julilili42/papers huggingface dataset:
P4‐300: Gene expression profiling to identify microvascular changes in Alzheimer's disease mouse models
2008-07-01

Background: Cerebral Amyloid Angiopathy (CAA) is present in most cases of Alzheimer's disease (AD), and it is characterized by the deposition of beta-amyloid (A␤) in cerebral cortical and meningeal blood vessels (Kawai M. et al., 1993), inducing degeneration of vascular cells.Semicarbazide-sensitive amine oxidase (SSAO) [E.C. 1.4.3.6] is present in vascular cells and in plasma.It metabolizes primary amines (Lyles GA., 1996) generating hydrogen peroxide (H 2 O 2 ), ammonia (NH 3 ) and the corresponding aldehyde, that contribute to the oxidative stress, advanced glycation end-product generation (Gubisne-Haberle D. et al., 2004), and beta amyloid aggregation (Chen K. et al., 2006).Furthermore in endothelial cells, SSAO is induced under inflammatory conditions (Smith D.J. et.al., 1998).We have reported that SSAO is overexpressed in cerebrovascular tissue of patients with CAA-AD, and that it colocalizes with beta-amyloid deposits (Ferrer I. et al., 2002).This over-expression correlates with high SSAO activity in plasma of severe AD patients (del Mar Hernandez M. et al., 2005).We have also described that plasma SSAO is able to induce apoptosis in vascular cells (Hernandez M. et.al., 2006).The aim of this work is to demonstrate whether A␤ is able to induce SSAO overexpression in HUVEC cells as vascular cell type.Methods: Because of the SSAO/ VAP-1 expression fenotype is lost in cultured cells, HUVEC (human umbilical vein endothelial cells) cells, were stably transfected with vector pcDNA 3.1 containing hVAP-1/SSAO.Cells were treated with A␤ 1-40 Dutch type (mutation E22Q) and/or Methylamine as SSAO substrate.Cell viability, SSAO activity and its expression were determined using specific antibodies against SSAO.Results: Herein we report that A␤ 1-40 E22Q induces the SSAO activity and expression in HUVEC cells.This increasing activity promotes oxidative stress that enhances the toxicity generated by A␤ alone.This toxicity is reverted by specific SSAO inhibitors, confirming SSAO as the responsible of such effect.Conclusions: These results allow us to postulate that deposits of A␤ in cerebrovascular tissue, induce SSAO expression that may contribute to the vascular damage associated to CAA-AD.
P1‐358: A novel, highly sensitive and specific enyzme‐linked immunosorbent assay (ELISA) for the measurement of total human alpha‐synuclein in plasma and cerebrospinal fluid
2008-07-01

Alpha-synuclein plays a role in the pathogenesis of neurodegenerative diseases, particularly synucleinopathies, such as Parkinson's disease (PD), dementia with Lewy-bodies (DLB), multiple system atrophy (MSA), and perhaps in a subset of Alzheimer's disease (AD) patients. In these diseases, alpha-synuclein is the main component of Lewy bodies, Lewy neurites or glial cytoplasmic inclusions. Similar to amyloid-beta, alpha-synuclein is found in CSF and plasma and can form toxic soluble intermediates, such as oligomers or protofibrils when reaching critical concentrations. These conformers may play a pivotal pathophysiological role in early stages of neurodegeneration. In addition, increased concentrations of alpha-synuclein have been detected in alpha-synuclein gene multiplications, which are associated with PD or DLB. Therefore, it is important to be able to reliably measure total alpha-synuclein concentrations not only in CSF, but also plasma, which has been difficult (van Geel et al. 2008). A highly specific and sensitive sandwich ELISA for the measurement of alpha-synuclein concentration in plasma and CSF was developed using mono- and polyclonal antibodies. The ELISA could reliably and specifically measure total concentrations of human alpha-synuclein not only in CSF but also plasma. The assay was highly reproducible and sensitive, showing an interassay variation <10 % and sensitivity <1 ng/ml. No cross-reactivity with beta-synuclein was observed. The recovery of added recombinant alpha-synuclein to plasma and CSF was greater than 95 %. Importantly, linear dilution of plasma and CSF yielded a proportional decrease of alpha-synuclein levels, and in healthy individuals, measured concentrations were within a narrow range. In addition, compared to monomer, equimolar oligomeric alpha-synuclein preparations showed no decreased protein concentration, which has been observed in ELISAs measuring amyloid-beta. This ELISA seems to be a valuable tool for the accurate measurement of small concentration differences of total human alpha-synuclein in plasma and CSF. This is a prerequisite for exploring alpha-synuclein as a potential biomarker for neurodegenerative diseases as well as for monitoring protein levels in disease-modifying treatment approaches targeting alpha-synuclein. In addition, this ELISA might be useful to assess the potential preclinical risk profile for a developing synucleinopathy in previously unaffected individuals.
P1‐456: Inverse association between amyloid‐beta 1–42 and SDF‐1 plasma levels in healthy older adults
2008-07-01

