julilili42/papers huggingface dataset:
Analysis of cGKI inhibition by Rp-cGMP analogs
2007-07-01

Although it is well established that cGMP has important (patho-)physiological functions, the downstream mediators of cGMP signalling are not well understood. The cGMP-dependent protein kinase type I (cGKI) is an attractive candidate receptor for cGMP. A common approach to distinguish between cGKI-dependent and cGKI-independent cGMP effects is the use of pharmacological inhibitors. However, it is increasingly recognized that some of these drugs, such as KT5823, may be less specific than previously thought or may not at all inhibit cGKI activity in intact cells. The Rp-cGMP analogs are reported to inhibit cGKI by binding to the cGMP-binding sites. In this study, we have analysed the effects of two popular RpcGMP analogs, Rp-8-Br-PET-cGMPS and Rp-8-pCPTcGMPS, on basal and cGMP/cGKI-stimulated growth of vascular smooth muscle cells. Surprisingly, neither compound showed a clear inhibition of cell growth and cGKI activity in intact cells as monitored by growth assays and phosphorylation of vasodilator-stimulated phosphoprotein (VASP), respectively. In vitro kinase assays with purified cGKI demonstrated that both Rp-cGMP analogs are partial agonists for cGKI rather than antagonists (see Figure 1). Thus, it appears difficult to interpret data obtained from experiments with Rp-8-Br-PET-cGMPS and Rp-8pCPT-cGMPS. Both compounds should be used with caution as inhibitors. from 3rd International Conference on cGMP Generators, Effectors and Therapeutic Implications Dresden, Germany. 15–17 June 2007
Activation of the cGMP/cGKI signalling pathway in primary murine VSMCs accelerates growth
2007-07-01

The endogenous signaling molecule nitric oxide (NO) exerts many of its actions via the cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase type I (cGKI) pathway. Recently, the analysis of an in vivo mouse model for atherosclerosis suggested that activation of cGKI in vascular smooth muscle cells (VSMCs) promotes the phenotypic modulation of medial VSMCs and, thus, vascular lesion formation. In contrast, many in vitro studies demonstrate an anti-proliferative role for cGKI. In the current study, primary and subcultured wild-type and cGKI-deficient VSMCs in response to the membrane permeable cGMP analogue 8-Br-cGMP were compared. In agreement with the common view an anti-proliferative effect of cGKI was found in repeatedly passaged VSMCs (P5–11). In contrast, the analysis of primary VSMCs revealed that activation of cGKI in primary VSMCs strongly promotes growth. Analysing proliferation, apoptosis, cytoskeletal dynamics and various signaling pathways indicated that an increase in cell adhesion is a major mechanism for cGKI-mediated growth in primary VSMCs. This pro-adhesive effect of cGKI might be mediated via an inhibition of Rho kinase (ROCK) and enhanced integrin signaling. These processes might contribute to inhibit anoikis, the programmed cell death induced by the loss of cell/matrix interactions. from 3rd International Conference on cGMP Generators, Effectors and Therapeutic Implications Dresden, Germany. 15–17 June 2007
The viral genetic background determines the outcome of coxsackievirus B3 infection in outbred NMRI mice
2007-07-02

Abstract The reasons for the different outcome of coxsackievirus B3 (CVB3)‐induced heart disease in humans are not well understood. Since there are no experimental data on the course of disease after infection with genetically different CVB3 in a natural variable population until now, we studied the outcome of virus infection in outbred NMRI mice after inoculation of genetically different CVB3 variants. Adult male mice were inoculated with seven closely related CVB3 variants. The histopathological changes of heart and pancreas tissue, antibody induction, virus titers, and persistence of viral positive‐ as well as negative‐strand RNA in spleen and heart tissue were compared at day 7 or day 28 after infection to detect prerequisites and predictive factors for chronic myocarditis. Six CVB3 variants infected NMRI mice. CVB3 infection (i) did not induce detectable myocardial injury, (ii) caused signs of healing up acute myocarditis or (iii) ongoing chronic myocarditis. Neither IgG antibody responses nor the extent of destruction of exocrine pancreatic tissue or viral RNA load in spleen did correlate with myocardial histopathology. In contrast, a high persistent viral RNA load in heart tissue specimens was characteristic for mice developing chronic myocarditis. The results of the present study corroborate high viral load in the acute stage of myocarditis and high amounts of persisting CVB3 RNA in heart tissue as predictive marker of chronic myocarditis. The outcome of CVB3‐induced heart disease in outbred NMRI mice depends strongly on the viral genetic background. In particular an important role of viral capsid proteins is suggested. J. Med. Virol. 79:1334–1342, 2007. © Wiley‐Liss, Inc.
MDR1‐P‐Glycoprotein (ABCB1) Mediates Transport of Alzheimer’s Amyloid‐β Peptides—Implications for the Mechanisms of Aβ Clearance at the Blood–Brain Barrier
2007-07-04

