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NOZIÈRE, Pierre, Solveig MENDOWSKI, Anne FERLAY, Corinne PEYRONNET, Francis ENJALBERT, Guillaume CHESNEAU, Antoine GERMAIN i Patrick CHAPOUTOT. "Améliorer l’utilisation des graines oléo-protéagineuses par l’extrusion : un enjeu technologique pour contribuer à l’autonomie protéique des élevages bovins laitiers". INRAE Productions Animales 35, nr 2 (26.08.2022): 121–38. http://dx.doi.org/10.20870/productions-animales.2022.35.2.7069.
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Dans le but d’assurer une meilleure autonomie protéique pour alimenter les animaux d’élevage, différents leviers, dont le développement de filières de protéagineux à graines, sont envisageables. Le projet Proleval s’inscrivait dans cette perspective. Les effets de traitements technologiques sur la valorisation des graines oléo-protéagineuses par les vaches laitières ont été évalués dans le cadre de ce projet. Une synthèse de la littérature a permis de quantifier l’effet bénéfique quasi-systématique des traitements thermiques ou thermomécaniques des graines sur l’utilisation de l’azote : diminution de la dégradabilité ruminale, augmentation de la digestibilité intestinale, de la fourniture d’acides aminés indispensables, et de la sécrétion de protéines dans le lait. Les effets observés sont toutefois quantitativement variables en fonction des traitements. Les essais expérimentaux conduits dans le cadre du projet ont permis de préciser les effets de certaines modalités d’extrusion des graines de féverole et de lupin : la température d’extrusion et la maturation par des procédés innovants intégrant des sucres réducteurs ou un cocktail enzymatique. Les résultats obtenus par différentes approches (mesures de dégradabilité et de digestibilité in situ, mesures in vivo du bilan azoté chez les vaches laitières) montrent que la température d’extrusion doit être limitée pour éviter une surprotection des protéines et que les prétraitements de maturation testés ne sont pas systématiquement efficaces. Les rares résultats publiés sur la fraction lipidique du lait rapportent une diminution du taux butyreux avec les graines traitées par rapport à la même graine crue. Peu d’études présentent des profils en acides gras du lait, mais les données du projet Proleval indiquent que les graines extrudées favorisent la production d’acides gras trans au niveau du rumen et du lait. La maîtrise des conditions d’extrusion permettant d’aboutir de façon répétable à un produit aux caractéristiques nutritionnelles optimales, qui semble passer par la maîtrise du développement des composés de Maillard, reste un enjeu.
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Raskovalova, Tatiana, Laura Scheffen, Marie-Christine Jacob, Simon Chevalier, Sylvie Tondeur, Bénédicte Bulabois, Mathieu Meunier i in. "Flow cytometry lyophilised-reagent tube for quantifying peripheral blood neutrophil myeloperoxidase expression in myelodysplastic syndromes (MPO-MDS-Develop): protocol for a diagnostic accuracy study". BMJ Open 12, nr 10 (październik 2022): e065850. http://dx.doi.org/10.1136/bmjopen-2022-065850.
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IntroductionSuspicion of myelodysplastic syndromes (MDS) is the most common reason for bone marrow aspirate in elderly patients. Peripheral blood neutrophil myeloperoxidase expression quantified by flow cytometric analysis might rule out MDS for up to 35% of patients referred for suspected disease, without requiring bone marrow aspiration. Yet laboratory-developed liquid antibody cocktails have practical limitations, because of lack of standardisation and poor stability. This research project aims to estimate the level of agreement and comparative accuracy between a single-use flow cytometry tube of lyophilised reagents (BD Lyotube Stain 468) and its laboratory-developed liquid reagent counterpart in quantifying peripheral blood neutrophil myeloperoxidase expression, among adult patients referred for suspected MDS.Methods and analysisThe MPO-MDS-Develop project is a cross-sectional diagnostic accuracy study of two index tests by comparison with a reference standard in consecutive unselected adult patients conducted at a single university hospital. Flow cytometry analysis of peripheral blood samples will be performed by independent operators blinded to the reference diagnosis, using either Lyotube Stain 468 or laboratory-developed liquid reagent cocktail. The reference diagnosis of MDS will be established by cytomorphological evaluation of bone marrow aspirate by two independent haematopathologists blinded to the index test results. Morphologic assessment will be complemented by bone marrow flow cytometric score, karyotype and targeted next-generation sequencing panel of 43 genes, where relevant. The target sample size is 103 patients.Ethics and disseminationAn institutional review board (Comité de Protection des Personnes Sud Est III, Lyon, France) approved the protocol prior to study initiation (reference number: 2020-028-B). Participants will be recruited using an opt-out approach. Efforts will be made to release the primary results within 6 months of study completion.Trial registration numberNCT04399018.
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Oschman, Alexandra, Amanda Gansen, Howard Kilbride i Tracy Sandritter. "Safety and Efficacy of Two Potassium Cocktail Formulations for Treatment of Neonatal Hyperkalemia". Annals of Pharmacotherapy 45, nr 11 (18.10.2011): 1371–77. http://dx.doi.org/10.1345/aph.1q292.
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Background:: A consensus has not been established for the standard treatment of hyperkalemia in the neonatal population. Most treatment regimens include a dextrose/insulin infusion. Additional agents used include calcium, sodium bicarbonate, polystyrene sulfonate, and albuterol. This study assessed the safety and efficacy of a potassium cocktail (k-cocktail) containing dextrose, insulin, calcium gluconate, and sodium lactate for treatment of neonatal hyperkalemia. Objective: To determine whether modifications to a potassium cocktail formulation, based on a prior quality improvement project, resulted in a decrease in the incidence of hyperglycemia and acidosis associated with its use, and to evaluate the effectiveness of the k-cocktail in lowering serum potassium levels and the incidence of adverse effects. Methods: We conducted a retrospective cohort study of neonates with hyperkalemia who received 2 k-cocktail formulations (group 1 [n = 13], original formulation, dextrose:insulin 5:1; group 2 [n = 26], modified formulation, dextrose: insulin 3.3:1). Group 2 subjects were matched 2:1 by gestational age and birth weight with those in group 1. Variables related to safety and effectiveness of therapy were assessed by medical record review. The following tests were used to assess group differences: χ2, Fisher exact, 2-tailed t-tests, and mixed linear models. Results: The incidence of hyperglycemia during the modified k-cocktail infusion in group 2 decreased from 76.9% to 217% (p = 0.001). Serum blood glucose concentrations increased during the infusion, on average, for group 1 infants and were unchanged during the infusion for those in group 2. The incidence of acidosis during the infusion was similar between groups (group 1 [76.9%] vs group 2 [68.2%]; p = 0.58). No significant adverse events were observed. Serum potassium concentrations decreased similarly in both groups. Conclusions: An intravenous infusion including a dextrose:insulin ratio of 3.3:1. compared with a higher ratio, results in less hyperglycemia and appears to be as effective in decreasing potassium concentrations in newborns.
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Binder, Jean, Leon IV Aillaud i Lionel Schilli. "The Project Management Cocktail Model: An Approach for Balancing Agile and ISO 21500". Procedia - Social and Behavioral Sciences 119 (marzec 2014): 182–91. http://dx.doi.org/10.1016/j.sbspro.2014.03.022.
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Krause, Rahel, Justin Kühn, Thomas Gries, Maren Gültner i Yvette Dietzel. "Molotov cocktail protection - protective clothing material for emergency forces". Communications in Development and Assembling of Textile Products 3, nr 2 (22.09.2022): 201–11. http://dx.doi.org/10.25367/cdatp.2022.3.p201-211.
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In order to better protect emergency personnel, a suitable material was sought that would meet various requirements. To achieve this, a project was carried out by the Saxon Textile Research Institute e. V. (STFI), Germany and the Institut für Textiltechnik (ITA) of RWTH Aachen University, Germany, called “Molotov cocktail protection – protective clothing material for emergency forces”. First, suitable fiber mixtures were selected and then tested for a high accuracy of fit. Afterwards, specially designed fabrics were developed and produced to realize a smooth surface. In addition, a coating for high hydrophobia was established. To examine these newly developed fabrics, a test procedure was developed and modified. Results show correlations between fiber selection as well as yarn and fabric construction with the resulting fabric properties. Findings can be given in the form of technological and product-related recommendations.
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Karapotkina, Yu G., i A. M. Agapkin. "On the problem of alcoholic cocktails in Russia". Tovaroved prodovolstvennykh tovarov (Commodity specialist of food products), nr 10 (20.10.2022): 653–56. http://dx.doi.org/10.33920/igt-01-2210-04.
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The introduction of sanctions against the Russian Federation had a strong impact on the bar industry as a whole. Now it is impossible to export any alcohol from the USA. The European Union announced a project to ban the supply of elite alcohol and wines more expensive than 300 euros. Problems with logistics have arisen since the times of COVID-19, and at the moment they have become even worse. In order to save their reputation, many companies do not want to interact directly with Russian entrepreneurs.Classic cocktails, almost entirely composed of foreign ingredients, will be difficult to replace with Russian counterparts, but it is possible.
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Stover, Carl P. "The University as A Subject of Policy Analysis". News for Teachers of Political Science 47 (1985): 10–12. http://dx.doi.org/10.1017/s0197901900003305.
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Going to alumni cocktail parties is a great idea. Not only are the drinks cheap, but you find out more about your teaching than the "Student Evaluation of Instruction" forms will ever tell you. When students are still talking enthusiastically about a class two to five years later, you know you did something right. When they explicitly mention it as the experience from which they learned most in their degree program, you may be inspired even to write it up for NEWS.What was this experience? It was a class project in which the students were divided into teams and required to investigate major policies that the University had under consideration or had recently enacted.
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Fees, Marine, Barbara Majoor i Annemarie Oord. "Hoe ziet de accountancysector eruit in 2050? AFM en stakeholders in gesprek". Maandblad voor Accountancy en Bedrijfseconomie 98, nr 5 (14.11.2024): 247–52. http://dx.doi.org/10.5117/mab.98.139887.
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De AFM is gestart met een project ‘visie 2050’ om een dialoog te stimuleren over hoe de accountancysector er in 2050 uit zou kunnen zien. Verdergaande digitalisering en AI, assurance op duurzaamheidsrapportering, de krappe arbeidsmarkt, veel meer en ook meer diverse stakeholders; vanuit die dagdagelijkse cocktail voor accountants is het een uitdagende vraag hoe het accountancylandschap vorm zal krijgen. Om de dialoog hierover te stimuleren, hebben we op basis van deze trends toekomstscenario’s opgesteld. Vervolgens zijn we als AFM in gesprek gegaan met vertegenwoordigers uit de accountancysector om inzichten op te halen hoe het accountancyberoep zich mogelijk gaat ontwikkelen. Dat gebeurde onder andere tijdens een door de AFM en het MAB georganiseerde rondetafelsessie op Nyenrode, eerder dit jaar.
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Nekita, A. G., i S. A. Malenko. ""COCKTAIL" CHEBURASHKA: MEDIA TECHNOLOGIES FOR CREATING AND PROMOTING AN IMAGE IN RUSSIANMASS CINEMA". Experience industries Socio-Cultural Research Technologies, nr 3 (2024): 238–75. http://dx.doi.org/10.34680/eiscrt-2024-3(8)-238-275.
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The Russian family comedy Cheburashka became not only an example of a successful commercial project, but also demonstrated an example of professional adaptation of Hollywood technologies in the modern domestic socio-cultural space. Against the background of a steady and continuously increasing nostalgia for the Soviet past, a creative product was created in which the audience’s illusions about the Soviet Cheburashka and new Western-oriented, ideologized cultural values were strangely combined, which turned out to be encoded in the characters, subject environment andplot twists of the film. The image of Cheburashka in Soviet culture evolved from an amorphous animal with an unspecified species to a common Soviet symbol of childhood with an appropriate set of existential meanings. According to the authors of the Russian Cheburashka, they created a new story of this character, at the same time, the retroatmosphere of the picture and the set of characters invariably refer viewers to the Soviet Cheburashka. But the new image can only formally be attributed to its visual prototype, since it was intentionally created as a visual and semantic structure appealing to the prevailing industrial thematism and consumer values in Russian society. That is why the new Cheburashka becomes an “Easter egg”, implicitly indicating the presence in one film of several dozen purposefully borrowed elements of images of popular characters from commercially successful Western, Soviet and Russian media projects of the past decades. Such technology makes it possible to fix the prevailing ideological trend associated with the comprehensive assimilation of Western values in the space of Russian culture.
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Rybin, Vyacheslav, Timur Karimov, Maria Sigaeva, Ekaterina Solomevich, Georgii Kolev i Ekaterina Kopets. "Design of a Smart Bartender with Peristaltic Pumps". Inventions 4, nr 2 (1.05.2019): 26. http://dx.doi.org/10.3390/inventions4020026.
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In this paper, the development of a smart scalable system for liquid supply based on high-precision peristaltic pumps is described. The architecture of software and hardware for the proposed system is considered. This liquid supply system can be used for mixed and layered cocktail preparation in public catering establishments, such as bars, as well as for home use. Due to the flexibility and scalability of the system, it is possible to apply it in various branches of human activity, where fine dosing of liquids is required, e.g., for beverage mixing, cooking, health and medical applications. By using open architecture and software, this system can be built in a smart home environment. The cross-platform control software and an embedded Bluetooth module allow using the developed setup in various use case scenarios. The result of the project is a DIY-kit, capable of mixing 6 to 32 different liquids in specified proportions and the programmable sequence.
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Jones, Marion, i Grant Stanley. "Mission Impossible". International Review of Qualitative Research 4, nr 2 (sierpień 2011): 231–51. http://dx.doi.org/10.1525/irqr.2011.4.2.231.