The role of amyloid-beta 1–42 in plasma is still not well understood. The chemokine stromal cell-derived factor 1 (SDF-1) controls many aspects of bone marrow-derived stem cell functions and has been associated with neurogenesis as well with recruitment of brain resident and non-resident circulating cells towards sites of lesion in the central nervous system (CNS). Disrupting this line of chemokine-mediated intercellular communication may contribute to the pathogenesis of Alzheimer‘s disease (AD). In this study, we examined in 20 healthy older adults (12 males, 8 females, mean age 69.6±11.6 years, mean MMSE score 28.3±1.5) amyloid-beta 1–42 and SDF-1 plasma levels by ELISA. As main result, we found a significant inverse correlation between amyloid-beta 1–42 and SDF-1 plasma levels (r=-0.552; p=0.012). Our findings indicate that amyloid-beta 1–42 in plasma may contribute to a deficient regenerative hematopoietic brain support, which might have important implications for pathogenesis of AD.
Plant sterols: cardiovascular risk factors?1
2008-07-01

Abstract Plant sterols are commonly used as cholesterol-lowering nutriceuticals. In subjects who regularly consume plant sterol enriched functional foods, plasma plant sterol concentration is modestly increased. Sitosterolemia, a very rare genetic disorder, is characterized by xanthomas and up to 100-fold elevation of plasma plant sterols. Because patients with sitosterolemia are at high risk to develop severe premature coronary artery disease, even modestly increased plasma plant sterols are suggested to be atherogenic. Thus, there is no consensus on the question if cardiovascular risk can be reduced by the use of plant sterol margarines. In addition to their efficacy to decrease plasma cholesterol, plant sterols together with other non-cholesterol sterols are important for the investigation of cholesterol metabolism. Analyzing plasma non-cholesterol sterols cholesterol absorption from the intestine and endogenous cholesterol biosynthesis can be estimated. The present review offers an overview of the topic “Plant Sterols”. In particular, the role of plant sterols and cholesterol metabolism in atherogenesis is discussed. We focus on cholesterol metabolism, sitosterolemia, and the use of plant sterols as cholesterol-lowering agents. Furthermore, the significance of plasma plant sterol measurement is explained.
P1‐035: Exogenous induction of Abeta‐amyloidosis: Peripheral and stainless‐steel‐wire inoculations
2008-07-01

Key pathologic characteristics of Alzheimer's disease (AD) are massive cerebral accumulation of amyloid, composed of fibrillar aggregates of the amyloid-beta peptide (Aβ), and intracellular accumulation of abnormally phosphorylated tau protein associated with widespread neurodegeneration. The misfolding and aggregation of these proteins in the pathogenesis of AD is well-established, but little is known about how protein aggregation is initiated in vivo. We have recently shown that intracerebral injection of dilute extracts from the brains of humans with AD or from aged amyloid precursor protein (APP) transgenic (tg) mice induces cerebral β-amyloidosis and associated pathology in young APP tg mice in a time- and concentration-dependent manner (Meyer-Luehmann et al., Science 313: 1781, 2006). As these observations are reminiscent of prion diseases, we investigated whether β-amyloidosis can be induced via peripheral inoculation routes. Since prion diseases can also be transmitted intracerebrally via contaminated steel material such as surgical instruments, we additionally studied this potential route of Aβ-seeding. APP23 tg mice (4–5 mo of age) were used as a model system to assess induction of Aβ-amyloidosis. The following routes of peripheral inoculation were investigated: oral, intraperitoneal, intravenous, intraocular and intranasal. Additionally, stainless-steel wires, previously coated with Aβ-rich brain extract, were implanted intracerebrally. Mice were analyzed 4–8 months later. None of the peripheral application routes yielded detectable induction of cerebral β-amyloidosis. In contrast, intracerebral implantation of Aβ-extract-coated wires was sufficient to induce β-amyloidosis in the vicinity of the steel wire, whereas wires coated with brain extract from a wildtype mouse did not induce Aβ deposition in the host. No evidence was found that Aβ-amyloidosis can be induced by the peripheral administration of Aβ-rich extracts. However, amyloid-induction via intracerebrally implanted stainless-steel wires coated with Aβ-rich brain extracts raises the possibility that contaminated surgical instruments are a potential source of Aβ seeds and induction of cerebral β-amyloidosis. A study investigating the effects of standard disinfection methods for surgical instruments on preventing the Aβ-seeding potential is currently ongoing.
Number filter for matter waves
2008-07-02

