Proteomics analysis of plasma for potential biomarkers in the diagnosis of Alzheimer's disease

The objective of this study was to search for biological markers associated with Alzheimer's disease (AD). Plasma specimens obtained from ten pathologically diagnosed AD patients and ten non-demented (ND) control subjects were analyzed by a combination of 2-DE and MS. This strategy allowed us to identify six plasma proteins (alpha-1-antitrypsin, vitamin D-binding protein, inter-alpha-trypsin inhibitor family heavy chain-related protein, apolipoprotein J precursor, cAMP-dependent protein kinase catalytic subunit alpha 1, and an orf) whose 2-DE spot densities were different between the AD and ND groups. Due to their involvements in AD amyloid plaque formation, the plasma concentrations of alpha-1-antitrypsin and apolipoprotein J were further validated using either ELISA or Western blot. The results revealed that the plasma levels of alpha-1-antitrypsin in AD were higher than those of controls, confirming the 2-DE findings. However, no difference in total apolipoprotein J concentration was observed between the AD and ND groups. Considering the difference in resolving power to differentially quantitate protein isoforms provided by 2-DE and Western blot, 2-DE analysis combined with MS protein identification offers distinctive advantages when a disease-related protein isoform-specific variance is investigated.     

Proteomic analysis of early urinary biomarkers of renal changes in type 2 diabetic patients

Diabetic nephropathy (DN) is a complication associated with diabetes, leading to end-stage renal disease (ESRD). Despite significant progress in understanding DN, the cellular mechanisms leading to the renal damage are incompletely defined. In this study, with the aim to identify urine biomarkers for the early renal alterations in type 2 diabetes mellitus (T2D), we performed urinary proteomic analysis of 10 normoalbuminuric patients with T2D, 12 patients with type 2 DN (T2DN), and 12 healthy subjects. Proteins were separated by 2-DE and identified with ESI-Q-TOF MS/MS. Comparing the patients proteomic profiles with those of normal subjects, we identified 11 gradually differently changed proteins. The decreased proteins were the prostatic acid phosphatase precursor, the ribonuclease and the kallikrein-3. Eight proteins were progressively increased in both patients groups: transthyretin precursor, Ig κ chain C region, Ig κ chain V-II region Cum, Ig κ-chain V-III region SIE, carbonic anhydrase 1, plasma retinol-binding protein, β-2-microglobulin precursor, β-2-glycoprotein 1. The proteomic analysis allowed us to identify several increased urinary proteins, not only in T2DN but also in T2D patients in which the microalbuminuria was in the normal range. These patterns of urinary proteins might represent a potential tool for a better understanding of diabetic renal damage.     

Redox proteomics identification of 4‐hydroxynonenal‐modified brain proteins in Alzheimer's disease: Role of lipid peroxidation in Alzheimer's disease pathogenesis

Numerous studies have shown that neuronal lipids are highly susceptible to oxidative stress including in those brain areas directly involved in the neurodegenerative process of Alzheimer's disease (AD). Lipid peroxidation directly damages membranes and also generates a number of secondary biologically active products (toxic aldehydes)that are capable of easily attacking lipids, proteins, and DNA. Accumulating evidence has demonstrated regionally increased brain lipid peroxidation in patients with AD; however, extensive studies on specific targets of lipid peroxidation‐induced damage are still missing. The present study represents a further step in understanding the relationship between oxidative modification of protein and neuronal death associated with AD. We used a proteomics approach to determine specific targets of lipid peroxidation in AD brain, both in hippocampus and inferior parietal lobule, by coupling immunochemical detection of 4‐hydroxynonenal‐bound proteins with 2‐D polyacrylamide gel electrophoresis and MS analysis. We identified 4‐hydroxynonenal‐bound proteins in the hippocampus and inferior parietal lobule brain regions of subjects with AD. The identified proteins play different biological functions including energy metabolism, antioxidant system, and structural proteins, thus impairing multiple molecular pathways. Our results provide further evidence for the role of lipid peroxidation in the pathogenesis of AD.     

