Novel mutations in the toll like receptor genes cause hyporesponsiveness to Mycobacterium avium subsp. paratuberculosis infection

Toll like receptors play a central role in the recognition of pathogen associated molecular patterns (PAMPs). Mutations in TLR1, TLR2 and TLR4 genes may change the PAMP reorganization ability which causes altered responsiveness to the bacterial pathogens. A case control study, performed to assess the association between TLR gene mutations and susceptibility to Mycobacterium avium subsp. paratuberculosis (MAP), revealed novel mutations (TLR1 - Ser150Gly and Val220Met; TLR2 - Phe670Leu) that hindered either PAMP recognition or further downstream TLR pathway activation. A cytokine expression experiments (IL-4, IL-8, IL-10, IL-12 and IFN-γ) in the challenged mutant and wild type moDCs (mocyte derived dendritic cells) confirmed the negative impact of these mutations and altered TLR downstream activation. Further In silico analysis of the TLR1 and TLR4 ectodomains (ECD) revealed the polymorphic nature of the central ECD and irregularities in the central LRR motifs. The most critical positions that may alter the pathogen recognition ability of TLR were: the 9th amino acid position in LRR motif (TLR1, LRR10) and 4th residue downstream to LRR domain (exta LRR region of TLR4). The study describes novel mutations in the TLRs and presents their association with the MAP infection

Specific aspects of researching the oncogenesis and metastatasing potential of laringeal squamous cell carcinoma

Malignant tumor metastasizing, comprised of several consecutive steps beginning with local cancer cell invasion, is a key factor which compromises the prognosis of cancer patients and is responsible for 90% of the lethal outcome. 2/3 of our diagnosed patients show with locally advanced process and/or metastatic disease (stage III/IV).Researching key molecular and cellular mechanisms tied to development and metastasizing of laryngeal squamous cell carcinoma is of clinical importance to developing and using molecular target therapy.Based on popular literature studies the emphasize was put on the following genes: TP53, CDKN2A – accentuating on exons 1,2,3, and PIK3CA – exons 9, 20, as primarily connected to the higher mutation potential of laryngeal squamous cell carcinoma.Researching the genetic similarity between carcinoma and metastasis could potentially help understanding the genotype and mutation potential of Head and Neck squamous cell carcinomas. The practical potential use of this knowledge is the developing of predictive markers and better therapeutic algorithms for diagnosed patients. ---------------------------------------------------------------------- Туморното метастазиране, включващо няколко последователни стъпки, започвайки от инвазия на раковите клетки в околните тъкани, е ключовият фактор, който компрометира прогнозата на раково болните пациенти и отговаря за 90% от смъртността. 2/3 от диагностицираните пациенти са с локално авансирал процес и/ или метастатична болест (стадий III или IV).Проучването на молекулярни и клетъчни механизми, водещи до формирането и метастазирането на плоскоклетъчния карцином от ларингеален произход, би било от клинична полза за разработването на молекулярна таргетна терапия.На базата на обширен литературен обзор акцентът е поставен върху следните гени – TP53, CDKN2A – exons 1,2,3 and PIK3CA – exons 9, 20, като потенциални отговорници за повишаване метастатичния потенциал на плосколетъчния карцином от ларингеален произход.Изследването на генетично сродство между карцином и метастаза би имало теоретичен принос към опознаването на генотипа и мутационния статус на плоскоклетъчните карциноми на глава и шия, чийто практически потенциал се изразява като прогностична стойност за преживяемостта на онкоболните и подобряване на терапевтичния алгоритъм при диагностицирани пациенти

Changes in gene expression of EGFR and LAD1 in patients with metastatic squamous cell laryngeal carcinoma

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Analysis of life expectancy in Russian regions

