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101.
Dr. Armin Welker Dr. Christian Kersten Dr. Christin Müller Dr. Ramakanth Madhugiri Collin Zimmer Patrick Müller Robert Zimmermann Stefan Hammerschmidt Hannah Maus Prof. John Ziebuhr Prof. Christoph Sotriffer Prof. Tanja Schirmeister 《ChemMedChem》2021,16(2):340-354
Inhibition of coronavirus (CoV)-encoded papain-like cysteine proteases (PLpro) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure-activity relationships (SAR) of the noncovalent active-site directed inhibitor (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl) benzamide ( 2 b ), which is known to bind into the S3 and S4 pockets of the SARS-CoV PLpro. Moreover, we report the discovery of isoindolines as a new class of potent PLpro inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS-CoV-2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS-CoV PLpro are valuable starting points for the development of new pan-coronaviral inhibitors. 相似文献
102.
Silvia Saturio Alicja M. Nogacka Marta Surez Nuria Fernndez Laura Mantecn Leonardo Mancabelli Christian Milani Marco Ventura Clara G. de los Reyes-Gaviln Gonzalo Solís Silvia Arboleya Miguel Gueimonde 《International journal of molecular sciences》2021,22(7)
The establishment of the gut microbiota poses implications for short and long-term health. Bifidobacterium is an important taxon in early life, being one of the most abundant genera in the infant intestinal microbiota and carrying out key functions for maintaining host-homeostasis. Recent metagenomic studies have shown that different factors, such as gestational age, delivery mode, or feeding habits, affect the gut microbiota establishment at high phylogenetic levels. However, their impact on the specific bifidobacterial populations is not yet well understood. Here we studied the impact of these factors on the different Bifidobacterium species and subspecies at both the quantitative and qualitative levels. Fecal samples were taken from 85 neonates at 2, 10, 30, 90 days of life, and the relative proportions of the different bifidobacterial populations were assessed by 16S rRNA–23S rRNA internal transcribed spacer (ITS) region sequencing. Absolute levels of the main species were determined by q-PCR. Our results showed that the bifidobacterial population establishment is affected by gestational age, delivery mode, and infant feeding, as it is evidenced by qualitative and quantitative changes. These data underline the need for understanding the impact of perinatal factors on the gut microbiota also at low taxonomic levels, especially in the case of relevant microbial populations such as Bifidobacterium. The data obtained provide indications for the selection of the species best suited for the development of bifidobacteria-based products for different groups of neonates and will help to develop rational strategies for favoring a healthy early microbiota development when this process is challenged. 相似文献
103.
Clarisse Roblin Steve Chiumento Cdric Jacqueline Eric Pinloche Cendrine Nicoletti Hamza Olleik Elise Courvoisier-Dezord Agns Amouric Christian Basset Louis Dru Marie Ollivier Aurlie Bogey-Lambert Nicolas Vidal Mohamed Atta Marc Maresca Estelle Devillard Victor Duarte Josette Perrier Mickael Lafond 《International journal of molecular sciences》2021,22(6)
The world is on the verge of a major antibiotic crisis as the emergence of resistant bacteria is increasing, and very few novel molecules have been discovered since the 1960s. In this context, scientists have been exploring alternatives to conventional antibiotics, such as ribosomally synthesized and post-translationally modified peptides (RiPPs). Interestingly, the highly potent in vitro antibacterial activity and safety of ruminococcin C1, a recently discovered RiPP belonging to the sactipeptide subclass, has been demonstrated. The present results show that ruminococcin C1 is efficient at curing infection and at protecting challenged mice from Clostridium perfringens with a lower dose than the conventional antibiotic vancomycin. Moreover, antimicrobial peptide (AMP) is also effective against this pathogen in the complex microbial community of the gut environment, with a selective impact on a few bacterial genera, while maintaining a global homeostasis of the microbiome. In addition, ruminococcin C1 exhibits other biological activities that could be beneficial for human health, as well as other fields of applications. Overall, this study, by using an in vivo infection approach, confirms the antimicrobial clinical potential and highlights the multiple functional properties of ruminococcin C1, thus extending its therapeutic interest. 相似文献
104.