Amyloid‐β (Aβ) is the major component of the insoluble amyloid plaques that accumulate intracerebrally in patients with Alzheimer’s disease (AD). It has been suggested that MDR1‐P‐glycoprotein (ABCB1, P‐gp) plays a substantial role in the elimination of Aβ from the brain. In the present study, MDR1 ‐transfected LLC cells growing in a polarized cell layer were used to characterize the interaction of Aβ1‐40/1‐42 with P‐gp. In this system, P‐gp‐mediated transport can be followed by the efflux of the fluorescent dye rhodamine‐123, or of Aβ itself from the cells into the apical extracellular space. Aβ significantly decreased the apical efflux of rhodamine‐123, and the transcellular transport of Aβ1‐40 and Aβ1‐42 into the apical chamber could be demonstrated using both ELISA and fluorescence (FITC)‐labeled peptides. This transport was inhibited by a P‐gp modulator. Furthermore, ATP‐dependent, P‐gp‐mediated transport of the fluorescence‐labeled peptides could be demonstrated in isolated, inside‐out membrane vesicles. Our data support the concept that P‐gp is important for the clearance of Aβ from brain, and thus may represent a target protein for the prevention and/or treatment of neurodegenerative disorders such as AD.
Reconstruction of deforming geometry from time-varying point clouds
2007-07-04

In this paper, we describe a system for the reconstruction of deforming geometry from a time sequence of unstructured, noisy point clouds, as produced by recent real-time range scanning devices. Our technique reconstructs both the geometry and dense correspondences over time. Using the correspondences, holes due to occlusion are filled in from other frames. Our reconstruction technique is based on a statistical framework: The reconstruction should both match the measured data points and maximize prior probability densities that prefer smoothness, rigid deformation and smooth movements over time. The optimization procedure consists of an inner loop that optimizes the 4D shape using continuous numerical optimization and an outer loop that infers the discrete 4D topology of the data set using an iterative model assembly algorithm. We apply the technique to a variety of data sets, demonstrating that the new approach is capable of robustly retrieving animated models with correspondences from data sets suffering from significant noise, outliers and acquisition holes.
The neurocognitive effects of 5 day anesthetic ketamine for the treatment of refractory complex regional pain syndrome
2007-07-05

Findings suggest that, at least at a 6-week follow up: (1) deep ketamine therapy is effective for relief of pain CRPS I and (2) there were no adverse cognitive effects of extended treatment with deep ketamine infusion. No definitive conclusions could be drawn about the relationship between mood and personality factors and the presence of CRPS I.
Quantitative EDX microanalysis of Bi2Te3 in the TEM
2007-07-05

Abstract Quantitative chemical analysis by energy dispersive X‐ray spectrometry (EDX) in a transmission electron microscope (TEM) Zeiss912Ω was applied to p‐type (Bi,Sb) 2 Te 3 and n‐type Bi 2 (Te,Se) 3 thermoelectric materials. Preliminary results yielded artifacts due to Bi spurious X‐rays and hole‐counts significantly beyond zero. A stray aperture was inserted in the TEM to absorb the stray radiation. With this aperture inserted a high‐accuracy quantitative chemical analysis was established. The hole‐counts decreased by a factor of 5 and the scatter of data decreased by a factor of 4 with respect to no aperture inserted. The mole fractions of Te and Se were 54.4 at% and 5.5 at% and varied by 0.5 at% for n‐type material. A similar behaviour was found for Sb and Bi in p‐type material. The variation in stoichiometry is smaller on the sub‐micrometer scale and increases with increasing length scale for both, n‐type and p‐type Bi 2 Te 3 . Measurements in the TEM confirmed the inhomogeneous chemical composition found by wavelength dispersive X‐ray spectrometry. The improved accuracy of the quantitative EDX analysis is also important for other compounds with unique physical properties. This was demonstrated on thin foils containing heavy elements and on powders of light elements dispersed on Cu‐grids, i.e., the high‐ T C superconductor Bi 2 Sr 2 CaCu 2 O 8 and the mineral salt hydroxyapatite Ca 10 (PO 4 ) 6 OH 2 . (© 2007 WILEY‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim)
Determination of First‐Order Degradation Rate Constants from Monitoring Networks
2007-07-05

