic model of increased myofibrillar Ca(2+)-sensitivity, SERCA2 haploinsufficiency caused rapid onset of hypertrophy, decompensation, and death. These effects were associated with reduced expression of the antiapoptotic Hax1, increased levels of the proapoptotic genes Chop and Casp12, and evidence of perturbations in energy metabolism. These data reveal myofibrillar Ca(2+)-sensitivity to be an important determinant of the cardiac effects of SERCA2 haploinsufficiency and raise the possibility that Darier disease patients are more susceptible to heart failure under certain conditions.

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.

PubMed

Sims, Rebecca; van der Lee, Sven J; Naj, Adam C; Bellenguez, Céline; Badarinarayan, Nandini; Jakobsdottir, Johanna; Kunkle, Brian W; Boland, Anne; Raybould, Rachel; Bis, Joshua C; Martin, Eden R; Grenier-Boley, Benjamin; Heilmann-Heimbach, Stefanie; Chouraki, Vincent; Kuzma, Amanda B; Sleegers, Kristel; Vronskaya, Maria; Ruiz, Agustin; Graham, Robert R; Olaso, Robert; Hoffmann, Per; Grove, Megan L; Vardarajan, Badri N; Hiltunen, Mikko; Nöthen, Markus M; White, Charles C; Hamilton-Nelson, Kara L; Epelbaum, Jacques; Maier, Wolfgang; Choi, Seung-Hoan; Beecham, Gary W; Dulary, Cécile; Herms, Stefan; Smith, Albert V; Funk, Cory C; Derbois, Céline; Forstner, Andreas J; Ahmad, Shahzad; Li, Hongdong; Bacq, Delphine; Harold, Denise; Satizabal, Claudia L; Valladares, Otto; Squassina, Alessio; Thomas, Rhodri; Brody, Jennifer A; Qu, Liming; Sánchez-Juan, Pascual; Morgan, Taniesha; Wolters, Frank J; Zhao, Yi; Garcia, Florentino Sanchez; Denning, Nicola; Fornage, Myriam; Malamon, John; Naranjo, Maria Candida Deniz; Majounie, Elisa; Mosley, Thomas H; Dombroski, Beth; Wallon, David; Lupton, Michelle K; Dupuis, Josée; Whitehead, Patrice; Fratiglioni, Laura; Medway, Christopher; Jian, Xueqiu; Mukherjee, Shubhabrata; Keller, Lina; Brown, Kristelle; Lin, Honghuang; Cantwell, Laura B; Panza, Francesco; McGuinness, Bernadette; Moreno-Grau, Sonia; Burgess, Jeremy D; Solfrizzi, Vincenzo; Proitsi, Petra; Adams, Hieab H; Allen, Mariet; Seripa, Davide; Pastor, Pau; Cupples, L Adrienne; Price, Nathan D; Hannequin, Didier; Frank-García, Ana; Levy, Daniel; Chakrabarty, Paramita; Caffarra, Paolo; Giegling, Ina; Beiser, Alexa S; Giedraitis, Vilmantas; Hampel, Harald; Garcia, Melissa E; Wang, Xue; Lannfelt, Lars; Mecocci, Patrizia; Eiriksdottir, Gudny; Crane, Paul K; Pasquier, Florence; Boccardi, Virginia; Henández, Isabel; Barber, Robert C; Scherer, Martin; Tarraga, Lluis; Adams, Perrie M; Leber, Markus; Chen, Yuning; Albert, Marilyn S; Riedel-Heller, Steffi; Emilsson, Valur; Beekly, Duane; Braae, Anne; Schmidt, Reinhold; Blacker, Deborah; Masullo, Carlo; Schmidt, Helena; Doody, Rachelle S; Spalletta, Gianfranco; Longstreth, W T; Fairchild, Thomas J; Bossù, Paola; Lopez, Oscar L; Frosch, Matthew P; Sacchinelli, Eleonora; Ghetti, Bernardino; Yang, Qiong; Huebinger, Ryan M; Jessen, Frank; Li, Shuo; Kamboh, M Ilyas; Morris, John; Sotolongo-Grau, Oscar; Katz, Mindy J; Corcoran, Chris; Dunstan, Melanie; Braddel, Amy; Thomas, Charlene; Meggy, Alun; Marshall, Rachel; Gerrish, Amy; Chapman, Jade; Aguilar, Miquel; Taylor, Sarah; Hill, Matt; Fairén, Mònica Díez; Hodges, Angela; Vellas, Bruno; Soininen, Hilkka; Kloszewska, Iwona; Daniilidou, Makrina; Uphill, James; Patel, Yogen; Hughes, Joseph T; Lord, Jenny; Turton, James; Hartmann, Annette M; Cecchetti, Roberta; Fenoglio, Chiara; Serpente, Maria; Arcaro, Marina; Caltagirone, Carlo; Orfei, Maria Donata; Ciaramella, Antonio; Pichler, Sabrina; Mayhaus, Manuel; Gu, Wei; Lleó, Alberto; Fortea, Juan; Blesa, Rafael; Barber, Imelda S; Brookes, Keeley; Cupidi, Chiara; Maletta, Raffaele Giovanni; Carrell, David; Sorbi, Sandro; Moebus, Susanne; Urbano, Maria; Pilotto, Alberto; Kornhuber, Johannes; Bosco, Paolo; Todd, Stephen; Craig, David; Johnston, Janet; Gill, Michael; Lawlor, Brian; Lynch, Aoibhinn; Fox, Nick C; Hardy, John; Albin, Roger L; Apostolova, Liana G; Arnold, Steven E; Asthana, Sanjay; Atwood, Craig S; Baldwin, Clinton T; Barnes, Lisa L; Barral, Sandra; Beach, Thomas G; Becker, James T; Bigio, Eileen H; Bird, Thomas D; Boeve, Bradley F; Bowen, James D; Boxer, Adam; Burke, James R; Burns, Jeffrey M; Buxbaum, Joseph D; Cairns, Nigel J; Cao, Chuanhai; Carlson, Chris S; Carlsson, Cynthia M; Carney, Regina