Marta Gmez-Ferrer Estela Villanueva-Badenas Rafael Snchez-Snchez Christian M. Snchez-Lpez Maria Carmen Baquero Pilar Sepúlveda Akaitz Dorronsoro 《International journal of molecular sciences》2021,22(7)
Despite the strong evidence for the immunomodulatory activity of mesenchymal stromal cells (MSCs), clinical trials have so far failed to clearly show benefit, likely reflecting methodological shortcomings and lack of standardization. MSC-mediated tissue repair is commonly believed to occur in a paracrine manner, and it has been stated that extracellular vesicles (EVs) secreted by MSCs (EVMSC) are able to recapitulate the immunosuppressive properties of parental cells. As a next step, clinical trials to corroborate preclinical studies should be performed. However, effective dose in large mammals, including humans, is quite high and EVs industrial production is hindered by the proliferative senescence that affects MSCs during massive cell expansion. We generated a genetically modified MSC cell line overexpressing hypoxia-inducible factor 1-alpha and telomerase to increase the therapeutic potency of EVMSC and facilitate their large-scale production. We also developed a cytokine-based preconditioning culture medium to prime the immunomodulatory response of secreted EVs (EVMSC-T-HIFc). We tested the efficacy of this system in vitro and in a delayed-type hypersensitivity mouse model. MSC-T with an HIF-1α-GFP lentiviral vector (MSC-T-HIF) can be effectively expanded to obtain large amounts of EVs without major changes in cell phenotype and EVs composition. EVMSC-T-HIFc suppressed the proliferation of activated T-cells more effectively than did EVs from unmodified MSC in vitro, and significantly blunted the ear-swelling response in vivo by inhibiting cell infiltration and improving tissue integrity. We have developed a long-lived EV source that secretes high quantities of immunosuppressive EVs, facilitating a more standard and cost-effective therapeutic product. 相似文献
105.
Oliver Schmutzler Sebastian Graf Nils Behm Wael Y. Mansour Florian Blumendorf Theresa Staufer Christian Krnig Dina Salah Yanan Kang Jan N. Peters Yang Liu Neus Feliu Wolfgang J. Parak Anja Burkhardt Elisabetta Gargioni Sabrina Gennis Sharah Chandralingam Finn Heg Wolfgang Maison Kai Rothkamm Florian Schulz Florian Grüner 《International journal of molecular sciences》2021,22(7)
Quantitative cellular in vitro nanoparticle uptake measurements are possible with a large number of different techniques, however, all have their respective restrictions. Here, we demonstrate the application of synchrotron-based X-ray fluorescence imaging (XFI) on prostate tumor cells, which have internalized differently functionalized gold nanoparticles. Total nanoparticle uptake on the order of a few hundred picograms could be conveniently observed with microsamples consisting of only a few hundreds of cells. A comparison with mass spectroscopy quantification is provided, experimental results are both supported and sensitivity limits of this XFI approach extrapolated by Monte-Carlo simulations, yielding a minimum detectable nanoparticle mass of just 5 pg. This study demonstrates the high sensitivity level of XFI, allowing non-destructive uptake measurements with very small microsamples within just seconds of irradiation time. 相似文献
106.
Sviatlana Kalinina Christian Freymueller Nilanjon Naskar Bjoern von Einem Kirsten Reess Ronald Sroka Angelika Rueck 《International journal of molecular sciences》2021,22(11)
Metabolic FLIM (fluorescence lifetime imaging) is used to image bioenergetic status in cells and tissue. Whereas an attribution of the fluorescence lifetime of coenzymes as an indicator for cell metabolism is mainly accepted, it is debated whether this is valid for the redox state of cells. In this regard, an innovative algorithm using the lifetime characteristics of nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) and flavin adenine dinucleotide (FAD) to calculate the fluorescence lifetime induced redox ratio (FLIRR) has been reported so far. We extended the FLIRR approach and present new results, which includes FLIM data of the various enzymes, such as NAD(P)H, FAD, as well as flavin mononucleotide (FMN). Our algorithm uses a two-exponential fitting procedure for the NAD(P)H autofluorescence and a three-exponential fit of the flavin signal. By extending the FLIRR approach, we introduced FLIRR1 as protein-bound NAD(P)H related to protein-bound FAD, FLIRR2 as protein-bound NAD(P)H related to free (unbound) FAD and FLIRR3 as protein-bound NAD(P)H related to protein-bound FMN. We compared the significance of extended FLIRR to the metabolic index, defined as the ratio of protein-bound NAD(P)H to free NAD(P)H. The statistically significant difference for tumor and normal cells was found to be highest for FLIRR1. 相似文献
107.
