Nostocyclopeptides as new inhibitors of 20s proteasome.

Nostocyclopeptides (Ncps) are a small class of bioactive nonribosomal peptides produced solely by cyanobacteria of the genus Nostoc. In the current work, six Ncps were isolated from Nostoc edaphicum strain CCNP1411. The bioactivity of these compounds was tested in vitro against 20S proteasome, a proteolytic complex that plays an important role in maintaining cellular proteostasis. Dysfunction of the complex leads to many pathological disorders. The assays indicated selective activity of specific Ncp variants. For two linear peptide aldehydes, Ncp-A2-L and Ncp-E2-L, the inhibitory effects on chymotrypsin-like activity were revealed, while the cyclic variant, Ncp-A2, inactivated the trypsin-like site of this enzymatic complex. The aldehyde group was confirmed to be an important element of the chymotrypsin-like activity inhibitors. The nostocyclopeptides, as novel inhibitors of 20S proteasome, increased the number of natural products that can be considered potential regulators of cellular processes

Pathological Q waves as an indicator of prior myocardial infarction in patients with coronary artery disease and diabetes mellitus: a comparison of the prevalence and diagnostic accuracy according to present and former criteria

Introduction. Electrocardiography (ECG) is a widely used diagnostic method for identification of patients with previous myocardial infarction (MI). The ECG manifestation of prior MI is the presence of the pathological Q waves. Patients with coronary artery disease (CAD) and diabetes are at high risk of MI. The aim of this study was to compare the prevalence and diagnostic accuracy of the pathological Q waves as an indicator of prior MI in patients with CAD and diabetes according to the present and former criteria. Methods. A cross-sectional, multi-centre study was conducted in outpatient clinics across Poland. Family physicians performed physical examinations, registered ECGs, and collected relevant information about onset of CAD and diabetes, presence and onset of hypertension, dyslipidaemia, heart failure, diabetic complications, history of MI, and pharmacotherapy. Centralised manual assessment of the obtained ECG tracings was performed. Two definitions of the pathological Q-waves were used — a present one according to the Universal Definition of MI and a former one based on the definition of MI developed by the World Health Organization. Results. We enrolled 796 patients (48.1% women, mean age 67.5 ± 10.2 years, and 51.9% men, mean age 64.3 ± 10.3 years) into the study. There were 158 patients (19.8%) — 102 men (24.7%) and 56 women (14.6%), who met the present definition of the pathological Q waves and 106 patients (13.3%) — 74 men (17.9%) and 32 women (8.4%), who met the former definition of the pathological Q waves. The prevalence of the pathological Q waves varied due to the certain group of leads. It was highest in the inferior leads — 104 and 75 according to the present and former definitions, respectively. Of note, the rate of the pathological Q waves increased up to 2.6 times in the lateral leads after the introduction of the less restrictive present definition. Sensitivity of prior MI detection by means of the present and former criteria was 26.8% and 19.8%, and specificity was 87.0% and 92.8%, respectively. The application of the present and former definitions detected prior MI with 65.6% and 71.6% positive predictive value, and with 56.3% and 55.6% negative predictive value, respectively. Conclusions. In the era of reperfusion therapy, ECG appears to be a poor diagnostic tool for detection of previous MI due to its low sensitivity. However, it may identify individuals without previous MI with rather high specificity. In diabetics with CAD, the present definition of the pathological Q waves increases sensitivity of prior MI detection by 7%, with a decrease in specificity by 6% as compared with the former definition

Cyanopeptolins with trypsin and chymotrypsin inhibitory activity from the cyanobacterium nostoc edaphicum CCNP1411.

Cyanopeptolins (CPs) are one of the most frequently occurring cyanobacterial peptides, many of which are inhibitors of serine proteases. Some CP variants are also acutely toxic to aquatic organisms, especially small crustaceans. In this study, thirteen CPs, including twelve new variants, were detected in the cyanobacterium Nostoc edaphicum CCNP1411 isolated from the Gulf of Gdańsk (southern Baltic Sea). Structural elucidation was performed by tandem mass spectrometry with verification by NMR for CP962 and CP985. Trypsin and chymotrypsin inhibition assays confirmed the significance of the residue adjacent to 3-amino-6-hydroxy-2-piperidone (Ahp) for the activity of the peptides. Arginine-containing CPs (CPs-Arg2) inhibited trypsin at low IC50 values (0.24–0.26 µM) and showed mild activity against chymotrypsin (IC50 3.1–3.8 µM), while tyrosine-containing CPs (CPs-Tyr2) were selectively and potently active against chymotrypsin (IC50 0.26 µM). No degradation of the peptides was observed during the enzyme assays. Neither of the CPs were active against thrombin, elastase or protein phosphatase 1. Two CPs (CP962 and CP985) had no cytotoxic effects on MCF-7 breast cancer cells. Strong and selective activity of the new cyanopeptolin variants makes them potential candidates for the development of drugs against metabolic disorders and other diseases

