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http://www.ncbi.nlm.nih.gov/pubmed/25430934 | 1. J Neurol Neurosurg Psychiatry. 2015 Aug;86(8):873-8. doi:
10.1136/jnnp-2014-308826. Epub 2014 Nov 27.
CMT subtypes and disease burden in patients enrolled in the Inherited
Neuropathies Consortium natural history study: a cross-sectional analysis.
Fridman V(1), Bundy B(2), Reilly MM(3), Pareyson D(4), Bacon C(5), Burns J(6),
Day J(7), Feely S(8), Finkel RS(9), Grider T(5), Kirk CA(2), Herrmann DN(10),
Laurá M(3), Li J(11), Lloyd T(12), Sumner CJ(12), Muntoni F(13), Piscosquito
G(4), Ramchandren S(14), Shy R(8), Siskind CE(7), Yum SW(15), Moroni I(4),
Pagliano E(4), Zuchner S(16), Scherer SS(17), Shy ME(8); Inherited Neuropathies
Consortium.
Author information:
(1)Departments of Neurology, Massachusetts General Hospital, Boston,
Massachusetts, USA.
(2)University of South Florida Epidemiology Center, Tampa, Florida, USA.
(3)MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London,
UK.
(4)Departments of Neurology, IRCCS Foundation, Carlo Besta Neurological
Institute, Milan, Italy.
(5)Departments of Neurology, University of Iowa Hospitals and Clinics, Iowa
City, Iowa, USA.
(6)Departments of Neurology, University of Sydney & Children's Hospital, Sydney,
Australia.
(7)Departments of Neurology, Stanford University, Stanford, California, USA.
(8)Departments of Neurology, University of Iowa Hospitals and Clinics, Iowa
City, Iowa, USA Departments of Neurology, Wayne State University, Detroit,
Michigan, USA.
(9)Departments of Neurology, Nemours Children's Hospital, Orlando, Florida, USA.
(10)Departments of Neurology, University of Rochester, Rochester, New York, USA.
(11)Departments of Neurology, Vanderbilt University, Nashville, Tennessee, USA.
(12)Departments of Neurology, John Hopkins University, Baltimore, Maryland, USA.
(13)Departments of Neurology, UCL Institute of Child Health & Great Ormond
Street Hospital, London, UK.
(14)Departments of Neurology, Wayne State University, Detroit, Michigan, USA
Departments of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
(15)Departments of Neurology, Children's Hospital of Philadelphia, Philadelphia,
Pennsylvania, USA Departments of Neurology, Hospital of the University of
Pennsylvania, Philadelphia, Pennsylvania, USA.
(16)Departments of Neurology, Center for Human Molecular Genomics, University of
Miami, Miami, Florida, USA.
(17)Departments of Neurology, Hospital of the University of Pennsylvania,
Philadelphia, Pennsylvania, USA.
BACKGROUND: The international Inherited Neuropathy Consortium (INC) was created
with the goal of obtaining much needed natural history data for patients with
Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from
patients in the INC to determine the distribution of CMT subtypes and the
clinical impairment associated with them.
METHODS: We analysed data from 1652 patients evaluated at 13 INC centres. The
distribution of CMT subtypes and pathogenic genetic mutations were determined.
The disease burden of all the mutations was assessed by the CMT Neuropathy Score
(CMTNS) and CMT Examination Score (CMTES).
RESULTS: 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most
common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation,
CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with
liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted
for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not
all subtypes were similar to those previously reported.
CONCLUSIONS: Our findings confirm that large numbers of patients with a
representative variety of CMT subtypes have been enrolled and that the frequency
of achieving a molecular diagnosis and distribution of the CMT subtypes reflects
those previously reported. Measures of severity are similar, though not
identical, to results from smaller series. This study confirms that it is
possible to assess patients in a uniform way between international centres,
which is critical for the planned natural history study and future clinical
trials. These data will provide a representative baseline for longitudinal
studies of CMT.
CLINICAL TRIAL REGISTRATION: ID number NCT01193075.
Published by the BMJ Publishing Group Limited. For permission to use (where not
already granted under a licence) please go to
http://group.bmj.com/group/rights-licensing/permissions.
DOI: 10.1136/jnnp-2014-308826
PMCID: PMC4516002
PMID: 25430934 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9042914 | 1. Am J Hum Genet. 1997 Mar;60(3):555-64.
A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3)
defines a new craniosynostosis syndrome.
Muenke M(1), Gripp KW, McDonald-McGinn DM, Gaudenz K, Whitaker LA, Bartlett SP,
Markowitz RI, Robin NH, Nwokoro N, Mulvihill JJ, Losken HW, Mulliken JB,
Guttmacher AE, Wilroy RS, Clarke LA, Hollway G, Adès LC, Haan EA, Mulley JC,
Cohen MM Jr, Bellus GA, Francomano CA, Moloney DM, Wall SA, Wilkie AO, et al.
Author information:
(1)Department of Pediatrics, University of Pennsylvania, Philadelphia, USA.
[email protected]
The underlying basis of many forms of syndromic craniosynostosis has been
defined on a molecular level. However, many patients with familial or sporadic
craniosynostosis do not have the classical findings of those craniosynostosis
syndromes. Here we present 61 individuals from 20 unrelated families where
coronal synostosis is due to an amino acid substitution (Pro250Arg) that results
from a single point mutation in the fibroblast growth factor receptor 3 gene on
chromosome 4p. In this instance, a new clinical syndrome is being defined on the
basis of the molecular finding. In addition to the skull findings, some patients
had abnormalities on radiographs of hands and feet, including thimble-like
middle phalanges, coned epiphyses, and carpal and tarsal fusions. Brachydactyly
was seen in some cases; none had clinically significant syndactyly or deviation
of the great toe. Sensorineural hearing loss was present in some, and
developmental delay was seen in a minority. While the radiological findings of
hands and feet can be very helpful in diagnosing this syndrome, it is not in all
cases clearly distinguishable on a clinical basis from other craniosynostosis
syndromes. Therefore, this mutation should be tested for in patients with
coronal synostosis.
PMCID: PMC1712518
PMID: 9042914 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23629963 | 1. J Cell Biol. 2013 Apr 29;201(3):361-72. doi: 10.1083/jcb.201302044.
Stress granules as crucibles of ALS pathogenesis.
Li YR(1), King OD, Shorter J, Gitler AD.
Author information:
(1)Medical Scientist Training Program and, Perelman School of Medicine at the
University of Pennsylvania, Philadelphia, PA 19104, USA.
Amyotrophic lateral sclerosis (ALS) is a fatal human neurodegenerative disease
affecting primarily motor neurons. Two RNA-binding proteins, TDP-43 and FUS,
aggregate in the degenerating motor neurons of ALS patients, and mutations in
the genes encoding these proteins cause some forms of ALS. TDP-43 and FUS and
several related RNA-binding proteins harbor aggregation-promoting prion-like
domains that allow them to rapidly self-associate. This property is critical for
the formation and dynamics of cellular ribonucleoprotein granules, the crucibles
of RNA metabolism and homeostasis. Recent work connecting TDP-43 and FUS to
stress granules has suggested how this cellular pathway, which involves protein
aggregation as part of its normal function, might be coopted during disease
pathogenesis.
DOI: 10.1083/jcb.201302044
PMCID: PMC3639398
PMID: 23629963 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24819634 | 1. Neuromolecular Med. 2014 Sep;16(3):540-50. doi: 10.1007/s12017-014-8307-9.
Epub 2014 May 13.
Mutation analysis of MFN2, GJB1, MPZ and PMP22 in Italian patients with axonal
Charcot-Marie-Tooth disease.
Bergamin G(1), Boaretto F, Briani C, Pegoraro E, Cacciavillani M, Martinuzzi A,
Muglia M, Vettori A, Vazza G, Mostacciuolo ML.
Author information:
(1)Department of Biology, University of Padova, Padua, Italy.
Charcot-Marie-Tooth (CMT) diseases include a group of clinically heterogeneous
inherited neuropathies subdivided into demyelinating (CMT1), axonal (CMT2) and
intermediate CMT forms. CMTs are associated with different genes, although
mutations in some of these genes may cause both clinical pictures. To date, more
than 50 CMT genes have been identified, but more than half of the cases are due
to mutations in MFN2, MPZ, GJB1 and PMP22. The aim of this study was to estimate
the frequency of disease mutations of these four genes in the axonal form of CMT
in order to evaluate their effectiveness in the molecular diagnosis of CMT2
patients. A cohort of 38 CMT2 Italian subjects was screened for mutations in the
MFN2, MPZ and GJB1 genes by direct sequencing and for PMP22 rearrangements using
the MLPA technique. Overall, we identified 15 mutations, 8 of which were novel:
11 mutations (28.9 %) were in the MFN2 gene, 2 (5.3 %) in MPZ and 2 (5.3 %) in
PMP22. No mutations were found in GJB1. Two patients showed rearrangements in
the PMP22 gene, which is commonly associated with CMT1 or HNPP phenotypes thus
usually not tested in CMT2 patients. By including this gene in the analysis, we
reached a molecular diagnosis rate of 39.5 %, which is one of the highest
reported in the literature. Our findings confirm the MFN2 gene as the most
common cause of CMT2 and suggest that PMP22 rearrangements should be considered
in the molecular diagnosis of CMT2 patients.
DOI: 10.1007/s12017-014-8307-9
PMID: 24819634 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22820099 | 1. Arch Biochem Biophys. 2012 Oct 1;526(1):38-43. doi: 10.1016/j.abb.2012.07.003.
Epub 2012 Jul 20.
Inhibition of c-Met activation sensitizes osteosarcoma cells to cisplatin via
suppression of the PI3K-Akt signaling.
Wang K(1), Zhuang Y, Liu C, Li Y.
Author information:
(1)Department of Pediatric Othopaedic Surgery, Qilu Hospital of Shandong
University, Jinan, China.
Osteosarcoma is a common malignant bone tumor. Cisplatin (CDDP) achieves a high
response rate in osteosarcoma. However, osteosarcoma usually exhibits cisplatin
resistance. Many members of receptor tyrosine kinases (RTKs)(1) have been
demonstrated to be overexpressed and constitutively activated in various tumors
including osteosarcoma, resulting in malignant progression and insensitivity to
chemotherapy. Hepatocyte growth factor receptor (HGFR/c-Met) also appears
overexpressed and activated in osteosarcoma cells. Nevertheless, which role of
c-Met activation in cisplatin efficacy against osteosarcoma cells remains still
elusive. This study found that inhibition of c-Met activity by PHA-665752 or
blockade of the interaction of autocrined HGF with c-Met with neutralizing
anti-HGF antibody promoted cisplatin efficacy in osteosarcoma cells, while
addition of recombinant human HGF (rh-HGF) counteracts cisplatin cytotoxicity.
Specifically, we demonstrated that inhibition of c-Met activity led to
suppression of the PI3K-Akt pathway, thus enhancing cisplatin chemosensitivity.
Our study clearly suggests that inhibition of c-Met activity can effectively
sensitize osteosarcoma cells to cisplatin via suppression of the PI3K-Akt
signaling.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.abb.2012.07.003
PMID: 22820099 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15870275 | 1. Mol Cell Biol. 2005 May;25(10):4023-33. doi: 10.1128/MCB.25.10.4023-4033.2005.
Human hHpr1/p84/Thoc1 regulates transcriptional elongation and physically links
RNA polymerase II and RNA processing factors.
Li Y(1), Wang X, Zhang X, Goodrich DW.
Author information:
(1)Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute,
Elm and Carlton Streets, Buffalo, NY 14263, USA.
Cotranscriptional loading of RNA processing factors onto nascent RNA facilitates
efficient gene expression. Mechanisms responsible for coupling transcription and
RNA processing are not well defined, but the Saccharomyces cerevisiae TREX
complex provides an example. TREX is composed of the subcomplex THO that
associates with RNA polymerase II and is required for normal transcriptional
elongation. THO associates with proteins involved in RNA splicing and export to
form the larger TREX complex. Hence, assembly of TREX physically couples
transcriptional elongation with RNA processing factors. Whether metazoan species
with long, intron-containing genes utilize a similar mechanism has not been
established. Here we show that human hHpr1/p84/Thoc1 associates with elongating
RNA polymerase II and the RNA splicing and export factor UAP56 in intact cells.
Depletion of hHpr1/p84/Thoc1 causes transcriptional elongation defects and
associated cellular phenotypes similar to those observed in THO-deficient yeast.
We conclude that hHpr1/p84/Thoc1 regulates transcriptional elongation and may
participate in a protein complex functionally analogous to yeast TREX,
physically linking elongating RNA polymerase II with RNA processing factors.
DOI: 10.1128/MCB.25.10.4023-4033.2005
PMCID: PMC1087710
PMID: 15870275 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17942284 | 1. Colloids Surf B Biointerfaces. 2008 Feb 15;61(2):290-7. doi:
10.1016/j.colsurfb.2007.09.009. Epub 2007 Sep 8.
HGF protects cultured cortical neurons against hypoxia/reoxygenation induced
cell injury via ERK1/2 and PI-3K/Akt pathways.
He F(1), Wu LX, Shu KX, Liu FY, Yang LJ, Zhou X, Zhang Y, Huang BS, Huang D,
Deng XL.
Author information:
(1)Department of Physiology, Xiangya School of Medicine, Central South
University, Changsha 410008, China.
Hepatocyte growth factor (HGF) has been revealed to exert multipotent activities
on a variety of cells. In this study, we investigated whether HGF had a direct
neuroprotection on cultured cerebral cortical neurons subjected to
hypoxia/reoxygenation (H/R) and explored the intracellular signalings mediated
the effects. The decrease in cell viability and increase in number of apoptotic
cells resulting from H/R were significantly prevented by HGF pre-treatment. HGF
stimulated both ERK1/2 and Akt activities in cortical neurons. Inhibition of ERK
activation completely abolished the protective effects of HGF, and inhibition of
Akt activation reduced, but did not completely eliminate the HGF mediated
neuroprotection. It is suggested that the neuroprotection of HGF depend on
ERK1/2 pathway, and, to a lesser extent, PI-3K/Akt pathway. In addition, we
found that pre-treatment with HGF remarkably attenuated the decrease in
expression of Bcl-2 and Bcl-xL induced by H/R, but failed to affect the amount
of Bax. It is likely that Bcl-2 and Bcl-xL contribute to the protective effects
of HGF.
DOI: 10.1016/j.colsurfb.2007.09.009
PMID: 17942284 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9864285 | 1. J Pharmacol Exp Ther. 1998 Dec;287(3):996-1006.
KN-93, an inhibitor of multifunctional Ca++/calmodulin-dependent protein kinase,
decreases early afterdepolarizations in rabbit heart.
Anderson ME(1), Braun AP, Wu Y, Lu T, Wu Y, Schulman H, Sung RJ.
Author information:
(1)The Cardiac Arrhythmia Section, Division of Cardiology, Departments of
Internal Medicine and Pharmacology, Vanderbilt University Medical Center,
Nashville, Tennessee, USA.
The multifunctional Ca++/calmodulin-dependent protein kinase II (CaM kinase)
mediates Ca++-induced augmentation of L-type Ca++ current (ICa); therefore it
may act as a proarrhythmic signaling molecule during early afterdepolarizations
(EADs) due to ICa. To investigate the hypothesis that ICa-dependent EADs are
favored by CaM kinase activation EADs were induced with clofilium in isolated
rabbit hearts. All EADs were rapidly terminated with ICa antagonists. Hearts
were pretreated with the CaM kinase inhibitor KN-93 or the inactive analog KN-92
(0.5 microM) for 10 min before clofilium exposure. EADs were significantly
suppressed by KN-93 (EADs present in 4/10 hearts) compared to KN-92 (EADs
present in 10/11 hearts) (P =.024). There were no significant differences in
parameters favoring EADs such as monophasic action potential duration or heart
rate in KN-93- or KN-92-treated hearts. CaM kinase activity in situ increased
37% in hearts with EADs compared to hearts without EADs (P =.015). This increase
in CaM kinase activity was prevented by pretreatment with KN-93. In vitro, KN-93
potently inhibited rabbit myocardial CaM kinase activity (calculated Ki </= 2.58
microM), but the inactive analog KN-92 did not (Ki > 100 microM). The actions of
KN-93 and KN-92 on ICa and other repolarizing K+ currents did not explain
preferential EAD suppression by KN-93. These data show a novel association
between CaM kinase activation and EADs and are consistent with the hypothesis
that the ICa and CaM kinase activation both contribute to EADs in this model.
PMID: 9864285 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20371350 | 1. Cell. 2010 Apr 2;141(1):129-41. doi: 10.1016/j.cell.2010.03.009.
Transcriptome-wide identification of RNA-binding protein and microRNA target
sites by PAR-CLIP.
Hafner M(1), Landthaler M, Burger L, Khorshid M, Hausser J, Berninger P,
Rothballer A, Ascano M Jr, Jungkamp AC, Munschauer M, Ulrich A, Wardle GS,
Dewell S, Zavolan M, Tuschl T.
Author information:
(1)Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, The
Rockefeller University, 1230 York Avenue, Box 186, New York, NY 10065, USA.
Comment in
Chem Biol. 2010 Apr 23;17(4):316-8. doi: 10.1016/j.chembiol.2010.04.003.
Nat Methods. 2010 Jun;7(6):422-3. doi: 10.1038/nmeth0610-422b.
RNA transcripts are subject to posttranscriptional gene regulation involving
hundreds of RNA-binding proteins (RBPs) and microRNA-containing
ribonucleoprotein complexes (miRNPs) expressed in a cell-type dependent fashion.
We developed a cell-based crosslinking approach to determine at high resolution
and transcriptome-wide the binding sites of cellular RBPs and miRNPs. The
crosslinked sites are revealed by thymidine to cytidine transitions in the cDNAs
prepared from immunopurified RNPs of 4-thiouridine-treated cells. We determined
the binding sites and regulatory consequences for several intensely studied RBPs
and miRNPs, including PUM2, QKI, IGF2BP1-3, AGO/EIF2C1-4 and TNRC6A-C. Our study
revealed that these factors bind thousands of sites containing defined sequence
motifs and have distinct preferences for exonic versus intronic or coding versus
untranslated transcript regions. The precise mapping of binding sites across the
transcriptome will be critical to the interpretation of the rapidly emerging
data on genetic variation between individuals and how these variations
contribute to complex genetic diseases.
Copyright 2010 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2010.03.009
PMCID: PMC2861495
PMID: 20371350 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24287896 | 1. Cell Mol Life Sci. 2014 May;71(10):1881-92. doi: 10.1007/s00018-013-1532-9.
Epub 2013 Nov 29.
Signaling pathways and the cerebral cavernous malformations proteins: lessons
from structural biology.
Fisher OS(1), Boggon TJ.
Author information:
(1)Department of Pharmacology, Yale University School of Medicine, SHM B-316A,
333 Cedar Street, New Haven, CT, 06520, USA.
Cerebral cavernous malformations (CCM) are neurovascular dysplasias that result
in mulberry-shaped lesions predominantly located in brain and spinal tissues.
Mutations in three genes are associated with CCM. These genes encode for the
proteins KRIT1/CCM1 (krev interaction trapped 1/cerebral cavernous malformations
1), cerebral cavernous malformations 2, osmosensing scaffold for MEKK3
(CCM2/malcavernin/OSM), and cerebral cavernous malformations 3/programmed cell
death 10 (CCM3/PDCD10). There have been many significant recent advances in our
understanding of the structure and function of these proteins, as well as in
their roles in cellular signaling. Here, we provide an update on the current
knowledge of the structure of the CCM proteins and their functions within
cellular signaling, particularly in cellular adhesion complexes and signaling
cascades. We go on to discuss subcellular localization of the CCM proteins, the
formation and regulation of the CCM complex signaling platform, and current
progress towards targeted therapy for CCM disease. Recent structural studies
have begun to shed new light on CCM protein function, and we focus here on how
these studies have helped inform the current understanding of these roles and
how they may aid future studies into both CCM-related biology and disease
mechanisms.
DOI: 10.1007/s00018-013-1532-9
PMCID: PMC3999170
PMID: 24287896 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24990152 | 1. Hum Mol Genet. 2014 Dec 1;23(23):6223-34. doi: 10.1093/hmg/ddu342. Epub 2014
Jul 2.
Lack of CCM1 induces hypersprouting and impairs response to flow.
Mleynek TM(1), Chan AC(1), Redd M(2), Gibson CC(3), Davis CT(4), Shi DS(4), Chen
T(5), Carter KL(5), Ling J(6), Blanco R(7), Gerhardt H(8), Whitehead K(9), Li
DY(10).
Author information:
(1)Department of Molecular Medicine, Department of Oncological Sciences.
(2)Flourescence Imaging Core.
(3)Department of Molecular Medicine, Department of Bioengineering.
(4)Department of Molecular Medicine, Department of Human Genetics.
(5)Department of Molecular Medicine, Small Animal Ultrasound Core, University of
Utah, Salt Lake City 84112, USA.
(6)Department of Molecular Medicine.
(7)Vascular Biology Laboratory, London Research Institute, Cancer Research UK,
London WC2A 3LY, UK.
(8)Vascular Patterning Laboratory, VIB3-Vesalius Research Center and CMVB,
Department of Oncology, KU Leuven Campus Gasthuisberg O&N4, Herestraat 49 box
912, Leuven B-3000, Belgium.
(9)Department of Molecular Medicine, Small Animal Ultrasound Core, University of
Utah, Salt Lake City 84112, USA, Division of Cardiovascular Medicine, Salt Lake
City 84132, USA and.
(10)Department of Molecular Medicine, Department of Oncological Sciences,
Division of Cardiovascular Medicine, Salt Lake City 84132, USA and The Key
Laboratory for Human Disease Gene Study of Sichuan Province, Institute of
Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial
People's Hospital, Chengdu, Sichuan 610072, China [email protected]
[email protected].
Cerebral cavernous malformation (CCM) is a disease of vascular malformations
known to be caused by mutations in one of three genes: CCM1, CCM2 or CCM3.
Despite several studies, the mechanism of CCM lesion onset remains unclear.
Using a Ccm1 knockout mouse model, we studied the morphogenesis of early lesion
formation in the retina in order to provide insight into potential mechanisms.
We demonstrate that lesions develop in a stereotypic location and pattern,
preceded by endothelial hypersprouting as confirmed in a zebrafish model of
disease. The vascular defects seen with loss of Ccm1 suggest a defect in
endothelial flow response. Taken together, these results suggest new mechanisms
of early CCM disease pathogenesis and provide a framework for further study.
Published by Oxford University Press 2014. This work is written by (a) US
Government employee (s) and is in the public domain in the US.
