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Author Lacovich, V.; Espindola, S.L.; Alloatti, M.; Pozo Devoto, V.; Cromberg, L.E.; Carna, M.E.; Forte, G.; Gallo, J.-M.; Bruno, L.; Stokin, G.B.; Avale, M.E.; Falzone, T.L.
Title Tau Isoforms Imbalance Impairs the Axonal Transport of the Amyloid Precursor Protein in Human Neurons Type Journal Article
Year 2017 Publication The Journal of Neuroscience : the Official Journal of the Society for Neuroscience Abbreviated Journal J Neurosci
Volume 37 Issue 1 Pages 58-69
Keywords App; Alzheimer's; axonal transport; splicing; tau; tauopathies
Abstract (down) Tau, as a microtubule (MT)-associated protein, participates in key neuronal functions such as the regulation of MT dynamics, axonal transport, and neurite outgrowth. Alternative splicing of exon 10 in the tau primary transcript gives rise to protein isoforms with three (3R) or four (4R) MT binding repeats. Although tau isoforms are balanced in the normal adult human brain, imbalances in 3R:4R ratio have been tightly associated with the pathogenesis of several neurodegenerative disorders, yet the underlying molecular mechanisms remain elusive. Several studies exploiting tau overexpression and/or mutations suggested that perturbations in tau metabolism impair axonal transport. Nevertheless, no physiological model has yet demonstrated the consequences of altering the endogenous relative content of tau isoforms over axonal transport regulation. Here, we addressed this issue using a trans-splicing strategy that allows modulating tau exon 10 inclusion/exclusion in differentiated human-derived neurons. Upon changes in 3R:4R tau relative content, neurons showed no morphological changes, but live imaging studies revealed that the dynamics of the amyloid precursor protein (APP) were significantly impaired. Single trajectory analyses of the moving vesicles showed that predominance of 3R tau favored the anterograde movement of APP vesicles, increasing anterograde run lengths and reducing retrograde runs and segmental velocities. Conversely, the imbalance toward the 4R isoform promoted a retrograde bias by a significant reduction of anterograde velocities. These findings suggest that changes in 3R:4R tau ratio has an impact on the regulation of axonal transport and specifically in APP dynamics, which might link tau isoform imbalances with APP abnormal metabolism in neurodegenerative processes. SIGNIFICANCE STATEMENT: The tau protein has a relevant role in the transport of cargos throughout neurons. Dysfunction in tau metabolism underlies several neurological disorders leading to dementia. In the adult human brain, two tau isoforms are found in equal amounts, whereas changes in such equilibrium have been associated with neurodegenerative diseases. We investigated the role of tau in human neurons in culture and found that perturbations in the endogenous balance of tau isoforms were sufficient to impair the transport of the Alzheimer's disease-related amyloid precursor protein (APP), although neuronal morphology was normal. Our results provide evidence of a direct relationship between tau isoform imbalance and defects in axonal transport, which induce an abnormal APP metabolism with important implications in neurodegeneration.
Address Instituto de Biologia y Medicina Experimental (IBYME-CONICET), Buenos Aires C1428ADN, Argentina
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0270-6474 ISBN Medium
Area Expedition Conference
Notes PMID:28053030 Approved no
Call Number ref @ user @ Serial 95902
Permanent link to this record
 

 
Author Mihu, M.R.; Cabral, V.; Pattabhi, R.; Tar, M.T.; Davies, K.P.; Friedman, A.J.; Martinez, L.R.; Nosanchuk, J.D.
