[Epithelial-stromal interactions in pancreatic adenocarcinoma: the role of stroma in disease progression]. / Epitelial'no-stromal'nye vzaimodeistviya v adenokartsinome podzheludochnoi zhelezy: rol' stromy v progressirovanii zabolevaniya.

Pancreatic ductal adenocarcinoma (PDAC) is the most common and difficult to treat form of pancreas cancer. PDAC and other solid cancers contain both tumor cells and normal connective tissue cells called stromal cells, which are responsible for the excess production of extracellular matrix. It is known that in more than 90% of PDAC tumors and in many other types of cancer, mutations of the KRAS gene are observed, the reciprocal signaling of which has been shown between tumor and stromal cells in vitro. Pancreatic stromal stellate cells are considered precursors of activated or tumor-associated fibroblasts (CAFs), which are an increasing population of cells that proliferate in situ or are recruited into the tumor. CAFs are a heterogeneous population of stromal fibroblasts with different molecular profiles that change during tumorigenesis. Both immunosuppressive and immunosuppressive subsets of CAFs can coexist in the stroma of a single tumor. Based on the heterogeneity of the intertumor stroma, attempts are being made to classify PDAC and predict the course of the disease.

Real life clinical study design supporting the effectiveness of extra-fine inhaled beclomethasone/formoterol at the level of small airways of asthmatics.

BACKGROUND: In an attempt to establish how treatment with inhaled extra-fine beclomethasone/formoterol (I-EF-BDP/F) formulation differs from other combinations of inhaled corticosteroid (ICS) and long acting beta-agonist (LABA), we studied lung function and markers of airway inflammation upon switching to the extra-fine formulation and after 8 weeks of treatment with it. METHODS: We carried out a real-life clinical observation of undercontrolled asthmatic patients switched over from dry powder inhalers of fluticasone/salmeterol and budesonide/formoterol to I-EF-BDP/F (Foster(®), Chiesi Farmaceutici S.p.A., Italy). The effects of 8-weeks of treatment were documented by means of visual analog scale (VAS), quality of life by Asthma Quality of Life Questionnaire (AQLQ), spirometry and markers of airway or systemic inflammation: exhaled breath temperature (EBT), blood eosinophils (Eos), and high sensitivity C-reactive protein (CRP). Before/after treatment differences between forced vital capacity percent of predicted (%FVC), a simple indicator of small airways involvement, were calculated and subjects were ranked accordingly to reflect the magnitude of the therapeutic response. Subjects above the 75th percentile (n = 15), "top responders", were then compared with those below the 25th percentile (n = 15) "poor responders". RESULTS: On average, the 59 patients completing the study (mean age ± SD 51 ± 12 years, 38 women) had significant improvement in VAS and QLQ scores at the end of the treatment period (49.1 ± 2.4 vs. 73.1 ± 2.05 and 146.1 ± 2.7 vs. 176.7.1 ± 3.4 respectively, P < 0.001), but not in the inflammatory indicators (EBT, CRP and Eos). However, when comparing the "top responders" with the "poor responders", significant improvement in these inflammatory indicators was observed: EBT significantly decreased from 34.04/mean/± 0.30/s.e.m./[°C] to 33.57 ± 0.33, P = 0.003, Eos in blood fell from 381.7 ± 91.2 [cells/µL] to 244.2 ± 43.2, P = 0.02. Before/after treatment differences in hsCRP decreased significantly in the top responders compared with the poor responders (Mann-Whitney test, P = 0.04). CONCLUSION: Asthmatic subjects who had the most improvement in FVC after transition to I-EF-BDP/F from other combined ICS/LABA preparations also demonstrated a significant decrease in some indicators of airway/systemic inflammation. These results support the notion that I-EF-BDP/F exerts an effect also at the level of the small airways through a reduction of the level of air trapping. Patients in whom inflammation of the small airways plays an important clinical role are the ones to derive most benefit from this small airways tailored treatment. However, improved compliance due to the "promise of a new drug" effect should also be considered as contributing to the treatment results.

[Botulinum therapy of spastic forms of cerebral palsy in various locomotor patterns]. / Botulinoterapiya spasticheskikh form detskogo tserebral'nogo paralicha pri razlichnykh lokomotornykh patternakh.

