The antigenic anatomy of SARS-CoV-2 receptor binding domain

1. Download : Download high-res image (220KB)
2. Download : Download full-size image

     

Die Plazenta des dorsiventralenCuphea-Gynözeums

zusammenfassung Die Plazenta vonCuphea cyanea, lanceolata undprocumbens, ein komplexes, aus den Medianplazenten der beiden peltaten Karpelle bestehendes und durch die Symmetrieverhältnisse modifiziertes Organ, erhält durch frühzeitige Degeneration der Scheidewände weitgehende Selbständigkeit innerhalb des Gynözeums. Dies führt zunächst zu einer charakteristischen, nicht durch die Karpelle regulierten Stellung und schließlich zu einem Herauskrümmen der Plazenta aus der zerbrechenden Frucht. Diese Bewegung wird durch eine Wachtumszone an der Ventralscite der Plazenta bewirkt.     

Human cytochromes P450 in health and disease

There are 18 mammalian cytochrome P450 (CYP) families, which encode 57 genes in the human genome. CYP2, CYP3 and CYP4 families contain far more genes than the other 15 families; these three families are also the ones that are dramatically larger in rodent genomes. Most (if not all) genes in the CYP1, CYP2, CYP3 and CYP4 families encode enzymes involved in eicosanoid metabolism and are inducible by various environmental stimuli (i.e. diet, chemical inducers, drugs, pheromones, etc.), whereas the other 14 gene families often have only a single member, and are rarely if ever inducible or redundant. Although the CYP2 and CYP3 families can be regarded as largely redundant and promiscuous, mutations or other defects in one or more genes of the remaining 16 gene families are primarily the ones responsible for P450-specific diseases—confirming these genes are not superfluous or promiscuous but rather are more directly involved in critical life functions. P450-mediated diseases comprise those caused by: aberrant steroidogenesis; defects in fatty acid, cholesterol and bile acid pathways; vitamin D dysregulation and retinoid (as well as putative eicosanoid) dysregulation during fertilization, implantation, embryogenesis, foetogenesis and neonatal development.     

Interaction of the C14-OH Group of Adriamycin with DNA Phosphate as Spectroscopically Evidenced

Abstract

Monitoring the band of the antisymmetric stretching vibration of the backbone PO₂ ^? group in DNA-anthracycline complexes demonstrates an extraordinary wavenumber shift for the adriamycin complex compared to that of daunomycin. The structures of both anthracyclines, however, are very closely related and differ only by a surplus hydroxyl group of adriamycin in the C14 position. The wavenumber shift observed for the DNA-adriamycin complex is unequivocally attributed to an additional linkage of the C14-OH of adriamycin to the phosphate group of DNA. Thus, serveral of the hypothetical structural models for the DNA-adriamycin complex for which a hydrogen bond between the C14 hydroxyl of the drug and DNA phosphate was postulated (S. Neidle, Cancer Treatment Rep. 61, 928 (1977); G. J. Quigley et. al., Proc. Natl. Acad Sci. USA 77, 7204 (1980)) get the first clear-cut experimental evidence.     

The Properties of Chondrocyte Membrane Reservoirs and Their Role in Impact-Induced Cell Death

Impact loading of articular cartilage causes extensive chondrocyte death. Cell membranes have a limited elastic range of 3–4% strain but are protected from direct stretch during physiological loading by their membrane reservoir, an intricate pattern of membrane folds. Using a finite-element model, we suggested previously that access to the membrane reservoir is strain-rate-dependent and that during impact loading, the accessible membrane reservoir is drastically decreased, so that strains applied to chondrocytes are directly transferred to cell membranes, which fail when strains exceed 3–4%. However, experimental support for this proposal is lacking. The purpose of this study was to measure the accessible membrane reservoir size for different membrane strain rates using membrane tethering techniques with atomic force microscopy. We conducted atomic force spectroscopy on isolated chondrocytes (n = 87). A micron-sized cantilever was used to extract membrane tethers from cell surfaces at constant pulling rates. Membrane tethers could be identified as force plateaus in the resulting force-displacement curves. Six pulling rates were tested (1, 5, 10, 20, 40, and 80 μm/s). The size of the membrane reservoir, represented by the membrane tether surface areas, decreased exponentially with increasing pulling rates. The current results support our theoretical findings that chondrocytes exposed to impact loading die because of membrane ruptures caused by high tensile membrane strain rates.     

Characterization of a surrogate murine antibody to model anti-human CD3 therapies

Fc-modified anti-human CD3ε monoclonal antibodies (mAbs) are in clinical development for the treatment of autoimmune diseases. These next generation mAbs have completed clinical trials in patients with type-1 diabetes and inflammatory bowel disease demonstrating a narrow therapeutic window. Lowered doses are ineffective, yet higher pharmacologically-active doses cause an undesirable level of adverse events. Thus, there is a critical need for a return to bench research to explore ways of improving clinical outcomes. Indeed, we recently reported that a short course of treatment affords synergy, providing long-term disease amelioration when combining anti-mouse CD3 and anti-mouse tumor necrosis factor mAbs in experimental arthritis. Such strategies may widen the window between risk and benefit; however, to more accurately assess experimentally the biology and pharmacology, reagents that mimic the current development candidates were required. Consequently, we engineered an Fc-modified anti-mouse CD3ε mAb, 2C11-Novi. Here, we report the functional characterization of 2C11-Novi demonstrating that it does not bind FcγR in vitro and elicits little cytokine release in vivo, while maintaining classical pharmacodynamic effects (CD3-TCR downregulation and T cell killing). Furthermore, we observed that oral administration of 2C11-Novi ameliorated progression of remitting-relapsing experimental autoimmune encephalitis in mice, significantly reducing the primary acute and subsequent relapse phase of the disease. With innovative approaches validated in two experimental models of human disease, 2C11-Novi represents a meaningful tool to conduct further mechanistic studies aiming at exploiting the immunoregulatory properties of Fc-modified anti-CD3 therapies via combination therapy using parenteral or oral routes of administration.