In current Bose-Einstein condensate experiments, the shot-to-shot variation of atom number fluctuates up to 10%. In here, we present a procedure to suppress such fluctuations by using a nonlinear p-pi-pbar matter wave interferometer for a Bose-Einstein condensate with two internal states and a high beam-splitter asymmetry (p, pbar not-equal 0.5). We analyze the situation for an inhomogeneous trap within the Gross-Pitaevskii mean-field theory, as well as a quantum mechanical Josephson model, which addresses complementary aspects of the problem and agrees well otherwise.
ChemInform Abstract: Crystal Structure of Ce3Ni2(BN)2N and Magnetic Behavior of (CeNi(BN))2(CeN)x with x = 0, 1.
2008-07-04

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Stimulus Dependence of the Action of Small‐Molecule Inhibitors in the CD3/CD28 Signalling Network
2008-07-05

Abstract Cells in the body are exposed simultaneously to a multitude of various signals. Inside a cell, molecular signalling networks integrate this information into a physiologically meaningful response. Interestingly, in the cellular testing of drug candidates, this complexity is largely ignored. Compounds are tested for cells that are challenged with one stimulus only. The activation of T lymphocytes through engagement of the T cell receptor (TCR)–CD3 complex and CD28 coreceptor is a prominent example for a cellular response that depends on the integration of signals. We investigated the cellular response characteristics of this network at different strengths of receptor and coreceptor activation. A novel cellular microarray‐based approach, in which various combinations of antibodies directed against the CD3 complex and CD28 were spotted, was employed for analysing the stimulus dependence of activation of the transcription factor NFAT and actin reorganisation. For both responses, quantitative differences in inhibitor activity were observed. Remarkably, for IL‐2 expression, which was detected by standard ELISA, low doses of the Src‐family kinase inhibitor PP2 strongly potentiated IL‐2 expression at high‐level, but not at low‐level, CD28 co‐engagement. Therefore, for a physiologically highly relevant signalling network, the cellular response might vary qualitatively with only quantitative variations of a stimulus. This level of complexity should be considered in early cellular drug testing.
The sugar porter gene family of Laccaria bicolor: function in ectomycorrhizal symbiosis and soil‐growing hyphae
2008-07-06

Formation of ectomycorrhizas, a symbiosis with fine roots of woody plants, is one way for soil fungi to overcome carbohydrate limitation in forest ecosystems. Fifteen potential hexose transporter proteins, of which 10 group within three clusters, are encoded in the genome of the ectomycorrhizal model fungus Laccaria bicolor. For 14 of them, transcripts were detectable. When grown in liquid culture, carbon starvation resulted in at least twofold higher transcript abundances for seven genes. Temporarily elevated transcript abundance after sugar addition was observed for three genes. Compared with the extraradical mycelium, ectomycorrhiza formation resulted in a strongly enhanced expression of six genes, of which four revealed their highest observed transcript abundances in symbiosis. A function as hexose importer was proven for three of them. Only three genes, of which just one was expressed at a considerable level, revealed a reduced transcript content in mycorrhizas. From gene expression patterns and import kinetics, the L. bicolor hexose transporters could be divided into two groups: those responsible for uptake of carbohydrates by soil-growing hyphae, for improved carbon nutrition, and to reduce nutrient uptake competition by other soil microorganisms; and those responsible for efficient hexose uptake at the plant-fungus interface.
Impaired Regulation of Brain Mitochondria by Extramitochondrial Ca2+ in Transgenic Huntington Disease Rats
2008-07-08

