Block of NMDA receptor channels by endogenous neurosteroids: implications for the agonist induced conformational states of the channel vestibule

N-methyl-D-aspartate receptors (NMDARs) mediate synaptic plasticity, and their dysfunction is implicated in multiple brain disorders. NMDARs can be allosterically modulated by numerous compounds, including endogenous neurosteroid pregnanolone sulfate. Here, we identify the molecular basis of the use-dependent and voltage-independent inhibitory effect of neurosteroids on NMDAR responses. The site of action is located at the extracellular vestibule of the receptor's ion channel pore and is accessible after receptor activation. Mutations in the extracellular vestibule in the SYTANLAAF motif disrupt the inhibitory effect of negatively charged steroids. In contrast, positively charged steroids inhibit mutated NMDAR responses in a voltage-dependent manner. These results, in combination with molecular modeling, characterize structure details of the open configuration of the NMDAR channel. Our results provide a unique opportunity for the development of new therapeutic neurosteroid-based ligands to treat diseases associated with dysfunction of the glutamate system

Fatigue in neuromuscular disorders: focus on Guillain–Barré syndrome and Pompe disease

Fatigue accounts for an important part of the burden experienced by patients with neuromuscular disorders. Substantial high prevalence rates of fatigue are reported in a wide range of neuromuscular disorders, such as Guillain–Barré syndrome and Pompe disease. Fatigue can be subdivided into experienced fatigue and physiological fatigue. Physiological fatigue in turn can be of central or peripheral origin. Peripheral fatigue is an important contributor to fatigue in neuromuscular disorders, but in reaction to neuromuscular disease fatigue of central origin can be an important protective mechanism to restrict further damage. In most cases, severity of fatigue seems to be related with disease severity, possibly with the exception of fatigue occurring in a monophasic disorder like Guillain–Barré syndrome. Treatment of fatigue in neuromuscular disease starts with symptomatic treatment of the underlying disease. When symptoms of fatigue persist, non-pharmacological interventions, such as exercise and cognitive behavioral therapy, can be initiated

Dermacentor reticulatus: a vector on the rise

Dermacentor reticulatus is a hard tick species with extraordinary biological features. It has a high reproduction rate, a rapid developmental cycle, and is also able to overcome years of unfavourable conditions. Dermacentor reticulatus can survive under water for several months and is cold-hardy even compared to other tick species. It has a wide host range: over 60 different wild and domesticated hosts are known for the three active developmental stages. Its high adaptiveness gives an edge to this tick species as shown by new data on the emergence and establishment of D. reticulatus populations throughout Europe. The tick has been the research focus of a growing number of scientists, physicians and veterinarians. Within the Web of Science database, more than a fifth of the over 700 items published on this species between 1897 and 2015 appeared in the last three years (2013–2015). Here we attempt to synthesize current knowledge on the systematics, ecology, geographical distribution and recent spread of the species and to highlight the great spectrum of possible veterinary and public health threats it poses. Canine babesiosis caused by Babesia canis is a severe leading canine vector-borne disease in many endemic areas. Although less frequently than Ixodes ricinus, D. reticulatus adults bite humans and transmit several Rickettsia spp., Omsk haemorrhagic fever virus or Tick-borne encephalitis virus. We have not solely collected and reviewed the latest and fundamental scientific papers available in primary databases but also widened our scope to books, theses, conference papers and specialists colleagues’ experience where needed. Besides the dominant literature available in English, we also tried to access scientific literature in German, Russian and eastern European languages as well. We hope to inspire future research projects that are necessary to understand the basic life-cycle and ecology of this vector in order to understand and prevent disease threats. We conclude that although great strides have been made in our knowledge of the eco-epidemiology of this species, several gaps still need to be filled with basic research, targeting possible reservoir and vector roles and the key factors resulting in the observed geographical spread of D. reticulatus. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13071-016-1599-x) contains supplementary material, which is available to authorized users

Adhesion and growth of vascular cells on porous polyethylene terephthalate scaffolds

Polymers such as polyethylene terephthalate (PET) have been used for large-caliber vascular prostheses with a relative success but their application is limited in small-caliber grafts. Blood vessel grafts with an internal diameter smaller than 6 mm are prone to fail mainly due to their thrombogenicity and poor haemodynamics. One of the possible solutions of these problems may be reconstruction of the tunica intima and media on the synthetic grafts. For this purpose, special PET foils were prepared. Six-μm thick foils were irradiated by copper ions or fission fragments from a radionuclide etalon source 252Cf and etched by 1M sodium hydroxide to obtain holes of a defined diameter (from 80 to100 nm in foils irradiated by copper ions and from 1.0 to 1.5 μm in foils irradiated by fission fragments) and density (1x106 cm-2 - fission fragments to 5x108 cm-2 – copper ions) (FIG.1). Afterward these materials were seeded with vascular smooth muscle cells (VSMC) derived from the rat aorta, or endothelial cells of the line CPAE. Adhesion, proliferation and viability of the cells were monitored after one, three and seven days. The cell proliferation was evaluated by changes in the cell number in several time intervals and construction of growth curves. Determination of cell viability was based on staining of live cells with calcein emitting green fluorescence, and the dead cells with ethidium bromide emitting red fluorescence. Experiments with the growth of vascular smooth muscle cells and endothelial cells on the PET scaffolds with different pore size showed that endothelial cells prefer pores around 1 μm while VSMC have no preferences concerning the pore size of the polymer scaffolds tested. Although the highest cell population densities were found on the glass coverslips used as control material, the number of cells growing on pristine PET did not differ from the densities on PET foils irradiated by Cu-ions or fission fragments of Cf. The obtained data showed applicability of our improved polymer foils as supporting scaffolds for vascular cells. In the further step, these porous PET membranes could serve as synthetic analogues of internal elastic lamina separating vascular smooth muscle cells and endothelial cells in a newly constructed bioartificial vascular wall

X-ray multi-foil optical system for CubeSat demonstrator

Copyright © 2018 SPIE. The paper presents the X-ray Multi-Foil Optical (MFO) system proposed for the CubeSat demonstrator. The Lobster Eye (LE) design represents wide field of view (FOV) X-ray optics. This feature is unique in comparison with classical Wolter types of X-ray optics that reaches a field of view of typically 1 degree or less. LE optics can theoretically achieve an unlimited field of view, but for practical reasons, modules with, for example, 6 deg x 6 deg large FOV can be designed, developed, and constructed. Presented theoretical study of the Multi-Foil wide-field X-ray "Lobster eye" based optics shows effects of focal length, foil spacing and reflective surface (Au versus Ir). The main parameters that have been compared are effective area, gain, FWHM and/or transmission. The system can be used as an all-sky monitor in future projects

X-ray multi-foil optical system for CubeSat demonstrator

Copyright © 2018 SPIE. The paper presents the X-ray Multi-Foil Optical (MFO) system proposed for the CubeSat demonstrator. The Lobster Eye (LE) design represents wide field of view (FOV) X-ray optics. This feature is unique in comparison with classical Wolter types of X-ray optics that reaches a field of view of typically 1 degree or less. LE optics can theoretically achieve an unlimited field of view, but for practical reasons, modules with, for example, 6 deg x 6 deg large FOV can be designed, developed, and constructed. Presented theoretical study of the Multi-Foil wide-field X-ray "Lobster eye" based optics shows effects of focal length, foil spacing and reflective surface (Au versus Ir). The main parameters that have been compared are effective area, gain, FWHM and/or transmission. The system can be used as an all-sky monitor in future projects