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[PMID]: 25083917
[Au] Autor:Nedd S; Redler RL; Proctor EA; Dokholyan NV; Alexandrova AN
[Ad] Address:Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA....
[Ti] Title:Cu,Zn-Superoxide Dismutase without Zn Is Folded but Catalytically Inactive.
[So] Source:J Mol Biol;426(24):4112-24, 2014 Dec 12.
[Is] ISSN:1089-8638
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Amyotrophic lateral sclerosis has been linked to the gain of aberrant function of superoxide dismutase, Cu,Zn-SOD1 upon protein misfolding. The mechanism of SOD1 misfolding is thought to involve mutations leading to the loss of Zn, followed by protein unfolding and aggregation. We show that the removal of Zn from SOD1 may not lead to an immediate unfolding but immediately deactivates the enzyme through a combination of subtle structural and electronic effects. Using quantum mechanics/discrete molecular dynamics, we showed that both Zn-less wild-type (WT)-SOD1 and its D124N mutant that does not bind Zn have at least metastable folded states. In those states, the reduction potential of Cu increases, leading to the presence of detectable amounts of Cu(I) instead of Cu(II) in the active site, as confirmed experimentally. The Cu(I) protein cannot participate in the catalytic Cu(I)-Cu(II) cycle. However, even without the full reduction to Cu(I), the Cu site in the Zn-less variants of SOD1 is shown to be catalytically incompetent: unable to bind superoxide in a way comparable to the WT-SOD1. The changes are more radical and different in the D124N Zn-less mutant than in the Zn-less WT-SOD1, suggesting D124N being perhaps not the most adequate model for Zn-less SOD1. Overall, Zn in SOD1 appears to be influencing the Cu site directly by adjusting its reduction potential and geometry. Thus, the role of Zn in SOD1 is not just structural, as was previously thought; it is a vital part of the catalytic machinery.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1412
[Cu] Class update date: 141206
[Lr] Last revision date:141206
[Js] Journal subset:IM
[St] Status:In-Data-Review

  2 / 180213 MEDLINE  
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[PMID]: 25342717
[Au] Autor:Shah KH; Nostramo R; Zhang B; Varia SN; Klett BM; Herman PK
[Ad] Address:Department of Molecular Genetics, The Ohio State University, Columbus, Ohio 43210....
[Ti] Title:Protein kinases are associated with multiple, distinct cytoplasmic granules in quiescent yeast cells.
[So] Source:Genetics;198(4):1495-512, 2014 Dec.
[Is] ISSN:1943-2631
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The cytoplasm of the eukaryotic cell is subdivided into distinct functional domains by the presence of a variety of membrane-bound organelles. The remaining aqueous space may be further partitioned by the regulated assembly of discrete ribonucleoprotein (RNP) complexes that contain particular proteins and messenger RNAs. These RNP granules are conserved structures whose importance is highlighted by studies linking them to human disorders like amyotrophic lateral sclerosis. However, relatively little is known about the diversity, composition, and physiological roles of these cytoplasmic structures. To begin to address these issues, we examined the cytoplasmic granules formed by a key set of signaling molecules, the protein kinases of the budding yeast Saccharomyces cerevisiae. Interestingly, a significant fraction of these proteins, almost 20%, was recruited to cytoplasmic foci specifically as cells entered into the G0-like quiescent state, stationary phase. Colocalization studies demonstrated that these foci corresponded to eight different granules, including four that had not been reported previously. All of these granules were found to rapidly disassemble upon the resumption of growth, and the presence of each was correlated with cell viability in the quiescent cultures. Finally, this work also identified new constituents of known RNP granules, including the well-characterized processing body and stress granule. The composition of these latter structures is therefore more varied than previously thought and could be an indicator of additional biological activities being associated with these complexes. Altogether, these observations indicate that quiescent yeast cells contain multiple distinct cytoplasmic granules that may make important contributions to their long-term survival.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1412
[Cu] Class update date: 141206
[Lr] Last revision date:141206
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1534/genetics.114.172031