DOI: 10.1093/hmg/ddu342
PMCID: PMC4222362
PMID: 24990152 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16100539 | 1. Tidsskr Nor Laegeforen. 2005 Aug 11;125(15):2008-10.
[Cerebral cavernous malformations].
[Article in Norwegian]
Koht J(1), Braathen GJ, Neubert D, Russell MB.
Author information:
(1)Nevrologisk avdeling, Akershus universitetssykehus, 1478 Lørenskog.
[email protected]
BACKGROUND: Cerebral cavernous malformations exist in sporadic and familial
forms. They have considerable genetic and clinical heterogeneity. Better
understanding of these disorders may improve management.
MATERIAL AND METHODS: This review is based on personal experience and recent
literature.
RESULTS: Cerebral cavernous malformations are venous malformations that can be
detected with gradient echo MRI of the brain. Approximately 0.5% of the general
population have the sporadic form with a single or a few cerebral cavernous
malformations which mostly are asymptomatic. Those with the familial form
usually have several cavernous malformations caused by an autosomal dominant
condition. So far, 3 loci have been identified: CCM1 on chromosome 7q, CCM2 on
chromosome 7p, and CCM3 on chromosome 3q, occurring in, respectively,
approximately 40%, 20% and 40% of the families. CCM1 is caused by a mutation in
the KRIT1 gene and CCM2 is caused by a mutation in the MGC4607 gene, while the
gene for CCM3 is not yet identified. Mean age at onset is 20-40, but onset can
occur at all ages. The most frequent symptoms are seizures, cerebral
haemorrhage, chronic headache and focal neurological deficits. Many carriers
are, however, asymptomatic.
INTERPRETATION: Sporadic cerebral cavernous malformation is often asymptomatic,
while the familial form shows phenotypic and genetic heterogeneity. The symptoms
are depending on the location of the malformations as well as whether
haemorrhage does occur.
PMID: 16100539 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12165118 | 1. Thyroid. 2002 Jun;12(6):527-33. doi: 10.1089/105072502760143935.
Clinical and experimental studies on the use of 3,5-diiodothyropropionic acid, a
thyroid hormone analogue, in heart failure.
Morkin E(1), Pennock GD, Spooner PH, Bahl JJ, Goldman S.
Author information:
(1)Department of Medicine, University of Arizona, Tucson, Arizona 85724, USA.
[email protected]
Thyroid hormone has unique actions that make it a novel and possibly useful
agent for treatment of heart failure. Because of potential adverse effects of
thyroid hormone, however, there has been interest in developing analogues with
fewer undesirable side effects. Screening of compounds structurally related to
levothyroxine identified 3,5-diiodothyropropionic acid (DITPA) as an analogue
with inotropic selectivity and low metabolic activity in hypothyroid rats. When
DITPA was administered alone or in combination with captopril in rat and rabbit
postinfarction models of heart failure, cardiac output was increased and left
ventricular end-diastolic pressure (LV EDP) was decreased without increasing
heart rate. A pilot clinical study was undertaken to evaluate the safety and
efficacy of DITPA. In a dose-ranging study in 7 normal volunteers the drug was
well tolerated. A double-blind comparison then was made of DITPA versus placebo
in a group of 19 patients with moderately severe heart failure. Patients were
randomly assigned to receive either 1.875 mg/kg of DITPA or placebo daily. After
2 weeks the drug was increased to 3.75 mg/kg daily for an additional 2 weeks. In
heart failure patients receiving the drug for 4 weeks, cardiac index was
increased (p = 0.04) and systemic vascular resistance index was decreased (p =
0.02). Total serum cholesterol (p = 0.013) and triglycerides (p = 0.005) also
were decreased significantly. These results indicate that DITPA is well
tolerated and could represent a useful new agent for treatment of congestive
heart failure.
DOI: 10.1089/105072502760143935
PMID: 12165118 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15148346 | 1. J Pharmacol Exp Ther. 2004 Oct;311(1):164-71. doi: 10.1124/jpet.104.069153.
Epub 2004 May 17.
Regulation of gene expression in cardiomyocytes by thyroid hormone and thyroid
hormone analogs 3,5-diiodothyropropionic acid and CGS 23425
[N-[3,5-dimethyl-4-(4'-hydroxy-3'-isopropylphenoxy)-phenyl]-oxamic acid].
Adamson C(1), Maitra N, Bahl J, Greer K, Klewer S, Hoying J, Morkin E.
Author information:
(1)Department of Medicine, Sarver Heart Center, University of Arizona, P.O. Box
245046, 1501 North Campbell AHSC, Tucson, AZ 85724, USA. [email protected]
The heart is an important target of thyroid hormone actions. Only a limited
number of cardiac target genes have been identified, and little is known about
their regulation by T(3) (3,3',5-triiodothyronine) and thyroid hormone analogs.
We used an oligonucleotide microarray to identify novel cardiac genes regulated
by T(3) and two thyroid hormone analogs, 3,5-diidodothyropropionic acid (DITPA)
and CGS 23425 [N-[3,5-dimethyl-4-(4'-hydroxy-3'-isopropylphenoxy)-phenyl]-oxamic
acid]. DITPA binds with lower affinity than T(3) to thyroid hormone receptor
alpha1 and beta1 isoforms, whereas CGS 23425 binds selectively to beta1.
Fluorescent-labeled cDNA was prepared from cultured heart cells maintained in
medium stripped of thyroid hormone ("hypothyroid" control) or treated with T(3),
DITPA, and CGS 23425 at concentrations 5 times their respective K(d) values for
48 h. The arrays were scanned and analyzed using an analysis of variance
program. Sixty-four genes were identified that were >1.5 times up- or
down-regulated by one of the treatments with P < 0.05. The genes regulated by
T(3) and DITPA were nearly identical. Thirteen genes were differentially
regulated by CGS 23425. Genes encoding contractile proteins, Ca(2+)-ATPase of
sarcoplasmic reticulum and several proteins of mitochondrial oxidative
phosphorylation, were up-regulated by T(3) and DITPA but not by CGS 23425. These
results indicate that some, but not all, of the actions of thyroid hormone
analogs can be explained by differences in gene activation.
DOI: 10.1124/jpet.104.069153
PMID: 15148346 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25385046 | 1. Sci Rep. 2014 Nov 11;4:6992. doi: 10.1038/srep06992.
Rer1 and calnexin regulate endoplasmic reticulum retention of a peripheral
myelin protein 22 mutant that causes type 1A Charcot-Marie-Tooth disease.
Hara T(1), Hashimoto Y(1), Akuzawa T(1), Hirai R(1), Kobayashi H(1), Sato K(1).
Author information:
(1)Laboratory of Molecular Traffic, Institute for Molecular and Cellular
Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan.
Peripheral myelin protein 22 (PMP22) resides in the plasma membrane and is
required for myelin formation in the peripheral nervous system. Many PMP22
mutants accumulate in excess in the endoplasmic reticulum (ER) and lead to the
inherited neuropathies of Charcot-Marie-Tooth (CMT) disease. However, the
mechanism through which PMP22 mutants accumulate in the ER is unknown. Here, we
studied the quality control mechanisms for the PMP22 mutants L16P and G150D,
which were originally identified in mice and patients with CMT. We found that
the ER-localised ubiquitin ligase Hrd1/SYVN1 mediates ER-associated degradation
(ERAD) of PMP22(L16P) and PMP22(G150D), and another ubiquitin ligase, gp78/AMFR,
mediates ERAD of PMP22(G150D) as well. We also found that PMP22(L16P), but not
PMP22(G150D), is partly released from the ER by loss of Rer1, which is a
Golgi-localised sorting receptor for ER retrieval. Rer1 interacts with the
wild-type and mutant forms of PMP22. Interestingly, release of PMP22(L16P) from
the ER was more prominent with simultaneous knockdown of Rer1 and the
ER-localised chaperone calnexin than with the knockdown of each gene. These
results suggest that CMT disease-related PMP22(L16P) is trapped in the ER by
calnexin-dependent ER retention and Rer1-mediated early Golgi retrieval systems
and partly degraded by the Hrd1-mediated ERAD system.
DOI: 10.1038/srep06992
PMCID: PMC4227013
PMID: 25385046 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25191117 | 1. RETRACTED ARTICLE
World J Nucl Med. 2014 Jan;13(1):67-70. doi: 10.4103/1450-1147.138579.
Multilocular disseminated tarlov cysts: importance of imaging.
Padma S(1), Sundaram PS(1).
Author information:
(1)Department of Nuclear Medicine and PETCT, Amrita Institute of Medical
Sciences and Research Centre, Cochin, Kerala, India.
Retraction in
World J Nucl Med. 2016 Jan-Apr;15(1):78. doi: 10.4103/1450-1147.172145.
With technological advancements and wider availability of multimodality imaging,
incidental lesions are frequently identified in patients undergoing various
imaging studies. We report here a case of multiloculated disseminated perineural
or Tarlov cysts (TCs). The primary aim of our study was to (1) provide a
comprehensive review of the clinical, imaging and histopathological features of
TCs (2) to draw attention to the fact that multiple lumbo-sacral and dorsal TCs
can produce nerve injuries and serious movement disturbances (3) to document the
usefulness of the magnetic resonance imaging (MRI) and bone scan in noninvasive
diagnosis and guiding management in such cases. These cysts are clearly
identified by MR and computerized tomography imaging of the lumbosacral spine.
However, there are no reports on the scintigraphic findings of TCs in
literature. TCs are typically benign, asymptomatic lesions that can simply be
monitored. Until date, no consensus exists about the best surgical strategy to
be followed for their management.
DOI: 10.4103/1450-1147.138579
PMCID: PMC4149775
PMID: 25191117
Conflict of interest statement: Conflict of Interest: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/21830055 | 1. Skeletal Radiol. 2012 Jan;41(1):97-101. doi: 10.1007/s00256-011-1243-y. Epub
2011 Aug 10.
A case of symptomatic cervical perineural (Tarlov) cyst: clinical manifestation
and management.
Kim K(1), Chun SW, Chung SG.
Author information:
(1)Department of Rehabilitation Medicine, Seoul National University College of
Medicine, Room # 12611, Seoul National University Hospital, 101 Daehak-ro,
Jongno-gu, Seoul, Korea.
Perineural (Tarlov) cysts are most often found in the sacral region and are rare
in the cervical spine. Although they are usually asymptomatic, a small number of
those at the lumbosacral level have been known to produce localized or radicular
pain. Few reports are available on symptomatic perineural cysts in the cervical
spine and it has not been discussed how they should be managed. We present here
a case of cervical perineural cysts with persistent radicular pain where the
pain was adequately managed with repetitive transforaminal epidural steroid
injection (TFESI). The patient had experienced intractable pain in the posterior
neck and left upper extremity for more than 7 years. The nature of the pain was
cramping and a tingling sensation, which was aggravated in the supine position.
Magnetic resonance imaging revealed a perineural cyst in the neural foramen of
left C7 root. The patient underwent three repetitive TFESIs targeted at the
root. Each injection provided incremental relief, which lasted more than
6 months. Follow-up image revealed shrinkage of the cyst. This case illustrates
in detail the clinical manifestation of a rare symptomatic perineural cyst in
the cervical region and to our knowledge is the first to report the beneficial
effect of repetitive TFESI.
DOI: 10.1007/s00256-011-1243-y
PMID: 21830055 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23126408 | 1. J Proteome Res. 2012 Dec 7;11(12):6008-18. doi: 10.1021/pr300709k. Epub 2012
Nov 19.
Coupling a detergent lysis/cleanup methodology with intact protein fractionation
for enhanced proteome characterization.
Sharma R(1), Dill BD, Chourey K, Shah M, VerBerkmoes NC, Hettich RL.
Author information:
(1)UT-ORNL Graduate School of Genome Science and Technology, University of
Tennessee, Knoxville-Tennessee 37996, United States.
The expanding use of surfactants for proteome sample preparations has prompted
the need to systematically optimize the application and removal of these
MS-deleterious agents prior to proteome measurements. Here we compare four
detergent cleanup methods (trichloroacetic acid (TCA) precipitation,
chloroform/methanol/water (CMW) extraction, a commercial detergent removal spin
column method (DRS) and filter-aided sample preparation (FASP)) to provide
efficiency benchmarks with respect to protein, peptide, and spectral
identifications in each case. Our results show that for protein-limited samples,
FASP outperforms the other three cleanup methods, while at high protein amounts,
all the methods are comparable. This information was used to investigate and
contrast molecular weight-based fractionated with unfractionated lysates from
three increasingly complex samples ( Escherichia coli K-12, a five microbial
isolate mixture, and a natural microbial community groundwater sample), all of
which were prepared with an SDS-FASP approach. The additional fractionation step
enhanced the number of protein identifications by 8% to 25% over the
unfractionated approach across the three samples.
DOI: 10.1021/pr300709k
PMID: 23126408 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19286941 | 1. Am J Physiol Heart Circ Physiol. 2009 May;296(5):H1551-7. doi:
10.1152/ajpheart.01293.2008. Epub 2009 Mar 13.
Thyroid hormone analog 3,5-diiodothyropropionic acid promotes healthy
vasculature in the adult myocardium independent of thyroid effects on cardiac
function.
Liu Y(1), Wang D, Redetzke RA, Sherer BA, Gerdes AM.
Author information:
(1)Cardiovascular Research Ctr., Sanford Research/Univ. of South Dakota, 1100 E.
21st St., 7th Fl., Sioux Falls, SD 57105, USA.
Patients with hypothyroidism are at a higher risk for coronary vascular disease.
Patients with diabetes and related vascular complications also have an increased
incidence of low thyroid function. While thyroid hormones (THs) may be key
regulators of a healthy vasculature, potential undesirable side effects hinder
their use in the treatment of vascular disorders. TH analogs such as
3,5-diiodothyropropionic acid (DITPA) may provide a safer treatment option.
However, the relative potency of DITPA on vascular growth, cardiac function, and
metabolism is poorly understood. We hypothesized that the vascular
growth-promoting effects of DITPA can be obtained with a minimum effect on
cardiac function. Thyroidectomized Sprague-Dawley rats were given slow-release
pellets with either thyroxine (T4, 2.7 or 5.2 mg) or DITPA (80 mg) for 6 wk and
were compared with placebo. Heart mass, body mass, body temperature, serum THs,
cardiac function (echocardiograms and hemodynamics), and myocardial arteriolar
density were determined. Hypothyroidism led to reductions in cardiac function,
heart mass, body temperature, and myocardial arterioles. High-dose T4 prevented
arteriolar loss and the development of hypothyroidism. Low-dose T4 partially
prevented the reduction in cardiac function but had minimal effects on
arteriolar loss. In contrast, DITPA treatment prevented myocardial arteriolar
loss but not the progression of hypothyroid-induced changes in cardiac function.
The results suggested that DITPA can promote a healthy vasculature independently
from its thyroid-related metabolic effects. Drugs in this class may provide new
therapeutic options for patients with vascular disease.
DOI: 10.1152/ajpheart.01293.2008
PMCID: PMC2685338
PMID: 19286941 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15572044 | 1. J Mol Cell Cardiol. 2004 Dec;37(6):1137-46. doi: 10.1016/j.yjmcc.2004.09.013.
Thyroid hormone analogs for treatment of hypercholesterolemia and heart failure:
past, present and future prospects.
Morkin E(1), Ladenson P, Goldman S, Adamson C.
Author information:
(1)Sarver Heart Center, University of Arizona, 1501 N. Campbell Avenue, LSN358,
P.O. Box 245046, Tucson, AZ 85724-5046, USA. [email protected]
Thyroid hormone has the unique properties of lowering cholesterol in hypothyroid
individuals and improving cardiac performance. Beginning in the 1950s, extensive
efforts were made to develop thyroid hormone analogs that could utilize the
cholesterol-lowering property in euthyroid individuals without affecting the
heart. These efforts culminated in the development of analogs that selectively
bind to beta1-type nuclear thyroid hormone receptors (TRs), which are
responsible for cholesterol-lowering activity, without activating alpha1-type
receptors in the heart. beta1-Selective compounds may be useful in lowering
cholesterol in euthyroid individuals who are intolerant to treatment with
'statins'. Screening of compounds for those that might be suitable for improving
cardiac performance in heart failure led to the identification of
3,5-diiodothyropropionic acid (DITPA). DITPA binds to both alpha- and beta-type
TRs with relatively low affinity. In postinfarction models of heart failure and
in a pilot clinical study, DITPA increased cardiac performance without affecting
heart rate. This compound also lowers cholesterol and may be a useful adjunct to
standard heart failure therapy. Although there is both experimental and clinical
evidence indicating that thyroid analogs act differently than thyroid hormones,
the details of their mechanism of action have not been completely elucidated. A
number of potential mechanisms are reviewed, including serum protein binding,
tissue disposition, receptor binding, and gene activation. Clinical trials for
thyroid hormone analogs are in prospect.
DOI: 10.1016/j.yjmcc.2004.09.013
PMID: 15572044 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12011073 | 1. J Biol Chem. 2002 Jul 26;277(30):26921-6. doi: 10.1074/jbc.M200620200. Epub
2002 May 13.
Centromere proteins Cenpa, Cenpb, and Bub3 interact with poly(ADP-ribose)
polymerase-1 protein and are poly(ADP-ribosyl)ated.
Saxena A(1), Saffery R, Wong LH, Kalitsis P, Choo KH.
Author information:
(1)Murdoch Childrens Research Institute, Royal Children's Hospital, Flemington
Rd., Parkville 3052, Australia.
Poly(ADP-ribose) polymerase-1 (PARP-1) is activated by DNA strand breaks during
cellular genotoxic stress response and catalyzes poly(ADP-ribosyl)ation of
acceptor proteins. These acceptor proteins include those involved in modulation
of chromatin structure, DNA synthesis, DNA repair, transcription, and cell cycle
control. Thus, PARP-1 is believed to play a pivotal role in maintaining genome
integrity through modulation of protein-protein and protein-DNA interactions. We
previously described the association of PARP-1 with normal mammalian centromeres
and human neocentromeres by affinity purification and immunofluorescence. Here
we investigated the interaction of this protein with, and poly(ADP-ribosyl)ation
of, three constitutive centromere proteins, Cenpa, Cenpb, and Cenpc, and a
spindle checkpoint protein, Bub3. Immunoprecipitation and Western blot analyses
demonstrate that Cenpa, Cenpb, and Bub3, but not Cenpc, interacted with PARP-1,
and are poly(ADP-ribosyl)ated following induction of DNA damage. The results
suggest a role of PARP-1 in centromere assembly/disassembly and checkpoint
control. Demonstration of PARP-1-binding and poly(ADP-ribosyl)ation in three of
the four proteins tested further suggests that many more centromere proteins may
behave similarly and implicates PARP-1 as an important regulator of diverse
centromere function.
DOI: 10.1074/jbc.M200620200
PMID: 12011073 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20192904 | 1. Expert Opin Ther Pat. 2010 Apr;20(4):593-6. doi: 10.1517/13543771003662636.
Diiodothyropropionic acid: WO2008106213.
Raval S(1).
Author information:
(1)Zydus Research Centre, Department of Medicinal Chemistry, Moraiya, Ahmedabad,
India. [email protected]
The patent application WO2008106213 describes the beneficial effects of thyroid
hormone analogue 3,5 diiodothyropropionic acid (DITPA) such as stimulating
weight loss in overweight mammals, lowering of triglyceride and treating
metabolic syndrome in humans. The human population of the patients selected in
the studies mentioned has a body mass index > 25. Two examples of the human
clinical studies employing DITPA have been mentioned, namely, the body weight
reduction and improvement in metabolic abnormalities in obese adults.
DOI: 10.1517/13543771003662636
PMID: 20192904 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22052799 | 1. Chembiochem. 2011 Dec 16;12(18):2786-90. doi: 10.1002/cbic.201100555. Epub
2011 Nov 4.
Tuning HP1α chromodomain selectivity for di- and trimethyllysine.
Eisert RJ(1), Waters ML.
Author information:
(1)Department of Chemistry, CB 3290, University of North Carolina, Chapel Hill,
NC 27599, USA.
Histone lysine methylation is a critical marker for controlling gene expression.
The position and extent of methylation (mono-, di-, or tri-) controls the
binding of effector proteins that determine whether the associated DNA is
expressed or not. Dysregulation of histone protein methylation has been
associated with a number of types of cancer, and development of inhibitors for
the effector proteins is becoming an active area of research. For this reason,
understanding the mechanism by which effector proteins obtain selectivity for
the different methylation states of lysine is of great interest. To this end, we
have performed mutation studies on the Drosophila HP1α chromodomain, which binds
H3K9Me(2) and H3K9Me(3) with approximately equal affinities. The selectivity of
HP1α chromodomain for H3K9Me(3) over H3K9Me(2) was investigated by mutating E52
to remove or weaken the hydrogen bond to K9Me(2) while maintaining affinity for
K9Me(3,) including E52F, E52I, E52V, E52D, an E52Q. The E52Q mutant exhibited
the greatest degree of selectivity for KMe3, with 3.5-fold weaker binding to the
dimethylated peptide (K(D) =52 μM) compared to the trimethylated peptide (K(D)
=15 μM). These studies provide insight into the role of electrostatic
interactions and hydrogen bonding in the differentiation of methylation states
and have implications regarding the evolutionary pressure for selectivity in
this protein-protein interaction. Moreover, the information from this study may
help guide inhibitor development for this class of proteins.
Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
DOI: 10.1002/cbic.201100555
PMID: 22052799 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19791828 | 1. Drugs. 2009 Oct 22;69(15):2103-14. doi: 10.2165/11201170-000000000-00000.
Saxagliptin.
Dhillon S(1), Weber J.
Author information:
(1)Adis, Auckland, New Zealand. [email protected]
Saxagliptin and its active metabolite M2 are dipeptidyl peptidase-4 inhibitors
that improve glycaemic control by preventing the inactivation of the incretin
hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic
polypeptide. This increases GLP-1 levels, stimulates insulin secretion and
reduces postprandial glucagon and glucose levels. In well designed, 24-week
trials in treatment-naive patients with type 2 diabetes mellitus, monotherapy
with oral saxagliptin 2.5 or 5 mg once daily significantly improved glycaemic
control, as measured by mean glycosylated haemoglobin (HbA(1c)) levels, relative
to placebo. In large, well designed, 24-week trials, combination therapy with
saxagliptin 5 mg once daily plus metformin significantly improved HbA(1c) levels
relative to single-agent saxagliptin or metformin in treatment-naive patients;
in treatment-experienced patients with inadequate glycaemic control, the
addition of saxagliptin 2.5 or 5 mg once daily to metformin, glyburide or a
thiazolidinedione, significantly improved HbA(1c) levels relative to continued
use of existing monotherapy. Saxagliptin as monotherapy or in combination with
other oral antihyperglycaemics was generally well tolerated, with most adverse
events being of mild to moderate severity. In clinical trials, the incidence of
hypoglycaemic events in patients receiving saxagliptin was generally similar to
that in patients receiving placebo or other oral antihyperglycaemic agents.