M; Carrasquillo, Minerva M; Carroll, Steven L; Diaz, Carolina Ceballos; Chui, Helena C; Clark, David G; Cribbs, David H; Crocco, Elizabeth A; DeCarli, Charles; Dick, Malcolm; Duara, Ranjan; Evans, Denis A; Faber, Kelley M; Fallon, Kenneth B; Fardo, David W; Farlow, Martin R; Ferris, Steven; Foroud, Tatiana M; Galasko, Douglas R; Gearing, Marla; Geschwind, Daniel H; Gilbert, John R; Graff-Radford, Neill R; Green, Robert C; Growdon, John H; Hamilton, Ronald L; Harrell, Lindy E; Honig, Lawrence S; Huentelman, Matthew J; Hulette, Christine M; Hyman, Bradley T; Jarvik, Gail P; Abner, Erin; Jin, Lee-Way; Jun, Gyungah; Karydas, Anna; Kaye, Jeffrey A; Kim, Ronald; Kowall, Neil W; Kramer, Joel H; LaFerla, Frank M; Lah, James J; Leverenz, James B; Levey, Allan I; Li, Ge; Lieberman, Andrew P; Lunetta, Kathryn L; Lyketsos, Constantine G; Marson, Daniel C; Martiniuk, Frank; Mash, Deborah C; Masliah, Eliezer; McCormick, Wayne C; McCurry, Susan M; McDavid, Andrew N; McKee, Ann C; Mesulam, Marsel; Miller, Bruce L; Miller, Carol A; Miller, Joshua W; Morris, John C; Murrell, Jill R; Myers, Amanda J; O'Bryant, Sid; Olichney, John M; Pankratz, Vernon S; Parisi, Joseph E; Paulson, Henry L; Perry, William; Peskind, Elaine; Pierce, Aimee; Poon, Wayne W; Potter, Huntington; Quinn, Joseph F; Raj, Ashok; Raskind, Murray; Reisberg, Barry; Reitz, Christiane; Ringman, John M; Roberson, Erik D; Rogaeva, Ekaterina; Rosen, Howard J; Rosenberg, Roger N; Sager, Mark A; Saykin, Andrew J; Schneider, Julie A; Schneider, Lon S; Seeley, William W; Smith, Amanda G; Sonnen, Joshua A; Spina, Salvatore; Stern, Robert A; Swerdlow, Russell H; Tanzi, Rudolph E; Thornton-Wells, Tricia A; Trojanowski, John Q; Troncoso, Juan C; Van Deerlin, Vivianna M; Van Eldik, Linda J; Vinters, Harry V; Vonsattel, Jean Paul; Weintraub, Sandra; Welsh-Bohmer, Kathleen A; Wilhelmsen, Kirk C; Williamson, Jennifer; Wingo, Thomas S; Woltjer, Randall L; Wright, Clinton B; Yu, Chang-En; Yu, Lei; Garzia, Fabienne; Golamaully, Feroze; Septier, Gislain; Engelborghs, Sebastien; Vandenberghe, Rik; De Deyn, Peter P; Fernadez, Carmen Muñoz; Benito, Yoland Aladro; Thonberg, Hakan; Forsell, Charlotte; Lilius, Lena; Kinhult-Stählbom, Anne; Kilander, Lena; Brundin, RoseMarie; Concari, Letizia; Helisalmi, Seppo; Koivisto, Anne Maria; Haapasalo, Annakaisa; Dermecourt, Vincent; Fievet, Nathalie; Hanon, Olivier; Dufouil, Carole; Brice, Alexis; Ritchie, Karen; Dubois, Bruno; Himali, Jayanadra J; Keene, C Dirk; Tschanz, JoAnn; Fitzpatrick, Annette L; Kukull, Walter A; Norton, Maria; Aspelund, Thor; Larson, Eric B; Munger, Ron; Rotter, Jerome I; Lipton, Richard B; Bullido, María J; Hofman, Albert; Montine, Thomas J; Coto, Eliecer; Boerwinkle, Eric; Petersen, Ronald C; Alvarez, Victoria; Rivadeneira, Fernando; Reiman, Eric M; Gallo, Maura; O'Donnell, Christopher J; Reisch, Joan S; Bruni, Amalia Cecilia; Royall, Donald R; Dichgans, Martin; Sano, Mary; Galimberti, Daniela; St George-Hyslop, Peter; Scarpini, Elio; Tsuang, Debby W; Mancuso, Michelangelo; Bonuccelli, Ubaldo; Winslow, Ashley R; Daniele, Antonio; Wu, Chuang-Kuo; Peters, Oliver; Nacmias, Benedetta; Riemenschneider, Matthias; Heun, Reinhard; Brayne, Carol; Rubinsztein, David C; Bras, Jose; Guerreiro, Rita; Al-Chalabi, Ammar; Shaw, Christopher E; Collinge, John; Mann, David; Tsolaki, Magda; Clarimón, Jordi; Sussams, Rebecca; Lovestone, Simon; O'Donovan, Michael C; Owen, Michael J; Behrens, Timothy W; Mead, Simon; Goate, Alison M; Uitterlinden, Andre G; Holmes, Clive; Cruchaga, Carlos; Ingelsson, Martin; Bennett, David A; Powell, John; Golde, Todd E; Graff, Caroline; De Jager, Philip L; Morgan, Kevin; Ertekin-Taner, Nilufer; Combarros, Onofre; Psaty, Bruce M; Passmore, Peter; Younkin, Steven G; Berr, Claudine; Gudnason, Vilmundur; Rujescu, Dan; Dickson, Dennis W; Dartigues, Jean-François; DeStefano, Anita L; Ortega-Cubero, Sara; Hakonarson, Hakon; Campion, Dominique; Boada, Merce; Kauwe, John Keoni; Farrer, Lindsay A; Van Broeckhoven, Christine; Ikram, M Arfan; Jones, Lesley; Haines, Jonathan L; Tzourio, Christophe; Launer, Lenore J; Escott-Price, Valentina; Mayeux, Richard; Deleuze, Jean-François; Amin, Najaf; Holmans, Peter A; Pericak-Vance, Margaret A; Amouyel, Philippe; van Duijn, Cornelia M; Ramirez, Alfredo; Wang, Li-San; Lambert, Jean-Charles; Seshadri, Sudha; Williams, Julie; Schellenberg, Gerard D