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This paper reports the reflective journey we undertook as the leaders of a collaborative action research project involving education practitioners and our navigation through a complex web of cooperation, conflict resolution, bargaining and defection. Drawing on these experiences, we seek to make explicit the cocktail of tensions and disordering of research contexts and practices that have remained largely disregarded both in the literature and in everyday self-accounting. By interweaving the plot-lines of ‘game,’ ‘ritual’ and ‘real’ we seek to gain an insight into the rational/irrational behaviour of the various players involved in this ethno-drama, including ourselves. Finally, we posit the claim that educational action research conceived as a ‘critical and (self-critical) collaborative inquiry’ (Zuber-Skerritt, 1996, p.85) has surrendered its democratic values to an all pervading performativity culture and conclude that collaborative action research conducted in the politicised educational contexts of today cannot be true to its ideal.
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DULIŃSKI, Robert, i Dagmara PONIEWSKA. "The Impact of Mash pH and Exogenous Phosphorolytic Enzymes on the Release of Inositol Phosphates, Fermentable Sugars and Polypeptide Profile in the Technology of Buckwheat Beer". Bulletin of University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca. Food Science and Technology 1, nr 79 (15.05.2022): 111. http://dx.doi.org/10.15835/buasvmcn-fst:2021.0045.
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The first - already published - stage of the project, which conducted optimization of the temperature mashing program, yielded promising results in the form of an increase in the pool of bioactive myo-inositol by 50% in buckwheat wort supplemented with phosphorolytic enzymes. In this study, it was possible to enhance this effect by adjusting the pH of the mash close to the optimal for phytases, which resulted in a nearly 3-fold increase in myo-inositol concentration, while anti-nutritional phytate was reduced by nearly 75% with a mash pH value at 5.0 and supplementation with a cocktail of commercial phosphorolytic enzymes: Finase P and Finase AP. Changes in the polypeptide profile observed in subsequent wort at a reduced pH of the mash indicate the dominant position of polypeptides in the middle range of molecular weights (10-45 kDa). Ion chromatography coupled with amperometric and conductometric detection modes was used to observe the profile of the key components and the changes that occur in fermentation broths at different pH ranges.
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Ikegami, Hiroko. "Pop as Translation Strategy: Makishi Tsutomu's Political Pop in Okinawa". ARTMargins 7, nr 2 (czerwiec 2018): 42–71. http://dx.doi.org/10.1162/artm_a_00208.
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This essay makes the first sustained study of the Okinawan artist Makishi Tsutomu (1941–2015) who used American Pop Art vocabularies to describe the complex realities of US-occupied Okinawa. Focusing on his 1972 installation Commemorating the Reversion to the Great Empire of Japan, the essay examines the critical ambivalence of Makishi's Political Pop as a translation strategy. Despite his critique of both American and Japanese imperialism, Makishi was aware that Okinawa was inseparably entangled in it, especially in the context of the Vietnam War, which brought violence, but also economic benefits, to Okinawa. Despite his use of the American Pop idiom as a new lingua franca for contemporary art, Makishi's work did not reach either mainland or international audiences as the artist exhibited almost exclusively in Okinawa. By comparing Makishi's artistic strategies with those of a representative Okinawan novelist, Ōshiro Tatsuhiro, especially as articulated in his 1967 novella The Cocktail Party, the essay situates the significance of Makishi's project within the emerging discourse on the global neo-avant-garde.
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Lopes, Paula, Diogo Coelho i José Prates. "Testimony on a Successful Lab Protocol to Disrupt Chlorella vulgaris Microalga Cell Wall". Current Developments in Nutrition 6, Supplement_1 (czerwiec 2022): 1146. http://dx.doi.org/10.1093/cdn/nzac072.018.
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Abstract Objectives Microalgae have recently gained popularity due to demand for novel environmental green solutions. Notwithstanding, there is a catch. Most species of microalgae, as Chlorella vulgaris (C. vulgaris) display a recalcitrant cell wall characterized by a complex matrix of polysaccharides, a major barrier for monogastrics digestibility and extraction of nutritional compounds. To overcome this limitation, the development of feed enzymes, in particular Carbohydrate-Active enZymes (CAZymes) with capacity to disrupt C. vulgaris cell wall may contribute to improve the bioavailability of these microalgae compounds. Methods In order to disclosure novel combination of feed enzymes to disrupt C. vulgaris cell wall, a lab protocol was implemented containing the following steps: after microalgae cultivation and having available a repertoire of pre-selected CAZymes produced by high-throughput technology, the step 1 is the individual screening of the most functional enzymes on disrupting C. vulgaris cell wall (versus a control with PBS) and the determination of reducing sugars released by DNSA method; step 2 concerns on finding the best CAZymes cocktail, testing the synergistic effect of enzymes, to disrupt C. vulgaris cell wall (in parallel with running the control); step 3 is the assessment of the degree on Chlorella vulgaris cell wall degradation by measuring reducing sugars released by DNSA method, fatty acids by GC-FID, oligosaccharides by HPLC, protein content by Kjeldahl method, and various pigments (chlorophylls a and b, and carotenoids) in the supernatant. In the residue, we assessed cell counting using a Neubauer chamber on a bright-field microscope and fluorescence intensity, after staining with Calcofluor White for both control and CAZymes cocktail treatments. Results This is a study protocol. Conclusions In addition to animal feed industry with impact on human nutrition, our lab protocol may increase the yield in obtaining valued constituents from C. vulgaris microalga for other biotechnological industries, namely those associated with biofuel, food, cosmetics and pharmaceutical applications. Funding Sources Fundação para a Ciência e a Tecnologia (FCT, Lisbon, Portugal) through project UIDB/00,276/2020 to CIISA, FCT Stimulus of Scientific Employment Program to PAL (DL57/2016/CP1438/CT0007) and a PhD fellowship to DC (SFRH/BD/126,198/2016).
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Fletcher, Julie, Robyn Manley, Christian Fitch, Christina Bugert, Karen Moore, Audrey Farbos, Michelle Michelsen i in. "The Citizen Phage Library: Rapid Isolation of Phages for the Treatment of Antibiotic Resistant Infections in the UK". Microorganisms 12, nr 2 (25.01.2024): 253. http://dx.doi.org/10.3390/microorganisms12020253.
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Antimicrobial resistance poses one of the greatest threats to global health and there is an urgent need for new therapeutic options. Phages are viruses that infect and kill bacteria and phage therapy could provide a valuable tool for the treatment of multidrug-resistant infections. In this study, water samples collected by citizen scientists as part of the Citizen Phage Library (CPL) project, and wastewater samples from the Environment Agency yielded phages with activity against clinical strains Klebsiella pneumoniae BPRG1484 and Enterobacter cloacae BPRG1482. A total of 169 and 163 phages were found for K. pneumoniae and E. cloacae, respectively, within four days of receiving the strains. A third strain (Escherichia coli BPRG1486) demonstrated cross-reactivity with 42 E. coli phages already held in the CPL collection. Seed lots were prepared for four K. pneumoniae phages and a cocktail combining these phages was found to reduce melanisation in a Galleria mellonella infection model. The resources and protocols utilised by the Citizen Phage Library enabled the rapid isolation and characterisation of phages targeted against multiple strains. In the future, within a clearly defined regulatory framework, phage therapy could be made available on a named-patient basis within the UK.
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Damerau, A., M. Pfeiffenberger, A. Lang, T. Gaber i F. Buttgereit. "THU0069 MIMICKING ARTHRITIS IN VITRO TO TEST DIFFERENT TREATMENT APPROACHES". Annals of the Rheumatic Diseases 79, Suppl 1 (czerwiec 2020): 247.1–247. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3051.
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Background:Our ultimate goal is to study potential drug candidates in an experimental setting of arthritis. Therefore, we aim to develop a valid humanin vitro3D joint model mimicking features of joint inflammation by applying inflammatory conditions namely immune cells and pro-inflammatory cytokines. Our in vitro3D joint model consists of different components including an osteogenic and chondrogenic part, the joint space filled with synovial fluid, and the synovial membrane. Developed as an alternative experimental setup to animal experiments, our 3D joint model will enable us to study efficiently the effects of potential drug candidates in a human-basedin vitromodel.Objectives:Here, we aimed to demonstrate the suitability of our human-basedin vitro3D osteochondral model by analyzing the influence of the main cytokines involved in the pathogenesis of RA as well as the impact of a specific therapeutic intervention.Methods:Based on human bone marrow-derived mesenchymal stromal cells (hMSCs), we developed 3D bone and cartilage tissue components that were characterized in detail (e.g. cell vitality, morphology, structural integrity) using histological, biochemical and molecular biological methods as well as µCT and scanning electron microscope (SEM). In brief, to establish the osteogenic component, we populated β-tricalcium phosphate (TCP) – mimicking the mineral bony part – with hMSCs, while the scaffold-free cartilage component was generated by cellular self-assembly and intermittent mechanical stimulation (fzmb GmbH). Subsequently, we co-cultivated both tissue components for three weeks to generate an interconnected 3D osteochondral model. To test the suitability, we applied a cocktail of TNFα, IL-6 and MIF using concentrations reported from RA synovial fluid alone or in combination with specific therapeutic drugs and analyzed their impact by qPCR.Results:We verified the osteogenic phenotype of our 3D bone tissue component by demonstrating an increase in mineralized bone volume and the induction of bone-related gene expression (RUNX2,SPP1andCOL1A1) as compared to the corresponding control. Secondly, we verified the chondrogenic phenotype of our cartilage tissue component by HE and Alcian Blue staining as well as by the reduced expression ofCOL1A1and an abundant expression ofCOL2A1. Interestingly, co-cultivation of both components for up to 3 weeks demonstrated colonization, connectivity and initial calcification implying a transitional bridging area. Cytokine stimulation with a cocktail of TNF, IL-6 and MIF leads to an upregulation of the metabolic markerLDHAand the angiogenic markerVEGFin both bone and cartilage. The inflammation markersIL8andTNFare also upregulated in both components, whileIL6is downregulated in bone compared to the unstimulated control. In addition, a cytokine-induced upregulation of matrix-metalloproteases was observed especially in the cartilage component. All these cytokine-related effects could be antagonized with a cocktail of therapeutics (milatuzumab, adalimumab and tocilizumab).Conclusion:The results of our study showed cytokine related effects of both tissue components, which can be therapeutically antagonized. By combining the components in a 96 well format, we aim to provide a mid-throughput system for preclinical drug testing.Acknowledgments:This project is funded by the Federal Ministery of Education and Research (BMBF)Disclosure of Interests:Alexandra Damerau: None declared, Moritz Pfeiffenberger: None declared, Annemarie Lang: None declared, Timo Gaber: None declared, Frank Buttgereit Grant/research support from: Amgen, BMS, Celgene, Generic Assays, GSK, Hexal, Horizon, Lilly, medac, Mundipharma, Novartis, Pfizer, Roche, and Sanofi.
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Uddin, Nazia, Paola Ostano, Giovanna Chiorino, Jeremy di Domizio, Michel Gilliet, Mike Philpott, Rosalind Hannen i Daniele Bergamaschi. "O09 Dynamic impact of chronic inflammation on epidermal autophagy pathway". British Journal of Dermatology 189, nr 1 (lipiec 2023): e7-e8. http://dx.doi.org/10.1093/bjd/ljad174.009.
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Abstract Chronic inflammatory signalling significantly affects epidermal homeostasis leading to different types of skin conditions characterized by a deregulated stratification of epidermal keratinocytes. Our project aims to investigate how chronic inflammation mechanistically influences autophagy signalling in the epidermis. We have previously reported impairment of the autophagic flux in an established psoriatic keratinocyte model (PSA cells) when compared to corresponding controls from healthy skin (KT2 and NTERT cells). To understand the dynamic impact of chronic inflammation on the epidermal autophagy pathway we have custom made a cytokine cocktail which induces interleukin-1β release at different times in keratinocyte cultures and stimulates keratinocyte proliferation. Stimulation of healthy keratinocytes with chronic inflammatory cocktail-induced activation of initial steps of the autophagy process. This is confirmed by the protein expression of key components of ULK1 and VPS34 complexes. Analysis of the elongation-stage markers confirmed the activation and correct proceeding of the pathway, until we observed LC3-I accumulation. In autophagy, the phospholipid phosphatidylethanolamine (PE) is crucial for LC3-I conversion to LC3-II. Changes in phospholipid metabolism have been reported in inflammatory skin conditions, including PE downregulation in psoriatic keratinocytes. By increasing PE expression in inflamed keratinocytes, we show increased LC3-II lipidation and restoration of the autophagy pathway functionality. Moreover, inflammation-induced p62 upregulation (a cargo degraded by the lysosomal autophagy compartment) and deregulated the lysosomal membrane permeability integrity, as confirmed by the expression of glycosylated and deglycosylated lysosomal protein (LAMP1, LAMP2 and LAMP3) expression. Our data are supported by independent transcriptomic data analysis from the GEO database, comparing autophagy gene expression in psoriatic and healthy matched or nonmatched controls. Spatial transcriptomic mapping of autophagic genes in lesional psoriatic skin provided further insight into the epidermal autophagy pathway regulation in inflammatory skin conditions. Immunofluorescence staining of both healthy and psoriatic human skin samples finally translate the differences in key autophagy marker expression observed in our two- and three-dimensional cell models, including deregulation of LC3, p62 and lysosomal membrane protein expression. Overall, our results exhibit a comprehensive and mechanistical analysis of how chronic inflammation could affect the integrity of this metabolic pathway, which significantly regulates epidermal homeostasis. Our data provide novel targets for therapeutic strategies and supports autophagy stimulation as viable modes of treatment to counteract chronic inflammatory skin conditions.
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Al-Shammary, Ali, i Moutaz Abdul Mounam. "Exodia phenomenon of foodborne Mycophages cocktails against chimeric strains of Candida albicans recovered from dairy chain ecosystems in Baghdad". Bionatura 8, nr 1 (15.03.2023): 1–5. http://dx.doi.org/10.21931/rb/2023.08.01.91.