Saxagliptin therapy was not associated with an increased risk of cardiovascular
events according to pooled data from eight clinical trials. Saxagliptin
generally had a weight-neutral effect.
DOI: 10.2165/11201170-000000000-00000
PMID: 19791828 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24251678 | 1. Clin Genet. 2014 Dec;86(6):585-8. doi: 10.1111/cge.12322. Epub 2013 Dec 20.
Deep intronic KRIT1 mutation in a family with clinically silent multiple
cerebral cavernous malformations.
Riant F(1), Odent S, Cecillon M, Pasquier L, de Baracé C, Carney MP,
Tournier-Lasserve E.
Author information:
(1)AP-HP, Groupe Hospitalier Saint Louis, Lariboisière, Fernand Widal,
Laboratoire de Génétique, Paris, France; INSERM UMR-S740, Paris, France; Centre
de référence pour les maladies rares des vaisseaux du cerveau et de l'œil
(CERVCO), INSERM U740, CHU Lariboisière, APHP, Paris, France; Paris Sorbonne
Cité, Université Paris Diderot, Paris, France.
Loss-of-function mutations in CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10 genes are
identified in the vast majority of familial cases with multiple cerebral
cavernous malformations (CCMs). However, genomic DNA sequencing combined to
large rearrangement screening fails to detect a mutation in 5% of those cases.
We report a family in which CCM lesions were discovered fortuitously because of
the investigation of a developmental delay in a boy. Three members of the family
on three generations had typical multiple CCM lesions and no clinical signs
related to CCM. No mutation was detected using genomic DNA sequencing and
quantitative multiplex PCR of short fluorescent fragments (QMPSF). cDNA
sequencing showed a 99-nucleotide insertion between exons 5 and 6 of CCM1,
resulting from a mutation located deep into intron 5 (c.262+132_262+133del) that
activates a cryptic splice site. This pseudoexon leads to a premature stop
codon. These data highly suggest that deep intronic mutations explain part of
the incomplete mutation detection rate in CCM patients and underline the
importance of analyzing the cDNA to provide comprehensive CCM diagnostic tests.
This kind of mutation may be responsible for apparent sporadic presentations due
to a reduced penetrance.
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
DOI: 10.1111/cge.12322
PMID: 24251678 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24996141 | 1. Eur J Med Chem. 2014 Aug 18;83:547-60. doi: 10.1016/j.ejmech.2014.06.044. Epub
2014 Jun 23.
Discovery of highly potent DPP-4 inhibitors by hybrid compound design based on
linagliptin and alogliptin.
Lai ZW(1), Li C(1), Liu J(2), Kong L(1), Wen X(3), Sun H(4).
Author information:
(1)State Key Laboratory of Natural Medicines and Center of Drug Discovery, China
Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China.
(2)Jiangsu Center for Drug Screening, China Pharmaceutical University, 24
Tongjia Xiang, Nanjing 210009, PR China.
(3)State Key Laboratory of Natural Medicines and Center of Drug Discovery, China
Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China.
Electronic address: [email protected].
(4)State Key Laboratory of Natural Medicines and Center of Drug Discovery, China
Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China.
Electronic address: [email protected].
Highly potent DPP-4 inhibitors have been identified by hybrid compound design
based on linagliptin and alogliptin. The most promising compound 2h
(IC50 = 0.31 nM) exhibited 8.5-fold and 2.5-fold more potent activity than that
of alogliptin (IC50 = 2.63 nM) and linagliptin (IC50 = 0.77 nM), respectively.
Compound 2h had a good inhibition selectivity for DPP-4 over DPP-8/9 and thus
was selected for further biological evaluation, including oral glucose
tolerance, plasma DPP-4 inhibitory activity, pharmacokinetic profile, acute
toxicity and hERG inhibition. The assay results showed that 2h displayed
significant in vivo glucose-lowering effect and low risk of toxicity. Further
studies are expected to confirm 2h as a potential drug candidate for the
treatment of type 2 diabetes.
Copyright © 2014. Published by Elsevier Masson SAS.
DOI: 10.1016/j.ejmech.2014.06.044
PMID: 24996141 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9605877 | 1. Cytogenet Cell Genet. 1997;79(3-4):298-301. doi: 10.1159/000134748.
Chromosomal localization of mouse Cenpa gene.
Fowler KJ(1), Newson AJ, MacDonald AC, Kalitsis P, Lyu MS, Kozak CA, Choo KH.
Author information:
(1)The Murdoch Institute for Research into Birth Defects, Royal Children's
Hospital, Parkville, Victoria, Australia. [email protected]
Using a previously isolated mouse centromere protein A (Cenpa) probe, we have
localized the gene to the proximal region of mouse Chromosome 5, between the
known Il6 and Yes1 loci near [Adra2C-D5H4S43-Hdh]. Comparison of this
localization with that of human CENPA, which maps to chromosome 2, is consistent
with the presence of a new region of conserved synteny between the two species.
DOI: 10.1159/000134748
PMID: 9605877 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26246098 | 1. Neuroradiol J. 2015 Jun;28(3):289-93. doi: 10.1177/1971400915591688.
Cerebral cavernous malformations associated to meningioma: High penetrance in a
novel family mutated in the PDCD10 gene.
Garaci F(1), Marsili L(2), Riant F(3), Marziali S(4), Cécillon M(5), Pasquarelli
R(6), Sangiuolo F(2), Floris R(1), Novelli G(2), Tournier-Lasserve E(3),
Brancati F(7).
Author information:
(1)Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology
and Radiotherapy, Policlinico Tor Vergata University Hospital, Italy Department
of Biomedicine and Prevention, Tor Vergata University, Italy.
(2)Medical Genetics Unit, Policlinico Tor Vergata University Hospital, Italy
Department of Biomedicine and Prevention, Tor Vergata University, Italy.
(3)Service de Génétique Moléculaire Neurovasculaire, Centre de Référence des
Maladies Vasculaires Rares du Cerveau et de l'Oeil (CERVCO), France Génétique
des Maladies Vasculaires UMR-S1161, Université Paris Diderot, France.
(4)Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology
and Radiotherapy, Policlinico Tor Vergata University Hospital, Italy.
(5)Service de Génétique Moléculaire Neurovasculaire, Centre de Référence des
Maladies Vasculaires Rares du Cerveau et de l'Oeil (CERVCO), France.
(6)Department of Biomedicine and Prevention, Tor Vergata University, Italy.
(7)Medical Genetics Unit, Policlinico Tor Vergata University Hospital, Italy
Department of Medical, Oral and Biotechnological Sciences, Gabriele D'Annunzio
University, Italy [email protected].
Multiple familial meningiomas occur in rare genetic syndromes, particularly
neurofibromatosis type 2. The association of meningiomas and cerebral cavernous
malformations (CCMs) has been reported in few patients in the medical
literature. The purpose of our study is to corroborate a preferential
association of CCMs and multiple meningiomas in subjects harbouring mutations in
the PDCD10 gene (also known as CCM3). Three members of an Italian family
affected by seizures underwent conventional brain Magnetic Resonance Imaging
(MRI) with gadolinium contrast agent including gradient echo (GRE) imaging. The
three CCM-causative genes were sequenced by Sanger method. Literature data
reporting patients with coexistence of CCMs and meningiomas were reviewed. MRI
demonstrated dural-based meningioma-like lesions associated to multiple
parenchymal CCMs in all affected individuals. A disease-causative mutation in
the PDCD10 gene (p.Gln112PhefsX13) was identified. Based on neuroradiological
and molecular data as well as on literature review, we outline a consistent
association between PDCD10 mutations and a syndrome of CCMs with multiple
meningiomas. This condition should be considered in the differential diagnosis
of multiple/familial meningioma syndromes. In case of multiple/familial
meningioma the use of appropriate MRI technique may include GRE and/or
susceptibility-weighted imaging (SWI) to rule out CCM. By contrast, proper
post-gadolinium scans may aid defining dural lesions in CCM patients and are
indicated in PDCD10-mutated individuals.
© The Author(s) 2015.
DOI: 10.1177/1971400915591688
PMCID: PMC4757286
PMID: 26246098 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12140362 | 1. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10677-82. doi:
10.1073/pnas.122354499. Epub 2002 Jul 24.
KRIT1, a gene mutated in cerebral cavernous malformation, encodes a
microtubule-associated protein.
Gunel M(1), Laurans MS, Shin D, DiLuna ML, Voorhees J, Choate K, Nelson-Williams
C, Lifton RP.
Author information:
(1)Department of Neurosurgery, Yale Neurovascular Surgery Program, Yale
University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
Mutations in Krev1 interaction trapped gene 1 (KRIT1) cause cerebral cavernous
malformation, an autosomal dominant disease featuring malformation of cerebral
capillaries resulting in cerebral hemorrhage, strokes, and seizures. The
biological functions of KRIT1 are unknown. We have investigated KRIT1 expression
in endothelial cells by using specific anti-KRIT1 antibodies. By both microscopy
and coimmunoprecipitation, we show that KRIT1 colocalizes with microtubules. In
interphase cells, KRIT1 is found along the length of microtubules. During
metaphase, KRIT1 is located on spindle pole bodies and the mitotic spindle.
During late phases of mitosis, KRIT1 localizes in a pattern indicative of
association with microtubule plus ends. In anaphase, the plus ends of the
interpolar microtubules show strong KRIT1 staining and, in late telophase, KRIT1
stains the midbody remnant most strongly; this is the site of cytokinesis where
plus ends of microtubules from dividing cells overlap. These results establish
that KRIT1 is a microtubule-associated protein; its location at plus ends in
mitosis suggests a possible role in microtubule targeting. These findings,
coupled with evidence of interaction of KRIT1 with Krev1 and integrin
cytoplasmic domain-associated protein-1 alpha (ICAP1 alpha), suggest that KRIT1
may help determine endothelial cell shape and function in response to cell-cell
and cell-matrix interactions by guiding cytoskeletal structure. We propose that
the loss of this targeting function leads to abnormal endothelial tube
formation, thereby explaining the mechanism of formation of cerebral cavernous
malformation (CCM) lesions.
DOI: 10.1073/pnas.122354499
PMCID: PMC125011
PMID: 12140362 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20712856 | 1. BMC Emerg Med. 2010 Aug 15;10:18. doi: 10.1186/1471-227X-10-18.
Confusion after spine injury: cerebral fat embolism after traumatic rupture of a
Tarlov cyst: case report.
Duja CM(1), Berna C, Kremer S, Géronimus C, Kopferschmitt J, Bilbault P.
Author information:
(1)Division of Emergency and Intensive Care, Faculty of Medicine, Hôpital de
Hautepierre, Strasbourg, France.
BACKGROUND: Acute low back pain is a very common symptom and reason for many
medical consultations. In some unusual circumstances it could be linked to a
rare aetiology.
CASE PRESENTATION: We report a 70-year-old man with an 8-month history of left
posterior thigh and leg pain who had sudden confusion after a fall from
standing. It was due to cerebral fat embolism suspected by computed tomography
scan, later confirmed by brain magnetic resonance imaging (MRI). A spinal MRI
scan was then performed and revealed a sacral fracture which drained into an
unknown perineurial cyst (Tarlov cyst). Under medical observation the patient
fully recovered within three weeks.
CONCLUSIONS: Sacral perineurial cysts are rare, however they remain a potential
cause of lumbosacral radiculopathy.
DOI: 10.1186/1471-227X-10-18
PMCID: PMC2930635
PMID: 20712856 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19894299 | 1. Zh Nevrol Psikhiatr Im S S Korsakova. 2009;109(5 Suppl 2):37-43.
[Amantadine sulfate (PK-Merz) in the treatment of ischemic stroke: a
clinical-experimental study].
[Article in Russian]
Khasanova DR, Saĭkhunov MV, Kitaeva EA, Khafiz'ianova RKh, Islaamov RR, Demin
TV.
A rat model of big brain ischemia with the middle brain artery occlusion was
used for the study of amantadine sulfate (PK-Merz) effect on the expression of
Hsp70 measured with immunohistochemical method and Western blot 12 h and 4 days
after surgery. The neuroprotective effect of PK-Merz associated with the
enhancement of Hsp70 expression in ischemic stroke in rats. To confirm the
multivector neuroprotective action of the drug, a comparative study of clinical
effectiveness of PK-Merz and magnesium sulfate was carried out in 40 patients
(20 patients in each group) in the most acute period of atherothrombotic and
cardioembolic strokes. Patients treated with PK-Merz exhibited the more
significant restoration of consciousness and better dynamics (regress) of
neurological deficit with the most intensive restoration of neurological deficit
in the first day that allows to recommend the use of amantadine sulfate in the
first hours of ischemic stroke and for the prevention of reperfusion damage in
recanalisation therapy of ischemic stroke.
PMID: 19894299 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23448600 | 1. Mob DNA. 2013 Mar 1;4(1):8. doi: 10.1186/1759-8753-4-8.
Highly diverse chromoviruses of Beta vulgaris are classified by chromodomains
and chromosomal integration.
Weber B(1), Heitkam T, Holtgräwe D, Weisshaar B, Minoche AE, Dohm JC,
Himmelbauer H, Schmidt T.
Author information:
(1)Institute of Botany, Dresden University of Technology, Dresden D-01062,
Germany. [email protected].
BACKGROUND: Chromoviruses are one of the three genera of Ty3-gypsy long terminal
repeat (LTR) retrotransposons, and are present in high copy numbers in plant
genomes. They are widely distributed within the plant kingdom, with
representatives even in lower plants such as green and red algae. Their hallmark
is the presence of a chromodomain at the C-terminus of the integrase. The
chromodomain exhibits structural characteristics similar to proteins of the
heterochromatin protein 1 (HP1) family, which mediate the binding of each
chromovirus type to specific histone variants. A specific integration via the
chromodomain has been shown for only a few chromoviruses. However, a detailed
study of different chromoviral clades populating a single plant genome has not
yet been carried out.
RESULTS: We conducted a comprehensive survey of chromoviruses within the Beta
vulgaris (sugar beet) genome, and found a highly diverse chromovirus population,
with significant differences in element size, primarily caused by their flanking
LTRs. In total, we identified and annotated full-length members of 16 families
belonging to the four plant chromoviral clades: CRM, Tekay, Reina, and
Galadriel. The families within each clade are structurally highly conserved; in
particular, the position of the chromodomain coding region relative to the
polypurine tract is clade-specific. Two distinct groups of chromodomains were
identified. The group II chromodomain was present in three chromoviral clades,
whereas families of the CRM clade contained a more divergent motif. Physical
mapping using representatives of all four clades identified a clade-specific
integration pattern. For some chromoviral families, we detected the presence of
expressed sequence tags, indicating transcriptional activity.
CONCLUSIONS: We present a detailed study of chromoviruses, belonging to the four
major clades, which populate a single plant genome. Our results illustrate the
diversity and family structure of B. vulgaris chromoviruses, and emphasize the
role of chromodomains in the targeted integration of these viruses. We suggest
that the diverse sets of plant chromoviruses with their different localization
patterns might help to facilitate plant-genome organization in a structural and
functional manner.
DOI: 10.1186/1759-8753-4-8
PMCID: PMC3605345
PMID: 23448600 |
http://www.ncbi.nlm.nih.gov/pubmed/23971808 | 1. Biosecur Bioterror. 2013 Sep;11 Suppl 1(Suppl 1):S207-14. doi:
10.1089/bsp.2012.0084.
Multiplex real-time PCR for detecting and typing Clostridium botulinum group III
organisms and their mosaic variants.
Anniballi F, Auricchio B, Woudstra C, Fach P, Fiore A, Skarin H, Bano L,
Segerman B, Knutsson R, De Medici D.
Botulism is a neuroparalytic disease that can occur in all warm-blooded animals,
birds, and fishes. The disease in animals is mainly caused by toxins produced by
Clostridium botulinum strains belonging to group III, although outbreaks due to
toxins produced by group I and II organisms have been recognized. Group III
strains are capable of producing botulinum toxins of type C, D, and C/D and D/C
mosaic variants. Definitive diagnosis of animal botulism is made by combining
clinical findings with laboratory investigations. Detection of toxins in
clinical specimens and feed is the gold standard for laboratory diagnosis. Since
toxins may be degraded by organisms contained in the gastrointestinal tract or
may be present at levels below the detection limit, the recovery of C. botulinum
from sick animal specimens is consistent for laboratory confirmation. In this
article we report the development and in-house validation of a new multiplex
real-time PCR for detecting and typing the neurotoxin genes found in C.
botulinum group III organisms. Validation procedures have been carried out
according to ISO 16140, using strains and samples recovered from cases of animal
botulism in Italy and France.
DOI: 10.1089/bsp.2012.0084
PMCID: PMC3752518
PMID: 23971808 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16014569 | 1. Blood. 2005 Nov 1;106(9):3175-82. doi: 10.1182/blood-2004-11-4516. Epub 2005
Jul 12.
Mutations in the ATM gene lead to impaired overall and treatment-free survival
that is independent of IGVH mutation status in patients with B-CLL.
Austen B(1), Powell JE, Alvi A, Edwards I, Hooper L, Starczynski J, Taylor AM,
Fegan C, Moss P, Stankovic T.
Author information:
(1)Cancer Research United Kingdom (CRUK) Institute for Cancer Studies,
University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom.
[email protected]
The ataxia telangiectasia mutated (ATM) protein is the principal activator of
the p53 protein in the response to DNA double-strand breaks. Mutations in the
ATM gene have been previously found in B-cell chronic lymphocytic leukemias
(B-CLLs) but their clinical significance is unknown. We analyzed 155 CLL tumors
and found 12% with ATM mutations and 4% with TP53 mutations; 2 tumors contained
mutations in both genes. Retrospective analysis on selected samples indicated
that the ATM mutations were usually present at diagnosis. Compared with patients
with wild-type ATM/TP53 genes, patients with ATM mutations had statistically
significantly reduced overall and treatment-free survival. Although present in
both IGVH mutation subgroups, ATM mutations were associated with unmutated IGVH
genes and they provided independent prognostic information on multivariate
analysis. Mutations in the ATM gene resulted in impaired in vitro DNA damage
responses. Tumors with ATM mutations only partially correlated with tumors with
loss of an ATM allele through an 11q deletion and, interestingly, those
11q-deleted tumors with a second wild-type ATM allele had a preserved DNA damage
response. The majority of patients with ATM mutations were refractory to DNA
damaging chemotherapeutic drugs and as such might benefit from therapies that
bypass the ATM/p53 pathway.
DOI: 10.1182/blood-2004-11-4516
PMID: 16014569 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20457215 | 1. Mol Cell Endocrinol. 2010 Sep 15;326(1-2):71-9. doi:
10.1016/j.mce.2010.05.001. Epub 2010 May 8.
AIP gene and familial isolated pituitary adenomas.
Ozfirat Z(1), Korbonits M.
Author information:
(1)Department of Endocrinology, William Harvey Research Institute, Bart's and
the London School of Medicine, Queen Mary University of London, Charterhouse
Square, London EC1M6BQ, UK.
Familial pituitary adenomas occurr in the classical syndromes of MEN1 and Carney
Complex as well as in Familial Isolated Pituitary Adenomas (FIPA), an autosomal
dominant disease with incomplete penetrance. In some families and also rarely in
sporadic tumours germline mutations of a gene located on chromosome 11q13 known
as the aryl hydrocarbon receptor interacting protein have been found. This
article discusses the AIP mutations in these groups and the different molecular
interactions of AIP that may play a role in pituitary tumour formation.
2010 Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.mce.2010.05.001
PMID: 20457215 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22727667 | 1. Mol Cell. 2012 Jul 27;47(2):228-41. doi: 10.1016/j.molcel.2012.05.017. Epub
2012 Jun 21.
Intrinsic nucleic acid-binding activity of Chp1 chromodomain is required for
heterochromatic gene silencing.
Ishida M(1), Shimojo H, Hayashi A, Kawaguchi R, Ohtani Y, Uegaki K, Nishimura Y,
Nakayama J.
Author information:
(1)Laboratory for Chromatin Dynamics, RIKEN Center for Developmental Biology,
Kobe, Hyogo 650-0047, Japan.
Comment in
Mol Cell. 2012 Jul 27;47(2):153-5. doi: 10.1016/j.molcel.2012.07.007.
Centromeric heterochromatin assembly in fission yeast requires the RNAi pathway.
Chp1, a chromodomain (CD) protein, forms the Ago1-containing RNA-induced
transcriptional silencing (RITS) complex and recruits siRNA-bound RITS to
methylated histone H3 lysine 9 (H3K9me) via its CD. Here, we show that the CD of
Chp1 (Chp1-CD) possesses unique nucleic acid-binding activities that are
essential for heterochromatic gene silencing. Detailed electrophoretic-mobility
shift analyses demonstrated that Chp1 binds to RNA via the CD in addition to its
central RNA-recognition motif. Interestingly, robust RNA- and DNA-binding
activity of Chp1-CD was strongly enhanced when it was bound to H3K9me, which was
revealed to involve a positively charged domain within the Chp1-CD by structural
analyses. These results demonstrate a role for the CD that provides a link
between RNA, DNA, and methylated histone tails to ensure heterochromatic gene
silencing.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2012.05.017
PMID: 22727667 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17993773 | 1. J Endocrinol Invest. 2007 Oct;30(9):787-90. doi: 10.1007/BF03350819.
Familial pituitary adenomas with a heterogeneous functional pattern: clinical
and genetic features.
Raverot G(1), Arnous W, Calender A, Trouillas J, Sassolas G, Bournaud C, Pugeat
M, Borson-Chazot F.
