Performance of a cryo-cooled crystal monochromator illuminated by hard X-rays with MHz repetition rate at the European X-ray Free-Electron Laser.

Due to the high intensity and MHz repetition rate of photon pulses generated by the European X-ray Free-Electron Laser, the heat load on silicon crystal monochromators can become large and prevent ideal transmission in Bragg diffraction geometry due to crystal deformation. Here, we present experimental data illustrating how heat load affects the performance of a cryogenically cooled monochromator under such conditions. The measurements are in good agreement with a depth-uniform model of X-ray dynamical diffraction taking beam absorption and heat deformation of the crystals into account.

Materials Imaging and Dynamics (MID) instrument at the European X-ray Free-Electron Laser Facility.

The Materials Imaging and Dynamics (MID) instrument at the European X-ray Free-Electron Laser (EuXFEL) facility is described. EuXFEL is the first hard X-ray free-electron laser operating in the MHz repetition range which provides novel science opportunities. The aim of MID is to enable studies of nano-structured materials, liquids, and soft- and hard-condensed matter using the bright X-ray beams generated by EuXFEL.

Characterization and preclinical evaluation of the cGMP grade DNA based vaccine, AV-1959D to enter the first-in-human clinical trials.

The DNA vaccine, AV-1959D, targeting N-terminal epitope of Aβ peptide, has been proven immunogenic in mice, rabbits, and non-human primates, while its therapeutic efficacy has been shown in mouse models of Alzheimer's disease (AD). Here we report for the first time on IND-enabling biodistribution and safety/toxicology studies of cGMP-grade AV-1959D vaccine in the Tg2576 mouse model of AD. We also tested acute neuropathology safety profiles of AV-1959D in another AD disease model, Tg-SwDI mice with established vascular and parenchymal Aβ pathology in a pre-clinical translational study.

MultiTEP platform-based DNA vaccines for alpha-synucleinopathies: preclinical evaluation of immunogenicity and therapeutic potency.

We have previously demonstrated that anti-beta amyloid DNA vaccine (AV-1959D) based on our proprietary MultiTEP platform technology is extremely immunogenic in mice, rabbits, and monkeys. Importantly, MultiTEP platform enables development of vaccines targeting pathological molecules involved in various neurodegenerative disorders. Taking advantage of the universality of MultiTEP platform, we developed DNA vaccines targeting 3 B-cell epitopes (amino acids [aa]85-99, aa109-126, and aa126-140) of human alpha-synuclein (hα-Syn) separately or all 3 epitopes simultaneously.

Humanized monoclonal antibody armanezumab specific to N-terminus of pathological tau: characterization and therapeutic potency.

Background: The experience from clinical trials indicates that anti-Aβ immunotherapy could be effective in early/pre-clinical stages of AD, whereas at the late stages promoting the clearing of Aβ alone may be insufficient to halt the disease progression. At the same time, pathological tau correlates much better with the degree of dementia than Aβ deposition. Therefore, targeting pathological tau may provide a more promising approach for the treatment of advanced stages of AD.

MultiTEP platform-based DNA epitope vaccine targeting N-terminus of tau induces strong immune responses and reduces tau pathology in THY-Tau22 mice.

Background: By the time clinical symptoms of Alzheimer's disease (AD) manifest in patients there is already substantial tau pathology in the brain. Recent evidence also suggests that tau pathology can become self-propagating, further accelerating disease progression. Over the last decade several groups have tested the efficacy of protein-based anti-tau immunotherapeutics in various animal models of tauopathy.

Alzheimer's disease Advax(CpG)- adjuvanted MultiTEP-based dual and single vaccines induce high-titer antibodies against various forms of tau and Aβ pathological molecules.

Although β-amyloid (Aβ) may be the primary driver of Alzheimer's disease (AD) pathology, accumulation of pathological tau correlates with dementia in AD patients. Thus, the prevention/inhibition of AD may require vaccine/s targeting Aβ and tau simultaneously or sequentially. Since high antibody titers are required for AD vaccine efficacy, we have decided to generate vaccines, targeting Aβ (AV-1959R), Tau (AV-1980R) or Aβ/tau (AV-1953R) B cell epitopes, based on immunogenic MultiTEP platform and evaluate the immunogenicity of these vaccines formulated with Advax(CpG), delta inulin, Alhydrogel(®), Montanide-ISA51, Montanide-ISA720, MPLA-SM pharmaceutical grade adjuvants.