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Influential, organized groups with natural antimicrobial and anti-biofilm broad-spectrum power exist within the food chain, like a hidden dormant mimic hygienic bio life nanobodies that can terminate multiple opportunistic disease entities owing multi-stress resistant forbidden recalcitrant power, such as Candida albicans. These wonderful dynamic forces created by ALLAH Almighty are the Mycophages or fungi-eating state of fungi foodborne phages, and this project was redirected to be a dare to leap from us towards the future. Multi-stress resistant C. albicans that are resistant to different antifungal agents with their genetic tolerance plasticity to thermal pasteurization decontamination module as well as to ultraviolet irradiation hurdle strategy recovered from raw milk (mastitis), yogurt and soft cheese with versatile phenotypes resident in topic sectors of Abu-Ghraib, Al-Fudhaliyah and Al-Sadrya in Baghdad. From the other side of trueness, we discover an abnormal deviated activity of bacteriophages cocktails that behave with broad-spectrum functions against Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant Streptococci (VRE) as lytic bactericidal and versus multi stress resistant C. albicans as redirected terminator lytic Mycophages thus objected to be a new nano-built hygienic phenomenon entity (Exodia). Keywords: Exodia, Lytic Mycophages, Multi stress-resistant Candida albicans, dairy chain ecosystems
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Mozafari, Arshavez. "Psychoanalysis and the Challenge of Islam". American Journal of Islam and Society 27, nr 3 (1.07.2010): 98–100. http://dx.doi.org/10.35632/ajis.v27i3.1308.
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As a particular outgrowth of modernity, Islamism has garnered the attentionof a great many theorists. In Psychoanalysis and the Challenge ofIslam, Fethi Benslama, a psychoanalyst and professor, elaborates upon theprecise undergirding apparatus that sustains the logic of Islamism as arecently conceived phenomenon. The book attempts to clearly define thelogical progression of Islamism since its point of conception. This point islocated in the colonial era, when “traditional” Islam was put under theintense strain of a developed European modernity. The violent break, alongwith all the baggage that was incapable of being properly allocated andrefined by “what Freud called the ‘cultural work’ (Kulturarbeit)” (p. ix),produced an explosive cocktail that has and continues to haunt the projectof modernity. Through the use of a unique theoretical style called deconstructionistpsychoanalysis, Banslama’s project seeks to account for thispervasive phenomenon.“Islam has never been a major concern for me or my generation. It wasbecause Islam began to take an interest in us that I decided to take an interestin it” (p. 1). This is the way Benslama begins the first section of his book.It marks not only his secular disposition but also the aggressivity associatedwith the burgeoning Islamist political movements. Islamism is strictly conceptualizedas a phenomenon that differs from fundamentalism. It has thecapacity to operate through the decomposition of traditionalism – one occurrence associated with this downfall is the “catastrophic collapse of [traditional]language” (p. 4) ...
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Olawoyin, Richard. "Modelling the health risks of exposure to respirable crystalline silica from hydraulic fracturing operations in the USA shale plays". Journal of Biomedical Engineering and Informatics 1, nr 1 (27.07.2015): 25. http://dx.doi.org/10.5430/jbei.v1n1p25.
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Respirable crystalline silica (RCS) is a known human carcinogen and a contaminant of potential concern. Proppants are used during the process of well stimulation (hydraulic fracturing) as additives in the fluid cocktail and sand is often used as a proppant which contains high percentage of silica determined by the quartz content. Empirical occupational exposure risk models were employed in this study to assess the potential health consequences from chronic RCS exposures based on RCS data from NIOSH and risk assessment formulas. Evaluating the lifetime (LT) excess cancer risk (LCR) potential, based on a risk target of 105, the job titles that are likely to experience any substantial potential effect of cancer induction are the sand mover (LCR = 16.1 × 105) and transfer belt (LCR = 19.2 × 105) operators. The sand truck driver and data Van operators are among the job functions with a cumulative disease burden of 7.2% that are unlikely to be affected by < 2% carcinogenic disease burden. The chemical truck, sand mover and transfer belt (T-belt) operators may potentially be at risk of other occupational nonmalignant respiratory diseases with hazard quotient (HQ) of 0.65, 1.79, and 2.13 respectively. It is recommended that continuous occupational health monitoring of potentially exposed workers should be included as part of the project plan and the engineering risk controls that have been put in place should be ranked to highlight the effectiveness of any risk reduction/prevention methodology employed.
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Vanleene, Daphne, Joris Voets i Bram Verschuere. "The co-production of public value in community development: can street-level professionals make a difference?" International Review of Administrative Sciences 86, nr 3 (15.01.2019): 582–98. http://dx.doi.org/10.1177/0020852318804040.
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This article deals with the different roles of the street-level professional in achieving public value in a co-productive community development project. The article focuses, in particular, on the question of how engaged street-level professionals combine different roles – as friend, leader, representative and mediator – in order to empower and include their target audience, thereby contributing to public value creation. This question was explored in a qualitative case study in a community development project in Ostend (Belgium). The study indicated that the street-level professional needed to adopt different role combinations in a well-considered way in order to influence the co-productive process that affected public value creation. More specifically, the combination of friend–leader, as well as the leader–mediator combination, can empower co-producers and thus create personal value for these co-producers. Moreover, professionals carefully consider the combination of friend–leader to support community value over personal value. Also, by combining the friend, leader and representative roles, professionals can include more co-producers and create a stronger sense of community value. This article concludes that there is a need for an engaged professional who has sufficient time and autonomy to apply the combinations as needed. Additionally, we note that more research on these different role cocktails is necessary in order to provide a clear framework of the different combinations that professionals can apply. Points for practitioners From our research, we can make two key recommendations for practitioners. First, in order to empower and include vulnerable participants to co-produce, professionals need to develop the right skill set to fulfil the roles needed to engage with participants. Second, and relatedly, this also implies sufficient autonomy (vis-a-vis policymakers) for the professionals at the street level, which will enable them to consider what is needed for the co-production project to become successful in terms of inclusion and empowerment.
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Radev, S. "DERMOELECTROPORATION IN THE TREATMENT OF OVERUSE INJURIES". Trakia Journal of Sciences 18, Suppl.1 (2020): 153–56. http://dx.doi.org/10.15547/tjs.2020.s.01.028.
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The musculoskeletal system can suffer from various types of overuse injuries which may affect the bone, muscles, tendons and ligaments. Iliotibial band syndrome (ITBS) is a common overuse injury typically seen in runners, cyclist and other endurance athletes, whose sport requires repetitive knee flexion. The majority of cases resolve with conservative treatment. Care in the acute phase focuses on activity limitation, NSAIDʼs, corticosteroids. Analgesia and pain management are two very important aspects in the therapeutic process. The research project is focused on the dermoelectroporation (pulse current iontophoresis), as a new method for transdermal drug delivery. It was evaluated the feasibility administering the cocktail of Diclofenac Sodium and Dexamethasone Sodium Phosphate by dermoelectroporation (pulse current iontophoresis), for treatment of ITBS. Diclofenac Natrium and Dexamethasone Sodium Phosphate was given locally, via dermoelectroporation (pulse current iontophoresis) in the area of pain (area of the damaged lateral femoral condyle), following microdermabrasion. The therapeutic procedures were performed every day, once a day, 3 times. The pain threshold was recorded objective with Pressure Algometer Somedic in kPa/cm2.. The subjective intensity of the painful sensation was assessed with 10 cm Visual Analogue Scale (VAS), ranging from 0 cm (no pain) to 10 cm (worst possible pain). Using this method of application of nonsteroidal and steroidal anti-inflammatory drugs has significant benefits like: quick pain relief, minimally invasive effect for the patient and minimum side effects. Based on these advantages it is thought that dermoelectroporation could be a preferable way of administering anti-inflammatory drugs in inflammatory-degenerative conditions related to the musculoskeletal system, such as overuse injuries like tendinopathies.
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Schmidt, Tiffany M., Kenichiro Taniguchi i Paulo Kofuji. "Intrinsic and Extrinsic Light Responses in Melanopsin-Expressing Ganglion Cells During Mouse Development". Journal of Neurophysiology 100, nr 1 (lipiec 2008): 371–84. http://dx.doi.org/10.1152/jn.00062.2008.
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Melanopsin (Opn4) is a photopigment found in a subset of retinal ganglion cells (RGCs) that project to various brain areas. These neurons are intrinsically photosensitive (ipRGCs) and are implicated in nonimage-forming responses to environmental light such as the pupillary light reflex and circadian entrainment. Recent evidence indicates that ipRGCs respond to light at birth, but questions remain as to whether and when they undergo significant functional changes. We used bacterial artificial chromosome transgenesis to engineer a mouse line in which enhanced green fluorescent protein (EGFP) is expressed under the control of the melanopsin promoter. Double immunolabeling for EGFP and melanopsin demonstrates their colocalization in ganglion cells of mutant mouse retinas. Electrophysiological recordings of ipRGCs in neonatal mice (postnatal day 0 [P0] to P7) demonstrated that these cells responded to light with small and sluggish depolarization. However, starting at P11 we observed ipRGCs that responded to light with a larger and faster onset (<1 s) and offset (<1 s) depolarization. These faster, larger depolarizations were observed in most ipRGCs by early adult ages. However, on application of a cocktail of synaptic blockers, we found that all cells responded to light with slow onset (>2.5 s) and offset (>10 s) depolarization, revealing the intrinsic, melanopsin-mediated light responses. The extrinsic, cone/rod influence on ipRGCs correlates with their extensive dendritic stratification in the inner plexiform layer. Collectively, these results demonstrate that ipRGCs make use of melanopsin for phototransduction before eye opening and that these cells further integrate signals derived from the outer retina as the retina matures.
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Greening, Gage, Rebecca McLennan, Eric Geanes, Santosh Khanal, Suryabalan Rangaraj i Todd Bradley. "Design and testing of mosaic enterovirus vaccine to prevent hand, foot and mouth disease". Journal of Immunology 212, nr 1_Supplement (1.05.2024): 1554_4624. http://dx.doi.org/10.4049/jimmunol.212.supp.1554.4624.
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Abstract Enterovirus A (EV-A) has been responsible for recent outbreaks of hand-foot-mouth disease (HFMD); however, there is no vaccine or effective antiviral treatment. The goal of our project is to develop broad vaccines targeting the diverse EV-A serotype viruses that cause HFMD. We used the EV-A viral capsid protein 1 (VP1) as the vaccine antigenic target, because of its genetic diversity across EV-A serotypes, and prior work that showed VP1 has linear neutralizing antibody epitopes. We computationally designed VP1 proteins to create mosaic antigens that optimize B and T cell epitopes among diverse EV-A viral sequences. We identified that a hexavalent mosaic vaccine cocktail had the highest EV-A sequence coverage. We then immunized mice in three groups with recombinant VP1 proteins in adjuvant; Group 1 was given the EV-A Consensus VP1 (Consensus), Group 2 was given the EV-A strain EVA-71 VP1 protein (EVA-71, strain specific) and Group 3 was given our newly designed hexavalent vaccine (EV-A Consensus + 5 mosaic VP1). We measured the antibody binding levels to 9 EV-A VP1 antigens after immunization and found that the EV-A hexavalent vaccine resulted in improved antibody binding breadth during in vivo vaccination. Our results demonstrate the feasibility of using polyvalent VP1 proteins to increase the breath of antibody epitopes among EV-A serotypes. Our approach has the potential to treat and block EV-A infection and serve as a model for responding to other emerging viral diseases.
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Ibrahim, Shifa S., Kamaleshwari Kesavaraj, Muthumani Arun, SA Mohamed Ameen i Raasi Sankar. "Review of Cervical Carcinoma Screening Program in Tamil Nadu – Current Trend and Recommendations from a Histopathologist’s Viewpoint". Journal of SAFOMS 5, nr 1 (2017): 1–7. http://dx.doi.org/10.5005/jp-journals-10032-1095.
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ABSTRACT Objectives Cervical carcinoma, the commonest carcinoma affecting Indian females, is caused by human papilloma virus (HPV) infection. Primordial prevention and primary prevention with HPV vaccine and cancer screening respectively, can go a long way in preventing this carcinoma. The health system project in Tamil Nadu has done a commendable job in reducing the disease burden by introducing screening programs for cervical carcinoma at the grassroots level, way back in 2005. This study was done to evaluate the cervical biopsy specimens received as a part of this program to compute its incidence, compare the incidence among various districts, and suggest future directions based on our observations. Materials and methods From visual inspection with acetic acid/visual inspection with Lugol’s iodine positive cervical biopsy specimens, 506 were chosen randomly from various districts. Based on histopathological examination, incidence of individual lesions and district-wise incidence were calculated. Predictive factors that determine the progression of these lesions were analyzed based on the literature. Results Out of the 506 cervical biopsy specimens, 34 were unsatisfactory. The incidence of high-grade dysplasia peaked around 31 to 40 years, and squamous cell carcinoma peaked among 51 to 60 years. Madurai ranked high in the incidence of both high-grade dysplasia and carcinoma. Conclusion Incidence of dysplasia and carcinoma in our study was comparable to those seen in the literature. Integration of HPV deoxyribonucleic acid studies into the program can increase the detection rate, detect the progressors, help to identify the HPV species prevalent in an area, and aid in formulating cost-effective HPV vaccine cocktail. How to cite this article Ibrahim SS, Kesavaraj K, Arun M, Ameen SAM, Sankar R. Review of Cervical Carcinoma Screening Program in Tamil Nadu – Current Trend and Recommendations from a Histopathologist’s Viewpoint. J South Asian Feder Menopause Soc 2017;5(1):1-7.
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Moraghebi, Roksana, Roger Emanuel Rönn, Aaron Parker, Margaret Lutz, Travis Berggren i Niels-Bjarne Woods. "Human Umbilical Cord Blood Derived IPS Cells as a Source of Hematopoietic Progenitors Cells". Blood 116, nr 21 (19.11.2010): 4790. http://dx.doi.org/10.1182/blood.v116.21.4790.4790.
