Novel Opioid-Neurotensin-Based Hybrid Peptide with Spinal Long-Lasting Antinociceptive Activity and a Propensity to Delay Tolerance Development

The behavioral responses exerted by spinal administration of the opioid-neurotensin hybrid peptide, PK23, were studied in adult male rats. The antinociceptive effect upon exposure to a thermal stimulus, as well as tolerance development, was assessed in an acute pain model. The PK23 chimera at a dose of 10 nmol/rat produced a potent pain-relieving effect, especially after its intrathecal administration. Compared with intrathecal morphine, this novel compound was found to possess a favourable side effect profile characterized by a reduced scratch reflex, delayed development of analgesic tolerance or an absence of motor impairments when given in the same manner, though some animals died following barrel rotation as a result of its i.c.v. administration (in particular at doses higher than 10 nmol/rat). Nonetheless, these results suggest the potential use of hybrid compounds encompassing both opioid and neurotensin structural fragments in pain management. This highlights the enormous potential of synthetic neurotensin analogues as promising future analgesics

Les motifs textuels « ouvrir la porte » et « regarder par la fenêtre » dans la littérature contemporaine : étude contrastive français-polonais.

The objective of this study is to identify and analyse textual motifs around the expressions open the door and look out the window in French and Polish in contemporary literature. The aim is to compare their paradigmatic variations, syntagmatic extensions and discursive functions from examples drawn from three digital corpuses. Our study is based on the work of the PhraseoRom project and on the semantic and stylistic grids developed within the framework of this project. For the French corpus, we use the corpus of the PhraséoRom project using the Lexicoscope 2.0 query platform. In addition, we use the monolingual corpus Le Corpus National de la Langue Polonaise (Narodowy Korpus Języka Polskiego) and the parallel French-Polish corpus Reverso Context. Then, a morpho-syntactic, discourse and comparative analysis is proposed to compare the expressions on the paradigmatic and syntactic level.L’objectif de ce mémoire est de dégager et d’analyser des motifs textuels autour des expressions ouvrir la porte et regarder par la fenêtre en français et en polonais dans la littérature contemporaine. Le but est de comparer leurs variations paradigmatiques, extensions syntagmatiques et fonctions discursives à partir des exemples tirés de trois corpus numériques. Notre étude et basé notamment sur les travaux du projet PhraséoRom et sur les grilles sémantiques et stylistiques élaborés dans le cadre de ce projet. Pour le corpus français, nous utilisons le corpus du projet PhraséoRom en se servant de la plateforme d’interrogation le Lexicoscope 2.0. De plus, nous utilisons le corpus monolingue Le Corpus National de la Langue Polonaise (Narodowy Korpus Języka Polskiego) et le corpus parallèle français-polonais Reverso Context. Ensuite, une analyse morpho-syntaxique, discursive et comparative est proposée pour comparer les expressions sur le plan paradigmatique et syntaxiques