Proteomic analysis of pericardial effusion: Characteristics of tuberculosis-related proteins

The aim of this study has been designed to identify the tuberculosis (TB)-related proteins in pericardial effusion by proteomic approaches. TB is one of the major infectious diseases causing pericardial effusion. This study details protein profiles in pericardial effusion from three TB patients and three heart failure patients. Pericardial effusions were analyzed using 2-DE combined with the nano-HPLC-ESI-MS/MS. Eleven protein spots with differential expression in pericardial effusion were identified between the two groups of TB and heart failure patients (the control group). Seven protein spots were upregulated and four were downregulated. The composition of the pericardial effusion proteome may reflect the pathophysiological conditions affecting the progression of tuberculous pericarditis. The proteins in the tuberculous pericardial effusion with differential expression may serve as new and direct indicators of drug treatment. A possible conclusion is indicated that fibrinogen may play an important role for fibrin assembly in tuberculous pericardial effusion.     

Proteomic identification and early validation of complement 1 inhibitor and pigment epithelium-derived factor: Two novel biomarkers of Alzheimer's disease in human plasma

Emerging disease modifying therapeutic strategies for Alzheimer's disease (AD) have generated a critical need for biomarkers of early stage disease. Here, we describe the identification and assessment of a number of candidate biomarkers in patients with mild to moderate probable AD. Plasma from 47 probable Alzheimer's patients and 47 matched controls were analysed by proteomics to define a significant number of proteins whose expression appeared to be associated with AD. These were compared to a similar proteomic comparison of a mouse transgenic model of amyloidosis, which showed encouraging overlap with the human data. From these studies a prioritised list of 31 proteins were then analysed by immunoassay and/or functional assay in the same human cohort to verify the changes observed. Eight proteins continued to show significance by either immunoassay or functional assay in the human plasma and these were tested in a further set of 100 probable AD patients and 100 controls from the original cohort. From our data it appeared that two proteins, serpin F1 (pigment epithelium-derived factor) and complement C1 inhibitor are down-regulated in plasma from AD patients.     

Proteomic profiling of cancer of the gingivo-buccal complex: Identification of new differentially expressed markers

Tobacco-related oral cancer is the most common cancer among Indian males, gingivo-buccal complex (GBC) being the most affected subsite due to the habit of chewing tobacco. Proteins from the lysates of microdissected normal and transformed epithelium from clinically well-characterized tissue samples of the GBC were separated by two-dimensional gel electrophoresis to identify differentially expressed proteins. Eleven protein spots showed differential expression, which could withstand the stringency of statistical evaluation. The observations were confirmed with additional tissues. Nine of these differentiators were identified by MS as lactate dehydrogenase B, α-enolase, prohibitin, cathepsin D, apolipoprotein A-I, tumor protein translationally controlled-1, an SFN family protein, 14-3-3σ and tropomyosin. Cluster analysis indicated that these proteins, as a coexpressed set, could distinguish normal and transformed epithelium. Functionally, these differentiator molecules are relevant to the pathways and processes that have been previously implicated in oral carcinogenesis and could therefore be investigated further as a panel of markers for management of cancer of the GBC.     

A closed‐form analysis of printed wide‐slot antennas

A mixed‐potential integral equation is formulated for the wide‐slot antenna, fed by a microstrip line, and solved using the method of moments (MoM). Our MoM implementation makes use of the Ge and Esselle (G–E) closed‐form Green's functions for layered substrates. The key advantage of this new approach is that all the MoM matrix elements are evaluated using closed‐form expressions, without any numerical integration, and with minimal approximations. Hence a significant increase in computational efficiency has been achieved while maintaining the high precision of the full‐wave MoM. The numerical results obtained from the new method are compared with measured results, and good agreements are observed. © 2003 Wiley Periodicals, Inc. Int J RF and Microwave CAE 13, 389–397, 2003.     