Spasticity in patients with cerebral palsy (CP) is the main impediment to normal locomotion. The function of the Central Pattern Generator (CPG), i.e. a group of neural chains in the spinal cord, stands at the core of any rhythmical movement. CPG can generate locomotion patterns without supraspinal control, which can have both positive and negative impact on the ability to move. Performing the motor tasks such as walking, running and swimming, creates the consistent rhythmical movement of legs and arms through interaction between CPGs of upper and lower extremities. This interaction can cause the activation of pathological movement patterns in lower extremities in response to upper limb spasticity. Thus, neural chains in the spinal cord become the generator of pathologically increased excitation which has developed as a result of a focal lesion in the CNS. All the statements described above show the importance of introducing the upper limb injections of bFotulinum toxin A in the protocol in order to develop normal locomotion. The PUL study approved the optimal level of efficacy and favourable safety profile of botulinum toxin A in children with CP and upper limb muscle spasticity.

The effect of energy-dependent electron scattering on thermoelectric transport in novel topological semimetal CoSi.

Cobalt monosilicide and its solid solutions with Fe or Ni crystallize in B20 cubic noncentrosymmetric structure. These compounds have long been known as promising thermoelectric materials. Recently it was revealed, that they also have unconventional electronic topology. This renewed interest to the investigation of their transport properties. In order to improve theoretical description of thermoelectric transport in these compounds, we take into account electron scattering beyond commonly used constant relaxation time approximation. Using first principle calculations, we investigate the scattering of charge carriers by phonons and point defects. The dependence of the scattering rate on the energy correlates with that for the total density of states. This implies that in this material not only the intraband, but also the interband scattering is important, especially for bands with low density of states. The Seebeck coefficient and the electrical resistivity of CoSi and of dilute solid solutions Co1-x M x Si (M = Fe or Ni, x < 0.1) are calculated as a function of temperature and the alloy composition. We show that the account of strong energy dependence of relaxation time is important for the description of experimentally observed rapid increase of the resistivity and qualitative change of its temperature dependence with the substitution of cobalt for iron, as well as for the description of the magnitude of the Seebeck coefficient, its temperature and composition dependence.

Band structure and unconventional electronic topology of CoSi.

Semimetals with certain crystal symmetries may possess unusual electronic structure topology, distinct from that of the conventional Weyl and Dirac semimetals. Characteristic property of these materials is the existence of band-touching points with multiple (higher than two-fold) degeneracy and nonzero Chern number. CoSi is a representative of this group of materials exhibiting the so-called 'new fermions'. We report on an ab initio calculation of the electronic structure of CoSi using density functional methods, taking into account the spin-orbit interactions. The linearized [Formula: see text] Hamiltonian, describing the anisotropic electronic structure of CoSi near the Γ point is derived. The topological features of band-touching nodes with four- and six-fold degeneracy located at the Γ and R points in the first Brillouin zone are analysed using the linearized Hamiltonians and first principle calculations. In particular, we show, using the non-Abelian Berry curvature, that these band-touching points carry topological charges of [Formula: see text], which change signs at certain values of parameters of the Hamiltonians. We describe the resulting Fermi arc surface states and their spin texture. We also discuss the influence of many body [Formula: see text] corrections on the electronic band structure and the topological properties of CoSi.

The detection of hepatitis c virus core antigen using afm chips with immobolized aptamers.

In the present study, the possibility of hepatitis C virus core antigen (HCVcoreAg) detection in buffer solution, using atomic force microscope chip (AFM-chip) with immobilized aptamers, has been demonstrated. The target protein was detected in 1mL of solution at concentrations from 10-10М to 10-13М. The registration of aptamer/antigen complexes on the chip surface was carried out by atomic force microscopy (AFM). The further mass-spectrometric (MS) identification of AFM-registered objects on the chip surface allowed reliable identification of HCVcoreAg target protein in the complexes. Aptamers, which were designed for therapeutic purposes, have been shown to be effective in HCVcoreAg detection as probe molecules.

Serologic Markers of Autism Spectrum Disorder.

According to WHO data, about 67 million people worldwide are affected by autism, and this number grows by 14% annually. Among the possible causes of autism are genetic modifications, organic lesions of the central nervous system, metabolic disorders, influence of viral and bacterial infections, chemical influence to the mother's body during pregnancy, etc. The conducted research shows that research papers published until today do not name any potential protein markers that meet the requirements of the basic parameters for evaluating the efficiency of disease diagnostics, in particular high sensitivity, specificity, and accuracy. Conducting proteomic research on a big scale in order to detect serologic markers of protein nature associated with development of autism spectrum disorders seems to be highly relevant.