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Abstract Abstract 4790 The ability to generate hematopoietic stem cells (HSCs) from an unlimited source of cells, such as from patient derived induced pluripotent stem (iPS) cells, would enable the generation of an unlimited supply of HLA matched transplantable HSCs for therapeutic purposes. Umbilical cord blood is an ideal source of fetal/neonatal cellular material for iPS reprogramming due to the proliferative capacity of the cells as well as the reduced exposure of these cells to environmental factors compare to commonly used skin fibroblasts. In addition, it has been proposed that the cellular starting material imparts an epigenetic memory to the iPS cell line that influences lineage predisposition upon its differentiation. This project seeks to evaluate human umbilical cord blood as a starting cell source for generating iPS cells, with the ultimate goal to generate transplantable HSCs. We have isolated, cultured, and characterized an adherent cell fraction from the hemato-endothelial lineage. These cells were found to have an endothelial progenitor phenotype with CD45neg, CD133neg, VE-Cadherinhi, VEGFR2med, CD31hi, CD34hi cell surface markers as determined by FACS and formed tubules in the matrigel tubular assay. The iPS cell lines were generated using a 5-factor cocktail of inducible lentiviral vectors with an efficiency of 0.02%. The iPS cell lines were then evaluated for blood cell lineage differentiation capacity using our state-of-the-art ES/iPS-to-blood differentiation protocol. From the 5 iPS lines we tested, we saw 30 +/− 20% hematopoietic (CD45+) cells in our differentiation cultures. Moreover, the percentage of hematopoietic progenitors (CD45+ CD34+) of the hematopoietic cell fraction was 19.8+/− 0.6%, and also showed the presence of the more primitive CD45+ CD34+ CD38- progenitor fraction. Clonogenic progenitor cell counts determined by methylcellulose colony assay showed 44 +/− 3 colony forming units per 10,000 plated CD45+ cells. This is in the range of colonies obtained from umbilical cord blood mononuclear cell isolates (mean= 35+/− 2). The efficiency of hematopoietic generation for the lines ranged from 8 to 60% CD45+ suggesting that there are significant differences between the lines in terms of the completeness of reprogramming towards the pluripotent state. Further investigation into the epigenetic status of these lines is being performed. These data demonstrate the utility of human umbilical cord blood derived iPS cells for generating and expanding hematopoietic progenitors. This project advances iPS technologies towards treating life threatening hematological malignancies and diseases. Disclosures: No relevant conflicts of interest to declare.
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McCONNELL, JENNIFER A., i DONALD W. SCHAFFNER. "Validation of Mathematical Models for Salmonella Growth in Raw Ground Beef under Dynamic Temperature Conditions Representing Loss of Refrigeration". Journal of Food Protection 77, nr 7 (1.07.2014): 1110–15. http://dx.doi.org/10.4315/0362-028x.jfp-14-038.
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Temperature is a primary factor in controlling the growth of microorganisms in food. The current U.S. Food and Drug Administration Model Food Code guidelines state that food can be kept out of temperature control for up to 4 h without qualifiers, or up to 6 h, if the food product starts at an initial 41°F (5°C) temperature and does not exceed 70°F (21°C) at 6 h. This project validates existing ComBase computer models for Salmonella growth under changing temperature conditions modeling scenarios using raw ground beef as a model system. A cocktail of Salmonella serovars isolated from different meat products (Salmonella Copenhagen, Salmonella Montevideo, Salmonella Typhimurium, Salmonella Saintpaul, and Salmonella Heidelberg) was made rifampin resistant and used for all experiments. Inoculated samples were held in a programmable water bath at 4.4°C (40°F) and subjected to linear temperature changes to different final temperatures over various lengths of time and then returned to 4.4°C (40°F). Maximum temperatures reached were 15.6, 26.7, or 37.8°C (60, 80, or 100°F), and the temperature increases took place over 4, 6, and 8 h, with varying cooling times. Our experiments show that when maximum temperatures were lower (15.6 or 26.7°C), there was generally good agreement between the ComBase models and experiments: when temperature increases of 15.6 or 26.7°C occurred over 8 h, experimental data were within 0.13 log CFU of the model predictions. When maximum temperatures were 37°C, predictive models were fail-safe. Overall bias of the models was 1.11. and accuracy was 2.11. Our experiments show the U.S. Food and Drug Administration Model Food Code guidelines for holding food out of temperature control are quite conservative. Our research also shows that the ComBase models for Salmonella growth are accurate or fail-safe for dynamic temperature conditions as might be observed due to power loss from natural disasters or during transport out of temperature control.
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Lee, Seong-Ho, Hee-Seop Lee, Ramasamy Perumal i Dmitriy Smolensky. "Effect of a Novel High Phenolic Sorghum Bran (PI570481) on Lipid Accumulation in 3T3-L1 Cells". Current Developments in Nutrition 5, Supplement_2 (czerwiec 2021): 1227. http://dx.doi.org/10.1093/cdn/nzab055_037.
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Abstract Objectives Obesity is the leading public health problem and the main cause of many other metabolic and chronic complications. Sorghum is the fifth most important cereal crop in the world and certain varieties contain significantly greater amounts of biologically active phenolic compounds than other strains. PI570481 is a novel strain of high phenolic sorghum bran and show anti-cancer activities. The objective of this study is to explore a potential use of PI570481 with other phenolic sorghum bran extracts (SC84 and Sumac) and a sorghum grain (white sorghum) for the differentiation of preadipocytes and to investigate cellular and molecular responses in differentiated adipocytes to elucidate related mechanisms. Methods 3T3-L1 preadipocytes were cultured with DMEM containing 10% FBS and differentiated using a differentiation cocktail containing 1 μM dexamethasone, 0.5 mM isobutylmethylxanthine, and 5 μg/mL insulin in 10% FBS/DMEM. Lipid accumulation was measured by Oil Red O (ORO) staining. Cellular reactive oxygen species (ROS) and glucose uptake were measured using DCFH-DA and 2-NBDG, respectively. Western blotting was performed to examine the expression of genes regulating adipogenesis, lipogenesis and cell signaling. Results Sorghum extracts (PI570481, SC84, Sumac, white) did not cause cytotoxicity in both undifferentiated and differentiated 3T3-L1 cells. Sorghum bran extracts (PI570481, SC84, Sumac) reduced intracellular lipid accumulation and expression of adipogenic and lipogenic proteins in dose-dependent manner in differentiated 3T3-L1 cells. Regarding anti-adipogenic mechanism, sorghum bran extracts (PI570481, SC84, Sumac) represses ROS production and MAPK signaling pathways in differentiated 3T3-L1 cells. Sorghum bran extracts (PI570481, SC84, Sumac) also represses insulin signaling and glucose uptake in differentiated 3T3-L1 cells. Conclusions These data propose a potential use of a novel high phenolic sorghum bran as functional food. Funding Sources Maryland Agricultural Experiment Station (MAES) and National Institute of Food and Agriculture (Project #: MD-NFSC-201,176) to S-HL Cooperative Agreement grant from USDA-ARS to S-HL.
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Tucker, Stephen, i Peter Pollard. "Identification of Cyanophage Ma-LBP and Infection of the Cyanobacterium Microcystis aeruginosa from an Australian Subtropical Lake by the Virus". Applied and Environmental Microbiology 71, nr 2 (luty 2005): 629–35. http://dx.doi.org/10.1128/aem.71.2.629-635.2005.
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ABSTRACT Viruses can control the structure of bacterial communities in aquatic environments. The aim of this project was to determine if cyanophages (viruses specific to cyanobacteria) could exert a controlling influence on the abundance of the potentially toxic cyanobacterium Microcystis aeruginosa (host). M. aeruginosa was isolated, cultured, and characterized from a subtropical monomictic lake—Lake Baroon, Sunshine Coast, Queensland, Australia. The viral communities in the lake were separated from cyanobacterial grazers by filtration and chloroform washing. The natural lake viral cocktail was incubated with the M. aeruginosa host growing under optimal light and nutrient conditions. The specific growth rate of the host was 0.023 h−1; generation time, 30.2 h. Within 6 days, the host abundance decreased by 95%. The density of the cyanophage was positively correlated with the rate of M. aeruginosa cell lysis (r 2 = 0.95). The cyanophage replication time was 11.2 h, with an average burst size of 28 viral particles per host cell. However, in 3 weeks, the cultured host community recovered, possibly because the host developed resistance (immunity) to the cyanophage. The multiplicity of infection was determined to be 2,890 virus-like particles/cultured host cell, using an undiluted lake viral population. Transmission electron microscopy showed that two types of virus were likely controlling the host cyanobacterial abundance. Both viruses displayed T7-like morphology and belonged to the Podoviridiae group (short tails) of viruses that we called cyanophage Ma-LBP. In Lake Baroon, the number of the cyanophage Ma-LBP was 5.6 × 104 cyanophage · ml−1, representing 0.23% of the natural viral population of 2.46 × 107 · ml−1. Our results showed that this cyanophage could be a major natural control mechanism of M. aeruginosa abundance in aquatic ecosystems like Lake Baroon. Future studies of potentially toxic cyanobacterial blooms need to consider factors that influence cyanophage attachment, infectivity, and lysis of their host alongside the physical and chemical parameters that drive cyanobacterial growth and production.
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Pavlykivska, Olha I., Evelina V. Kamyshnykova i Lesia O. Halyniak. "Furniture Environment in Today’s Conditions: Challenges and Opportunities". Business Inform 10, nr 537 (2022): 83–88. http://dx.doi.org/10.32983/2222-4459-2022-10-83-88.
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The article explores how Ukrainian economy continues to develop despite terrorist attacks by the russian aggressor. The challenges faced by Ukrainian furniture manufacturers during the wartime economy are identified: problems with logistics, refusal to use raw materials from Belarus, and labor changes. Among the new opportunities for furniture makers, temporary housing projects for wartime needs, apartments intended for internally displaced persons are considered: the modular town project RE: UKRAINE, the projects «Ukryttya 22» and LIM Capsule. It is found that the prospect may consist in occupying new niches in the world furniture market due to the refusal of a number of countries to remain consumers of Russian and Belarusian furniture products. It is proposed for Ukrainian businesses to insure their property against wartime risks by using the new insurance product War, terrorism and political violence insurance. The adaptation of the economic activity of the private enterprise «Husiatyn furniture factory «Elegant» to the realities of today is analyzed. As part of charitable activities, the company produced a flammable mixture for Molotov cocktails, barrier road devices «hedgehogs», sewed «plate carriers», blankets and pillows, fabricated the economy-class «student beds». The adjustments made by the militarized situation in the innovative activity of the furniture enterprise are described, namely: the renewal of the technological process was planned by the management for 2023, however, owing to labor changes (some men were mobilized, some went abroad) it was necessary to implement modernization plans somewhat faster – in the second half of 2022. It is substantiated that such changes primarily allowed to improve the quality of operations of technological processes and products in general.
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Raposo, B., M. Gomes Afonso, L. Israelsson, R. Stålesen, H. Wähämaa, M. Hansson, A. Hensvold i in. "POS1040 PATIENT-DERIVED ACPA CLONES DISPLAY BOTH PRO- AND ANTI-INFLAMMATORY POTENTIAL IN VIVO". Annals of the Rheumatic Diseases 82, Suppl 1 (30.05.2023): 837.2–837. http://dx.doi.org/10.1136/annrheumdis-2023-eular.3793.
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BackgroundAnti-citrullinated protein autoantibodies (ACPA) are known to associate with strong risk factors for rheumatoid arthritis (RA), as well as worse clinical prognosis[1]. Due to their high specificity in RA, ACPA are part of the classification criteria and regarded as being essential in the identification of individuals at risk of developing RA. However, not every ACPA-positive at-risk individual progresses to a clinical diagnosis[2], suggesting that the presence of ACPA per se does not dictate the clinical outcome. We have recently shown that ACPA are in fact predominantly anti-inflammatory and present different biological effects in a murine model of arthritis[3]. Having a wide diversity of ACPA clones isolated from different tissues of RA patients at our disposal, we have continued to analyze different monoclonal as well as polyclonal ACPA in their capacity to affect inflammatory processes in vivo.ObjectivesTo determine whether ACPA with pathogenic features, i.e. capable of increasing or sustaining joint inflammation, can be found among different isolated ACPA clones from patients with established RA.MethodsImmunoglobulin from single B cells from RA patients were sequenced and recombinantly expressed as monoclonal human (h)IgG1 in Expi293F cells, followed by validation of citrulline reactivity. Here, we tested 5 new monoclonal ACPA isolated based on anti-citrullinated tetramer staining of B cells[4]. Polyclonal ACPA IgG from 34 RA patients were enriched via a CCP2 affinity column. The unbound IgG fraction was used as the flow-through control. Arthritis was induced in BALB/c mice by i.v. transfer of 1.5mg of an arthritogenic cocktail of anti-type II collagen (CII) antibodies (Chondrex, USA) followed by administration of 25ug of LPS (E. colistrain O55:B5) 3 days later. Individually, 1mg of purified ACPA monomers, 2mg of ACPA-pool or 2mg flow-through IgG were transferred i.v. together with the arthritogenic antibody cocktail. An isotype control antibody and a previously identified anti-inflammatory ACPA clone (hE02 and hC03, respectively)[3]were used as experimental reference conditions. Arthritis development was monitored daily by a quantitative scoring system of inflamed joints – toes, knuckles, and wrist/ankle of front/hind paws. Statistical analysis was performed with repetitive-measure one-way ANOVA with Geisser-Greenhouse correction and Holm-Šidák’s multiple comparisons test.ResultsAdding to our previous data with 8 monoclonal ACPA[3], where 3 of them did not alter the disease course, and 4 displayed strong anti-inflammatory properties, we observed an additional 4 newly tested ACPA clones that did not influence arthritis development. Furthermore, we identified one novel monoclonal ACPA (hF2C05) that displays a pro-arthritogenic effect (p<0.01). When assessing a polyclonal ACPA sample, we observed a dominant anti-inflammatory effect of the ACPA-pool in comparison to its non-ACPA flow-through IgG fraction, displayed by a significantly reduced disease prevalence (p<0.001).ConclusionOur preliminary data focusing on distinct monoclonal ACPA, as well as a new set of patient-derived polyclonal ACPA-pool, strengthens the notion that ACPA clones differ significantly between them, and within the same individual. Although we were able to identify an ACPA clone with arthritogenic potential, the majority of ACPA display no aptitude to affect joint inflammation or are anti-inflammatory. Together, this diversity of inflammatory effects calls for a re-evaluation of the proposed role of ACPA in RA, where their heterogeneity must be considered.References[1] Hair, M. J. H.et al. Arthritis Rheumatol66, 513–522 (2014)[2] Chirivi, R. G. S.et al. Cell Mol Immunol18, 1528–1544 (2021)[3] Raposo, B.et al. Ann Rheum Disard-2022-223417 (2023) doi:10.1136/ard-2022-223417[4] Titcombe, P. J.et al. Arthritis Rheumatol70, 1933–1945 (2018)AcknowledgementsWe would like to acknowledge the following agencies for financial support of the current work: IMI project RTCure (777357), ERC consolidation grant (2017-7722209_PREVENT RA), the Swedish Research Council (VR; 2019-01664) and Ulla and Gustaf af Uggla Foundation (2020-0009).Disclosure of InterestsNone Declared.
