julilili42/papers huggingface dataset:
Lipids modulate ligand binding to sulphonylurea receptors
2005-05-16

ATP‐sensitive K + channels (K ATP channels) are complexes of inwardly rectifying K + channels (Kir6.x) and sulphonylurea receptors (SURs). Kir6.2‐containing channels are closed by ATP binding to Kir6.2, and opened by MgADP binding to SUR. Channel activity is modulated by synthetic compounds such as the channel‐blocking sulphonylureas and the K ATP channel openers, which both act by binding to SUR. By interacting with Kir6.2, phosphatidylinositol‐4,5‐bisphosphate (PIP 2 ) and oleoyl‐coenzyme A (OCoA) decrease the ATP‐sensitivity of the channel and abolish the effect of the synthetic channel modulators. Here, we have investigated whether lipids and related compounds interfered with the binding of the sulphonylurea, glibenclamide (GBC) and of the opener, N ‐cyano‐ N ′‐(1,1‐dimethylpropyl)‐ N ′′‐3‐pyridylguanidine (P1075), to the SUR subtypes. Lipids (100–300 μ M ) inhibited binding of [ 3 H]GBC and [ 3 H]P1075 to SUR subtypes in the rank order OCoA&gt;dioleylglycerol‐succinyl‐nitriloacetic acid (DOGS‐NTA)&gt;oleate&gt;malonyl‐CoA&gt;PIP 2. OCoA inhibited radioligand binding to SUR completely, with IC 50 values ranging from 6 to 44 μ M . Inhibition was reversed by increasing the concentration of the radioligands in agreement with an essentially competitive mechanism. MgATP and coexpression with Kir6.2 decreased the potency of OCoA. DOGS‐NTA inhibited radioligand binding to SUR by 40–88%, with IC 50 values ranging from 38 to 120 μ M . Poly‐lysine increased radioligand binding to SUR by up to 30% but did not affect much the inhibition of ligand binding by OCoA and DOGS‐NTA. Radioligand binding to SUR2A but not to the other SUR subtypes was slightly (10–20%) stimulated by lipids at concentrations ∼10 × lower than required for inhibition. The data show that certain lipids, at high concentrations, interact with SUR and inhibit the binding of GBC and P1075; with SUR2A, a modest stimulation of ligand binding precedes inhibition. Regarding K ATP channel activity, these effects will be overruled by the interaction of the lipids with Kir6.2 at lower (physiological) concentrations. They are, however, of pharmacological importance and must be taken into account if high concentrations of these compounds (e.g. OCoA&gt;10 μ M ) are used to interfere with the action of sulphonylureas and openers on K ATP channel activity. British Journal of Pharmacology (2005) 145 , 907–915. doi: 10.1038/sj.bjp.0706252
Resection of residual disease in patients with metastatic gastrointestinal stromal tumors responding to treatment with imatinib
2005-05-17

Abstract Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Long‐term survival of patients with metastatic disease has only been observed in patients with completely resected disease. Recently, the tyrosine kinase inhibitor imatinib has been found to yield responses in the majority of patients with metastatic GIST suggesting improved resectability in responding patients. Combined treatment approaches including resective surgery after imatinib treatment in patients with advanced metastatic disease have rarely been explored. We report a series of 90 patients with metastatic GIST in whom treatment with imatinib enabled 12 patients with mostly recurrent and extensive disease to be considered for resection of residual disease. In 11 of these patients, complete resection could be achieved. Viable tumor cells were found in all but one resected specimens suggesting that despite favorable radiological or clinical responses, imatinib is unlikely to induce pathological complete responses. Until more mature data from prospective trials are available, these data suggest that an early aggressive surgical approach should be considered for all patients with metastatic GIST. Further trials investigating a combined surgical and pre/postoperative treatment with imatinib in patients with advanced metastatic GIST are warranted. © 2005 Wiley‐Liss, Inc.
Combinatorial microelectrochemistry: Development and evaluation of an electrochemical robotic system
2005-05-17

