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Shingo Matsumoto, Shun Kishimoto, Keita Saito, Yoichi Takakusagi, Jeeva P Munasinghe, Nallathamby Devasahayam, Charles Hart, Robert J Gillies, James B Mitchell, Murali C Krishna
Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxic niches that lead to treatment resistance. Therefore, studies of tumor oxygenation and metabolic profiling should contribute to improved treatment strategies. Here we define two imaging biomarkers that predict differences in tumor response to therapy: 1) partial oxygen pressure (pO2), measured by EPR imaging; and 2) [1-13C] pyruvate metabolism rate, measured by hyperpolarized 13C MRI. Three human PDAC xenografts with varying treatment sensitivity (Hs766t, MiaPaCa-2, and Su...
May 23, 2018: Cancer Research
Sorana Ciura, Masha Prager-Khoutorsky, Zahra S Thirouin, Joshua C Wyrosdic, James E Olson, Wolfgang Liedtke, Charles W Bourque
The maintenance of hydromineral homeostasis requires bidirectional detection of changes in extracellular fluid osmolality by primary osmosensory neurons (ONs) in the organum vasculosum laminae terminalis (OVLT). Hypertonicity excites ONs in part through the mechanical activation of a variant transient receptor potential vanilloid-1 channel (dn-Trpv1). However, the mechanism by which local hypotonicity inhibits ONs in the OVLT remains unknown. Here, we show that hypotonicity can reduce the basal activity of dn-Trpv1 channels and hyperpolarize acutely isolated ONs...
May 22, 2018: Cell Reports
Kondo C, R B Clark, T Y Kim, Belke D, Banderali U, R T Szerencsei, A H Jalloul, P P M Schnetkamp, Spitzer Kw, Giles Wr
NEW FINDINGS: What is the central question of this study? In human articular joints, the synovial fibroblast HSF cell population has essential functions including secretion of lubricants. We address some remaining questions concerning activation-secretion coupling by characterizing the main [Ca2+ ]i signalling pathways activated by ATP. What is the main finding and its importance? In HSF ATP acts through a linked G-protein (Gq ) and phospholipase C signalling mechanisms to produce IP-3 which markedly enhances release of Ca2+ from the endoplasmic reticulum...
May 23, 2018: Experimental Physiology
Jie Liu, Jason D Bayer, Roozbeh Aschar-Sobbi, Marianne Wauchop, Danna Spears, Michael Gollob, Edward J Vigmond, Robert Tsushima, Peter H Backx, Vijay S Chauhan
BACKGROUND: The SCN5A mutation, P1332L, is linked to a malignant form of congenital long QT syndrome, type 3 (LQT3), and affected patients are highly responsive to the Na+ channel blocking drug, mexiletine. In contrast, A647D is an atypical SCN5A mutation causing Brugada syndrome. An asymptomatic male with both P1332L and A647D presented with varying P wave/QRS aberrancy and mild QTc prolongation which did not shorten measurably with mexiletine. OBJECTIVE: We characterized the biophysical properties of P1332L, A647D and wild-type (WT) Na+ channels as well as their combinations in order to understand our proband's phenotype and to guide mexilitine therapy...
2018: PloS One
Kirill Viktorovich Kovtunov, Ekaterina Pokochueva, Oleg Salnikov, Samuel Cousin, Dennis Kurzbach, Basile Vuichoud, Sami Jannin, Eduard Chekmenev, Boyd Goodson, Danila Barskiy, Igor Koptyug
NMR signals intensities can be enhanced by several orders of magnitude via utilization of techniques for hyperpolarization of different molecules, and it allows one to overcome the main sensitivity challenge of modern NMR/MRI techniques. Hyperpolarized fluids can be successfully used in different applications of material science and biomedicine. This focus review covers the fundamentals of the preparation of hyperpolarized liquids and gases via dissolution dynamic nuclear polarization (d-DNP) and parahydrogen-based techniques such as signal amplification by reversible exchange (SABRE) and parahydrogen-induced polarization (PHIP) in both heterogeneous and homogeneous processes...
May 23, 2018: Chemistry, An Asian Journal
A V Chizhov, D V Amakhin, A V Zaizev, L G Magazanik
The mechanisms of interictal discharges (IID) were studied under the conditions of the 4-aminopyridine model of spontaneous epileptiform activity in surviving rat brain slice preparations. Addition of the agents blocking GABA and NMDA receptors failed to inhibit IID generation in the entorhinal cortex. A mathematical model of IID has been developed on the basis of the excitatory neuron interaction mediated by the AMPA receptor. Short-term synaptic depression and slow afterspike-hyperpolarization are the key factors required to terminate a single IID...
March 2018: Doklady Biological Sciences: Proceedings of the Academy of Sciences of the USSR, Biological Sciences Sections
Atara Nardi-Schreiber, Ayelet Gamliel, Talia Harris, Gal Sapir, Jacob Sosna, J Moshe Gomori, Rachel Katz-Brull
The original version of the Supplementary Information associated with this Article contained an error in Supplementary Figure 2 and Supplementary Figure 5 in which the 31 P NMR spectral lines were missing. The HTML has been updated to include a corrected version of the Supplementary Information.