Isatin interaction with glyceraldehyde-3-phosphate dehydrogenase, a putative target of neuroprotective drugs: partial agonism with deprenyl.

There is evidence that the binding of deprenyl, a monoamine oxidase (MAO) B inhibitor, and other propargylamines to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is primarily responsible for their neuroprotective and antiapoptotic effects. Thus, GAPDH may be a target for other neuroprotective drugs. Using two independent approaches, radioligand analysis and an optical biosensor technique, we demonstrate here that GAPDH also interacts with the endogenous, reversible MAO B inhibitor, isatin. Deprenyl inhibited both [3H]isatin binding to GAPDH, and the binding of this enzyme to an isatin analogue, 5-aminoisatin, immobilized on to an optical biosensor cell. Another MAO inhibitor, tranylcypromine, was ineffective. Both deprenyl and isatin inhibited GAPDH-mediated cleavage of E. coli tRNA, and their effects were not additive. We suggest that isatin may be an endogenous partial functional agonist of deprenyl in its effect on GAPDH and GAPDH-mediated RNA cleavage. Changes in level of endogenous isatin may influence the neuroprotective effect of deprenyl in vivo.

Diagnosing sub-acute rumen acidosis in cows in the post-calving period with digital technologies / [Diagnóstico de acidose ruminal subaguda em vacas no período pós-parto usando tecnologias digitais]

This study aims to determine the relationship between indicators of the motor activity, pH factor, rumen and rectal temperature within 10 days after calving and to analyze the possibility of using the studied parameters as prognostic signs for diagnosing sub-acute rumen acidosis (SARA). The measurements were taken using bolus with sensors designed to monitor cow health. The motor activity, pH factor and ruminal temperature of 10 cows were measured during 10 days at a measurement interval of every 60 seconds. Next, the researchers calculated the average values of the obtained readings, which were divided into 2 groups according to a measurement interval of every 12 hours. Rectal temperature was measured using a veterinary thermometer every 12 hours (at 8 a.m. and at 8 p.m.). As a result, 200 measurements were obtained. Descriptive sampling statistics were calculated using the SPSS Statistics program. An increase in motor activity reduces the pH level of the rumen environment. Lowering the pH factor of the rumen environment leads to an increase in ruminal temperature. There is a positive statistically significant correlation between ruminal and rectal temperature. The nosology of SARA can be predicted by measuring the motor activity and rectal temperature of dairy cows.(AU)

Este estudo visa determinar a relação entre indicadores de atividade motora, fator de pH, temperatura ruminal e retal em até 10 dias após o parto e analisar a possibilidade de utilizar os parâmetros estudados como sinais prognósticos para o diagnóstico de acidose ruminal subaguda (SARA). As medições foram feitas usando bolus com sensores projetados para monitorar a saúde das vacas. A atividade motora, o fator de pH e a temperatura ruminal de 10 vacas foram medidos durante 10 dias em intervalos de medição de 60 segundos. A seguir, os pesquisadores calcularam os valores médios das leituras obtidas, que foram divididos em 2 grupos de acordo com um intervalo de medição a cada 12 horas. A temperatura retal foi medida com um termômetro veterinário a cada 12 horas (às 8h e às 20h). Como resultado, foram obtidas 200 medições. As estatísticas de amostragem descritiva foram calculadas usando o programa SPSS Statistics. Um aumento na atividade motora reduz o nível de pH do ambiente ruminal. A redução do fator de pH do ambiente ruminal leva a um aumento da temperatura ruminal. Existe uma correlação positiva estatisticamente significativa entre a temperatura ruminal e retal. A nosologia com SARA pode ser prevista medindo a atividade motora e a temperatura retal de vacas leiteiras.(AU)

Determination of the secondary structure of epoxide hydrolase by Raman spectroscopy.

The secondary structure of microsomal epoxide hydrolase was determined by Raman spectroscopy and the effect of the membrane microenvironment studied. The ratios of the four secondary structure contents, alpha-helix: beta-strand:turn:undefined, were found to be 47:24:17:11 and 58:17:15:10 for the solubilized and the membrane-bound epoxide hydrolase, respectively. Based on the spectral analysis in the 2800-2900 cm-1 range, it was concluded that the protein studied produces the disordering effect on the lipid dimyristoylphosphatidylcholine bilayer at 16 degrees C.