An electrochemical robotic system using standard microtiter plates as reaction wells for potentiostatic and galvanostatic electrosynthesis and high-throughput electroanalysis was conceived and realized using stepmotor driven positioning stages in combination with a flexible software. Electrode bundles specifically adapted to the experimental needs are accurately positioned in the wells of a microtiter plate followed by the automatic performance of sequences of electrosynthetic or electroanalytical techniques. The system allows us to work under inert-gas atmosphere, in aqueous and organic solvents, and to add or remove solutions by means of integrated syringe pumps. A specifically developed script language permits the user to perform very complex experimental sequences in the different wells of the microtiter plate. The hardware and software features of the developed electrochemical robotic system, the design of suitable electrode arrangements for electrosynthesis and electroanalytical techniques, as well as the reproducibility in aqueous and organic electrolytes are described. The performance of the system is demonstrated by redox screening of a Ru-complex library and by electrosynthesis with in situ analysis of a compound library.
Phase-Sensitive Detection of Bragg Scattering at 1D Optical Lattices
2005-05-17

We report on the observation of Bragg scattering at 1D atomic lattices. Cold atoms are confined by optical dipole forces at the antinodes of a standing wave generated by the two counterpropagating modes of a laser-driven high-finesse ring cavity. By heterodyning the Bragg-scattered light with a reference beam, we obtain detailed information on phase shifts imparted by the Bragg scattering process. Being deep in the Lamb-Dicke regime, the scattered light is not broadened by the motion of individual atoms.
Generation of RAGE‐1 and MAGE‐9 peptide‐specific cytotoxic T‐Lymphocyte lines for transfer in patients with renal cell carcinoma
2005-05-17

Abstract Renal cell carcinomas (RCCs) are supposed to be immunogenic, and several clinical trials of immunotherapy using tumor lysate‐pulsed dendritic cells (DCs) have been performed. We report on the generation of RAGE‐1 and MAGE‐9 peptide‐specific CTL lines. RAGE‐1 and MAGE‐9 are expressed in 56% and 38% of RCCs. Seven MAGE‐9‐ and 13 RAGE‐1‐derived peptides were found to be immunogenic in the context of the HLA‐A*0201 MHC. CTLs were generated by coculture with peptide‐pulsed, activated B cells, which were easily generated in great quantities and displayed functional activity for a prolonged period of time. MAGE‐9 and RAGE‐1 peptide‐specific CTL lines were strictly peptide‐specific and displayed high cytotoxic activity not only against peptide‐loaded T2 cells but also against HLA‐A*0201‐positive RCC lines, which naturally express MAGE‐9, RAGE‐1 or both. Thus, B cells are well suited as APCs for the generation of large numbers of tumor peptide‐specific CTLs for adoptive transfer. MAGE‐9 as well as RAGE‐1 may well provide suitable targets for immunotherapy of RCC. © 2005 Wiley‐Liss, Inc.
Attentional Modulation of Cortical Neuromagnetic Gamma Response to Biological Movement
2005-05-18

Processing of biological motion represented solely by a set of lights on the joints of a human body is traditionally viewed as largely independent of attention. Here, by manipulating attention-related task demands, we assess changes in the neuromagnetic cortical response to a point-light walker. Irrespective of task demands, biological motion evokes an increase in oscillatory gamma activity over the left parieto-occipital region at 80 ms post-stimulus. Only an attended walker, however, yielded further peaks over the right parietal (120 ms) and temporal (155 ms) cortices. By contrast, the magnetoencephalographic (MEG) response to an ignored walker is restricted to the left parieto-occipital region. In addition, peaks in oscillatory activity occur in response to both attended (canonical and scrambled) configurations at 180-200 ms from stimulus onset over the right fronto-temporal regions, most likely reflecting maintenance of the target configuration in working memory. For the first time, we demonstrate that the time course and topographic dynamics of oscillatory gamma activity in response to biological movement undergoes top-down influences and can be profoundly modulated by the withdrawal of attention.
Tolerance induction by bone marrow transplantation in a multiple sclerosis model
2005-05-18

