Inhibition of inflammatory response in human keratinocytes by magnetic nanoparticles functionalized with PBP10 peptide derived from the PIP2-binding site of human plasma gelsolin

Background: Human plasma gelsolin (pGSN) is a multifunctional actin-binding protein involved in a variety of biological processes, including neutralization of pro-infammatory molecules such as lipopolysaccharide (LPS) and lipoteichoic acid (LTA) and modulation of host infammatory response. It was found that PBP10, a synthetic rhodamine B-conjugated peptide, based on the phosphoinositide-binding site of pGSN, exerts bactericidal activity against Grampositive and Gram-negative bacteria, interacts specifcally with LPS and LTA, and limits microbial-induced infammatory efects. The therapeutic efciency of PBP10 when immobilized on the surface of iron oxide-based magnetic nanoparticles was not evaluated, to date. Results: Using the human keratinocyte cell line HaCaT stimulated by bacterially-derived LPS and LTA as an in vitro model of bacterial infection, we examined the anti-infammatory efects of nanosystems consisting of iron oxidebased magnetic nanoparticles with aminosilane (MNP@NH2) or gold shells (MNP@Au) functionalized by a set of peptides, derived from the phosphatidylinositol 4,5-bisphosphate (PIP2)-binding site of the human plasma protein gelsolin, which also binds LPS and LTA. Our results indicate that these nanosystems can kill both Gram-positive and Gram-negative bacteria and limit the production of infammatory mediators, including nitric oxide (NO), reactive oxygen species (ROS), and interleukin-8 (IL-8) in the response to heat-killed microbes or extracted bacterial cell wall components. The nanoparticles possess the potential to improve therapeutic efcacy and are characterized by lower toxicity and improved hemocompatibility when compared to free peptides. Atomic force microscopy (AFM) showed that these PBP10-based nanosystems prevented changes in nanomechanical properties of cells that were otherwise stimulated by LPS. Conclusions: Neutralization of endotoxemia-mediated cellular efects by gelsolin-derived peptides and PBP10-containing nanosystems might be considered as potent therapeutic agents in the improved therapy of bacterial infections and microbial-induced infammation.This work was fnancially supported by the National Science Center, Poland under Grant: UMO-2015/17/B/NZ6/03473 (to RB) and Medical University of Bialystok (N/ST/ZB/18/002/1162 and N/ST/ZB/18/001/1162 (to RB) and N/ST/MN/18/002/1162 (to EP). Part of the study was conducted with the use of equipment purchased by the Medical University of Białystok as part of the RPOWP 2007-2013 funding, Priority I, Axis 1.1, contract No. UDARPPD.01.01.00-20-001/15-00 dated 26.06.2015. The physicochemical studies were performed in Centre of Synthesis and Analysis BioNanoTechno of the University of Bialystok (POPW.01.03.00-20-034/09-00 and POPW.01.03.00-20004/11 projects). EP acknowledges a doctoral scholarship from Polpharma Scientifc Foundation, Poland. PAJ and RB acknowledge support from NIH grant GM111942-01.Robert Bucki: [email protected] Piktel - Department of Microbiological and Nanobiomedical Engineering, Medical University of BialystokUrszula Wnorowska - Department of Microbiological and Nanobiomedical Engineering, Medical University of BialystokMateusz Cieśluk - Department of Microbiological and Nanobiomedical Engineering, Medical University of BialystokPiotr Deptula - Department of Microbiological and Nanobiomedical Engineering, Medical University of BialystokKatarzyna Pogoda - IInstitute of Nuclear Physics Polish Academy of SciencesIwona Misztalewska‑Turkowicz - Institute of Chemistry, University of BiałystokPaulina Paprocka - Department of Microbiology and Immunology, The Faculty of Medicine and Health Sciences of the Jan Kochanowski University in KielceKatarzyna Niemirowicz‑Laskowska - Department of Microbiological and Nanobiomedical Engineering, Medical University of BialystokAgnieszka Z. 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Mortality Following Clostridioides difficile Infection in Europe : A Retrospective Multicenter Case-Control Study

We aimed to describe the clinical presentation, treatment, outcome and report on factors associated with mortality over a 90-day period in Clostridioides difficile infection (CDI). Descriptive, univariate, and multivariate regression analyses were performed on data collected in a retrospective case-control study conducted in nine hospitals from seven European countries. A total of 624 patients were included, of which 415 were deceased (cases) and 209 were still alive 90 days after a CDI diagnosis (controls). The most common antibiotics used previously in both groups were β-lactams; previous exposure to fluoroquinolones was significantly (p = 0.0004) greater in deceased patients. Multivariate logistic regression showed that the factors independently related with death during CDI were older age, inadequate CDI therapy, cachexia, malignancy, Charlson Index, long-term care, elevated white blood cell count (WBC), C-reactive protein (CRP), bacteraemia, complications, and cognitive impairment. In addition, older age, higher levels of WBC, neutrophil, CRP or creatinine, the presence of malignancy, cognitive impairment, and complications were strongly correlated with shortening the time from CDI diagnosis to death. CDI prevention should be primarily focused on hospitalised elderly people receiving antibiotics. WBC, neutrophil count, CRP, creatinine, albumin and lactate levels should be tested in every hospitalised patient treated for CDI to assess the risk of a fatal outcome