Scanning tunneling microscopy study of cytochrome P450 2B4 incorporated in proteoliposomes.

In the present paper, the application of scanning tunneling microscopy in cytochrome P450s membrane topology is discussed. The method enables visualization of heme location in the lipid-bilayer-incorporated protein. It is supposed that the membrane-bound cytochrome P450 on the tunneling microscope substrate should behave as 'molecular diode'. A model explaining the liposome and the proteoliposome images observed is proposed.

The influence of motor nerve tetanization on the effect of organophosphorus cholinesterase inhibitors on neuromuscular transmission.

1. The changes in the activity of synaptic cholinesterases (ChE) of the ant. tibial muscle in the anaesthetized cat were detected by recording the changes of the blocking activity of acetylcholine (ACh) and comparing them with the blocking activity of carbaminoylcholine (carbachol) injected intra-arterially or intravenously. After the administration of organophosphorus inhibitors (OPI) of ChE the ACh blocking dose diminished 500 to 2000-fold but the carbachol blocking dose did not change. In 4-6 h after the injection of OPI the ACh blocking dose increased again 8 to 15-fold, but the dose of carbachol still remained unchanged. The transmission of high frequency impulses improved after OPI in parallel with the decrease of the ACh blocking activity. Thus the synaptic ChE is partly restored in a few hours after its irreversible inhibition with OPI. 2. Tetanization of the motor nerve (50-60 Hz, 10 min), started simultaneously with the intravenous injection of OPI (armine Gd-42), diminished the impairment of neuromuscular transmission. On the side of tetanization the ACh blocking action was less pronounced and the transmission of high frequency impulses better than on the control side. Thus the tetanization produced some protection of synaptic ChE against inhibition by OPI. The protective effect of tetanization was absent when the tetanization was performed before the injection of OPI or was started 10-20 min after the injection of OPI. 3. The protective effect of tetanization was also observed on the isolated phrenic nerve diaphragm preparation of the rat. 4. The possible mechanisms of the protective effect of tetanization are discussed.

Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer.

Dimebon, launched earlier in Russia as an antihistamine drug, was evaluated as a representative of a new generation of anti-Alzheimer's drugs that have two beneficial actions: (1) to alleviate symptoms, and (2) to prevent progression of the disease. The drug demonstrated cognition and memory-enhancing properties in the active avoidance test in rats treated with the neurotoxin AF64A, which selectively destroys cholinergic neurons. Dimebon protected neurons in the cerebellum cell culture against the neurotoxic action of beta-amyloid fragment (A beta 25-35, EC50 = 25 microM). In vitro, Dimebon displayed Ca(2+)-blocking properties (IC50 = 57 microM, on isolated rat ileum intestine) and pronounced anticholinesterase activity (IC50 = 7.9 microM and 42 microM for butyrylcholine esterase and acetylcholine esterase, respectively). It also exhibited strong anti-NMDA activity in the prevention of NMDA-induced seizures in mice (EC50 = 42 +/- 6 mg/kg i.p.). A beneficial effect of Dimebon in the therapy of Alzheimer's disease was demonstrated in a pilot clinical trial performed in the Moscow Center of Gerontology. Fourteen patients who participated in the trial were evaluated for their state of personality and for the severity of the disease. The evaluation included orientation (space, place, time, and patient personality), memory for the past and present, life in present, speech, irritability, and so forth. During and after the eight-week therapy with Dimebon, cognitive and self-service functions of patients improved significantly, and psychopathic symptoms, anxiety, depression, tearfulness, and headache were substantially diminished. The results of these studies suggest Dimebon as a new candidate for the therapy of Alzheimer's-like disorders.

The problem of the morphological noise in reconstructed dendritic arborizations.

For technical, instrumental and operator-related reasons, three-dimensional (3D) reconstructions of neurons obtained from intracellularly stained neuronal pieces scattered in serial sections are blurred by some morphological noise. This noise may strongly invalidate conclusions drawn from models built using the 3D reconstructions and it must be taken into account when retrieving digitized neurons from available databases. We analyse on several vertebrate neurons examples the main noise-generating sources and the consequences of the noise on the 'quality' of the data. We show how the noise can be detected and evaluated in any database, if sufficient information is presented in this database.

