Requirement for a Uroplakin 3a-like protein in the development of zebrafish pronephric tubule epithelial cell function, morphogenesis, and polarity

Uroplakin (UP)3a is critical for urinary tract development and function; however, its role in these processes is unknown. We examined the function of the UP3a-like protein Upk3l, which was expressed at the apical surfaces of the epithelial cells that line the pronephric tubules (PTs) of the zebrafish pronephros. Embryos treated with upk3l-targeted morpholinos showed decreased pronephros function, which was attributed to defects in PT epithelial cell morphogenesis and polarization including: loss of an apical brush border and associated phospho-ERM proteins, apical redistribution of the basolateral Na+/K+-ATPase, and altered or diminished expression of the apical polarity complex proteins Prkcz (atypical protein kinase C zeta) and Pard3 (Par3). Upk3l missing its C-terminal cytoplasmic domain or containing mutations in conserved tyrosine or proline residues did not rescue, or only partially rescued the effects of Upk3l depletion. Our studies indicate that Upk3l promotes epithelial polarization and morphogenesis, likely by forming or stimulating interactions with cytoplasmic signaling or polarity proteins, and that defects in this process may underlie the pathology observed in UP3a knockout mice or patients with renal abnormalities that result from altered UP3a expression. © 2012 Mitra et al

О ПРОМЫШЛЕННОЙ БЕЗОПАСНОСТИ В МОСТОСТРОЕНИИ

Industrial safety system evolved on the railways for decades. In new economic conditions, many of its basic principles remain, but also those factors have arisen that require scientific analysis, experimental verification, modern technical and technological means. At the example of construction and maintenance of bridgeworks, the authors examine and evaluate the situation with safety, injury rate, fire hazard in railway transport.Система промышленной безопасности складывалась на железных дорогах десятилетиями. В новых экономических условиях многие ее базовые принципы сохранились, но появились и те факторы, которые требуют научного анализа, экспериментальной проверки, современных технико-технологических средств. На примере строительства и обслуживания мостовых сооружений авторы исследуют и оценивают ситуацию с безопасностью труда, травматизмом, пожароопасностью на объектах железнодорожного транспорта

A Multimodal Approach to Analgesia in Anorectal Surgery

Аim: Evaluation of methods for pain prevention and pain reduction after anorectal surgery at all stages of treatment based on publications found in available databases.Key points. Most anorectal diseases are benign and do not affect life expectancy, meanwhile about 40 % of the population suffer from it. Mainly anorectal disorders affect middle-aged people reducing their life quality. At the same time many articles aimed at studying only postoperative anesthesia. 2 researchers independently searched for articles published in Medline, Scopus, Cochrane, Web of Science, E-library databases using keywords. A total of 54 publications were included. A multimodal approach should include the pain prevention during pre-, intra- and postoperative periods. Acetaminophen is recommended for pain reduction according to the dosing protocols. Acetaminophen combined with other systemic analgesics is advisable for patients with severe pain. The opioids use is justified only for moderate-severe postoperative pain. Metronidazole and lidocaine with nitroglycerin ointment/ nifedipine/сorticosteroids effectiveness has been proven for local postoperative anesthesia. Prophylactic use of antibiotics and bowel preparation do not reduce postoperative pain. Stool softeners are recommended for reducing postoperative pain severity. Additional local anesthesia such as nerve blockade or infiltration anesthesia is recommended for all patients. Modern minimally invasive treatment methods of hemorrhoid are associated with less severe postoperative pain.Conclusion. The recommended scheme of multimodal anesthesia for patients after anorectal surgery is shown on Fig.1. Further studies are needed to evaluate preoperative anesthesia effectiveness, the feasibility of the perioperative flavonoids use, as well as comparisons of various minimally invasive treatment methods of anorectal diseases

