S28 peptidases: lessons from a seemingly 'dysfunctional' family of two

<p>Abstract</p> <p>A recent paper in <it>BMC Structural Biology </it>reports the crystal structure of human prolylcarboxypeptidase (PRCP), one of the two members of the S28 peptidase family. Comparison of the substrate-binding site of PRCP with that of its family partner, dipeptidyl dipeptidase 7 (DPP7), helps to explain the different enzymatic activities of these structurally similar proteins, and also reveals a novel apparent charge-relay system in PRCP involving the active-site catalytic histidine.</p> <p>See research article: <url>http://www.biomedcentral.com/1472-6807/10/16/</url></p> <p>Commentary</p> <p>The S28 serine peptidase family is something of an enzymatic odd couple. While showing low sequence similarity to all proteins except each other, the two known family members appear to be at odds functionally; one, prolylcarboxypeptidase (PRCP), is a carboxypeptidase that cleaves single hydrophobic residues from the carboxyl termini of proteins that end with a Pro-X motif (where X is any hydrophobic amino acid), while the other, human dipeptidyl peptidase (DPP7), is an aminopeptidase that cleaves amino-terminal X-Pro dipeptides. The structural basis of this orthogonal specificity would undoubtedly be interesting, and a recent report in <it>BMC Structural Biology </it>from the Merck Global Structural Biology group (Soisson <it>et al</it>. <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>) has now met that expectation. In addition they reveal a new wrinkle to the iconic catalytic triad common to most serine hydrolases.</p> <p>The practical pharmaceutical interest in both these enzymes as potential drug targets is at present speculative. PRCP can inactivate a number of peptide hormones, such as angiotensin II, III and prekallikrein, implicating a role for the enzyme in hypertension, tissue proliferation and smooth-muscle growth. These properties suggest that this enzyme may well be a useful target for hypertension and anti-inflammatory therapy <abbrgrp><abbr bid="B2">2</abbr></abbrgrp>. Another (non-S28 family) dipeptidyl dipeptidase (DPP4) is a major drug target in type 2 diabetes, and Merck has already developed a successful inhibitor of DPP4, the anti-hyperglycemic drug sitagliptin, for the treatment of type 2 diabetes. The DPP enzymes are rich in biological functions and other drug targets emerging from the group are possible <abbrgrp><abbr bid="B3">3</abbr></abbrgrp>.</p

АНАЛИЗ РЫНКА ИНТРАНАЗАЛЬНЫХ ГЛЮКОКОРТИКОСТЕРОИДОВ ЛИПЕЦКОГО РЕГИОНА

in the present paper we have studied a group of pharmaceutical drugs used in the treatment of a widely spread today medical condition – allergic rhinitis. We have developed a conceptual approach to the analysis of the local market, which allowed us to elicit the main trends and peculiarities of the pharmaceutical market of nasal glucocorticosteroids of Lipetsk. As a result of research we identified the leaders of sales on the market nasal glucocorticosteroid, Lipetsk: drugs Nasobek market share – 31.1%, Nasonex with a market share of 26.4%, Awami and Flixonase – 20.4% and 14.8%, respectively.в данной работе представлены результаты комплексного анализа препаратов группы интраназальных глюкокортикостероидов, применяемых для терапии широко распространенного заболевания – аллергический ринит. Разработан концептуальный подход, включающий анализ производственного признака, стоимостной анализ, методика расчета показателей эффективности для каждого препарата. В результате исследования нами выявлены лидеры продаж на рынке интраназальных глюкокортикостероидов г. Липецк: препараты Насобек – доля рынка 31,1%, Назонекс – доля рынка 26,4%, Авамис и Фликсоназе – 20,4 и 14,8% соответственно. Выявлены основные тенденции и особенности фармацевтического рынка интраназальных глюкокортикостероидов города Липецка