  3 / 180213 MEDLINE  
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[PMID]: 25437209
[Au] Autor:Graham KL; Zhang JV; Lewén S; Burke TM; Dang T; Zoudilova M; Sobel RA; Butcher EC; Zabel BA
[Ad] Address:Palo Alto Veterans Institute for Research and Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America....
[Ti] Title:A Novel CMKLR1 Small Molecule Antagonist Suppresses CNS Autoimmune Inflammatory Disease.
[So] Source:PLoS One;9(12):e112925, 2014.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Therapies that target leukocyte trafficking pathways can reduce disease activity and improve clinical outcomes in multiple sclerosis (MS). Experimental autoimmune encephalomyelitis (EAE) is a widely studied animal model that shares many clinical and histological features with MS. Chemokine-like receptor-1 (CMKLR1) is a chemoattractant receptor that is expressed by key effector cells in EAE and MS, including macrophages, subsets of dendritic cells, natural killer cells and microglia. We previously showed that CMKLR1-deficient (CMKLR1 KO) mice develop less severe clinical and histological EAE than wild-type mice. In this study, we sought to identify CMKLR1 inhibitors that would pharmaceutically recapitulate the CMKLR1 KO phenotype in EAE. We identified 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA) as a CMKLR1 small molecule antagonist that inhibits chemerin-stimulated ß-arrestin2 association with CMKLR1, as well as chemerin-triggered CMKLR1+ cell migration. α-NETA significantly delayed the onset of EAE induced in C57BL/6 mice by both active immunization with myelin oligodendrocyte glycoprotein peptide 35-55 and by adoptive transfer of encephalitogenic T cells. In addition, α-NETA treatment significantly reduced mononuclear cell infiltrates within the CNS. This study provides additional proof-of-concept data that targeting CMKLR1:chemerin interactions may be beneficial in preventing or treating MS.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1412
[Cu] Class update date: 141206
[Lr] Last revision date:141206
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1371/journal.pone.0112925

  4 / 180213 MEDLINE  
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[PMID]: 25436769
[Au] Autor:Llufriu S; Sepúlveda M; Blanco Y; Marín P; Moreno B; Berenguer J; Gabilondo I; Martínez-Heras E; Sola-Valls N; Arnaiz JA; Andreu EJ; Fernández B; Bullich S; Sánchez-Dalmau B; Graus F; Villoslada P; Saiz A
[Ad] Address:Center of Neuroimmunology, Service of Neurology, Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain....
[Ti] Title:Randomized Placebo-Controlled Phase II Trial of Autologous Mesenchymal Stem Cells in Multiple Sclerosis.
[So] Source:PLoS One;9(12):e113936, 2014.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:OBJECTIVE: Uncontrolled studies of mesenchymal stem cells (MSCs) in multiple sclerosis suggested some beneficial effect. In this randomized, double-blind, placebo-controlled, crossover phase II study we investigated their safety and efficacy in relapsing-remitting multiple sclerosis patients. Efficacy was evaluated in terms of cumulative number of gadolinium-enhancing lesions (GEL) on magnetic resonance imaging (MRI) at 6 months and at the end of the study. METHODS: Patients unresponsive to conventional therapy, defined by at least 1 relapse and/or GEL on MRI scan in past 12 months, disease duration 2 to 10 years and Expanded Disability Status Scale (EDSS) 3.0-6.5 were randomized to receive IV 1-2×106 bone-marrow-derived-MSCs/Kg or placebo. After 6 months, the treatment was reversed and patients were followed-up for another 6 months. Secondary endpoints were clinical outcomes (relapses and disability by EDSS and MS Functional Composite), and several brain MRI and optical coherence tomography measures. Immunological tests were explored to assess the immunomodulatory effects. RESULTS: At baseline 9 patients were randomized to receive MSCs (n = 5) or placebo (n = 4). One patient on placebo withdrew after having 3 relapses in the first 5 months. We did not identify any serious adverse events. At 6 months, patients treated with MSCs had a trend to lower mean cumulative number of GEL (3.1, 95% CI = 1.1-8.8 vs 12.3, 95% CI = 4.4-34.5, p = 0.064), and at the end of study to reduced mean GEL (-2.8±5.9 vs 3±5.4, p = 0.075). No significant treatment differences were detected in the secondary endpoints. We observed a non-significant decrease of the frequency of Th1 (CD4+ IFN-γ+) cells in blood of MSCs treated patients. CONCLUSION: Bone-marrow-MSCs are safe and may reduce inflammatory MRI parameters supporting their immunomodulatory properties. ClinicalTrials.gov NCT01228266.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1412
[Cu] Class update date: 141206
[Lr] Last revision date:141206
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1371/journal.pone.0113936

