Mechanisms of Hybrid Oligomer Formation in the Pathogenesis of Combined Alzheimer's and Parkinson's Diseases

Background: Misfolding and pathological aggregation of neuronal proteins has been proposed to play a critical role in the pathogenesis of neurodegenerative disorders. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are frequent neurodegenerative diseases of the aging population. While progressive accumulation of amyloid b protein (Ab) oligomers has been identified as one of the central toxic events in AD, accumulation of a-synuclein (a-syn) resulting in the formation of oligomers and protofibrils has been linked to PD and Lewy body Disease (LBD). We have recently shown that Ab promotes a-syn aggregation and toxic conversion in vivo, suggesting that abnormal interactions between misfolded proteins might contribute to disease pathogenesis. However the molecular characteristics and consequences of these interactions are not completely clear. Methodology/Principal Findings: In order to understand the molecular mechanisms involved in potential Ab/a-syn interactions, immunoblot, molecular modeling, and in vitro studies with a-syn and Ab were performed. We showed in vivo in the brains of patients with AD/PD and in transgenic mice, Ab and a-synuclein co-immunoprecipitate and form complexes. Molecular modeling and simulations showed that Ab binds a-syn monomers, homodimers, and trimers, forming hybrid ringlike pentamers. Interactions occurred between the N-terminus of Ab and the N-terminus and C-terminus of a-syn. Interacting a-syn and Ab dimers that dock on the membrane incorporated additional a-syn molecules, leading to th

Effect of agitation on the efficiency of enzymatic hydrolysis of highly concentrated media of extruded corn starch

The influence of the mixing factor and its intensity was investigated at the stage of developing a technology for processing highly concentrated hydrolysates (50% solids) of extruded corn starch. The starch was extruded using a twin-screw extruder at a temperature of 185 °C and a pressure at the die of 2 MPa. Extruded substrate was hydrolyzed with enzyme preparations of ?-amylase and glucoamylase for 4 hours with different stirring modes. The significance of the stirring speed on the degree of hydrolysis of extruded starch, especially in the first 2 hours of enzymatic treatment, has been established. As a result of 4-hour exposure, the dextrose equivalent of the hydrolyzate incubated without stirring was 52.2. Dextrose equivalent of the hydrolysates stirred at speed of 100, 200 and 500 rpm was 54.5, 59.3, and 59.8, respectively. The study of rheological properties showed that the dynamic viscosity of a medium without stirring significantly differed from the viscosity of a medium with stirring throughout the entire hydrolysis period. As a result, the dynamic viscosity of the sample without stirring and with stirring decreased from 3 Pa?s to 0.35 Pa?s and from 2.5-2.8 Pa?s to 0.145-0.221 Pa?s, respectively. An double increase of the glucoamylase dosage made the mixing factor after 4 hours of hydrolysis insignificant and increased the dextrose equivalent value by 18-35%. The dextrose equivalents of samples without stirring and with stirring at a frequency of 200 rpm were 70 and 71, respectively. But in the first 2 hours of hydrolysis, the stirring factor for samples with an increased dosage of glucoamylase was also statistically significant. The study showed that hydrolysis of highly concentrated media of extruded starch under the condition of high-quality homogenization with the enzymes provides a high degree of bioconversion without the requirement for continuous mixing

Coherent Expression Chromosome Cluster Analysis Reveals Differential Regulatory Functions of Amino-Terminal and Distal Parathyroid Hormone-Related Protein Domains in Prostate Carcinoma