Author information:
(1)Fédération d'Endocrinologie du Pôle Est, Hospices Civils de Lyon, Lyon,
France. [email protected]
Familial pituitary adenoma is a rare syndrome which may present either as
isolated lesions, or in association with other endocrine tumors, for example in
the frame of multiple endocrine neoplasia (MEN-1) or Carney complex (CNC). The
most frequently described forms of familial isolated pituitary adenoma (FIPA)
are familial somatotropinomas or prolactinomas. Recently, some cases of familial
isolated somatotropinoma have been associated with germline mutations in the
aryl hydrocarbon receptor interacting protein (AIP) gene. The present report
shows heterogeneous FIPA with 3 subtypes of tumor in 3 individuals of the same
family: somatotropinoma in the proband, giant prolactinoma in a brother, and
gonadotroph cell macroadenoma in the father. A prospective survey also suggested
the occurrence of a silent microadenoma in the proband's sister. Clinical
screening was performed in the 3 affected members, the 4th suspected case, and 9
additional, asymptomatic relatives. They had no clinical evidence of associated
endocrine lesion suggesting MEN-1 or CNC. Genetic screening for germline
mutation of the MEN-1, the gene encoding the protein kinase A (PKA) type 1 alpha
regulatory subunit (R1 alpha) (PRKAR1alpha) and AIP gene was negative in 2
affected members. In conclusion, these data suggest that familial pituitary
adenomas can occur with a heterogeneous functional pattern that is distinguished
from MEN-1 or CNC. The absence of mutation of the recently described AIP gene
suggests the implication of other predisposing gene(s). Collaborative,
multicentric studies are needed to further define the location of gene(s)
involved in heterogeneous FIPA.
DOI: 10.1007/BF03350819
PMID: 17993773 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23271156 | 1. Clin Adv Hematol Oncol. 2012 Nov;10(11 Suppl 21):1-16.
Clinical roundtable monograph: Paroxysmal nocturnal hemoglobinuria: a case-based
discussion.
Szer J(1), Hill A, Weitz IC.
Author information:
(1)Department of Clinical Haematology & BMT Service, Royal Melbourne Hospital,
Melbourne, Australia.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disorder
characterized by chronic intravascular hemolysis as the primary clinical
manifestation and morbidities that include anemia, thrombosis, renal impairment,
pulmonary hypertension, and bone marrow failure. The prevalence of the PNH clone
(from <1-100% PNH granulocytes) is approximately 16 per million, and careful
monitoring is required. The average age of onset of the clinical disease is the
early 30s, although it can present at all ages. PNH is caused by the acquisition
of a somatic mutation of the gene phosphatidylinositol glycan anchor (PIG-A) in
a multipotent hematopoietic stem cell (HSC), with clonal expansion of the
mutated HSC. The mutation causes a deficiency in the synthesis of
glycosylphosphatidylinositol (GPI). In cells derived from normal HSCs, the
complement regulatory proteins CD55 and CD59 are anchored to the hematopoietic
cell membrane surface via GPI, protecting the cells from complement-mediated
lysis. However, in patients with PNH, these 2 proteins, along with numerous
other GPI-linked proteins, are absent from the cell surface of red cells,
granulocytes, monocytes, and platelets, resulting in complement-mediated
intravascular hemolysis and other complications. Lysis of red blood cells is the
most obvious manifestation, but as other cell lineages are also affected, this
complement-mediated attack contributes to additional complications, such as
thrombosis. Eculizumab, a humanized monoclonal antibody against the C5
complement protein, is the only effective drug therapy for PNH patients. The
antibody prevents cleavage of the C5 protein by C5 convertase, in turn
preventing generation of C5b-9 and release of C5a, thereby protecting from
hemolysis of cells lacking the CD59 surface protein and other complications
associated with complement activation. Drs. Ilene C. Weitz, Anita Hill, and Jeff
Szer discuss 3 recent cases of patients with PNH.
PMID: 23271156 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23417793 | 1. Biomol NMR Assign. 2014 Apr;8(1):137-9. doi: 10.1007/s12104-013-9469-3. Epub
2013 Feb 17.
¹H, ¹³C and ¹⁵N resonance assignments of an N-terminal domain of CHD4.
Silva AP(1), Kwan AH, Mackay JP.
Author information:
(1)School of Molecular Bioscience, The University of Sydney, Building G08,
Corner Butlin Avenue and Maze Crescent, Sydney, NSW, 2006, Australia,
[email protected].
Chromatin-remodeling proteins have a pivotal role in normal cell function and
development, catalyzing conformational changes in DNA that ultimately result in
changes in gene expression patterns. Chromodomain helicase DNA-binding protein 4
(CHD4), the defining subunit of the nucleosome remodeling and deacetylase (NuRD)
complex, is a nucleosome-remodeling protein of the SNF2/ISWI2 family, members of
which contain two chromo domains and an ATP-dependent helicase module. CHD3,
CHD4 and CHD5 also contain two contiguous PHD domains and have an extended
N-terminal region that has not previously been characterized. We have identified
a stable domain in the N-terminal region of CHD4 and report here the backbone
and side chain resonance assignments for this domain at pH 7.5 and 25 °C (BMRB
No. 18906).
DOI: 10.1007/s12104-013-9469-3
PMID: 23417793 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22683269 | 1. Mol Cell. 2012 Jul 27;47(2):215-27. doi: 10.1016/j.molcel.2012.05.009. Epub
2012 Jun 7.
HP1(Swi6) mediates the recognition and destruction of heterochromatic RNA
transcripts.
Keller C(1), Adaixo R, Stunnenberg R, Woolcock KJ, Hiller S, Bühler M.
Author information:
(1)Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66,
4058 Basel, Switzerland.
Comment in
EMBO J. 2012 Aug 1;31(15):3237-8. doi: 10.1038/emboj.2012.172.
Nat Rev Mol Cell Biol. 2012 Jul 11;13(8):478-9. doi: 10.1038/nrm3400.
Mol Cell. 2012 Jul 27;47(2):153-5. doi: 10.1016/j.molcel.2012.07.007.
HP1 proteins are major components of heterochromatin, which is generally
perceived to be an inert and transcriptionally inactive chromatin structure.
Yet, HP1 binding to chromatin is highly dynamic and robust silencing of
heterochromatic genes can involve RNA processing. Here, we demonstrate by a
combination of in vivo and in vitro experiments that the fission yeast HP1(Swi6)
protein guarantees tight repression of heterochromatic genes through RNA
sequestration and degradation. Stimulated by positively charged residues in the
hinge region, RNA competes with methylated histone H3K9 for binding to the
chromodomain of HP1(Swi6). Hence, HP1(Swi6) binding to RNA is incompatible with
stable heterochromatin association. We propose a model in which an ensemble of
HP1(Swi6) proteins functions as a heterochromatin-specific checkpoint, capturing
and priming heterochromatic RNAs for the RNA degradation machinery. Sustaining a
functional checkpoint requires continuous exchange of HP1(Swi6) within
heterochromatin, which explains the dynamic localization of HP1 proteins on
heterochromatin.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2012.05.009
PMID: 22683269 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23388053 | 1. Genes Cells. 2013 Apr;18(4):327-39. doi: 10.1111/gtc.12038. Epub 2013 Feb 6.
Transcription-induced chromatin association of RNA surveillance factors mediates
facultative heterochromatin formation in fission yeast.
Tashiro S(1), Asano T, Kanoh J, Ishikawa F.
Author information:
(1)Graduate School of Biostudies, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku,
Kyoto, 606-8501, Japan.
Facultative heterochromatin is reversibly established and disrupted during
differentiation, but its regulation remains mechanistically unclear. Here, we
show that two meiotic gene loci in fission yeast, mei4 and ssm4, comprise
facultative heterochromatin that is regulated in a developmental stage-dependent
manner. This heterochromatin coordinates expression levels by associating with a
chromodomain protein Chp1 and an antisilencing factor Epe1. It has been recently
shown that an RNA surveillance machinery for eliminating meiotic gene
transcripts, which involves a cis-element called the determinant of selective
removal (DSR) and transacting factors, Mmi1 and Red1, also participates in
heterochromatin formation at the meiotic genes, but the molecular mechanism
underlying the process is largely unknown. By dissecting the mei4 gene, we
identified a region that promotes DSR-dependent methylation of histone H3 lysine
9 (H3K9). Integration of this mei4 region together with DSR into an unrelated
gene results in ectopic H3K9 methylation. Moreover, our results suggest that
transcription of these elements induces chromatin association of Mmi1, which, in
turn, recruits Red1 interacting with Clr4/Suv39h H3K9 methyltransferase. Mmi1
remains associated in cells lacking Red1, suggesting that the recruitment of
Red1 follows the chromatin association of Mmi1. Overall, we provide detailed
insights into the facultative heterochromatin regulation in fission yeast.
© 2013 The Authors Genes to Cells © 2013 by the Molecular Biology Society of
Japan and Wiley Publishing Asia Pty Ltd.
DOI: 10.1111/gtc.12038
PMID: 23388053 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22728643 | 1. J Mol Biol. 2012 Sep 28;422(4):519-31. doi: 10.1016/j.jmb.2012.06.013. Epub
2012 Jun 21.
Sequence requirements for combinatorial recognition of histone H3 by the MRG15
and Pf1 subunits of the Rpd3S/Sin3S corepressor complex.
Kumar GS(1), Chang W, Xie T, Patel A, Zhang Y, Wang GG, David G, Radhakrishnan
I.
Author information:
(1)Department of Molecular Biosciences, Northwestern University, Evanston, IL
60208, USA.
The transcriptional output at a genomic locus in eukaryotes is determined, in
part, by the pattern of histone modifications that are read and interpreted by
key effector proteins. The histone deacetylase activity of the evolutionarily
conserved Rpd3S/Sin3S complex is crucial for suppressing aberrant transcription
from cryptic start sites within intragenic regions of actively transcribed
genes. Precise targeting of the complex relies on the chromatin binding
activities of the MRG15 (MRG stands for mortality factor on chromosome 4 related
gene) and Pf1 subunits. Whereas the molecular target of the MRG15 chromodomain
(CD) has been suggested to be H3K36me(2/3), the precise molecular target of the
Pf1 plant homeodomain 1 (PHD1) has remained elusive. Here, we show that Pf1 PHD1
binds preferentially to the unmodified extreme N-terminus of histone H3
(H3K4me(0)) but not to H3K4me(2/3), which are enriched in the promoter and 5'
regions of genes. Unlike previously characterized CD and PHD domains that bind
to their targets with micromolar affinity, both MRG15 CD and Pf1 PHD1 bind to
their targets with >100 μM affinity, offering an explanation for why both MRG15
CD and Pf1 PHD1 domains are required to target the Rpd3S/Sin3S complex to
chromatin. Our results also suggest that bivalency, rather than cooperativity,
is the operative mechanism by which Pf1 and MRG15 combine to engage H3 in a
biologically significant manner. Finally, the studies reveal an unanticipated
role of Pf1 PHD1 in engaging the MRG15 MRG domain, albeit in a Pf1
MRG-binding-domain-dependent manner, implying a key role for the MRG15 MRG-Pf1
MBD interaction in chromatin targeting of the Rpd3S/Sin3S complex.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.jmb.2012.06.013
PMCID: PMC3428507
PMID: 22728643 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22897906 | 1. Genome Biol. 2012 Aug 16;13(8):R68. doi: 10.1186/gb-2012-13-8-r68.
Proteogenomic characterization and mapping of nucleosomes decoded by Brd and HP1
proteins.
LeRoy G, Chepelev I, DiMaggio PA, Blanco MA, Zee BM, Zhao K, Garcia BA.
BACKGROUND: Histone post-translational modifications (PTMs) constitute a branch
of epigenetic mechanisms that can control the expression of eukaryotic genes in
a heritable manner. Recent studies have identified several PTM-binding proteins
containing diverse specialized domains whose recognition of specific PTM sites
leads to gene activation or repression. Here, we present a high-throughput
proteogenomic platform designed to characterize the nucleosomal make-up of
chromatin enriched with a set of histone PTM binding proteins known as histone
PTM readers. We support our findings with gene expression data correlating to
PTM distribution.
RESULTS: We isolated human mononucleosomes bound by the bromodomain-containing
proteins Brd2, Brd3 and Brd4, and by the chromodomain-containing heterochromatin
proteins HP1β and HP1α. Histone PTMs were quantified by mass spectrometry
(ChIP-qMS), and their associated DNAs were mapped using deep sequencing. Our
results reveal that Brd- and HP1-bound nucleosomes are enriched in histone PTMs
consistent with actively transcribed euchromatin and silent heterochromatin,
respectively. Data collected using RNA-Seq show that Brd-bound sites correlate
with highly expressed genes. In particular, Brd3 and Brd4 are most enriched on
nucleosomes located within HOX gene clusters, whose expression is reduced upon
Brd4 depletion by short hairpin RNA.
CONCLUSIONS: Proteogenomic mapping of histone PTM readers, alongside the
characterization of their local chromatin environments and transcriptional
information, should prove useful for determining how histone PTMs are bound by
these readers and how they contribute to distinct transcriptional states.
DOI: 10.1186/gb-2012-13-8-r68
PMCID: PMC3491368
PMID: 22897906 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22081016 | 1. Nat Struct Mol Biol. 2011 Nov 13;18(12):1358-65. doi: 10.1038/nsmb.2153.
Recognition of enhancer element-specific histone methylation by TIP60 in
transcriptional activation.
Jeong KW(1), Kim K, Situ AJ, Ulmer TS, An W, Stallcup MR.
Author information:
(1)Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive
Cancer Center, University of Southern California, Los Angeles, California, USA.
Many co-regulator proteins are recruited by DNA-bound transcription factors to
remodel chromatin and activate transcription. However, mechanisms for
coordinating actions of multiple co-regulator proteins are poorly understood. We
demonstrate that multiple protein-protein interactions by the protein
acetyltransferase TIP60 are required for estrogen-induced transcription of a
subset of estrogen receptor alpha (ERα) target genes in human cells.
Estrogen-induced recruitment of TIP60 requires direct binding of TIP60 to ERα
and the action of chromatin-remodeling ATPase BRG1, leading to increased
recruitment of histone methyltransferase MLL1 and increased monomethylation of
histone H3 at Lys4. TIP60 recruitment also requires preferential binding of the
TIP60 chromodomain to histone H3 containing monomethylated Lys4, which marks
active and poised enhancer elements. After recruitment, TIP60 increases
acetylation of histone H2A at Lys5. Thus, complex cooperation of TIP60 with ERα
and other chromatin-remodeling enzymes is required for estrogen-induced
transcription.
DOI: 10.1038/nsmb.2153
PMCID: PMC3230772
PMID: 22081016 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19956676 | 1. PLoS One. 2009 Aug 26;4(8):e6789. doi: 10.1371/journal.pone.0006789.
Epigenome microarray platform for proteome-wide dissection of
chromatin-signaling networks.
Bua DJ(1), Kuo AJ, Cheung P, Liu CL, Migliori V, Espejo A, Casadio F, Bassi C,
Amati B, Bedford MT, Guccione E, Gozani O.
Author information:
(1)Department of Biology, Stanford University, Stanford, California, United
States of America.
Knowledge of protein domains that function as the biological effectors for
diverse post-translational modifications of histones is critical for
understanding how nuclear and epigenetic programs are established. Indeed,
mutations of chromatin effector domains found within several proteins are
associated with multiple human pathologies, including cancer and
immunodeficiency syndromes. To date, relatively few effector domains have been
identified in comparison to the number of modifications present on histone and
non-histone proteins. Here we describe the generation and application of human
modified peptide microarrays as a platform for high-throughput discovery of
chromatin effectors and for epitope-specificity analysis of antibodies commonly
utilized in chromatin research. Screening with a library containing a majority
of the Royal Family domains present in the human proteome led to the discovery
of TDRD7, JMJ2C, and MPP8 as three new modified histone-binding proteins. Thus,
we propose that peptide microarray methodologies are a powerful new tool for
elucidating molecular interactions at chromatin.
DOI: 10.1371/journal.pone.0006789
PMCID: PMC2777412
PMID: 19956676 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/21623345 | 1. EMBO J. 2011 May 27;30(13):2596-609. doi: 10.1038/emboj.2011.166.
The DNA-binding domain of the Chd1 chromatin-remodelling enzyme contains SANT
and SLIDE domains.
Ryan DP(1), Sundaramoorthy R, Martin D, Singh V, Owen-Hughes T.
Author information:
(1)Wellcome Trust Centre for Gene Regulation and Expression, College of Life
Sciences, University of Dundee, Dundee, UK.
The ATP-dependent chromatin-remodelling enzyme Chd1 is a 168-kDa protein
consisting of a double chromodomain, Snf2-related ATPase domain, and a
C-terminal DNA-binding domain. Here, we show the DNA-binding domain is required
for Saccharomyces cerevisiae Chd1 to bind and remodel nucleosomes. The crystal
structure of this domain reveals the presence of structural homology to SANT and
SLIDE domains previously identified in ISWI remodelling enzymes. The presence of
these domains in ISWI and Chd1 chromatin-remodelling enzymes may provide a means
of efficiently harnessing the action of the Snf2-related ATPase domain for the
purpose of nucleosome spacing and provide an explanation for partial redundancy
between these proteins. Site directed mutagenesis was used to identify residues
important for DNA binding and generate a model describing the interaction of
this domain with DNA. Through inclusion of Chd1 sequences in homology searches
SLIDE domains were identified in CHD6-9 proteins. Point mutations to conserved
amino acids within the human CHD7 SLIDE domain have been identified in patients
with CHARGE syndrome.
DOI: 10.1038/emboj.2011.166
PMCID: PMC3155300
PMID: 21623345 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/23071553 | 1. PLoS One. 2012;7(10):e46316. doi: 10.1371/journal.pone.0046316. Epub 2012 Oct
10.
Chromodomain helicase binding protein 8 (Chd8) is a novel A-kinase anchoring
protein expressed during rat cardiac development.
Shanks MO(1), Lund LM, Manni S, Russell M, Mauban JR, Bond M.
Author information:
(1)Department of Physiology, University of Maryland Baltimore, Baltimore,
Maryland, United States of America.
A-kinase anchoring proteins (AKAPs) bind the regulatory subunits of protein
kinase A (PKA) and localize the holoenzyme to discrete signaling microdomains in
multiple subcellular compartments. Despite emerging evidence for a nuclear pool
of PKA that rapidly responds to activation of the PKA signaling cascade, only a
few AKAPs have been identified that localize to the nucleus. Here we show a
PKA-binding domain in the amino terminus of Chd8, and demonstrate subcellular
colocalization of Chd8 with RII. RII overlay and immunoprecipitation assays
demonstrate binding between Chd8-S and RIIα. Binding is abrogated upon
dephosphorylation of RIIα. By immunofluorescence, we identified nuclear and
perinuclear pools of Chd8 in HeLa cells and rat neonatal cardiomyocytes. We also
show high levels of Chd8 mRNA in RNA extracted from post-natal rat hearts. These
data add Chd8 to the short list of known nuclear AKAPs, and implicate a function
for Chd8 in post-natal rat cardiac development.
DOI: 10.1371/journal.pone.0046316
PMCID: PMC3468582
PMID: 23071553 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/22083954 | 1. Mol Cell Biol. 2012 Jan;32(2):251-65. doi: 10.1128/MCB.05229-11. Epub 2011 Nov
14.
Novel roles of Caenorhabditis elegans heterochromatin protein HP1 and linker
histone in the regulation of innate immune gene expression.
Studencka M(1), Konzer A, Moneron G, Wenzel D, Opitz L, Salinas-Riester G, Bedet
C, Krüger M, Hell SW, Wisniewski JR, Schmidt H, Palladino F, Schulze E,
Jedrusik-Bode M.
Author information:
(1)Max Planck Institute for Biophysical Chemistry, Department of Genes and
Behavior, Epigenetics in C elegans Group, Göttingen, Germany.
Linker histone (H1) and heterochromatin protein 1 (HP1) are essential components
of heterochromatin which contribute to the transcriptional repression of genes.
It has been shown that the methylation mark of vertebrate histone H1 is
specifically recognized by the chromodomain of HP1. However, the exact
biological role of linker histone binding to HP1 has not been determined. Here,
we investigate the function of the Caenorhabditis elegans H1 variant HIS-24 and
the HP1-like proteins HPL-1 and HPL-2 in the cooperative transcriptional
regulation of immune-relevant genes. We provide the first evidence that HPL-1
interacts with HIS-24 monomethylated at lysine 14 (HIS-24K14me1) and associates
in vivo with promoters of genes involved in antimicrobial response. We also
report an increase in overall cellular levels and alterations in the
distribution of HIS-24K14me1 after infection with pathogenic bacteria.
HIS-24K14me1 localization changes from being mostly nuclear to both nuclear and
cytoplasmic in the intestinal cells of infected animals. Our results highlight
an antimicrobial role of HIS-24K14me1 and suggest a functional link between
epigenetic regulation by an HP1/H1 complex and the innate immune system in C.
elegans.
DOI: 10.1128/MCB.05229-11
PMCID: PMC3255762
PMID: 22083954 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23282990 | 1. Neuroreport. 2013 Feb 13;24(3):114-9. doi: 10.1097/WNR.0b013e32835cf179.
Generation and neuronal differentiation of induced pluripotent stem cells in
Cdyl-/- mice.
Wan L(1), Hu XJ, Yan SX, Chen F, Cai B, Zhang XM, Wang T, Yu XB, Xiang AP, Li
WQ.
Author information:
(1)Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem
Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University,
Guangzhou 510080, People’s Republic of China.
Chromodomain on Y-like (CDYL) is a chromodomain protein that has sequence
homology to members of the enoyl CoA hydratase family. Although the chromodomain
of CDYL has been implicated in chromatin remodeling during mammalian
spermatogenesis, the function of the Cdyl gene remains unclear. Recently,
induced pluripotent stem cells (iPS cells) have been derived from somatic cells
by the forced expression of several transcription factors. iPS cells resemble
embryonic stem cells in many respects. Therefore, iPS cells represent a powerful
tool for the study of gene function. In this study, we have investigated whether
iPS cells derived from Cdyl-/- and Cdyl+/+ fibroblasts have different
characteristics. Our results showed that both Cdyl-/- and Cdyl+/+ fibroblasts
could be induced to become iPS cells, but the spontaneous neuronal
differentiation capacity of Cdyl-/- iPS cells was much greater than that of the
Cdyl+/+ iPS cells. These results provide some insight into the molecular
function of the Cdyl gene, showing that it inhibited the neuronal
differentiation of iPS cells.
DOI: 10.1097/WNR.0b013e32835cf179
PMID: 23282990 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21177652 | 1. Nucleic Acids Res. 2011 Apr;39(8):3103-15. doi: 10.1093/nar/gkq1298. Epub 2010
Dec 21.
The chromodomains of CHD1 are critical for enzymatic activity but less important
for chromatin localization.
Morettini S(1), Tribus M, Zeilner A, Sebald J, Campo-Fernandez B, Scheran G,
Wörle H, Podhraski V, Fyodorov DV, Lusser A.
Author information:
(1)Division of Molecular Biology, Biocenter, Innsbruck Medical University,
Fritz-Pregl Strasse 3, 6020 Innsbruck, Austria.