This study deals with the analysis of the factors that determine life expectancy in Russia at the macro level. Among the available statistical indicators, those were selected that can be considered as a macroeconomic alternative to the basic microeconomic determinants affecting the life expectancy of an individual. As a result of the regression analysis, significant indicators were identified, which included the marriage rate, the unemployment rate, the number of students, the number of hospital beds, the gross regional product, budget expenditures on health care, and the region’s subtropical climate. A cluster analysis of the regions was also carried out for these indicators, with the exception of the last one, and it was shown that the regions are distributed into 5 clusters. The cluster, which includes Moscow and St. Petersburg, where there is a high life expectancy due to the metropolitan area of these regions and good medicine, is singled out separately. The regions of the North Caucasus are also characterized by high life expectancy, but here it is due to completely different reasons: religious and climatic features. The Tyumen, Magadan, Sakhalin regions and the Chukotka Autonomous Okrug are united into a separate cluster. These regions are characterized by the highest GRP, but low life expectancy and the lowest number of students

Comparison of welfare of cows kept on organic and conventional farms using Animal needs index system

The aim of the study was to compare and evaluate the welfare of cows kept on two conventional and two organic farms using Animal Needs Index (ANI) system. The system is rapid and easy to use. Its most important advantage is that it provides a final score and thus allows one to rate the evaluated object on a scale reflecting the level of welfare on the respective farm and thus compare farms with different ways of housing. The system showed a very good welfare level on two of four evaluated farms, both with free housing of cows, one organic and one conventional

Designing organometallic compounds for catalysis and therapy

Bioorganometallic chemistry is a rapidly developing area of research. In recent years organometallic compounds have provided a rich platform for the design of effective catalysts, e.g. for olefin metathesis and transfer hydrogenation. Electronic and steric effects are used to control both the thermodynamics and kinetics of ligand substitution and redox reactions of metal ions, especially Ru II. Can similar features be incorporated into the design of targeted organometallic drugs? Such complexes offer potential for novel mechanisms of drug action through incorporation of outer-sphere recognition of targets and controlled activation features based on ligand substitution as well as metal- and ligand-based redox processes. We focus here on η 6-arene, η 5-cyclopentadienyl sandwich and half-sandwich complexes of Fe II, Ru II, Os II and Ir III with promising activity towards cancer, malaria, and other conditions. © 2012 The Royal Society of Chemistry