Abstract In this article, different strategies for estimating first‐order degradation rate constants from measured field data are compared by application to multiple, synthetic, contaminant plumes. The plumes were generated by numerical simulation of contaminant transport and degradation in virtual heterogeneous aquifers. These sites were then individually and independently investigated on the computer by installation of extensive networks of observation wells. From the data measured at the wells, that is, contaminant concentrations, hydraulic conductivities, and heads, first‐order degradation rates were estimated by three 1D centerline methods, which use only measurements located on the plume axis, and a two‐dimensional method, which uses all concentration measurements available downgradient from the contaminant source. Results for both strategies show that the true rate constant used for the numerical simulation of the plumes in general tends to be overestimated. Overestimation is stronger for narrow plumes from small source zones, with an average overestimation factor of about 5 and single values ranging from 0.5 to 20, decreasing for wider plumes, with an average overestimation factor of about 2 and similar spread. Reasons for this overestimation are identified in the velocity calculation, the dispersivity parameterization, and off‐centerline measurements. For narrow plumes, the one‐ and the two‐dimensional strategies show approximately the same amount of overestimation. For wider plumes, however, incorporation of all measurements in the two‐dimensional approach reduces the estimation error. No significant relation between the number of observation wells in the monitoring network and the quality of the estimated rate constant is found for the two‐dimensional approach.
Optical sensors in water monitoring
2007-07-05

An upcoming problem in Europe is the protection of water resources and control of water quality. Coastal areas, rivers, ground water, wetlands, and especially drinking water require permanent monitoring to avoid pollution by small organic molecules or especially endocrine disrupting compounds. Biosensors have demonstrated the proof-of-principle of immunochemistry for these applications. It turns out that especially optical methods based on fluorescence detection can be successfully used for the development of fast, sensitive, cost-effective, and easy-to-use analytical systems meeting the requirements given by European Community Directives and national legislation. Results obtained with the RIANA and AWACSS systems are discussed here.
Upregulation of IL-6 mRNA by IL-6 in skeletal muscle cells: role of IL-6 mRNA stabilization and Ca2+-dependent mechanisms
2007-07-06

Skeletal muscle cells have been established as significant producers of IL-6 during exercise. This IL-6 production is discussed as one possible mediator of the beneficial effects of physical activity on glucose and fatty acid metabolism. IL-6 itself could be the exercise-related factor that upregulates and maintains its own production. We investigated this hypothesis and the underlying molecular mechanism in cultured C 2 C 12 cells. IL-6 led to a rapid and prolonged increase in IL-6 mRNA, which was also found in human myotubes. Because IL-6 has been shown to activate AMP-activated kinase (AMPK), we studied whether, in turn, activated AMPK induces IL-6 expression. Pharmacological activation of AMPK with 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside upregulated IL-6 mRNA expression, which was blocked by knockdown of AMPK α 1 and α 2 using small, interfering RNA (siRNA) oligonucleotides. However, the effect of IL-6 was shown to be independent of AMPK, since the siRNA approach silencing the AMPK α-subunits did not reduce the upregulation of IL-6 induced by IL-6 stimulation. The self-stimulatory effect of IL-6 partly involves a Ca 2+ -dependent pathway: IL-6 increased intracellular Ca 2+ , and intracellular blockade of Ca 2+ with a Ca 2+ chelator reduced the IL-6-mediated increase in IL-6 mRNA levels. Moreover, inhibition of Ca 2+ /calmodulin-dependent kinase kinase with STO-609 or the siRNA approach decreased IL-6 mRNA levels of control and IL-6-stimulated cells. A major, STO-609-independent mechanism is the IL-6-mediated stabilization of its mRNA. The data suggest that IL-6 could act as autocrine factor upregulating its mRNA levels, thereby supporting its function as an exercise-activated factor in skeletal muscle cells.
Ca2+ signaling in antigen receptor‐activated B lymphocytes
2007-07-09

