julilili42/papers huggingface dataset:
Resistance of mice lacking the serum- and glucocorticoid-inducible kinase SGK1 against salt-sensitive hypertension induced by a high-fat diet
2006-09-26

Mineralocorticoids enhance expression and insulin stimulates activity of the serum- and glucocorticoid-inducible kinase SGK1, which activates the renal epithelial Na + channel (ENaC). Under a salt-deficient diet, SGK1 knockout mice ( sgk1 −/− ) excrete significantly more NaCl than their wild-type littermates ( sgk1 +/+ ) and become hypotensive. The present experiments explored whether SGK1 participates in the hypertensive effects of a high-fat diet and high-salt intake. Renal SGK1 protein abundance of sgk1 +/+ mice was significantly elevated after a high-fat diet. Under a control diet, fluid intake, blood pressure, urinary flow rate, and urinary Na + , K + , and Cl − excretion were similar in sgk1 −/− and sgk1 +/+ mice. Under a standard diet, high salt (1% NaCl in the drinking water for 25 days) increased fluid intake, urinary flow rate, and urinary Na + , K + , and Cl − excretion similarly in sgk1 −/− and sgk1 +/+ mice without significantly altering blood pressure. A high-fat diet alone (17 wk) did not significantly alter fluid intake, urinary flow rate, urinary Na + , K + , or Cl − excretion, or plasma aldosterone levels but increased plasma insulin, total cholesterol, triglyceride concentrations, and systolic blood pressure to the same extent in both genotypes. Additional salt intake (1% NaCl in the drinking water for 25 days) on top of a high-fat diet did not affect hyperinsulinemia or hyperlipidemia but increased fluid intake, urinary flow rate, and urinary NaCl excretion significantly more in sgk1 −/− than in sgk1 +/+ mice. Furthermore, in animals receiving a high-fat diet, additional salt intake increased blood pressure only in sgk1 +/+ mice (to 132 ± 3 mmHg) but not in sgk1 −/− mice (120 ± 4 mmHg). Thus lack of SGK1 protects against the hypertensive effects of a combined high-fat/high-salt diet.
Anaesthetic Drugs: Linking Molecular Actions to Clinical Effects
2006-09-27

The use of general anaesthetics has facilitated great advantages in surgery within the last 150 years. General anaesthesia is composed of several components including analgesia, amnesia, hypnosis and immobility. To achieve these components, general anaesthetics have to act via multiple molecular targets at different anatomical sites in the central nervous system. Much of our current understanding of how anaesthetics work has been obtained within the last few years on the basis of genetic approaches, in particular knock-out or knock-in mice. Anaesthetic drugs can be grouped into volatile and intravenous anaesthetics according to their route of administration. Common volatile anaesthetics induce immobility via molecular targets in the spinal cord, including glycine receptors, GABA(A) receptors, glutamate receptors, and TREK-1 potassium channels. In contrast, intravenous anaesthetics cause immobility almost exclusively via GABA(A) receptors harbouring beta3 subunits. Hypnosis is predominantly mediated by beta3-subunit containing GABA(A) receptors in the brain, whereas beta2 subunit containing receptors, which make up more than 50% of all GABA(A) receptors in the central nervous system, mediate sedation. At clinically relevant concentrations, ketamine and nitrous oxide block NMDA receptors. Unlike all other anaesthetics in clinical use they produce analgesia. Not only desired actions of anaesthetics, but also undesired side effects are linked to certain receptors. Respiratory depression involves beta3 containing GABA(A) receptors whereas hypothermia is largely mediated by GABA(A) receptors containing beta2 subunits. These recent insights into the clinically desired and undesired actions of anaesthetic agents provide new avenues for the design of drugs with an improved side-effect profile. Such agents would be especially beneficial for the treatment of newborn children, elderly patients and patients undergoing ambulatory surgery.
Technical Note on Microcatheter Implantation for Local Inner Ear Drug Delivery
2006-09-27

If the pharmacokinetics or pharmacodynamics of a specific local inner ear therapy approach requires a continuous intratympanic drug application (e.g., to restore hearing in patients with severe or profound hearing loss), the temporary implantation of a microcatheter by a standardized surgical technique is a feasible and appropriately safe method for providing continuous drug delivery to the inner ear.
Hypusination of eukaryotic initiation factor 5A (eIF5A): a novel therapeutic target in BCR-ABL–positive leukemias identified by a proteomics approach
2006-09-28