  5 / 180213 MEDLINE  
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[PMID]: 25426719
[Au] Autor:Sulkowski G; Dabrowska-Bouta B; Salinska E; Struzynska L
[Ad] Address:Laboratory of Pathoneurochemistry, Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland....
[Ti] Title:Modulation of Glutamate Transport and Receptor Binding by Glutamate Receptor Antagonists in EAE Rat Brain.
[So] Source:PLoS One;9(11):e113954, 2014.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The etiology of multiple sclerosis (MS) is currently unknown. However, one potential mechanism involved in the disease may be excitotoxicity. The elevation of glutamate in cerebrospinal fluid, as well as changes in the expression of glutamate receptors (iGluRs and mGluRs) and excitatory amino acid transporters (EAATs), have been observed in the brains of MS patients and animals subjected to experimental autoimmune encephalomyelitis (EAE), which is the predominant animal model used to investigate the pathophysiology of MS. In the present paper, the effects of glutamatergic receptor antagonists, including amantadine, memantine, LY 367583, and MPEP, on glutamate transport, the expression of mRNA of glutamate transporters (EAATs), the kinetic parameters of ligand binding to N-methyl-D-aspartate (NMDA) receptors, and the morphology of nerve endings in EAE rat brains were investigated. The extracellular level of glutamate in the brain is primarily regulated by astrocytic glutamate transporter 1 (GLT-1) and glutamate-aspartate transporter (GLAST). Excess glutamate is taken up from the synaptic space and metabolized by astrocytes. Thus, the extracellular level of glutamate decreases, which protects neurons from excitotoxicity. Our investigations showed changes in the expression of EAAT mRNA, glutamate transport (uptake and release) by synaptosomal and glial plasmalemmal vesicle fractions, and ligand binding to NMDA receptors; these effects were partially reversed after the treatment of EAE rats with the NMDA antagonists amantadine and memantine. The antagonists of group I metabotropic glutamate receptors (mGluRs), including LY 367385 and MPEP, did not exert any effect on the examined parameters. These results suggest that disturbances in these mechanisms may play a role in the processes associated with glutamate excitotoxicity and the progressive brain damage in EAE.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1411
[Cu] Class update date: 141206
[Lr] Last revision date:141206
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1371/journal.pone.0113954

  6 / 180213 MEDLINE  
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[PMID]: 25429138
[Au] Autor:Coyne AN; Siddegowda BB; Estes PS; Johannesmeyer J; Kovalik T; Daniel SG; Pearson A; Bowser R; Zarnescu DC
[Ad] Address:Departments of Molecular and Cellular Biology, Neuroscience, and....
[Ti] Title:Futsch/MAP1B mRNA Is a Translational Target of TDP-43 and Is Neuroprotective in a Drosophila Model of Amyotrophic Lateral Sclerosis.
[So] Source:J Neurosci;34(48):15962-74, 2014 Nov 26.
[Is] ISSN:1529-2401
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:TDP-43 is an RNA-binding protein linked to amyotrophic lateral sclerosis (ALS) that is known to regulate the splicing, transport, and storage of specific mRNAs into stress granules. Although TDP-43 has been shown to interact with translation factors, its role in protein synthesis remains unclear, and no in vivo translation targets have been reported to date. Here we provide evidence that TDP-43 associates with futsch mRNA in a complex and regulates its expression at the neuromuscular junction (NMJ) in Drosophila. In the context of TDP-43-induced proteinopathy, there is a significant reduction of futsch mRNA at the NMJ compared with motor neuron cell bodies where we find higher levels of transcript compared with controls. TDP-43 also leads to a significant reduction in Futsch protein expression at the NMJ. Polysome fractionations coupled with quantitative PCR experiments indicate that TDP-43 leads to a futsch mRNA shift from actively translating polysomes to nontranslating ribonuclear protein particles, suggesting that in addition to its effect on localization, TDP-43 also regulates the translation of futsch mRNA. We also show that futsch overexpression is neuroprotective by extending life span, reducing TDP-43 aggregation, and suppressing ALS-like locomotor dysfunction as well as NMJ abnormalities linked to microtubule and synaptic stabilization. Furthermore, the localization of MAP1B, the mammalian homolog of Futsch, is altered in ALS spinal cords in a manner similar to our observations in Drosophila motor neurons. Together, our results suggest a microtubule-dependent mechanism in motor neuron disease caused by TDP-43-dependent alterations in futsch mRNA localization and translation in vivo.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1411
[Cu] Class update date: 141206
[Lr] Last revision date:141206
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1523/JNEUROSCI.2526-14.2014

