A Chronic Longitudinal Characterization of Neurobehavioral and Neuropathological Cognitive Impairment in a Mouse Model of Gulf War Agent Exposure.

Gulf War Illness (GWI) is a chronic multisymptom illness with a central nervous system component that includes memory impairment as well as neurological and musculoskeletal deficits. Previous studies have shown that in the First Persian Gulf War conflict (1990-1991) exposure to Gulf War (GW) agents, such as pyridostigmine bromide (PB) and permethrin (PER), were key contributors to the etiology of GWI. For this study, we used our previously established mouse model of GW agent exposure (10 days PB+PER) and undertook an extensive lifelong neurobehavioral characterization of the mice from 11 days to 22.

Plasma Lipidomic Profiling in a Military Population of Mild Traumatic Brain Injury and Post-Traumatic Stress Disorder with Apolipoprotein E ɛ4-Dependent Effect.

In the military population, there is high comorbidity between mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) due to the inherent risk of psychological trauma associated with combat. These disorders present with long-term neurological dysfunction and remain difficult to diagnose due to their comorbidity and overlapping clinical presentation. Therefore, we performed cross-sectional analysis of blood samples from demographically matched soldiers (total, n = 120) with mTBI, PTSD, and mTBI+PTSD and those who were considered cognitively and psychologically normal.

Gulf War agent exposure causes impairment of long-term memory formation and neuropathological changes in a mouse model of Gulf War Illness.

Gulf War Illness (GWI) is a chronic multisymptom illness with a central nervous system component such as memory deficits, neurological, and musculoskeletal problems. There are ample data that demonstrate that exposure to Gulf War (GW) agents, such as pyridostigmine bromide (PB) and pesticides such as permethrin (PER), were key contributors to the etiology of GWI post deployment to the Persian GW. In the current study, we examined the consequences of acute (10 days) exposure to PB and PER in C57BL6 mice.

Complement protective epitopes and CD55-microtubule complexes facilitate the invasion and intracellular persistence of uropathogenic Escherichia coli.

Background:  Escherichia coli-bearing Dr-adhesins (Dr+ E. coli) cause chronic pyelonephritis in pregnant women and animal models. This chronic renal infection correlates with the capacity of bacteria to invade epithelial cells expressing CD55.

Proteomic CNS profile of delayed cognitive impairment in mice exposed to Gulf War agents.

Gulf War Illness (GWI) is a chronic multisymptom condition with a central nervous system (CNS) component, for which there is no treatment available. It is now believed that the combined exposure to Gulf War (GW) agents, including pyridostigmine bromide (PB) and pesticides, such as permethrin (PER), was a key contributor to the etiology of GWI. In this study, a proteomic approach was used to characterize the biomolecular disturbances that accompany neurobehavioral and neuropathological changes associated with combined exposure to PB and PER.

Identification of plasma biomarkers of TBI outcome using proteomic approaches in an APOE mouse model.

The current lack of diagnostic and prognostic biomarkers for traumatic brain injury (TBI) confounds treatment and management of patients and is of increasing concern as the TBI population grows. We have generated plasma proteomic profiles from mice receiving TBI by controlled cortical impact at either 1.3 mm or 1.

Impaired orthotopic glioma growth and vascularization in transgenic mouse models of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia among the aging population and is characterized pathologically by the progressive intracerebral accumulation of beta-amyloid (Abeta) peptides and neurofibrillary tangles. The level of proangiogenic growth factors and inflammatory mediators with proangiogenic activity is known to be elevated in AD brains which has led to the supposition that the cerebrovasculature of AD patients is in a proangiogenic state. However, angiogenesis depends on the balance between proangiogenic and antiangiogenic factors and the brains of AD patients also show an accumulation of endostatin and Abeta peptides which have been shown to be antiangiogenic.

A 3D-QSAR model based screen for dihydropyridine-like compound library to identify inhibitors of amyloid beta (Aβ) production.

Abnormal accumulation of amyloid beta peptide (Aβ) is one of the hallmarks of Alzheimer's disease progression. Practical limitations such as cost , poor hit rates and a lack of well characterized targets are a major bottle neck in the in vitro screening of a large number of chemical libraries and profiling them to identify Aβ inhibitors. We used a limited set of 1,4 dihydropyridine (DHP)-like compounds from our model set (MS) of 24 compounds which inhibit Aβ as a training set and built 3D-QSAR (Three-dimensional Quantitative Structure-Activity Relationship) models using the Phase program (SchrÖdinger, USA).