Abstract Inhibition of BCR-ABL tyrosine kinase with imatinib represents a major breakthrough in the treatment of patients with chronic myeloid leukemia (CML). However, resistance to imatinib develops frequently, particularly in late-stage disease. To identify new cellular BCR-ABL downstream targets, we analyzed differences in global protein expression in BCR-ABL–positive K562 cells treated with or without imatinib in vitro. Among the 19 proteins found to be differentially expressed, we detected the down-regulation of eukaryotic initiation factor 5A (eIF5A), a protein essential for cell proliferation. eIF5A represents the only known eukaryotic protein activated by posttranslational hypusination. Hypusination inhibitors (HIs) alone exerted an antiproliferative effect on BCR-ABL–positive and –negative leukemia cell lines in vitro. However, the synergistic dose-response relationship found for the combination of imatinib and HI was restricted to Bcr-Abl–positive cells. Furthermore, this synergistic effect was confirmed by cytotoxicity assays, cell-cycle analysis, and CFSE labeling of primary CD34+ CML cells. Specificity of this effect could be demonstrated by cotreatment of K562 cells with imatinib and siRNA against eIF5. In conclusion, through a comparative proteomics approach and further functional analysis, we identified the inhibition of eIF5A hypusination as a promising new approach for combination therapy in BCR-ABL–positive leukemias.
Structure–Activity Relationships in Chromatography: Retention Prediction of Oligonucleotides with Support Vector Regression
2006-09-29

Secondary structures of biopolymers have a significant influence on their molecular interactions with surfaces. With the aid of machine learning through support vector regression, the retention of oligonucleotides was modeled in ion-pair reversed-phase chromatography with high prediction accuracy (see diagram).
Postnatally Elevated Levels of Insulin-Like Growth Factor (IGF)-II Fail to Rescue the Dwarfism of IGF-I-Deficient Mice except Kidney Weight
2006-09-29

This study tested whether elevated levels of IGF-II in the postnatal period can rescue the dwarfism in IGF-I-deficient mice. Heterozygous Igf1 mutant mice [I+/− IIwt] were crossed with heterozygous Igf1 mutant, phosphoenolpyruvate carboxykinase promoter IGF-II transgenic mice [I+/− IItg], and [I+/+ IIwt], [I+/+ IItg], [I−/− IIwt], and [I−/− IItg] offspring were investigated. IGF-II levels were 11- and 6-fold higher in male and female [I−/− IItg] vs. [I−/− IIwt] animals. Western ligand blot analysis revealed markedly reduced activities of 30- and 32-kDa IGF binding proteins (IGFBPs) (most likely IGFBP-1 and IGFBP-2) and the 39- to 43-kDa IGFBP-3 double band in serum from IGF-I-deficient mice. These binding proteins were partially restored by overexpression of IGF-II. Analysis of weight data from the early postnatal period until d 60 showed that, in the absence of IGF-I, elevated levels of IGF-II have no effect on body weight gain. A detailed analysis of body proportions, bone parameters, and organ weights of 60-d-old mice also failed to show effects of IGF-II with one important exception: in Igf1 mutant and also Igf1 intact male mice, IGF-II overexpression significantly increased absolute (+32.4 and +28.6%; P &amp;lt; 0.01) and relative kidney weights (+29.0 and +22.4%; P &amp;lt; 0.001). These changes in kidney weight were associated with reduced phosphorylation of p38 MAPK. In summary, our genetic model shows that substantial amounts of IGF-II in the circulation do not rescue the postnatal growth deficit of IGF-I-deficient mice but increase absolute and relative kidney weights of normal and IGF-I-deficient male mice, suggesting a gender-specific role of IGF-II for kidney growth.
MEAN-FIELD EXPANSION IN BOSE–EINSTEIN CONDENSATES WITH FINITE-RANGE INTERACTIONS
2006-09-30

We present a formal derivation of the mean-field expansion for dilute Bose–Einstein condensates with two-particle interaction potentials which are weak and finite-range, but otherwise arbitrary. The expansion allows for a controlled investigation of the impact of microscopic interaction details (e.g. the scaling behavior) on the mean-field approach and the induced higher-order corrections beyond the s-wave scattering approximation.
On local CR-transformations of Levi-degenerate group orbits in compact Hermitian symmetric spaces
2006-09-30