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Lutsenko, O. H., N. Ye Horban, T. Yu Safir, M. L. Zinovieva i N. V. Kurdil. "Research of peculiarities of consumption of low-alcohol beverages by children and adolescents in Ukraine and identification of risks to public health". One Health and Nutrition Problems of Ukraine 57, nr 2 (9.01.2023): 26–40. http://dx.doi.org/10.33273/2663-9726-2022-57-2-26-40.
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Abstract. Recently, the problem of low-alcohol consumption among adolescents and young people has become especially relevant, which was confirmed by the results of global WHO research and the ESPAD project in Ukraine (2019). Aim. Study the age and gender characteristics of low-alcohol beverages among children and adolescents, identify risks and identify ways to minimize the negative impact of low-alcohol beverages on public health. Materials and Methods. The data of the WHO and the ESPAD project, separate national researches on alcohol use by teenagers are studied; analyzed the results of the long-term epidemiological study "Family and Children of Ukraine", which is part of the WHO long-term European long-term study program on parenting and childhood "ELSPAC" (European Longitudinal Study of Parenthood and Childhood). Results. According to the latest ESPAD study in Ukraine (2019), 85.7 % of all adolescents surveyed (more than 2,000 people) have consumed alcohol at least once in their lifetime, and the share of those who have consumed alcohol in their lifetime is ten and more times amounted to 46.3 %. According to the Family and Children of Ukraine study (989 people), the youngest age when alcohol was first consumed by adolescents of both sexes was 9 years of age and younger, with adolescent girls being more active than boys in their age. The analysis of the questionnaires ("Adolescent Questionnaires 15-18 years") revealed that among the surveyed adolescents, 67.4 % (725) people drank alcohol at least once in their lives, and there were more girls (69.5 % – 370 people) than boys (65.4 % – 355 people). The highest rates among adolescent boys were recorded in the 14-year-old group: 19.0 % drank beer for the first time, 14.5 % drank wine or champagne, 9.4% drank alcohol, and 7.4% drank strong alcohol. The highest rates of adolescent girls were found in the 15-year age group: beer was consumed for the first time by 16.9%, wine or champagne – 22.4%, alcoholic cocktail – 16.9 %, spirits – 8.6 %. Analysis of the degree of involvement of adolescents in beer consumption showed that at the age of 9 years and younger 3.9% (21) boys and 5.3 % (28) girls tried beer for the first time; at the age of 14 – 19.0 % (103) boys and 14.5 % (77) girls; at the age of 15 – 16.0 % (87) boys and 16.9 % (90) girls. Thus, the first time the interviewed teenagers tried beer was at the age of 14-15. Conclusions. Consumption of low-alcohol beverages among children and adolescents in Ukraine is an acute social problem, the solution of which requires a systematic approach, which should include the formation and promotion of alcohol-free norms among young people, as well as marketing tools focus on priority consumption of soft drinks. Key Words: low alcohol drinks, adolescents, food safety.
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Abid, Hinnah, Corey Hart i Ian Lanza. "3540 Effects of Local Interleukin-6 on Mitochondrial Physiology in Skeletal Muscle". Journal of Clinical and Translational Science 3, s1 (marzec 2019): 10. http://dx.doi.org/10.1017/cts.2019.27.
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OBJECTIVES/SPECIFIC AIMS: In the context of skeletal muscle, IL-6 plays a major role in muscle quality. The goal of this project was to study the influence of systemic IL-6 on skeletal muscle mitochondrial physiology, most notably mitochondrial function (respiration and ROS production) and mitochondrial content. METHODS/STUDY POPULATION: To determine the influence of interleukin-6 (IL-6) on skeletal muscle mitochondria, high-resolution respirometry was performed to simultaneously measure oxygen consumption (JO2) and ROS production in differentiated myotubes incubated with increasing IL-6 (0, 10, 50, 100 ng/mL) for 18 hours in serum free conditions. To evaluate the impact of IL-6 on mitochondrial content we performed western blots on cell lysates from treated cells, measuring proteins of the mitochondrial electron transport chain (ETC) using a cocktail antibody and PGC-1α/PGC-1ß for mitochondrial biogenesis. To determine the role of mitochondrial ROS production on JO2 and mitochondrial content, we co-treated differentiated myotubes for 18 hours with 50 and 100ng/mL IL-6 and the mitochondrial specific antioxidant, MitoQ and performed respirometry for mitochondrial functional measurements and western blots for mitochondrial content.Statistical significance was evaluated by using a 2-tailed Student’s t-test and two-way ANOVA. Post hoc all-group analyses were conducted to determine which groups were different when the model was significant. RESULTS/ANTICIPATED RESULTS: Mitochondrial functional measurements show increased JO2 and increased ROS production in an IL-6 dose-dependent manner. Targeting mitochondrial ROS production with 0.5µm MitoQ attenuated IL-6 induced increases in JO2 and ROS production. Complexes I and II (CI, CII) of the ETC increased significantly in an IL-6 dose-wise fashion, and co-treatment with MitoQ normalized increases at 100ng/mL Il-6. 100ng/mL IL-6 significantly increased protein expression of PGC-1α and PGC-1ß. Co-treatment with MitoQ normalized IL-6 induced increase in PGC-1α. DISCUSSION/SIGNIFICANCE OF IMPACT: Our data suggest that when treated chronically at a high dose, IL-6 increases mitochondrial respiration, ROS production, and content. Targeting mitochondrial ROS production normalizes these mitochondrial adaptations. The present study provides new insights into mitochondrial physiology in the context of inflammation. Therapeutically targeting mitochondrial ROS production may impact skeletal muscle quality in certain populations.
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He, Aiwu Ruth, Fung-Lung Chung, Monika Aggarwal, Zizhao Zhu, Sophie Gould, Kevin Zhang, Mark Kuo i in. "Detection of DNA adduct γ-OHPdG in circulating tumor cells (CTCs) and its use as a prognostic biomarker in patients with hepatocellular carcinoma (HCC)." Journal of Clinical Oncology 41, nr 4_suppl (1.02.2023): 594. http://dx.doi.org/10.1200/jco.2023.41.4_suppl.594.
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594 Background: A blood-based biomarker to predict the risk of hepatocellular carcinoma (HCC), and its recurrence is needed. Previously, we showed that γ-OHPdG, a mutagenic DNA adduct formed by lipid peroxidation, in liver biopsies from HCC patients, as detected by IHC, is inversely associated with overall survival (p<0.0001) and recurrence-free survival (p<0.007) after surgical resection. This finding suggests that γ-OHPdG may serve as a prognostic biomarker of HCC and its recurrence. A non-invasive method to detect γ-OHPdG is needed. Liquid biopsy is preferred over tissue biopsy because it is non-invasive, allows repeated sampling, lower risk to patient, and lower medical care cost. We developed a non-invasive method for detecting and quantifying γ-OHPdG using CTCs from HCC patient. Methods: The method involved following steps. First, CTCs from blood samples were isolated using a RosetteSep CD45 Depletion Cocktail and Ficoll Paque-based method. Isolated cells were identified as liver CTCs using asialoglycoprotein receptor 1 (ASGPR1), a cell surface protein expressed solely on the surface of hepatic cells, and γ-OHPdG by immunocytochemistry. The percentage of ASGPR1 and γ-OHPdG-positive stained CTCs and γ-OHPdG staining intensity was quantified using Metamorph software. The staining intensities in livers CTCs will be compared with that found in liver biopsies by IHC. Results: To determine the sensitivity and specificity of testing -γ-OHPdG level in circulating tumor cells using an-anti γ-OHPdG antibody, we showed that the proportion of γ-OHPdG-positively stained cells and staining intensity increased in HepG2 liver cancer cells upon acrolein treatment at increasing concentration. Furthermore, when the HepG2 was used to spike blood of healthy volunteers’, the recovery rate of γ-OHPdG positivity was > 50-60%. CTCs from 32 HCC patients, detected at a positivity rate of ~97%, were tested for γ-OHPdG levels using the method developed in this project. The clinical factors including demographics, risk factors, alpha-fetoprotein (AFP), HCC size, multifocality, vascular invasion, extrahepatic metastasis have been correlated with the levels of γ-OHPdG in CTCs. Conclusions: The CTC method developed for detecting and quantifying γ-OHPdG warrant validations as a prognostic biomarker for predicting HCC risk and recurrence in clinical trials.
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Mallekh, R., S. Rejaibi, A. Silini, M. Zid, I. Ben Slema, N. Zoghlami, S. Ben Youssef, M. Zribi, N. Ben Salah i H. Aounallah-Skhiri. "Prevalence and associated factors to alcohol use in Tunisian high school adolescents: MedSPAD 2021". European Psychiatry 66, S1 (marzec 2023): S866. http://dx.doi.org/10.1192/j.eurpsy.2023.1835.
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IntroductionDespite its well-known acute and long-term harmful effects on a person’s mental health and well-being, alcohol remains the most commonly used psychoactive substance among adolescents after tobacco products in many countries.ObjectivesWe aimed at studying the prevalence of alcohol use, and identify associated factors in Tunisian high school adolescents.MethodsWe used national data from the 2021-Mediterranean School Survey Project on Alcohol and Other Drugs (MedSPAD). Based on a clustered two-stage stratification sampling method, a representative sample of teenagers aged 16 to 18 years, was selected. Data collection was performed using a self-administered standardized questionnaire, assessing socio-demographic characteristics and risky behaviours, and including questions about alcoholic beverages patterns of use. Binary logistic regression model was used to assess associated factors and adjusted Odds Ratios (AORs) were presented with 95% confidence intervals (CI). Cspro software was used for data entry and all statistical analysis were performed with STATA software.ResultsA total of 6201 adolescents with a mean age of 16.8 years and a sex ratio female/male of 1.5 were enrolled.Lifetime prevalence of alcoholic beverages consumption was 8.0%, 95% CI [7.0, 9,1] (n=6196). The prevalence of alcohol consumption during the previous year and month were 5.1 % and 1.7% respectively. Cocktails and beer were the most frequently consumed beverages.Prevalence of alcohol use was significantly associated with tobacco, cannabis and e-cigarettes use (AOR 9.5, 6.0 and 1.9 respectively; p≤10-3), a higher frequency of nights spent away from home, school absenteeism for non-medical reasons and enrolment in the private sector.Alcohol intoxication was reported by 2.9% of respondents during their lifetime.Early onset was reported by 17.2% of respondents for alcohol use and 10.1% for alcohol intoxication.ConclusionsAlthough the prevalence of alcohol use was relatively low among Tunisian adolescents compared to European adolescents, early onset- indicating an increased risk of developing an alcohol use disorder- warrant the implementation of primary prevention interventions through mental health promotion and life skill trainings to halt these trends and avert the raising burden of morbidity and mortality attributable to alcohol use.Disclosure of InterestNone Declared
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Vogt, Antonia, Isobel Darlington, Roger Brooks, Mark Birch, Andrew McCaskie i Wasim Khan. "THE EFFECT OF CHRONOLOGICAL AGE AND GENDER AND DIFFERENT SOURCE OF TISSUE ON THE IN VITRO PROPERTIES OF MESENCHYMAL STROMAL CELLS". Orthopaedic Proceedings 105-B, SUPP_16 (17.11.2023): 51. http://dx.doi.org/10.1302/1358-992x.2023.16.051.
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AbstractObjectivesOsteoarthritis is a common articular cartilage disorder and causes a significant global disease burden. Articular cartilage has a limited capacity of repair and there is increasing interest in the use of cell-based therapies to facilitate repair including the use of Mesenchymal Stromal Cells (MSCs). There is some evidence in the literature that suggests that advancing age and gender is associated with declining MSC function, including reduced proliferation and differentiation potential, and greater cellular apoptosis. In our study, we first performed a systematic review of the literature to determine the effects of chronological age and gender on the in vitro properties of MSCs, and then performed a laboratory study to investigate these properties.Methods and ResultsWe initially conducted a PRISMA systematic review of the literature to review the evidence base for the effects of chronological age and gender on the in vitro properties of MSCs including cell numbers, expansion, cell surface characterization and differentiation potential. This was followed by laboratory-based experiments to assess these properties. Compare the extent of the effect of age on MSC cell marker expression, proliferation and pathways. Tissue from patients undergoing total knee replacement surgery was used to isolate MSCs from the synovium, fat pad and bone fragments using a method developed in our laboratory. The growth kinetics was determined by calculating the population doublings per day. Following expansion in culture, MSCs at P2 were characterised for a panel of cell surface markers using flow cytometry. The cells were positive for CD73, CD90 and CD105, and negative for antibody cocktail (eg included CD34, CD45). The differentiation potential of the MSCs was assessed through tri-lineage differentiation assays. At P2 after extracting RNA, we investigate the gene analysis using Bulk seq. Clear differences between the younger and older patients and gender were indicated.ConclusionsChronological age and gender-related changes in MSC function have important implications on the use of these cells in clinical applications for an ageing population. The results from this study will be used to plan further work looking at the effects of chronological age and gender on cellular senescence and identify pathways that could be targeted to potentially reverse any age and gender-related changes.Declaration of Interest(b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
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Verezhinskyi, Valerii, Andrii Danylenko, Serhii Rupich i Serhii Tsybulnyk. "DESIGN OF GENERATION SYSTEM BASED ON ARTIFICIAL INTELLIGENCE ALGORITHM. PART 1". Bulletin of Kyiv Polytechnic Institute. Series Instrument Making, nr 65(1) (30.06.2023): 110–16. http://dx.doi.org/10.20535/1970.65(1).2023.283455.