Summary: B cells respond to antigen stimulation with mobilization of the Ca 2+ second messenger in two phases operated by two distinct sets of effector proteins. First, an antigen receptor‐specific Ca 2+ initiation complex is assembled, activated, and targeted to the plasma membrane to trigger the transient release of Ca 2+ from intracellular stores of the endoplasmic reticulum. Second, more ubiquitously expressed Ca 2+ channels of the plasma membrane are opened to allow for sustained Ca 2+ influx from the extracellular medium. Depending on the developmental stage of the B cell, the kinetics and profile of the two phases are adjusted at multiple levels of positive and negative regulation. A molecular basis for the Ca 2+ signaling plasticity is provided by cytosolic and transmembrane adapter proteins. They act as signal organizers, which control enzyme/substrate interactions by directing the different signaling modules into specific subcellular compartments. These arrangements orchestrate a graduated activation of Ca 2+ ‐sensitive downstream pathways, which ultimately determine appropriate cellular responses, namely elimination of autoreactive B cells or proliferation and differentiation of immunocompetent B cells into antibody‐secreting plasma cells.
Charge-exchange reaction cross sections and the Gamow-Teller strength for double β decay
2007-07-09

The proportionality between single charge-exchange reaction cross sections in the forward direction as found, for example from and He, and from and He) reactions, and the Gamow-Teller (GT) strength into the same final nuclear states has been studied and/or assumed often in the past. Using the most physically justified theory we have at our disposal and for the specific example of the Ge- Se system that may undergo double beta-decay, we demonstrate that the proportionality is a relative good assumption for reactions changing a neutron into a proton, i.e. Ge As. In this channel, the main contribution to the GT strengths comes from the removal of a neutron from an occupied single-particle (SP) state and putting a proton into an unoccupied SP state having either the same state quantum numbers or those of the spin-orbit partner. In contrast to this, in the second leg of the double beta decay a single proton must be taken from an occupied SP state and a neutron placed in an unoccupied one. This second process often is Pauli forbidden in medium-heavy nuclei and only can be effected if the Fermi surface is smeared out. Such is the case for Se As. Our results suggest that one may not always assume a proportionality between the forward-angle cross sections of the charge-exchange reactions and the GT strength in any such medium-heavy nuclei. The discrepancy originates from a pronounced effect of the radial dependence of the nucleon-nucleon ( ) interaction in connection with the Pauli principle on the cross sections in the reaction channel. Such a radial dependence is completely absent in the GT transition operator.
The Effect of Potassium Channel Opener Pinacidil on the Non‐Pregnant Rat Uterus
2007-07-10

Abstract: The effects of the K + channel opener, pinacidil on the spontaneous rhythmic contractions and contractions provoked by electrical field stimulation (50 Hz) or by oxytocin were investigated in the isolated uterus of the non‐pregnant rat in oestrus. Pinacidil produced more potent inhibition of oxytocin‐elicited contractions than of spontaneous rhythmic contractions or electrical field stimulation‐induced contractions. Glibenclamide, a selective blocker of adenosine triphosphate (ATP)‐sensitive K + (K ATP ) channels, antagonized the pinacidil‐induced inhibition of contractions elicited by oxytocin in a competitive manner. However, the pinacidil‐induced inhibition of electrical field stimulation‐elicited contractions and spontaneous rhythmic contractions was antagonized non‐competitively by glibenclamide. In the uterine strips pre‐contracted with 80 mM K + , the pinacidil‐induced maximal relaxation was not affected. The present data show that pinacidil exhibits potent relaxant properties in the rat non‐pregnant uterus in oestrus and therefore should be taken into account as a possible agent for treatment of dysmenorrhoea. Based on glibenclamide affinity, it appears that the inhibitory response to pinacidil involves K ATP channels. We need further investigations to explain why the interaction between glibenclamide and pinacidil in this experimental model depends on the nature of contractions. The ability of pinacidil to completely relax the rat non‐pregnant uterus pre‐contracted with K + ‐rich solution suggests that K + channel‐independent mechanism(s) also play a part in its relaxant effect.
Nuclear Localization of Ataxin-3 Is Required for the Manifestation of Symptoms in SCA3:In VivoEvidence
2007-07-11