Title Sustained Nitric Oxide-Releasing Nanoparticles Interfere with Methicillin-Resistant Staphylococcus aureus Adhesion and Biofilm Formation in a Rat Central Venous Catheter Model Type Journal Article
Year 2017 Publication Antimicrobial Agents and Chemotherapy Abbreviated Journal Antimicrob Agents Chemother
Volume 61 Issue 1 Pages
Keywords Animals; Anti-Bacterial Agents/chemistry/*pharmacology; Bacterial Adhesion/drug effects; Biofilms/*drug effects/growth & development; Catheter-Related Infections/*drug therapy/microbiology; Central Venous Catheters; Chitosan/chemistry/pharmacology; Delayed-Action Preparations; Disease Models, Animal; Female; Glucose/chemistry; Humans; Methicillin-Resistant Staphylococcus aureus/*drug effects/growth & development/ultrastructure; Nanoparticles/*administration & dosage/chemistry; Nitric Oxide/chemical synthesis/*pharmacology; Oxidation-Reduction; Plankton/drug effects/growth & development; Rats; Rats, Sprague-Dawley; Sodium Nitrite/chemistry; Staphylococcal Infections/*drug therapy/microbiology; Staphylococcus aureus; antimicrobials; biofilms; nanoparticles; nitric oxide
Abstract (down) Staphylococcus aureus is frequently isolated in the setting of infections of indwelling medical devices, which are mediated by the microbe's ability to form biofilms on a variety of surfaces. Biofilm-embedded bacteria are more resistant to antimicrobial agents than their planktonic counterparts and often cause chronic infections and sepsis, particularly in patients with prolonged hospitalizations. In this study, we demonstrate that sustained nitric oxide-releasing nanoparticles (NO-np) interfere with S. aureus adhesion and prevent biofilm formation on a rat central venous catheter (CVC) model of infection. Confocal and scanning electron microscopy showed that NO-np-treated staphylococcal biofilms displayed considerably reduced thicknesses and bacterial numbers compared to those of control biofilms in vitro and in vivo, respectively. Although both phenotypes, planktonic and biofilm-associated staphylococci, of multiple clinical strains were susceptible to NO-np, bacteria within biofilms were more resistant to killing than their planktonic counterparts. Furthermore, chitosan, a biopolymer found in the exoskeleton of crustaceans and structurally integrated into the nanoparticles, seems to add considerable antimicrobial activity to the technology. Our findings suggest promising development and translational potential of NO-np for use as a prophylactic or therapeutic against bacterial biofilms on CVCs and other medical devices.
Address Department of Microbiology and Immunology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0066-4804 ISBN Medium
Area Expedition Conference
Notes PMID:27821454 Approved no
Call Number ref @ user @ Serial 99131
Permanent link to this record
 

 
Author Mihu, M.R.; Cabral, V.; Pattabhi, R.; Tar, M.T.; Davies, K.P.; Friedman, A.J.; Martinez, L.R.; Nosanchuk, J.D.
Title Sustained Nitric Oxide-Releasing Nanoparticles Interfere with Methicillin-Resistant Staphylococcus aureus Adhesion and Biofilm Formation in a Rat Central Venous Catheter Model Type Journal Article
Year 2017 Publication Antimicrobial Agents and Chemotherapy Abbreviated Journal Antimicrob Agents Chemother
Volume 61 Issue 1 Pages
Keywords Animals; Anti-Bacterial Agents/chemistry/*pharmacology; Bacterial Adhesion/drug effects; Biofilms/*drug effects/growth & development; Catheter-Related Infections/*drug therapy/microbiology; Central Venous Catheters; Chitosan/chemistry/pharmacology; Delayed-Action Preparations; Disease Models, Animal; Female; Glucose/chemistry; Humans; Methicillin-Resistant Staphylococcus aureus/*drug effects/growth & development/ultrastructure; Nanoparticles/*administration & dosage/chemistry; Nitric Oxide/chemical synthesis/*pharmacology; Oxidation-Reduction; Plankton/drug effects/growth & development; Rats; Rats, Sprague-Dawley; Sodium Nitrite/chemistry; Staphylococcal Infections/*drug therapy/microbiology; Staphylococcus aureus; antimicrobials; biofilms; nanoparticles; nitric oxide
Abstract (down) Staphylococcus aureus is frequently isolated in the setting of infections of indwelling medical devices, which are mediated by the microbe's ability to form biofilms on a variety of surfaces. Biofilm-embedded bacteria are more resistant to antimicrobial agents than their planktonic counterparts and often cause chronic infections and sepsis, particularly in patients with prolonged hospitalizations. In this study, we demonstrate that sustained nitric oxide-releasing nanoparticles (NO-np) interfere with S. aureus adhesion and prevent biofilm formation on a rat central venous catheter (CVC) model of infection. Confocal and scanning electron microscopy showed that NO-np-treated staphylococcal biofilms displayed considerably reduced thicknesses and bacterial numbers compared to those of control biofilms in vitro and in vivo, respectively. Although both phenotypes, planktonic and biofilm-associated staphylococci, of multiple clinical strains were susceptible to NO-np, bacteria within biofilms were more resistant to killing than their planktonic counterparts. Furthermore, chitosan, a biopolymer found in the exoskeleton of crustaceans and structurally integrated into the nanoparticles, seems to add considerable antimicrobial activity to the technology. Our findings suggest promising development and translational potential of NO-np for use as a prophylactic or therapeutic against bacterial biofilms on CVCs and other medical devices.