A new approach to ticagrelor-based de-escalation of antiplatelet therapy after acute coronary syndrome. A rationale for a randomized, double-blind, placebo-controlled, investigator-initiated, multicenter clinical study

© 2021 Via Medica. This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license. https://creativecommons.org/licenses/by/4.0/The risk of ischemic events gradually decreases after acute coronary syndrome (ACS), reaching a stable level after 1 month, while the risk of bleeding remains steady during the whole period of dual antiplatelet treatment (DAPT). Several de-escalation strategies of antiplatelet treatment aiming to enhance safety of DAPT without depriving it of its efficacy have been evaluated so far. We hypothesized that reduction of the ticagrelor maintenance dose 1 month after ACS and its continuation until 12 months after ACS may improve adherence to antiplatelet treatment due to better tolerability compared with the standard dose of ticagrelor. Moreover, improved safety of treatment and preserved anti-ischemic benefit may also be expected with additional acetylsalicylic acid (ASA) withdrawal. To evaluate these hypotheses, we designed the Evaluating Safety and Efficacy of Two Ticagrelor-based De-escalation Antiplatelet Strategies in Acute Coronary Syndrome — a randomized clinical trial (ELECTRA-SIRIO 2), to assess the influence of ticagrelor dose reduction with or without continuation of ASA versus DAPT with standard dose ticagrelor in reducing clinically relevant bleeding and main-taining anti-ischemic efficacy in ACS patients. The study was designed as a phase III, randomized, multicenter, double-blind, investigator-initiated clinical study with a 12-month follow-up.Peer reviewedFinal Published versio

Ecological and energy saving solutions at the universal exposition EXPO 2015

Tematem wystawy Expo 2015 zorganizowanej w Mediolanie było „Wyżywienie planety, energia dla życia”. Organizatorzy zaproponowali zerwanie z dotychczasową formułą wystawy. Położono nacisk na ekologię, która znalazła przełożenie w architekturze pawilonów wystawowych. Teren Expo to pełnoprawne miasteczko wykorzystujące inteligentne rozwiązania dla zintegrowanego zarządzania energią. Pawilony wystawowe wyposażono w rozwiązania wykorzystujące odnawialne źródła energii, a do ich budowy użyto materiałów przyjaznych dla środowiska. W niniejszym artykule podjęto tematykę inteligentnego zarządzania energią w kontekście wystawy Expo 2015. Omówiono kluczowe zagadnienia związane z oszczędzaniem i wytwarzaniem energii oraz jej zintegrowanym gospodarowaniem. Przedstawiono rozwiązania wykorzystujące odnawialne źródła energii oraz proekologiczne rozwiązania zastosowane w wybranych pawilonach wybudowanych na potrzeby wystawy.The theme of Expo 2015 in Milan was „Feeding the Planet, Energy for Life”. The event organizers proposed a break with the previous form of the exhibition. The emphasis was on ecology, which translated into the architecture of expo pavilions. The area of Expo was a proper town that uses smart solutions for integrated energy management. The pavilions were equipped with solutions using renewable energy sources and were built with the use of environment-friendly materials. The present article refers to the problem of smart energy management in the context of Expo 2015. It describes key issues related to energy producing and saving and its integrated management. Moreover, the paper presents solutions that use renewable energy sources as well as proecological solutions used in chosen pavilions built for the needs of the exposition