2017-09-01

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10 -4 ) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10 -8 ) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10 -10 , odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 -10 , OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 -14 , OR = 1.67, MAF cases = 0.0143, MAF controls = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Anti-Saccharomyces cerevisiae antibodies (ASCA) in Crohn's disease are associated with disease severity but not NOD2/CARD15 mutations.

PubMed

Walker, L J; Aldhous, M C; Drummond, H E; Smith, B R K; Nimmo, E R; Arnott, I D R; Satsangi, J

2004-03-01

Anti-Saccharomyces cerevisiae antibodies (ASCAs) have been proposed as serological markers, which may differentiate Crohn's disease (CD) from ulcerative colitis (UC) and predict disease phenotype. Their importance in pathogenesis is unproven. We investigated the relationship between ASCAs, disease phenotype and NOD2/CARD15 genotype in CD and whether ASCAs were related to antibodies to other fungal proteins. Serum from 228 patients [143 CD, 75 UC, 10 with indeterminate colitis (IC)] and 78 healthy controls (HC) were assayed for ASCA. Antibodies (IgA, IgG) to other fungal proteins (Fusarium species ATC20334, Mycoprotein) were measured in the same samples using an in-house enzyme-linked immunosorbent assay (ELISA) assay. ASCAs were present in 57% of CD, 19% of UC, 30% of IC and 8% of HCs. ASCA-positive status was a predictor for CD with sensitivity of 57%, specificity of 87%, positive predictive value of 78% and negative predictive value of 68%. ASCA was associated with proximal (gastroduodenal and small bowel involvement) rather than purely colonic disease (P < 0.001) and with a more severe disease phenotype and requirement for surgery over a median follow-up time of 9 years (P < 0.0001). No associations with NOD2/CARD15 mutations were seen. There was no association between ASCA and antibodies to MP (IgA or IgG). These data implicate ASCA as a specific marker of disease location and progression in CD, emphasizing the heterogeneity within IBD.

Anti-Saccharomyces cerevisiae antibodies (ASCA) in Crohn's disease are associated with disease severity but not NOD2/CARD15 mutations

PubMed Central

WALKER, L J; ALDHOUS, M C; DRUMMOND, H E; SMITH, B R K; NIMMO, E R; ARNOTT, I D R; SATSANGI, J

2004-01-01

Anti-Saccharomyces cerevisiae antibodies (ASCAs) have been proposed as serological markers, which may differentiate Crohn's disease (CD) from ulcerative colitis (UC) and predict disease phenotype. Their importance in pathogenesis is unproven. We investigated the relationship between ASCAs, disease phenotype and NOD2/CARD15 genotype in CD and whether ASCAs were related to antibodies to other fungal proteins. Serum from 228 patients [143 CD, 75 UC, 10 with indeterminate colitis (IC)] and 78 healthy controls (HC) were assayed for ASCA. Antibodies (IgA, IgG) to other fungal proteins (Fusarium species ATC20334, Mycoprotein) were measured in the same samples using an in-house enzyme-linked immunosorbent assay (ELISA) assay. ASCAs were present in 57% of CD, 19% of UC, 30% of IC and 8% of HCs. ASCA-positive status was a predictor for CD with sensitivity of 57%, specificity of 87%, positive predictive value of 78% and negative predictive value of 68%. ASCA was associated with proximal (gastroduodenal and small bowel involvement) rather than purely colonic disease (P < 0·001) and with a more severe disease phenotype and requirement for surgery over a median follow-up time of 9 years (P < 0·0001). No associations with NOD2/CARD15 mutations were seen. There was no association between ASCA and antibodies to MP (IgA or IgG). These data implicate ASCA as a specific marker of disease location and progression in CD, emphasizing the heterogeneity within IBD. PMID:15008984

Graves' disease in 2.5 years old girl - 6-years-long observation.

