Wpływ fłurazepamu i zewnątrzkomórkowego pH na amplitudę i kinetykę GABA ergicznych prądów synaptycznych w hodowanych neuronach z hipokampa szczura

Stężenie jonów wodorowych (pH) i benzodiazepiny (BDZ) są czynnikami modulującymi receptory GABAa. W szczególności, wartość pH środowiska zewnątrzkomórkowego może zmieniać się w zależności od stanu fizjologicznego lub patologicznego. W niniejszej pracy przedstawiono wyniki badań wpływu flurazepamu (benzodiazepiny) przy różnych wartościach zewnątrzkomórkowego pH (z zakresu 5.5 - 7.2) na amplitudę miniaturowych GABA-ergicznych inhibujących prądów synaptycznych (mIPSCs). Stwierdzono, że obecność flurazepamu prowadzi do zwiększenia amplitudy mIPSCs, ale efekt ten zależy od pH i je st największy przy silnie kwaśnych wartościach. Wpływ flurazepamu na amplidudę mIPSC osiąga nasycenie przy stężeniu ok. I цМ dla wszystkich badanych wartości pH. Wyniki te wskazują na to, że modulacja Prądów GABAergicznych przez benzodiazepiny jest zależna od odczynu środowiska.Praca dofinansowana przez KBN grant nr PBZ-M1N-001/P05/28Zadanie pt. „Digitalizacja i udostępnienie w Cyfrowym Repozytorium Uniwersytetu Łódzkiego kolekcji czasopism naukowych wydawanych przez Uniwersytet Łódzki” nr 885/P-DUN/2014 dofinansowane zostało ze środków MNiSW w ramach działalności upowszechniającej naukę

GABA transient sets the susceptibility of mIPSCs to modulation by benzodiazepine receptor agonists in rat hippocampal neurons

Benzodiazepines (BDZs) are known to increase the amplitude and duration of IPSCs. Moreover, at low [GABA], BDZs strongly enhance GABAergic currents suggesting the up-regulation of agonist binding while their action on gating remains a matter of debate. In the present study we have examined the impact of flurazepam and zolpidem on mIPSCs by investigating their effects on GABAAR binding and gating and by considering dynamic conditions of synaptic receptor activation. Flurazepam and zolpidem enhanced the amplitude and prolonged decay of mIPSCs. Both compounds strongly enhanced responses to low [GABA] but, surprisingly, decreased the currents evoked by saturating or half-saturating [GABA]. Analysis of current responses to ultrafast GABA applications indicated that these compounds enhanced binding and desensitization of GABAA receptors. Flurazepam and zolpidem markedly prolonged deactivation of responses to low [GABA] but had almost no effect on deactivation at saturating or half-saturating [GABA]. Moreover, at low [GABA], flurazepam enhanced desensitization–deactivation coupling but zolpidem did not. Recordings of responses to half-saturating [GABA] applications revealed that appropriate timing of agonist exposure was sufficient to reproduce either a decrease or enhancement of currents by flurazepam or zolpidem. Recordings of currents mediated by recombinant (‘synaptic’) α1β2γ2 receptors reproduced all major findings observed for neuronal GABAARs. We conclude that an extremely brief agonist transient renders IPSCs particularly sensitive to the up-regulation of agonist binding by BDZs

Thermal Decomposition Kinetics of Woods with an Emphasis on Torrefaction

The pyrolysis kinetics of Norwegian spruce and birch wood was studied to obtain information on the kinetics of torrefaction. Thermogravimetry (TGA) was employed with nine different heating programs, including linear, stepwise, modulated and constant reaction rate (CRR) experiments. The 18 experiments on the 2 feedstocks were evaluated simultaneously via the method of least-squares. Part of the kinetic parameters could be assumed common for both woods without a considerable worsening of the fit quality. This process results in better defined parameters and emphasizes the similarities between the woods. Three pseudo-components were assumed. Two of them were described by distributed activation energy models (DAEMs), while the decomposition of the cellulose pseudo-component was described by a self-accelerating kinetics. In another approach, the three pseudo-components were described by n-order reactions. Both approaches resulted in nearly the same fit quality, but the physical meaning of the model, based on three n-order reactions, was found to be problematic. The reliability of the models was tested by checking how well the experiments with higher heating rates can be described by the kinetic parameters obtained from the evaluation of a narrower subset of 10 experiments with slower heating. A table of data was calculated that may provide guidance about the extent of devolatilization at various temperature residence time values during wood torrefaction