The molecular motor protein CHD1 has been implicated in the regulation of
transcription and in the transcription-independent genome-wide incorporation of
H3.3 into paternal chromatin in Drosophila melanogaster. A key feature of CHD1
is the presence of two chromodomains, which can bind to histone H3 methylated at
lysine 4 and thus might serve to recruit and/or maintain CHD1 at the chromatin.
Here, we describe genetic and biochemical approaches to the study of the
Drosophila CHD1 chromodomains. We found that overall localization of CHD1 on
polytene chromosomes does not appreciably change in chromodomain-mutant flies.
In contrast, the chromodomains are important for transcription-independent
activities of CHD1 during early embryonic development as well as for
transcriptional regulation of several heat shock genes. However, neither CHD1
nor its chromodomains are needed for RNA polymerase II localization and H3K4
methylation but loss of CHD1 decreases transcription-induced histone eviction at
the Hsp70 gene in vivo. Chromodomain mutations negatively affect the chromatin
assembly activities of CHD1 in vitro, and they appear to be involved in linking
the ATP-dependent motor to the chromatin assembly function of CHD1.
DOI: 10.1093/nar/gkq1298
PMCID: PMC3082874
PMID: 21177652 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22569290 | 1. Breast Cancer Res. 2012 May 8;14(3):R73. doi: 10.1186/bcr3182.
Chromodomain helicase DNA binding protein 5 plays a tumor suppressor role in
human breast cancer.
Wu X(1), Zhu Z, Li W, Fu X, Su D, Fu L, Zhang Z, Luo A, Sun X, Fu L, Dong JT.
Author information:
(1)Department of Genetics and Cell Biology, Nankai University College of Life
Sciences, 94 Weijin Road, Tianjin 300071, China.
INTRODUCTION: The chromodomain helicase DNA binding protein 5 (CHD5) has
recently been identified as a tumor suppressor in a mouse model. The CHD5 locus
at 1p36 is deleted, and its mutation has been detected in breast cancer. We,
therefore, evaluated whether CHD5 plays a role in human breast cancer.
METHODS: We screened mutations in 55 tumors, determined promoter methylation in
39 tumors, measured RNA expression in 90 tumors, analyzed protein expression in
289 tumors, and correlated expression changes with clinicopathological
characteristics of breast cancer. Functional effects of CHD5 on cell
proliferation, invasion and tumorigenesis were also tested.
RESULTS: Although only one mutation was detected, CHD5 mRNA expression was
significantly reduced, accompanied by frequent genomic deletion and promoter
methylation, in breast cancer. The extent of methylation was significantly
associated with reduced mRNA expression, and demethylating treatment restored
CHD5 expression. Lower CHD5 mRNA levels correlated with lymph node metastasis (P
= 0.026). CHD5 protein expression was also reduced in breast cancer, and lack of
CHD5 expression significantly correlated with higher tumor stage,
ER/PR-negativity, HER2 positivity, distant metastasis and worse patient survival
(P ≤ 0.01). Functionally, ectopic expression of CHD5 in breast cancer cells
inhibited cell proliferation and invasion in vitro and tumorigenesis in nude
mice. Consistent with the inhibition of invasion, CHD5 down-regulated
mesenchymal markers vimentin, N-cadherin and ZEB1 in breast cancer cells.
CONCLUSION: Down-regulation of CHD5, mediated at least in part by promoter
methylation, contributes to the development and progression of human breast
cancer.
DOI: 10.1186/bcr3182
PMCID: PMC3446335
PMID: 22569290 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22172672 | 1. Dev Cell. 2011 Dec 13;21(6):1092-103. doi: 10.1016/j.devcel.2011.09.019.
The chromodomain protein MRG-1 facilitates SC-independent homologous pairing
during meiosis in Caenorhabditis elegans.
Dombecki CR(1), Chiang AC, Kang HJ, Bilgir C, Stefanski NA, Neva BJ, Klerkx EP,
Nabeshima K.
Author information:
(1)Department of Cell and Developmental Biology, University of Michigan Medical
School, Ann Arbor, MI 48109-2200, USA.
Homologous chromosome pairing is a prerequisite to establish physical linkage
between homologs, which is critical for faithful chromosome segregation during
meiosis I. The establishment of pairing is genetically separable from subsequent
synapsis, defined as stabilization of pairing by the synaptonemal complex (SC).
The underlying mechanism of presynaptic pairing is poorly understood. In the
nematode Caenorhabditis elegans, a unique cis-acting element, the pairing center
(PC), is essential for presynaptic pairing; however, it is not known whether and
how the remainder of the chromosome contributes to presynaptic pairing. Here we
report direct evidence for presynaptic pairing activity intrinsic to non-PC
regions, which is facilitated by a conserved chromodomain protein, MRG-1. In
mrg-1 loss-of-function mutants, pairing is compromised specifically in non-PC
regions, leading to nonhomologous SC assembly. Our data support a model in which
presynaptic alignment in non-PC regions collaborates with initial PC pairing to
ensure correct homologous synapsis.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.devcel.2011.09.019
PMID: 22172672 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21730028 | 1. Physiol Genomics. 2011 Sep 22;43(18):1049-55. doi:
10.1152/physiolgenomics.00134.2010. Epub 2011 Jul 5.
Four out of eight genes in a mouse chromosome 7 congenic donor region are
candidate obesity genes.
Sarahan KA(1), Fisler JS, Warden CH.
Author information:
(1)Department of Neurobiology, University of California-Davis, Davis, CA, USA.
We previously identified a region of mouse chromosome 7 that influences body fat
mass in F2 littermates of congenic × background intercrosses. Current analyses
revealed that alleles in the donor region of the subcongenic B6.C-D7Mit318 (318)
promoted a twofold increase in adiposity in homozygous lines of 318 compared
with background C57BL/6ByJ (B6By) mice. Parent-of-origin effects were discounted
through cross-fostering studies and an F1 reciprocal cross. Mapping of the donor
region revealed that it has a maximal size of 2.8 Mb (minimum 1.8 Mb) and
contains a maximum of eight protein coding genes. Quantitative PCR in whole
brain, liver, and gonadal white adipose tissue (GWAT) revealed differential
expression between genotypes for three genes in females and two genes in males.
Alpha-2,8-sialyltransferase 8B (St8sia2) showed reduced 318 mRNA levels in brain
for females and males and in GWAT for females only. Both sexes of 318 mice had
reduced Repulsive guidance molecule-a (Rgma) expression in GWAT. In brain,
Family with sequence similarity 174 member b (Fam174b) had increased expression
in 318 females, whereas Chromodomain helicase DNA binding protein 2 (Chd2-2) had
reduced expression in 318 males. No donor region genes were differentially
expressed in liver. Sequence analysis of coding exons for all genes in the 318
donor region revealed only one single nucleotide polymorphism that produced a
nonsynonymous missense mutation, Gln7Pro, in Fam174b. Our findings highlight the
difficulty of using expression and sequence to identify quantitative trait genes
underlying obesity even in small genomic regions.
DOI: 10.1152/physiolgenomics.00134.2010
PMCID: PMC3180740
PMID: 21730028 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20688032 | 1. J Am Coll Cardiol. 2010 Sep 7;56(11):867-74. doi: 10.1016/j.jacc.2010.05.010.
Epub 2010 Jun 25.
Prognostic significance of myocardial fibrosis in hypertrophic cardiomyopathy.
O'Hanlon R(1), Grasso A, Roughton M, Moon JC, Clark S, Wage R, Webb J, Kulkarni
M, Dawson D, Sulaibeekh L, Chandrasekaran B, Bucciarelli-Ducci C, Pasquale F,
Cowie MR, McKenna WJ, Sheppard MN, Elliott PM, Pennell DJ, Prasad SK.
Author information:
(1)Department of Cardiovascular Magnetic Resonance, Royal Brompton and Harefield
NHS Foundation Trust, London, UK.
Comment in
J Am Coll Cardiol. 2010 Sep 7;56(11):888-9. doi: 10.1016/j.jacc.2010.06.004.
OBJECTIVES: We investigated the significance of fibrosis detected by late
gadolinium enhancement cardiovascular magnetic resonance for the prediction of
major clinical events in hypertrophic cardiomyopathy (HCM).
BACKGROUND: The role of myocardial fibrosis in the prediction of sudden death
and heart failure in HCM is unclear with a lack of prospective data.
METHODS: We assessed the presence and amount of myocardial fibrosis in HCM
patients and prospectively followed them for the development of morbidity and
mortality in patients over 3.1 +/- 1.7 years.
RESULTS: Of 217 consecutive HCM patients, 136 (63%) showed fibrosis. Thirty-four
of the 136 patients (25%) in the fibrosis group but only 6 of 81 (7.4%) patients
without fibrosis reached the combined primary end point of cardiovascular death,
unplanned cardiovascular admission, sustained ventricular tachycardia or
ventricular fibrillation, or appropriate implantable cardioverter-defibrillator
discharge (hazard ratio [HR]: 3.4, p = 0.006). In the fibrosis group, overall
risk increased with the extent of fibrosis (HR: 1.18/5% increase, p = 0.008).
The risk of unplanned heart failure admissions, deterioration to New York Heart
Association functional class III or IV, or heart failure-related death was
greater in the fibrosis group (HR: 2.5, p = 0.021), and this risk increased as
the extent of fibrosis increased (HR: 1.16/5% increase, p = 0.017). All
relationships remained significant after multivariate analysis. The extent of
fibrosis and nonsustained ventricular tachycardia were univariate predictors for
arrhythmic end points (sustained ventricular tachycardia or ventricular
fibrillation, appropriate implantable cardioverter-defibrillator discharge,
sudden cardiac death) (HR: 1.30, p = 0.014). Nonsustained ventricular
tachycardia remained an independent predictor of arrhythmic end points after
multivariate analysis, but the extent of fibrosis did not.
CONCLUSIONS: In patients with HCM, myocardial fibrosis as measured by late
gadolinium enhancement cardiovascular magnetic resonance is an independent
predictor of adverse outcome. (The Prognostic Significance of Fibrosis Detection
in Cardiomyopathy; NCT00930735).
Copyright © 2010 American College of Cardiology Foundation. Published by
Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jacc.2010.05.010
PMID: 20688032 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8460153 | 1. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2414-8. doi:
10.1073/pnas.90.6.2414.
A mammalian DNA-binding protein that contains a chromodomain and an
SNF2/SWI2-like helicase domain.
Delmas V(1), Stokes DG, Perry RP.
Author information:
(1)Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA
19111.
Two overlapping cDNAs that encode a 197-kDa sequence-selective DNA-binding
protein were isolated from libraries derived from mouse lymphoid cell mRNA. In
addition to a DNA-binding domain, the protein contains both a chromodomain,
which occurs in proteins that are implicated in chromatin compaction, and an
SNF2/SWI2-like helicase domain, which occurs in proteins that are believed to
activate transcription by counteracting the repressive effects of chromatin
structure. A Southern blot analysis indicated that this protein, which we have
named CHD-1, for chromodomain-helicase-DNA-binding protein, is present in most,
if not all, mammalian species. A Northern blot analysis revealed multiple CHD
mRNA components that differed both qualitatively and quantitatively among
various cell types. The various mRNAs, which are probably produced by
alternative RNA processing, could conceivably encode tissue-specific and
developmental stage-specific isoforms of the protein. Based on its interesting
combination of features, we suspect that CHD-1 plays an important role in gene
regulation.
DOI: 10.1073/pnas.90.6.2414
PMCID: PMC46097
PMID: 8460153 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24901761 | 1. Am J Phys Med Rehabil. 2014 Nov;93(11):938-47. doi:
10.1097/PHM.0000000000000109.
Effect of postural balance training on gait parameters in children with cerebral
palsy.
Abd El-Kafy EM(1), El-Basatiny HM.
Author information:
(1)From the Department of Physical Therapy for Disturbances of Growth and
Developmental Disorders in Children and Its Surgery, Faculty of Physical
Therapy, Cairo University, Giza, Egypt (EMAE-K, HMYME-B); and Department of
Physical Therapy, Faculty of Applied Medical Sciences, Umm Al Qura University,
Makkah, Saudi Arabia (EMAE-K).
OBJECTIVE: The aim of this study was to evaluate the effect of dynamic bilateral
postural stability on balance control and gait parameters in children with
cerebral palsy.
DESIGN: Thirty children with spastic diplegia (8-10 yrs) were included in this
study. The children were randomly assigned into two groups: control group A and
study group B. The children in both groups received traditional physical therapy
program, 2 hrs per day for group A and 1.5 hrs followed by 30 mins of dynamic
postural stability training program using the Biodex Stability System for group
B. The treatment frequency was three sessions per week for 8 consecutive weeks
on two stability levels (7 and 8). The participating children received
pretreatment and posttreatment assessments using the Biodex Stability System to
evaluate the stability indices (anteroposterior, mediolateral, and overall) at
the two stability levels (7 and 8) and three-dimensional motion analysis system
(pro-reflex system) to evaluate the spatiotemporal parameters including step
length, velocity, cycle time, stance, and swing phase percentage.
RESULTS: The children in both groups showed significant improvements in the mean
values of all measured variables after treatment indexed by a significant
reduction in stability indices and improvement in gait parameters. The results
also showed significant differences in all measured parameters in favor of group
B, when compared with those in group A (P < 0.01).
CONCLUSIONS: Balance training on the Biodex Stability System could be a useful
tool in conjunction with traditional physical therapy program for improving
balance control and gait functions in children with spastic diplegic cerebral
palsy.
DOI: 10.1097/PHM.0000000000000109
PMID: 24901761 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21195088 | 1. J Mol Biol. 2011 Feb 25;406(3):527-41. doi: 10.1016/j.jmb.2010.12.030. Epub
2010 Dec 30.
The recognition specificity of the CHD1 chromodomain with modified histone H3
peptides.
Stein RS, Wang W.
Histone tail peptides comprise the flexible portion of chromatin, the substance
which serves as the packaging for the eukaryotic genome. According to the
histone code hypothesis, reader protein domains (chromodomains) can recognize
modifications of amino acid residues within these peptides, regulating the
expression of genes. We have performed simulations on models of chromodomain
helicase DNA-binding protein 1 complexed with a variety of histone H3
modifications. Binding free energies for both the overall complexes and the
individual residues within the protein and peptides were computed with molecular
mechanics-generalized Born surface area. The simulation results agree well with
experimental data and identify several chromodomain helicase DNA-binding protein
1 residues that play key roles in the interaction with each of the H3
modifications. We identified one class of protein residues that bind to H3 in
all of the complexes (generally interacting hydrophobically), and a second class
of residues that bind only to particular H3 modifications (generally interacting
electrostatically). Additionally, we found that modifications of H3R2 and H3T3
have a dominant effect on the binding affinity; methylation of H3K4 has little
effect on the interaction strength when H3R2 or H3T3 is modified. Our findings
with regard to the specificity shown by the latter class of protein residues in
their binding affinity to certain modifications of H3 support the histone code
hypothesis.
Copyright © 2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.jmb.2010.12.030
PMCID: PMC3034827
PMID: 21195088 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12819141 | 1. Genome Res. 2003 Jun;13(6B):1416-29. doi: 10.1101/gr.1015703.
Identification and analysis of chromodomain-containing proteins encoded in the
mouse transcriptome.
Tajul-Arifin K(1), Teasdale R, Ravasi T, Hume DA, Mattick JS; RIKEN GER Group;
GSL Members.
Author information:
(1)ARC Special Research Centre for Functional and Applied Genomics, Institute
for Molecular Bioscience, University of Queensland, St.Lucia, Queensland 4072,
Australia.
The chromodomain is 40-50 amino acids in length and is conserved in a wide range
of chromatic and regulatory proteins involved in chromatin remodeling.
Chromodomain-containing proteins can be classified into families based on their
broader characteristics, in particular the presence of other types of domains,
and which correlate with different subclasses of the chromodomains themselves.
Hidden Markov model (HMM)-generated profiles of different subclasses of
chromodomains were used here to identify sequences encoding
chromodomain-containing proteins in the mouse transcriptome and genome. A total
of 36 different loci encoding proteins containing chromodomains, including 17
novel loci, were identified. Six of these loci (including three apparent
pseudogenes, a novel HP1 ortholog, and two novel Msl-3 transcription factor-like
proteins) are not present in the human genome, whereas the human genome contains
four loci (two CDY orthologs and two apparent CDY pseudogenes) that are not
present in mouse. A number of these loci exhibit alternative splicing to produce
different isoforms, including 43 novel variants, some of which lack the
chromodomain. The likely functions of these proteins are discussed in relation
to the known functions of other chromodomain-containing proteins within the same
family.
DOI: 10.1101/gr.1015703
PMCID: PMC403676
PMID: 12819141 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2816867 | 1. Am J Dis Child. 1989 Nov;143(11):1356-60. doi:
10.1001/archpedi.1989.02150230114038.
Early diagnosis of spastic diplegia, spastic hemiplegia, and quadriplegia.
Harris SR(1).
Author information:
(1)Physical Therapy Program, University of Wisconsin, Madison.
Comment in
Am J Dis Child. 1990 Sep;144(9):958-9. doi:
10.1001/archpedi.1990.02150330016010.
A retrospective study examined early neurodevelopmental behaviors of children
with spastic diplegia, spastic hemiplegia, and quadriplegia (spastic, athetoid,
or mixed) who had been followed up longitudinally in a high-risk infant
follow-up clinic. Compared with peers with normal outcomes, children with all
three types of cerebral palsy had significantly lower scores on the Bayley
Mental Scale at 4 months of age; children with hemiplegia and quadriplegia also
scored significantly lower on the Bayley Motor Scale. On the Movement Assessment
of Infants at 4 months of age, the children with hemiplegia and quadriplegia
showed significantly higher risk scores than the nonhandicapped group. The
Movement Assessment of Infants was more than three times as sensitive as the
Bayley Motor Scale in detecting motor abnormalities in 4-month-old infants with
diplegia and more than twice as sensitive in detecting early abnormalities of
hemiplegia. At 1 year of age, however, the Bayley Motor Scale was extremely
sensitive in picking up motor deficits in children with all three types of
cerebral palsy.
DOI: 10.1001/archpedi.1989.02150230114038
PMID: 2816867 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24297251 | 1. Nucleic Acids Res. 2014 Jan;42(Database issue):D92-7. doi:
10.1093/nar/gkt1248. Epub 2013 Dec 1.
starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction
networks from large-scale CLIP-Seq data.
Li JH(1), Liu S, Zhou H, Qu LH, Yang JH.
Author information:
(1)RNA Information Center, Key Laboratory of Gene Engineering of the Ministry of
Education, State Key Laboratory for Biocontrol, Sun Yat-sen University,
Guangzhou 510275, PR China.
Although microRNAs (miRNAs), other non-coding RNAs (ncRNAs) (e.g. lncRNAs,
pseudogenes and circRNAs) and competing endogenous RNAs (ceRNAs) have been
implicated in cell-fate determination and in various human diseases,
surprisingly little is known about the regulatory interaction networks among the
multiple classes of RNAs. In this study, we developed starBase v2.0
(http://starbase.sysu.edu.cn/) to systematically identify the RNA-RNA and
protein-RNA interaction networks from 108 CLIP-Seq (PAR-CLIP, HITS-CLIP, iCLIP,
CLASH) data sets generated by 37 independent studies. By analyzing millions of
RNA-binding protein binding sites, we identified ∼9000 miRNA-circRNA, 16 000
miRNA-pseudogene and 285,000 protein-RNA regulatory relationships. Moreover,
starBase v2.0 has been updated to provide the most comprehensive CLIP-Seq
experimentally supported miRNA-mRNA and miRNA-lncRNA interaction networks to
date. We identified ∼10,000 ceRNA pairs from CLIP-supported miRNA target sites.
By combining 13 functional genomic annotations, we developed miRFunction and
ceRNAFunction web servers to predict the function of miRNAs and other ncRNAs
from the miRNA-mediated regulatory networks. Finally, we developed interactive
web implementations to provide visualization, analysis and downloading of the
aforementioned large-scale data sets. This study will greatly expand our
understanding of ncRNA functions and their coordinated regulatory networks.
DOI: 10.1093/nar/gkt1248
PMCID: PMC3964941
PMID: 24297251 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20079992 | 1. Eur J Radiol. 2010 Aug;75(2):e88-91. doi: 10.1016/j.ejrad.2009.12.012. Epub
2010 Jan 15.
Correlation between myocardial fibrosis and the occurrence of atrial
fibrillation in hypertrophic cardiomyopathy: a cardiac magnetic resonance
imaging study.
Pujadas S(1), Vidal-Perez R, Hidalgo A, Leta R, Carreras F, Barros A,
Bayes-Genis A, Subirana MT, Pons-Llado G.
Author information:
(1)Cardiac Imaging Unit, Cardiology Department, Hospital de la Santa Creu i Sant
Pau, Av Pare M Claret 167, 08025 Barcelona, Spain. [email protected]
Cardiac magnetic resonance imaging (CMR) in hypertrophic cardiomyopathy (HCM)
often shows delayed contrast enhancement (DE) representing regions of focal
myocardial fibrosis. Atrial fibrillation (AF) is a commonly reported
complication of HCM. We determined the relationship between the presence of left
ventricular myocardial fibrosis (LVMF) detected by DE-CMR and the occurrence AF
in a series of patients with HCM. 67 patients with HCM (47 males; mean age
50.1+/-18.5 years) were studied by CMR measuring mass of LVMF, left ventricular
mass, volume and function, and left atrial (LA) area. AF was present in 17 (25%)
patients. LVMF was observed in 57% of patients. AF was significantly more
frequent in patients who also showed LVMF, compared with the group without LVMF
(42.1% vs. 3.4%, respectively; p<0.0001). LA size was larger in patients showing
DE (LA area: 37.4+/-11.1 vs. 25.9+/-6.8 cm(2); respectively, p=0.0001). AF in
HCM is related with myocardial fibrosis detected by DE-CMR and dilatation of the
LA. This fact adds to the proven adverse prognostic value of myocardial fibrosis
in HCM, thus, reinforcing the usefulness of this technique in the assessment of
these patients.
Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.ejrad.2009.12.012
PMID: 20079992 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24076358 | 1. Antiviral Res. 2013 Nov;100(2):500-19. doi: 10.1016/j.antiviral.2013.09.013.
Epub 2013 Sep 27.
Ten years of dengue drug discovery: progress and prospects.
Lim SP(1), Wang QY, Noble CG, Chen YL, Dong H, Zou B, Yokokawa F, Nilar S, Smith
P, Beer D, Lescar J, Shi PY.
