Most gene therapies exert their actions via manipulation of hepatocytes (parenchymal cells) and the reasons behind the suboptimal performance of synthetic mRNA in non-parenchymal cells (NPC) such as Kupffer cells (KC), and liver macrophages, remain unclear. Here, the spatio-temporal distribution of mRNA encoding enhanced green fluorescent protein (Egfp), siRNA, or both co-encapsulated into lipid nanoparticles (LNP) in the liver in vivo using real-time intravital imaging is investigated. Although both KC and hepatocytes demonstrate comparable high and rapid uptake of mRNA-LNP and siRNA-LNP in vivo, the translation of Egfp mRNA occurs exclusively in hepatocytes during intravital imaging.
View Article and Find Full Text PDFElimination of microbes in the root canal system is crucial for achieving long-term success in endodontic treatment. Further efforts in study design and standardization are needed in order to improve the validity and comparability of in vitro results on endodontic disinfection procedures, in turn improving clinical outcomes. This study optimizes two models at all steps: tooth selection, pretreatment, inoculation method (by growth or centrifugation), and confocal laser scanning microscopy (CLSM)-guided imaging of LIVE/DEAD-stained specimens.
View Article and Find Full Text PDFMyeloproliferative neoplasms (MPN) are rare hematologic disorders characterized by clonal hematopoiesis. Familial clustering is observed in a subset of cases, with a notable proportion exhibiting heterozygous germline mutations in DNA double-strand break repair genes (e.g.
View Article and Find Full Text PDFMutations in RNA binding proteins (RBPs) and in genes regulating autophagy are frequent causes of familial amyotrophic lateral sclerosis (fALS). The P56S mutation in vesicle-associated membrane protein-associated protein B (VAPB) leads to fALS (ALS8) and spinal muscular atrophy (SMA). While VAPB is primarily involved in the unfolded protein response (UPR), vesicular trafficking and in initial steps of the autophagy pathway, the effect of mutant P56S-VAPB on autophagy regulation in connection with RBP homeostasis has not been explored yet.
View Article and Find Full Text PDFSeptic cardiomyopathy is a life-threatening organ dysfunction caused by sepsis. Ribonuclease 1 (RNase 1) belongs to a group of host-defense peptides that specifically cleave extracellular RNA (eRNA). The activity of RNase 1 is inhibited by ribonuclease-inhibitor 1 (RNH1).
View Article and Find Full Text PDFSignal transducer and activator of transcription (STAT) proteins are transcription factors that in the latent state are located predominantly in the cytoplasm. Activation of STATs through phosphorylation of a single tyrosine residue results in nuclear translocation. The requirement of tyrosine phosphorylation for nuclear accumulation is shared by all STAT family members but mechanisms of nuclear translocation vary between different STATs.
View Article and Find Full Text PDFHigh-performance oxide ceramics (HPOC), such as alumina, zirconia, and dispersion ceramics thereof are successfully used as articulating components in joint arthroplasty. HPOC exhibit excellent wear resistance, high strength, and cytocompatible behavior; however, they lack sufficient tissue bonding capability. Thus, they are primarily deployed as low-wear-bearing articulating components in arthroplasty without direct tissue contact, although proper cellular stimulation would hold significant advantages.
View Article and Find Full Text PDFMacrodomains are conserved protein folds associated with ADP-ribose binding and turnover. ADP-ribosylation is a posttranslational modification catalyzed primarily by ARTD (aka PARP) enzymes in cells. ARTDs transfer either single or multiple ADP-ribose units to substrates, resulting in mono- or poly-ADP-ribosylation.
View Article and Find Full Text PDFHaploinsufficiency of is a cause of a neurodevelopmental syndrome termed mental retardation autosomal dominant 7 (MRD7). Several truncation mutations, microdeletions and missense variants have been identified and result in a recognizable phenotypic profile, including microcephaly, intellectual disability, epileptic seizures, autism spectrum disorder and language delay. DYRK1A is an evolutionary conserved protein kinase which achieves full catalytic activity through tyrosine autophosphorylation.
View Article and Find Full Text PDFSTAT5 is an essential transcription factor in hematopoiesis, which is activated through tyrosine phosphorylation in response to cytokine stimulation. Constitutive activation of STAT5 is a hallmark of myeloid and lymphoblastic leukemia. Using homology modeling and molecular dynamics simulations, a model of the STAT5 phosphotyrosine-SH2 domain interface was generated providing first structural information on the activated STAT5 dimer including a sequence, for which no structural information is available for any of the STAT proteins.
View Article and Find Full Text PDFA facile enzymatic synthesis of the methylumbelliferyl β-glycoside of the type 2 A blood group tetrasaccharide in good yields is reported. Using this compound, we developed highly sensitive fluorescence-based high-throughput assays for both endo-β-galactosidase and α-N-acetylgalactosaminidase activity specific for the oligosaccharide structure of the blood group A antigen. We further demonstrate the potential to use this assay to screen the expressed gene products of metagenomic libraries in the search for efficient blood group antigen-cleaving enzymes.
View Article and Find Full Text PDFThe crystal structure of β-galactosidase from Bacillus circulans (BgaC) was determined at 1.8Å resolution. The overall structure of BgaC consists of three distinct domains, which are the catalytic domain with a TIM-barrel structure and two all-β domains (ABDs).
View Article and Find Full Text PDFObjectives: The aim of this study was to compare two different surfaces of one uniform macro-implant design in order to focus exclusively on the osseointegration properties after 2, 4 and 8 weeks and to discuss the animal model chosen.
Material And Methods: In six mature sheep, n = 36 implants with a highly crystalline and phosphate-enriched anodized titanium oxide surface (TiU) and n = 36 implants with a hydrophilic, sandblasted, large grit and acid-etched surface (SLA) were placed in the pelvic bone. TiU implants were custom-made to match the SLA implant design.
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