Address Department of Microbiology and Immunology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0066-4804 ISBN Medium
Area Expedition Conference
Notes PMID:27821454 Approved no
Call Number ref @ user @ Serial 100161
Permanent link to this record
 

 
Author Klumpp, L.; Sezgin, E.C.; Skardelly, M.; Eckert, F.; Huber, S.M.
Title KCa3.1 channels and glioblastoma: in vitro studies Type Journal Article
Year 2017 Publication Current Neuropharmacology Abbreviated Journal Curr Neuropharmacol
Volume Issue Pages
Keywords γH2AX foci; Aldh1a3; Gbm; GSCs; IKCa; Kcnn4; Sk4; radioresistance
Abstract (down) Several tumor entities including brain tumors aberrantly overexpress intermediate conductance Ca2+ activated KCa3.1 K+ channels. These channels contribute significantly to the transformed phenotype of the tumor cells. By modulating membrane potential, cell volume, Ca2+ signals and the respiration chain, KCa3.1 channels in both, plasma and inner mitochondrial membrane, have been demonstrated to regulate many cellular processes such as migration and tissue invasion, metastasis, cell cycle progression, oxygen consumption and metabolism, DNA damage response and cell death of cancer cells. Moreover, KCa3.1 channels have been shown to crucially contribute to resistance against radiotherapy suggesting KCa3.1 channels as promising new targets of future anti-cancer therapies. The present article summarizes our current knowledge of the molecular signaling upstream and downstream and the effector functions of KCa3.1 channel activity in tumor cells in general and in glioblastoma cells in particular. In addition, it presents original in vitro data on KCa3.1 channel expression in subtypes of glioblastoma stem(-like) cells proposing KCa3.1 as marker for the mesenchymal subgroup of cancer stem cells. Moreover, the data suggest that KCa3.1 contributes to the therapy resistance of mesenchymal glioblastoma stem cells.
Address Department of Radiation Oncology University of Tubingen Hoppe-Seyler-Str. 3 72076 Tubingen. Germany
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 1570-159X ISBN Medium
Area Expedition Conference
Notes PMID:28786347 Approved no
Call Number ref @ user @ Serial 96571
Permanent link to this record
 

 
Author Roy, A.; Attarha, S.; Weishaupt, H.; Edqvist, P.-H.; Swartling, F.J.; Bergqvist, M.; Siebzehnrubl, F.A.; Smits, A.; Ponten, F.; Tchougounova, E.
Title Serglycin as a potential biomarker for glioma: association of serglycin expression, extent of mast cell recruitment and glioblastoma progression Type Journal Article
Year 2017 Publication Oncotarget Abbreviated Journal Oncotarget
Volume 8 Issue 15 Pages 24815-24827
Keywords Cd44; Zeb1; glioma; mast cell; serglycin
Abstract (down) Serglycin is an intracellular proteoglycan with a unique ability to adopt highly divergent structures by glycosylation with variable types of glycosaminoglycans (GAGs) when expressed by different cell types. Serglycin is overexpressed in aggressive cancers suggesting its protumorigenic role. In this study, we explored the expression of serglycin in human glioma and its correlation with survival and immune cell infiltration. We demonstrate that serglycin is expressed in glioma and that increased expression predicts poor survival of patients. Analysis of serglycin expression in a large cohort of low- and high-grade human glioma samples reveals that its expression is grade dependent and is positively correlated with mast cell (MC) infiltration. Moreover, serglycin expression in patient-derived glioma cells is significantly increased upon MC co-culture. This is also accompanied by increased expression of CXCL12, CXCL10, as well as markers of cancer progression, including CD44, ZEB1 and vimentin.In conclusion, these findings indicate the importance of infiltrating MCs in glioma by modulating signaling cascades involving serglycin, CD44 and ZEB1. The present investigation reveals serglycin as a potential prognostic marker for glioma and demonstrates an association with the extent of MC recruitment and glioma progression, uncovering potential future therapeutic opportunities for patients.
Address Uppsala University, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 1949-2553 ISBN Medium
Area Expedition Conference
Notes PMID:28445977 Approved no
Call Number ref @ user @ Serial 96590
Permanent link to this record