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The development of modern tools and methods of artificial intelligent provides a wide range of functionality for various scientific and applied tasks, and also allows obtaining new results. A question arises about how to apply elements of artificial intelligence to obtain new combinations and connections obtained by generation. As a purpose of the article is considered applying a neural network technology for the formation of new, unique recipes for cocktails with the aim of demonstrating the effectiveness of implementation and verification methods and models of artificial intelligence. To solve generation problems according to ingredient recipes, in the article all stages of the technological process are analyzed from data collection, analysis, preprocessing to the selection of a mathematical algorithm and modeling of the trained system. Each stage of the work contains a separate description of the steps necessary to solve the task. The machine learning algorithm has the ability to process thousands of examples to find a certain pattern of combinations of ingredients. And important attention is paid to the formation of a training date.
At the stage of data collection, individuals and main problems are considered, which are checked during the work of the parser. The important part is the partial use of encrypted technologies when using Internet resources and reading the DOM tree with the code of the HTML page. The paper shows settings for the automated algorithm of information collection. For the parser development, a tool for rapid project development and effective management as Docker and Docker Compose add-ons were used. Completed the stage with the acquisition of the data set and the data for neural network models has been analyzed. The stage consists in preprocessing, decoding and compositions collected data in relevant tables. During the automated data collection process, information with significant noise and redundant elements is processed. Considerable attention is paid to the process of cleaning and preparation of useful information, because the purity of the data and their completeness in the most cases determine the quality of the mathematical model and the modeling process for finding new laws and combinations in generation.
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Chakritbudsabong, W., S. Pamonsupornvichit, L. Sariya, R. Pronarkngver, S. Chaiwattanarungruengpaisan, S. Klinsrithong, J. N. Ferreira i S. Rungarunlert. "185 Directed Differentiation of Porcine Induced Pluripotent Stem Cells into all Three Germ Layers via Embryoid Body Formation". Reproduction, Fertility and Development 30, nr 1 (2018): 232. http://dx.doi.org/10.1071/rdv30n1ab185.
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Human induced pluripotent stem cells (iPSC) have been generated by reprogramming somatic cells using a cocktail of stem cell transcription factors but the application has been limited in transplantation therapies. The pig represents an ideal model for human clinical research, in part because of its similarity to human physiology and immunology but also because of its use in assessing side effects in long-term preclinical studies. Porcine induced pluripotent stem cells (piPSC) have been established in many studies but their differentiation pattern has not been reported. The aim of this study was to estimate the efficiency and pattern of differentiated piPSC into all 3 germ layers using embryoid body (EB) formation. Two piPSC lines (VSMUi001-A and VSMUi001-D) were induced from porcine embryonic fibroblasts by retroviral overexpression of 5 human reprogramming transcription factors (OCT4, SOX2, KLF4, c-MYC, and LIN28). For EB formation, the piPSC were harvested by treating with TrypLE™ Select (Thermo Fisher Scientific, Waltham, MA, USA) and the cells were cultured in nonadherent 96-well plates in piPSC media without growth factors. Data are expressed as mean ± SEM of at least 3 independent experiments. Statistical analyses were evaluated with Student t-tests for comparison between the 2 cell lines. Statistical significance was set at a P-value of < 0.05. The percentages of EB formation, which were calculated as the number of wells containing EB on Day 3 of differentiation, were 95.3 ± 3.42 and 89.1 ± 5.34 (VSMUi001-A and VSMUi001-D, respectively). However, there was no significant difference between the percentages of EB formation derived from the 2 cell lines. For EB size measurement, 20 EB per experiment were taken after incubation for 3, 7, 14, and 21 days. Both EB sizes increased over time (average diameter of 238.1 ± 6.18, 297.9 ± 4.10, 438.6 ± 13.33, and 728.8 ± 24.92 mm from VSMUi001-A, and 255.8 ± 5.12, 357.9 ± 3.94, 459.6 ± 11.88, and 439.4 ± 20.31 mm from VSMUi001-D). Moreover, both EB displayed homogeneity in size and shape (Day 3, 7), exhibited a cystic structure (Day 14), and a vesicular cavity was present (Day 21). For immunohistochemical analysis, both EB had lower levels of cleaved caspase 3, a marker of apoptotic cells, on Day 3 but higher levels of cleaved caspase 3 from Day 7 through 21. On the contrary, EB showed higher levels of Ki67, a marker of proliferating cells, on Day 3 but lower levels of Ki67 on Days 7, 14, and 21, respectively. In gene expression assessment, EB exhibited ectoderm gene (NeuroD1), mesoderm genes (TNNT2 and TNNI1), and endoderm genes (SOX17 and Endolase) at Day 7 and 21 by using RT-PCR. In conclusion, we report the successful in vitro formation of cystic EB from 2 piPSC lines, indicating that the piPSC could differentiate into 3 germ layers. This will allow researchers to unveil the roadmap of molecular cues needed for piPSC differentiation. This research project is supported by grants from the Mahidol University, Thailand.
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Eggleston, Heather, Nina Shoemaker, Christina Gariepy, Julie Norton, Kelsey Beauman, Aaron Kim, Christine Fedorchuk, James Roberts, Frederic Poly i Renee Laird. "Immunopathogenesis of Campylobacter jejuniinfection in a small animal model". Journal of Immunology 210, nr 1_Supplement (1.05.2023): 82.17. http://dx.doi.org/10.4049/jimmunol.210.supp.82.17.
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Abstract We set out to develop and characterize a small animal model of Campylobacter jejuni(CJ) infection that recapitulates human campylobacteriosis. Adult C57BL/6J mice are rendered susceptible to colonization and disease by pre-treatment with a zinc deficient diet and a broad-spectrum antibiotic cocktail. We have established this model with four strains with diverse capsular serotypes and flagellar groups, two key virulence factors for CJ pathogenesis. We measured colonization, weight loss, diarrhea, fecal inflammatory markers, and cytokine production by mesenteric lymphocytes and splenocytes. Diarrhea containing visible mucous and/or blood and degree of weight loss vary in severity depending on the strain and dose. Interestingly, we identified an inverse relationship between inoculum dose and levels of fecal inflammatory markers, with lower inoculum doses inducing significantly higher inflammation. We also observed production of IFNγ and IL-17 at day 9 post infection and despite no decrease in CJ colonization, IFNγ and IL-17 levels decreased by day 21 with a subsequent increase in IL-10 production. We also observed higher levels of IFNγ and IL-17 in mice challenged with strain CG8486 relative to those challenged with strain 81–176 pointing to potential strain differences. These differences observed were more striking in mesenteric lymphocytes versus splenocytes, indicating that local cellular responses differed from systemic responses. We have developed a model of inflammatory diarrhea in adult mice that exhibits hallmarks of CJ infection and further identified significant shifts in cytokine expression associated with the duration of infection, bacterial strain utilized, and therapeutic treatment. Research reported in this presentation is supported by Navy work unit number: 6000.RAD1.DA3.A0308 and CARB-X. CARB-X’s funding for this project is sponsored by the Cooperative Agreement Number IDSEP160030 from ASPR/BARDA and by awards from Wellcome Trust, the UK Global Antimicrobial Resistance Innovation Fund (GAMRIF) funded by the UK Government Department of Health and Social Care (DHSC) and the Bill & Melinda Gates Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of CARB-X or any of its funders. Disclaimers: The views expressed in this work are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. Government. F. Poly is an employee of the U.S. Government. This work was prepared as part of official duties. Title 17 U.S.C. §105 provides that ‘Copyright protection under this title is not available for any work of the United States Government.’ Title 17 U.S.C. §101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties.The animal study protocol was reviewed and approved by the Naval Medical Research Center IACUC in compliance with all applicable Federal regulations governing the protection of animals in research.
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Coppola, Canaan, Brooks Hopkins, Steven Huhn, Zhimei Du, Zuyi Huang i William J. Kelly. "Investigation of the Impact from IL-2, IL-7, and IL-15 on the Growth and Signaling of Activated CD4+ T Cells". International Journal of Molecular Sciences 21, nr 21 (22.10.2020): 7814. http://dx.doi.org/10.3390/ijms21217814.
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While CAR-T therapy is a growing and promising area of cancer research, it is limited by high cost and the difficulty of consistently culturing T-cells to therapeutically relevant concentrations ex-vivo. Cytokines IL-2, IL-7 and IL-15 have been found to stimulate the growth of T cells, however, the optimized combination of these three cytokines for T cell proliferation is unknown. In this study, we designed an integrated experimental and modeling approach to optimize cytokine supplementation for rapid expansion in clinical applications. We assessed the growth data for statistical improvements over no cytokine supplementation and used a systems biology approach to identify genes with the highest magnitude of expression change from control at several time points. Further, we developed a predictive mathematical model to project the growth rate for various cytokine combinations, and investigate genes and reactions regulated by cytokines in activated CD4+ T cells. The most favorable conditions from the T cell growth study and from the predictive model align to include the full range of IL-2 and IL-7 studied, and at lower levels of IL-15 (6 ng/mL or 36 ng/mL). The highest growth rates were observed where either IL-2 or IL-7 was at the highest concentration tested (15 ng/mL for IL-2 and 80 ng/mL for IL-7) while the other was at the lowest (1 ng/mL for IL-2 and 6 ng/mL for IL-7), or where both IL-2 and IL-7 concentrations are moderate-corresponding to condition keys 200, 020, and 110 respectively. This suggests a synergistic interaction of IL-2 and IL-7 with regards to promoting optimal proliferation and survival of the activated CD4+ T cells. Transcriptomic data analysis identified the genes and transcriptional regulators up/down-regulated by each of the cytokines IL-2, IL-7, and IL-15. It was found that the genes with persistent expressing changes were associated with major pathways involved in cell growth and proliferation. In addition to influencing T cell metabolism, the three cytokines were found to regulate specific genes involved in TCR, JAK/STAT, MAPK, AKT and PI3K-AKT signaling. The developed Fuzzy model that can predict the growth rate of activated CD4+ T cells for various combinations of cytokines, along with identified optimal cytokine cocktails and important genes found in transcriptomic data, can pave the way for optimizing activated CD4 T cells by regulating cytokines in the clinical setting.
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Pavlovic, Zoran Miroslav, i Ana Miodrag Kupresanin. "Enhancing NPK Detection in Agriculture through Electrochemical Sensors Utilizing 2D Nanomaterials". ECS Meeting Abstracts MA2024-02, nr 64 (22.11.2024): 4273. https://doi.org/10.1149/ma2024-02644273mtgabs.
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NPK electrochemical soil sensors are essential tools for sustainable agriculture, enabling farmers to optimize nutrient management practices, improve crop productivity, and protect the environment for future generations. Those sensors are designed to primarily measure the levels of nitrogen (N), phosphorus (P), and potassium (K) in the soil. These are essential nutrients for plant growth and health, and monitoring their levels can help optimize fertilizer application and improve crop yield, while minimizing environmental impact, effectively supporting precision agriculture practices. Novel 2D nanomaterials can enhance the electrochemical properties of the sensors, enabling them to detect trace levels of nutrients with high precision. The operation principle of the sensors is based on the electrochemical reactions occurring at the surface of 2D nanomaterials when they come into contact with target ions in the soil solution through an ion-selective membrane. The presence and concentration of these ions cause changes in the electrical properties of the nanomaterial, which are then measured and correlated with the nutrient levels. By applying specially designed composite nanomaterials made of transition metal dichalcogenides, Mxenes, Graphene-based materials, conjugated conducting polymers, and ion-selective membranes, it is possible to precisely and stably measure soil ion content as batch, or continuous readout. These materials offer high surface area-to-volume ratios, excellent electrical conductivity, and sensitivity to changes in the chemical environment, making them ideal candidates for sensing applications. The laboratory experiments show that various combinations of nanomaterials in composites at the sensor working electrode have a high impact in increasing the selectivity of the ISM towards omitting ions in soil, repeatability of measurements, and durability of the sensor, compared to the electrodes with only ISM on top. Several nitrate ionophores and ISM cocktails are tested and compared toward ionic selectivity. The electrochemical sensors are controlled by the electronic circuitry, designed to give input and readout of the data from the sensing elements, as well as for sensor conditioning and calibration, data storage, and wireless communication. Various electrochemical methods through controlling electronics, like Open circuit potentiometry, Chronopotentiometry, and Chronoamperometry are employed for sensor control and data collection. Those methods were tested and compared in terms of the response time and durability of the sensor. Overall, the integration of electrochemical sensors with 2D nanomaterials represents a significant advancement in precision agriculture, offering farmers the tools they need to efficiently manage nutrient levels in soil and improve crop productivity, contributing to traceability and quality assurance in food production. *This work is supported through the ANTARES project that has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement SGA-CSA. No. 739570 under FPA No. 664387. https://doi.org/10.3030/739570 Figure 1
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Kramer, Michael H., Qiang Zhang, Robert W. Sprung, Petra Erdmann-Gilmore, Daniel R. George, Nichole M. Helton, Sharon E. Heath i in. "Analysis of the Proteomes of Primary, De Novo Acute Myeloid Leukemia Cells from Adults". Blood 138, Supplement 1 (5.11.2021): 3427. http://dx.doi.org/10.1182/blood-2021-148819.