Оценка состояния зеленых насаждений в скверах Улан - Удэ

Research on green area in Ulan-Ude has not been carried out since the moment of planting in 1970. The researchers didn’t study hardy-shrub species and factors of their strengthening and weakening. The research aims at evaluation of green areas in the mini-parks of UlanUde. The authors assess green areas in all mini-parks of the city and define species composition of hardy-shrub species and their condition. The researchers found out 23 species of trees and shrubs used in landscaping of Ulan-Ude. The identified species belong to 12 families and 23 genera. The largest number of species belongs to Rosaceae-7 species, the smallest number of hardy-shrub species belong to Cornaceae, Adoxaceae, Oleaceae and Ulmaceae. The researchers observed hardy-shrub species and found out that trees predominate (56.3%) the shrubs (43.5 %). Dominating tree species in the mini-parks are the balsamifera (L.) and Ulmus pumila (L.). The bushes commonly observed are Caragana arborescens (Lam.). The vital state of tree and shrubbery plantings is generally characterized as medium-stable, damaged, ranging from stable, healthy to unstable, severely damaged. The range of tree and shrubbery plantings used in gardening of Ulan-Ude is completed. The conducted research revealed that the main factors of lower resistance of green area in the city mini parks are seen as damaged development of the crown and drying of branches, mechanical damages of a trunk; stripping of bark and small deformations and cracks in a trunk, damages in axial escape and the crown related to high density of landings, curvature of a trunk and break of boughs of trees and bushes as a result of influence of wind or anthropogenic activity; careless attitude to requirements of cutting trees and bushes; twisting of leaves, modification of shoots, colorful Gauls due to attacks on them aphids; the presence of bacterial diseases in balsamic poplar; infectious pathologies of trunks and leaves.Обследования зеленых насаждений г. Улан-Удэ не проводились с момента посадок в 1970-х годах, детально не изучалось состояние древесно-кустарниковых насаждений, факторы их ослабления и усыхания. Цель исследований – дать оценку состояния зеленых насаждений в скверах г. Улан-Удэ. Впервые в условиях г. Улан-Удэ проведена детальная инвентаризация зеленых насаждений на территории всех скверов, где определен видовой состав древесно-кустарниковых насаждений, дана первичная оценка их состояния. Установлено 23 вида деревьев и кустарников, которые используются в озеленении г. Улан-Удэ. Выявленные виды относятся к 12 семействам и 23 родам. Наибольшее число видов принадлежит семейству Rosaceae – 7 видов, наименьшее количество видов деревьев и кустарников представлено семействами Cornaceae, Adoxaceae, Oleaceae и Ulmaceae. Среди выявленных деревьев и кустарников преобладают деревья (56,3 %), кустарники составляют 43,5 %. Преобладающими древесными породами в скверах города являются Рopulus balsamifera (L.) и Ulmus pumila (L.). Среди кустарников чаще встречается Caragana arborescens (Lam.). Жизненное состояние древесно-кустарниковых насаждений в целом характеризуется как среднеустойчивое, повреждённое, варьируя от устойчивых, здоровых до неустойчивых, сильно повреждённых. Ассортимент деревьев и кустарников, который используется в озеленении г. Улан-Удэ, в целом сложился. На основе проведенных исследований к основным факторам снижения устойчивости городских зеленых насаждений на территории скверов города следует отнести: нарушения развития кроны и усыхание ветвей, наличие механических повреждений ствола; обдир коры и образование небольших деформаций и трещин ствола, нарушения развития осевого побега и кроны, связанные с высокой плотностью посадок, искривление ствола и слом сучьев деревьев и кустарников в результате воздействия ветра или антропогенной деятельности, а также отсутствие должного ухода и нарушения общепринятых требований обрезки деревьев и кустарников; скручивание листьев, видоизменение побегов, появление разноцветных галлов вследствие нападения на них тлей; наличие бактериальных болезней у тополя бальзамического; поражаемость инфекционными патологиями стволов и листьев

Novel mutations in TLR genes cause hyporesponsiveness to Mycobacterium avium subsp. paratuberculosis infection

<p>Abstract</p> <p>Background</p> <p>Toll like receptors (TLR) play the central role in the recognition of pathogen associated molecular patterns (PAMPs). Mutations in the TLR1, TLR2 and TLR4 genes may change the ability to recognize PAMPs and cause altered responsiveness to the bacterial pathogens.</p> <p>Results</p> <p>The study presents association between TLR gene mutations and increased susceptibility to <it>Mycobacterium avium </it>subsp. <it>paratuberculosis </it>(MAP) infection. Novel mutations in TLR genes (TLR1- Ser150Gly and Val220Met; TLR2 – Phe670Leu) were statistically correlated with the hindrance in recognition of MAP legends. This correlation was confirmed subsequently by measuring the expression levels of cytokines (IL-4, IL-8, IL-10, IL-12 and IFN-γ) in the mutant and wild type moDCs (mocyte derived dendritic cells) after challenge with MAP cell lysate or LPS. Further <it>in silico </it>analysis of the TLR1 and TLR4 ectodomains (ECD) revealed the polymorphic nature of the central ECD and irregularities in the central LRR (leucine rich repeat) motifs.</p> <p>Conclusion</p> <p>The most critical positions that may alter the pathogen recognition ability of TLR were: the 9^thamino acid position in LRR motif (TLR1–LRR10) and 4^thresidue downstream to LRR domain (exta-LRR region of TLR4). The study describes novel mutations in the TLRs and presents their association with the MAP infection.</p

Conjugation of a Ru(II) Arene Complex to Neomycin or to Guanidinoneomycin Leads to Compounds with Differential Cytotoxicities and Accumulation between Cancer and Normal Cells