The aim of this work is to propose an original solution to the acoustic impedance mismatch between a PZT transducer and a water load. The characteristic acoustic impedance of the PZT is around 33 MRayl. Theoretically, a quarter-wave layer with characteristic acoustic impedance equal to 7 MRayl is necessary to match the transducer to water. In practice, it is difficult to find a material with this particular impedance. Two or more quarter-wave layers may also be used. The following proposed solution consists in using two matching layers where one of them is the glue. Moreover, their thicknesses are not equal to a quarter of their individual wavelength. Once the glue is taken as the first matching layer, the specific material of the second layer can easily be found. In this work, the second layer, which is also the front layer, is made of glass. The thickness of each matching layer is then calculated as a function of the characteristic acoustic impedance of the two layers. The influence of the thickness of these layers is discussed. The proposed matching configuration is analyzed and theoretical results have been carefully and successfully compared with measurements. 相似文献
108.
109.
Dirk Anderheiden Otto Brenner Doris Klee Robert Kaufmann Horst A. Richter Christian Mittermayer Hartwig Hcker 《大分子材料与工程》1991,185(1):109-127
Different polyurethanes were synthesized by varying the diol as well as the diisocyanate components and chain extenders. Polyurethanes with OH-groups were obtained by photo- and thermoinitiation of the radical polymerization of hydroxy alkyl acrylates in the presence of the polyurethanes. The polymers were evaluated with respect to their biocompatibility by measuring the cell spreading, the rates of DNA- and protein synthesis and the swelling behaviour. The differences in the surfaces and the bulks between the selected basic polyurethane and the functionalized modification were determined and characterized by XPS, FTIR-ATR and 13C-FT-NMR-spectroscopy. The mechanical data of Tecoflex EG 60D® and Pellethane 2363–80AE® were compared with the data of the synthesized polyurethanes. 相似文献
110.
Mass transfer rates were determined in a 3.4 cm i.d. trickle-bed reactor in the absence of reaction by absorption measurements and in presence of reaction. Gas flow rates were varied from 0-100 l/h and liquid flow rates from 0-1.5 l/h. The catalyst particles were crushed to an average diameter of 0.054 and 0.09 cm. Mass transfer coefficients remained unaffected by change in gas flow rate but increased with liquid rate. The data from absorption measurements were evaluated with predictions based upon plug-flow and axial dispersion model. Mass transfer coefficients were found greater in case of axial dispersion model than that of plug-flow model specially at low Reynolds number (Re1 < 1).Hydrogenation of α-methylstyrene to cumene using a Pd/Al2O3 catalyst was taken as a model reaction. Intrinsic kinetic studies were made in a laboratory-stirred-autoclave. Mass transfer coefficients were determined using these intrinsic kinetic data from the process kinetic measurements in trickle-bed reactor. Mass transfer coefficients under reaction conditions were found to be considerably higher than those obtained by absorption measurements.Correlations were suggested for predicting mass transfer coefficients at low Reynolds number.The gas to liquid mass transfer coefficients for lower gas and liquid flow rates were determined in a laboratory trickle-bed reactor. The effect of axial dispersion on mass transfer was considered in order to evaluate the experimental data. Three correlations were formulated to calculate the mass transfer coefficients, which included the effect of liquid loading, particle size and the properties of the reacting substances. The gas flow rate influences the gas to liquid mass transfer only in the region of low gas velocities. In the additional investigations of gas to liquid mass transfer without reaction in trickle-bed reactor, the mass transfer coefficients were determined under reaction conditions and the intrinsic kinetics was studied in a laboratory scale stirred autoclave with suspended catalyst. A few correlations are formulated for the mass transfer coefficients. A comparison with the gas-liquid mass transfer coefficient obtained by absorption measurements showed considerable deviations, which were illustrated phenomenologically. 相似文献