Various diseases cause over-expression of the serum amyloid A protein (SAA), which leads in some, but not all, cases to amyloidosis as a secondary disease. The response to the over-expression involves dissociation of SAA hexamer and subsequent cleavage of the released monomers, most commonly yielding fragments SAA1−76 of the full-sized SAA1−104. We report results from molecular dynamic simulations that probe the role of this cleavage for down-regulating activity and the concentration of SAA. We propose a mechanism that relies on two elements. First, the probability to assemble into hexamers is lower for the fragments than it is for the full-sized protein. Second, unlike other fragments SAA1−76 can switch between two distinct configurations. The first kind is easy to proteolyze (allowing a fast reduction of SAA concentration) but prone to aggregation, while the situation is opposite for the second kind. If the time scale for amyloid formation is longer than the one for proteolysis, the aggregation-prone species dominates. However, if environmental conditions such as low pH increase the risk of amyloid formation, the ensemble shifts toward the more protected form. We speculate that SAA amyloidosis is a failure of the switching mechanism leading to accumulation of the aggregation-prone species and subsequent amyloid formation.

In systemic amyloidosis, serum amyloid A (SAA) fibril deposits cause widespread damages to tissues and organs that eventually may lead to death. A therapeutically intervention therefore has either to dissolve these fibrils or inhibit their formation. However, only recently has the human SAA fibril structure been resolved at a resolution that is sufficient for development of drug candidates. Here, we use molecular dynamic simulations to probe the factors that modulate the stability of this fibril model. Our simulations suggest that fibril formation starts with the stacking of two misfolded monomers into metastable dimers, with the stacking depending on the N-terminal amyloidogenic regions of different chains forming anchors. The resulting dimers pack in a second step into a 2-fold two-layer tetramer that is stable enough to nucleate fibril formation. The stability of the initial dimers is enhanced under acidic conditions by a strong salt bridge and side-chain hydrogen bond network in the C-terminal cavity (residues 23-51) but is not affected by the presence of the disordered C-terminal tail.

Single cell MS (SCMS) techniques are under rapid development for molecular analysis of individual cells among heterogeneous populations. Lipids are basic cellular constituents playing essential functions in energy storage and the cellular signaling processes of cells. Unsaturated lipids are characterized with one or multiple carbon-carbon double (C═C) bonds, and they are critical for cell functions and human diseases. Characterizing unsaturated lipids in single cells allows for better understanding of metabolomic biomarkers and therapeutic targets of rare cells (e.g., cancer stem cells); however, these studies remain challenging. We developed a new technique using a micropipette needle, in which Paternò-Büchi (PB) reactions at C═C bond can be induced, to determine locations of C═C bonds in unsaturated lipids at the single-cell level. The micropipette needle is produced by combining a pulled glass capillary needle with a fused silica capillary. Cell lysis solvent and PB reagent (acetone or benzophenone) are delivered into the micropipette needle (tip size ≈ 15 um) through a fused silica capillary. The capillary needle plays multiple functions (i.e., single cell sampling probe, cell lysis container, microreactor, and nano-ESI emitter) in the experiments. Both regular (no reaction) and reactive (with PB reaction) SCMS analyses of the same cell can be achieved. C═C bond locations were determined from MS scan and MS/MS of PB products assisted by Python programs. This technique can potentially be used for other reactive SCMS studies to enhance molecular analysis for broad ranges of single cells.

Colonic amyloidosis is the result of overexpression of the serum amyloid A (SAA) protein in inflammatory bowel disease or colon cancer. Crucial for amyloid formation are the first ten N-terminal residues, which in the crystal structure are a part of a 27-residue long helix. Here, we study this 27-residue N-terminal region of SAA by a multiexchange variant of replica exchange molecular dynamics. An ensemble of configurations is observed, dominated by three motifs: the single helix of the crystal structure, a helix-turn-helix configurations, and such where the residues 14-27 are the part of a helix but the first 13 residues form an extended and disordered segment that is prone to aggregation. The single point mutation E9A shifts the equilibrium to the latter motif, indicating the importance of interactions involving this residue for the stability of the SAA protein.

Amyloid-β peptides form polymorphous amyloid fibrils are correlated with the pathogenesis of Alzheimer's disease. Recently, a new ssNMR high-resolution structure has been reported for wild-type Aβ1-42 fibrils that is characterized by a strand-turn-strand-turn-strand motif instead of the U-shape form seen in previously known wild-type Aβ-fibril structures. Analyzing molecular dynamics simulations we comment on the relative weight of the new fibril structure and present evidence that its stability depends on hydrophobic contacts involving the C-terminal residues I41 and A42, but not on the salt bridge K28-A42. We further argue that Aβ1-42 peptides with this structure may assemble in fibrils with a 2-fold packing symmetry and discuss two possible arrangements.

Flake-like carbon-based iron oxide composites were preparedviaa hydrothermal reaction, followed by a carbonization processes, and they exhibit excellent recycling durability.

Herein, we report the in situ growth of single-crystalline Ni(OH)2 nanoflakes on a Ni support by using facile hydrothermal processes. The as-prepared Ni/Ni(OH)2 sponges were well-characterized by using X-ray diffraction (XRD), SEM, TEM, and X-ray photoelectron spectroscopy (XPS) techniques. The results revealed that the nickel-skeleton-supported Ni(OH)2 rope-like aggregates were composed of numerous intercrossed single-crystal Ni(OH)2 flake-like units. The Ni/Ni(OH)2 hybrid sponges served as electrodes and displayed ultrahigh specific capacitance (SC=3247 F g(-1)) and excellent rate-capability performance, likely owing to fast electron and ion transport, sufficient Faradic redox reaction, and robust structural integrity of the Ni/Ni(OH)2 hybrid electrode. These results support the promising application of Ni(OH)2 nanoflakes as advanced pseudocapacitor materials.