A straightforward methodology for the synthesis of conjugates between a cytotoxic organometallic ruthenium(II) complex and amino- and guanidinoglycosides, as potential RNA-targeted anticancer compounds, is described. Under microwave irradiation, the imidazole ligand incorporated on the aminoglycoside moiety (neamine or neomycin) was found to replace one triphenylphosphine ligand from the ruthenium precursor [(η6-p-cym)RuCl(PPh3)2]+, allowing the assembly of the target conjugates. The guanidinylated analogue was easily prepared from the neomycin-ruthenium conjugate by reaction with N,N′-di-Boc-N″-triflylguanidine, a powerful guanidinylating reagent that was compatible with the integrity of the metal complex. All conjugates were purified by semipreparative high-performance liquid chromatography (HPLC) and characterized by electrospray ionization (ESI) and matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) and NMR spectroscopy. The cytotoxicity of the compounds was tested in MCF-7 (breast) and DU-145 (prostate) human cancer cells, as well as in the normal HEK293 (Human Embryonic Kidney) cell line, revealing a dependence on the nature of the glycoside moiety and the type of cell (cancer or healthy). Indeed, the neomycin-ruthenium conjugate (2) displayed moderate antiproliferative activity in both cancer cell lines (IC50 ≈ 80 μM), whereas the neamine conjugate (4) was inactive (IC50 ≈ 200 μM). However, the guanidinylated analogue of the neomycin-ruthenium conjugate (3) required much lower concentrations than the parent conjugate for equal effect (IC50 = 7.17 μM in DU-145 and IC50 = 11.33 μM in MCF-7). Although the same ranking in antiproliferative activity was found in the nontumorigenic cell line (3 2 > 4), IC50 values indicate that aminoglycoside-containing conjugates are about 2-fold more cytotoxic in normal cells (e.g., IC50 = 49.4 μM for 2) than in cancer cells, whereas an opposite tendency was found with the guanidinylated conjugate, since its cytotoxicity in the normal cell line (IC50 = 12.75 μM for 3) was similar or even lower than that found in MCF-7 and DU-145 cancer cell lines, respectively. Cell uptake studies performed by ICP-MS with conjugates 2 and 3 revealed that guanidinylation of the neomycin moiety had a positive effect on accumulation (about 3-fold higher in DU-145 and 4-fold higher in HEK293), which correlates well with the higher antiproliferative activity of 3. Interestingly, despite the slightly higher accumulation in the normal cell than in the cancer cell line (about 1.4-fold), guanidinoneomycin-ruthenium conjugate (3) was more cytotoxic to cancer cells (about 1.8-fold), whereas the opposite tendency applied for neomycin-ruthenium conjugate (2). Such differences in cytotoxic activity and cellular accumulation between cancer and normal cells open the way to the creation of more selective, less toxic anticancer metallodrugs by conjugating cytotoxic metal-based complexes such as ruthenium(II) arene derivatives to guanidinoglycosides

PSYCHOLOGICAL AND PEDAGOGICAL CONDITIONS FOR THE DEVELOPMENT OF MORAL BEHAVIOR IN OLDER PRESCHOOLERS WITH MENTAL RETARDATION

The article presents the results of an experimental study of the moral behavior of older preschoolers with mental retardation. The relevance of the study in the context of modern requirements of the Federal State Standard of Preschool Education is indicated. The author analyzes modern studies of the moral sphere of normally developing preschoolers and their peers with mental retardation. The methodological substantiation of experimental approaches to the study of moral behavior in preschool childhood is given. The main stages of the psychological and pedagogical program for the development and correction of moral behavior of older preschoolers with mental retardation are presented. The article describes the main correctional and developmental tools used in working with children: didactic and story-role-playing games, reading children's fiction, watching cartoons, listening to music, dramatization games, problem situations. Determined by the psychological and pedagogical conditions for the development of moral behavior of preschool children with mental retardation: development of special humanistically directional relations to peers and adults; developing children's conscious decision to follow moral norms; the introduction of preschoolers to practice moral behavior; creating conditions for the development of children moral habits on the basis of the consolidation standards of moral conduct. Further prospects of psychological and pedagogical research in this direction are indicated