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https://www.readbyqxmd.com/read/28921655/fast-dynamic-ventilation-mri-of-hyperpolarized-129-xe-using-spiral-imaging
#1
Ozkan Doganay, Tahreema N Matin, Anthony Mcintyre, Brian Burns, Rolf F Schulte, Fergus V Gleeson, Daniel Bulte
PURPOSE: To develop and optimize a rapid dynamic hyperpolarized (129) Xe ventilation (DXeV) MRI protocol and investigate the feasibility of capturing pulmonary signal-time curves in human lungs. THEORY AND METHODS: Spiral k-space trajectories were designed with the number of interleaves Nint  = 1, 2, 4, and 8 corresponding to voxel sizes of 8 mm, 5 mm, 4 mm, and 2.5 mm, respectively, for field of view = 15 cm. DXeV images were acquired from a gas-flow phantom to investigate the ability of Nint  = 1, 2, 4, and 8 to capture signal-time curves...
September 16, 2017: Magnetic Resonance in Medicine: Official Journal of the Society of Magnetic Resonance in Medicine
https://www.readbyqxmd.com/read/28917666/hippocampal-neurophysiology-is-modified-by-a-disease-associated-c-terminal-fragment-of-tau-protein
#2
Francesco Tamagnini, Darren A Walsh, Jon T Brown, Marie K Bondulich, Diane P Hanger, Andrew D Randall
The accumulation of cleaved tau fragments in the brain is associated with several tauopathies. For this reason, we recently developed a transgenic mouse that selectively accumulates a C-Terminal 35 kDa human tau fragment (Tau35). These animals develop progressive motor and spatial memory impairment, paralleled by increased hippocampal glycogen synthase kinase 3β activity. In this neurophysiological study, we focused on the CA1 subfield of the hippocampus, a brain area involved in memory encoding. The accumulation of Tau35 results in a significant increase of short-term facilitation of the synaptic response in the theta frequency range (10 Hz), without affecting basal synaptic transmission and long-term synaptic plasticity...
July 20, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28916775/measuring-glucose-cerebral-metabolism-in-the-healthy-mouse-using-hyperpolarized-13-c-magnetic-resonance
#3
Mor Mishkovsky, Brian Anderson, Magnus Karlsson, Mathilde H Lerche, A Dean Sherry, Rolf Gruetter, Zoltan Kovacs, Arnaud Comment
The mammalian brain relies primarily on glucose as a fuel to meet its high metabolic demand. Among the various techniques used to study cerebral metabolism, (13)C magnetic resonance spectroscopy (MRS) allows following the fate of (13)C-enriched substrates through metabolic pathways. We herein demonstrate that it is possible to measure cerebral glucose metabolism in vivo with sub-second time resolution using hyperpolarized (13)C MRS. In particular, the dynamic (13)C-labeling of pyruvate and lactate formed from (13)C-glucose was observed in real time...
September 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28916726/the-nqo1-bioactivatable-drug-%C3%AE-lapachone-alters-the-redox-state-of-nqo1-pancreatic-cancer-cells-causing-perturbation-in-central-carbon-metabolism
#4
Molly A Silvers, Stanislaw Deja, Naveen Singh, Robert A Egnatchik, Jessica Sudderth, Xiuquan Luo, Muhammad S Beg, Shawn C Burgess, Ralph J DeBerardinis, David A Boothman, Matthew E Merritt
Many cancer treatments, such as those for managing recalcitrant tumors like pancreatic ductal adenocarcinoma, cause off-target toxicities in normal, healthy tissue, highlighting the need for more tumor-selective chemotherapies. β-Lapachone is bioactivated by NAD(P)H:quinone oxidoreductase 1 (NQO1). This enzyme exhibits elevated expression in most solid cancers and therefore is a potential cancer-specific target. β-Lapachone's therapeutic efficacy partially stems from the drug's induction of a futile NQO1-mediated redox cycle that causes high levels of superoxide, then peroxide formation, which damages DNA and causes hyperactivation of poly (ADP-ribose) polymerase (PARP), resulting in extensive NAD+/ATP depletion...
September 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28912901/can-a-selective-serotonin-reuptake-inhibitor-act-as-a-glutamatergic-modulator
#5
Marcos Emilio Frizzo
Sertraline (Zoloft) and fluoxetine (Prozac) are selective serotonin reuptake inhibitors whose antidepressant mechanism of action is classically attributed to an elevation of the extracellular levels of serotonin in the synaptic cleft. However, the biological effects of these drugs seem to be more complex than their traditionally described mechanism of action. Among their actions is the inhibition of different types of Na(+) and K(+) channels, as well as of glutamate uptake activity. The clearance of extracellular glutamate is essential to maintain the central nervous system within physiological conditions, and this excitatory neurotransmitter is removed from the synaptic cleft by astrocyte transporters...
