Brain accumulation of amyloid-β (Aβ) peptides (resulting from a disrupted balance between biosynthesis and clearance) occurs during the progression of Alzheimer’s disease (AD). Aβ peptides have diverse posttranslational modifications (PTMs) that variously modulate Aβ aggregation into fibrils, but understanding the mechanistic roles of PTMs in these processes remains a challenge. Here, we chemically synthesized three homogeneously modified isoforms of Aβ (1–42) peptides bearing Tyr10 O-glycosylation, an unusual PTM initially identified from the cerebrospinal fluid samples of AD patients. We discovered that O-glycans significantly affect both the aggregation and degradation of Aβ42. By combining cryo-EM and various biochemical assays, we demonstrate that a Galβ1-3GalNAc modification redirects Aβ42 to form a new fibril polymorphic structure that is less stable and more vulnerable to Aβ-degrading enzymes (e.g., insulin-degrading enzyme). Thus, beyond showing how particular O-glycosylation modifications affect Aβ42 aggregation at the molecular level, our study provides powerful experimental tools to support further investigations about how PTMs affect Aβ42 fibril aggregation and AD-related neurotoxicity.

The access to methionine sulfoxide [Met(O)]containing proteins is particularly valuable for studying this important type of post-translational modification (PTM). However, the lack of selective in vitro oxidation methods makes it difficult to obtain homogeneous proteins with accurate and controllable incorporation of Met(O), particularly the ones with multiple methionines. Here, we report a chemical approach to synthesize methionine-oxidized human chemokine CXCL14 in a site-selective manner. The in vitro chemotaxis activities of synthetic proteins have also been evaluated. Note pubs.acs.org/joc

Safe and effective biomaterials are in urgent clinical need for tissue regeneration and bone repair. While numerous advances have been made on hydrogels promoting osteogenesis in bone formation, co-stimulation of the angiogenic pathways in this process remains to be exploited. Here, we have developed a gelatin-based blue-light-curable hydrogel system, functionalized with an angiogenic vascular endothelial growth factor (VEGF) mimetic peptide, KLTWQELYQLKYKGI (KLT), and an osteoanabolic peptide, parathyroid hormone (PTH) 1–34. We have discovered that the covalent modification of gelatin scaffold with peptides can modulate the physical properties and biological activities of the produced hydrogels. Furthermore, we have demonstrated that those two peptides orchestrate synergistically and promote bone regeneration in a rat cranial bone defect model with remarkable efficacy. This dual-peptide-functionalized hydrogel system may serve as a promising lead to functional biomaterials in bone repair and tissue engineering.

Marine derived cyclic imine toxins, portimine A and B, have attracted extensive attention owing to their intriguing chemical structure and promising anti-cancer therapeutic potential. However, access to large quantities is currently unfeasible and the molecular mechanism behind their potent activity is unknown. To address this, a scalable 15-step total synthesis of portimines is presented, which benefits from the logic used in two-phase terpenoid synthesis along with unique tactics such as exploiting ring-chain tautomerization and skeletal reorganization to minimize protecting group chemistry through “self-protection”. Critically, this total synthesis enabled a structural reassignment of portimine B and an in-depth functional evaluation of portimine A, revealing that it induces apoptosis selectively in human cancer cell lines with high potency. Finally, practical access to the portimines and analogs thereof simplified the development of photoaffinity analogs, which were used in chemical proteomic experiments to identify a primary target of portimine A as the 60S ribosomal export protein NMD3.

Abstract. Along with the development of the Internet, the information stream is experiencing an unprecedented burst. The methods of information transmission become more and more important and people receiving effective information is a hot topic in the both research and industry field. As one of the most common methods of information communication, email has its own advantages. However, spams always flood the inbox and automatic filtering is needed. This paper is going to discuss this issue from the perspective of Naive Bayes Classifier, which is one of the applications of Bayes Theorem. Concepts and process of Naive Bayes Classifier will be introduced, followed by two examples. Discussion with Machine Learning is made in the last section. Naive Bayes Classifier has been proved to be surprisingly effective, with the limitation of the interdependence among attributes which are usually email words or phrases.