Parathyroid hormone-related protein (PTHrP) has a number of cancer-related actions. While best known for causing hypercalcemia of malignancy, it also has effects on cancer cell growth, apoptosis, and angiogenesis. Studying the actions of PTHrP in human cancer is complicated because there are three isoforms and many derived peptides. Several peptides are biologically active at known or presumed cell surface receptors; in addition, the PTHrP-derived molecules can exert effects at the cell nucleus. To address this complexity, we studied gene expression in a DU 145 prostate cancer cell line that was stably transfected with control vector, PTHrP 1-173 and PTHrP 33-173. With this model, regulatory effects of the amino-terminal portion of PTHrP would result only from transduction with the full-length molecule, while effects pertaining to distal sequences would be evident with either construct. Analysis of the expression profiles by microarrays demonstrated nonoverlapping groups of differentially expressed genes. Amino-terminal PTHrP affected groups of genes involved in apoptosis, prostaglandin and sex steroid metabolism, cell-matrix interactions, and cell differentiation, while PTHrP 33-173 caused substantial increases in MHC class I antigen expression. This work demonstrates the distinct biological actions of the amino-terminus compared to distal mid-molecule or carboxy-terminal sequences of PTHrP in prostate carcinoma cells and provides targets for further study of the malignant process

Coherent Expression Chromosome Cluster Analysis Reveals Differential Regulatory Functions of Amino-Terminal and Distal Parathyroid Hormone-Related Protein Domains in Prostate Carcinoma

Parathyroid hormone-related protein (PTHrP) has a number of cancer-related actions. While best known for causing hypercalcemia of malignancy, it also has effects on cancer cell growth, apoptosis, and angiogenesis. Studying the actions of PTHrP in human cancer is complicated because there are three isoforms and many derived peptides. Several peptides are biologically active at known or presumed cell surface receptors; in addition, the PTHrP-derived molecules can exert effects at the cell nucleus. To address this complexity, we studied gene expression in a DU 145 prostate cancer cell line that was stably transfected with control vector, PTHrP 1-173 and PTHrP 33-173. With this model, regulatory effects of the amino-terminal portion of PTHrP would result only from transduction with the full-length molecule, while effects pertaining to distal sequences would be evident with either construct. Analysis of the expression profiles by microarrays demonstrated nonoverlapping groups of differentially expressed genes. Aminoterminal PTHrP affected groups of genes involved in apoptosis, prostaglandin and sex steroid metabolism, cell-matrix interactions, and cell differentiation, while PTHrP 33-173 caused substantial increases in MHC class I antigen expression. This work demonstrates the distinct biological actions of the amino-terminus compared to distal mid-molecule or carboxy-terminal sequences of PTHrP in prostate carcinoma cells and provides targets for further study of the malignant process

Cereal extrusion with steam recuperation process

The extrusion process advantage of agricultural raw materials processing into food and feed over traditional technologies is the high specific productivity, energy efficiency and versatility of use. The presence of a large number of control factors and influence on the raw materials quality, such as operating parameters and structural elements, make extrusion a difficult reproducible process when scaling or moving from one installation to another. But this aspect is the reason for the maximum flexibility of extrusion systems and the possibility of their continuous improvement. One of the ways for the extrusion technology development is the improvement of equipment and design solutions in the field of energy saving. Investigations of the thermoplastic extrusion process of wheat grinding with the application of the recovery of steam heat generated by a special configuration of screw elements and its degassing with the feeding into the processed material were carried out in the work. The modernized extruder Werner & Phleiderer Continua 37, supplemented by a developed recuperative unit and a steam line, was used to achieve this goal. An assessment of changes in energy consumption during steam recovery was carried out. The physicochemical properties of the experimental and control samples of wheat grain extrudates obtained under various operating conditions were investigated and determined. It was found out that the steam recovery mode is a statistically significant reason for increasing the humidity of the extruded product from 3.8 to 5.0 bulk density - by 15% relative to the mode without recovery. A decrease in the explosion coefficient and the water-holding capacity of the extrudates during operation in the regenerative mode of extrusion was noticed. The presented method with additional thermal effects on the processed raw materials allows us to expand the technological capabilities of the process of thermoplastic extrusion in obtaining products of various functional and technological purposes

Dimethyl-​silyl-​bridged-​1-​substituted-​2-​indenyl metallocene complexes for olefin polymerization, polymerization of olefins and to polymers

The metallocene complex is dimethylsilylene-​bridged-​1-​substituted-​2-​indenyl ligand of Ti, Zr or Hf. The metallocene complex catalyst is for prepg. polyolefins, a process for polymg. olefins and to polymers prepd. by the catalyst system