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Abstract Introduction: Proteins, despite being the primary effectors of cellular processes, are often studied only indirectly through analysis of the transcriptome. However, it is clear that the relationship between mRNA expression and protein expression is approximate at best. In Acute Myeloid Leukemia (AML), the genome and transcriptome have been thoroughly characterized, but the proteome has been less well studied. Here, we present a deep-scale study of the proteomes of 44 primary AML bone marrow samples representing a wide range of AML across the spectrum of cytogenetic risk, common mutations, and driver fusions. Methods: Bone marrow samples were collected at presentation from 44 adult patients with de novo AML as part of an institutional banking protocol, and buffy coat cells were immediately cryopreserved without further manipulation. Cryovials were thawed in the presence of the cell permeable serine protease inhibitor diisopropyl fluorophosphate (DFP) to inactivate the abundant neutrophil serine proteases (ELANE, CTSG, PRTN3, and PRSS57), and further processed for nano-liquid chromatography mass spectrometry in the presence of an extensive cocktail of protease inhibitors. Both label-free quantification (LFQ) and tandem-mass-tag (TMT) deep-scale proteomics were performed on these 44 patient samples, as well as 3 lineage-depleted bone marrow samples from healthy adult donors. Matching RNA-seq and exome sequencing data were available for the same samples as part of The Cancer Genome Atlas (TCGA) AML project. Results: 10,651 and 6,679 unique proteins were detected in the TMT and LFQ experiments, respectively. Correlations between measurements derived from the independent proteomic platforms (i.e. TMT and LFQ) is higher (mean Spearman correlation, 0.60, Figure 1A) than correlation between proteomic (TMT) and transcriptomic measurements from bulk RNA-seq data (Spearman 0.43, Figure 1B). Quality checks of the proteomic data strongly supported the reliability of quantification of protein measurements; for example, the mean ratio of beta globin protein (HBB) to alpha globin (HBA1) was 1.2 +/- 0.25 (Figure 1C), and several proteins known to be dysregulated by specific AML-initiating fusion proteins (for PML-RARA, HGF and RARA; for RUNX1-RUNX1T1, RUNX1T1; and for CBFB-MYH11, MYH11) were detected in the expected samples (Figure 1D). Globally, 1,364 proteins were differentially expressed in the AML samples (corrected p-value <0.05, fold change ≥ 1.5) compared to the lineage-depleted, healthy bone marrow samples. Globally overexpressed proteins were enriched for ribosomal RNA modification, mitochondrial protein import, nuclear export, and the mitochondrial electron transport chain, among others. These overexpressed proteins include 61 cell surface proteins that could potentially represent therapeutic targets (overexpressed on average in 82% of AML samples, range 25-97%). Globally downregulated proteins in AML samples were enriched for glycogen metabolism and protein groups associated with mature neutrophils (reflecting the expected maturation block in AML), among others. 771 of the 1364 differentially expressed proteins (56.5%) showed only minimal variability in mRNA expression levels (fold change of <1.1 between AML and normal marrow CD34 cell mRNA) that could not explain dysregulated protein expression. Several protein complexes likewise showed coordinated differential expression in the proteomic data, but no change in the transcriptome, including the THO complex (Figure 1E) and the phosphorylase kinase complex (Figure 1F), among others, indicating the presence of posttranscriptional regulation of the levels of many proteins in AML samples. Conclusion: We have created a deep-scale proteomic database from a set of well-characterized AML samples, allowing for a proteogenomic study of AML. We have identified many examples of post-transcriptional regulation of key metabolic pathways that may be relevant for better understanding AML cell metabolism and therapeutic vulnerabilities. Additional studies linking patterns of protein dysregulation with a variety of AML covariates are underway. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Mallardo, Domenico, Giosuè Scognamiglio, Khrystyna North, Mariaelena Capone, Michael Bailey, Luigi Scarpato, Sarah Church i in. "934 Biological mechanisms in the different etiologies of Merkel cell carcinoma patients: polyomavirus or UV exposure". Journal for ImmunoTherapy of Cancer 9, Suppl 2 (listopad 2021): A980. http://dx.doi.org/10.1136/jitc-2021-sitc2021.934.
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BackgroundMerkel cell carcinoma (MCC) is a rare and aggressive skin cancer with neuroendocrine features, and it is associated with elevated mortality. The pathogenesis is associated with presence of clonally integrated Merkel cell polyomavirus (MCPyV) or ultraviolet light (UV) exposure.1 The MCPyV causes up to 80% of MCC tumors in North America and Europe.2–4 Recently immunotherapy is having good results,5 the phase 2 trial JAVELIN Merkel 200 indicated that treatment with Avelumab (PDL1 inhibitor) in patients with metastatic MCC pre-treated have a meaningful long-term survival outcomes respect chemotherapy. Moreover, ORRs were highest in patients with high TMB that were also MCPyV−, PD-L1+ or had a greater CD8+ T cell density at the invasive margin.6 In this study, we investigated the biological signatures in patients with MCPyV or not.MethodsFrom April 2011 to June 2018, we collected retrospectively 50 FFPE (Formalin-Fixed Paraffin-Embed) from 37 patients with metastatic MCC and 13 tissues from a secondary metastatic site. All patients have appropriately signed informed consent. We performed an immunohistochemistry assays (IHC) for MCPyV and PDL1. In addition, through the NanoString GeoMx DSP (Digital Spatial Profiling), we analysed 11 patients (6 MCPyV+; 5 MCPyV-) with cutaneous metastasis using a 44-plex antibody cocktail. For each slide we selected three different areas: Intratumoral, extratumoral and tumour border, in each area we selected CD4+ and CD8+ cells in 4 different ROIs (Region of Interest). Statistical analysis was performed via Bonferroni correction, P< 0.05 was considered statistically significant for median stratification.ResultsThe DSP analysis showed that the tumour border cells have an overexpression of IDO respect intratumoral area (adj. p<0.01). Instead, extratumoral area of MCPyV- patients have a higher expression of B7-H3 respect MCPyV+ as well as FOXP3 is higher in the tumour border of MCPyV+ patients and EpCAM in the intratumoral area (p<0.05). PDL1 is overexpressed in MCPyV+ CD4+ cells respect CD8+ (p<0.05). The IHC assay shown that viral status does not change in multiple metastases and PDL1 is elevated in the tumour border (p<0.05).ConclusionsIn this retrospective study, our preliminary data shown that tumour edge have an important role in the modulations of immune infiltrate and patients with Merkel cell polyomavirus could have a different pathway of immunosuppression compared to patients with non-virus related etiology. Further investigations are needed to get additional information.AcknowledgementsThe study was supported by the Institutional Project ”Ricerca Corrente” of Istituto Nazionale Tumori IRCCS Fondazione ”G. Pascale” of Napoli, Italy.ReferencesKaae J, Hansen AV, Biggar RJ, et al. Merkel cell carcinoma: incidence, mortality, and risk of other cancers. J Natl Cancer Inst 2010 June 2;102(11):793–801.Feng H, Shuda M, Chang Y, et al. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008 February 22;319(5866):1096–100.Garneski KM, Warcola AH, Feng Q, et al. Merkel cell polyomavirus is more frequently present in North American than Australian Merkel cell carcinoma tumors. J Invest Dermatol 2009 January;129(1):246–8.Goh G, Walradt T, Markarov V, et al. Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy. Oncotarget 2016 January 19;7(3):3403–15.Bichakjian CK, Olencki T, Aasi SZ, et al. Merkel cell carcinoma, version 1.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2018 June;16(6):742–774.D’Angelo SP, Bhatia S, Brohl AS, et al. Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial. J Immunother Cancer 2020 May;8(1):e000674.Ethics ApprovalThe study was approved by internal ethics board of the Istituto Nazionale Tumori IRCCS Fondazione ”G. Pascale” of Napoli Italy, approval number of registry 33/17 OSS.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
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Di Stefano, Rosalia, Elena Baiamonte, Melania Lo Iacono, Barbara Spina, Flavia Contino, Claudia Coronnello, Massimiliano Sacco i in. "The Challenge of Using CB-HSCs As Source for Gene Therapy: Lentiviral Vector Transduction, Phenotypic Characterization and Global Gene Expression Profile of Ex-Vivo Expanded CB CD34+ Cells". Blood 126, nr 23 (3.12.2015): 5548. http://dx.doi.org/10.1182/blood.v126.23.5548.5548.
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Abstract Introduction: Genetic modification of autologous hematopoietic stem and progenitor cells (HSPC) is a promising clinical intervention to cure inherited monogenic diseases. Successful gene therapy trials have already been conducted using CD34+ cells from bone marrow and from mobilized peripheral blood. In this regard, cord blood (CB) represents an attractive source of HSCs due to its high concentration of high proliferative HSPC and increased susceptibility to be transduced by lentiviral vectors. Unfortunately, the major disadvantage is the limited number of HSC in the CB collection. Consequently, ex-vivo expansion of CB-HSC is desirable to extend clinical applications. Purposes: To investigate the ability of UCB-cd34+ cells to be expanded in serum-free media supplemented with the early acting hematopoietic cytokines SCF,TPO and Flt-3 ligant (STF) and to characterize CD34+ cells subtypes, clonogenic capacity and gene expression profile during expansion. We also wanted to investigate the susceptibility of the expanded cd34+ cells to be transduced by a GFP-lentiviral vector (LV-GFP) Material and Methods: CD34+ immunoselected cells from 10 UCB were grown for 8 days in customized serum-free medium formulated for HSC expansion, supplemented with STF cytokines. Numbers end frequency of CD34+cells and co-expression of the primitive surface antigens (CD38, CD133, CD90) was evaluated during expansion. Colonies developed in methylcellulose were scored for enumeration ad typing. LV-GFP transduction efficiency was evaluated in CD34+ cells cultured for 4 days in expansion medium plus STF and for 24 hrs in X-vivo10 medium with STF±IL-3 cytokines; the last condition slightly expands CD34+ cells (1.3 fold) and are currently used for HSPC-lentivector transduction in gene therapy clinical trials. The transduction efficiency was evaluated by measuring the percentage of GFP+ cells in the bulk and in colonies developed in methylcellulose and the VCN/cell by Q-PCR. Gene expression profiles were analyzed by human whole genome Agilent microarray Technology to detect differentially expressed genes between expanded, ex-vivo medium cultured and un-cultured cells. Results: We found an average of 8 fold-increase CD34+cells at day 4 and of 22 fold- increase at day 8 of culture. The frequency of CD34+ was maintained at day 4 and declined of about 50% at day 8. CD34+/CD38- early progenitors doublet as early as day 4, differences in CD34+/CD133+ and CD34+/CD90+cells were not significant. The number of CFU slightly increased during expansion while the relative frequency of colonies type did not significantly changed. Four days expanded CD34+ cells were transduced more efficiently than those grown in ex-vivo medium even in presence of IL-3 added to the STF cytokine cocktail. Comprehensive gene expression profile analysis highlighted about 4000 genes differentially expressed in CD34+ cells expanded for 4 and for 8 days compared to that of the un-cultured cells. Conversely, the expression profiles analysis did not show any clear separation between different cell culture methods (expansion vs ex-vivo medium). Specifically, the number of differentially expressed genes in common between the different culture conditions compared with the un-cultured cells was statistically significant. Unsurprisingly, the common up-regulated genes were related to the cell cycle. The likeness between the gene expression profiles of the different culture conditions was also validated by the identification of a significantly small number of differentially expressed genes between them. Conclusions: UCB-CD34+ cells can be efficiently expanded and transduced in serum free conditions. The expanded cells exhibited phenotypic marchers typical of early progenitors and developed colonies in number and in type similar to the unmanipulated cells and exhibited whole gene expression profile that is consisted with that of CD34+ cells exposed for the short term culture conditions currently used in gene therapy trial mediated by lentiviral vectors. Results from this study open a window on the future possibility of using homologous UCB-HSC as target for gene correction in patients diagnosed for a genetic disorder in prenatal time. The genetically modified cells would be stored and used for gene therapy in the same individual in pediatric age. This work was funded by the F and P Cutino Foundation - Project RiMedRi CUP G73F12000150004 Disclosures No relevant conflicts of interest to declare.
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O’Donnell, Darren. "Home Tours". Canadian Theatre Review 126 (marzec 2006): 62–63. http://dx.doi.org/10.3138/ctr.126.012.
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Mammalian Diving Reflex’s Social Acupuncture wing induces encounters between strangers in public galleries and theatres. The inaugural project, The Talking Creature, involved inviting audience/participants to a predetermined spot, dispersing, and approaching random strangers to invite them back for an unstructured, unagendaed conversation about whatever (see O’Donnell). It was like a spontaneous cocktail party in the middle of a street, park or gallery populated by people who, for the most part, didn’t know each other. Home Tours extended this dynamic into the homes of strangers by inviting audience/participants to walk through random neighbourhoods, knock on random doors and ask for a quick peek. In August 2005 – as part of the Summerworks Festival – thirteen of us checked out the houses surrounding the Factory Theatre, walking east along Adelaide. Since all characters require a nice juicy super-objective, I proposed that we make it ours to get fed. Our first encounter was surprising — the young nightclub promoter seemed to barely register our request before throwing open his door and giving us a thorough tour of his tiny digs, stating that he “would never stand in the way of theatre.”The whirlwind tour included the beer fridge in his bedroom, a few chin-ups on the bar in the doorway and some artwork created by local graffiti luminaries. Just down the street, a marriage counsellor working from home regretfully didn’t want to disrupt his current session, but his wife agreeably hung out with us on their side-yard patio under a canopy of grape vines. Around the corner on Portland and Richmond, we toured a live—work architecture firm that was currently designing the new super-jail for juveniles. The assistant gestured to drawings on the wall, self-consciously assuring us that the kids would have lots of green space to roam. And across Richmond was the live—work space of a couple of high-end graphic designers, responsible for products like Cat Chow and Stouffer’s frozen dinners. There is obviously money in that field; their beautiful house had been repeatedly photographed and had recently been featured in the Globe and Mail. It was a stunning place, complete with a rooftop garden and a system to recycle rainwater. There were, of course, plenty of people not home, one place with an open door but no one answering (proving that Michael Moore tells the truth) and one home-alone kid who didn’t think it was such a good idea. In September 2005, eight of us walked north from the Bathurst subway station to explore the Annex, finding a little more reluctance and paranoia, but with persistence we managed to take a tour through the digs of a couple of newly weds, a grad student and a U of T English professor. We hung out in the prof’s back yard and spent some time getting to know each other — the group of participants as strange to each other as our various subjects. When we departed, the prof gave us full access to his herb garden encouraging us to take home handfuls of pungent sage, oregano, rosemary and basil, thus rending the super-objective of a little nosh a modest success. The only conflict in that neighbourhood was with the woman who nervously turned down our request and demanded to know if we had ripped off the herbs. In February of 2006, I took the experiment to Calgary’s wealthy Mount Royal neighbourhood, with Mammalian Diving Reflex’s Diplomatic Immunities, which was being presented as part of the Alberta Theatre Projects’ PlayRites festival. Reception there was a little chillier. But maybe it was the weather. Turns out the big cash in the heart of conservative country aren’t as excited to see you at their doors, with a couple of complaints dangling the threat of “further action” being directed at our host theatre. We met a few local luminaries, but only the young, recently wealthy house builder would let us get past the vestibule, while Cliff Fryers, Preston Manning’s former chief of staff and the man who called Stockwell Day an “abomination” on national TV, only felt comfortable letting us photograph his tie. But it was a nice tie.