We present a large class of homogeneous 2 -nondegenerate CR-manifolds M , both of hypersurface type and of arbitrarily high CR-codimension, with the following property: Every CR-equivalence between domains U,V in M extends to a global real-analytic CR-automorphism of M . We show that this class contains G -orbits in Hermitian symmetric spaces Z of compact type, where G is a real form of the complex Lie group \\mathsf{Aut}(Z)^{0} and G has an open orbit that is a bounded symmetric domain of tube type.
(Patho)physiological Significance of the Serum- and Glucocorticoid-Inducible Kinase Isoforms
2006-10-01

The serum- and glucocorticoid-inducible kinase-1 (SGK1) is ubiquitously expressed and under genomic control by cell stress (including cell shrinkage) and hormones (including gluco- and mineralocorticoids). Similar to its isoforms SGK2 and SGK3, SGK1 is activated by insulin and growth factors via phosphatidylinositol 3-kinase and the 3-phosphoinositide-dependent kinase PDK1. SGKs activate ion channels (e.g., ENaC, TRPV5, ROMK, Kv1.3, KCNE1/KCNQ1, GluR1, GluR6), carriers (e.g., NHE3, GLUT1, SGLT1, EAAT1–5), and the Na + -K + -ATPase. They regulate the activity of enzymes (e.g., glycogen synthase kinase-3, ubiquitin ligase Nedd4–2, phosphomannose mutase-2) and transcription factors (e.g., forkhead transcription factor FKHRL1, β-catenin, nuclear factor κB). SGKs participate in the regulation of transport, hormone release, neuroexcitability, cell proliferation, and apoptosis. SGK1 contributes to Na + retention and K + elimination of the kidney, mineralocorticoid stimulation of salt appetite, glucocorticoid stimulation of intestinal Na + /H + exchanger and nutrient transport, insulin-dependent salt sensitivity of blood pressure and salt sensitivity of peripheral glucose uptake, memory consolidation, and cardiac repolarization. A common (∼5% prevalence) SGK1 gene variant is associated with increased blood pressure and body weight. SGK1 may thus contribute to metabolic syndrome. SGK1 may further participate in tumor growth, neurodegeneration, fibrosing disease, and the sequelae of ischemia. SGK3 is required for adequate hair growth and maintenance of intestinal nutrient transport and influences locomotive behavior. In conclusion, the SGKs cover a wide variety of physiological functions and may play an active role in a multitude of pathophysiological conditions. There is little doubt that further targets will be identified that are modulated by the SGK isoforms and that further SGK-dependent in vivo physiological functions and pathophysiological conditions will be defined.
Boswellic Acids in Chronic Inflammatory Diseases
2006-10-01

Oleogum resins from BOSWELLIA species are used in traditional medicine in India and African countries for the treatment of a variety of diseases. Animal experiments showed anti-inflammatory activity of the extract. The mechanism of this action is due to some boswellic acids. It is different from that of NSAID and is related to components of the immune system. The most evident action is the inhibition of 5-lipoxygenase. However, other factors such as cytokines (interleukins and TNF-alpha) and the complement system are also candidates. Moreover, leukocyte elastase and oxygen radicals are targets. Clinical studies, so far with pilot character, suggest efficacy in some autoimmune diseases including rheumatoid arthritis, Crohn's disease, ulcerative colitis and bronchial asthma. Side effects are not severe when compared to modern drugs used for the treatment of these diseases.
Vibration-based Terrain Classification Using Support Vector Machines
2006-10-01

In outdoor environments, there is a variety of different types of ground surfaces. If some of them are slippery or bumpy, for example, the ground surface itself is a possible hazard for an autonomous mobile vehicle traversing the surface. Therefore, it is beneficial if the vehicle is able to estimate, which terrain it is currently traversing. Using this estimation, the vehicle can adapt its driving style to the terrain. In this paper, we present a method for terrain classification based on vibration induced in the vehicle's body. An accelerometer mounted on the vehicle measures the vibration perpendicular to the ground surface. We experimentally compare representations of the data based on the fast Fourier transform (FFT) and on the power spectral density (PSD). Additionally, we suggest a simpler and more compact representation based on features calculated from the raw data vectors and a combination of this representation with the PSD. We train and classify the data with a support vector machine (SVM). Experiments on a large real-world dataset containing seven different terrain types evaluate our approach
Crossmodal temporal discrimination: Assessing the predictions of a general pacemaker-counter model
2006-10-01