ROLE OF LEUCOCYTES IN LIVER DAMAGE IN EXPERIMENTAL MODELS OF TYPE 1 AND 2 DIABETES MELLITUS

Diabetes mellitus is a metabolic disorder, which results from insufficient secretion of insulin and/or its action, thus leading to hyperglycemia. Liver damage is known to be among the most common complications of type 2 diabetes mellitus (T2D) and is common in T1D. Comparison of the leukocyte phenotypes in liver tissue with appropriate blood parameters may assess degree of liver damage and search for approaches to correction of liver destruction in diabetes mellitus. Therefore, we aimed for assessment of changes in liver injury markers in blood and the numbers of leucocytes (CD45+ cells), T lymphocytes (CD3+ cells) and macrophages in the liver in experimental models of types 1 and 2diabetes. The experiment was conducted on 30 male Wistar rats. Alloxan at the dose of 170 mg/kg of body weight was used for T1D modeling. To provide a model of T2D, streptozotocin and nicotinamide were injected at the doses of 65 mg/kg, and 110 mg/kg respectively. Intact animals were used as a comparison control. Biochemical, hematological, immunohistochemical and morphometrical methods were used in the study. In T1D and T2D groups, levels of glucose (10.88±0.47 mmol/l and 10.78±0.42 mmol/l) and glycosylated hemoglobin (6.73±0.78% and 6.60±0.20% correspondingly) were rather close to each other and exceeded the values of intact rats (5.20±0.40 mmol/l and 4.07±0.30%). At the same time, the increase in total leucocyte number and fraction of peripheral blood leucocytes against normal levels were more pronounced in the T2D group than in T2D group. In liver of rats from the both diabetic groups, increased numbers of sinusoidal cells, macrophages, CD45+ cells and CD3+ cells relative to intact rats were detected. However, in rats from T1D group, CD45+ cells were distributed, mainly, in the liver parenchyma, whereas in rats in T2D group they showed sinusoidal location. At a similar degree of increasing macrophage numbers, and total CD45+ cells number, higher counts of sinusoidal cells and CD3+ cells, located both in the parenchyma and perivascular area, were found in rats of T2DM group compared with this parameter in T1DM group. An increase in ALT activity confirms a more significant damage to liver cells in animals of the T2DM group, whereas, in T1DM group, an increased AST activity and a less pronounced increase in ALT activity indicate uniformly distributed cytolysis. The results of our study showed, that, despite similar hyperglycemia level, the inflammatory process at the level of the whole organism and local inflammatory process in the liver are more pronounced in the T2DM group. A more significant severity of inflammatory process and liver damage corresponds to increase in sinusoidal cells and CD3+ cell infiltration of liver tissue. © 2022 Russian Association of Allergologists and Clinical Immunologists, St. Petersburg Regional Branch (SPb RAACI). All rights reserved

High energy hadrons in EAS at mountain altitude

An extensive simulation has been carried out to estimate the physical interpretation of dynamical factors such as , in terms of high energy interaction features, concentrated in the present analysis on the average transverse momentum. It appears that the large enhancement observed for versus primary energy, suggesting in earliest analysis a significant rise of with energy, is only the result of the limited resolution of the detectors and remains in agreement with a wide range of models used in simulations.Comment: 13 pages, 6 PostScript figures, LaTeX Subm. to JPhys

Advertising Native-Speakerism in the Russian Market of English: A case study

Переход от офлайна к онлайну в образовании подразумевает тщательную оценку услуг по обучению иностранным языкам с точки зрения их надежности и потенциала для достижения ожидаемых результатов; однако отсутствие исследований в этой области мешает академическим кругам информировать общественность о неэтичной, обманчивой рекламе. Основываясь на мультимодальном дискурс-анализе, в данной статье представлено исследование двух текстов: интервью с "англоговорящим учителем" на местном новостном портале, использованном в качестве двери для рекламы услуги по обучению языку BritSpeak в Великобритании. Основываясь на проявлениях native speakerism, определяемого в научных кругах как идеология, утверждающая врожденное превосходство носителя языка в обучении иностранцев своему языку, результаты показывают, что предыдущее знание российского рынка предпочтений в английском языке и использование этой пресловутой идеологии являются инструментами, используемыми для принуждения потенциальных потребителей к покупке услуги. Исследование BritSpeak, хотя и затрудненное отсутствием доступа к учебным материалам, показало, что, всегда находясь в этих идеологических рамках, интервьюируемый-рекламодатель не только очерняет через индексальность российское сообщество преподавателей иностранных языков и систему образования в целом, но и обманывает потенциальных потребителей в качестве рекламируемых преподавателей. Значимость статьи заключается в призыве к деколонизации преподавания иностранных языков путем разрушения мифа о носителе языка и признания возможностей коренного преподавательского сообщества. В статье предлагается изучить аналогичную практику в отношении услуг на других европейских языках и необходимость исследовать роль местных новостных служб в рекламе иностранных продуктов.The offline to online turn in education implies a careful evaluation of foreign languages teaching services regarding their reliability and potential to deliver the expected results; however, the lack of studies in the field impede academia to inform the public about unethical, deceitful advertising. Based on multimodal discourse analysis, this paper presents a case study of two texts: an interview with an ‘English-speaking teacher’ in a local news portal used as the door to advertise the BritSpeak language teaching service in the UK. Grounded on the manifestations of native speakerism defined in academia as the ideology claiming the innate superiority of the native speaker to teach his language to foreigners, the results demonstrate that previous knowledge of the Russian market of English preferences and the use of this infamous ideology are the tools employed to compel potential consumers to buy the service. The study of BritSpeak, though hindered by lack of access to the teaching materials, revealed that, always within this ideological framework, the interviewee-advertiser not only denigrates through indexicality the Russian foreign language teaching community and educational system in general but also deceives potential consumers in the quality of advertised teachers. The paper significance resides on its call to decolonize foreign language teaching by eroding the native speaker myth and with it acknowledge the capabilities of the indigenous teaching community. The paper suggests the study of similar practices regarding services in other European languages and the need to examine the role of local news services in advertising foreign products