PubMed

Jonak, Olimpia; Połubok, Joanna; Barg, Ewa

2016-01-01

Pediatric Graves' disease is rare in young children, more frequent in children with other autoimmune diseases or with family history of autoimmune thyroid disease. The 2.5 year old girl was admitted to the hospital with tachycardia and subfebrile temperature. The girl presented symptoms of atopic dermatitis. Child's mother was diagnosed with Hashimoto disease two months after the child's diagnosis. In physical examination of the child, enlarged thyroid was found. At the admission, the laboratory tests revealed decreased TSH (0.001 uIU/ml), increased both FT3 (>30 pg/ml) and FT4 (3.43 ng/dl), but normal levels of anti-thyreoglobulin antibodies (ATG - 0.64 IU/ml) and anti-thyroid peroxidase antibodies (ATPO - 0 IU/ml); thyrotropin receptor antibodies (TRAb) were not identified. The Graves' disease was diagnosed. The girl started treatment with methimazole (2x5mg) and propranolol (due to tachycardia, 2x5mg). The thyroid function (TSH, FT4 and FT3) normalized 1 year after diagnosis and hormone levels remained within normal reference values, but she received methimazole for 18 months. At presen, the patient is 8 years old. She is not receiving any treatment and her thyroid function is correct. The girl still presents symptoms of atopy. In case of symptoms of tachycardia in children, the hyperthyroidism should be taken into consideration. Numerous methods of treatment provide a therapy appropriate to the age and condition of patients. Long remission after treatment with antithyroid drugs could also be achieved in younger (prepubertal) children. © Polish Society for Pediatric Endocrinology and Diabetology.

ABCG2 variant has opposing effects on onset ages of Parkinson's disease and gout

PubMed Central

Matsuo, Hirotaka; Tomiyama, Hiroyuki; Satake, Wataru; Chiba, Toshinori; Onoue, Hiroyuki; Kawamura, Yusuke; Nakayama, Akiyoshi; Shimizu, Seiko; Sakiyama, Masayuki; Funayama, Manabu; Nishioka, Kenya; Shimizu, Toru; Kaida, Kenichi; Kamakura, Keiko; Toda, Tatsushi; Hattori, Nobutaka; Shinomiya, Nariyoshi

2015-01-01

Uric acid (urate) has been suggested to play a protective role in Parkinson's disease onset through its antioxidant activity. Dysfunction of ABCG2, a high-capacity urate exporter, is a major cause for early-onset gout based on hyperuricemia. In this study, the effects of a dysfunctional ABCG2 variant (Q141K, rs2231142) were analyzed on the ages at onset of gout patients (N = 507) and Parkinson's disease patients (N = 1015). The Q141K variant hastened the gout onset (P = 0.0027), but significantly associated with later Parkinson's disease onset (P = 0.025). Our findings will be helpful for development of more effective prevention of Parkinson's disease. PMID:25815357

ABCG2 variant has opposing effects on onset ages of Parkinson's disease and gout.

PubMed

Matsuo, Hirotaka; Tomiyama, Hiroyuki; Satake, Wataru; Chiba, Toshinori; Onoue, Hiroyuki; Kawamura, Yusuke; Nakayama, Akiyoshi; Shimizu, Seiko; Sakiyama, Masayuki; Funayama, Manabu; Nishioka, Kenya; Shimizu, Toru; Kaida, Kenichi; Kamakura, Keiko; Toda, Tatsushi; Hattori, Nobutaka; Shinomiya, Nariyoshi

2015-03-01

Uric acid (urate) has been suggested to play a protective role in Parkinson's disease onset through its antioxidant activity. Dysfunction of ABCG2, a high-capacity urate exporter, is a major cause for early-onset gout based on hyperuricemia. In this study, the effects of a dysfunctional ABCG2 variant (Q141K, rs2231142) were analyzed on the ages at onset of gout patients (N = 507) and Parkinson's disease patients (N = 1015). The Q141K variant hastened the gout onset (P = 0.0027), but significantly associated with later Parkinson's disease onset (P = 0.025). Our findings will be helpful for development of more effective prevention of Parkinson's disease.

Crystal structure of N-(3-chloro-1-methyl-1H-indazol-5-yl)-4-meth-oxy-benzene-sulfonamide.

PubMed

Chicha, Hakima; Rakib, El Mostapha; Gamouh, Ahmed; Saadi, Mohamed; El Ammari, Lahcen

2014-09-01

In the title compound, C15H14ClN3O3S, the dihedral angle between the planes of the indazole ring system (r.m.s. deviation = 0.007 Å) and the benzene ring is 89.05 (7)°. The meth-oxy C atom deviates from its attached ring by 0.196 (3) Å. In the crystal, inversion dimers linked by pairs of N-H⋯O hydrogen bonds generate R 2 (2)(8) loops. The dimers are connected into [010] chains by C-H⋯O inter-actions.