Author information:
(1)Novartis Institute for Tropical Diseases, 10 Biopolis Road, 05-01 Chromos,
Singapore 138670, Singapore.
To combat neglected diseases, the Novartis Institute of Tropical Diseases (NITD)
was founded in 2002 through private-public funding from Novartis and the
Singapore Economic Development Board. One of NITD's missions is to develop
antivirals for dengue virus (DENV), the most prevalent mosquito-borne viral
pathogen. Neither vaccine nor antiviral is currently available for DENV. Here we
review the progress in dengue drug discovery made at NITD as well as the major
discoveries made by academia and other companies. Four strategies have been
pursued to identify inhibitors of DENV through targeting both viral and host
proteins: (i) HTS (high-throughput screening) using virus replication assays;
(ii) HTS using viral enzyme assays; (iii) structure-based in silico docking and
rational design; (iv) repurposing hepatitis C virus inhibitors for DENV. Along
the developmental process from hit finding to clinical candidate, many
inhibitors did not advance beyond the stage of hit-to-lead optimization, due to
their poor selectivity, physiochemical or pharmacokinetic properties. Only a few
compounds showed efficacy in the AG129 DENV mouse model. Two nucleoside analogs,
NITD-008 and Balapiravir, entered preclinical animal safety study and clinic
trial, but both were terminated due to toxicity and lack of potency,
respectively. Celgosivir, a host alpha-glucosidase inhibitor, is currently under
clinical trial; its clinical efficacy remains to be determined. The knowledge
accumulated during the past decade has provided a better rationale for ongoing
dengue drug discovery. Though challenging, we are optimistic that this
continuous, concerted effort will lead to an effective dengue therapy.
Copyright © 2013 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.antiviral.2013.09.013
PMID: 24076358 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22935464 | 1. J Am Coll Cardiol. 2012 Sep 4;60(10):922-9. doi: 10.1016/j.jacc.2012.03.076.
Progression of myocardial fibrosis assessed with cardiac magnetic resonance in
hypertrophic cardiomyopathy.
Todiere G(1), Aquaro GD, Piaggi P, Formisano F, Barison A, Masci PG, Strata E,
Bacigalupo L, Marzilli M, Pingitore A, Lombardi M.
Author information:
(1)Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy.
Comment in
J Am Coll Cardiol. 2012 Sep 4;60(10):930-1. doi: 10.1016/j.jacc.2012.05.023.
OBJECTIVES: This study sought to assess the rate of progression of fibrosis by 2
consecutive cardiac magnetic resonance (CMR) examinations and its relation with
clinical variables.
BACKGROUND: In hypertrophic cardiomyopathy (HCM) myocardial fibrosis, detected
by late gadolinium enhancement (LGE), is associated to a progressive ventricular
dysfunction and worse prognosis.
METHODS: A total of 55 HCM patients (37 males; mean age 43 ± 18 years) underwent
2 CMR examinations (CMR-1 and CMR-2) separated by an interval of 719 ± 410 days.
Extent of LGE was measured, and the rate of progression of LGE (LGE-rate) was
calculated as the ratio between the increment of LGE (in grams) and the time
(months) between the CMR examinations.
RESULTS: At CMR-1, LGE was detected in 45 subjects, with an extent of 13.3 ±
15.2 g. At CMR-2, 53 (96.4%) patients had LGE, with an extent of 24.6 ± 27.5 g.
In 44 patients, LGE extent increased significantly (≥1 g). Patients with apical
HCM had higher increments of LGE (p = 0.004) and LGE-rate (p < 0.001) than those
with other patterns of hypertrophy. The extent of LGE at CMR-1 and the apical
pattern of hypertrophy were independent predictors of the increment of LGE.
Patients with worsened New York Heart Association functional class presented
higher increase of LGE (p = 0.031) and LGE-rate (p < 0.05) than those with
preserved functional status.
CONCLUSIONS: Myocardial fibrosis in HCM is a progressive and fast phenomenon.
LGE increment, related to a worse clinical status, is more extensive in apical
hypertrophy than in other patterns.
Copyright © 2012 American College of Cardiology Foundation. Published by
Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jacc.2012.03.076
PMID: 22935464 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23376948 | 1. Heart. 2013 Apr;99(8):511-3. doi: 10.1136/heartjnl-2012-303363. Epub 2013 Feb
2.
Risk assessment in hypertrophic cardiomyopathy: contemporary guidelines hampered
by insufficient evidence.
McKeown PP, Muir AR.
Comment on
Heart. 2013 Apr;99(8):534-41. doi: 10.1136/heartjnl-2012-303271.
DOI: 10.1136/heartjnl-2012-303363
PMCID: PMC3607114
PMID: 23376948 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23403278 | 1. Biochim Biophys Acta. 2013 May;1833(5):1212-21. doi:
10.1016/j.bbamcr.2013.02.001. Epub 2013 Feb 8.
Dysregulation of cell cycle control caused by overexpression of the oncogene
pp32r1 (ANP32C) and the Tyr>His mutant pp32r1Y140H.
Buddaseth S(1), Göttmann W, Blasczyk R, Huyton T.
Author information:
(1)Institute for Transfusion Medicine, Hannover Medical School, Hannover,
Germany.
The pp32 (ANP32A) gene acts as a tumor suppressor while its closely related
homologue pp32r1 (ANP32C) is oncogenic and is overexpressed in breast, prostate
and pancreatic tumors. The transduction of p53wt cell lines (ACHN and HeLa) with
pp32r1 or pp32r1Y140H lentivirus increased the proliferation of p53wt cell lines
compared to the untransduced control cells while transduction of the p53(R248W)
MiaPaCa2 cell line had no effect. Cell cycle analysis of transduced ACHN cells
by PI staining and BrdU incorporation illustrated a pronounced shift toward the
S-phase of the cell cycle in cells overexpressing the pp32r1 and pp32r1Y140H
proteins. Confocal microscopy and western blotting demonstrated that pp32r1 and
the pp32r1Y140H mutant protein reside predominantly in the cytoplasm in
constrast to pp32 which is a nuclear/cytoplasmic shuttling protein. To determine
the effects of pp32r1 or pp32r1Y140H overexpression at the proteomic level we
performed a comprehensive proteome analysis on ACHN, ACHN-pp32r1 and
ACHN-pp32r1Y140H cell lysates using the isotope-coded protein label (ICPL)
method. Among those proteins with >40% regulation were Macrophage Capping
protein (CAPG) and Chromodomain Helicase DNA binding protein 4 (CHD4) proteins
which were significantly upregulated by pp32r1 and pp32r1Y140H overexpression.
This increase in CHD4 also appears to influence a number of cell cycle regulator
genes including; p53, p21 and cyclinD1 as judged by western blotting. Silencing
of CHD4 in ACHN-pp32r1Y140H cells using specific shRNA reverted the cell cycle
dysregulation caused by pp32r1Y140H expression to that of the untransduced ACHN
cell line, suggesting that CHD4 is the prominent effector of the
pp32r1/pp32r1Y140H phenotype.
Copyright © 2013 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bbamcr.2013.02.001
PMID: 23403278 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23142031 | 1. Gene. 2013 Jan 15;513(1):63-70. doi: 10.1016/j.gene.2012.10.077. Epub 2012 Nov
6.
Cloning and characterization of two genes coding for the histone
acetyltransferases, Elp3 and Mof, in brown planthopper (BPH), Nilaparvata lugens
(Stål).
Zhu Y(1), Xie Z, Wang J, Liu Y, Wang J.
Author information:
(1)College of Horticulture and Plant Protection, Yangzhou University, Yangzhou,
225009, China.
Histone acetylation is a vital mechanism for the post-translational
modifications of chromatin components. Histone acetyltransferases (HATs) are
critical elements that determine histone acetylation and regulate chromatin
dynamics and gene expression. While histone acetyltransferases have been well
studied in mammals and Drosophila melanogaster, information from agriculturally
important insect pests is still limited. In our effort to understand the
epigenetic mechanisms regulating development in the brown planthopper,
Nilaparvata lugens (Stål) (Hemiptera: Geometroidea), a major rice pest in many
parts of Asia, two full-length cDNA sequences encoding HAT members of the GNAT
and MYST family, namely NlElp3 and NlMof, respectively, were isolated and
structurally and phylogenetically characterized. The NlElp3 contains an open
reading frame (ORF) of 1656bp encoding a protein of 551 amino acids. The NlMof
contains a 1353bp ORF encoding a protein of 450 amino acids. Sequence analysis
showed that NlElp3 contains GNAT-type HAT domain and Radical SAM domain, and
NlMof contains chromodomain and MOZ-SAS acetyltransferase domain. Multiple
sequence alignments showed that NlElp3 and NlMof have high amino acid sequence
identity with other insect homologues. Expression analysis of the NlElp3 and
NlMof revealed significant differences in mRNA expression levels among N. lugens
developmental stages, suggesting that HAT activities of NlElp3 and NlMof may be
controlled, at least in part, by their developmental regulation. Remarkably, the
mRNA expression levels of NlElp3 and NlMof in female adults were significantly
higher than that in male adults, supporting an important role for both genes in
female reproductive function in N. lugens.
Copyright © 2012 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.gene.2012.10.077
PMID: 23142031 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22687593 | 1. Prog Cardiovasc Dis. 2012 May-Jun;54(6):512-6. doi:
10.1016/j.pcad.2012.04.005.
Cardiovascular magnetic resonance imaging in hypertrophic cardiomyopathy.
Uretsky S(1).
Author information:
(1)Division of Cardiology, Department of Medicine, St. Luke's and Roosevelt
Hospitals, New York, NY 10025, USA. [email protected]
The use of cardiovascular magnetic resonance in patients with hypertrophic
cardiomyopathy over the last decade has helped elucidate the diagnosis,
prognosis, pathophysiology, and management of this disease. Studies have shown
that the use of magnetic resonance imaging in a patient with a permanent
pacemaker and implantable cardioverter defibrillator is safe.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.pcad.2012.04.005
PMID: 22687593 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20226168 | 1. Biochem Biophys Res Commun. 2010 Apr 2;394(2):418-23. doi:
10.1016/j.bbrc.2010.03.042. Epub 2010 Mar 10.
Aire regulates the expression of differentiation-associated genes and
self-renewal of embryonic stem cells.
Gu B(1), Zhang J, Chen Q, Tao B, Wang W, Zhou Y, Chen L, Liu Y, Zhang M.
Author information:
(1)The Institute of Cell Biology and Genetics, College of Life Sciences,
Zhejiang University, 388 Yuhangtang Road, Hangzhou, China.
Embryonic stem cells (ESCs) are pluripotent stem cells from early embryos. It
has been well recognized that ESC genomes are maintained in a globally
transcriptional hyperactive state, which genetically poised ESCs to the high
differentiation potential. However, the transcription factors regulating the
global transcription activities in ESCs are not well defined. We show here that
mouse and human ESCs express two transcription factors, Aire and Deaf1.
Previously known to function in the thymus stromal cells and peripheral lymphoid
organs respectively, Aire and Deaf1 help regulate the ectopic expression of
diverse tissue-specific antigens to establish self-immune tolerance.
Differentiation of ESCs greatly reduced Aire and Deaf1 expression, in a pattern
similar to the pluripotent factors, Oct4 and Nanog. Knockdown of Aire in mouse
ESCs resulted in significantly decreased clone-forming efficiency as well as
attenuated cell cycle, suggesting Aire plays a role in ESC self-renewal. In
addition, some differentiation-associated genes that are sporadically expressed
in ESCs were reduced in expression upon Aire knockdown. These results suggest
that transcription factors such as Aire and Deaf1, which exert global
transcriptional regulatory functions, may play important roles in self-renewal
of ESCs and maintaining ESC in a transcriptionally hyperactive state.
2010 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.bbrc.2010.03.042
PMCID: PMC2885885
PMID: 20226168 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24256889 | 1. Euro Surveill. 2013 Nov 14;18(46):20635. doi:
10.2807/1560-7917.es2013.18.46.20635.
Tick-borne encephalitis in Bulgaria, 2009 to 2012.
Mohareb E(1), Christova I, Soliman A, Younan R, Kantardjiev T.
Author information:
(1)United States Naval Medical Research Unit-3, Cairo, Egypt.
For the last 60 years, only a few cases of tick-borne encephalitis (TBE) have
been detected in Bulgaria. Considering the remarkable increase in TBE morbidity
in Europe over the past two decades, we conducted a study of TBE among patients
with acute viral meningitis who were hospitalised in Bulgaria during 2009 to
2012. A total of 86 patients with viral meningitis of unknown aetiology during
this period were tested. Acute TBE was confirmed in three of these patients. The
last TBE case was detected in October 2012; the other two were diagnosed in
2009. To the best of our knowledge, these three patients are the first confirmed
TBE cases reported in Bulgaria. The risk of TBE is underestimated in Bulgaria
due to the low awareness of medical doctors.
DOI: 10.2807/1560-7917.es2013.18.46.20635
PMID: 24256889 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18208827 | 1. Heart. 2008 Nov;94(11):1485-95. doi: 10.1136/hrt.2007.119016. Epub 2008 Jan
20.
Advances in clinical applications of cardiovascular magnetic resonance imaging.
Bandettini WP(1), Arai AE.
Author information:
(1)Laboratory of Cardiac Energetics, National Heart, Lung, and Blood Institute,
National Institutes of Health, Bethesda, Maryland 20892-1061, USA.
[email protected]
Cardiovascular magnetic resonance (CMR) is an evolving technology with growing
indications within the clinical cardiology setting. This review article
summarises the current clinical applications of CMR. The focus is on the use of
CMR in the diagnosis of coronary artery disease with summaries of validation
literature in CMR viability, myocardial perfusion, and dobutamine CMR. Practical
uses of CMR in non-coronary diseases are also discussed.
DOI: 10.1136/hrt.2007.119016
PMCID: PMC2582334
PMID: 18208827 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: None. |
http://www.ncbi.nlm.nih.gov/pubmed/20339815 | 1. Arq Bras Cardiol. 2010 Apr;94(4):535-40. doi: 10.1590/s0066-782x2010005000017.
Epub 2010 Mar 26.
[Myocardial fibrosis in patients with hypertrophic cardiomyopathy and high risk
for sudden death].
[Article in Portuguese]
Shiozaki AA(1), Senra T, Arteaga E, Pita CG, Martinelli Filho M, Avila LF, Parga
Filho JR, Mady C, Rochitte CE.
Author information:
(1)Instituto do Coração (InCor), Hospital das Clínicas, Faculdade de Medicina,
Universidade de São Paulo, São Paulo, SP - Brazil.
BACKGROUND: The stratification of risk for sudden death in hypertrophic
cardiomyopathy (HCM) continues to be a true challenge due to the great
heterogeneity of this disease's presentation, as most individuals remain
asymptomatic during their entire lives and others present sudden death as first
symptom. Recent studies have suggested that myocardial fibrosis may represent an
important substrate for the malignant ventricular arrhythmias, that are
responsible for the cases of sudden death related to this disease.
OBJECTIVE: To assess the prevalence and quantification of myocardial fibrosis
(MF) in hypertrophic cardiomyopathy (HCM) patients with implantablecardioverter
- defibrillator (ICD) indicated due to their high risk or recovered from cardiac
sudden death.
METHODS: Twenty-eight HCM patients with ICD were submitted to multidetector
computed tomography to assess myocardial fibrosis by delayed enhancement
technique.
RESULTS: Myocardial fibrosis was present in 96% of these HCM patients with
(20.38 +/- 15.55 g) comprising 15.96 +/- 10.20% of the total myocardial mass. MF
was observed in a significantly higher prevalence as compared to other classical
risk factors for sudden death.
CONCLUSION: It is possible to conclude that there is a high prevalence of
myocardial fibrosis in hypertrophic cardiomyopathy patients with high-risk or
recovered from cardiac sudden death, like those with clinical indication to
implantable cardioverter -defibrillator. The higher prevalence of myocardial
fibrosis in comparison to classical risk factors of worse prognosis raise the
hypothesis that the myocardial fibrosis may be an important substrate in the
genesis of lifethreatening arrhythmias in these high risk HCM population.
DOI: 10.1590/s0066-782x2010005000017
PMID: 20339815 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20667520 | 1. J Am Coll Cardiol. 2010 Sep 7;56(11):875-87. doi: 10.1016/j.jacc.2010.05.007.
Epub 2010 Jun 25.
Myocardial scar visualized by cardiovascular magnetic resonance imaging predicts
major adverse events in patients with hypertrophic cardiomyopathy.
Bruder O(1), Wagner A, Jensen CJ, Schneider S, Ong P, Kispert EM, Nassenstein K,
Schlosser T, Sabin GV, Sechtem U, Mahrholdt H.
Author information:
(1)Department of Cardiology and Angiology, Elisabeth Hospital, Essen, Germany.
Comment in
J Am Coll Cardiol. 2010 Sep 7;56(11):888-9. doi: 10.1016/j.jacc.2010.06.004.
J Am Coll Cardiol. 2011 Mar 22;57(12):1402; author reply 1402-3. doi:
10.1016/j.jacc.2010.09.076.
OBJECTIVES: We sought to establish the prognostic value of a comprehensive
cardiovascular magnetic resonance (CMR) examination in risk stratification of
hypertrophic cardiomyopathy (HCM) patients.
BACKGROUND: With annual mortality rates ranging between 1% and 5%, depending on
patient selection, a small but significant number of HCM patients are at risk
for an adverse event. Therefore, the identification of and prophylactic therapy
(i.e., defibrillator placement) in patients with HCM who are at risk of dying
are imperative.
METHODS: Two-hundred forty-three consecutive patients with HCM were
prospectively enrolled. All patients underwent initial CMR, and 220 were
available for clinical follow-up. The mean follow-up time was 1,090 days after
CMR. End points were all-cause and cardiac mortality.
RESULTS: During follow-up 20 of the 220 patients died, and 2 patients survived
sudden cardiac death due to adequate implantable cardioverter-defibrillator
discharge. Most events (n = 16) occurred for cardiac reasons; the remaining 6
events were related to cancer and accidents. Our data indicate that the presence
of scar visualized by CMR yields an odds ratio of 5.47 for all-cause mortality
and of 8.01 for cardiac mortality. This might be superior to classic clinical
risk factors, because in our dataset the presence of 2 risk factors yields an
odds ratio of 3.86 for all-cause and of 2.20 for cardiac mortality,
respectively. Multivariable analysis also revealed the presence of late
gadolinium enhancement as a good independent predictor of death in HCM patients.
CONCLUSIONS: Among our population of largely low or asymptomatic HCM patients,
the presence of scar indicated by CMR is a good independent predictor of
all-cause and cardiac mortality.
Copyright © 2010 American College of Cardiology Foundation. Published by
Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jacc.2010.05.007
PMID: 20667520 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19474054 | 1. Eur Heart J. 2009 Aug;30(16):2003-10. doi: 10.1093/eurheartj/ehp152. Epub 2009
May 27.
Usefulness of cardiac magnetic resonance in assessing the risk of ventricular
arrhythmias and sudden death in patients with hypertrophic cardiomyopathy.
Leonardi S(1), Raineri C, De Ferrari GM, Ghio S, Scelsi L, Pasotti M, Tagliani
M, Valentini A, Dore R, Raisaro A, Arbustini E.
Author information:
(1)Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Viale
Golgi 19, Pavia (PV) 27100, Italy.
AIMS: To assess the relationship between cardiovascular magnetic resonance (CMR)
parameters and both spontaneous ventricular tachycardia (VT) and risk of sudden
cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) patients.
METHODS AND RESULTS: One hundred and eight consecutive HCM patients (mean age 42
+/- 15 years, 76% males) underwent CMR evaluation and risk assessment. Delayed
contrast enhancement (DCE) was quantified with a specifically designed score.
Endpoints were either the presence of clinical VT/ventricular fibrillation (VF)
or of acknowledged risk factors for SCD. Compared to patients without
arrhythmia, those with VT/VF (n = 33) had a higher DCE score [median 8 (2-13)
vs. 11 (6-20); P = 0.01]; DCE score was also the only independent predictor of
VT/VF in the multivariable model. DCE score [median 6 (1-10.5) vs. 12 (6-18); P
= 0.001], mean and maximal left ventricular (LV) wall thickness (MaxLVWT), as
well as LV mass index were significantly greater among patients at risk for SCD
(n = 51) compared with the remaining 57 patients at low risk. DCE score and
MaxLVWT were independent predictors of SCD risk.
CONCLUSION: In HCM patients several CMR parameters are associated with risk for
SCD. A semi-quantitative index of DCE is a significant multivariable predictor
of both clinical VT/VF and of risk for SCD and may contribute to risk assessment
in borderline or controversial cases.
DOI: 10.1093/eurheartj/ehp152
PMID: 19474054 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23096037 | 1. Zh Nevrol Psikhiatr Im S S Korsakova. 2012;112(8):34-8.
[Mexidol in the complex treatment of patients in the acute period of tick borne
encephalitis].
[Article in Russian]
Udintseva IN, Bartfel't NN, Zhukova NG, Poponina AM.
Therapeutical action of mexidol as compared to piracetam was evaluated in groups
of patients with tick borne encephalitis in the acute period of disease. Mexidol
was administered as add-on to antiviral treatment in 72 patients while 89
patients received piracetam. The drugs were introduced intravenously during the
first 10 days and then were given as tablets during 2 months. Based on these
results, we can recommend the inclusion of mexidol in the pathogenetic treatment
(fever symptoms) of tick born encephalitis. The use of mexidol as compared to
piracetam led to more pronounced positive changes, higher percentage of
favorable outcomes and lower frequency of residual signs.
PMID: 23096037 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22128204 | 1. Heart. 2012 Mar;98(6):438-42. doi: 10.1136/heartjnl-2011-300814. Epub 2011 Nov
29.
Prognostic importance of late gadolinium enhancement cardiovascular magnetic
resonance in cardiomyopathy.
Ismail TF(1), Prasad SK, Pennell DJ.
Author information:
(1)CMR Unit, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.
Cardiovascular magnetic resonance has revolutionised the diagnosis of
cardiomyopathy, particularly through the use of late gadolinium enhancement
imaging which provides the unique opportunity to assess myocardial fibrosis in
vivo. More recently, the prognostic capability of cardiovascular magnetic
resonance to predict outcomes has been assessed. Traditional risk markers do not
at present adequately predict outcomes in either dilated cardiomyopathy or
hypertrophic cardiomyopathy, which are the two most common causes of primary
heart muscle disease. Many of these existing markers reflect underlying disease
severity. Given the important role fibrosis is thought to play in the
pathogenesis and sequelae of these cardiomyopathies, the presence and amount of
fibrosis has been proposed as a potential novel risk factor for adverse events.