Pilot proteomic analysis of cerebrospinal fluid in Alzheimer's disease

Proteomic analysis of cerebrospinal fluid (CSF) holds great promise in understanding the progression of neurodegenerative diseases, including Alzheimer's disease (AD). As one of the primary reservoirs of neuronal biomolecules, CSF provides a window into the biochemical and cellular aspects of the neurological environment. CSF can be drawn from living participants allowing the potential alignment of clinical changes with these biochemical markers. Using cutting-edge mass spectrometry technologies, we perform a streamlined proteomic analysis of CSF. We quantify greater than 700 proteins across 10 pairs of age- and sex-matched participants in approximately one hour of analysis time each. Using the paired participant study structure, we identify a small group of biologically relevant proteins that show substantial changes in abundance between cognitive normal and AD participants, which were then analyzed at the peptide level using parallel reaction monitoring experiments. Our findings suggest the utility of fractionating a single sample and using matching to increase proteomic depth in cerebrospinal fluid, as well as the potential power of an expanded study.     

Thymosin β4 is differentially expressed in the cerebrospinal fluid of Creutzfeldt‐Jakob disease patients: a MALDI‐TOF MS protein profiling study

MALDI‐TOF protein profiling analysis permits the detection of peptides and small proteins in complex protein mixtures with great accuracy. We applied this analysis to cerebrospinal fluid (CSF) from 15 patients affected by Creutzfeldt‐Jakob disease (CJD). We compared the levels of the normalized ion signals of 11 sporadic and 4 genetic CJD forms with those from ten healthy control subjects and eight non‐CJD relapsing‐remitting multiple sclerosis patients. In so doing, we detected 61 differentially expressed ion signals in CJD samples compared to controls. Among the 61 signals, 3 signals had significantly increased levels with high statistical significance (p <0.0001) and were located at 3238.3 m/z, 4963.7 m/z, and 8565.3 m/z. We characterized the 5.0 and 8.6 kDa proteins as thymosin β4 N‐acetylated and free ubiquitin, respectively, while the 3.2‐kDa peptide remained uncharacterized. Although elevated ubiquitin levels have previously been described in CJD, we have demonstrated for the first time the involvement of thymosin β4 in a neurodegenerative disease. To support the validity of thymosin β4 levels obtained by MALDI‐TOF analysis, an independent enzyme immunoassay analysis was performed. Moreover, a validation cohort consisting of CSF from three CJD patients, five healthy subjects, and six non‐CJD relapsing‐remitting multiple sclerosis patients was analyzed in a similar way, yielding superimposable results. We propose that thymosin β4 is a potential new candidate marker for the ante mortem diagnosis of CJD disease.     

Wideband description of the finite‐ground coplanar waveguide‐type structures with discontinuities

Some mathematical models are proposed to accurately describe the frequency‐dependent series conductance and susceptance of the discontinuities in various finite‐ground capacitive series‐connected coplanar waveguides (FGCPWs). These models can predict the wideband self‐resonance characteristics in the air gap regions. Also, it is pointed out that the Heinrich's equation is applicable to compute the per‐unit‐length parameters of the uniform FGCPWs, though it was rarely used in the past 10 years. It is shown that Heinrich's equation can be used to capture the frequency‐dependent distributed resistance and inductance in a real chip environment. Using our proposed models with Heinrich's equation, numerical calculations are performed to show the effects of metallization surface conductivity and thickness of both capacitive and inductive series‐connected FGCPW geometries on their frequency‐dependent series resistances, series inductances and shunt capacitances. © 2007 Wiley Periodicals, Inc. Int J RF and Microwave CAE, 2007.     

The metabolic consequences of reduced habitual activities in patients with muscle pain and disease

Abstract

Activities of mitochondrial enzymes have been measured in percutaneous muscle biopsies obtained from 23 patients with non-specific muscle pains (e.g. effort syndromes and post-viral fatigue syndromes), in biopsies obtained from eight patients with McArdle's disease (myophosphorylase deficiency), an enzyme defect known to lead to muscle pain during exercise, and, for comparison, in biopsies obtained from 14 untrained controls. Exercise performance was studied during incremental cycle ergometry in six typical patients with non-specific muscle pains and in six patients with McArdle's disease. The patients in general had a lower content of mitochondria in their muscles than the controls. The patients with nonspecific pain studied during cycle ergometry could not exercise at high intensities and showed decreased endurance, tachycardia, a high degree of exercise stress and an increased dependence on glycolysis at low exercise intensities. Many of the biochemical changes during exercise and many of the symptoms of these patients could be a consequence of their reduced habitual activities. The patients with McArdle's disease also could not exercise at high intensities because of their metabolic defect. The most ‘active’ patients had a normal content of mitochondria in their muscles and performed better during cycle ergometry. Furthermore, in contrast to the others they managed to remain successful in their profession. This study appears to suggest that the physical and mental well-being of patients with muscle pain and disease could be improved by the enhancement of their habitual activity.     