2017: Current Therapeutic Research, Clinical and Experimental
https://www.readbyqxmd.com/read/28912640/spike-frequency-adaptation-in-neurons-of-the-central-nervous-system
#6
REVIEW
Go Eun Ha, Eunji Cheong
Neuronal firing patterns and frequencies determine the nature of encoded information of the neurons. Here we discuss the molecular identity and cellular mechanisms of spike-frequency adaptation in central nervous system (CNS) neurons. Calcium-activated potassium (KCa) channels such as BKCa and SKCa channels have long been known to be important mediators of spike adaptation via generation of a large afterhyperpolarization when neurons are hyper-activated. However, it has been shown that a strong hyperpolarization via these KCa channels would cease action potential generation rather than reducing the frequency of spike generation...
August 2017: Experimental Neurobiology
https://www.readbyqxmd.com/read/28912160/dopamine-d2-receptors-modulate-pyramidal-neurons-in-mouse-medial-prefrontal-cortex-through-a-stimulatory-g-protein-pathway
#7
Sarah E Robinson, Vikaas S Sohal
Dopaminergic modulation of prefrontal cortex is believed to play key roles in many cognitive functions and to be disrupted in pathological conditions such as schizophrenia. We have previously described a phenomenon whereby dopamine D2 receptor (D2R) activation elicits afterdepolarizations (ADPs) in subcortically-projecting (SC) pyramidal neurons within L5 of the prefrontal cortex. These D2R-induced ADPs only occur following synaptic input which activates NMDA receptors (NMDARs) even when the delay between the synaptic input and afterdepolarizations is relatively long, e...
September 14, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28904107/hyperpolarization-activated-cyclic-nucleotide-gated-channels-potentially-modulate-axonal-excitability-at-different-thresholds
#8
Dinushi Weerasinghe, Parvathi Menon, Steve Vucic
Hyperpolarization-activated cyclic-nucleotide gated (HCN) channels mediate differences in sensory and motor axonal excitability at different thresholds in animal models. Importantly, HCN channels are responsible for voltage-gated inward rectifying (Ih) currents activated during hyperpolarization. The Ih currents exert a crucial role in determining the resting membrane potential and have been implicated in a variety of neurological disorders, including neuropathic pain. In humans, differences in biophysical properties of motor and sensory axons at different thresholds remain to be elucidated and could provide crucial pathophysiological insights in peripheral neurological diseases...
September 13, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28899772/change-in-plasma-membrane-potential-of-rat-thymocytes-by-tert-butylhydroquinone-a-food-additive-possible-risk-on-lymphocytes
#9
Maki Takeda, Keisuke Oyama, Norio Kamemura, Kaori Kanemaru, Keizo Yuasa, Kumio Yokoigawa, Yasuo Oyama
Tertiary butylhydroquinone (TBHQ) is a food additive and has various beneficial actions under in vitro and in vivo experimental conditions. Therefore, it is necessary to collect additional data on the toxicity of TBHQ in order to avoid adverse effects during clinical applications. Changes in plasma membrane potential are associated with changes in physiological functions even in non-excitable cells such as lymphocytes. Thus, compounds that affect membrane potential may modify some lymphocytic functions. The effect of TBHQ on plasma membrane potential was examined in rat thymocytes using flow cytometric techniques...
September 9, 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/28899749/cyp4a-cyp2c-modulation-of-the-interaction-of-calcium-channel-blockers-with-cyclosporine-on-edhf-mediated-renal-vasodilations-in-rats
#10
Safaa H Hammoud, Amal G Omar, Assaad A Eid, Mahmoud M El-Mas
The endothelium-derived hyperpolarizing factor (EDHF) serves as a back-up mechanism that compensates for reduced nitric oxide (NO)/prostanoids bioavailability. Here we investigated whether (i) under conditions of vascular endothelium dysfunction, the immunosuppressant drug cyclosporine (CSA) upregulates EDHF-dependent renal vasodilations through altering CYP4A/CYP2C signaling, and (ii) calcium channel blockers modulate the CSA/EDHF/CYP interaction. Rats were treated with CSA, verapamil, nifedipine, or their combinations for 7days...