Alzheimer's beta-amyloid peptide blocks vascular endothelial growth factor mediated signaling via direct interaction with VEGFR-2.

Beta-amyloid peptides (Abeta) are the major constituents of senile plaques and cerebrovascular deposits in the brains of Alzheimer's disease patients. We have shown previously that soluble forms of Abeta are anti-angiogenic both in vitro and in vivo. However, the mechanism of the anti-angiogenic activity of Abeta peptides is unclear.

A novel physico-chemical property based model for studying the effects of mutation on the aggregation of peptides.

Macromolecular events like protein aggregation are complex processes involving physico-chemical properties of their constituting residues. In this study, we used 5-dimensional physico-chemical property (PCP-descriptors) descriptors of amino acids, derived from 237 physico-chemical properties, to develop linear (LM) and neural network (NM) based regression models. We demonstrate their prediction performance in log values of aggregation rates (psi) for 15 human muscle acyl-phosphatase (AcP) mutants.

Diagnostic utility of APOE, soluble CD40, CD40L, and Abeta1-40 levels in plasma in Alzheimer's disease.

A continuous inflammatory state is associated with Alzheimer's disease (AD) evidenced by an increase in proinflammatory cytokines around beta-amyloid (Abeta) deposits. In addition, functional loss of CD40L is shown to result in diminished Amyloid precursor proton (APP) processing and microglial activation, supporting a prominent role of CD40-CD40L in AD etiology. We therefore hypothesize that a peripheral increase in Abeta may result in corresponding increase of sCD40 and sCD40L further contributing to AD pathogenesis.

Potent anti-angiogenic motifs within the Alzheimer beta-amyloid peptide.

Abeta peptides are the major constituents of senile plaques and cerebrovascular deposits in the brains of patients with Alzheimer's disease. We have shown previously that Abeta1-40 and Abeta1-42 peptides are potently anti-angiogenic both in vitro and in vivo. The current study characterizes important sequences within the Abeta peptide that are required to exert its anti-angiogenic activity.

The influence of diagnosis, intra- and inter-person variability on serum and plasma Abeta levels.

Evidence suggests that high peripheral beta-amyloid (Abeta)(1-40) levels and low ratios of Abeta(1-42)/Abeta(1-40) are associated with increased risk for Alzheimer's disease (AD). In this cross-sectional design, serum and plasma samples from 67 AD patients and 146 controls (similar in age and gender) were evaluated using Abeta(1-40) and Abeta(1-42) ELISA. Coefficient of variance was calculated for intra- and inter-person variability of Abeta(1-40) and Abeta(1-42).

Genomic analysis of response to traumatic brain injury in a mouse model of Alzheimer's disease (APPsw).

Numerous studies have shown that the beta-amyloid peptide (Abeta) or beta-amyloid deposits impact many processes that can contribute to neurodegeneration, ranging from immune and inflammatory processes to cell death and apoptosis, processes characteristic of both Alzheimer's disease and head injury. Human and animal studies of traumatic brain injury (TBI) have shown that Abeta production is increased acutely following injury, and there is evidence for increased amyloid deposition and risk for Alzheimer's disease following TBI. Given the poorer outcome after injury observed both in transgenic mice overproducing Abeta, as well as in humans subjected to repetitive head injury, one may conclude that the presence of elevated brain levels of Abeta, whether endogenous or as a consequence of previous injury, exacerbates many of the deleterious processes triggered by TBI.

APDbase: Amino acid Physico-chemical properties Database.

Unlabelled: Physico-chemical properties of amino acids can be used to study protein sequence profiles, folding and function. We collated 242 properties for the 20 naturally occurring amino acids and created a dataset. The dataset is available as a database named APDbase( Amino acid Physico-chemical properties Data base).

CliniProteus: A flexible clinical trials information management system.

Unlabelled: Clinical trials involve multi-site heterogeneous data generation with complex data input-formats and forms. The data should be captured and queried in an integrated fashion to facilitate further analysis. Electronic case-report forms (eCRF) are gaining popularity since it allows capture of clinical information in a rapid manner.

Cocaine induced inflammatory response in human neuronal progenitor cells.