This paper reviews the evidence for late gadolinium enhancement as a prognostic
marker in dilated and hypertrophic cardiomyopathy and highlights the challenges
ahead.
DOI: 10.1136/heartjnl-2011-300814
PMID: 22128204 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7946779 | 1. Br Heart J. 1994 Sep;72(3):266-8. doi: 10.1136/hrt.72.3.266.
Two cases of amiodarone-induced thyrotoxicosis successfully treated with a short
course of antithyroid drugs while amiodarone was continued.
Trip MD(1), Düren DR, Wiersinga WM.
Author information:
(1)Department of Cardiology, Academic Medical Center, Amsterdam, The
Netherlands.
Two patients with amiodarone-induced thyrotoxicosis were treated successfully
with potassium perchlorate and carbimazole while treatment with amiodarone was
continued. These antithyroid drugs were stopped after the patients had became
clinically and biochemically euthyroid. During follow up, when treatment with
amiodarone continued, thyrotoxicosis did not recur. Amiodarone-induced
thyrotoxicosis seems to be a transient condition that can be treated
successfully with a short course of antithyroid drugs without stopping
amiodarone treatment.
DOI: 10.1136/hrt.72.3.266
PMCID: PMC1025514
PMID: 7946779 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23784447 | 1. J Gen Virol. 2013 Sep;94(Pt 9):2129-2139. doi: 10.1099/vir.0.054478-0. Epub
2013 Jun 19.
Molecular phylogeography of tick-borne encephalitis virus in central Europe.
Weidmann M(1), Frey S(2), Freire CCM(3), Essbauer S(2), Růžek D(4)(5), Klempa
B(6)(7), Zubrikova D(8), Vögerl M(9), Pfeffer M(10), Hufert FT(1), Zanotto
PM(3), Dobler G(2).
Author information:
(1)Department of Virology, University Medical Center, 37075 Göttingen, Germany.
(2)Bundeswehr Institute of Microbiology, 80937 Munich, Germany.
(3)Department of Microbiology, Biomedical Sciences Institute - ICB II University
of São Paulo, 05508-000 São Paulo, Brazil.
(4)Institute of Parasitology, Biology Centre of the Czech Academy of Sciences,
Branisovska 31, CZ-37005 Ceske Budejovice, Czech Republic.
(5)Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100
Brno, Czech Republic.
(6)Institute of Virology Charité University Hospital, Berlin, Germany.
(7)Institute of Virology, Slovak Academy of Science, Dubravska cesta 9, 84505
Bratislava, Slovakia.
(8)Institute of Parasitology, Slovak Academy of Science, Kosice, Slovakia.
(9)Comparative Tropical Medicine and Parasitology, Faculty of Veterinary
Medicine, Ludwig-Maximilians-University, Munich, Germany.
(10)Institute of Animal Hygiene and Veterinary Public Health, University of
Leipzig, Leipzig, Germany.
In order to obtain a better understanding of tick-borne encephalitis virus
(TBEV) strain movements in central Europe the E gene sequences of 102 TBEV
strains collected from 1953 to 2011 at 38 sites in the Czech Republic, Slovakia,
Austria and Germany were determined. Bayesian analysis suggests a 350-year
history of evolution and spread in central Europe of two main lineages, A and B.
In contrast to the east to west spread at the Eurasian continent level, local
central European spreading patterns suggest historic west to east spread
followed by more recent east to west spread. The phylogenetic and network
analyses indicate TBEV ingressions from the Czech Republic and Slovakia into
Germany via landscape features (Danube river system), biogenic factors (birds,
red deer) and anthropogenic factors. The identification of endemic foci showing
local genetic diversity is of paramount importance to the field as these will be
a prerequisite for in-depth analysis of focal TBEV maintenance and long-distance
TBEV spread.
DOI: 10.1099/vir.0.054478-0
PMID: 23784447 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24225644 | 1. Int J Environ Res Public Health. 2013 Nov 12;10(11):6049-83. doi:
10.3390/ijerph10116049.
Flaviviruses in Europe: complex circulation patterns and their consequences for
the diagnosis and control of West Nile disease.
Beck C(1), Jimenez-Clavero MA, Leblond A, Durand B, Nowotny N, Leparc-Goffart I,
Zientara S, Jourdain E, Lecollinet S.
Author information:
(1)UMR1161 Virologie INRA, ANSES, ENVA, EU-RL on equine West Nile disease,
Animal Health Laboratory, ANSES, Maisons-Alfort 94704, France.
[email protected].
In Europe, many flaviviruses are endemic (West Nile, Usutu, tick-borne
encephalitis viruses) or occasionally imported (dengue, yellow fever viruses).
Due to the temporal and geographical co-circulation of flaviviruses in Europe,
flavivirus differentiation by diagnostic tests is crucial in the adaptation of
surveillance and control efforts. Serological diagnosis of flavivirus infections
is complicated by the antigenic similarities among the Flavivirus genus. Indeed,
most flavivirus antibodies are directed against the highly immunogenic envelope
protein, which contains both flavivirus cross-reactive and virus-specific
epitopes. Serological assay results should thus be interpreted with care and
confirmed by comparative neutralization tests using a panel of viruses known to
circulate in Europe. However, antibody cross-reactivity could be advantageous in
efforts to control emerging flaviviruses because it ensures partial
cross-protection. In contrast, it might also facilitate subsequent diseases,
through a phenomenon called antibody-dependent enhancement mainly described for
dengue virus infections. Here, we review the serological methods commonly used
in WNV diagnosis and surveillance in Europe. By examining past and current
epidemiological situations in different European countries, we present the
challenges involved in interpreting flavivirus serological tests and setting up
appropriate surveillance programs; we also address the consequences of
flavivirus circulation and vaccination for host immunity.
DOI: 10.3390/ijerph10116049
PMCID: PMC3863887
PMID: 24225644 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19280114 | 1. J Neural Transm (Vienna). 2009 Jun;116(6):689-97. doi:
10.1007/s00702-009-0205-1. Epub 2009 Mar 11.
Decreased anxiety in mice lacking the organic cation transporter 3.
Wultsch T(1), Grimberg G, Schmitt A, Painsipp E, Wetzstein H, Breitenkamp AF,
Gründemann D, Schömig E, Lesch KP, Gerlach M, Reif A.
Author information:
(1)Section of Clinical and Molecular Psychobiology, Department of Psychiatry and
Psychotherapy, University of Würzburg, Füchsleinstr. 15, 97080 Würzburg,
Germany. [email protected]
The organic cation transporter 3 (OCT3; synonymous: extraneuronal monoamine
transporter, EMT, Slc22a3) encodes an isoform of the organic cation transporters
and is expressed widely across the whole brain. OCTs are a family of
high-capacity, bidirectional, multispecific transporters of organic cations.
These also include serotonin, dopamine and norepinephrine making OCTs attractive
candidates for a variety of neuropsychiatric disorders including anxiety
disorders. OCT3 has been implicated in termination of monoaminergic signalling
in the central nervous system. Interestingly, OCT3 mRNA is however also
significantly up-regulated in the hippocampus of serotonin transporter knockout
mice where it might serve as an alternative reuptake mechanism for serotonin.
The examination of the behavioural phenotype of OCT3 knockout mice thus is
paramount to assess the role of OCT3. We have therefore subjected mice lacking
the OCT3 gene to a comprehensive behavioural test battery. While cognitive
functioning in the Morris water maze test and aggression levels measured with
the resident-intruder paradigm were in the same range as the respective control
animals, OCT3 knockout animals showed a tendency of increased activity and were
significantly less anxious in the elevated plus-maze test and the open field
test as compared to their respective wild-type controls arguing for a role of
OCT3 in the regulation of fear and anxiety, probably by modulating the
serotonergic tone in limbic circuitries.
DOI: 10.1007/s00702-009-0205-1
PMID: 19280114 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21352605 | 1. Fluids Barriers CNS. 2011 Feb 28;8(1):13. doi: 10.1186/2045-8118-8-13.
Transport characteristics of guanidino compounds at the blood-brain barrier and
blood-cerebrospinal fluid barrier: relevance to neural disorders.
Tachikawa M(1), Hosoya K.
Author information:
(1)Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical
Sciences, University of Toyama, Toyama, Japan. [email protected].
Guanidino compounds (GCs), such as creatine, phosphocreatine, guanidinoacetic
acid, creatinine, methylguanidine, guanidinosuccinic acid, γ-guanidinobutyric
acid, β-guanidinopropionic acid, guanidinoethane sulfonic acid and
α-guanidinoglutaric acid, are present in the mammalian brain. Although creatine
and phosphocreatine play important roles in energy homeostasis in the brain,
accumulation of GCs may induce epileptic discharges and convulsions. This review
focuses on how physiologically important and/or neurotoxic GCs are distributed
in the brain under physiological and pathological conditions. Transporters for
GCs at the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF)
barrier (BCSFB) have emerged as substantial contributors to GCs distribution in
the brain. Creatine transporter (CRT/solute carrier (SLC) 6A8) expressed at the
BBB regulates creatine concentration in the brain, and represents a major
pathway for supply of creatine from the circulating blood to the brain. CRT may
be a key factor facilitating blood-to-brain guanidinoacetate transport in
patients deficient in S-adenosylmethionine:guanidinoacetate N-methyltransferase,
the creatine biosynthetic enzyme, resulting in cerebral accumulation of
guanidinoacetate. CRT, taurine transporter (TauT/SLC6A6) and organic cation
transporter (OCT3/SLC22A3) expressed at the BCSFB are involved in
guanidinoacetic acid or creatinine efflux transport from CSF. Interestingly, BBB
efflux transport of GCs, including guanidinoacetate and creatinine, is
negligible, though the BBB has a variety of efflux transport systems for
synthetic precursors of GCs, such as amino acids and neurotransmitters. Instead,
the BCSFB functions as a major cerebral clearance system for GCs. In conclusion,
transport of GCs at the BBB and BCSFB appears to be the key determinant of the
cerebral levels of GCs, and changes in the transport characteristics may cause
the abnormal distribution of GCs in the brain seen in patients with certain
neurological disorders.
DOI: 10.1186/2045-8118-8-13
PMCID: PMC3058069
PMID: 21352605 |
http://www.ncbi.nlm.nih.gov/pubmed/23815903 | 1. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2013 Jun;21(3):587-90. doi:
10.7534/j.issn.1009-2137.2013.03.010.
[Influence of TIEG1 on apoptosis of HL-60 cells and expression of Bcl-2/Bax].
[Article in Chinese]
Yao K(1), Yang Y, Hu R, Miao M, Liao AJ, Yang W, Liu ZG.
Author information:
(1)Department of Hematology, China Medical University, Shengyang, China.
This study was aimed to investigate the influence of TIEG1 on apoptosis of HL-60
cells and the expression of Bcl-2/Bax. Different concentration of TIEG1 were
used to treat HL-60 cells, the cell growth inhibition rate was detected by MTT
method. After treating HL-60 cells with 12.03 ng/ml TIEG1, cell apoptosis was
detected with flow cytometry. Bcl-2 and Bax was detected with RT-PCR. The
results showed that TIEG1 had inhibitory effect on HL-60 cell proliferation, and
in time-and dose-dependent manners. The more obvious inhibitory effect was
observed in HL-60 cells treated with TIEG1 of 12.03 ng/ml. During the course of
cell apoptosis, Bax expression increased, but Bcl-2 expression decreased (P <
0.05). It is concluded that TIEG1 inhibits HL-60 cell proliferation and induces
apoptosis in time and dose-dependent manners. During the course of HL-60 cells
apoptosis induced by TIEG1, Bcl-2/Bax are associated with HL-60 cell apoptosis
induced by TIEG1.
DOI: 10.7534/j.issn.1009-2137.2013.03.010
PMID: 23815903 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11825323 | 1. Expert Opin Pharmacother. 2001 Nov;2(11):1877-90. doi:
10.1517/14656566.2.11.1877.
Amiodarone -- waxed and waned and waxed again.
Doggrell SA(1).
Author information:
(1)Department of Physiology and Pharmacology, University of Queensland,
Brisbane, 4072 Australia. [email protected]
Amiodarone has been used as an anti-arrhythmic drug since the 1970s and has an
established role in the treatment of ventricular tachyarrhythmias. Although
considered to be a class III anti-arrhythmic, amiodarone also has class I, II
and IV actions, which gives it a unique pharmacological and anti-arrhythmic
profile. Amiodarone is a structural analogue of thyroid hormone and some of its
anti-arrhythmic properties and toxicity may be attributable to interactions with
nuclear thyroid hormone receptors. The lipid solubility of amiodarone gives it
an exceptionally long half-life. Oral amiodarone takes days to work in
ventricular tachyarrhythmias, but iv. amiodarone has immediate effect and can be
used in life threatening ventricular arrhythmias. Intravenous amiodarone
administered after out-of-hospital cardiac arrest due to ventricular
fibrillation improves survival to hospital admission. Many survivors of
myocardial infarction (MI) die during the subsequent year, probably due to
ventricular arrhythmia. Amiodarone reduces sudden death after MI and this
benefit is predominantly observed in patients with preserved cardiac function.
Sudden cardiac death, predominantly due to ventricular arrhythmias, is also
commonly seen in patients with heart failure. The Grupo de Estudio de la
Sobrevida en lsuficiencia Cardiaca en Argentina (GESICA) and Estudio Piloto
Argentino de Muerte Subita y Amiodarona (EPAMSA) trials showed survival benefit
of amiodarone in heart failure, whereas Congestive Heart Failure-Survival Trial
of Anti-arrhythmic Therapy (CHF-STAT) did not. Subsequent meta-analysis
established a survival benefit of amiodarone in heart failure. Implanted
Cardioverter Def ibrillators (ICDs) also give survival benefit to patients at
risk of sudden death. In patients with a history of ventricular fibrillation or
haemodynamically-compromising ventricular tachycardia, ICDs have been shown to
be superior to anti-arrhythmic drugs, principally amiodarone. Further analysis
has been undertaken to ascertain which patients are most likely to benefit from
ICDs, as these are more expensive than treatment with amiodarone. Patients with
severely depressed ejection fractions should be the first to be considered for
ICDs. A new indication for amiodarone is atrial fibrillation or flutter.
Amiodarone is effective in chronic and recent onset atrial fibrillation and
orally or iv. for atrial fibrillation after heart surgery. In atrial
fibrillation amiodarone is more than or equi-effective with flecainide,
quinidine, racemic sotalol, propafenone and diltiazem and therefore should be
considered for first line therapy. Amiodarone is also safe and effective in
controlling refractory tachyarrhythmias in infants and is safe after cardiac
surgery.
DOI: 10.1517/14656566.2.11.1877
PMID: 11825323 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18513366 | 1. J Neurochem. 2008 Aug;106(3):1471-82. doi: 10.1111/j.1471-4159.2008.05506.x.
Epub 2008 May 30.
Altered aminergic neurotransmission in the brain of organic cation transporter
3-deficient mice.
Vialou V(1), Balasse L, Callebert J, Launay JM, Giros B, Gautron S.
Author information:
(1)Inserm U513, Université Paris VI, Paris, France, and UPMC, Université Paris
VI, Paris, France.
Organic cation transporters (OCTs) are carrier-type polyspecific permeases known
to participate in low-affinity extraneuronal catecholamine uptake in peripheral
tissues. OCT3 is the OCT subtype most represented in the brain, yet its
implication in central aminergic neurotransmission in vivo had not been directly
demonstrated. In a detailed immunohistochemistry study, we show that OCT3 is
expressed in aminergic pathways in the mouse brain, particularly in dopaminergic
neurons of the substantia nigra compacta, non-aminergic neurons of the ventral
tegmental area, substantia nigra reticulata (SNr), locus coeruleus, hippocampus
and cortex. Although OCT3 was found mainly in neurons, it was also occasionally
detected in astrocytes in the SNr, hippocampus and several hypothalamic nuclei.
In agreement with this distribution, OCT3/Slc22a3-deficient mice show evidence
of altered monoamine neurotransmission in the brain, with decreased
intracellular content and increased turnover of aminergic transmitters. The
behavioral characterization of these mutants reveal subtle behavioral
alterations such as increased sensitivity to psychostimulants and increased
levels of anxiety and stress. Altogether our data support a role of OCT3 in the
homeostatic regulation of aminergic neurotransmission in the brain.
DOI: 10.1111/j.1471-4159.2008.05506.x
PMID: 18513366 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18798273 | 1. Int J Cancer. 2008 Dec 15;123(12):2759-66. doi: 10.1002/ijc.23833.
Bone marrow stroma cells regulate TIEG1 expression in acute lymphoblastic
leukemia cells: role of TGFbeta/BMP-6 and TIEG1 in chemotherapy escape.
Døsen-Dahl G(1), Munthe E, Nygren MK, Stubberud H, Hystad ME, Rian E.
Author information:
(1)Department of Immunology, Institute for Cancer Research, Norwegian Radium
Hospital, Rikshospitalet University Hospital, Montebello, Oslo, Norway.
Erratum in
Int J Cancer. 2009 May 1;24(9):2250.
The bone marrow microenvironment regulates early B lymphopoiesis and protects
leukemia cells against chemotherapy treatment, thus the microenvironment may
serve as a sanctuary site for these cells. Yet, few factors that contribute to
this process are known. We have explored the role of transforming growth factor
beta (TGFbeta) and bone morphogenetic protein-6 (BMP-6) and one target gene,
TGFbeta inducible early gene 1 (TIEG1), in the communication between stroma
cells and acute lymphoblastic leukemia (ALL) cell lines and their escape from
chemotherapy. Here, we have demonstrated TIEG1 expression in both normal B
progenitor cells and ALL cells, which increased rapidly upon TGFbeta and BMP-6
treatment. Stimulation with TGFbeta or BMP-6, as well as overexpression of TIEG1
inhibited proliferation. Furthermore, interaction with stroma cells induced
TIEG1 expression in ALL cells, inhibited their proliferation and protected the
cells against chemotherapeutic treatment. Similarly, treatment with TGFbeta or
BMP-6, as well as overexpression of TIEG1, protected ALL cells against
chemotherapy-induced cell death. These data suggest that TGFbeta and BMP-6 in
the bone marrow microenvironment allow leukemia cells to escape therapy.
Further, the data indicate that TIEG1 might be involved in mediating this effect
from the microenvironment onto the leukemia cells.
(c) 2008 Wiley-Liss, Inc.
DOI: 10.1002/ijc.23833
PMID: 18798273 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12065093 | 1. Cancer Lett. 2002 Sep 26;183(2):179-83. doi: 10.1016/s0304-3835(01)00802-3.
Absence of mutations in the transforming growth factor-beta inducible early gene
1, TIEG1, in pancreatic cancer.
Antonello D(1), Moore PS, Zamboni G, Falconi M, Scarpa A.
Author information:
(1)Department of Pathology, Università di Verona, Strada Le Grazie 8, 37134,
Verona, Italy.
Pancreatic cancers frequently have defects in components of the transforming
growth factor-beta (TGF-beta) signaling pathway. TIEG1 (TGF-beta inducible early
gene) is a recently characterized transcription factor regulated by TGF-beta
that induces apoptosis when overexpressed in pancreatic adenocarcinoma cell
lines. Alterations on chromosome 8q, where TIEG1 is located, are also relatively
frequent in pancreatic cancers. To determine if TIEG1 may be involved in the
tumorigenesis of pancreatic cancer, we performed mutational screening of this
gene in 22 pancreatic cancer cell lines. No sequence alterations were observed.
Reverse transcription-polymerase chain reaction analysis was also performed to
rule out the possibility that the expression of the gene is altered by genetic
events other than mutation. Likewise, no alterations in expression were found.
Thus, an essential role of TIEG1 in pancreatic cancer can be excluded.
DOI: 10.1016/s0304-3835(01)00802-3
PMID: 12065093 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23244828 | 1. Reprod Fertil Dev. 2012;25(1):48-61. doi: 10.1071/RD12272.
Associations between lipid metabolism and fertility in the dairy cow.
Wathes DC(1), Clempson AM, Pollott GE.
Author information:
(1)Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts AL9
7TA, UK. [email protected]
Dairy cows mobilise body tissues to support milk production and, because glucose
supplies are limited, lipids are used preferentially for energy production.
Lipogenic activity is switched off and lipolytic mechanisms in adipose tissue
increase through changes in the expression of several key enzymes. This results
in a loss of body condition, together with high circulating concentrations of
non-esterified fatty acids. Changes in the synthesis, secretion and signalling
pathways of somatotrophic hormones (insulin, growth hormone, insulin-like growth
factor 1) and adipokines (e.g. leptin) are central to the regulation of these
processes. A high reliance on fatty acids as an energy source in the peripartum
period causes oxidative damage to mitochondria in metabolically active tissues,
including the liver and reproductive tract. The expression of genes involved in
insulin resistance (PDK4, AHSG) is increased, together with expression of TIEG1,
a transcription factor that can induce apoptosis via the mitochondrial pathway.
Polymorphisms in TFAM and UCP2, two autosomal mitochondrial genes, have been
associated with longevity in dairy cows. Polymorphisms in many other genes that
affect lipid metabolism also show some associations with fertility traits. These
include DGAT1, SCD1, DECR1, CRH, CBFA2T1, GH, LEP and NPY. Excess lipid
accumulation in oocytes and the regenerating endometrium reduces fertility via
reductions in embryo survival and increased inflammatory changes, respectively.
DOI: 10.1071/RD12272
PMID: 23244828 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17545159 | 1. J Biol Chem. 2007 Aug 3;282(31):22977-83. doi: 10.1074/jbc.M700679200. Epub
2007 Jun 1.
Mitochondrial fission and fusion mediators, hFis1 and OPA1, modulate cellular
senescence.
Lee S(1), Jeong SY, Lim WC, Kim S, Park YY, Sun X, Youle RJ, Cho H.
Author information:
(1)Department of Biochemistry, Ajou University School of Medicine, Ajou
University, 5 Wonchon-dong, Yeongtong-gu, Suwon 443-721, Korea.
The number and morphology of mitochondria within a cell are precisely regulated
by the mitochondrial fission and fusion machinery. The human protein, hFis1,
participates in mitochondrial fission by recruiting the Drp1 into the
mitochondria. Using short hairpin RNA, we reduced the expression levels of hFis1
in mammalian cells. Cells lacking hFis1 showed sustained elongation of
mitochondria and underwent significant cellular morphological changes, including
enlargement, flattening, and increased cellular granularity. In these cells,
staining for acidic senescence-associated beta-galactosidase activity was
elevated, and the rate of cell proliferation was greatly reduced, indicating
that cells lacking hFis1 undergo senescence-associated phenotypic changes.