In this study, an extended pacemaker-counter model was applied to crossmodal temporal discrimination. In three experiments, subjects discriminated between the durations of a constant standard stimulus and a variable comparison stimulus. In congruent trials, both stimuli were presented in the same sensory modality (i.e., both visual or both auditory), whereas in incongruent trials, each stimulus was presented in a different modality. The model accounts for the finding that temporal discrimination depends on the presentation order of the sensory modalities. Nevertheless, the model fails to explain why temporal discrimination was much better with congruent than with incongruent trials. The discussion considers possibilities to accommodate the model to this and other shortcomings.
Therapeutic anti‐tumor immunity triggered by injections of immunostimulating single‐stranded RNA
2006-10-01

Abstract Stabilized synthetic RNA oligonucleotides (ORN) and protected messenger RNA (mRNA) were recently discovered to possess an immunostimulatory capacity through their recognition by TLR 7 and 8. We wanted to find out whether this danger signal is capable of triggering anti‐tumor immunity when injected locally into an established tumor. Using the mouse glioma tumor cell line SMA‐560 in syngenic VM/Dk mice, we were able to show that intra‐tumor injections of protamine‐stabilized mRNA do indeed induce tumor regression and long‐term anti‐tumor immunity. Residual RNA‐injected tumors show CD8 infiltration. Distant injections of protamine‐protected mRNA and intra‐tumor injection of naked mRNA also result in anti‐tumor immunity. Although they are strong danger signals, RNA are labile molecules with a short half‐life: they do not trigger side effects such as long‐term, uncontrolled immunostimulation evidenced by splenomegaly in CpG DNA‐treated mice. In conclusion, RNA molecules are potent and safe danger signals that are relevant for active immunotherapy strategies aimed at the eradication of solid tumors.
Impaired expression of CYP2D6 in intermediate metabolizers carrying the *41 allele caused by the intronic SNP 2988G>A: evidence for modulation of splicing events
2006-10-01

We investigated the molecular basis for low expression and activity of CYP2D6 associated with the CYP2D6*41 allele in about 10-15% of Caucasians with intermediate metabolizer phenotype. With respect to two previously described polymorphisms in the promoter (-1584C>G) and in intron 6 (2988G>A; c.985+39G>A), the three most frequent functional alleles have the distinct haplotypes 2D6*1[CG], 2D6*2[GG] and 2D6*41[CA], respectively. Reporter gene analyses in transiently transfected HepG2 and Huh7 hepatoma cells did not indicate changes in transcription rate by these polymorphisms. By reverse-transcription polymerase chain reaction analysis of liver RNA of genotyped patients, however, we discovered that the 2988G>A change was associated with increased levels of a nonfunctional splice variant lacking exon 6. Quantification by denaturing high-performance liquid chromatography revealed up to 7.3-fold increased levels of the splice variant and up to 2.9-fold less functional transcript in carriers of 2D6*41, in good concordance with concomitant changes in immunoquantified CYP2D6 protein. Recombinant expression of the entire genomic sequence coding for 2D6*41, 2D6*2 and 2D6*1 alleles but lacking the upstream region in COS-1 and Huh7 cell lines resulted in two-fold to five-fold reduced levels of CYP2D6 mRNA containing exon 6, apoprotein and enzyme activity of 2D6*41. These experiments establish the causal relationship between the intron 6 single-nucleotide polymorphism 2988G>A and the low expression phenotype associated with allele 2D6*41. These data improve the CYP2D6 genotype-phenotype relationship and they demonstrate that major phenotype changes occurring in large population subgroups can be caused by intronic polymorphisms outside of splice site consensus sequences.
Geochronology of Eocene plutonism and metamorphism in northwest
2006-10-01