Checklist for Mapping Business Processes

Vid framtagandet av kravspecifikationen i ett IT-projekt är det viktigt att sammanställa verksamhetens krav på ett optimalt sätt. Detta är inte en enkel process då det finns många aspekter som behöver tas upp och utarbetas. I den här rapporten utvärderar vi IRM-bolagens arbetssätt, utifrån två kravspecifikationer framtagna åt två olika verksamheter och två genomförda intervjuer i syfte att skapa en checklista för kartläggning av verksamhetsprocesser i kravspecifikationen. För detta ändamål använder vi oss av RAKPIL konstruktionsmodell (Roller, Ansvarsområde, Kund, Process, Information, Läge)med valda kriterier som: Roller och ansvarsområden, Kundsamarbete, Processdefiniering och modellering, Information, Utgångsläge, Kommunikation, Dokumentation och Komplexitet. Dessa kriterier antas vara vägande och fungerar som byggstenar till materialinsamling. Intervjufrågorna tas fram och kategoriseras i grupper enligt de framtagna kriterierna. Vidare presenteras svaren från intervjun i resultatet, som i sin tur ger ett underlag för analys och diskussion. Utifrån ovanstående arbetsmoment sammanställs RAKPIL checklista med förslagskriterier. RAKPIL Checklistan är ändamålet i vår studie och innehåller de viktigaste faktorerna kring processkartläggning inom kravspecifikationen. Tanken bakom detta är att underlätta dagliga rutiner och skapa en effektivare arbetsmetod. Studieresultat visar att samtliga kriterier i RAKPIL konstruktionsmodellen är lika viktiga för framtagande av den optimala lösningen inom modelleringen av affärsprocesser. Vid analysen kom det fram att, trots etablerade rutiner, IRMs arbetssätt kan förbättras. Därför lämnas ett förslag till förbättring, i form av rekommendationer för framtida handlingsplanering, och RAKPIL checklistan med viktiga kriterier och rekommendationer, som kan användas vid framtagandet av kravspecifikationen. RAKPIL checklistan anses fungera som ett ramverk för IRM i deras dagliga arbetssätt, och kan byggas på och utvecklas vidare beroende på de olika ändamålen.During development of the requirement specifications in an IT project, it is important to collate business requirements in an optimal way. This is not an easy process, as there are many aspects that need to be considered. In this report we evaluate working methods of IRM Company, based on two separate cases and an interview with two of their consultants, conducted with the aim of creating a checklist for mapping business processes in the requirement specification. For this purpose, we use a RAKPIL (Swe. Roller, Ansvarsområde, Kund, Process, Information, Läge) construction model with selected criteria such as: Roles and responsibilities, Customers, Communications, Information, Process defining and modelling, Starting point, Complexity and Documentation. These criteria, assumed being mostly essential, serve as building blocks for collection of materials. Further, the interview questions are developed and categorized into groups, according to the developed criteria. The responses from interviewees are being presented in the result, and provide a foundation for analysis and discussion. Based on the work activities from above, a compiled RAKPIL checklist of the proposal criteria was performed. The RAKPIL checklist serves as the results of our study, where the most important factors in a process mapping within the requirement specifications were compiled, in order to obtain a more effective approach. The final result confirms that all criteria included in the RAKPIL construction model are equally important, and must be considered during the preparation of a business process development. The analysis revealed that despite IRM´s established procedures, there is room for improvement of their methods. Suggestions for the improvement were provided in a form of future recommendations and the RAKPIL checklist, which contains a list of important criteria to be considered during the preparation of business processes. The template is considered to serve as a framework for IRM in their daily work, and can be built upon and further developed according to different purposes

Effect of dimethyl fumarate on heme oxygenase-1 expression in experimental allergic encephalomyelitis in rats

Multiple sclerosis (MS) is an autoimmunological disease leading to neurodegeneration. The etiology of the disease remains unknown, which strongly impedes the development of effective therapy. Most MS treatments focus on modulating the activity of the immune system. Dimethyl fumarate (DMF) exerts a broad spectrum of action, such as modulating immune cell differentiation towards anti-inflammatory subtypes, influencing cytokine production, regulating immune cell migration into the central nervous system, and activating intracellular antioxidant mechanisms. It is well established that activation of the nuclear factor E2 (Nrf2)-dependent pathway, leading to expression of the second-phase antioxidant enzymes, is influenced by DMF. In our experiments we used female Lewis rats in an animal model of MS – experimental allergic encephalomyelitis (EAE). The rats were fed with dimethyl fumarate to test the expression of heme oxygenase-1 (HO-1), one of the second-phase antioxidant enzymes, at specific time points of the symptomatic phases of the disease: on the first day of the occurrence of clinical symptoms (10th day post immunization, DPI); at the peak of clinical symptoms (14th DPI); and at the end of the relapse (21st DPI). The results showed that HO-1 expression, at both the mRNA and protein level, is influenced by DMF administration only at the very beginning of the symptomatic phase of EAE, and not at the peak of clinical symptoms, nor at the end of the relapse. This indicates that the regulation of the Nrf2-dependent antioxidant pathway by DMF occurs at a certain time interval (early EAE/MS) and strongly underlines the importance of the earliest introduction of the therapy to the patient

Rosiglitazone Ameliorates Cardiac and Skeletal Muscle Dysfunction by Correction of Energetics in Huntington’s Disease