Optimal Control of Forward‐Backward Stochastic Jump‐Diffusion Differential Systems with Observation Noises: Stochastic Maximum Principle

This paper is concerned with a partially observed optimal control problem for a controlled forward‐backward stochastic system with correlated noises between the system and the observation, which generalizes the result of a previous work to a jump‐diffusion system. Under some convexity assumptions, necessary and sufficient optimality conditions for such an optimal control are established in the form of Pontryagin type maximum principle in a unified way by means of duality analysis and convex variational techniques     

Proteome analysis of substantia nigra and striatal tissue in the mouse MPTP model of Parkinson's disease

The dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) replicates many of the pathological hallmarks of Parkinson's disease (PD) in mice via selective destruction of dopamine neurons of the substantia nigra and striatum. Although MPTP has been widely used to study downstream effects following the degeneration of dopaminergic neurons, the underlying mechanisms of MPTP action remain poorly understood. To determine the underlying mechanisms of MPTP action at the protein level, a 2-DE-based proteomics approach was used to evaluate the changes in protein expression in substantia nigra and striatal tissue in C57BL/6 mice after MPTP administration. We identified nine proteins that were markedly altered and are likely to be involved in mitochondrial function, heat shock protein activity, and which contribute enzyme activities for energy metabolism and protein degradation.     

Investigation of the firing voltage in a shadow‐mask PDP

Abstract— A numerical method was used to investigate the firing characteristics of the discharge cell in an AC shadow‐mask PDP (SM‐PDP). The firing voltages for the various discharge paths in the addressing and sustaining periods were calculated, and the effects of the metal barrier rib and the dielectric layer in the discharge cell on the firing characteristics were studied. Furthermore, the advantages of the SM‐PDP in terms of the firing characteristics will be discussed.     

Finite‐Time Stabilization of Coupled Systems on Networks with Time‐Varying Delays via Periodically Intermittent Control

In this paper, finite‐time stabilization of coupled systems on networks with time‐varying delays (CSNTDs) via periodically intermittent control is studied. Both delayed subsystems and delayed couplings are considered; the self‐delays of different subsystems in delayed couplings are not identical. A periodically intermittent controller is designed to stabilize CSNTDs within finite time, and the stabilization duration is closely related to the topological structures of networks. Furthermore, two sufficient criteria are developed to ensure CSNTDs under periodically intermittent control can be stabilized within finite time by using an approach that combines the Lyapunov method with Kirchhoff's Matrix Tree Theorem. Then finite‐time stabilization of coupled oscillators with time‐varying delays is given as a practical application and sufficient criteria is obtained. Finally, a numerical simulation is proposed to support our results and show the effectiveness of the controller.     

Decomposition of meta‐frontier inefficiency in the two‐stage network directional distance function with quasi‐fixed inputs

Few studies have considered the quasi‐fixed inputs that have an impact on hospitality. The number of guest rooms and the area of the catering department of international tourist hotels are shown to be constant in Taiwan from 2008 to 2009. Therefore, this paper proposes the use of the two‐stage network directional distance function with quasi‐fixed inputs to explore the productive and service efficiencies of tourist hotel formats (chained versus independent). In addition, a new approach is developed to decompose the technical inefficiency of the hotels within the meta‐frontier; this approach helps to identify the source of the meta‐frontier inefficiency. Demonstration of this new approach with practical data reveals that the average productive efficiency is greater than the average service efficiency for Taiwanese tourist hotels. Additionally, the causes of the overall productive inefficiency and the overall service inefficiency are mainly derived from the input excess of the productive process and the output shortfall of the service process, respectively.