Abstract Experimental autoimmune encephalomyelitis (EAE) in rats is a highly valuable model of multiple sclerosis (MS) because it mimics major hallmarks of the human disease. EAE induced with myelin-oligodendrocyte-glycoprotein (MOG) in DA rats is relapsing/remitting, and lesions in the central nervous system show inflammation, demyelination, and axonal and neuronal loss. Recently, bone marrow transplantation (BMT) was introduced as a novel strategy to treat MS, but its efficiency and the underlying mechanism are debatable. In MOG-induced EAE we found that BMT at the peak of EAE but not in the chronic phase leads to disease attenuation. In both settings, rats receiving bone marrow (BM) transplants were protected from subsequently induced relapses. These findings could be confirmed by histopathology in which rats receiving BM transplants did not have lesions compared with controls not receiving transplants. Importantly, the protective effect was achieved by allogeneic, syngeneic, and BM grafts from diseased rats. BMT resulted in increased numbers of CD4+CD25bright regulatory T cells, increased Foxp3 expression, a shift in T-cell epitope recognition, and a strong reduction of autoantibodies even after rechallenge with MOG. Thus, our results indicate potential mechanisms of how BMT may contribute to the improvement of MS and provide a rationale for its application in patients suffering from various autoimmune diseases. (Blood. 2005;106:1875-1883)
Protein microarrays for antibody profiling: Specificity and affinity determination on a chip
2005-05-19

Abstract Protein microarray technology facilitates the detection and quantification of hundreds of binding reactions in one reaction from a minute amount of sample. Proof‐of‐concept studies have shown that the set‐up of sensitive assay systems based on protein arrays is possible, however, the lack of specific capture reagents limits their use. Therefore, the generation and characterisation of capture molecules is one of the key topics for the development of protein array based systems. Recombinant antibody technologies, such as HuCAL® (human combinatorial antibody library; MorphoSys, Munich, Germany), allow the fast generation of highly specific binders to nearly any given target molecule. Although antibody libraries comprise billions of members, it is not the selection process, but the detailed characterisation of the pre‐selected monoclonal antibodies that presents the bottleneck for the production of high numbers of specific binders. In order to obtain detailed information on the properties of such antibodies, a microarray‐based method has been developed. We show that it is possible to define the specificity of recombinant Fab fragments by protein and peptide microarrays and that antibodies can be classified by binding patterns. Since the assay uses a miniaturised system for the detection of antibody‐antigen interactions, the observed binding occurs under ambient analyte conditions as defined by Ekins ( J. Pharm. Biomed. Anal. 1989, 7 , 155–168). This allows the determination of a relative affinity value for each binding event, and a ranking according to affinity is possible. The new microarray based approach has an extraordinary potential to speed up the screening process for the generation of recombinant antibodies with pre‐defined selection criteria, since it is intrinsically a high‐throughput technology.
Preoperative Magnetic Resonance Imaging-Guided Localization of 131 Breast Lesions With Modified Embolization Coils
2005-05-19

Exact MRI-guided preoperative localization of exclusively MRI-detected breast lesions by using a modified embolization coil is feasible with excellent precision. Advantages over wire localization procedures are the possibility of specimen x-ray and the independence from time and place of operation.
The long‐term course of alcoholism, 5, 10 and 16 years after treatment
2005-05-20

ABSTRACT Aims To discover the long‐term stability of drinking behaviour following an in‐patient treatment episode. Design Three follow‐up periods were used at 5, 10 and 16 years. The patients were classified as being abstinent, improved or unimproved on the basis of self‐reported drinking behaviour. Patients who could not be interviewed at follow‐up were classified as unimproved. Setting An alcohol dependence treatment programme at the University Hospital Tuebingen, Germany. Participants We were able to locate all 96 patients at the 16‐year follow‐up. Seventy were alive and 26 had died. We collected information from 59 of the 70 surviving patients. The remaining 11 patients could be located and were definitely alive. Findings Thirty‐eight of the 70 patients were abstinent, 10 were improved and 22 (including the 11 living patients without further information) were classified as unimproved. Our main finding indicates that the so‐called ‘improved drinking’ is very inconsistent over time. In contrast, the abstinent and unimproved patients were much more stable in their drinking behaviour. Conclusions This study extends our knowledge of the drinking trajectory and outcome from only a few years of follow‐up to 16 years. Complete abstinence and unimproved drinking behaviour were the most stable drinking patterns observed over the long term, confirming study results obtained primarily from English‐speaking countries.
Safety and Enhanced Immunogenicity of a Hepatitis B Core ParticlePlasmodium falciparumMalaria Vaccine Formulated in Adjuvant Montanide ISA 720 in a Phase I Trial
2005-05-20

