julilili42/papers huggingface dataset:
Palmitoylation gates phosphorylation-dependent regulation of BK potassium channels
2008-12-20

Large conductance calcium- and voltage-gated potassium (BK) channels are important regulators of physiological homeostasis and their function is potently modulated by protein kinase A (PKA) phosphorylation. PKA regulates the channel through phosphorylation of residues within the intracellular C terminus of the pore-forming α-subunits. However, the molecular mechanism(s) by which phosphorylation of the α-subunit effects changes in channel activity are unknown. Inhibition of BK channels by PKA depends on phosphorylation of only a single α-subunit in the channel tetramer containing an alternatively spliced insert (STREX) suggesting that phosphorylation results in major conformational rearrangements of the C terminus. Here, we define the mechanism of PKA inhibition of BK channels and demonstrate that this regulation is conditional on the palmitoylation status of the channel. We show that the cytosolic C terminus of the STREX BK channel uniquely interacts with the plasma membrane via palmitoylation of evolutionarily conserved cysteine residues in the STREX insert. PKA phosphorylation of the serine residue immediately upstream of the conserved palmitoylated cysteine residues within STREX dissociates the C terminus from the plasma membrane, inhibiting STREX channel activity. Abolition of STREX palmitoylation by site-directed mutagenesis or pharmacological inhibition of palmitoyl transferases prevents PKA-mediated inhibition of BK channels. Thus, palmitoylation gates BK channel regulation by PKA phosphorylation. Palmitoylation and phosphorylation are both dynamically regulated; thus, cross-talk between these 2 major posttranslational signaling cascades provides a mechanism for conditional regulation of BK channels. Interplay of these distinct signaling cascades has important implications for the dynamic regulation of BK channels and physiological homeostasis.
Very high energy gamma-ray observations of the galaxy clusters Abell 496 and Abell 85 with HESS
2008-12-22

Aims. The nearby galaxy clusters Abell 496 and Abell 85 are studied in the very high-energy (VHE, E &gt; 100 GeV) band to investigate VHE cosmic rays (CRs) in this class of objects which are the largest gravitationally bound systems in the Universe. Methods. HESS, an array of four imaging atmospheric cherenkov telescopes (IACT), was used to observe the targets in the range of VHE gamma rays. Results. No significant gamma-ray signal is found at the respective position of the two clusters with several different source size assumptions for each target. In particular, emission regions corresponding to the high-density core, to the extension of the entire X-ray emission in these clusters, and to the very extended region where the accretion shock is expected are investigated. Upper limits are derived for the gamma-ray flux at energies E &gt; 570 GeV for Abell 496 and E &gt; 460 GeV for Abell 85. Conclusions. From the non-detection in VHE gamma rays, upper limits on the total energy of hadronic CRs in the clusters are calculated. If the cosmic-ray energy density follows the large-scale gas density profile, the limit on the fraction of energy in these non-thermal particles with respect to the total thermal energy of the intra-cluster medium (ICM) is 51% for Abell 496 and only 8% for Abell 85 due to its higher mass and higher gas density. These upper limits are compared with theoretical estimates. They predict about ~10% of the thermal energy of the ICM in non-thermal particles. The observations presented here can constrain these predictions especially for the case of the Abell 85 cluster.
Two ~35 day clocks in Hercules X-1: evidence for neutron star free precession
2008-12-22

\\n We present evidence for the existence of two ~35 day clocks in the \\nHer X-1/HZ Her binary system. ~35 day modulations are observed\\n1) in the Turn-On cycles with two on- and two off-states \\nand 2) in the changing shape of the pulse profiles which \\nre-appears regularly. The two ways of counting the 35 day cycles are generally \\nin synchronization. This synchronization did apparently break down temporarily \\nduring the long Anomalous Low (AL3), which Her X-1 experienced in \\n1999/2000, in the sense that there must have been one extra Turn-On cycle.\\nOur working hypothesis is that there are two clocks in the system, \\nboth with a period of about ~35 days: precession of the accretion disk (the less \\nstable “Turn-On clock”) and free precession of the neutron star (the more stable \\n“Pulse profile clock”). We suggest that free precession of the \\nneutron star is the master clock and that the precession of the accretion disk is\\nbasically synchronized to that of the neutron star through a feedback mechanism \\nin the binary system. However, the Turn-On clock can slip against its master\\nwhen the accretion disk has a very low inclination, as is observed to be the case \\nduring AL3. We take the apparent correlation between the histories of the Turn-Ons, \\nof the Anomalous Lows and of the pulse period evolution, with a 5 yr quasi-periodicity, \\nas evidence for strong physical interaction and feedback between the major \\ncomponents in the system. We speculate that the 5 yr (10 yr) period is \\ndue either to a corresponding activity cycle of HZ Her or a natural\\nringing period of the physical system of coupled components. The question of whether \\nfree precession really exists in neutron stars is very important for understanding\\nmatter with supra-nuclear density.\\n\\n\\n
Probing Protein Conformations by in Situ Non-Covalent Fluorescence Labeling
2008-12-22