  7 / 180213 MEDLINE  
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[PMID]: 25422930
[Au] Autor:Tsao WC; Lyu RK; Ro LS; Lao MF; Chen CM; Wu YR; Huang CC; Chang HS; Kuo HC; Chu CC; Chang KH
[Ad] Address:Department of Neurology, Chang Gung Memorial Hospital-Linkou Medical Center, Chang Gung University College of Medicine, Taoyuan, Taiwan; Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan....
[Ti] Title:Clinical correlations of motor and somatosensory evoked potentials in neuromyelitis optica.
[So] Source:PLoS One;9(11):e113631, 2014.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUND: Motor and somatosensory evoked potentials (MEPs and SSEPs) are sensitive tools for detecting subclinical lesions, assessing disease severity, and determining the prognosis for outcomes of patients with inflammatory neurological diseases such as multiple sclerosis. However, their roles in neuromyelitis optica (NMO), a severe inflammatory neurological disease that predominantly involves optic nerves and spinal cord, have not yet been clarified. METHODS AND FINDINGS: Clinical symptoms and examination findings at relapses of 30 NMO patients were retrospectively reviewed. Abnormal MEPs were observed in 69.2% of patients. Patients with abnormal motor central conduction time (CCT) of the lower limbs had higher Kurtzke Expanded Disability Status Scale (EDSS) scores than those with normal responses (P = 0.027). Abnormal SSEPs were found in 69.0% of patients. Patients with abnormal lower limb sensory CCT had higher EDSS scores than those with normal responses (P = 0.019). In 28 patients followed up more than 6 months, only one of 11 patients (9.1%) with normal SSEPs of the lower limbs had new relapses within 6 months, whereas 8 of 17 patients (47.1%, P = 0.049) with abnormal SSEPs of the lower limbs had new relapses. CONCLUSIONS: These results indicate MEPs and SSEPs of the lower limbs are good indicators for the disability status at relapses of NMO. Lower limb SSEPs may be a good tool for reflecting the frequency of relapses of NMO.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1411
[Cu] Class update date: 141206
[Lr] Last revision date:141206
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1371/journal.pone.0113631

  8 / 180213 MEDLINE  
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[PMID]: 25108040
[Au] Autor:Ash PE; Vanderweyde TE; Youmans KL; Apicco DJ; Wolozin B
[Ad] Address:Depts. of Pharmacology and Neurology, Boston University School of Medicine, Boston, MA 02118, United States....
[Ti] Title:Pathological stress granules in Alzheimer's disease.
[So] Source:Brain Res;1584:52-8, 2014 Oct 10.
[Is] ISSN:1872-6240
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:A feature of neurodegenerative disease is the accumulation of insoluble protein aggregates in the brain. In some conditions, including Amyotrophic Lateral Sclerosis and Frontotemporal lobar degeneration, the primary aggregating entities are RNA binding proteins. Through regulated prion-like assembly, RNA binding proteins serve many functions in RNA metabolism that are essential for the healthy maintenance of cells of the central nervous system. Those RNA binding proteins that are the core nucleating factors of stress granules (SGs), including TIA-1, TIAR, TTP and G3BP1, are also found in the pathological lesions of other neurological conditions, such as Alzheimer's disease, where the hallmark aggregating protein is not an RNA binding protein. This discovery suggests that the regulated cellular pathway, which utilizes assembly of RNA binding proteins to package and silence mRNAs during stress, may be integral in the aberrant pathological protein aggregation that occurs in numerous neurodegenerative conditions.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1409
[Cu] Class update date: 141206
[Lr] Last revision date:141206
[Js] Journal subset:IM
[St] Status:In-Process