Huntington’s disease (HD) is a rare neurodegenerative disease that is accompanied by skeletal muscle atrophy and cardiomyopathy. Tissues affected by HD (central nervous system [CNS], skeletal muscle, and heart) are known to suffer from deteriorated cellular energy metabolism that manifests already at presymptomatic stages. This work aimed to test the effects of peroxisome proliferator-activated receptor (PPAR)-γ agonist—rosiglitazone on grip strength and heart function in an experimental HD model—on R6/1 mice and to address the mechanisms. We noted that rosiglitazone treatment lead to improvement of R6/1 mice grip strength and cardiac mechanical function. It was accompanied by an enhancement of the total adenine nucleotides pool, increased glucose oxidation, changes in mitochondrial number (indicated as increased citric synthase activity), and reduction in mitochondrial complex I activity. These metabolic changes were supported by increased total antioxidant status in HD mice injected with rosiglitazone. Correction of energy deficits with rosiglitazone was further indicated by decreased accumulation of nucleotide catabolites in HD mice serum. Thus, rosiglitazone treatment may not only delay neurodegeneration but also may ameliorate cardio- and myopathy linked to HD by improvement of cellular energetics

prostate cancer disease progression

Background: Mitochondria are suggested to be important organelles for cancer initiation and promotion. This study was designed to evaluate the prognostic value of MTC02, a marker for mitochondrial content, in prostate cancer. Methods: Immunohistochemistry of using an antibody against MTC02 was performed on a tissue microarray (TMA) containing 11,152 prostate cancer specimens. Results were compared to histological phenotype, biochemical recurrence, ERG status and other genomic deletions by using our TMA attached molecular information. Results: Tumor cells showed stronger MTC02 expression than normal prostate epithelium. MTC02 immunostaining was found in 96.5 % of 8,412 analyzable prostate cancers, including 15.4 % tumors with weak, 34.6 % with moderate, and 46.5 % with strong expression. MTC02 expression was associated with advanced pathological tumor stage, high Gleason score, nodal metastases (p < 0.0001 each), positive surgical margins (p = 0.0005), and early PSA recurrence (p < 0.0001) if all cancers were jointly analyzed. Tumors harboring ERG fusion showed higher expression levels than those without (p < 0.0001). In ERG negative prostate cancers, strong MTC02 immunostaining was linked to deletions of PTEN, 6q15, 5q21, and early biochemical recurrence (p < 0.0001 each). Moreover, multiple scenarios of multivariate analyses suggested an independent association of MTC02 with prognosis in preoperative settings. Conclusions: Our study demonstrates high-level MTC02 expression in ERG negative prostate cancers harboring deletions of PTEN, 6q15, and 5q21. Additionally, increased MTC02 expression is a strong predictor of poor clinical outcome in ERG negative cancers, highlighting a potentially important role of elevated mitochondrial content for prostate cancer cell biology

Winter temperature and forest cover have shaped red deer distribution in Europe and the Ural Mountains since the Late Pleistocene

Aim The Expansion-Contraction model has been used to explain the responses of species to climatic changes. During periods of unfavourable climatic conditions, species retreat to refugia from where they may later expand. This paper focuses on the palaeoecology of red deer over the past 54 ka across Europe and the Urals, to reveal patterns of change in their range and explore the role of environmental conditions in determining their distribution. Location Europe and western Asia to 63 degrees E. Taxon Red deer (Cervus elaphus). Methods We collected 984 records of radiocarbon-dated red deer subfossils from the Late Pleistocene and the Holocene, including 93 original dates. For each deer sample we compiled climatic and biome type data for the corresponding time intervals. Results During the last 54 ka changes in red deer range in Europe and the Urals were asynchronous and differed between western and eastern Europe and western Asia due to different environmental conditions in those regions. The range of suitable areas for deer during the Last Glacial Maximum (LGM) was larger than previously thought and covered vast regions not only in southern but also in western and eastern Europe. Throughout the period investigated the majority of specimens inhabited forests in the temperate climatic zone. The contribution of forests in deer localities significantly decreased during the last 4 ka, due to deforestation of Europe caused by humans. Mean January temperature was the main limiting factor for species distribution. Over 90% of the samples were found in areas where mean January temperature was above -10 degrees C. Main conclusions Red deer response to climatic oscillations are in agreement with the Expansion-Contraction model but in contradiction to the statement of only the southernmost LGM refugia of the species. During the last 54 ka red deer occurred mostly in forests of the temperate climatic zone