A disease-associated mutation in the adhesion GPCR BAI2 (ADGRB2) increases receptor signaling activity.

PubMed

Purcell, Ryan H; Toro, Camilo; Gahl, William A; Hall, Randy A

2017-12-01

Mutations in G protein-coupled receptors (GPCRs) that increase constitutive signaling activity can cause human disease. A de novo C-terminal mutation (R1465W) in the adhesion GPCR BAI2 (also known as ADGRB2) was identified in a patient suffering from progressive spastic paraparesis and other neurological symptoms. In vitro studies revealed that this mutation strongly increases the constitutive signaling activity of an N-terminally cleaved form of BAI2, which represents the activated form of the receptor. Further studies dissecting the mechanism(s) underling this effect revealed that wild-type BAI2 primarily couples to Gα z , with the R1465W mutation conferring increased coupling to Gα i . The R1465W mutation also increases the total and surface expression of BAI2. The mutation has no effect on receptor binding to β-arrestins, but does perturb binding to the endocytic protein endophilin A1, identified here as a novel interacting partner for BAI2. These studies provide new insights into the signaling capabilities of the adhesion GPCR BAI2/ADGRB2 and shed light on how an apparent gain-of-function mutation to the receptor's C-terminus may lead to human disease. © 2017 Wiley Periodicals, Inc.

Polycystic kidneys and GM2 gangliosidosis-like disease in neonatal springboks (Antidorcas marsupialis).

PubMed

Herder, V; Kummrow, M; Leeb, T; Sewell, A C; Hansmann, F; Lehmbecker, A; Wohlsein, P; Baumgärtner, W

2015-05-01

Clinical, gross, histopathologic, electron microscopic findings and enzymatic analysis of 4 captive, juvenile springboks (Antidorcas marsupialis) showing both polycystic kidneys and a storage disease are described. Springbok offspring (4 of 34; 12%) were affected by either one or both disorders in a German zoo within a period of 5 years (2008-2013). Macroscopic findings included bilaterally severely enlarged kidneys displaying numerous cysts in 4 animals and superior brachygnathism in 2 animals. Histopathologically, kidneys of 4 animals displayed cystic dilation of the renal tubules. In addition, abundant cytoplasmic vacuoles with a diameter ranging from 2 to 10 μm in neurons of the central and peripheral nervous system, hepatocytes, thyroid follicular epithelial cells, pancreatic islets of Langerhans and renal tubular cells were found in 2 springbok neonates indicative of an additional storage disease. Ultrastructurally, round electron-lucent vacuoles, up to 4 μm in diameter, were present in neurons. Enzymatic analysis of liver and kidney tissue of 1 affected springbok revealed a reduced activity of total hexosaminidase (Hex) with relatively increased HexA activity at the same level of total Hex, suggesting a hexosaminidase defect. Pedigree analysis suggested a monogenic autosomal recessive inheritance for both diseases. In summary, related springboks showed 2 different changes resembling both polycystic kidney and a GM2 gangliosidosis similar to the human Sandhoff disease. Whether the simultaneous occurrence of these 2 entities represents an incidental finding or has a genetic link needs to be investigated in future studies. © The Author(s) 2014.

Phenotypic and Genotypic Characterisation of Inflammatory Bowel Disease Presenting Before the Age of 2 years.

PubMed

Kammermeier, Jochen; Dziubak, Robert; Pescarin, Matilde; Drury, Suzanne; Godwin, Heather; Reeve, Kate; Chadokufa, Sibongile; Huggett, Bonita; Sider, Sara; James, Chela; Acton, Nikki; Cernat, Elena; Gasparetto, Marco; Noble-Jamieson, Gabi; Kiparissi, Fevronia; Elawad, Mamoun; Beales, Phil L; Sebire, Neil J; Gilmour, Kimberly; Uhlig, Holm H; Bacchelli, Chiara; Shah, Neil

2017-01-01

Inflammatory bowel disease [IBD] presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of 2 years and establish phenotypic features associated with underlying monogenicity. Phenotype data of 62 children with disease onset before the age of 2 years presenting over the past 20 years were reviewed. Children without previously established genetic diagnosis were prospectively recruited for next-generation sequencing. In all, 62 patients [55% male] were identified. The median disease onset was 3 months of age (interquartile range [IQR]: 1 to 11). Conventional IBD classification only applied to 15 patients with Crohn's disease [CD]-like [24%] and three with ulcerative colitis [UC]-like [5%] phenotype; 44 patients [71%] were diagnosed with otherwise unclassifiable IBD. Patients frequently required parenteral nutrition [40%], extensive immunosuppression [31%], haematopoietic stem-cell transplantation [29%], and abdominal surgery [19%]. In 31% of patients, underlying monogenic diseases were established [EPCAM, IL10, IL10RA, IL10RB, FOXP3, LRBA, SKIV2L, TTC37, TTC7A]. Phenotypic features significantly more prevalent in monogenic IBD were: consanguinity, disease onset before the 6th month of life, stunting, extensive intestinal disease and histological evidence of epithelial abnormalities. IBD in children with disease onset before the age of 2 years is frequently unclassifiable into Crohn's disease and ulcerative colitis, particularly treatment resistant, and can be indistinguishable from monogenic diseases with IBD-like phenotype. Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Rediscovering Beta-2 Microglobulin As a Biomarker across the Spectrum of Kidney Diseases

PubMed Central

Argyropoulos, Christos P.; Chen, Shan Shan; Ng, Yue-Harn; Roumelioti, Maria-Eleni; Shaffi, Kamran; Singh, Pooja P.; Tzamaloukas, Antonios H.