The conformational dynamics of proteins plays a key role in their complex physiological functions. Fluorescence resonance energy transfer (FRET) is a particular powerful tool for studying protein conformational dynamics, but requires efficient site-specific labeling with fluorescent reporter probes. We have employed different tris-NTA/fluorophore conjugates, which bind histidine-tagged proteins with high affinity, for site-specific incorporation of FRET acceptors into proteins, which were covalently labeled with a donor fluorophore. We demonstrate versatile application of this approach for exploring the conformation of the type I interferon receptor ectodomains ifnar1-EC and ifnar2-EC. Substantial ligand-induced conformational changes of ifnar1-EC, but not ifnar2-EC, were observed by monitoring the fluorescence intensity and the fluorescence lifetime of the FRET donor. Time-resolved fluorescence correlation spectroscopy revealed a substantial conformational flexibility of ifnar1-EC and a ligand-induced tightening. Our results demonstrate that protein labeling with tris-NTA/fluorophores enables for efficient quantitative intramolecular FRET analysis.
Design of a light stimulator for fetal and neonatal magnetoencephalography
2008-12-22

The design, safety analysis and performance of a fetal visual stimulation system suitable for fetal and neonatal magnetoencephalography studies are presented. The issue of fetal, neonatal and maternal safety is considered and the maximum permissible exposure is computed for the maternal skin and the adult eye. The risk for neonatal eye exposure is examined. It is demonstrated that the fetus, neonate and mother are not at risk.
Identification and Characterization of Metabolically Benign Obesity in Humans
2008-12-22

Although obese individuals are at high risk of being insulin resistant and developing type 2 diabetes mellitus, as well as having atherosclerosis, it is possible that a phenotype exists with a metabolically benign fat distribution that protects such individuals from type 2 diabetes or cardiovascular disease. In an attempt to identify subjects with metabolically benign obesity, the investigators used magnetic resonance (MR) tomography to measure total body, visceral, and subcutaneous fat, and proton (1H)–MR spectroscopy to determine fat deposition in ectopic tissues (liver and skeletal muscle). The oral glucose tolerance test was used to estimate insulin resistance. The study subjects—314 individuals (121 men and 193 women) with a mean age of 45 (range, 18–69) years—were divided into three groups based on body mass index (BMI) [calculated as weight in kilograms divided by height in meters squared]: normal weight (BMI, ≤25.0), overweight (BMI, 25.0–29.9), and obese (BMI, ≥30.0). The obese group was further divided into 2 subgroups: obese–insulin sensitive (IS)–placement in the upper quartile of insulin sensitivity, and obese–insulin resistant (IR)–placement in the lower three quartiles of insulin sensitivity. The percentage of total body and visceral fat was higher in the overweight and obese groups than the normal-weight group (P < .05), but no statistically significant differences were found between the obese–IS and obese–IR groups. In contrast, compared to the obese–IR group, the obese–IS group had a lower percentage of ectopic fat in skeletal muscle (P < .001) and especially the liver (4.3% ± 0.6% versus 9.5% ± 0.8%), lower intima-media thickness of the common carotid artery (0.54 ± 0.02 versus 0.59 ± 0.01 mm, P < .05), and higher insulin sensitivity (17.4 ± 0.3 versus 7.3 ± 0.3 AU, P < .05). Surprisingly, insulin sensitivity in the normal weight group (18.2 ± 0.9 AU) was almost identical to that in the obese–IS group. Moreover, there was no statistically significantly difference in intima-media thickness between these two groups. These data provide evidence for the existence of a metabolically benign obesity profile that may provide protection against insulin resistance and atherosclerosis.
Inflammatory nodules around the axilla: an uncommon localization of orf virus infection
2008-12-22

