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Protein signatures of centenarians and their offspring suggest centenarians age slower than other humans
No full textUsing samples from the New England Centenarian Study (NECS), we sought to characterize the serum proteome of 77 centenarians, 82 centenarians' offspring, and 65 age-matched controls of the offspring (mean ages: 105, 80, and 79 years). We identified 1312 proteins that significantly differ between centenarians and their offspring and controls (FDR < 1%), and two different protein signatures that predict longer survival in centenarians and in younger people. By comparing the centenarian signature with 2 independent proteomic studies of aging, we replicated the association of 484 proteins of aging and we identified two serum protein signatures that are specific of extreme old age. The data suggest that centenarians acquire similar aging signatures as seen in younger cohorts that have short survival periods, suggesting that they do not escape normal aging markers, but rather acquire them much later than usual. For example, centenarian signatures are significantly enriched for senescence-associated secretory phenotypes, consistent with those seen with younger aged individuals, and from this finding, we provide a new list of serum proteins that can be used to measure cellular senescence. Protein co-expression network analysis suggests that a small number of biological drivers may regulate aging and extreme longevity, and that changes in gene regulation may be important to reach extreme old age. This centenarian study thus provides additional signatures that can be used to measure aging and provides specific circulating biomarkers of healthy aging and longevity, suggesting potential mechanisms that could help prolong health and support longevity
Neutrophils require SKAP2 for reactive oxygen species production following C-type lectin and stimulation.
No full textSignaling cascades converting the recognition of pathogens to efficient inflammatory responses by neutrophils are critical for host survival. SKAP2, an adaptor protein, is required for reactive oxygen species (ROS) generation following neutrophil stimulation by integrins, formyl peptide receptors, and for host defense against the Gram-negative bacterial pathogens, and . Using neutrophils from murine HoxB8-immortalized progenitors, we show that SKAP2 in neutrophils is crucial for maximal ROS response to purified C-type lectin receptor agonists and to the fungal pathogens, and , and for robust killing of . Inside-out signaling to integrin and Syk phosphorylation occurred independently of SKAP2 after infection. However, Pyk2, ERK1/2, and p38 phosphorylation were significantly reduced after infection with and in neutrophils. These data demonstrate the importance of SKAP2 in ROS generation and host defense beyond antibacterial immunity to include CLRs and specie
International harmonization of nomenclature and diagnostic criteria (INHAND): Non-proliferative and proliferative lesions of the non-human primate (M. fascicularis)
No full textThe INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions Project (www.toxpath.org/inhand. asp) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in most tissues and organs from the nonhuman primate used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. Relevant infectious and parasitic lesions are included as well. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists
Full therapeutic IgG1 antibody complex with FcγIIa/b and FcγIIIa receptors examined using all-atom molecular dynamics simulations
No full textABSTRACT
Monoclonal antibodies are emerging as the predominant type of biological drug. Their inherent advantages such as target specificity, long serum half-life and lower toxicity profile ensure that pharmaceutical companies will continue develop this technology ([1]). We have performed molecular dynamics simulations of full therapeutic antibody- Fcγ receptor complexes to obtain insights into their interactions with various FcγRs to discover possible future improvements of mAbs. Affinity of bound monoclonal antibodies was assessed using two different free energy calculation methods the MM/GBSA and the Bennet acceptance ration (BAR)[2,3]. Obtained results for MM/GBSA binding affinity between different FcγRs were in agreement with the reference experiment. G236A mutation was assessed but we could not establish an increase in affinity. BAR results show increased affinity across all FcγRs for the mutated mAb, but this result is not in line with the data in reference article. Novel interactions between the Fab region of the antibody and the FcγRs were discovered which may hold possible leads for future improvement of antibodies
Prostaglandin D2 drives tissue remodelling functions and prostaglandin D2 autocrine production in type 2 cytotoxic T cells
No full textHuman type 2 cytotoxic T (Tc2) cells are enriched in severe eosinophilic asthma and can contribute to airway eosinophilia. Prostaglandin D2 (PGD2) and its receptor prostaglandin D2 receptor 2 (DP2) play important roles in Tc2 cell activation including migration, cytokine production and survival. In this study, we revealed novel functions of the PGD2/DP2 axis in Tc2 cells to induce pro-tissue remodelling effects and immunoglobulin E (IgE)-independent PGD2 autocrine production. PGD2 upregulated the expression of tissue remodelling genes in Tc2 cells, which enhanced fibroblast proliferation and protein production required for tissue repairing and myofibroblast differentiation. PGD2 stimulated Tc2 cells to produce PGD2 using the routine PGD2 synthesis pathway, which also contributed to T cell receptor-dependent PGD2 production in Tc2 cells. Using fevipiprant, a specific DP2 antagonist, we demonstrated that competitive inhibition of DP2 not only completely blocked the cell migration, adhesion, proinflammatory cytokine production and survival of Tc2 cells triggered by PGD2, but also attenuated pro-tissue remodelling effects and autocrine PGD2 production in Tc2 induced by PGD2 and other stimulators. These findings further confirmed the anti-inflammatory effect of fevipiprant and provided a better understanding on the role of Tc2 cells in the pathogenesis of asthma