2017-01-01

There is currently an unmet need for better biomarkers across the spectrum of renal diseases. In this paper, we revisit the role of beta-2 microglobulin (β2M) as a biomarker in patients with chronic kidney disease and end-stage renal disease. Prior to reviewing the numerous clinical studies in the area, we describe the basic biology of β2M, focusing in particular on its role in maintaining the serum albumin levels and reclaiming the albumin in tubular fluid through the actions of the neonatal Fc receptor. Disorders of abnormal β2M function arise as a result of altered binding of β2M to its protein cofactors and the clinical manifestations are exemplified by rare human genetic conditions and mice knockouts. We highlight the utility of β2M as a predictor of renal function and clinical outcomes in recent large database studies against predictions made by recently developed whole body population kinetic models. Furthermore, we discuss recent animal data suggesting that contrary to textbook dogma urinary β2M may be a marker for glomerular rather than tubular pathology. We review the existing literature about β2M as a biomarker in patients receiving renal replacement therapy, with particular emphasis on large outcome trials. We note emerging proteomic data suggesting that β2M is a promising marker of chronic allograft nephropathy. Finally, we present data about the role of β2M as a biomarker in a number of non-renal diseases. The goal of this comprehensive review is to direct attention to the multifaceted role of β2M as a biomarker, and its exciting biology in order to propose the next steps required to bring this recently rediscovered biomarker into the twenty-first century. PMID:28664159

ChemProt-2.0: visual navigation in a disease chemical biology database

PubMed Central

Kim Kjærulff, Sonny; Wich, Louis; Kringelum, Jens; Jacobsen, Ulrik P.; Kouskoumvekaki, Irene; Audouze, Karine; Lund, Ole; Brunak, Søren; Oprea, Tudor I.; Taboureau, Olivier

2013-01-01

ChemProt-2.0 (http://www.cbs.dtu.dk/services/ChemProt-2.0) is a public available compilation of multiple chemical–protein annotation resources integrated with diseases and clinical outcomes information. The database has been updated to >1.15 million compounds with 5.32 millions bioactivity measurements for 15 290 proteins. Each protein is linked to quality-scored human protein–protein interactions data based on more than half a million interactions, for studying diseases and biological outcomes (diseases, pathways and GO terms) through protein complexes. In ChemProt-2.0, therapeutic effects as well as adverse drug reactions have been integrated allowing for suggesting proteins associated to clinical outcomes. New chemical structure fingerprints were computed based on the similarity ensemble approach. Protein sequence similarity search was also integrated to evaluate the promiscuity of proteins, which can help in the prediction of off-target effects. Finally, the database was integrated into a visual interface that enables navigation of the pharmacological space for small molecules. Filtering options were included in order to facilitate and to guide dynamic search of specific queries. PMID:23185041

The Use of Protein-Protein Interactions for the Analysis of the Associations between PM2.5 and Some Diseases.

PubMed

Zhang, Qing; Zhang, Pei-Wei; Cai, Yu-Dong

2016-01-01

Nowadays, pollution levels are rapidly increasing all over the world. One of the most important pollutants is PM2.5. It is known that the pollution environment may cause several problems, such as greenhouse effect and acid rain. Among them, the most important problem is that pollutants can induce a number of serious diseases. Some studies have reported that PM2.5 is an important etiologic factor for lung cancer. In this study, we extensively investigate the associations between PM2.5 and 22 disease classes recommended by Goh et al., such as respiratory diseases, cardiovascular diseases, and gastrointestinal diseases. The protein-protein interactions were used to measure the linkage between disease genes and genes that have been reported to be modulated by PM2.5. The results suggest that some diseases, such as diseases related to ear, nose, and throat and gastrointestinal, nutritional, renal, and cardiovascular diseases, are influenced by PM2.5 and some evidences were provided to confirm our results. For example, a total of 18 genes related to cardiovascular diseases are identified to be closely related to PM2.5, and cardiovascular disease relevant gene DSP is significantly related to PM2.5 gene JUP.

Aquaporin-2 Regulation in Health and Disease

PubMed Central

Radin, M. Judith; Yu, Ming-Jiun; Stoedkilde, Lene; Miller, R. Lance; Hoffert, Jason D.; Frokiaer, Jorgen; Pisitkun, Trairak; Knepper, Mark A.