Huntington disease (HD) is characterized by polyglutamine expansions of huntingtin (htt), but the underlying pathomechanisms have remained unclear. We studied brain mitochondria of transgenic HD rats with 51 glutamine repeats (htt(51Q)), modeling the adult form of HD. Ca(free)(2+) up to 2 mum activated state 3 respiration of wild type mitochondria with glutamate/malate or pyruvate/malate as substrates. Ca(free)(2+) above 2 mum inhibited respiration via cyclosporin A-dependent permeability transition (PT). Ruthenium red, an inhibitor of the mitochondrial Ca(2+) uniporter, did not affect the Ca(2+)-dependent activation of respiration but reduced Ca(2+)-induced inhibition. Thus, Ca(2+) activation was mediated exclusively by extramitochondrial Ca(2+), whereas inhibition was promoted also by intramitochondrial Ca(2+). In contrast, htt(51Q) mitochondria showed a deficient state 3 respiration, a lower sensitivity to Ca(2+) activation, and a higher susceptibility to Ca(2+)-dependent inhibition. Furthermore htt(51Q) mitochondria exhibited a diminished membrane potential stability in response to Ca(2+), lower capacities and rates of Ca(2+) accumulation, and a decreased Ca(2+) threshold for PT in a substrate-independent but cyclosporin A-sensitive manner. Compared with wild type, Ca(2+)-induced inhibition of respiration of htt(51Q) mitochondria was less sensitive to ruthenium red, indicating the involvement of extramitochondrial Ca(2+). In conclusion, we demonstrate a novel mechanism of mitochondrial regulation by extramitochondrial Ca(2+). We suggest that specific regulatory Ca(2+) binding sites on the mitochondrial surface, e.g. the glutamate/aspartate carrier (aralar), mediate this regulation. Interactions between htt(51Q) and distinct targets such as aralar and/or the PT pore may underlie mitochondrial dysregulation leading to energetic depression, cell death, and tissue atrophy in HD.
Manual Stimulation of the Suprahyoid-Sublingual Region Diminishes Polynnervation of the Motor Endplates and Improves Recovery of Function After Hypoglossal Nerve Injury in Rats
2008-07-08

Background. Using the rat facial nerve axotomy model, the authors recently showed that manual stimulation of denervated whiskerpad muscles reduced the posttransectional polyinnervation at the neuromuscular junctions and promoted full recovery of vibrissal whisking. Objective. Prompted by implications for rehabilitation therapy, the authors examined whether manual stimulation of denervated supra- and infrahyoid muscles would also improve recovery after unilateral lesion on the hypoglossal nerve. Methods. Adult rats underwent transection of the right hypoglossal nerve. Half of the animals received no postoperative treatment, and the other half were subjected to daily manual stimulation of the suprahyoid/sublingual region for 2 months. Recovery was assessed by measuring the angle of tongue-tip deviation from the midline, degree of collateral axonal branching at the lesion site (counts after retrograde labeling with 2 fluorescent dyes), synaptic input to the hypoglossal motoneurons using synaptophysin immunocytochemistry, tongue-muscles motor representation in the cerebral cortex after c-Fos immunocytochemistry, and portion of polyinnervated neuromuscular junctions. Results. In animals receiving manual stimulation, the tongue-tip deviation was 37.0 ± 49.37°, whereas values in control nonstimulated rats were significantly higher (50.1 ± 9.01°; P &lt; .05; mean ± SD). Improved recovery was not associated with reduced collateral axonal branching; there were also no differences in tongue-muscles representation in the motor cortex. However, manual stimulation restored the total synaptic input to levels in intact animals and reduced the proportion of polyinnervated neuromuscular junctions compared with nonstimulated animals. Conclusion. The data show that manual stimulation of denervated muscles improves functional outcome following peripheral nerve injury. This suggests immediate potential for enhancing clinical rehabilitation strategies.
Mature cerebellar teratoma in adulthood
2008-07-08