  9 / 180213 MEDLINE  
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[PMID]: 25216440
[Au] Autor:Dimitroulis D; Patsouras D; Katsargyris A; Charalampoudis P; Anastasiou I; Kouraklis G
[Ad] Address:2nd Propedeutic Department of Surgery, Athens University Medical School, Laikon Hospital Athens, Greece.
[Ti] Title:Primary enteric-type mucinous adenocarcinoma of the urethra in a patient with ulcerative colitis.
[So] Source:Int Surg;99(5):669-72, 2014 Sep-Oct.
[Is] ISSN:0020-8868
[Cp] Country of publication:Italy
[La] Language:eng
[Ab] Abstract:Abstract Primary carcinoma of the male urethra accounts for less than 1% of malignancies in men. Mucinous adenocarcinoma of the urethra is extremely rare, and its biologic behavior is poorly understood. We present herein a rare case of mucinous urethral adenocarcinoma in a male patient with longstanding ulcerative colitis and multiple sclerosis. The patient presented with a voluminous pelvic mass; core biopsy of the lesion demonstrated a mucus-producing adenocarcinoma. Given the patient's history of subtotal colectomy, preoperative diagnosis was oriented towards a rectal stump adenocarcinoma. The patient underwent a pelvic exenteration: surprisingly, histology marked the prostatic urethra as the primary lesion site.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1409
[Cu] Class update date: 141206
[Lr] Last revision date:141206
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.9738/INTSURG-D-13-00073.1

  10 / 180213 MEDLINE  
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[PMID]: 25446164
[Au] Autor:Kundu D; Abraham D; Black CM; Denton CP; Bruckdorfer KR
[Ad] Address:Centre for Rheumatology and Connective Tissue Diseases, UCL Medical School, London NW3 2PF, UK. Electronic address: Devi.Kundu@ucl.ac.uk....
[Ti] Title:Reduced levels of S-nitrosothiols in plasma of patients with systemic sclerosis and Raynaud's phenomenon.
[So] Source:Vascul Pharmacol;63(3):178-81, 2014 Dec.
[Is] ISSN:1879-3649
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:OBJECTIVE: S-Nitrosothiols (RSNOs) are bioactive forms of nitric oxide which are involved in cell signalling and redox regulation of vascular function. Circulating S-nitrosothiols are predominantly in the form of S-nitrosoalbumin. In this study plasma concentrations of S-nitrosothiols were measured in patients with systemic sclerosis (SSc) where NO metabolism is known to be abnormal. PATIENTS AND METHODS: Venous blood was collected from 16 patients with Raynaud's phenomenon (RP), 45 with systemic sclerosis (SSc) (34 patients had limited SSc (IcSSc) and 11 diffuse cutaneous disease (dcSSc)). Twenty six healthy subjects were used as controls. Plasma S-nitrosothiol concentrations were measured by chemiluminescence. The measurements were related to the extent of biological age, capillary/skin scores and disease duration. RESULTS: Plasma RSNO levels in patients with Raynaud's phenomenon (RP) and in those with SSc was significantly lower compared to the concentrations in control subjects. In SSc, plasma S-nitrosothiols were often below the level of detection (1nM). CONCLUSIONS: Low S-nitrosothiol concentrations were observed in the blood of patients with SSc and patients with RP indicating a profound disturbance of nitric oxide metabolism.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1412
[Js] Journal subset:IM
[St] Status:In-Data-Review


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