Tick-borne encephalitis virus (TBEV) is a flavivirus which causes an acute or sometimes chronic infection that frequently has severe neurological consequences, and is a major public health threat in ...Eurasia. TBEV is genetically classified into three distinct subtypes; however, at least one group of isolates, the Baikal subtype, also referred to as "886-84-like", challenges this classification. Baikal TBEV is a persistent group which has been repeatedly isolated from ticks and small mammals in the Buryat Republic, Irkutsk and Trans-Baikal regions of Russia for several decades. One case of meningoencephalitis with a lethal outcome caused by this subtype has been described in Mongolia in 2010. While recombination is frequent in Flaviviridae, its role in the evolution of TBEV has not been established. Here, we isolate and sequence four novel Baikal TBEV samples obtained in Eastern Siberia. Using a set of methods for inference of recombination events, including a newly developed phylogenetic method allowing for formal statistical testing for such events in the past, we find robust support for a difference in phylogenetic histories between genomic regions, indicating recombination at origin of the Baikal TBEV. This finding extends our understanding of the role of recombination in the evolution of this human pathogen.
Rheumatoid arthritis (RA), a chronic inflammatory disease affecting primarily the joints, is frequently characterized by the presence of autoimmune anticitrullinated protein antibodies (ACPA) during ...preclinical stages of disease and accumulation of hypercitrullinated proteins in arthritic joints. A strong association has been reported between RA and periodontal disease, and Porphyromonas gingivalis, a known driver of periodontitis, has been proposed as the microbial link underlying this association. We recently demonstrated P. gingivalis–mediated gut barrier breakdown and exacerbation of joint inflammation during inflammatory arthritis. In the present study, we investigated another potential role for P. gingivalis in RA etiopathogenesis, based on the generation of ACPA through the activity of a unique P. gingivalis peptidylarginine deiminase (PPAD) produced by this bacterium, which is capable of protein citrullination. Using a novel P. gingivalis W50 PPAD mutant strain, incapable of protein citrullination, and serum from disease-modifying antirheumatic drug–naïve early arthritis patients, we assessed whether autocitrullinated proteins in the P. gingivalis proteome serve as cross-activation targets in the initiation of ACPA production. We found no evidence for patient antibody activity specific to autocitrullinated P. gingivalis proteins. Moreover, deletion of PPAD did not prevent P. gingivalis–mediated intestinal barrier breakdown and exacerbation of disease during inflammatory arthritis in a murine model. Together, these findings suggest that the enzymatic activity of PPAD is not a major virulence mechanism during early stages of inflammatory arthritis.
Porphyromonas gingivalis is a Gram‐negative black pigmenting anaerobe that is unable to synthesize heme Fe(II)‐protoporphyrin IX or hemin Fe(III)‐protoporphyrin IX‐Cl, which are important ...growth/virulence factors, and must therefore derive them from the host. Porphyromonas gingivalis expresses several proteinaceous hemin‐binding sites, which are important in the binding/transport of heme/hemin from the host. It also synthesizes several virulence factors, namely cysteine‐proteases Arg‐ and Lys‐gingipains and two lipopolysaccharides (LPS), O‐LPS and A‐LPS. The gingipains are required for the production of the black pigment, μ‐oxo‐bisheme {Fe(III)PPIX2 O}, which is derived from hemoglobin and deposited on the bacterial cell‐surface leading to the characteristic black colonies when grown on blood agar. In this study we investigated the role of LPS in the deposition of μ‐oxo‐bisheme on the cell‐surface. A P. gingivalis mutant defective in the biosynthesis of Arg‐gingipains, namely rgpA/rgpB, produces brown colonies on blood agar and mutants defective in Lys‐gingipain (kgp) and LPS biosynthesis namely porR, waaL, wzy, and pg0129 (α‐1, 3‐mannosyltransferase) produce non‐pigmented colonies. However, only those mutants lacking A‐LPS showed reduced hemin‐binding when cells in suspension were incubated with hemin. Using native, de‐O‐phosphorylated and de‐lipidated LPS from P. gingivalis W50 and porR strains, we demonstrated that hemin‐binding to O‐polysaccharide (PS) and to the lipid A moiety of LPS was reduced compared with hemin‐binding to A‐PS. We conclude that A‐LPS in the outer‐membrane of P. gingivalis serves as a scaffold/anchor for the retention of μ‐oxo‐bisheme on the cell surface and pigmentation is dependent on the presence of A‐LPS.
Requirements to high performances of modern Free Electron Lasers (FEL) facilities transform to requirements of high stability of their electron injectors, which are typically based on photocathode RF ...guns. To provide high brightness bunches, gun cavities operate in the injector with high pulsed electric, hence, magnetic fields. The effects, related to a pulsed RF heating, result in the change of resonance frequency and quality factor of the cavity even during few μs RF pulse that, in turn leads to the amplitude and the phase change of RF oscillations in the gun cavity. Cavity deformations due to pulsed heating are considered and corresponding deviations in the cavity resonance frequency are evaluated. Resulting deviations in the phase and the amplitude of the RF field in the cavity are estimated in dependence on the RF pulse duration.