Conflict of interest: none declared. Ecthyma contagiosum is a zoonosis of worldwide prevalence, caused by the orf virus. Orf is the type species of the parapoxvirus genus in the familiy Poxviridae. The virus primarily affects sheep and goats, with lesions on the lips and oral mucosa. Transmission to humans occurs in most cases by direct contact with infected animals or occasionally with contaminated fomites.1 In humans, solitary, red, infiltrated papulovesicular nodules are usually located on the fingers, hands and forearms,2 and may sometimes be partially necrotic or crusted.3 A 17‐year‐old man presented with inflammatory nodules located around the left axilla. He was living in a rural district of Germany and was not working professionally in agriculture. The referring physician considered an initial cutaneous anthrax infection. The nodules were noticed 5 days before presentation, and the patient reported rapid growth until his attendance. The three skin lesions appeared as solitary, well‐circumscribed, painless, red, solid nodules with a diameter of 6 mm on an erythematous ground (Fig. 1).
Perception of global gestalt by temporal integration in simultanagnosia
2008-12-22

Abstract Patients with bilateral parieto‐occipital brain damage may show intact processing of individual objects, while their perception of multiple objects is disturbed at the same time. The deficit is termed ‘simultanagnosia’ and has been discussed in the context of restricted visual working memory and impaired visuo‐spatial attention. Recent observations indicated that the recognition of global shapes can be modulated by the spatial distance between individual objects in patients with simultanagnosia and thus is not an all‐or‐nothing phenomenon depending on spatial continuity. However, grouping mechanisms not only require the spatial integration of visual information, but also involve integration processes over time. The present study investigated motion‐defined integration mechanisms in two patients with simultanagnosia. We applied hierarchical organized stimuli of global objects that consisted of coherently moving dots (‘shape‐from‐motion’). In addition, we tested the patients’ ability to recognize biological motion by presenting characteristic human movements (‘point‐light‐walker’). The data revealed largely preserved perception of biological motion, while the perception of motion‐defined shapes was impaired. Our findings suggest separate mechanisms underlying the recognition of biological motion and shapes defined by coherently moving dots. They thus argue against a restriction in the overall capacity of visual working memory over time as a general explanation for the impaired global shape recognition in patients with simultanagnosia.
Unscheduled Akt-Triggered Activation of Cyclin-Dependent Kinase 2 as a Key Effector Mechanism of Apoptin's Anticancer Toxicity
2008-12-23

Apoptin, a protein from the chicken anemia virus, has attracted attention because it specifically kills tumor cells while leaving normal cells unharmed. The reason for this tumor selectivity is unclear and depends on subcellular localization, as apoptin resides in the cytoplasm of normal cells but in the nuclei of transformed cells. It was shown that nuclear localization and tumor-specific killing crucially require apoptin's phosphorylation by an as yet unknown kinase. Here we elucidate the pathway of apoptin-induced apoptosis and show that it essentially depends on abnormal phosphatidylinositol 3-kinase (PI3-kinase)/Akt activation, resulting in the activation of the cyclin-dependent kinase CDK2. Inhibitors as well as dominant-negative mutants of PI3-kinase and Akt not only inhibited CDK2 activation but also protected cells from apoptin-induced cell death. Akt activated CDK2 by direct phosphorylation as well as by the phosphorylation-induced degradation of the inhibitor p27(Kip1). Importantly, we also identified CDK2 as the principal kinase that phosphorylates apoptin and is crucially required for apoptin-induced cell death. Immortalized CDK2-deficient fibroblasts and CDK2 knockdown cells were markedly protected against apoptin. Thus, our results not only decipher the pathway of apoptin-induced cell death but also provide mechanistic insights for the selective killing of tumor cells.
Separation of phasic arousal and expectancy effects in a speeded reaction time task via fMRI
2008-12-23