Ecological housing estates in Poland : tenders and perspectives

Idea osiedla ekologicznego wywodzi się z zasad zrównoważonego rozwoju. W ciągu ostatniej dekady nastąpiła wyraźna ewolucja i rozwój dominujących tendencji w podejściu do kształtowania środowiska mieszkaniowego. Związane jest to z rozwojem myśli ekologicznej oraz nowymi możliwościami w dziedzinie technologii. Osiedle ekologiczne jest pojęciem szeroko rozumianym i często nadużywanym przy określaniu różnego rodzaju inwestycji. Stałym problemem jest wyegzekwowanie od deweloperów wysokiej jakości środowiska mieszkaniowego. Związane jest to z brakiem regulacji prawnych, które obecnie odnoszą się głównie do efektywności energetycznej. Mimo to powstało w Polsce kilka zespołów zabudowy, gdzie podjęto próbę realizacji idei osiedla ekologicznego z jej głównymi założeniami. Pokazuje to, że Polacy stają się bardziej świadomi i chętniej wybierają mieszkania w komfortowych i ekologicznych zespołach mieszkaniowych. W artykule opisano najważniejsze kryteria osiedla ekologicznego. Przedstawiono możliwości egzekwowania i wdrażania założeń przy pomocy certyfikacji. Opisano widoczne tendencje oraz innowacje w podejściu do kształtowania zabudowy mieszkaniowej. Przeanalizowano przykłady polskich osiedli mieszkaniowych, w których podjęto realizację założeń zrównoważonego rozwoju. Celem artykułu jest próba odpowiedzi na pytanie, czym jest współczesne osiedle ekologiczne, jakie elementy powinny je charakteryzować, jak wobec powyższego realizowane są osiedla ekologiczne w Polsce. W pracy wykorzystano literaturę przedmiotu z zakresu budownictwa ekologicznego.The idea of an ecological housing estate comes from the principles of sustainable development. Over the past decade, there has been a clear evolution and development of the dominant tendencies in the approach to shaping the housing environment. This is related to the development of ecological thought and new possibilities in the field of technology. An ecological housing estate is a widely understood concept and is often abused in defining various types of investments. It is a constant problem to compel the developers to construct a high-quality housing environment. This is due to the lack of regulations which currently mainly mention the issue of energy efficiency. Despite this, several urban units where an attempt was made to implement the idea of an ecological settlement with its main assumptions were created in Poland. This shows that Poles are becoming more aware and more eager to choose flats in comfortable and ecological housing complexes. The article describes the most important criteria for an ecological settlement. The ability to enforce and implement assumptions through certification was outlined. The visible tendencies and innovations in handling residential development were described. Examples of Polish housing estates in which attempts were made to implement the assumptions of sustainable development were analyzed. The aim of the article is to try to answer the question what a modern ecological estate is, what elements should characterize it, how ecological settlements in Poland are implemented in the light of the above. The literature of the subject was used in the work in the field of ecological construction

Domy, które nie są prawdziwymi domami: nawiedzone rezydencje w literaturze amerykańskiej

Niniejsza praca poświęcona jest dwóm książkom o nawiedzonych domach, napisanym w różnych okresach czasu: The Turn of the Screw Henry'ego Jamesa i The Haunting of Hill House Shirley Jackson. Analiza obejmuje trzy podobne motywy, a każdy rozdział poświęcony jest jednemu z nich. Najpierw przeanalizowano fizyczną przestrzeń domu, w którym mają miejsce nawiedzenia; przeanalizowano biografię i psychikę głównych bohaterów; a w ostatnim rozdziale przeprowadzono analizę wiarygodności opisanych wydarzeń. Choć początkowo dom nie był ważnym elementem nawiedzenia, z czasem stał się nie tylko scenerią, ale niemal jedną z postaci. Celem niniejszej pracy jest pokazanie, jak te motywy funkcjonują w obu książkach, w jakim stopniu są do siebie podobne i co w dużej mierze je od siebie odróżnia.This thesis looks at two books about haunted houses written in different time periods, The Turn of the Screw by Henry James and The Haunting of Hill House by Shirley Jackson. The analysis looks at and compares three similar themes between the novels, with each chapter studying a separate theme. First, a physical space of the house in which the hauntings take place is looked at; the biography and psyche of the main characters are analysed; and in the final chapter, a credibility analysis of the events described is conducted. Although the house was not initially an important element of the haunting, as time passed it became not only a setting but almost one of the characters. This thesis aims to show how these motifs function in both books, to what extent they are similar, and what largely distinguishes them from each other

Nostoc edaphicum CCNP1411 from the Baltic Sea—A New Producer of Nostocyclopeptides

Nostocyclopeptides (Ncps) constitute a small class of nonribosomal peptides, exclusivelyproduced by cyanobacteria of the genusNostoc. The peptides inhibit the organic anion transporters,OATP1B3 and OATP1B1, and prevent the transport of the toxic microcystins and nodularin intohepatocytes. So far, only three structural analogues, Ncp-A1, Ncp-A2 and Ncp-M1, and their linearforms were identified inNostocstrains as naturally produced cyanometabolites. In the current work,the whole genome sequence of the new Ncps producer,N.edaphicumCCNP1411 from the BalticSea, has been determined. The genome consists of the circular chromosome (7,733,505 bps) andfive circular plasmids (from 44.5 kb to 264.8 kb). The nostocyclopeptide biosynthetic gene cluster(located between positions 7,609,981–7,643,289 bps of the chromosome) has been identified andcharacterizedin silico. The LC-MS/MS analyzes ofN.edaphicumCCNP1411 cell extracts preparedin aqueous methanol revealed several products of the genes. Besides the known peptides, Ncp-A1and Ncp-A2, six other compounds putatively characterized as new noctocyclopeptide analogueswere detected. This includes Ncp-E1 and E2 and their linear forms (Ncp-E1-L and E2-L), a cyclicNcp-E3 and a linear Ncp-E4-L. Regardless of the extraction conditions, the cell contents of the linearnostocyclopeptides were found to be higher than the cyclic ones, suggesting a slow rate of themacrocyclization process