Clostridium difficile is an anaerobic, gram‐positive bacterium and a common gastrointestinal pathogen. Two virulence factors of C. difficile known to mediate disease are Toxin A (TcdA) and Toxin B (TcdB). These toxins are glucosyltransferase‐containing multi‐domain proteins that enter the host's epithelial cells by binding to cell–surface carbohydrate antigens. Once inside the cell, the toxins undergo a pH‐induced conformational change and release their glucosyltransferase domains (GTD), leading to disruption of cell cytoskeleton integrity. Existing treatments for C. difficile such as fecal transplants and antibiotics have not proven highly effective. Passive immunotherapy with inhibitory antibodies recognizing TcdA and TcdB is a promising alternative. Recombinant Camelidae antibodies (V H Hs) that neutralize the toxins' function have been identified. TcdA's receptor‐binding domain has seven repetitive elements known to interact with cell‐surface carbohydrates. The V H H antibodies A20.1 and A26.8, which are known to neutralize TcdA, do not block the carbohydrate‐binding site on TcdA directly, suggesting a novel mode of TcdA inhibition. The Ashbury College MSOE Center for BioMolecular Modeling SMART Team used 3‐D modelling and printing technology to examine the structure‐function relationships of a TcdA fragment (TcdA‐A2) simultaneously bound to A20.1 and A26.8. The structure shows that the V H Hs target distinct epitopes on the toxin and neutralize TcdA by a novel mechanism independent of the carbohydrate binding sites, providing a rationale for designing highly potent biparatopic TcdA‐neutralizing antibodies. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
Inhibitor of apoptosis proteins (IAPs) prevents programmed cell death by interfering with the activation of caspases that cleave cytoskeleton fibres. X‐chromosome‐linked inhibitor of apoptosis protein (XIAP) is believed to be the most potent natural apoptosis inhibitor in the IAP family, as it effectively suppresses both intrinsic and extrinsic pathways of apoptosis. XIAP is characterized by three Baculoviral IAP Repeat (BIR) domains, a ubiquitin‐associated (UBA) domain, and one Really Interesting New Gene (RING) domain. The BIR‐2 domain binds with caspases 3 and 7, whereas the BIR‐3 domain binds with caspase 9. XIAP is closely associated with several neurodegenerative disorders, including Alzheimer’s Disease (AD), which affects over 44 million individuals worldwide. AD is characterized by the formation of ß‐amyloid plaques and tau tangles, which obstruct nutrients from reaching the nerve cells and result in cell death. Caspases cleave tau proteins that consequently collapse into tangles. Since XIAP prevents the activation of caspases, a lower level of XIAP leads to the acceleration of nerve cell death and cognitive impairment. While XIAP is unable to arrest tangle formation, an increase of XIAP will lessen cognitive decline. Support or Funding Information The Ashbury MSOE Center for BioMolecular Modeling SMART Team used 3D modelling and printing technology to examine the effects of the XIAP BIR‐3 and BIR‐2 domains on the caspases that interact with the Alzheimer’s pathway.
The paper presents the transcript of the discussions during the first scientonomy workshop that took place on February 25, 2023. The participants discussed and voted on several modifications concerning the scientonomic workflow (Sciento-2019-0007, Sciento-2019-0001, Sciento-2019-0002, Sciento-2019-0003, Sciento-2019-0004, Sciento-2019-0005, Sciento-2019-0006) as well as two modifications concerning the idea of scientificity as an epistemic stance (Sciento-2018-0013) and the respective law of theory demarcation (Sciento-2018-0014).
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