Methods for Mesh Implantation Efficacy Assessment in Rectocele

Aim. A methodological review on mesh implantation efficacy assessment in surgery for rectocele.Key points. Specialised quiz surveys are among the most appropriate methods to assess surgical intervention efficacy. The questionnaires that enable pre- and postsurgery rectocele grading include PFDI-20 (Pelvic Floor Distress Inventory), the colonic evacuation disorder scale and Cleveland Constipation Scoring System. These surveys determine the surgical intervention efficacy dynamically in conjunction with instrumental surgery assessment techniques.Conclusion. Clinical practice at the Ryzhikh National Medical Research Centre for Coloproctology combines the originally developed colonic evacuation disorder scale (2003) and PFDI-20. The combined scales allow for a comprehensive symptom assessment in patients with rectocele and other descending perineum syndrome manifestations prior to surgery, as well as symptom dynamics evaluation postoperatively, which, in link with defecography, enables a complete appraisal of the surgical effect

EXCESSIVE MORTALITY IN WINTER IN MOSCOW AND ITS ECONOMIC VALUE DURING THE YEARS 2007-2014

Aim. To study the excessive mortality during the winter (EMW) from all causes and CVD, monthly values of mortality; to evaluate social and economic harm due to EMW in Moscow.Material and methods. The calculation of EMW (%) was done for Moscow by the mortality from all causes and from CVD by a special equation. For monthly values of mortality we estimated the average range per month by absolute number of the deaths — absolute parameters of mortality by every analyzed year were ranged from 1 to 12, and mean value of the range was calculated.Results. Mean EMW per 8 years was 5,1%, for CVD higher — 8,8%. In Moscow there is an influence of the anomaly heat of 2010 — EMW was 4,5% from all causes, from CVD — 6,0%. Maximum number of deaths was registered in January and march. Gross EH by 2007-2013 from EMW was 7,9 billion rubles in Moscow.Conclusion. A significant part of EMW are the deaths from CVD. The amount of EH from EMW has confirmed the shown previously relation from two factors — number of deaths and size of GRP in region. For Moscow — the capital of Russia, having the highest values of economic development, the harm, that is quite significant, grounds the necessity of investments into excessive mortality and search for effective by decrease of mortality in winter time

Abstract OR-4: New Antibiotic Binding Site on the 30S Ribosomal Subunit

Background: Antibiotic resistance becomes one of the main problems of modern medicine; therefore, the development of new antibacterial compounds is absolutely necessary. The ribosome is the target for a lot of different antibiotics; there are several main binding sites on the ribosome – decoding center, peptidyl-transferase center, and ribosome exit tunnel. Modification or mutation of nucleotides in these sites could make cells resistant to structurally different antibiotics. Methods: pDualrep2 reporter system was used for detection of the protein synthesis inhibitors in cultural broths of new soil bacteria. By means of a cell-free translation system, the inhibitory activity and mechanism of action of Auraplanin were estimated. CryoEM data collection was performed on a Titan Krios operated at 300 kV, equipped with a Falcon II direct electron detector. Results: In this work, we have found a new inhibitor of protein synthesis, which binds in a completely new binding site. This compound is produced by Actinoplanes sp. VKM Ac-2862 and by Cryo-EM study of its complex with E.coli ribosome, it was shown, that it binds close to 560 loop of 30S ribosomal subunit. The new compound is a derivative of tetramic acid and we called it Auraplanin, because of bright orange color of the producer strain. Structural data are in good agreement with genetic results – resistant mutations were located close determined binding site. Substitutions C564G, G558U, and G566A significantly increase minimal inhibitory concentration, all these mutations were not detected previously. We also observed resistant mutation in ribosomal protein S4, this mutation was previously identified as error-prone. Interestingly, ribosomal ambiguity mutations, G299A and G347U, also increased resistance to Auraplanin. Conclusion: On the basis of the genetic, structural and biochemical studies we hypothesized that Auraplanin acts prevent the transfer from an open to a closed conformation of 30S subunit, in contrast to streptomycin, which promotes the formation of a closed state

Протон-ініційована циклізація N-aлкіламідів стирилоцтових кислот. Синтез 5-арилпіролідин-2-онів