Abstract Sixteen neurologically normal volunteers performed a 2‐choice speeded reaction time (RT) task in which the imperative was the change in color of a clock hand. During trial blocks with low temporal uncertainty (good clock condition), this imperative stimulus occurred at a fixed location (e.g., 2:00). In the bad clock condition, the clock was unpredictive of imperative onset. On half of both good and bad clock trials, a task‐irrelevant, cutaneous accessory stimulus accompanied the imperative. The speeding of reactions by the accessory was associated with activation primarily in and near the supramarginal gyrus of the parietal lobe. Contrasts of good‐ versus bad‐clock conditions revealed activation in a variety of perceptual, motor, and executive control regions. Apart from interactions within the cerebellum and left anterior insula, there was little overlap between structures influenced by the arousal and expectancy manipulations.
Metamictization in zircon: Raman investigation following a Rietveld approach. Part II: Sampling depth implication and experimental data
2008-12-23

Abstract Profile line deconvolution following a Rietveld approach is applied to Raman spectra obtained from natural zircon grains from the European Alps. The corrected bandwidths are in perfect agreement with the values obtained from an established correction method (after Irmer) as far as the area of validity of the latter is concerned. For Raman active modes smaller than that, the Rietveld approach also yields accurate values for the true Raman bandwidth. Moreover, changes to instrument parameters are compensated by the correction routine. As for the studied zircon grains, Raman spectroscopy was shown to be a suitable tool for the examination of zoning (i.e. regions which show a variable degree of radiation‐induced damage because of a different amount of incorporated uranium and/or thorium). This is complicated by the fact that the measured Raman signal is not restricted to the depth expected from the axial resolution (several micrometers) but a significant contribution comes from a comparatively large excitation volume (tens of micrometer deep). This sampling volume, however, lies within the same order of magnitude as zoning, which itself is blurred by the range of amorphization‐causing alpha‐particles. Copyright © 2008 John Wiley &amp; Sons, Ltd.
Phylogeography of the greater horseshoe bat,Rhinolophus ferrumequinum: contrasting results from mitochondrial and microsatellite data
2008-12-24

Abstract Phylogeographical studies are typically based on haplotype data, occasionally on nuclear markers such as microsatellites, but rarely combine both. This is unfortunate because the use of markers with contrasting modes of inheritance and rates of evolution might provide a more accurate and comprehensive understanding of a species’ history. Here we present a detailed study of the phylogeography of the greater horseshoe bat, Rhinolophus ferrumequinum , using 1098 bp of the mitochondrial ND2 gene from 45 localities from across its Palaearctic range to infer population history. In addition, we re‐analysed a large microsatellite data set available for this species and compared the results of both markers to infer population relationships and the historical processes influencing them. We show that mtDNA, the most popular marker in phylogeography studies, yielded a misleading result, and would have led us to conclude erroneously that a single expansion had taken place in Europe. Only by combining the mitochondrial and microsatellite data sets are we able to reconstruct the species’ history and show two colonization events in Europe, one before the Last Glacial Maximum (LGM) and one after it. Combining markers also revealed the importance of Asia Minor as an ancient refugium for this species and a source population for the expansion of the greater horseshoe bat into Europe before the LGM.
Mitogen-Activated Protein Kinase Cascades and Ethylene: Signaling, Biosynthesis, or Both?: Figure 1.
2008-12-24

Mitogen-activated protein kinase (MAPK) cascades serve as important signaling pathways in all eukaryotic cells, as they link the perception of external stimuli to cellular responses. Since the discovery of CONSTITUTIVE TRIPLE RESPONSE1 (CTR1), a Raf-like MAPK kinase kinase (MAPKKK), there has been
Phototrophic Fe(II) oxidation in an atmosphere of H2: implications for Archean banded iron formations
2008-12-25

ABSTRACT The effect of hydrogen on the rate of phototrophic Fe(II) oxidation by two species of purple bacteria was measured at two different bicarbonate concentrations. Hydrogen slowed Fe(II) oxidation to varying degrees depending on the bicarbonate concentration, but even the slowest rate of Fe(II) oxidation remained on the same order of magnitude as that estimated to have been necessary to deposit the Hamersley banded iron formations. Given the hydrogen and bicarbonate concentrations inferred for the Archean, our data suggest that Fe(II) phototrophy could have been a viable process at this time.
A Mathematical Framework for the Selection of an Optimal Set of Peptides for Epitope-Based Vaccines
2008-12-26