September 9, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28898996/the-expression-of-the-rare-caveolin-3-variant-t78m-alters-cardiac-ion-channels-function-and-membrane-excitability
#11
Giulia Campostrini, Mattia Bonzanni, Alessio Lissoni, Claudia Bazzini, Raffaella Milanesi, Elena Vezzoli, Maura Francolini, Mirko Baruscotti, Annalisa Bucchi, Ilaria Rivolta, Matteo Fantini, Stefano Severi, Riccardo Cappato, Lia Crotti, Peter J Schwartz, Dario DiFrancesco, Andrea Barbuti
Aims: Caveolinopathies are a family of genetic disorders arising from alterations of the caveolin-3 (cav-3) gene. The T78M cav-3 variant has been associated with both skeletal and cardiac muscle pathologies but its functional contribution, especially to cardiac diseases, is still controversial. Here, we evaluated the effect of the T78M cav-3 variant on cardiac ion channel function and membrane excitability. Methods and results: We transfected either the wild type (WT) or T78M cav-3 in caveolin-1 knock-out mouse embryonic fibroblasts and found by immunofluorescence and electron microscopy that both are expressed at the plasma membrane and form caveolae...
August 1, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28898267/depolarization-of-the-conductance-voltage-relationship-in-the-nav1-5-mutant-e1784k-is-due-to-altered-fast-inactivation
#12
Colin H Peters, Alec Yu, Wandi Zhu, Jonathan R Silva, Peter C Ruben
E1784K is the most common mixed long QT syndrome/Brugada syndrome mutant in the cardiac voltage-gated sodium channel NaV1.5. E1784K shifts the midpoint of the channel conductance-voltage relationship to more depolarized membrane potentials and accelerates the rate of channel fast inactivation. The depolarizing shift in the midpoint of the conductance curve in E1784K is exacerbated by low extracellular pH. We tested whether the E1784K mutant shifts the channel conductance curve to more depolarized membrane potentials by affecting the channel voltage-sensors...
2017: PloS One
https://www.readbyqxmd.com/read/28895268/lithium-reduces-the-span-of-g-protein-activated-k-girk-channel-inhibition-in-hippocampal-neurons
#13
Nathan Dascal, Moran Rubinstein
OBJECTIVES: Lithium (Li(+) ) is one of the most widely used treatments for bipolar disorder (BD). However, the molecular and neuronal basis of BD, as well as the mechanisms of Li(+) actions are poorly understood. Cellular and biochemical studies identified G proteins as being among the cellular targets for Li(+) action, while genetic studies indicated an association with the KCNJ3 gene, which encodes the G protein-activated inwardly rectifying K(+) (GIRK) channels. GIRK channels regulate neuronal excitability by mediating the inhibitory effects of multiple neurotransmitters and contribute to the resting potassium conductance...
September 12, 2017: Bipolar Disorders
https://www.readbyqxmd.com/read/28891518/temperature-effects-on-accommodative-processes-in-simulated-amyotrophic-lateral-sclerosis-in-the-physiological-range
#14
D I Stephanova, A Kossev
The present study investigates the temperature dependence of electrotonic potentials in mathematically-simulated myelinated axons with one of three increasingly-severe type of amyotrophic lateral sclerosis (ALS) pathology, termed as ALS1, ALS2 and ALS3, respectively, in the physiological range (30-37∘C). These potentials were elicited by long-lasting (100 ms) subthreshold polarizing current stimuli (±40% of the threshold). Numerical solutions were computed using our temperature-dependent multi-layered model...
2017: Journal of Integrative Neuroscience
https://www.readbyqxmd.com/read/28889099/the-impact-of-heterozygous-kcnk3-mutations-associated-with-pulmonary-arterial-hypertension-on-channel-function-and-pharmacological-recovery
#15
Michael S Bohnen, Danilo Roman-Campos, Cecile Terrenoire, Jack Jnani, Kevin J Sampson, Wendy K Chung, Robert S Kass
BACKGROUND: Heterozygous loss of function mutations in the KCNK3 gene cause hereditary pulmonary arterial hypertension (PAH). KCNK3 encodes an acid-sensitive potassium channel, which contributes to the resting potential of human pulmonary artery smooth muscle cells. KCNK3 is widely expressed in the body, and dimerizes with other KCNK3 subunits, or the closely related, acid-sensitive KCNK9 channel. METHODS AND RESULTS: We engineered homomeric and heterodimeric mutant and nonmutant KCNK3 channels associated with PAH...