ABSTRACT Highly purified subunit vaccines require potent adjuvants in order to elicit optimal immune responses. In a previous phase I trial, an alum formulation of ICC-1132, a malaria vaccine candidate comprising hepatitis B core (HBc) virus-like particle containing Plasmodium falciparum circumsporozoite (CS) protein epitopes, was shown to elicit Plasmodium falciparum -specific antibody and cellular responses. The present study was designed as a single-blind, escalating-dose phase I trial to evaluate the safety and immunogenicity of single intramuscular doses of ICC-1132 formulated in the more potent water-in-oil adjuvant Montanide ISA 720 (ICC-1132/ISA 720). The vaccine was safe and well tolerated, with transient injection site pain as the most frequent complaint. All vaccinees that received either 20 μg or 50 μg of ICC-1132/ISA 720 developed antiimmunogen and anti-HBc antibodies. The majority of volunteers in these two groups developed sporozoite-specific antibodies, predominantly of opsonizing immunoglobulin G subtypes. Peak titers and persistence of parasite-specific antibody following a single injection of the ISA 720 formulated vaccine were comparable to those obtained following two to three immunizations with alum-adsorbed ICC-1132. Peripheral blood mononuclear cells of ICC-1132/ISA 720 vaccinees proliferated and released cytokines (interleukin 2 and gamma interferon) when stimulated with recombinant P. falciparum CS protein, and CS-specific CD4 + T-cell lines were established from volunteers with high levels of antibodies to the repeat region. The promising results obtained with a single dose of ICC-1132 formulated in Montanide ISA 720 encourage further clinical development of this malaria vaccine candidate.
Transport theories for heavy-ion collisions in the 1AGeV regime
2005-05-23

We compare multiplicities as well as rapidity and transverse momentum\\ndistributions of protons, pions and kaons calculated within presently available\\ntransport approaches for heavy ion collisions around 1 AGeV. For this purpose,\\nthree reactions have been selected: Au+Au at 1 and 1.48 AGeV and Ni+Ni at 1.93\\nAGeV.\\n
Anisotropic flow of strange particles at RHIC
2005-05-23

Space-time picture of the anisotropic flow evolution in Au+Au collisions at BNL RHIC is studied for strange hadrons within the microscopic quark-gluon string model. The directed flow of both mesons and hyperons demonstrates wiggle structure with the universal antiflow slope at |y| < 2 for minimum bias events. This effect increases as the reaction becomes more peripheral. The development of both components of the anisotropic flow is closely related to particle freeze-out. Hadrons are emitted continuously, and different hadronic species are decoupled from the system at different times. These hadrons contribute differently to the formation and evolution of the elliptic flow, which can be decomposed onto three components: (i) flow created by hadrons emitted from the surface at the onset of the collision; (ii) flow produced by jets; (iii) hydrodynamic flow. Due to these features, the general trend in elliptic flow formation is that the earlier mesons are frozen, the weaker their elliptic flow. In contrast, baryons frozen at the end of the system evolution have stronger v2.
Vinyl or isopropenyl substituents as experimental and theoretical probes for diamagnetic anisotropies of aromatic hydrocarbons
2005-05-23

Abstract Vinyl or isopropenyl substituents can be used to indicate anisotropy effects in the surroundings of benzenoid hydrocarbons by experiments together with APUDI model and ab initio GIAO MO calculations from the difference in geminal proton splittings of the olefinic substituents. Geometry optimizations as a function of the torsional angle between substituents and aromatic planes were performed in two polarized basis sets for the HF, B3LYP and MP2 methods. Calculated splittings range between −0.70 and 0.48 ppm. Comparison with experimental 1 H NMR shifts does not lead precisely to the determination of the experimentally apparent effective torsional angle. Copyright © 2005 John Wiley &amp; Sons, Ltd.
Object-dependent and Property dependent Contents
2005-05-23

In a theory of representational or intentional states content is generally supposed to play various roles. It has to be the bearer of a truth-value, it has to determine the way a representation is about something (its mode of presentation), and finally it has to 6e used in order to give intra- and interpersonal psychological explanations. It has been argued that no unique kind of content can play all these roles. What criterion should one adopt in order to draw the dividing line? We suggest that the divide be based on ontological considerations related to the way content depends on external factors. There is a fundamental difference, we submit, between object-dependent and property-dependent contents. The requirements concerning modes of presentation as well as cognitive significance can be met by one kind of content. This content, it will appear, is property-dependent, but never object-dependent.
Glare sensitivity and professional drivers' safety: a case of rod‐cone dystrophy with negative electroretinogram
2005-05-24