Extragonadal teratomas in adulthood are exceptionally rare and usually not located within the cerebellum. We here report on a 66‐year‐old male patient clinically presenting with chronic occipital headache and episodes of severe vertigo. Neuroradiological investigations revealed a hemorrhagic tumor mass in the cerebellar vermis which was surgically removed and histologically diagnosed as mature teratoma. Hence, the presented case is extraordinary with regard to age, late clinical onset of symptoms and cerebellar location. Late clinical manifestation of the tumor in this case is probably due to an acute late‐onset hemorrhage within the tumor.
Tax Overpayments, Tax Evasion, and Book‐Tax Differences
2008-07-08

Abstract A strictly risk‐averse manager makes joint decisions on a firm's tax payments and book profit declarations according to accounting standards. It is analyzed how the incentives to overpay or evade taxes and to inflate book profits are influenced by (1) the composition of the manager's remuneration, (2) the ability to control the manager's actions, (3) the costs of making untruthful profit declarations, and (4) the tax rate. If the firm's owner or the government take into account these effects when pursuing their own objectives, the changes in tax payments and book profit declarations become theoretically more ambiguous.
The clinical impact of pharmacogenetics on the treatment of epilepsy
2008-07-09

Summary Drug treatment of epilepsy is characterized by unpredictability of efficacy, adverse drug reactions, and optimal doses in individual patients, which, at least in part, is a consequence of genetic variation. Since genetic variability in drug metabolism was reported to affect the treatment with phenytoin more than 25 years ago, the ultimate goal of pharmacogenetics is to use the genetic makeup of an individual to predict drug response and efficacy, as well as potential adverse drug events. However, determining the practical relevance of pharmacogenetic variants remains difficult, in part because of problems with study design and replication. This article reviews the published work with particular emphasis on pharmacogenetic alterations that may affect efficacy, tolerability, and safety of antiepileptic drugs (AEDs), including variation in genes encoding drug target (SCN1A), drug transport (ABCB1), drug metabolizing (CYP2C9, CYP2C19), and human leucocyte antigen (HLA) proteins. Although the current studies associating particular genes and their variants with seizure control or adverse events have inherent weaknesses and have not provided unifying conclusions, several results, for example that Asian patients with a particular HLA allele, HLA‐B*1502, are at a higher risk for Stevens‐Johnson syndrome when using carbamazepine, are helpful to increase our knowledge how genetic variation affects the treatment of epilepsy. Although genetic testing raises ethical and social issues, a better understanding of the genetic influences on epilepsy outcome is key to developing the much needed new therapeutic strategies for individuals with epilepsy.
Compound-Specific Factors Influencing Sorption Nonlinearity in Natural Organic Matter
2008-07-09

Nonlinear sorption by natural organic matter may have a significant impact on the behavior of organic contaminants in soils and sediments. This study presents a molecular probe approach based on linear solvation energy relationships (LSERs) to identify and quantify the molecular interactions causing concentration-dependent sorption and proposes estimation methods for sorption nonlinearities. Sorption isotherms ranging over concentrations of more than 4 orders of magnitude were determined in batch systems for 23 and 16 chemically diverse probe compounds in a lignite sample and a peat soil, respectively. Each sorbent showed characteristic nonlinear sorption with Freundlich exponents (1/n) being 0.7-1. The LSER-based analysis revealed that the strength of nonspecific interactions did not vary with concentration for both sorbents. In lignite, specific interactions did not affect sorption nonlinearity either, suggesting that compound-independent factors of lignite were responsible for the nonlinear sorption. In the peat soil, by contrast, the specific interactions related to the solute polarizability/dipolarity parameter (S) decreased with increasing concentration. Consequently, compounds of higher S values were more susceptible to nonlinear sorption in the peat soil. Phenol probes have shown that hydrogen bond donating properties of sorbate compounds have a substantial impact on the overall strength of sorption with organic matter, but no significant influence on sorption nonlinearity. Heterocyclic aromatic compounds appear to undergo additional interactions that are not accounted for by the LSER. These additional interactions considerably enhance both sorption capacity and nonlinearity.