Unique Structure and Stability of HmuY, a Novel Heme-Binding Protein of Porphyromonas gingivalis

Infection, survival, and proliferation of pathogenic bacteria in humans depend on their capacity to impair host responses and acquire nutrients in a hostile environment. Among such nutrients is heme, a co-factor for oxygen storage, electron transport, photosynthesis, and redox biochemistry, which is indispensable for life. Porphyromonas gingivalis is the major human bacterial pathogen responsible for severe periodontitis. It recruits heme through HmuY, which sequesters heme from host carriers and delivers it to its cognate outer-membrane transporter, the TonB-dependent receptor HmuR. Here we report that heme binding does not significantly affect the secondary structure of HmuY. The crystal structure of heme-bound HmuY reveals a new all-β fold mimicking a right hand. The thumb and fingers pinch heme iron through two apical histidine residues, giving rise to highly symmetric octahedral iron co-ordination. The tetrameric quaternary arrangement of the protein found in the crystal structure is consistent with experiments in solution. It shows that thumbs and fingertips, and, by extension, the bound heme groups, are shielded from competing heme-binding proteins from the host. This may also facilitate heme transport to HmuR for internalization. HmuY, both in its apo- and in its heme-bound forms, is resistant to proteolytic digestion by trypsin and the major secreted proteases of P. gingivalis, gingipains K and R. It is also stable against thermal and chemical denaturation. In conclusion, these studies reveal novel molecular properties of HmuY that are consistent with its role as a putative virulence factor during bacterial infection

Axial Concentration Profiles and NO Flue Gas in a Pilot-Scale Bubbling Fluidized Bed Coal Combustor

Atmospheric bubbling fluidized bed coal combustion of a bituminous coal and anthracite with particle diameters in the range 500-4000 ím was investigated in a pilot-plant facility. The experiments were conducted at steady-state conditions using three excess air levels (10, 25, and 50%) and bed temperatures in the 750-900 °C range. Combustion air was staged, with primary air accounting for 100, 80, and 60% of total combustion air. For both types of coal, high NO concentrations were found inside the bed. In general, the NO concentration decreased monotonically along the freeboard and toward the exit flue; however, during combustion with high air staging and low to moderate excess air, a significant additional NO formation occurred near the secondary air injection point. The results show that the bed temperature increase does not affect the NO flue gas concentration significantly. There is a positive correlation between excess air and the NO flue gas concentration. The air staging operation is very effective in lowering the NO flue gas, but there is a limit for the first stage stoichiometry below which the NO flue gas starts rising again. This effect could be related with the coal rank

An interlaboratory comparison of mid-infrared spectra acquisition: Instruments and procedures matter

Diffuse reflectance spectroscopy has been extensively employed to deliver timely and cost-effective predictions of a number of soil properties. However, although several soil spectral laboratories have been established worldwide, the distinct characteristics of instruments and operations still hamper further integration and interoperability across mid-infrared (MIR) soil spectral libraries. In this study, we conducted a large-scale ring trial experiment to understand the lab-to-lab variability of multiple MIR instruments. By developing a systematic evaluation of different mathematical treatments with modeling algorithms, including regular preprocessing and spectral standardization, we quantified and evaluated instruments' dissimilarity and how this impacts internal and shared model performance. We found that all instruments delivered good predictions when calibrated internally using the same instruments' characteristics and standard operating procedures by solely relying on regular spectral preprocessing that accounts for light scattering and multiplicative/additive effects, e.g., using standard normal variate (SNV). When performing model transfer from a large public library (the USDA NSSC-KSSL MIR library) to secondary instruments, good performance was also achieved by regular preprocessing (e.g., SNV) if both instruments shared the same manufacturer. However, significant differences between the KSSL MIR library and contrasting ring trial instruments responses were evident and confirmed by a semi-unsupervised spectral clustering. For heavily contrasting setups, spectral standardization was necessary before transferring prediction models. Non-linear model types like Cubist and memory-based learning delivered more precise estimates because they seemed to be less sensitive to spectral variations than global partial least square regression. In summary, the results from this study can assist new laboratories in building spectroscopy capacity utilizing existing MIR spectral libraries and support the recent global efforts to make soil spectroscopy universally accessible with centralized or shared operating procedures

The European Hematology Association Roadmap for European Hematology Research. A Consensus Document

Abstract The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at Euro 23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine sections in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients. Received December 15, 2015. Accepted January 27, 2016. Copyright © 2016, Ferrata Storti Foundatio