Reintroduction of the hFis1 gene into hFis1-depleted cells restored
mitochondrial fragmentation and suppressed senescence-associated
beta-galactosidase activity. Moreover, depletion of both hFis1 and OPA1, a
critical component of mitochondrial fusion, resulted in extensive mitochondrial
fragmentation and markedly rescued cells from senescence-associated phenotypic
changes. Intriguingly, sustained elongation of mitochondria was associated with
decreased mitochondrial membrane potential, increased reactive oxygen species
production, and DNA damage. The data indicate that sustained mitochondrial
elongation induces senescence-associated phenotypic changes that can be
neutralized by mitochondrial fragmentation. Thus, one of the key functions of
mitochondrial fission might be prevention of the sustained extensive
mitochondrial elongation that triggers cellular senescence.
DOI: 10.1074/jbc.M700679200
PMID: 17545159 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12771931 | 1. Br J Cancer. 2003 May 19;88(10):1615-21. doi: 10.1038/sj.bjc.6600961.
Quinazoline-based alpha 1-adrenoceptor antagonists induce prostate cancer cell
apoptosis via TGF-beta signalling and I kappa B alpha induction.
Partin JV(1), Anglin IE, Kyprianou N.
Author information:
(1)Division of Urology, Department of Surgery, University of Kentucky Medical
Center, Lexington, KY 40536, USA.
Previous studies documented the ability of quinazoline-based alpha1-adrenoceptor
antagonists to induce apoptosis in prostate cancer cells via an alpha
1-adrenoceptor-independent mechanism. In this study we investigated the
molecular events initiating this apoptotic effect. Since transforming growth
factor-beta 1 (TGF-beta 1) mediates prostate epithelial cell apoptosis, we
hypothesised that the activation of the TGF-beta 1 pathway underlies the
quinazoline-based apoptotic effect in prostate cancer cells. Treatment of the
androgen-independent human prostate cancer cells PC-3 with doxazosin resulted in
a strong caspase-3 activation within 24 h, whereas tamsulosin, a
sulphonamide-based alpha 1-adrenoceptor antagonist, had no significant apoptotic
effect against prostate cancer cells. To identify the molecular components
involved in this quinazoline-mediated apoptosis, cDNA microarray analysis of
PC-3 prostate cancer cells treated with doxazosin (3 h) was performed. Induced
expression of several genes was observed including p21(WAF-1) and I kappa B
alpha (inhibitor of NF-kappa B alpha). Relative quantitative reverse
transcription-polymerase chain reaction analysis revealed induction of several
TGF-beta1 signalling effectors: Induction of mRNA for Smad4 and the
TGF-beta1-regulated apoptosis-inducing transcription factor TGF-beta1-inducible
early gene (TIEG1) was detected within the first 6 h of doxazosin treatment.
Upregulation of I kappa B alpha at both the mRNA and protein level was also
detected after 6 h of treatment. Furthermore, doxazosin resulted in a
considerable elevation in Smad4 and TIEG protein expression (6 h). A 'latent'
increase in TGF-beta mRNA expression was detected after 48 h of treatment. These
findings suggest that the quinazoline-based doxazosin mediates prostate cancer
apoptosis by initially inducing the expression of TGF-beta1 signalling effectors
and subsequently I kappa B alpha. The present study provides an initial insight
into the molecular targets of the apoptotic action of quinazolines against
prostate cancer cells.
DOI: 10.1038/sj.bjc.6600961
PMCID: PMC2377124
PMID: 12771931 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20201061 | 1. Anat Rec (Hoboken). 2010 May;293(5):858-64. doi: 10.1002/ar.21108.
Dynamic transcriptional changes of TIEG1 and TIEG2 during mouse tissue
development.
Jiang L(1), Chen Y, Chan CY, Lu G, Wang H, Li JC, Kung HF.
Author information:
(1)Institute of Cell Biology, Zhejiang University, Hangzhou, People's Republic
of China.
TGF-beta-inducible early-response gene (TIEG) is a family of primary response
genes induced by TGF-beta, which are well recognized in regulating cellular
proliferation and apoptosis. However, their expression profile has never been
investigated during embryogenesis in different organs. In this study, we aimed
to investigate the transcriptional level of both TIEG1 and TIEG2 during
development in various mice organs, including the brain cortex, cerebellum and
stem, brain striatum, muscle, heart, liver, kidney, and lung. Quantitative
real-time PCR was used to profile the change of transcriptional level of the two
TIEG members in the mice tissues at six developmental stages. Taken together,
the expression of TIEG1 and TIEG2 was specific in different organs yet varied
with different developmental time points. Their dynamic changes were moderately
consistent in most organs including the brain cortex, striatum, liver, kidney,
and lung. However, their mRNA expression in both the heart and muscle was
significantly different at all developmental stages, which might propose a
compensation of functions in the TIEG family. Nevertheless, our data indicate
that both the TIEG genes are essential in regulating the normal organ
development and functioning in murine model, as their expressions were
ubiquitous and tissue specific at various developmental stages.
DOI: 10.1002/ar.21108
PMID: 20201061 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17709430 | 1. J Cell Biol. 2007 Aug 27;178(5):757-64. doi: 10.1083/jcb.200704112. Epub 2007
Aug 20.
Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic
cleavage.
Griparic L(1), Kanazawa T, van der Bliek AM.
Author information:
(1)Department of Biological Chemistry, David Geffen School of Medicine,
University of California, Los Angeles, Los Angeles, CA 90095, USA.
The dynamin-related protein Opa1 is localized to the mitochondrial intermembrane
space, where it facilitates fusion between mitochondria. Apoptosis causes Opa1
release into the cytosol and causes mitochondria to fragment. Loss of
mitochondrial membrane potential also causes mitochondrial fragmentation but not
Opa1 release into the cytosol. Both conditions induce the proteolytic cleavage
of Opa1, suggesting that mitochondrial fragmentation is triggered by Opa1
inactivation. The opposite effect was observed with knockdown of the
mitochondrial intermembrane space protease Yme1. Knockdown of Yme1 prevents the
constitutive cleavage of a subset of Opa1 splice variants but does not affect
carbonyl cyanide m-chlorophenyl hydrazone or apoptosis-induced cleavage.
Knockdown of Yme1 also increases mitochondrial connectivity, but this effect is
independent of Opa1 because it also occurs in Opa1 knockdown cells. We conclude
that Yme1 constitutively regulates a subset of Opa1 isoforms and an unknown
mitochondrial morphology protein, whereas the loss of membrane potential induces
the further proteolysis of Opa1.
DOI: 10.1083/jcb.200704112
PMCID: PMC2064541
PMID: 17709430 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18281461 | 1. Genes Dev. 2008 Feb 15;22(4):476-88. doi: 10.1101/gad.460708.
Prohibitins control cell proliferation and apoptosis by regulating
OPA1-dependent cristae morphogenesis in mitochondria.
Merkwirth C(1), Dargazanli S, Tatsuta T, Geimer S, Löwer B, Wunderlich FT, von
Kleist-Retzow JC, Waisman A, Westermann B, Langer T.
Author information:
(1)Institute for Genetics, Centre for Molecular Medicine, University of Cologne,
50674 Cologne, Germany.
Comment in
Curr Biol. 2017 Jan 23;27(2):R73-R76. doi: 10.1016/j.cub.2016.11.055.
Prohibitins comprise an evolutionarily conserved and ubiquitously expressed
family of membrane proteins with poorly described functions. Large assemblies of
PHB1 and PHB2 subunits are localized in the inner membrane of mitochondria, but
various roles in other cellular compartments have also been proposed for both
proteins. Here, we used conditional gene targeting of murine Phb2 to define
cellular activities of prohibitins. Our experiments restrict the function of
prohibitins to mitochondria and identify the processing of the dynamin-like
GTPase OPA1, an essential component of the mitochondrial fusion machinery, as
the central cellular process controlled by prohibitins. Deletion of Phb2 leads
to the selective loss of long isoforms of OPA1. This results in an aberrant
cristae morphogenesis and an impaired cellular proliferation and resistance
toward apoptosis. Expression of a long OPA1 isoform in PHB2-deficient cells
suppresses these defects, identifying impaired OPA1 processing as the primary
cellular defect in the absence of prohibitins. Our results therefore assign an
essential function for the formation of mitochondrial cristae to prohibitins and
suggest a coupling of cell proliferation to mitochondrial morphogenesis.
DOI: 10.1101/gad.460708
PMCID: PMC2238669
PMID: 18281461 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15028779 | 1. J Neurosci. 2004 Mar 17;24(11):2846-51. doi: 10.1523/JNEUROSCI.5147-03.2004.
Organic cation transporter 3 (Slc22a3) is implicated in salt-intake regulation.
Vialou V(1), Amphoux A, Zwart R, Giros B, Gautron S.
Author information:
(1)Institut National de la Santé et de la Recherche Médicale U513, Faculté de
Médecine, 94010 Créteil, France.
Organic cation transporters (OCTs) are carrier-type permeases known to
participate in general detoxification functions in peripheral tissues. Previous
in vitro studies have suggested that OCTs ensure Uptake2, a low-affinity,
corticosteroid-sensitive catecholamine removal system, which was characterized
initially in sympathetically innervated tissues. Although the presence of both
Uptake(2)-like transport and most OCT subtypes has also been demonstrated in the
brain, the physiological role of this family of transporters in CNS remained
totally unknown. In the present work, we show that the OCT3 transporter is found
throughout the brain and highly expressed in regions regulating fluid exchange,
including circumventricular organs such as area postrema and subfornical organ
(SFO), and in other structures implicated in the sensing of changes in blood
osmolarity and regulation of salt and water ingestion. OCT3/Slc22a3-deficient
mice show an increase in the level of ingestion of hypertonic saline under
thirst and salt appetite conditions, as well as alterations of the neural
response in the SFO after sodium deprivation, as monitored by Fos
immunoreactivity. This work demonstrates that the presence of OCT3 is critical
for the balanced neural and behavioral responses to environmentally induced
variations in osmolarity and provides for the first time physiological evidence
of the importance of OCTs for CNS function.
DOI: 10.1523/JNEUROSCI.5147-03.2004
PMCID: PMC6729503
PMID: 15028779 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21983901 | 1. EMBO J. 2011 Oct 7;30(21):4371-86. doi: 10.1038/emboj.2011.365.
Optic atrophy 1 is an A-kinase anchoring protein on lipid droplets that mediates
adrenergic control of lipolysis.
Pidoux G(1), Witczak O, Jarnæss E, Myrvold L, Urlaub H, Stokka AJ, Küntziger T,
Taskén K.
Author information:
(1)Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of
Oslo, Oslo, Norway.
Comment in
EMBO J. 2011 Nov 02;30(21):4337-9. doi: 10.1038/emboj.2011.371.
Adrenergic stimulation of adipocytes yields a cAMP signal that activates protein
kinase A (PKA). PKA phosphorylates perilipin, a protein localized on the surface
of lipid droplets that serves as a gatekeeper to regulate access of lipases
converting stored triglycerides to free fatty acids and glycerol in a
phosphorylation-dependent manner. Here, we report a new function for optic
atrophy 1 (OPA1), a protein known to regulate mitochondrial dynamics, as a
dual-specificity A-kinase anchoring protein associated with lipid droplets. By a
variety of protein interaction assays, immunoprecipitation and
immunolocalization experiments, we show that OPA1 organizes a supramolecular
complex containing both PKA and perilipin. Furthermore, by a combination of
siRNA-mediated knockdown, reconstitution experiments using full-length OPA1 with
or without the ability to bind PKA or truncated OPA1 fused to a lipid droplet
targeting domain and cellular delivery of PKA anchoring disruptor peptides, we
demonstrate that OPA1 targeting of PKA to lipid droplets is necessary for
hormonal control of perilipin phosphorylation and lipolysis.
DOI: 10.1038/emboj.2011.365
PMCID: PMC3230380
PMID: 21983901 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/20569065 | 1. Clin Infect Dis. 2010 Aug 1;51(3):322-5. doi: 10.1086/653945.
Multilocus outbreak of foodborne botulism linked to contaminated sausage in
Hebei province, China.
Zhang S(1), Wang Y, Qiu S, Dong Y, Xu Y, Jiang D, Fu X, Zhang J, He J, Jia L,
Wang L, Zhang C, Sun Y, Song H.
Author information:
(1)National Institute for Communicable Diseases Prevention and Control, Chinese
Center for Disease Control and Prevention, China.
In 2007, an outbreak of foodborne botulism occurred in Hebei province, China. An
epidemiological investigation and laboratory detection studies showed that
sausage contaminated by type A Clostridium botulinum caused this outbreak of
food poisoning. Its clinical and epidemiological features were different from
previous reports of food poisoning.
DOI: 10.1086/653945
PMID: 20569065 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17659279 | 1. FEBS Lett. 2007 Aug 7;581(20):3826-32. doi: 10.1016/j.febslet.2007.07.008.
Epub 2007 Jul 16.
TIEG1 induces apoptosis through mitochondrial apoptotic pathway and promotes
apoptosis induced by homoharringtonine and velcade.
Jin W(1), Di G, Li J, Chen Y, Li W, Wu J, Cheng T, Yao M, Shao Z.
Author information:
(1)Breast Cancer Institute, Cancer Hospital/Cancer Institute, Department of
Oncology, Institute of Biomedical Science, Fudan University, Shanghai 200032,
China.
Overexpression of TGFbeta inducible early gene (TIEG1) mimics TGFbeta action and
induces apoptosis. In this study, we found that TIEG1 was significantly
up-regulated during apoptosis induced by homoharringtonine or velcade.
Overexpression of TIEG1 could induce apoptosis in K562 cells and promote
apoptosis induced by HHT or velcade. TIEG1-induced apoptosis was shown to
involve Bax and Bim up-regulation, Bcl-2 and Bcl-XL down-regulation, release of
cytochrome c from mitochondria into the cytosol, activation of caspase 3 and
disruption of the mitochondrial membrane potential (DeltaPsim). We concluded
that TIEG1 is a key regulator which induces and promotes apoptosis through the
mitochondrial apoptotic pathway.
DOI: 10.1016/j.febslet.2007.07.008
PMID: 17659279 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20691807 | 1. Int J Biochem Cell Biol. 2010 Nov;42(11):1831-9. doi:
10.1016/j.biocel.2010.07.019. Epub 2010 Aug 6.
The human papillomavirus-16 (HPV-16) oncoprotein E7 conjugates with and mediates
the role of the transforming growth factor-beta inducible early gene 1 (TIEG1)
in apoptosis.
Chang HS(1), Lin CH, Yang CH, Liang YJ, Yu WC.
Author information:
(1)Department of Life Sciences, College of Bioscience and Biotechnology,
National Cheng Kung University, Taiwan, ROC. [email protected]
The human papillomavirus (HPV) oncoprotein E7 is a major transforming protein.
The E7 protein does not possess intrinsic enzymatic activity, but rather
functions through direct and indirect interactions with cellular proteins,
several of which are well known cellular tumor suppressors. Using the yeast
two-hybrid system, we found that transforming growth factor-beta inducible early
gene 1 (TIEG1), a member of the Krüppel-like family (KLF) that has been
implicated as a putative tumor suppressor, interacts and forms a specific
complex with HPV-16 E7. TIEG1 has been shown to mimic the effects of TGF-beta in
various carcinoma cells and plays a critical role in the apoptotic cascade. Our
results indicate that E7 binds to the C-terminus of TIEG1 and induces its
degradation via the ubiquitin pathway. E7 not only increased the ubiquitination
of TIEG1 but also influenced the ability of TIEG1 to affect apoptosis. Our
results suggest that suppression of TIEG1-mediated signaling by E7 may
contribute to HPV-associated carcinogenesis.
Copyright © 2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.biocel.2010.07.019
PMID: 20691807 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19837207 | 1. J Psychosom Res. 2009 Nov;67(5):443-8. doi: 10.1016/j.jpsychores.2009.01.013.
Epub 2009 Feb 28.
Group psychotherapy: an additional approach to burning mouth syndrome.
Miziara ID(1), Filho BC, Oliveira R, Rodrigues dos Santos RM.
Author information:
(1)Division of Otorhinolaryngology, University Hospital of the Faculty
ofMedicine, University of São Paulo, São Paulo - SP - Brazil. [email protected]
INTRODUCTION: Glossodynia or burning mouth syndrome (BMS) is a common and poorly
understood disorder. Its treatment is uncertain. Otherwise, there is some
evidence of the importance of psychological factors in the genesis of this
disease.
OBJECTIVES: Verify the usefulness of group psychotherapy as an adjuvant
therapeutic method in the treatment of BMS. CASUISTICS AND METHODS: The study
group consisted of 64 consecutive patients with a clinical diagnosis of BMS seen
at the Stomatology Outpatient Clinic, ENT Department, Sao Paulo University
Medical School, between May 2002 and May 2007. All the patients were submitted
to physical examination, laboratorial screening tests, psychological assessment
(Crown-Crisp Experimental Inventory), and answered a short form of the McGill
Pain Questionnaire. Only 44 patients who did not show any abnormality in the
protocol exams entered the study. Twenty-four of them underwent group
psychotherapy. Twenty patients received placebo. Chi-square test was applied to
compare the results of treatment with or without psychotherapy.
RESULTS: There were 15 men and 29 women in the study group. Tongue burning was
the main complaint of the patients. Improvement of symptoms was reported by 17
(70.8%) of the patients undergoing psychotherapy, while among those who did not
eight (40%) had improvement of symptoms (P=.04).
CONCLUSION: Psychological assessment demonstrated a close correlation between
symptoms and psychological factors, suggesting that group psychotherapy is an
important alternative to conventional treatment methods.
DOI: 10.1016/j.jpsychores.2009.01.013
PMID: 19837207 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16413305 | 1. Methods Enzymol. 2005;404:620-31. doi: 10.1016/S0076-6879(05)04054-1.
Assay and properties of the mitochondrial dynamin related protein Opa1.
Griparic L(1), van der Bliek AM.
Author information:
(1)Department of Biological Chemistry, David Geffen School of Medicine at
University of California at Los Angeles, USA.
Opa1, also known as Mgm1 in yeast, is a mitochondrial member of the dynamin
family. Unlike other dynamin family members, Opa1 has an N-terminal
mitochondrial targeting sequence, suggesting that this protein is imported into
mitochondria. Here, we describe biochemical techniques, such as mitochondrial
isolation, digitonin extraction, a protease protection assay, and carbonate
extraction, that were used to determine that mammalian Opa1 resides in the
intermembrane space where it is tightly bound to the inner membrane. In
addition, we describe bacterial expression of the Opa1 GTPase domain, methods
for purification, and an in vitro assay for GTP hydrolysis.
DOI: 10.1016/S0076-6879(05)04054-1
PMID: 16413305 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21223496 | 1. Pain Med. 2011 Mar;12(3):466-9. doi: 10.1111/j.1526-4637.2010.01035.x. Epub
2011 Jan 11.
Burning mouth syndrome responsive to duloxetine: a case report.
Mignogna MD(1), Adamo D, Schiavone V, Ravel MG, Fortuna G.
Author information:
(1)Oral Medicine Unit, Department of Odontostomatological and Maxillofacial
Sciences, Federico II University of Naples, Naples, Italy. [email protected]
INTRODUCTION: Burning mouth syndrome (BMS) is a chronic, idiopathic, intraoral
mucosal pain condition in the absence of specific oral lesions and systemic
disease. Among evidence-based pharmacological treatments for this disorder,
topical and systemic clonazepam, levosulpiride, selective serotonin reuptake
inhibitors have been used with partial results.
CASE: We report a case of a 65-year-old otherwise healthy woman with a 3-year
history of oral burning. Clinical and laboratory evaluations allowed us to make
a diagnosis of burning mouth syndrome. She was treated with duloxetine (60 mg
p.o. qd), a selective serotonin, and norepinephrine reuptake inhibitor,
obtaining a complete remission of symptoms, evaluated via standardized clinical
rating scales, and an improvement of her quality of life and level of
functioning.
DISCUSSION: The pathogenesis of BMS still remains unclear. Recently, it has been
suggested an underlying neuropathic mechanism, demonstrating a dysfunction in
the trigeminal nociceptive pathways at peripheral and/or central nervous system
level. The rationale behind the administration of duloxetine resides in its
central mechanism of action, and analgesic effects previously demonstrated in
diabetic peripheral neuropathy, and fibromyalgia. Also, it has been shown to
reduce painful physical symptoms associated with depression.
CONCLUSION: We hypothesize that duloxetine might represent a useful, effective,
and additional therapeutic option in the treatment of BMS.
Wiley Periodicals, Inc.
DOI: 10.1111/j.1526-4637.2010.01035.x
PMID: 21223496 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19168126 | 1. Cell Signal. 2009 May;21(5):767-77. doi: 10.1016/j.cellsig.2009.01.020. Epub
2009 Jan 9.
Regulation of OPA1-mediated mitochondrial fusion by leucine
zipper/EF-hand-containing transmembrane protein-1 plays a role in apoptosis.
Piao L(1), Li Y, Kim SJ, Sohn KC, Yang KJ, Park KA, Byun HS, Won M, Hong J, Hur
GM, Seok JH, Shong M, Sack R, Brazil DP, Hemmings BA, Park J.
Author information:
(1)Department of Pharmacology, Daejeon Regional Cancer Center, Cancer Research
Institute, Research Institute for Medical Sciences, College of Medicine,
Chungnam National University, Taejeon, 301-131, Republic of Korea.
Carboxyl-terminal modulator protein (CTMP) is a tumor suppressor-like binding
partner of Protein kinase B (PKB/Akt) that negative regulates this kinase. In
the course of our recent work, we identified that CTMP is consistently
associated with leucine zipper/EF-hand-containing transmembrane-1 (LETM1). Here,
we report that adenovirus-LETM1 increased the sensitivity of HeLa cells to
apoptosis, induced by either staurosporine or actinomycin D. As shown
previously, LETM1 localized to the inner mitochondrial membrane.
Electron-microscopy analysis of adenovirus-LETM1 transduced cells revealed that
mitochondrial cristae were swollen in these cells, a phenotype similar to that
observed in optic atrophy type-1 (OPA1)-ablated cells. OPA1 cleavage was
increased in LETM1-overexpressing cells, and this phenotype was reversed by
overexpression of OPA1 variant-7, a cleavage resistant form of OPA1. Taken
together, these data suggest that LETM1 is a novel binding partner for CTMP that
may play an important role in mitochondrial fragmentation via OPA1-cleavage.
DOI: 10.1016/j.cellsig.2009.01.020
PMID: 19168126 [Indexed for MEDLINE] |