Predicting Biotransformations with a Molecular Transformer
No full textThe use of enzymes for organic synthesis allows for simplified, more economical and selective synthetic routes not accessible to conventional reagents. However, predicting whether a particular molecule might undergo a specific enzyme transformation is very difficult. Here we exploited recent advances in computer assisted synthetic planning (CASP) by considering the molecular transformer, which is a sequence-to-sequence machine learning model that can be trained to predict the products of organic transformations, including their stereochemistry, from the structure of reactants and reagents. We used multi-task transfer learning to train the molecular transformer with one million reactions from the US Patent Office (USPTO) database as a source of general chemistry knowledge combined with 32,000 enzymatic transformations, each one annotated with a text description of the enzyme. We show that the resulting Enzymatic Transformer model predicts the products formed from a given substrate and enzyme with remarkable accuracy, including typical kinetic resolution processes
EndoBind - Real-time detection of endogenous protein-protein interactions
No full textWe present two methods to detect the interaction of ectopically expressed (RT-Bind) or endogenously tagged (EndoBind) proteins of interest. Both approaches provide temporal evaluation of dimer over an extended duration. Using examples of the NRF2-KEAP1 and the CRAF-KRAS_G12V interaction, we demonstrate that our method allows for the detection of signal for more than 2 days after substrate addition, allowing for continuous monitoring of the protein-protein interaction in real time
Hydrogen Bond Acceptor Propensity of different Fluorine Atom Types: An Analysis of Experimentally- and Computationally-derived Parameters
No full textThe propensity of organic fluorine acting as a weak hydrogen bond acceptor (HBA) in intermolecular and intramolecular interactions has been the subject of many experimental and theoretical studies often reaching different conclusions. Over the last few years new and stronger evidences have emerged for the direct involvement of fluorine in weak hydrogen bond (HB) formation. However, not all the fluorine atom types can act as weak HBA. In this work we have analyzed the differential HBA propensity of various types of fluorine atoms with a particular emphasis for the different types of alkyl fluorides. This is carried out by evaluating ab initio computed parameters, experimental 19 F NMR chemical shifts and small molecule crystallographic structures (extracted from the CSD database). According to this analysis, shielded (with reference to the 19 F NMR chemical shift) mono-fluorinated alkyl motifs display the highest HBA propensity in agreement with solution studies. Although much weaker than other well characterized HB complexes, the fragile HBs formed by these fluorinated motifs have important implications for the chemical-physical and structural properties of the molecules, chemical reactions and protein/ligand recognition
Multi-Species Phenotypic Screening across Disease Models of Mucolipidosis Type IV
No full textInvertebrate model organisms (mainly the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster) are valuable tools to bridge the gap between traditional in vitro discovery and preclinical animal models. Invertebrate model organisms are poised to serve as better disease models than 2D cellular monocultures for drug discovery. A strength of model organisms is the opportunity to probe conserved biology such as lysosomal function and offers an attractive approach to exploring autophagy in a natural setting. Invertebrate models are however, not without challenges, such as poor tissue penetration and confidence in a compound’s mechanism of action. To confront these challenges we took advantage of the Novartis’ mechanism-of-action box (MoA Box), a chemogenetic library of well-annotated and drug-like chemical probes. Curious as to how the MoA Box, comprised of chemical probes optimized for mammalian targets, would fair in an invertebrate setting we screened the MoA Box across three different model systems of the lysosomal storage disease Mucolipidosis Type IV (MLIV). MLIV is caused by mutations in the lysosomal transient receptor potential ion channel mucolipin-1 (TRPML1) resulting in hyperacidic lysosomes and disregulated autophagy. We leveraged the overlap of screening hits to prioritize efforts and validate that CDK inhibition could resolve several phenotypes of MLIV disease in patient fibroblasts
Discovery, X-ray structure and CPP-conjugation enabled uptake of p53/MDM2 macrocyclic peptide inhibitors
No full textMouse double minute 2 homolog (MDM2, Hdm2) is an important negative regulator of the tumor suppressor p53. Using a mRNA based display technique to screen a library of >1012 in vitro-translated cyclic peptides, we have identified a macrocyclic ligand that shows picomolar potency on MDM2. X-ray crystallography reveals a novel binding mode utilizing a unique pharmacophore to occupy the Phe/Trp/Leu pockets on MDM2. Conjugation of a cyclic cell-penetrating peptide (cCPP) to the initially non cell-permeable ligand enables cellular uptake and a pharmacodynamic response in SJSA-1 cells. The demonstrated enhanced intracellular availability of cyclic peptides that are identified by a display technology exemplifies a process for the application of intracellular tools for drug discovery projects