Recombinant Human Plasma Gelsolin Stimulates Phagocytosis while Diminishing Excessive Inflammatory Responses in Mice with Pseudomonas aeruginosa Sepsis

Plasma gelsolin (pGSN) is a highly conserved abundant circulating protein, characterized by diverse immunomodulatory activities including macrophage activation and the ability to neutralize pro-inflammatory molecules produced by the host and pathogen. Using a murine model of Gram-negative sepsis initiated by the peritoneal instillation of Pseudomonas aeruginosa Xen 5, we observed a decrease in the tissue uptake of IRDye®800CW 2-deoxyglucose, an indicator of inflammation, and a decrease in bacterial growth from ascitic fluid in mice treated with intravenous recombinant human plasma gelsolin (pGSN) compared to the control vehicle. Pretreatment of the murine macrophage line RAW264.7 with pGSN, followed by addition of Pseudomonas aeruginosa Xen 5, resulted in a dose-dependent increase in the proportion of macrophages with internalized bacteria. This increased uptake was less pronounced when cells were pretreated with pGSN and then centrifuged to remove unbound pGSN before addition of bacteria to macrophages. These observations suggest that recombinant plasma gelsolin can modulate the inflammatory response while at the same time augmenting host antibacterial activity.This work was supported by the National Science Center, Poland under Grant: UMO-2015/17/B/NZ6/03473 (to RB), National Institutes of Health: GM111942 (to PAJ) and Medical University of Bialystok: SUB/1/DN/19/001/1162 (to RB), N/ST/MN/18/001/1162 (to MC). Part of the study was conducted with the use of equipment purchased by the Medical University of Białystok as part of the RPOWP 2007-2013 funding, Priority I, Axis 1.1, contract No. UDA- RPPD.01.01.00-20-001/15-00 dated 26.06.2015. This work was supported by the program of the Minister of Science and Higher Education under the name “Regional Initiative of Excellence in 2019–2022”, project number: 024/RID/2018/19, financing amount: 11.999.000,00 PLN.Ewelina Piktel: [email protected] Wnorowska: [email protected] Cieśluk: [email protected] Deptuła: [email protected] V. Prasad: [email protected] Król: [email protected] Durnaś: [email protected] Namiot: [email protected] H. Markiewicz: [email protected] Niemirowicz-Laskowska: [email protected] Z. Wilczewska: [email protected] A. Janmey: [email protected] Reszeć: [email protected] Bucki: [email protected] Piktel - Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of BialystokUrszula Wnorowska - Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of BialystokMateusz Cieśluk - Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of BialystokPiotr Deptuła - Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of BialystokSuhanya V. Prasad - Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of BialystokGrzegorz Król - Department of Microbiology and Immunology, the Faculty of Medicine and Health Sciences of the Jan Kochanowski University in KielceBonita Durnaś - Department of Microbiology and Immunology, the Faculty of Medicine and Health Sciences of the Jan Kochanowski University in KielceAndrzej Namiot - Department of Anatomy, Medical University of BialystokKarolina H. Markiewicz - Institute of Chemistry, University of BiałystokKatarzyna Niemirowicz-Laskowska - Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of BialystokAgnieszka Z. Wilczewska - Institute of Chemistry, University of BiałystokPaul A. Janmey - Institute for Medicine and Engineering, University of PennsylvaniaJoanna Reszeć - Department of Pathology, Medical University of BialystokRobert Bucki - Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Bialystok; Department of Microbiology and Immunology, the Faculty of Medicine and Health Sciences of the Jan Kochanowski University in KielceLee, P.S.; Patel, S.R.; Christiani, D.C.; Bajwa, E.; Stossel, T.P.; Waxman, A.B. Plasma gelsolin depletion and circulating actin in sepsis: A pilot study. PLoS ONE 2008, 3, e3712.Li-ChunHsieh, K.; Schob, S.; Zeller, M.W.; Pulli, B.; Ali, M.; Wang, C.; Chiou, T.T.; Tsang, Y.M.; Lee, P.S.; Stossel, T.P.; et al. Gelsolin decreases actin toxicity and inflammation in murine multiple sclerosis. J. Neuroimmunol. 2015, 287, 36–42.Bucki, R.; Kulakowska, A.; Byfield, F.J.; Zendzian-Piotrowska, M.; Baranowski, M.; Marzec, M.; Winer, J.P.; Ciccarelli, N.J.; Górski, J.; Drozdowski, W.; et al. 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Unique Role of Vimentin Networks in Compression Stiffening of Cells and Protection of Nuclei from Compressive Stress