Synthesis and antituberculosis activity of indole-pyridine derived hydrazides, hydrazide-hydrazones, and thiosemicarbazones.

We describe the design, synthesis, and in vitro antimycobacterial activity of a series of novel simple hybrid hydrazides and hydrazide-hydrazones combining indole and pyridine nuclei. The compounds are derivatives of 1-acetylindoxyl or substituted indole-3-carboxaldehydes tethered via a hydrazine group by simple C-N or double C=N bonds with 3- and 4-pyridines, 1-oxide 3- and 4-pyridine carbohydrazides. The most active of 15 compounds showed MICs values against an INH-sensitive strain of Mycobacterium tuberculosis H37Rv equal to that of INH (0.

[Blood supply as a factor regulating pacemaker activity of the rat uterine horn].

Effect of ischemia of the uterine artery supplying with blood the main rhythmogenic zone (the ovarian region) of the uterine horn on parameters of activity both of this locus and of all subsequent pacemaker areas up to the uterine cervix was studied in non-pregnant rats. The most pronounced changes in characteristics of the activity (amplitude, frequency, and burst genesis duration) were revealed in the ovarian horn end. The uterine corpus and the horn cervical end were less affected by ischemia.

[Role of acetylcholine in coordination od spontaneous electrical activity of various areas of the rat uterus].

Spontaneous electrical activity of myometrium was studied in areas of the uterine corpus, zone of its connection with uterine tube and cervix at intravenous administration of various acetylcholine concentrations. Under these conditions, changes of the frequency and amplitude characteristics of rhythmogenesis were studied both separately and in their combined active state. The presence of 10(-3) M acetylcholine in the animal blood creates the most optimal conditions for synchronization and coordination of activities of all studied uterus areas.

[The role of histamine in regulation of spontaneous electrical activity of the rat ureter and bordering to bladder area].

The nature of the influence of histamine on the slow wave and spike spontaneous activity of both perirenal and peribladder bordering areas of the bladder zone has been studied. It is shown that under these conditions of activated renal section of the organ, in the distal part, the decrease in frequency of the slow waves occurred. The histamine effect also contributes to improvement of the conduction of the excitation wave propagating to the bladder, which destroys the coordination of spike activity of the latter with slow waves of ureteral bordering zone.

[Role of oxytocin in activation of spontaneous electrical activity of uterine body and uterine tubes in non-pregnant rats].

The work studies effects of various doses of oxytocin (0.01, 0.1, 1 and 10 microg/kg) on duration of discharges of spontaneous electrical activity and frequency of spikes in various parts of uterine tubes and of uterine body of non-pregnant rats.

[Effect of acetylcholine on coordination of spontaneous activities registered from different areas of uterus in rats].

Spontaneous electrical activities of uterine corpus, periuterine part of horn and uterine cervix in response to intravenous injections of different concentrations of acetylcholine were observed. The changes of frequency and amplitude characteristics of rhythmogenesis in these conditions, both separately and with their co-active state were analysed. Acetylcholine in concentration of 10(-3) M in the blood of the animal creates the optimal conditions for synchronization and coordination of electrical activities in the above areas of the uterus.

[Effect of nifedipine on electrophysiological properties of rat ureter spontaneous activity].

The work studied effect of various concentrations of nifedipine on the slow and fast spontaneous activities evoked in the perivesical and perirenal areas of the rat ureter. Whereas in the proximal zone of the organ at the low dose of nifedipine (0.06 and 0.

[Effect of oxytocin on activation of spontaneous electrical activities registered from uterine corpus and uterine tubes in rats].