May 22, 2018: Nature Communications
Hecong Qin, Valerie N Carroll, Renuka Sriram, Javier E Villanueva-Meyer, Cornelius von Morze, Zhen Jane Wang, Christopher A Mutch, Kayvan R Keshari, Robert R Flavell, John Kurhanewicz, David M Wilson
Oxidative stress is a critical feature of several common neurologic disorders. The brain is well adapted to neutralize oxidative injury by maintaining a high steady-state concentration of small-molecule intracellular antioxidants including glutathione in astrocytes and ascorbic acid in neurons. Ascorbate-derived imaging probes for hyperpolarized 13 C magnetic resonance spectroscopy and positron emission tomography have been used to study redox changes (antioxidant depletion and reactive oxygen species accumulation) in vivo...
May 21, 2018: Scientific Reports
Melvin A Felton, Alfred B Yu, David L Boothe, Kelvin S Oie, Piotr J Franaszczuk
Evidence suggests that layer 5 pyramidal neurons can be divided into functional zones with unique afferent connectivity and membrane characteristics that allow for post-synaptic integration of feedforward and feedback inputs. To assess the existence of these zones and their interaction, we characterized the resonance properties of a biophysically-realistic compartmental model of a neocortical layer 5 pyramidal neuron. Consistent with recently published theoretical and empirical findings, our model was configured to have a "hot zone" in distal apical dendrite and apical tuft where both high- and low-threshold Ca2+ ionic conductances had densities 1-2 orders of magnitude higher than anywhere else in the apical dendrite...
2018: Frontiers in Computational Neuroscience
Hyeonglim Seo, Ikjang Choi, Nicholas Whiting, Jingzhe Hu, Quy Son Luu, Shivanand Pudakalakatti, Caitlin McCowan, Yaewon Kim, Niki Zacharias, Seunghyun Lee, Pratip Bhattacharya, Youngbok Lee
Porous silicon nanoparticles have recently garnered attention as potentially-promising biomedical platforms for drug delivery and medical diagnostics. Here, we demonstrate porous silicon nanoparticles as contrast agents for ²⁹Si magnetic resonance imaging. Size-controlled porous silicon nanoparticles were synthesized by magnesiothermic reduction of silica nanoparticles and were surface activated for further functionalization. Particles were hyperpolarized via dynamic nuclear polarization to enhance their ²⁹Si MR signals; the particles demonstrated long ²⁹Si spin-lattice relaxation (T₁) times (~ 25 mins), which suggests potential applicability for medical imaging...
May 20, 2018: Chemphyschem: a European Journal of Chemical Physics and Physical Chemistry
A O S Cunha, C C Ceballos, J L de Deus, R M Leão
Afferent neurotransmission to hippocampal pyramidal cells can lead to long-term changes to their intrinsic membrane properties and affect many ion currents. One of the most plastic neuronal currents is the hyperpolarization activated cationic current (Ih ), which changes in CA1 pyramidal cells in response to many types of physiological and pathological processes, including auditory stimulation. Recently we demonstrated that long-term potentiation (LTP) in rat hippocampal Schaffer-CA1 synapses is depressed by high-intensity sound stimulation...
May 19, 2018: European Journal of Neuroscience
Konstantin L Ivanov, Geoffrey Bodenhausen
A novel conceptual approach is described that is based on the transfer of hyperpolarization from para-hydrogen in view of generating a population imbalance between the two spin isomers of H2 O. The approach is analogous to SABRE (Signal Amplification By Reversible Exchange) and makes use of the transfer of spin order from para-hydrogen to H2 O in a hypothetical organometallic complex. The spin order transfer is expected to be most efficient at avoided level crossings. The highest achievable enrichment levels of para- and ortho-water are discussed...
May 17, 2018: Journal of Magnetic Resonance
Yoon-Sil Yang, Sook Jin Son, Joon Ho Choi, Jong-Cheol Rah
Although a number of experimental and clinical studies have shown that hypoxia typically accompanies acute inflammatory responses, the combinatorial effect of the two insults on basic neural function has not been thoroughly investigated. Previous studies have predominantly suggested that hypoxia reduces network activity; however, several studies suggest the opposite effect. Of note, inflammation is known to increase neural activity. In the current study, we examined the effects of limited oxygen in combination with an inflammatory stimulus, as well as the effects of reoxygenation, on synaptic transmission and excitability...
May 15, 2018: Neuropharmacology
Diana Braun, Christa Zollbrecht, Stefanie Dietze, Rudolf Schubert, Stefan Golz, Holger Summer, Pontus B Persson, Mattias Carlström, Marion Ludwig, Andreas Patzak
Ischemia/reperfusion injury holds a key position in many pathological conditions such as acute kidney injury and in the transition to chronic stages of renal damage. We hypothesized that besides a reported disproportional activation of vasoconstrictor response, hypoxia/reoxygenation (H/R) adversely affects endothelial dilatory systems and impairs relaxation in renal arteries. Rat renal interlobar arteries were studied under isometric conditions. Hypoxia was induced by application of 95% N2 , 5% CO2 for 60 min to the bath solution, followed by a 10 min period of reoxygenation (95% O2 , 5% CO2 )...