In this work, we investigate whether stiffening in compression is a feature of single cells and whether the intracellular polymer networks that comprise the cytoskeleton (all of which stiffen with increasing shear strain) stiffen or soften when subjected to compressive strains. We find that individual cells, such as fibroblasts, stiffen at physiologically relevant compressive strains, but genetic ablation of vimentin diminishes this effect. Further, we show that unlike networks of purified F-actin or microtubules, which soften in compression, vimentin intermediate filament networks stiffen in both compression and extension, and we present a theoretical model to explain this response based on the flexibility of vimentin filaments and their surface charge, which resists volume changes of the network under compression. These results provide a new framework by which to understand the mechanical responses of cells and point to a central role of intermediate filaments in response to compression

Healthcare-associated pneumonia in acute care hospitals in European union/European economic area countries: an analysis of data from a point prevalence survey, 2011 to 2012

An aim of the ECDC point prevalence survey (PPS) in European Union/European Economic Area acute care hospitals was to acquire standardised healthcare-associated infections (HAI) data. We analysed one of the most common HAIs in the ECDC PPS, healthcare-associated pneumonia (HAP). Standardised HAI case definitions were provided and countries were advised to recruit nationally representative subsets of hospitals. We calculated 95% confidence intervals (CIs) around prevalence estimates and adjusted for clustering at hospital level. Of 231,459 patients in the survey, 2,902 (1.3%; 95% CI: 1.2–1.3) fulfilled the case definition for a HAP. HAPs were most frequent in intensive care units (8.1%; 95% CI: 7.4–8.9) and among patients intubated on the day of the survey (15%; 95% CI: 14–17; n = 737 with HAP). The most frequently reported microorganism was Pseudomonas aeruginosa (17% of 1,403 isolates), followed by Staphylococcus aureus (12%) and Klebsiella spp. (12%). Antimicrobial resistance was common among isolated microorganisms. The most frequently prescribed antimicrobial group was penicillins, including combinations with beta-lactamase inhibitors. HAPs occur regularly among intubated and non-intubated patients, with marked differences between medical specialities. HAPs remain a priority for preventive interventions, including surveillance. Our data provide a reference for future prevalence of HAPs at various settings

Organization and training at national level of antimicrobial stewardship and infection control activities in Europe: an ESCMID cross-sectional survey

Antimicrobial stewardship (AMS) and Infection prevention and control (IPC) are two key complementary strategies that combat development and spread of antimicrobial resistance. The ESGAP (ESCMID Study Group for AMS), EUCIC (European Committee on Infection Control) and TAE (Trainee Association of ESCMID) investigated how AMS and IPC activities and training are organized, if present, at national level in Europe. From February 2018 to May 2018, an internet-based cross-sectional survey was conducted through a 36-item questionnaire, involving up to three selected respondents per country, from 38 European countries in total (including Israel), belonging to the ESGAP/EUCIC/TAE networks. All 38 countries participated with at least one respondent, and a total of 81 respondents. Education and involvement in AMS programmes were mandatory during the postgraduate training of clinical microbiology and infectious diseases specialists in up to one-third of countries. IPC was acknowledged as a specialty in 32% of countries. Only 32% of countries had both guidance and national requirements regarding AMS programmes, in contrast to 61% for IPC. Formal national staffing standards for AMS and IPC hospital-based activities were present in 24% and 63% of countries, respectively. The backgrounds of professionals responsible for AMS and IPC programmes varied tremendously between countries. The organization and training of AMS and IPC in Europe are heterogeneous and national requirements for activities are frequently lacking

Application of multi-valued weighting logical functions in the analysis of a degree of importance of construction parameters on the example of hydraulic valves

In the optimization process, changes in the construction parameters value influence the behaviour of functions depending on time. Weighting logical coefficients for the stabilisation time are taken into consideration here, i.e., a shorter (better) stabilisation time has a more important (bigger) value of the weighting coefficient. An example of applying weighting logical functions in the analysis of a degree of importance of construction parameters of a hydraulic valve is presented in the paper

Optimization of machine systems including a complex coefficient of complexity for multi-valued decision trees

Skierowany graf zależności przepływu informacji opisuje powiązania wielkości wejściowych, wyjściowych oraz zmiennych decyzyjnych w analizowanym układzie maszynowym. Przetłumaczenie skierowanego grafu zależności na strukturę rozgrywającą parametrycznie, pozwala na określenie obszaru rozwiązań dopuszczalnych i wybór procedury optymalizacyjnej. Struktura drzewiasta, o najmniejszej wartości kompleksowego współczynnika posiada najmniejszy stopień złożoności decyzyjnej. Możliwe jest zastosowanie kompleksowego współczynnika złożoności dla wielowartościowych drzew decyzyjnych w opisie strukturalnych procesów optymalizacji układów maszynowych, według zagadnień minimalizacji funkcji logicznych.Different graph solutions mean connections between input and output data as well as decision variables of the analyzed system (eg in the machine system). The graph distribution from any vertex in the first stage leads to a tree structure with cycles, and next to a general tree game structure. Algorithmic way to create graphical structures out of a mathematical model describes the optimization method of systematic exploration. Tree structure, with the lowest values of complexity level is the simplest structure. It is possible to apply a complex coefficient of complexity for multi valued decision trees in the description of the processes of structural optimization of the machine according to the issues of minimizing logic functions