Aim. To study the effect of the structural parameters of styrylacetic acid amides on the course of the reaction of the electrophilic intramolecular cyclization under the action of polyphosphoric acid and search the rational approaches to obtain N-unsubstituted 5-arylpyrrolidine-2-ones.Results and discussion. The literature sources related to the main methods of synthesis, as well as the biological activity of 5-arylpyrrolidine-2-ones, have been analyzed and systematized. The regiochemistry of the cyclization of N-unsubstituted and N-alkyl amides of styrylacetic acids has been studied using polyphosphoric acid (PPA).Experimental part. It has been found that N-unsubstituted styrylacetic acid amides when heating at 100 °C in PPA are cyclized to 5-arylpyrrolidine-2-ones with the yields of 44-58 %. For N-tert-butylamides with donor substituents in the styrenic moiety of the molecule the cyclization under similar conditions is accompanied with elimination of the N-alkyl fragment resulting in N-unsubstituted 5-arylpyrrolidine-2-ones with the yields of 50-95 %. Lactamization of N-benzylamide and N-isopropylamides under the action of PPA proceeds with formation of 1-alkyl-5-arylpyrrolidine-2-ones.Conclusions. It has been found that the proton-initiated cyclization of N-unsubstituted and N-tert-butylamides of styrylacetic acid with donor substituents in the styrene fragment in polyphosphoric acid when heating at 100 °C is a preparative convenient method for the synthesis of 1-unsubstituted 5-arylpyrrolidine-2-ones. A similar reaction of N-benzyl (isopropyl) amides leads to the preferential formation of 1-alkyl-5-arylpyrrolidine-2-ones.Целью работы является исследование влияния структурных параметров амидов стирилуксусных кислот на протекание реакции электрофильной внутримолекулярной циклизации под действием полифосфорной кислоты и поиск рациональных подходов к получению N-незамещенных 5-арилпирролидин-2-онов.Результаты и их обсуждение. Проанализированы и систематизированы литературные источники, относящиеся к основным методам синтеза, а также биологической активности пирролидин-2-онов.Исследована региохимия циклизации N-незамещенных и N-алкиламидов стирилуксусных кислот под действием полифосфорной кислоты (ПФК).Экспериментальная часть. Выявлено, что N-незамещенные амиды стирилуксусных кислот при нагревании до 100 °С в ПФК циклизуются в 5-арилпирролидин-2-оны с выходами 44-58 %. Для N-трет-бутиламидов с донорными заместителями в стирольной части молекулы циклизация в аналогичных условиях сопровождается отщеплением N-алкильного фрагмента и приводит к N-незамещенным 5-арилпирролидин-2-онам с выходами 50-95 %. Лактамизация N-бензиламида и N-изопропиламидов под действием ПФК протекает без фрагментации с образованием 1-алкил-5-арилпирролидин-2-онов.Выводы. Найдено, что протон-инициированная циклизация N-трет-бутиламидов стирилуксусных кислот с донорными заместителями в стирольном фрагменте при 100 °С в полифосфорной кислоте является препаративно удобным методом синтеза 1-незамещенных 5-арилпирролидин-2-онов. Аналогичная реакция N-бензил(изопропил)амидов приводит к преимущественному образованию 1-алкил-5-арилпирролидин-2-онов.Метою роботи є дослідження впливу структурних параметрів амідів стирилоцтових кислот на перебіг реакції електрофільної внутрішньомолекулярної циклізації під дією поліфосфорної кислоти та пошук раціональних підходів до отримання N-незаміщених 5-арилпіролідин-2-онів.Результати та їх обговорення. Проаналізовані та систематизовані літературні джерела, які стосуються основних методів синтезу та біологічної активності 5-арилпіролідин-2-онів. Досліджена регіохімія циклізації N-незаміщених та N-алкіламідів стирилоцтових кислот під дією поліфосфорної кислоти (ПФК).Експериментальна частина. Знайдено, що N-незаміщені аміди стирилоцтових кислот при нагріванні до 100 оС в ПФК циклізуються у 5-арилпіролідин-2-они із виходами 44-58 %. Для N-трет-бутиламідів з донорними замісниками в стирильній частині молекули циклізація в аналогічних умовах супроводжується відщепленням N-алкільного фрагмента, що приводить до N-незаміщених 5-арилпіролідин-2-онів з виходaми 50-95 %. Лактамізація N-бензил- та N-ізопропіламідів під дією ПФК перебігає з утворенням відповідних 1-алкіл-5-арилпіролідин-2-онів.Висновки. Знайдено, що протон-ініційована циклізація N-незаміщених та N-трет-бутиламідів стирилоцтових кислот з донорними замісниками в стирильному фрагменті при 100 °С в поліфосфорній кислоті є препаративно зручним методом синтезу 1-незаміщених 5-арилпіролідин-2-онів. Аналогічна реакція N-бензил(ізопропіл)амідів приводить до переважного утворення 1-заміщених 5-арилпіролідин-2-онів

