声波驻波场中颗粒聚合特征模拟

该文在两相流动的理论框架下,建立驻波声-流场中颗粒的运动模型,研究流体和颗粒的物性参数以及超声驻波的声学参数对颗粒声波聚合运动的影响;研究结果表明,驻波场中颗粒聚合现象发生是有条件的,凝聚点不一定在声压节处,可能有一个偏差,驻波的频率、流体和颗粒密度、颗粒半径和时均声能密度对颗粒聚合的时间、凝聚点偏移都有影响;研究结果对声波聚合运动机理的认识和微尺度细颗粒处理设备的设计具有现实意义。     

Single‐Molecule Imaging Reveals that Small Amyloid‐β1–42 Oligomers Interact with the Cellular Prion Protein (PrPC)

Oligomers of the amyloid‐β peptide (Aβ) play a central role in the pathogenesis of Alzheimer’s disease and have been suggested to induce neurotoxicity by binding to a plethora of cell‐surface receptors. However, the heterogeneous mixtures of oligomers of varying sizes and conformations formed by Aβ42 have obscured the nature of the oligomeric species that bind to a given receptor. Here, we have used single‐molecule imaging to characterize Aβ42 oligomers (oAβ42) and to confirm the controversial interaction of oAβ42 with the cellular prion protein (PrP^C) on live neuronal cells. Our results show that, at nanomolar concentrations, oAβ42 interacts with PrP^C and that the species bound to PrP^C are predominantly small oligomers (dimers and trimers). Single‐molecule biophysical studies can thus aid in deciphering the mechanisms that underlie receptor‐mediated oAβ‐induced neurotoxicity, and ultimately facilitate the discovery of novel inhibitors of these pathways.     

The Constituents of Roots and Stems of Illigera luzonensis and Their Anti-Platelet Aggregation Effects

Phytochemical investigation of the roots and stems of Illigera luzonensis afforded two new aporphine alkaloids (1) and (2), one new bisdehydroaporphine alkaloid (3), and one new benzenoid (4), along with 28 known structures. The structures of new compounds were elucidated by spectral and MS analysis. Among the isolated compounds, (1) and (4–13) were subjected into the examination for their inhibitory effects on the aggregation of washed rabbit platelets.     

Characterization of aggregation factors and associated compounds from the argentine ant,Iridomyrmex humilis

(Z)-9-Hexadecenal (I), 13-(1-methylpropyl)tridecanolide (II), and (Z)-10-nonadecene-2-one (IV) have been characterized from a lipid fraction of the total extract ofI. humilis. Glycerides of normal fatty acids constitute the bulk of the lipid fraction. Compound I, a general aggregation factor ofI. humilis, is a constituent of the ventral gland secretion. Actinidine has been characterized from the pyrazine-containing fraction of the total extract.     

Aggregation-induced Phosphorescence Enhancement in IrIII Complexes

Transition metal complexes that efficiently emit from an excited state with formally triplet character are an appealing class of compounds. However, they typically suffer from severe quenching, e. g. triplet-triplet annihilation, in aggregated phase that often hampers their use in the solid-state. Nonetheless, an intriguing effect, namely aggregation-induced phosphorescence enhancement, has been sometimes observed, but clear elucidation of the mechanisms underlying this phenomenon is far from trivial. Nowadays, cyclometalated Ir^III emitters play a leading role due to their outstanding features. Aiming at a rationalization of the AIPE effect, an overview of the different classes of Ir^III emitters displaying enhancement of the emission upon aggregation will be herein provided along with their potential applications. Their photophysical properties will be discussed jointly with their X-ray structural analysis. Ir^III complexes represent the largest family of AIPE-active compounds to date.     