Abstract. Background: To obtain a driver's licence certain requirements for visual acuity and visual field have to be fulfilled. Mesopic contrast and glare sensitivity are not regularly tested and are not crucial to passing the driving test. Case report: We report a case of a 39‐year‐old professional bus driver whose only complaint was increased glare sensitivity. After he had been involved in four traffic accidents, ophthalmological investigations revealed binocular annular scotomata and night blindness, leading to the diagnosis of rod‐cone dystrophy. Discussion: Enhanced glare sensitivity is a common complaint in elderly people or people with the beginnings of cataract but may also represent an initial symptom of a retinal disorder. It is therefore advisable for traffic safety if drivers with such complaints undergo a complete ophthalmological investigation including visual field testing.
Modified Linear Dextrins (“Acyclodextrins”) as New Chiral Selectors for the Gas‐Chromatographic Separation of Enantiomers
2005-05-25

Cyclic or acyclic: Not only modified cyclodextrins but also modified linear dextrins like the silylated (R)and acetylated (R1) maltoheptaose derivatives 1 are suitable selectors for separating racemic N-trifluoroacetyl-O-alkyl esters of α-amino acids by gas chromatography. In the example shown, racemic N-trifluoroacetylserine O-ethyl ester is resolved.
Human p53 knock-in ( hupki ) mice do not differ in liver tumor response from their counterparts with murine p53
2005-05-25

Mouse models are important tools in toxicologic research. Differences between species in pathways contributing to tumor development, however, raise the question in how far mouse models are valid for human risk assessment. One striking difference relates to the frequency of spontaneous liver cancer which is high in certain mouse strains but rather low in humans. Similarly, mutation frequencies in cancer genes are characteristically different, i.e. P53 mutations are frequent in human but very rare in murine liver tumors, whereas Ras genes are often mutated in mouse liver tumors but hardly ever in human liver cancers. Since P53 has been shown to control oncogenic RAS in human cells, we hypothesized that this function of the tumor suppressor could differ in mouse hepatocytes. To test this hypothesis, we used hupki (human p53 knock-in) mice which carry a partly humanized P53 sequence (P53KI). In this study, we report the results of the first hepatocarcinogenesis experiment with this strain of mice. Mice of the genotypes P53KI/KI, P53WT/KI and P53WT/WT were treated with N-nitrosodiethylamine at 2 weeks of age and killed 35 weeks later. The frequency of liver tumors and glucose-6-phosphatase-altered liver lesions was almost identical in all three P53 genotypes and approximately 40-50% of liver tumors showed activating mutations in codon 61 of the Ha-Ras gene independent of genotype. Moreover, only very few P53-positive lesions were observed but without nuclear localization of the protein, suggesting the absence of P53 mutations. These data suggest that the hupki allele behaves like its murine ortholog in mouse hepatocarcinogenesis.
A New family with frontotemporal dementia with intronic 10+3 splice site mutation in the tau gene: neuropathology and molecular effects
2005-05-25

Mutations in the tau gene cause familial frontotemporal dementia with parkinsonism linked to chromosome 17 characterized by filamentous tau protein deposits. Here we describe the clinical and neuropathological features of a case from a newly identified family with an intron 10+3‐splice site mutation in the tau gene. The proband presented with severe personality changes and stereotyped speech followed by parkinsonian symptoms. He died at age 56 after a disease duration of approximately 6 years. At autopsy, there was marked frontotemporal degeneration with abundant tau‐immunoreactive neuronal and glial inclusions widespread in the cortex and brainstem. RT‐PCR analysis revealed a 3.7‐fold increase of tau transcripts with exon 10, resulting in an 1.7‐fold higher expression level of 4‐repeat tau isoforms in soluble tau fractions when compared to control brains and exclusively 4‐repeat tau isoforms in the sarcosyl‐insoluble tau fractions. In accordance with the hypothesis that the overexpression leads to saturation of microtubule binding sites and an increase of unbound 4‐repeat tau isoforms which assemble into filaments, the neuronal and glial inclusions in this case were exclusively composed of 4‐repeat tau isoforms. The clinical and neuropathological data of this family are compared with results from the two other published families with the intron 10 + 3 mutation, the MSTD and the SOT 254 family.