This paper synthesizes the available scientific information connecting atmospheric nucleation with subsequent cloud condensation nuclei (CCN) formation. We review both observations and model studies ...related to this topic, and discuss the potential climatic implications. We conclude that CCN production associated with atmospheric nucleation is both frequent and widespread phenomenon in many types of continental boundary layers, and probably also over a large fraction of the free troposphere. The contribution of nucleation to the global CCN budget spans a relatively large uncertainty range, which, together with our poor understanding of aerosol-cloud interactions, results in major uncertainties in the radiative forcing by atmospheric aerosols. In order to better quantify the role of atmospheric nucleation in CCN formation and Earth System behavior, more information is needed on (i) the factors controlling atmospheric CCN production and (ii) the properties of both primary and secondary CCN and their interconnections. In future investigations, more emphasis should be put on combining field measurements with regional and large-scale model studies.
Dysregulation of the developmentally important Notch signaling pathway is implicated in several types of cancer, including breast cancer. However, the specific roles and regulation of the four ...different Notch receptors have remained elusive. We have previously reported that the oncogenic PIM kinases phosphorylate Notch1 and Notch3. Phosphorylation of Notch1 within the second nuclear localization sequence of its intracellular domain (ICD) enhances its transcriptional activity and tumorigenicity. In this study, we analyzed Notch3 phosphorylation and its functional impact. Unexpectedly, we observed that the PIM target sites are not conserved between Notch1 and Notch3. Notch3 ICD (N3ICD) is phosphorylated within a domain, which is essential for formation of a transcriptionally active complex with the DNA-binding protein CSL. Through molecular modeling, X-ray crystallography, and isothermal titration calorimetry, we demonstrate that phosphorylation of N3ICD sterically hinders its interaction with CSL and thereby inhibits its CSL-dependent transcriptional activity. Surprisingly however, phosphorylated N3ICD still maintains tumorigenic potential in breast cancer cells under estrogenic conditions, which support PIM expression. Taken together, our data indicate that PIM kinases modulate the signaling output of different Notch paralogs by targeting distinct protein domains and thereby promote breast cancer tumorigenesis via both CSL-dependent and CSL-independent mechanisms.
Bulk boron carbide (B4C) ceramics was fabricated from a boron and carbon mixture by use of one-step reactive spark plasma sintering (RSPS). It was also demonstrated that preliminary high-energy ball ...milling (HEBM) of the B+C powder mixture leads to the formation of B/C composite particles with enhanced reactivity. Using these reactive composites in RSPS permits tuning of synthesized B4C ceramic microstructure. Optimization of HEBM + RSPS conditions allows rapid (less than 30min of SPS) fabrication of B4C ceramics with porosity less than 2%, hardness of ~35GPa and fracture toughness of ~ 4.5MPam 1/2
The research relevance on improving the thermal energy recovery efficiency of gas turbine technology is caused by the need to reduce the fuel and energy consumption when generating the electric ...energy. The research objective is to define the technically and economically feasible heat recovery ratio of exhaust gases after gas turbine in the heat regenerator. The optimization problem of the heat potential recovery process was solved. The algorithm to calculate the optimal temperature of heating the air supplied to the combustion chamber of the gas turbine unit was developed. Methods of mathematical modelling of heat exchange processes, methods of choosing the rational option in solving the optimization problem, and mathematical methods of solving the optimization problems were used in the paper. The influence analysis of the optimal air temperature required for burning the fuel in the combustion chamber on the technical and economic efficiency of the Siemens SGT-100 gas turbine equipment was carried out. The expediency of applying the performed studies results of practical application in designing and operating gas turbine machines was substantiated.
Alzheimer disease (AD) is a widespread neurodegenerative disease characterized by the accumulation of oligomeric toxic forms of β-amyloid (Aβ1-42) and dysfunction of the cholinergic system in the ...different brain regions. However, the exact mechanisms of AD pathogenesis and the role of the nicotinic acetylcholine receptors (nAChRs) in the disease progression remain unclear. Here, we revealed a decreased expression of a number of the Ly6/uPAR proteins targeting nAChRs in the cerebellum of 2xTg-AD mice (model of early AD) in comparison with non-transgenic mice both at mRNA and protein levels. We showed that co-localization of one of them, – neuromodulator Lynx1, with α7-nAChR was diminished in the vicinity of cerebellar astrocytes of 2xTg-AD mice, while Aβ1-42 co-localization with this receptor present was increased. Moreover, the expression of anti-inflammatory transcription factor KLF4 regulating transcription of the Ly6/uPAR genes was decreased in the cerebellum of 2xTg-AD mice, while expression of inflammatory cytokine TNF-α was increased. Based on these data together with observed astrocyte degeneration in the cerebellum of 2xTg-AD mice, we suggest the mechanism by which expression of the Ly6/uPAR proteins upon Aβ pathology results in dysregulation of the cholinergic system and particularly of α7-nAChR function in the cerebellum. This leads to enhanced neuroinflammation and cerebellar astrocyte degeneration.
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