Characteristics of air showers created by extremely high energy gamma-rays

The technique of adjoint cascade equations has been applied to calculate the properties of extremely high energy gamma-rays in the energy range 10^18--10^22 eV with taking into account the LPM effect and interactions of gamma-rays with the geomagnetic field. Such characteristics are analysed as the electron and muon contents at the observation level, the electron cascade curves, the lateral distribution functions of photoproduced muons.Comment: 36 pages, 19 figures, submitted to J.Phys.G: Nucl.Part.Phy

Features of Muon Arrival Time Distributions of High Energy EAS at Large Distances From the Shower Axis

In view of the current efforts to extend the KASCADE experiment (KASCADE-Grande) for observations of Extensive Air Showers (EAS) of primary energies up to 1 EeV, the features of muon arrival time distributions and their correlations with other observable EAS quantities have been scrutinised on basis of high-energy EAS, simulated with the Monte Carlo code CORSIKA and using in general the QGSJET model as generator. Methodically various correlations of adequately defined arrival time parameters with other EAS parameters have been investigated by invoking non-parametric methods for the analysis of multivariate distributions, studying the classification and misclassification probabilities of various observable sets. It turns out that adding the arrival time information and the multiplicity of muons spanning the observed time distributions has distinct effects improving the mass discrimination. A further outcome of the studies is the feature that for the considered ranges of primary energies and of distances from the shower axis the discrimination power of global arrival time distributions referring to the arrival time of the shower core is only marginally enhanced as compared to local distributions referring to the arrival of the locally first muon.Comment: 24 pages, Journal Physics G accepte

Physicochemical and biochemical properties of the Keplerate-type nanocluster polyoxomolybdates as promising components for biomedical use

The paper discusses the results of a research on physicochemical and biochemical properties of the Keplerate-type molybdenum-based nanocluster polyoxometalates (POMs), which show promise in the field of biomedicine as a means of targeted drug delivery, including the transport to immune privileged organs. POMs can be considered as components of releasing systems, including the long-acting ones with feedback (for controlling the drug active component release rate). POMs are promising drugs for the treatment of anemia. Also, the paper deals with the results of studies of POM effect on living systems at the molecular and cellular levels, at that of individual organs, and on the organism as a whole. The mechanism and kinetics of POM destruction and possibilities of stabilization, the oscillatory phenomena manifestation, the formation of POM conjugates with bioactive substances which can be released during the destruction of POM, with polymer components, and with indicator fluorescent dyes, as well as forecasts for further research, are considered. © 2021, ITMO University. All rights reserved.The paper was prepared in the framework of implementation of the State Assignment from the Ministry of Education and Science of the Russian Federation (Projects Nos. AAAA-A20-120061990010-7 (FEUZ-2020-0052) and AAAA-A18-118020590107-0), as well as of the Program for Increasing Competitiveness of UrFU (financially supported according to the Decree No. 211 of the Government of the Russian Federation, Contract No. 02.A03.21.0006). The research aimed at creating the long-time drug release systems with feedback was carried out within the framework of the project of the Russian Science Foundation No. 19-73-00177

Atmospheric Muon Flux at Sea Level, Underground, and Underwater

The vertical sea-level muon spectrum at energies above 1 GeV and the underground/underwater muon intensities at depths up to 18 km w.e. are calculated. The results are particularly collated with a great body of the ground-level, underground, and underwater muon data. In the hadron-cascade calculations, the growth with energy of inelastic cross sections and pion, kaon, and nucleon generation in pion-nucleus collisions are taken into account. For evaluating the prompt muon contribution to the muon flux, we apply two phenomenological approaches to the charm production problem: the recombination quark-parton model and the quark-gluon string model. To solve the muon transport equation at large depths of homogeneous medium, a semi-analytical method is used. The simple fitting formulas describing our numerical results are given. Our analysis shows that, at depths up to 6-7 km w. e., essentially all underground data on the muon intensity correlate with each other and with predicted depth-intensity relation for conventional muons to within 10%. However, the high-energy sea-level data as well as the data at large depths are contradictory and cannot be quantitatively decribed by a single nuclear-cascade model.Comment: 47 pages, REVTeX, 15 EPS figures included; recent experimental data and references added, typos correcte