The Importance of N186 in the Alpha-1-Antitrypsin Shutter Region Is Revealed by the Novel Bologna Deficiency Variant

Alpha-1-antitrypsin (AAT) deficiency causes pulmonary disease due to decreased levels of circulating AAT and consequently unbalanced protease activity in the lungs. Deposition of specific AAT variants, such as the common Z AAT, within hepatocytes may also result in liver disease. These deposits are comprised of ordered polymers of AAT formed by an inter-molecular domain swap. The discovery and characterization of rare variants of AAT and other serpins have historically played a crucial role in the dissection of the structural mechanisms leading to AAT polymer formation. Here, we report a severely deficient shutter region variant, Bologna AAT (N186Y), which was identified in five unrelated subjects with different geographical origins. We characterized the new variant by expression in cellular models in comparison with known polymerogenic AAT variants. Bologna AAT showed secretion deficiency and intracellular accumulation as detergent-insoluble polymers. Extracellular polymers were detected in both the culture media of cells expressing Bologna AAT and in the plasma of a patient homozygous for this variant. Structural modelling revealed that the mutation disrupts the hydrogen bonding network in the AAT shutter region. These data support a crucial coordinating role for asparagine 186 and the importance of this network in promoting formation of the native structure.     

Impaired 26S Proteasome Assembly Precedes Neuronal Loss in Mutant UBQLN2 Rats

Proteasomal dysfunction is known to be associated with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD). Our previous reports have shown that a mutant form of ubiquilin-2 (UBQLN2) linked to ALS/FTD leads to neurodegeneration accompanied by accumulations of the proteasome subunit Rpt1 in transgenic rats, but the precise pathogenic mechanisms of how this mutation impairs the proteasome remains to be elucidated. Here, we reveal that this UBQLN2 mutation in rats disrupted the proteasome integrity prior to neurodegeneration, that it dissociated the 26S proteasome in vitro, and that its depletion did not affect 26S proteasome assembly. During both disease progression and in an age-dependent manner, we found that proteasome subunits were translocated to the nucleus, including both of the 20S core particles (PSMA1 and PSMB7) and the 19S regulatory particles (Rpt1 and Rpn1), suggesting that defective proteasome function may result from the proteasome-subunit mislocalization. Taken together, the present data demonstrate that impaired proteasome assembly is an early event in the pathogenesis of UBQLN2-associated neurodegeneration in mutant UBQLN2 rats.     

A Combined Activity of Thrombin and P-Selectin Is Essential for Platelet Activation by Pancreatic Cancer Cells

Pancreatic cancer patients have an elevated risk of suffering from venous thrombosis. Among several risk factors that contribute to hypercoagulability of this malignancy, platelets possess a key role in the initiation of clot formation. Although single mechanisms of platelet activation are well-known in principle, combinations thereof and their potential synergy to mediate platelet activation is, in the case of pancreatic cancer, far from being clear. Applying an inhibitor screening approach using light transmission aggregometry, dense granule release, and thrombin formation assays, we provide evidence that a combination of tissue factor-induced thrombin formation by cancer cells and their platelet P-selectin binding is responsible for AsPC-1 and Capan-2 pancreatic cancer cell-mediated platelet activation. While the blockade of one of these pathways leads to a pronounced inhibition of platelet aggregation and dense granule release, the simultaneous blockade of both pathways is inevitable to prevent platelet aggregation completely and minimize ATP release. In contrast, MIA PaCa-2 pancreatic cancer cells express reduced levels of tissue factor and P-selectin ligands and thus turn out to be poor platelet activators. Consequently, a simultaneous blockade of thrombin and P-selectin binding seems to be a powerful approach, as mediated by heparin to crucially reduce the hypercoagulable state of pancreatic cancer patients.     

Promotion and Inhibition of Amyloid-β Peptide Aggregation: Molecular Dynamics Studies

Aggregates of amyloid-β (Aβ) peptides are known to be related to Alzheimer’s disease. Their aggregation is enhanced at hydrophilic–hydrophobic interfaces, such as a cell membrane surface and air-water interface, and is inhibited by polyphenols, such as myricetin and rosmarinic acid. We review molecular dynamics (MD) simulation approaches of a full-length Aβ peptide, Aβ40, and Aβ(16–22) fragments in these environments. Since these peptides have both hydrophilic and hydrophobic amino acid residues, they tend to exist at the interfaces. The high concentration of the peptides accelerates the aggregation there. In addition, Aβ40 forms a β-hairpin structure, and this structure accelerates the aggregation. We also describe the inhibition mechanism of the Aβ(16–22) aggregation by polyphenols. The aggregation of Aβ(16–22) fragments is caused mainly by the electrostatic attraction between charged amino acid residues known as Lys16 and Glu22. Since polyphenols form hydrogen bonds between their hydroxy and carboxyl groups and these charged amino acid residues, they inhibit the aggregation.