September 9, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28888841/implications-of-the-n-terminal-heterogeneity-for-the-neuronal-k-cl-cotransporter-kcc2-function
#16
Marika Markkanen, Anastasia Ludwig, Stanislav Khirug, Evgeny Pryazhnikov, Shetal Soni, Leonard Khiroug, Eric Delpire, Claudio Rivera, Matti S Airaksinen, Pavel Uvarov
The neuron-specific K-Cl cotransporter KCC2 maintains the low intracellular chloride concentration required for the fast hyperpolarizing responses of the inhibitory neurotransmitters γ-aminobutyric acid (GABA) and glycine. The two KCC2 isoforms, KCC2a and KCC2b differ by their N-termini as a result of alternative promoter usage. Whereas the role of KCC2b in mediating the chloride transport is unequivocal, the physiological role of KCC2a in neurons has remained obscure. We show that KCC2a isoform can decrease the intracellular chloride concentration in cultured neurons and attenuate calcium responses evoked by application of the GABAA receptor agonist muscimol...
September 6, 2017: Brain Research
https://www.readbyqxmd.com/read/28887304/allostery-between-two-binding-sites-in-the-ion-channel-subunit-trip8b-confers-binding-specificity-to-hcn-channels
#17
Kyle A Lyman, Ye Han, Robert J Heuermann, Xiangying Cheng, Jonathan E Kurz, Reagan E Lyman, Paul P Van Veldhoven, Dane M Chetkovich
Tetratricopeptide repeat (TPR) domains are ubiquitous structural motifs that mediate protein-protein interactions. For example, the TPR domains in the peroxisomal import receptor PEX5 enable binding to a range of type 1 peroxisomal targeting signal (PTS1) motifs. A homolog of PEX5, tetratricopeptide repeat-containing Rab8b interacting protein (TRIP8b), binds to and functions as an auxiliary subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Given the similarity between TRIP8b and PEX5, this difference in function raises the question of what mechanism accounts for their binding specificity...
September 8, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28887303/dynamic-nuclear-polarization-facilitates-monitoring-of-pyruvate-metabolism-in-trypanosoma-brucei
#18
You Zhuo, Ciro D Cordeiro, S Khan Hekmatyar, Roberto Docampo, James H Prestegard
Dynamic nuclear polarization (DNP) provides sensitivity improvements that make NMR a viable method for following metabolic conversions in real time. There are now many in vivo applications to animal systems and even to diagnosis of human disease. However, application to microbial systems is rare. Here we demonstrate its application to the pathogenic protozoan, Trypanosoma brucei, using hyperpolarized (13)C1- pyruvate as a substrate and compare the parasite metabolism to that of commonly cultured mammalian cell lines, HEK-293 and Hep-G2...
September 8, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28883439/t-cells-display-mitochondria-hyperpolarization-in-human-type-1-diabetes
#19
Jing Chen, Anna V Chernatynskaya, Jian-Wei Li, Matthew R Kimbrell, Richard J Cassidy, Daniel J Perry, Andrew B Muir, Mark A Atkinson, Todd M Brusko, Clayton E Mathews
T lymphocytes constitute a major effector cell population in autoimmune type 1 diabetes. Despite essential functions of mitochondria in regulating activation, proliferation, and apoptosis of T cells, little is known regarding T cell metabolism in the progression of human type 1 diabetes. In this study, we report, using two independent cohorts, that T cells from patients with type 1 diabetes exhibited mitochondrial inner-membrane hyperpolarization (MHP). Increased MHP was a general phenotype observed in T cell subsets irrespective of prior antigen exposure, and was not correlated with HbA1C levels, subject age, or duration of diabetes...
September 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28881289/efficacy-of-a-series-of-alpha-pyrone-derivatives-against-leishmania-l-infantum-and-trypanosoma-cruzi
#20
Andre Gustavo Tempone, Daiane Dias Ferreira, Marta Lopes Lima, Thais Alves Costa Silva, Samanta E T Borborema, Juliana Quero Reimão, Mariana K Galuppo, Juliana Mariotti Guerra, Angelie J Russell, Graham M Wynne, Roy Y L Lai, Melissa M Cadelis, Brent R Copp
The neglected tropical diseases Chagas disease and leishmaniasis affect together more than 20 million people living mainly in developing countries. The mainstay of treatment is chemotherapy, however the drugs of choice, which include benznidazole and miltefosine, are toxic and have numerous side effects. Safe and effective therapies are urgently needed. Marine alpha-pyrones have been previously identified as scaffolds with potential antiprotozoan activities. In this work, using a phenotypic screen, twenty-seven examples of 3-substituted 4-hydroxy-6-methyl alpha-pyrones were synthesized and their antiparasitic efficacy evaluated against Leishmania (L...
September 1, 2017: European Journal of Medicinal Chemistry
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