2012-01-01

Aquaporin-2 (AQP2), the vasopressin-regulated water channel of the renal collecting duct, is dysregulated in numerous water balance disorders in humans and animals including those associated with polyuria (e.g. urinary tract obstruction, hypokalemia, inflammation, and lithium toxicity) and dilutional hyponatremia (e.g. SIADH). Normal regulation of AQP2 by vasopressin involves two independent regulatory mechanisms: 1) short-term regulation of AQP2 trafficking to and from the apical plasma membrane, and 2) long term regulation of the total abundance of the AQP2 protein in the cells. Most water balance disorders are the result of dysregulation of processes that regulate the total abundance of AQP2 in collecting duct cells. In general, the level of AQP2 in a collecting duct cell is determined by a balance between production via translation of AQP2 mRNA and removal via degradation and/or secretion into the urine in exosomes. AQP2 abundance increases in response to vasopressin chiefly due to increased translation subsequent to increases in AQP2 mRNA. Vasopressin-mediated regulation AQP2 gene transcription is poorly understood, although several transcription factor binding elements in the 5’ flanking region of the AQP2 gene have been identified and candidate transcription factors corresponding to these element have been discovered in proteomics studies. Here we review progress in this area and discuss elements of vasopressin signaling in the collecting duct that may impinge on regulation of AQP2 in health and in the context of examples of polyuric diseases. PMID:23130944

On the 2-Row Rule for Infectious Disease Transmission on Aircraft.

PubMed

Hertzberg, Vicki Stover; Weiss, Howard

With over two billion airline passengers annually, in-flight transmission of infectious diseases is an important global health concern. Many instances of in-flight transmission have been documented, but the relative influence of the many factors (see below) affecting in-flight transmission has not been quantified. Long-standing guidance by public health agencies is that the primary transmission risk associated with air travel for most respiratory infectious diseases is associated with sitting within two rows of an infectious passenger. The effect of proximity may be one of these factors. The aim of this study was to determine the risk of infection within and beyond the 2-row rule given by public health guidance. We searched the literature for reports of in-flight transmission of infection which included seat maps indicating where the infectious and infected passengers were seated. There is a ∼ 6% risk to passengers seated within the 2-rows of infected individual(s) and there is ∼ 2% risk to passengers seated beyond 2-rows from the infectious individual. Contact tracing limited to passengers within 2-rows of the infectious individual(s) could fail to detect other cases of infections. This has important consequences for assessing the spread of infectious diseases. Infection at a distance from the index case indicates other factors, such as airflow, movement of passenger/crew members, fomites and contacts between passengers in the departure gate before boarding, or after deplaning, are involved. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Mitochondrial Ca2+ handling in Huntington's and Alzheimer's diseases - Role of ER-mitochondria crosstalk.

PubMed

Naia, Luana; Ferreira, Ildete Luísa; Ferreiro, Elisabete; Rego, A Cristina

2017-02-19

Mitochondria play a relevant role in Ca 2+ buffering, governing energy metabolism and neuronal function. Huntington's disease (HD) and Alzheimer's disease (AD) are two neurodegenerative disorders that, although clinically distinct, share pathological features linked to selective brain damage. These include mitochondrial dysfunction, intracellular Ca 2+ deregulation and mitochondrial Ca 2+ handling deficits. Both diseases are associated with misfolding and aggregation of specific proteins that physically interact with mitochondria and interfere with endoplasmic reticulum (ER)/mitochondria-contact sites. Cumulating evidences indicate that impairment of mitochondrial Ca 2+ homeostasis underlies the susceptibility to selective neuronal death observed in HD and AD; however data obtained with different models and experimental approaches are not always consistent. In this review, we explore the recent literature on deregulation of mitochondrial Ca 2+ handling underlying the interplay between mitochondria and ER in HD and AD-associated neurodegeneration. Copyright © 2016 Elsevier Inc. All rights reserved.

ABCG8 polymorphisms and renal disease in type 2 diabetic patients.

PubMed

Nicolas, Anthony; Fatima, Sehrish; Lamri, Amel; Bellili-Muñoz, Naima; Halimi, Jean-Michel; Saulnier, Pierre-Jean; Hadjadj, Samy; Velho, Gilberto; Marre, Michel; Roussel, Ronan; Fumeron, Frédéric

2015-06-01

Sterols, bile acids and their receptors have been involved in diabetic nephropathy. The ATP-binding cassette transporters G5 and G8 (ABCG5 and ABCG8) play an important role in intestinal sterol absorption and bile acid secretion. The aim of our study was to assess the associations between two ABCG8 coding polymorphisms, T400K and D19H, and the incidence of renal events in type 2 diabetic subjects. Participants were the 3137 French type 2 diabetic subjects with micro- or macro-albuminuria from the genetic substudy of the DIABHYCAR trial. The mean duration of follow-up was 4years. Renal events were defined as a doubling of serum creatinine concentration or end-stage renal disease at follow-up. We then used a second population (DIAB2NEPHROGENE) of 2140 type 2 diabetic patients for the purpose of validation. In DIABHYCAR, the 400K allele was significantly associated with a higher risk of incident renal events in a multiple adjusted model (HR: 1.75 [95% CI 1.20-2.56], P=0.003). This association was still significant after further adjustments for baseline values of estimated glomerular filtration rate and urinary albumin excretion. In the validation population, the 400K allele was associated with the prevalence of end-stage renal disease (OR=2.01 [95% CI 1.15-3.54], P=0.015). No significant association was found between the D19H polymorphism and the risk of diabetic nephropathy. A polymorphism of the sterol transporter ABCG8 has been associated with the prevalence of end-stage renal disease and with the incidence of new renal events in type 2 diabetic patients. Copyright © 2015. Published by Elsevier Inc.

The roles of the exoribonucleases DIS3L2 and XRN1 in human disease.