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Naik, Swati, Spyridoula Vasileiou, Ifigeneia Tzannou, Manik Kuvalekar, Ayumi Watanabe, Catherine Robertson, Adrian P. Gee i in. "Donor-Derived Adoptive T-Cell Therapy Targeting Multiple Tumor Associated Antigens to Prevent Post-Transplant Relapse in Patients with ALL". Blood 138, Supplement 1 (5.11.2021): 471. http://dx.doi.org/10.1182/blood-2021-149332.
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Abstract Background: Hematopoietic stem cell transplant (HSCT) is a curative option for patients with high-risk Acute Lymphoblastic Leukemia (HR-ALL), but relapse remains a major cause of treatment failure. Strategies to enhance the graft-versus-leukemia (GVL) effect have been employed to prevent relapse, including modulating immune suppression post-HSCT to hasten immune reconstitution or with the use of donor lymphocyte infusions (DLIs). However, DLIs carry a significant risk of graft-versus-host disease (GVHD) due to the concurrent transfer of alloreactive T cells. To enhance the GVL effect while minimizing GVHD, we developed a protocol for the generation of ex vivo expanded, donor-derived T-cell lines targeting PRAME, WT1 and Survivin - tumor associated antigens that are frequently expressed in both B- and T-cell ALL. These multi-antigen-targeted T cells (multiTAAs) were adoptively transferred to pediatric and adult patients with HR-ALL who had undergone an allogeneic HSCT. Methods: Donor-derived multiTAA-specific T cells were generated by co-culturing PBMCs with autologous DCs loaded with pepmixes (15 mer peptides overlapping by 11 amino acids) spanning all 3 target antigens in the presence of a Th1-polarizing/pro-proliferative cytokine cocktail. Following 2-4 rounds of stimulation these multiTAA-specific T cells were infused to patients with ALL who had undergone an HSCT but remained at a high risk for disease relapse. Results: We have generated 15 clinical grade multiTAA-specific T cell lines comprising CD3+ T cells (mean 95.1±1.9%) with a mixture of CD4+ (mean 22.8±6.3%) and CD8+ (mean 52.5±5.3%) cells, which expressed central [CD45RO+/CD62L+: 13.5±2.8%] and effector memory markers [CD45RO+/CD62L-: 56.4±3.8%]. The expanded lines recognized the targeted antigens PRAME (range 0-370 SFC/2x10 5), WT1 (0-363 SFC/2x10 5), and Survivin (0-65 SFC/2x10 5) in an IFNg ELIspot. None of the lines reacted against non-malignant patient-derived cells (3.7±0.8% specific lysis; E: T 20:1) - a study release criterion indicating lack of alloreactivity. We have infused 11 HR-ALL patients (8 pediatric and 3 adult) with donor-derived multiTAA-specific T cells to prevent disease relapse (Table 1). Patients were administered with up to 4 infusions of cells at 3 escalating dose levels, ranging from 0.5 - 2x10 7 cells/m 2. Infusions were well tolerated with no dose-limiting toxicity, GVHD, cytokine release syndrome or other adverse events. Three patients were not evaluable per study criteria as they received >0.5mg/kg of steroids (2 patients received stress doses for septic shock and 1 for elevated liver enzymes presumed to be GVHD that was later ruled out) within 4 weeks of infusion and were replaced. Six of the 8 remaining patients infused remain in CR on long-term follow up at a median of 46.5 months post-infusion (range 9-51 months). In patients who remained in long term CR we detected an expansion of tumor-reactive T cells in their peripheral blood post-infusion against both targeted (WT1, Survivin, PRAME) and non-targeted antigens (SSX2, MAGE-A4, -A1, -A2B, -C1, MART1, AFP and NYESO1) reflecting epitope and antigen spreading, which correlated temporally (within 4 weeks) with multiTAA infusions. By contrast in the two patients who relapsed we saw no evidence of in vivo T cell amplification within the first 4 weeks after infusion. Conclusion: The preparation and infusion of donor-derived multiTAA-specific T cells to patients with B- and T-ALL post allogeneic HSCT is feasible, safe and as evidenced by in vivo tumor-directed T cell expansion and antigen spreading in patients, may contribute to disease control. This strategy may present a promising addition to current immunotherapeutic approaches for prophylaxis for leukemic relapse in HSCT recipients. Figure 1 Figure 1. Disclosures Vasileiou: Allovir: Consultancy. Tzannou: Gileas: Honoraria; Allovir: Current equity holder in publicly-traded company. Kuvalekar: Allovir: Consultancy. Watanabe: Allovir: Consultancy. Grilley: QB Regulatory Consulting: Other: Ownership, project management support, Research Funding; Marker: Consultancy, Other: Regulatory and project management support; Allovir: Current equity holder in publicly-traded company, Other: Leadership. Hill: Incyte: Membership on an entity's Board of Directors or advisory committees. Omer: Allovir: Research Funding. Gottschalk: Tessa Therapeutics: Consultancy; Immatics: Membership on an entity's Board of Directors or advisory committees; Other: Other: patents and patent applications in the field of cancer cell and gene therapy ; Tidal: Consultancy; Novartis: Consultancy; Catamaran Bio: Consultancy. Heslop: Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Kuur Therapeutics: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Allovir: Current equity holder in publicly-traded company; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Marker Therapeutics: Current equity holder in publicly-traded company; Fresh Wind Biotherapies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Rooney: Allogene: Patents & Royalties; Bellicum: Patents & Royalties; Bluebird: Current equity holder in publicly-traded company; Allovir: Current equity holder in publicly-traded company; Alimera: Consultancy; Memgen: Consultancy; TScan Therapeutics: Consultancy; Takeda: Patents & Royalties; Marker: Current equity holder in publicly-traded company; Tessa: Consultancy, Other: Leadership, Research Funding. Vera: Allovir: Consultancy, Current equity holder in publicly-traded company, Other: Leadership, travel , accomodations, expenses, Patents & Royalties; Marker: Current Employment, Other: Travel, Accomodations, Expenses, Patents & Royalties, Research Funding. Leen: Allovir: Consultancy, Current equity holder in publicly-traded company; Marker: Current equity holder in publicly-traded company.
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Sun, Hui, Tingting Deng, Yali Zhang, Yanling Lin, Yanan Jiang, Yichao Jiang, Yang Huang i in. "Two antibodies show broad, synergistic neutralization against SARS-CoV-2 variants by inducing conformational change within the RBD". Protein & Cell, 20.07.2023. http://dx.doi.org/10.1093/procel/pwad040.
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Abstract Continual evolution of the SARS-CoV-2 virus has allowed for its gradual evasion of neutralizing antibodies (nAbs) produced in response to natural infection or vaccination. The rapid nature of these changes has incited a need for the development of superior broad nAbs and/or the rational design of an antibody cocktail that can protect against the mutated virus strain. Here, we report two ACE2 competing nAbs—8H12 and 3E2—with synergistic neutralization but evaded by some Omicron subvariants. Cryo-EM reveals the two nAbs synergistic neutralizing virus through a rigorous pairing permitted by rearrangement of the 472-489 loop in the RBD to avoid steric clashing. Bispecific antibodies based on these two nAbs tremendously extend the neutralizing breadth and restore neutralization against recent variants including currently dominant XBB.1.5. Together, these findings expand our understanding of the potential strategies for the neutralization of SARS-CoV-2 variants toward the design of broad-acting antibody therapeutics and vaccines.
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Koh, Junhao, Junqing Liu, Chi Him Poon, Jun Kang, Mohammed S. Basabrain, Lee Wei Lim i Chengfei Zhang. "Transplantation of Neural Progenitor Cells Derived from Stem Cells from Apical Papilla Through Small-Molecule Induction in a Rat Model of Sciatic Nerve Injury". Tissue Engineering and Regenerative Medicine, 21.06.2024. http://dx.doi.org/10.1007/s13770-024-00648-y.
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Abstract Background: Stem cell-based transplantation therapy holds promise for peripheral nerve injury treatment, but adult availability is limited. A cell culture protocol utilizing a small-molecule cocktail effectively reprogrammed stem cells from apical papilla (SCAPs) into neural progenitor cells, subsequently differentiating into neuron-like cells. This study aims to evaluate neural-induced SCAPs, with and without small-molecule cocktail, for sciatic nerve repair potential. Methods: A scaffold-free cell sheet technique was used to construct a three-dimensional cell sheet. Subsequently, this cell sheet was carefully rolled into a tube and seamlessly inserted into a collagen conduit, which was then transplanted into a 5 mm sciatic nerve injury rat model. Functional sciatic nerve regeneration was evaluated via toe spread test, walking track analysis and gastrocnemius muscle weight. Additionally, degree of sciatic nerve regeneration was determined based on total amount of myelinated fibers. Results: Small-molecule cocktail induced SCAPs enhanced motor function recovery, evident in improved sciatic function index and gastrocnemius muscle retention. We also observed better host myelinated fiber retention than undifferentiated SCAPs or neural-induced SCAPs without small-molecule cocktail. However, clusters of neuron-like cell bodies (surrounded by sparse myelinated fibers) were found in all cell sheet-implanted groups in the implantation region. This suggests that while the implanted cells likely survived transplantation, integration was poor and would likely hinder long-term recovery by occupying the space needed for host nerve fibers to project through. Conclusion: Neural-induced SCAPs with small-molecule cocktail demonstrated promising benefits for nerve repair; further research is needed to improve its integration and optimize its potential for long-term recovery.
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Bhat, Shriya, Surya Tripathi i Emily Gan. "Cocktail therapy to inhibit multispecies biofilm in cystic fibrosis patients". Journal of Emerging Investigators, 2022. http://dx.doi.org/10.59720/22-014.
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Bacterial biofilms cause 80% of life-threatening chronic infections such as urinary tract infections, wound infections, indwelling catheter infections, and severe pneumonia in immunocompromised patients such as those with cystic fibrosis (CF). ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter) pathogens are known to form dense biofilms highly resistant to antibacterial treatments. This can lead to antibiotic use at higher concentrations, resulting in antibiotic resistance and toxicity. Furthermore, biofilms exist in a dense multispecies form where they communicate with each other by a mechanism called Quorum Sensing (QS), making them hostile to several antibiotics. The focus of our project was to use a combination treatment consisting of FDA-approved concentrations of three different Quorum Quenching (QQ) agents that specifically target the QS mechanisms between the three major interspecies biofilm-pathways within the CF lung: chlorogenic acid to inhibit Pseudomonas fluorescens-Staphylococcus epidermidis signaling, carvacrol to inhibit P. fluorescens-Burkholderia pyrrociniaP. fluorescens-Candida albicans signaling. Computational analysis of the CF lung microbiome using QIIME2 and PICRUSt2 confirmed the necessity of QS in multispecies biofilm pathways. Docking analysis further supported the binding affinities of each treatment and targeted enzymes. The combination treatment demonstrated a near 80% efficacy in inhibiting P. fluorescens-S. epidermidis-B. pyrrocinia-C. albicans biofilm. Treatment safety was supported by a cytotoxicity assay on human alveolar epithelial cells. These findings can be translated into developing novel adjuvants to deliver the cocktail treatment in vivo, thus reducing morbidity and mortality from chronic biofilm-related infections and saving millions of dollars in product decontamination.
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Ballerstedt, Hendrik, Till Tiso, Nick Wierckx, Ren Wei, Luc Averous, Uwe Bornscheuer, Kevin O’Connor i in. "MIXed plastics biodegradation and UPcycling using microbial communities: EU Horizon 2020 project MIX-UP started January 2020". Environmental Sciences Europe 33, nr 1 (21.08.2021). http://dx.doi.org/10.1186/s12302-021-00536-5.
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AbstractThis article introduces the EU Horizon 2020 research project MIX-UP, "Mixed plastics biodegradation and upcycling using microbial communities". The project focuses on changing the traditional linear value chain of plastics to a sustainable, biodegradable based one. Plastic mixtures contain five of the top six fossil-based recalcitrant plastics [polyethylene (PE), polyurethane (PUR), polypropylene (PP), polyethylene terephthalate (PET), polystyrene (PS)], along with upcoming bioplastics polyhydroxyalkanoate (PHA) and polylactate (PLA) will be used as feedstock for microbial transformations. Consecutive controlled enzymatic and microbial degradation of mechanically pre-treated plastics wastes combined with subsequent microbial conversion to polymers and value-added chemicals by mixed cultures. Known plastic-degrading enzymes will be optimised by integrated protein engineering to achieve high specific binding capacities, stability, and catalytic efficacy towards a broad spectrum of plastic polymers under high salt and temperature conditions. Another focus lies in the search and isolation of novel enzymes active on recalcitrant polymers. MIX-UP will formulate enzyme cocktails tailored to specific waste streams and strives to enhance enzyme production significantly. In vivo and in vitro application of these cocktails enable stable, self-sustaining microbiomes to convert the released plastic monomers selectively into value-added products, key building blocks, and biomass. Any remaining material recalcitrant to the enzymatic activities will be recirculated into the process by physicochemical treatment. The Chinese–European MIX-UP consortium is multidisciplinary and industry-participating to address the market need for novel sustainable routes to valorise plastic waste streams. The project's new workflow realises a circular (bio)plastic economy and adds value to present poorly recycled plastic wastes where mechanical and chemical plastic recycling show limits.