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly inherited neurodegenerative disorder caused by the expansion of a CAG repeat in the MJD1 gene resulting in an expanded polyglutamine repeat in the ataxin-3 protein. To study the course of the disease, we generated transgenic mice for SCA3 using full-length ataxin-3 constructs containing 15, 70, or 148 CAG repeats, respectively. Control mice (15 CAGs) were phenotypically normal and had no neuropathological findings. However, mice transgenic for ataxin-3 with expanded polyglutamine repeats were severely affected by a strong neurological phenotype with tremor, behavioral deficits, strongly reduced motor and exploratory activity, a hunchback, and premature death at 3 to 6 months of age. Neuropathological examination by immunohistochemical staining revealed ubiquitin- and ataxin-3-positive intranuclear inclusion bodies in a multitude of neurons. Directing ataxin-3 with 148 CAGs to the nucleus revealed an even more pronounced phenotype with more inclusions and earlier death, whereas mice transgenic with the same construct but attached to a nuclear export signal developed a milder phenotype with less inclusions. These studies indicate that nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3 in vivo .
A Point Mutation in the Activation Function 2 Domain of Thyroid Hormone Receptor α1 Expressed after CRE-Mediated Recombination Partially Recapitulates Hypothyroidism
2007-07-11

Thyroid hormones act directly on transcription by binding to TRalpha1, TRbeta1, and TRbeta2 nuclear receptors, regulating many aspects of postnatal development and homeostasis. To analyze precisely the implication of the widely expressed TRalpha1 isoform in this pleiotropic action, we have generated transgenic mice with a point mutation in the TRalpha1 coding sequence, which is expressed only after CRE/loxP-mediated DNA recombination. The amino acid change prevents interaction between TRalpha1 and histone acetyltransferase coactivators and the release of corepressors. Early expression of this dominant-negative receptor deeply affects postnatal development and adult homeostasis, recapitulating many aspects of congenital and adult hypothyroidism, except in tissues and cells where TRbeta1 and TRbeta2 are predominantly expressed. Both respective abundance and intrinsic properties of TRalpha1 and TRbeta1/2 seem to govern specificity of action.
Gleevec Increases Levels of the Amyloid Precursor Protein Intracellular Domain and of the Amyloid-β–degrading Enzyme Neprilysin
2007-07-12

Amyloid-β (Aβ) deposition is a major pathological hallmark of Alzheimer's disease. Gleevec, a known tyrosine kinase inhibitor, has been shown to lower Aβ secretion, and it is considered a potential basis for novel therapies for Alzheimer's disease. Here, we show that Gleevec decreases Aβ levels without the inhibition of Notch cleavage by a mechanism distinct from γ-secretase inhibition. Gleevec does not influence γ-secretase activity in vitro; however, treatment of cell lines leads to a dose-dependent increase in the amyloid precursor protein intracellular domain (AICD), whereas secreted Aβ is decreased. This effect is observed even in presence of a potent γ-secretase inhibitor, suggesting that Gleevec does not activate AICD generation but instead may slow down AICD turnover. Concomitant with the increase in AICD, Gleevec leads to elevated mRNA and protein levels of the Aβ-degrading enzyme neprilysin, a potential target gene of AICD-regulated transcription. Thus, the Gleevec mediated-increase in neprilysin expression may involve enhanced AICD signaling. The finding that Gleevec elevates neprilysin levels suggests that its Aβ-lowering effect may be caused by increased Aβ-degradation.
Hypomagnesemia and nephrocalcinosis in a patient with two heterozygous mutations in the CLDN16 gene.
2007-07-12

We report the case of a 20-year-old male Caucasian patient with diagnosed nephrocalcinosis and a medical history of seizures and recurrent urinary tract infections. Laboratory investigations revealed clinical and biochemical abnormalities characteristic of familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). Since FHHNC is caused by mutations in the CLDN16 gene encoding a renal tight junction protein, we sequenced the complete coding region of this gene and detected two heterozygous mutations, the known Leu151Phe (+453G-->T) mutation and a novel Cys120Arg (+358T-->C) mutation. Due to their location within the primary structure of Claudin-16, both mutations are suggested to interfere with renal paracellular magnesium conductance.
Stanna‐closo‐dodecaborate Chemistry
2007-07-12

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, please click on HTML or PDF.