Epitope-based vaccines (EVs) have a wide range of applications: from therapeutic to prophylactic approaches, from infectious diseases to cancer. The development of an EV is based on the knowledge of target-specific antigens from which immunogenic peptides, so-called epitopes, are derived. Such epitopes form the key components of the EV. Due to regulatory, economic, and practical concerns the number of epitopes that can be included in an EV is limited. Furthermore, as the major histocompatibility complex (MHC) binding these epitopes is highly polymorphic, every patient possesses a set of MHC class I and class II molecules of differing specificities. A peptide combination effective for one person can thus be completely ineffective for another. This renders the optimal selection of these epitopes an important and interesting optimization problem. In this work we present a mathematical framework based on integer linear programming (ILP) that allows the formulation of various flavors of the vaccine design problem and the efficient identification of optimal sets of epitopes. Out of a user-defined set of predicted or experimentally determined epitopes, the framework selects the set with the maximum likelihood of eliciting a broad and potent immune response. Our ILP approach allows an elegant and flexible formulation of numerous variants of the EV design problem. In order to demonstrate this, we show how common immunological requirements for a good EV (e.g., coverage of epitopes from each antigen, coverage of all MHC alleles in a set, or avoidance of epitopes with high mutation rates) can be translated into constraints or modifications of the objective function within the ILP framework. An implementation of the algorithm outperforms a simple greedy strategy as well as a previously suggested evolutionary algorithm and has runtimes on the order of seconds for typical problem sizes.
Influence of the preparation conditions on the morphology of perylene thin films on Si(111) and Si(100)
2008-12-28

Thin films of perylene on Si(111) and Si(100) substrates have been investigated using a variety of experimental techniques. We find that the structural and morphological properties as well as the growth modes strongly depend on the preparation parameters. In general, we observe the existence of a relatively weak coupling between perylene and the two single crystal substrates. However, under special preparation conditions, it is possible to obtain a multilayer phase on the Si(111) substrate that is characterized by flat-lying, parallel-oriented molecules, and strong coupling with the substrate in the first layer. This phase has different structural, electronic, and intermolecular bonding properties as compared to the known crystalline phases. On Si(100), by varying the deposition rate between 0.1 and 10 nm/min, it is possible to observe a transition from island growth mode, with large and isolated crystallites, to homogeneous film growth. These findings contribute to the basic knowledge for film engineering. Thus, the film morphology could be designed ranging from the growth of very large single grains suitable for a complete nanodevice to homogenous films for application in large displays.
Enforced expression of protein kinase C in skeletal muscle causes physical inactivity, fatty liver and insulin resistance in the brain
2008-12-28

Abstract Among the multitude of dysregulated signalling mechanisms that comprise insulin resistance in divergent organs, the primary events in the development of type 2 diabetes are not well established. As protein kinase C (PKC) activation is consistently present in skeletal muscle of obese and insulin resistant subjects, we generated a transgenic mouse model that overexpresses constitutively active PKC‐β 2 in skeletal muscle to test whether activation of PKC is sufficient to cause an aversive whole‐body phenotype. Upon this genetic modification, increased serine phosphorylation in Irs1 was observed and followed by impaired 3 H‐deoxy‐glucose uptake and muscle glycogen content, and transgenic mice exhibited insulin and glucose intolerance as they age. Muscle histochemistry revealed an increase in lipid deposition (intramyocellular lipids), and transgenic mice displayed impaired expression of transcriptional regulators of genes involved in fatty acid oxidation (peroxisome proliferator‐activated receptor‐γ, PGC‐1β, acyl‐CoA oxidase) and lipolysis (hormone‐sensitive lipase). In this regard, muscle of transgenic mice exhibited a reduced capacity to oxidize palmitate and contained less mitochondria as determined by citrate synthase activity. Moreover, the phenotype included a profound decrease in the daily running distance, intra‐abdominal and hepatic fat accumulation and impaired insulin action in the brain. Together, our data suggest that activation of a classical PKC in skeletal muscle as present in the pre‐diabetic state is sufficient to cause disturbances in whole‐body glucose and lipid metabolism followed by profound alterations in oxidative capacity, ectopic fat deposition and physical activity.