2018: Frontiers in Physiology
Satoshi Kamijo, Yuichiro Ishii, Shin-Ichiro Horigane, Kanzo Suzuki, Masamichi Ohkura, Junichi Nakai, Hajime Fujii, Sayaka Takemoto-Kimura, Haruhiko Bito
In spite of many association studies linking gene polymorphisms and mutations of L-type Voltage-Gated Ca2+ Channels (VGCC) in neurodevelopmental disorders, such as autism and schizophrenia, specific L-type VGCC roles during brain development remain unclear. Yet, calcium signaling has been shown to be essential for neurodevelopmental processes such as sculpting of neurites, functional wiring and fine tuning of growing networks. To bridge this gap, we performed submembraneous calcium imaging using a membrane-tethered genetically-encoded calcium indicator (GECI) Lck-G-CaMP7...
May 17, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Yuhei Takado, Tian Cheng, Jessica A M Bastiaansen, Hikari Yoshihara, Bernard Lanz, Mor Mishkovsky, Sylvain Lengacher, Arnaud Comment
The dynamics of L-lactate transport across the blood-brain barrier (BBB) and its cerebral metabolism are still subject to debate. We studied lactate uptake and intracellular metabolism in the mouse brain using hyperpolarized 13C magnetic resonance spectroscopy (MRS). Following the intravenous injection of hyperpolarized [1-13C]lactate, we observed that the distribution of 13C label between lactate and pyruvate, which has been shown to be representative of their pool size ratio, is different in NMRI and C57BL/6 mice, the latter exhibiting a higher cerebral lactate dehydrogenase A (Ldha) expression...
May 17, 2018: ACS Chemical Neuroscience
Vesselin Z Miloushev, Kristin L Granlund, Rostislav Boltyanskiy, Serge K Lyashchenko, Lisa M DeAngelis, Ingo K Mellinghoff, Cameron W Brennan, Viviane Tabar, T Jonathan Yang, Andrei I Holodny, Ramon E Sosa, YanWei W Guo, Albert P Chen, James Tropp, Fraser Robb, Kayvan R Keshari
Hyperpolarized (HP) magnetic resonance imaging using [1-13C] pyruvate is a novel method that can characterize energy metabolism in the human brain and brain tumors. Here we present the first dynamically acquired human brain HP 13C metabolic spectra and spatial metabolite maps in cases of both untreated and recurrent tumors. In vivo production of HP lactate from HP pyruvate by tumors was indicative of altered cancer metabolism, while production of HP lactate in the entire brain was likely due to baseline metabolism...
May 16, 2018: Cancer Research
Hideto Yamamura, Yoshiaki Suzuki, Hisao Yamamura, Kiyofumi Asai, Wayne Giles, Yuji Imaizumi
Brain capillary endothelial cells (BCECs) play a central role in maintenance of blood-brain barrier (BBB) function and therefore are essential for central nervous system homeostasis and integrity. Although brain ischemia damages BCECs and causes disruption of BBB, the related influence of hypoxia on BCECs is not well understood. Hypoxic stress can up-regulate functional expression of specific K+ currents in endothelial cells, e.g., Kir2.1 channels without any alterations in the mRNA level, in t-BBEC117, a cell line derived from bovine BCECs...
May 16, 2018: American Journal of Physiology. Cell Physiology
Alshaimaa A Elgarf, David C B Siebert, Friederike Steudle, Angelika Draxler, Guanguan Li, Shengming Huang, James M Cook, Margot Ernst, Petra Scholze
Benzodiazepines are clinically relevant drugs, which bind to GABAA neurotransmitter receptors at the α+/γ2- interfaces and thereby enhance GABA induced chloride ion flux leading to neuronal hyperpolarization. However, the structural basis of benzodiazepine interactions with their high affinity site at GABAA receptors is controversially debated in the literature and in silico studies led to discrepant binding mode hypotheses. In the current study computational docking of diazepam into α+/γ2- homology models suggested that a chiral methyl group, which is known to promote preferred binding to α5-containing GABAA receptors (position 3 of the 7-membered diazepine ring), could possibly provide experimental evidence in favor of or against the so far proposed binding modes...
May 16, 2018: ACS Chemical Biology
Jessica Rae Parker, Brain Bondy, Boris I Prilutsky, Gennady S Cymbalyuk
The ability of the same neuronal circuit to control different motor functions is an actively debated concept. Previously, we have shown in a model that a single multistable CPG could produce two different rhythmic motor patterns, slow and fast, corresponding to cat locomotion and paw-shaking. A locomotor-like rhythm (~2 Hz) and a paw-shake-like rhythm (~10 Hz) did coexist and, by applying a single pulse of current, we could switch the CPG from one regime to another (Bondy et al. 2016). Here, we investigate roles of slow intrinsic ionic currents in this multistability...
May 16, 2018: Journal of Neurophysiology
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