О ПОЖАРООПАСНОСТИ ДРЕВЕСИНЫ ПРИ ВОЗВЕДЕНИИ МОСТОВ

Successful construction and operation of bridges both depend on many factors. One of them is fire protection of bridgeworks and structures , that requires proper use of timber and other inflammable materials.Успешность строительства  и эксплуатации мостов зависит  от многих факторов. Один из них –  пожарная защита конструкции  и элементов сооружения, которая  связана в том числе и с грамотным  использованием строительной  древесины и других горючих  материалов

Experimental Tests of Neutron Shielding for the ATLAS Forward Region

Experimental tests devoted to the optimization of the neutron shielding for the ATLAS forward region were performed at the CERN-PS with a 4 GeV/c proton beam. Spectra of fast neutrons, slow neutrons and gamma rays escaping a block of iron (40$\times$40$\times$80 cm$^3$) shielded with different types of neutron and gamma shields (pure polyethylene - PE, borated polyethylene - BPE, lithium filled polyethylene - LiPE, lead, iron) were measured by means of plastic scintillators, a Bonner spectrometer, a HPGe detector and a slow neutron detector. Effectiveness of different types of shielding agaisnt neutrons and $\gamma$-rays were compared. The idea of a segmented outer layer shielding (iron, BPE, iron, LiPE) for the ATLAS Forward Region was also tested

Merkel cell polyomavirus small t antigen induces cancer and embryonic merkel cell proliferation in a transgenic mouse model

Merkel cell polyomavirus (MCV) causes the majority of human Merkel cell carcinomas (MCC) and encodes a small T (sT) antigen that transforms immortalized rodent fibroblasts in vitro. To develop a mouse model for MCV sT-induced carcinogenesis, we generated transgenic mice with a flox-stop-flox MCV sT sequence homologously recombined at the ROSA locus (ROSAsT), allowing Cre-mediated, conditional MCV sT expression. Standard tamoxifen (TMX) administration to adult UbcCreERT2; ROSAsT mice, in which Cre is ubiquitously expressed, resulted in MCV sT expression in multiple organs that was uniformly lethal within 5 days. Conversely, most adult UbcCreERT2; ROSAsT mice survived low-dose tamoxifen administration but developed ear lobe dermal hyperkeratosis and hypergranulosis. Simultaneous MCV sT expression and conditional homozygous p53 deletion generated multi-focal, poorly-differentiated, highly anaplastic tumors in the spleens and livers of mice after 60 days of TMX treatment. Mouse embryonic fibroblasts from these mice induced to express MCV sT exhibited anchorage-independent cell growth. To examine Merkel cell pathology, MCV sT expression was also induced during mid-embryogenesis in Merkel cells of Atoh1CreERT2/+; ROSAsT mice, which lead to significantly increased Merkel cell numbers in touch domes at late embryonic ages that normalized postnatally. Tamoxifen administration to adult Atoh1CreERT2/+; ROSAsT: Atoh1CreERT2/+; ROSAsT; p53flox/flox mice had no effects on Merkel cell numbers and did not induce tumor formation. Taken together, these results show that MCV sT stimulates progenitor Merkel cell proliferation in embryonic mice and is a bona fide viral oncoprotein that induces full cancer cell transformation in the p53-null setting