In northwest Turkey Eocene calc-alkaline intrusions with isotopic ages of 53 Ma to 35 Ma form a WNW-ESE trending belt, ~400 km long and ~60 km wide. In the east, the plutons intrude blueschists representing a subducted passive continental margin sequence with Late Cretaceous (~80 Ma) metamorphic ages. In the vicinity of one of these granitoids a low pressure - high temperature metamorphism has resulted in complete transformation of the blueschist metapelites into andalusite micaschists. The andalusite + cordierite + biotite + muscovite + quartz + K-feldspar + plagioclase paragenesis in the micaschists indicates a pressure of 2 ± 1 kbar and a temperature of 575 ± 50° C during the metamorphism. Rb-Sr muscovite and biotite ages of a micaschist sample are 46 ± 3 and 39 ± 1 Ma, respectively, similar to the 45.0 ± 0.2 Ma U-Pb zircon and Rb-Sr biotite ages from the neighbouring pluton. Development of folds and a new foliation in the andalusite micaschists suggest regional rather than contact metamorphism. The Eocene granitic magmatism and associated LP/HT metamorphism in northwest Turkey have probably formed above a NE directed subduction zone located along the Vardar suture.
Paleozoic magmatic events in the Strandja Massif, NW Turkey
2006-10-01

The Strandja massif consists of metamorphic basement intruded by large Early Permian plutons of the Kirklareli type and overlain by Triassic metasedimentary cover. Together with its continuation in Bulgaria this massif forms an important link between the Pontides and the orogenic belts of Europe. Various types of orthogneisses constitute a significant part of the metamorphic basement however these rocks have until now escaped a particular study and therefore the Paleozoic history of the massif is essentially unknown. In this study these rocks are classified and mapped as hornblende-biotite, biotite-muscovite, and leucocratic orthogneisses. Their modal compositions correspond to quartz diorite, tonalite, granodiorite and trondhjemite. Geochemical data suggest a calc-alkaline trend of differentiation and metaluminous character of the parent magmas. Isotopic dating using the single zircon evaporation method has shown that magmatic ages of these orthogneisses cluster within a short time interval between 312±2 and 315 ±5 Ma in the Carboniferous. At the same time inherited ages of magmatic zircons in these rocks record a long lived magmatic activity between 340 and 650 Ma. We infer that the Carboniferous orthogneisses were formed in a magmatic arc that evolved atop of a mature continental basement. Previously established ([1, 2]) Early Permian magmatic event has been confirmed by additional age determinations constraining it at 257±6 Ma. Tectonic setting of this episode is also interpreted as subduction related taking into consideration its geochemical features and relationships with surrounding tectonic units.
Activation of muscarinic cholinergic receptors inhibits giant neurones in the caudal pontine reticular nucleus
2006-10-01

Abstract Giant neurones in the caudal pontine reticular nucleus (PnC) play a crucial role in mediating the mammalian startle response. They receive input from cochlear, trigeminal and vestibular nuclei and project directly to motoneurones. Furthermore, they integrate modulatory input from different brain regions either enhancing or inhibiting startle responses. One prominent startle modulation is prepulse inhibition where a non‐startling stimulus presented prior to the startle stimulus inhibits a subsequent startle response. Several behavioural studies have indicated that this inhibition is mediated by muscarinic receptors at the level of the PnC. Here, we performed whole‐cell patch‐clamp recordings from PnC giant neurones in acute rat brain slices in order to examine muscarinic inhibition. We stimulated afferent trigeminal and auditory fibres and applied muscarinic agonists and antagonists in order to investigate their effect on excitatory postsynaptic current amplitudes, paired‐pulse ratio and passive membrane properties of PnC giant neurones. The cholinergic agonist carbachol and the muscarinic agonist oxotremorine significantly reduced excitatory postsynaptic current amplitudes and increased the paired‐pulse ratio. Carbachol additionally reduced the membrane resistance of postsynaptic PnC giant neurones. The subtype‐specific antagonists AF‐DX116 (M2 preferring) and tropicamide (M4 preferring) antagonized the oxotremorine effect indicating that M4 and possibly M2 receptor subtypes are involved in this inhibition. The G‐protein‐activated inward rectifying potassium channel blocker tertiapin‐Q had no effect on oxotremorine‐induced inhibition of giant neurones. Our results show a mainly presynaptically mediated strong inhibition of PnC giant neurones by activation of M4 and possibly M2 receptors that presumably contribute to prepulse inhibition.