PubMed

Pashler, Amy L; Towler, Benjamin P; Jones, Christopher I; Newbury, Sarah F

2016-10-15

RNA degradation is a vital post-transcriptional process which ensures that transcripts are maintained at the correct level within the cell. DIS3L2 and XRN1 are conserved exoribonucleases that are critical for the degradation of cytoplasmic RNAs. Although the molecular mechanisms of RNA degradation by DIS3L2 and XRN1 have been well studied, less is known about their specific roles in the development of multicellular organisms or human disease. This review focusses on the roles of DIS3L2 and XRN1 in the pathogenesis of human disease, particularly in relation to phenotypes seen in model organisms. The known diseases associated with loss of activity of DIS3L2 and XRN1 are discussed, together with possible mechanisms and cellular pathways leading to these disease conditions. © 2016 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

The preparation, surface structure, zeta potential, surface charge density and photocatalytic activity of TiO2 nanostructures of different shapes

NASA Astrophysics Data System (ADS)

Grover, Inderpreet Singh; Singh, Satnam; Pal, Bonamali

2013-09-01

Titania based nanocatalysts such as sodium titanates of different morphology having superior surface properties are getting wide importance in photocatalysis research. Despite having sodium (Na) contents and its high temperature synthesis (that generally deteriorate the photoreactivity), these Na-titanates often exhibit better photoactivity than P25-TiO2 catalyst. Hence, this work demonstrated the influence of crystal structure, BET surface area, surface charge, zeta potential (ζ) and metal loading on the photocatalytic activity of as-prepared sodium titanate nanotube (TNT) and titania nanorod (TNR). Straw like hollow orthorhombic-TNT (Na2Ti2O5·H2O) particles (W = 9-12 nm and L = 82-115 nm) and rice like pure anatase-TNR particles (W = 8-13 nm and L = 81-134 nm) are obtained by the hydrothermal treatment of P25-TiO2 with NaOH, which in fact, altered the net surface charge of TNT and TNR particles. The observed ζ = -2.82 (P25-TiO2), -13.5 (TNT) and -22.5 mV (TNR) are significantly altered by the Ag and Cu deposition. It has been found here that TNT displayed best photocatalytic activity for the imidacloprid insecticide (C9H10ClN5O2) degradation to CO2 formation under UV irradiation because of its largest surface area 176 m2 g-1 among the catalysts studied.

Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2).

PubMed

Grieben, Mariana; Pike, Ashley C W; Shintre, Chitra A; Venturi, Elisa; El-Ajouz, Sam; Tessitore, Annamaria; Shrestha, Leela; Mukhopadhyay, Shubhashish; Mahajan, Pravin; Chalk, Rod; Burgess-Brown, Nicola A; Sitsapesan, Rebecca; Huiskonen, Juha T; Carpenter, Elisabeth P

2017-02-01

Mutations in either polycystin-1 (PC1 or PKD1) or polycystin-2 (PC2, PKD2 or TRPP1) cause autosomal-dominant polycystic kidney disease (ADPKD) through unknown mechanisms. Here we present the structure of human PC2 in a closed conformation, solved by electron cryomicroscopy at 4.2-Å resolution. The structure reveals a novel polycystin-specific 'tetragonal opening for polycystins' (TOP) domain tightly bound to the top of a classic transient receptor potential (TRP) channel structure. The TOP domain is formed from two extensions to the voltage-sensor-like domain (VSLD); it covers the channel's endoplasmic reticulum lumen or extracellular surface and encloses an upper vestibule, above the pore filter, without blocking the ion-conduction pathway. The TOP-domain fold is conserved among the polycystins, including the homologous channel-like region of PC1, and is the site of a cluster of ADPKD-associated missense variants. Extensive contacts among the TOP-domain subunits, the pore and the VSLD provide ample scope for regulation through physical and chemical stimuli.

Mannose-binding lectin-associated serine protease 2 (MASP-2) contributes to poor disease outcome in humans and mice with pneumococcal meningitis.

PubMed

Kasanmoentalib, E Soemirien; Valls Seron, Mercedes; Ferwerda, Bart; Tanck, Michael W; Zwinderman, Aeilko H; Baas, Frank; van der Ende, Arie; Brouwer, Matthijs C; van de Beek, Diederik

2017-01-03

Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the pro-inflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies. We investigated mannose-binding lectin-associated serine protease (MASP-2) levels in cerebrospinal fluid (CSF) samples derived from the diagnostic lumbar puncture, which was available for 307 of 792 pneumococcal meningitis episodes included in our prospective nationwide cohort study (39%), and the association between these levels and clinical outcome. Subsequently, we studied the role of MASP-2 in our experimental pneumococcal meningitis mouse model using Masp2 -/- mice and evaluated the potential of adjuvant treatment with MASP-2-specific monoclonal antibodies in wild-type (WT) mice. MASP-2 levels in cerebrospinal fluid of patients with bacterial meningitis were correlated with poor functional outcome. Consistent with these human data, Masp2-deficient mice with pneumococcal meningitis had lower cytokine levels and increased survival compared to WT mice. Adjuvant treatment with MASP-2-specific monoclonal antibodies led to reduced complement activation and decreased disease severity. MASP-2 contributes to poor disease outcome in human and mice with pneumococcal meningitis. MASP-2-specific monoclonal antibodies can be used to attenuate the inflammatory response in pneumococcal meningitis.

A role for MCP-1/CCR2 in interstitial lung disease in children