Demonstration of rabbit haemorrhagic disease virus antigen by Staphylococcus protein A coagglutination test.

The Staphylococcus protein A coagglutination test (Sp A COAT) was developed for the diagnosis of rabbit haemorrhagic disease (RHD). Liver, spleen, lungs and kidneys from 176 rabbits dead from viral haemorrhagic disease as well as the same organs from 64 healthy animals were examined by Sp A COAT and haemaglutination test (HAT). The Sp A COAT was specific and considerably more simple to carry out than the HAT, which made it very useful for rapid identification of RHD.

Revelation of ternary complexes between redox partners in cytochrome P450-containing monooxygenase systems by the optical biosensor method.

Formation of binary and ternary complexes in the water-soluble cytochrome P450cam (P450cam)-containing as well as in the membrane P4502B4(2B4)- and the mixed P450scc-containing monooxygenase systems was investigated in real time by the 'resonant mirror' optical biosensor method. It was shown that the inter-protein electron transfer occurs not only during complex formation but also upon random collision--as was the case with the d-Fp/d-b5 pair (2B4 system). Binary complexes may be either facilitative to electron transfer (electron-transfer complexes) or prohibitive to it (non-productive complexes). Although the binary PdR/Pd and P450cam/Pd complex formation (within the P450cam-system) as well as the binary AdR/Ad and P450scc/Ad complex formation (within the P450scc-system) does occur, the lifetimes of these complexes formed are several orders of magnitude higher than the time required for realization of a complete hydroxylation cycle. At the same time, the lifetimes of the ternary PdR/Pd/P450cam and AdR/Ad/P450scc complexes are sufficient to permit the realization of a complete hydroxylation cycle in either of these systems. For the membrane P450 2B4 system, the formation of both the binary (Fp/2B4 and 2B4/b5) and ternary (Fp/2B4/b5) complexes was registered. The lifetimes of the binary Fp/2B4 and the ternary Fp/2B4/b5 complexes are sufficient for realization of a complete hydroxylation cycle in each of them.

Melting and heating of two-dimensional Coulomb clusters in dusty plasmas.

The heating and melting of two-dimensional dust clusters with one additional particle in the lower layer has been investigated experimentally in a gas discharge. The full dynamical properties of the system during the entire phase transition were determined in terms of the spectral power densities of the crystal modes. A two-step melting transition is identified when the gas pressure in the discharge is reduced: first, a sudden increase of the dust temperature takes place due to an instability of the lower-layer particle resulting in a hot crystalline state of the cluster, and second, the actual transition into a fluid state is observed at a decisively lower gas pressure.

Electron density of KNiF3: analysis of the atomic interactions

The topological analysis of the electron density in the perovskite KNiF3, potassium nickel trifluoride, based on the accurate X-ray diffraction data, has been performed. The topological picture of the atomic interactions differs from that resulting from the classic crystal chemistry consideration. The shapes of atoms in KNiF3 defined by zero-flux surfaces in the electron density are, in general, far from spherical. At the same time, their asphericity in the close-packed layer is very small. The topological coordination numbers of K and Ni are the same as the geometrical ones, whereas topological coordination for the F atom (6) differs from the geometrical value. The latter results from a specific shape of the Ni-atom basin preventing the bond-path formation between F atoms in the same atomic close-packed layer, in spite of the fact that the closest F-F distance is the same as K-F. Judging by the electron density value and curvature at the bond critical points, the K-F interaction in KNiF3 can be considered ionic, while the Ni-F bond belongs to the polar covalent type. No correlation of the topological ionic radii with crystal or ionic radii was found in KNiF3. Critical points in the electrostatic potential have also been studied.

Electron density and electrostatic potential of KNiF3: multipole, orbital and topological analyses of vacuum-camera-imaging plate and four-circle diffractometer data.

The electron density and electrostatic potential of KNiF(3), nickel potassium trifluoride, were studied using multipole and orbital model treatment of the precision X-ray diffraction data measured by vacuum-camera-imaging plate and four-circle diffractometer methods. Different experimental methods lead to similar multipole and atomic displacement parameters and to qualitatively the same electron densities. Good agreement was also achieved for the Laplacians of the electron density and the electrostatic potentials. Some pitfalls of the vacuum-camera-imaging plate method that could be improved are discussed.