The effects if different concentrations of oxytocin (10(-2), 10(-1), 1 and 10 microg/kg) on burst duration and spikes frequency of spontaneous electrical activity in various parts of uterine horns and uterine corpus in non-pregnant rats have been shown. The changes in given parameters for ovarian parts of horns had similar characters unlike cervical parts of horns and middle part of uterine corpus under these conditions, so the last mentioned areas could be grouped together by the reason of similar changes in their parameters. Oxytocin in a concentration of 10(-1) microg/kg promoted the longest duration of spike electrical activity genesis in ovarian parts of horns.

Expression, purification and characterization of UvrD2 helicase from Mycobacterium tuberculosis.

Helicases appear to be important for genome stability of dormant Mycobacterium tuberculosis responsible for latent tuberculosis infection and big proportion of active disease cases caused by reactivation. It was demonstrated that in both M. tuberculosis and Mycobacterium smegmatis, a helicase termed UvrD2 is essential for bacterial growth making it a promising target to fight tuberculosis.

[Autonomy of spontaneous rhythmogenesis of perivesicular area of cat ureter].

The work present data indicating no dependence of the pacemaker activity located in the zone of junction of cat ureter with urinary bladder on genesis of the main perirenal pacemaker. Data are presented on effect of clamping the renal artery supplying with blood flow the renal area on rhythmogenesis of the ureter perivesicular area. An inhibition of the pacemaker activity of the pyeloureteral anasomosis is observed.

[Analysis of electrical activities of the junction region of the ureter with bladder and surrounding zones in rats].

Spontaneous electrical activity of the rat ureters per bladder zone was studied. In area of ureter connection with bladder, slow-wave activity was revealed. In bladder bordering ureter zone, rapid spike activity was found that was fully correlated with the genesis of upper located fluctuation processes.

[Study of volatile fatty acids in the blood of patients with periodic disease].

Microecological "failures" are an important pathogenetic factor of different diseases and, in the authors' opinion, periodic disease (PD) is one of them. PD is a recessive disease characterized by fever attacks and neutrophil-mediated serous inflammation. A genetic factor has been established to be responsible for half the cases of PD, the influence of non-hereditary factors, particularly a role of the host automicroflora in the genesis of an inflammatory process, has been little studied.

[Pacemaker activity in distal parts of the cat ureter].

Existence of two types of uncoordinated spontaneous activities of the cat ureterbladder area was shown: spikes and slow waves. The oscillation frequency of this area is two-fold lesser than the rhythm of renal waves. The activity concordance of these pacemakers occurs under conditions of ureter dissection in the middle.

Proteins of the Rpf family: immune cell reactivity and vaccination efficacy against tuberculosis in mice.

It was shown recently that Mycobacterium tuberculosis expresses five proteins that are homologous to Rpf (resuscitation promoting factor), which is secreted by growing cells of Micrococcus luteus. Rpf is required to resuscitate the growth of dormant Micrococcus luteus organisms, and its homologues may be involved in mycobacterial reactivation. Mycobacterial Rpf-like products are secreted proteins, which makes them candidates for recognition by the host immune system and anti-Rpf immune responses potentially protective against reactivated tuberculosis.

[Effect of histamine on spontaneous rhythmogenesis of the guinea pig ureter].

Histamine changed characteristics of the perinephric spontaneous spike activity and of the spreading electrical wave. It was shown that histamine could activate latent pacemakers of the ureter's middle area. Morphological picture of the histamine effect was also shown.

The rpf gene of Micrococcus luteus encodes an essential secreted growth factor.

Micrococcus luteus secretes a small protein called Rpf, which has autocrine and paracrine signalling functions and is required for the resuscitation of dormant cells. Originally isolated from the supernatant of actively growing cultures, Rpf was also detected on the surface of actively growing bacteria. Most molecules may be sequestered non-productively at the cell surface, as a truncated form of the protein, encompassing only the 'Rpf domain' is fully active.

[The differentiation of rhythmogenic characteristics of the ureter's different regions in guinea pigs].

Characteristics of rhythmogenic pacemakers of the ureter's perirenal middle and peribladder region morphologically and electrophysiologically are analysed in guinea pigs both in presence of spreading activity and breach of conductivity. It was shown that the action potential's amplitude of the middle region is the highest and duration of the spike activities from perirenal zone is maximal and all three regions are characterised by different functional conditions.