We have employed a genomic approach in homogenous cell culture to investigate the fundamental transcriptional responses which occur in neurons over time as a consequence of a single 30-min exposure to cocaine. Data from 24 Affymetrix microarrays, representing eight treatment groups, were analyzed by GeneChip Operating Software and then further mined by hierarchical clustering, anova, and Ingenuity Pathway Analysis software to examine known molecular pathways impacted by the observed transcriptional changes. For each time point under investigation, the data sets of genes exhibiting altered expression in treated cells compared with control were interrogated with a specific focus on differential expression of genes involved in immunomodulation and inflammation.

Genomic regulation after CD40 stimulation in microglia: relevance to Alzheimer's disease.

Key pathological processes in Alzheimer's disease (AD) include the accumulation of amyloid beta peptide (Abeta) which, in excess, triggers pathological cascades including widespread inflammation, partly reflected by chronic microglial activation. It has previously been suggested that CD40/CD40L interaction promotes AD like pathology in transgenic mice. Thus, amyloid burden, gliosis and hyperphosphorylation of tau are all reduced in transgenic models of AD lacking functional CD40L.

Structural basis for epitope sharing between group 1 allergens of cedar pollen.

The group 1 allergens are a major cause of cedar pollen hypersensitivity in several geographic areas. Allergens from several taxa have been shown to cross-react. The goal of these studies was to compare the structural features of the shared and unique epitopes of the group 1 allergen from mountain cedar (Jun a 1) and Japanese cedar (Cry j 1).

Model of Alzheimer's disease amyloid-beta peptide based on a RNA binding protein.

Although Alzheimer's Abeta peptide has been shown to form beta-sheet structure, a high-resolution molecular structure is still unavailable to date. A search for a sequence neighbor using Abeta(10-42) as the query in the Protein Data-Bank (PDB) revealed that an RNA binding protein, AF-Sm1 from Archaeoglobus fulgidus (PDB entry: 1i4k chain Z), shared 36% identical residues. Using AF-Sm1 as a template, we built a molecular model of Abeta(10-42) by applying comparative modeling methods.

Anti-angiogenic activity of the mutant Dutch A(beta) peptide on human brain microvascular endothelial cells.

Cerebral amyloid angiopathy is a common pathological feature of patients with Alzheimer's disease (AD) and it is also the hallmark of individuals with a rare autosomal dominant disorder known as hereditary cerebral hemorrhage with amyloidosis-Dutch type. We have shown previously that wild type A(beta) peptides are anti-angiogenic both in vitro and in vivo and could contribute to the compromised cerebrovascular architecture observed in AD. In the present study, we investigated the potential anti-angiogenic activity of the Dutch A(beta)(1-40) (E22Q) peptide.

Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer's disease.

BACKGROUND: Inflammation is believed to play an important role in the pathology of Alzheimer's disease (AD) and cytokine production is a key pathologic event in the progression of inflammatory cascades. The current study characterizes the cytokine expression profile in the brain of two transgenic mouse models of AD (TgAPPsw and PS1/APPsw) and explores the correlations between cytokine production and the level of soluble and insoluble forms of Abeta. METHODS: Organotypic brain slice cultures from 15-month-old mice (TgAPPsw, PS1/APPsw and control littermates) were established and multiple cytokine levels were analyzed using the Bio-plex multiple cytokine assay system.

Identification of critical heterodimer protein interface parameters by multi-dimensional scaling in euclidian space.

Protein subunit dimers are either homodimers (consisting of identical polypeptides) or heterodimers (consisting of different polypeptides). Protein dimers are involved in several cellular processes and an understanding of their molecular principle in complexations (subunit-subunit interaction) is essential. This is generally studied using 3D structures of homodimers and heterodimers determined by X-ray crystallography.

Molego-based definition of the architecture and specificity of metal-binding sites.

Decomposing proteins into "molegos," building blocks that are conserved in sequence and 3D-structure, can identify functional elements. To demonstrate the specificity of the decomposition method, the PCPMer program suite was used to numerically define physical chemical property motifs corresponding to the molegos that make up the metal-containing active sites of three distinct enzyme families, from the dimetallic phosphatases, DNase 1 related nucleases/phosphatases, and dioxygenases. All three superfamilies bind metal ions in a beta-strand core region but differ in the number and type of ions needed for activity.