Tonically Active α2 Subunit-Containing Glycine Receptors Regulate the Excitability of Striatal Medium Spiny Neurons

Medium spiny neurons (MSNs) of the dorsal striatum represent the first relay of cortico-striato-thalamic loop, responsible for the initiation of voluntary movements and motor learning. GABAergic transmission exerts the main inhibitory control of MSNs. However, MSNs also express chloride-permeable glycine receptors (GlyRs) although their subunit composition and functional significance in the striatum is unknown. Here, we studied the function of GlyRs in MSNs of young adult mice. We show that MSNs express functional GlyRs, with α2 being the main agonist binding subunit. These receptors are extrasynaptic and depolarizing at resting state. The pharmacological inhibition of GlyRs, as well as inactivation of the GlyR α2 subunit gene hyperpolarize the membrane potential of MSNs and increase their action potential firing offset. Mice lacking GlyR α2 showed impaired motor memory consolidation without any changes in the initial motor performance. Taken together, these results demonstrate that tonically active GlyRs regulate the firing properties of MSNs and may thus affect the function of basal ganglia

Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis

Distribution of trace gases with adverse effects on fuel cells

The introduction of fuel cell technology into the field of motor vehicle propulsionenables both a reduction in primary energy consumption and a reduction independence on the primary energy source mineral oil. A major advantage of thispropulsion technology is reduction of greenhouse gas emissions when renewableenergy is used for fuels as hydrogen [Robinius, 2019]. Moreover, fluctuations inelectricity energy supply from renewable sources can be dampened when electricityis efficiently converted and stored as hydrogen.For the competitive application of this technology of fuel cell technology in the field ofvehicle propulsion, however, considerable research is still required in some areas. Inaddition to the necessary cost and weight reduction, this also applies to the long-termstability and robustness of fuel cell stack itself.It is known that fuel cell stacks react to the admixture of harmful gases into the intakecathode air with performance losses, which primarily result from the poisoning of thecatalysts. The effect does not only depend on the total burden of pollutants but on theirpeak concentrations. With this regard there is a need for research into both the effectsof pollutants on fuel stacks and their distribution in the atmosphere.The work presented here was funded by BMWi in the period from December 2014 toNovember 2017 and describes the results of the subproject 03ET6036D, which wascarried out by Forschungszentrum Jülic

Brentuximab vedotin for relapsed or refractory Hodgkin lymphoma: experience in Turkey

Bu çalışma, 12-15 Haziran 2014 tarihleri arasında Milan[İtalya]’da düzenlenen 19. Congress of the European-Hematology-Association’da bildiri olarak sunulmuştur

Crizotinib Efficacy in ALK-Positive Advanced Stage Non-Small Cell Lung Cancer Patients: A Real-World Experience from Turkey

WOS: 00045401450123