bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative languages
Authors: Chatterjee Krishnendu , Doyen Laurent , Henzinger Thomas A.
Published: July 2010

Quantitative generalizations of classical languages, which assign to each word a real number instead of a Boolean value, have applications in modeling resource-constrained computation. We use weighted automata (finite automata with transition weights) to define several natural classes of quantitative languages over finite and infinite words; in particular, the real value of an infinite run is computed as the maximum, limsup, liminf, limit average, or discounted sum of the transition weights. We define the classical decision problems of automata theory (emptiness, universality, language inclusion, and language equivalence) in the quantitative setting and study their computational complexity. As the decidability of the language-inclusion problem remains open for some classes of weighted automata, we introduce a notion of quantitative simulation that is decidable and implies language inclusion. We also give a complete characterization of the expressive power of the various classes of weighted automata. In particular, we show that most classes of weighted automata cannot be determinized.
Activation of the TASK-2 channel after cell swelling is dependent on tyrosine phosphorylation
Authors: Kirkegaard Signe Skyum , Lambert Ian Henry , Gammeltoft Steen , Hoffmann Else Kay
Published: July 2010

The swelling-activated K+ currents ( IK,vol) in Ehrlich ascites tumor cells (EATC) has been reported to be through the two-pore domain (K2p), TWIK-related acid-sensitive K+ channel 2 (TASK-2). The regulatory volume decrease (RVD), following hypotonic exposure in EATC, is rate limited by IK,vol indicating that inhibition of RVD reflects inhibition of TASK-2. We find that in EATC the tyrosine kinase inhibitor genistein inhibits RVD by 90%, and that the tyrosine phosphatase inhibitor monoperoxo(picolinato)-oxo-vanadate(V) [mpV(pic)] shifted the volume set point for inactivation of the channel to a lower cell volume. Swelling-activated K+ efflux was impaired by genistein and the Src kinase family inhibitor 4-amino-5-(4-chloro-phenyl)-7-( t-butyl)pyrazolo[3,4- d]pyrimidine (PP2) and enhanced by the tyrosine phosphatase inhibitor mpV(pic). With the use of the TASK-2 inhibitor clofilium, it is demonstrated that mpV(pic) increased the volume-sensitive part of the K+ efflux 1.3 times. To exclude K+ efflux via a KCl cotransporter, cellular Cl− was substituted with NO3−. Also under these conditions K+ efflux was completely blocked by genistein. Thus tyrosine kinases seem to be involved in the activation of the volume-sensitive K+ channel, whereas tyrosine phosphatases appears to be involved in inactivation of the channel. Overexpressing TASK-2 in human embryonic kidney (HEK)-293 cells increased the RVD rate and reduced the volume set point. TASK-2 has tyrosine sites, and precipitation of TASK-2 together with Western blotting and antibodies against phosphotyrosines revealed a cell swelling-induced, time-dependent tyrosine phosphorylation of the channel. Even though we found an inhibiting effect of PP2 on RVD, neither Src nor the focal adhesion kinase (FAK) seem to be involved. Inhibitors of the epidermal growth factor receptor tyrosine kinases had no effect on RVD, whereas the Janus kinase (JAK) inhibitor cucurbitacin inhibited the RVD by 40%. It is suggested that the cytokine receptor-coupled JAK/STAT pathway is upstream of the swelling-induced phosphorylation and activation of TASK-2 in EATC.
STIM1 translocation to the plasma membrane enhances intestinal epithelial restitution by inducing TRPC1-mediated Ca2+ signaling after wounding
Authors: Rao Jaladanki N. , Rathor Navneeta , Zou Tongtong , Liu Lan , Xiao Lan , Yu Ting-Xi , Cui Yu-Hong , Wang Jian-Ying
Published: July 2010

Early epithelial restitution is an important repair modality in the gut mucosa and occurs as a consequence of epithelial cell migration. Canonical transient receptor potential-1 (TRPC1) functions as a store-operated Ca2+ channel (SOCs) in intestinal epithelial cells (IECs) and regulates intestinal restitution, but the exact upstream signals initiating TRPC1 activation after mucosal injury remain elusive. Stromal interaction molecule 1 (STIM1) is a single membrane-spanning protein and is recently identified as essential components of SOC activation. The current study was performed to determine whether STIM1 plays a role in the regulation of intestinal epithelial restitution by activating TRPC1 channels. STIM1 translocation to the plasma membrane increased after wounding, which was followed by an increase in IEC migration to reseal wounds. Increased STIM1 levels at the plasma membrane by overexpressing EF-hand mutant STIM1 enhanced Ca2+ influx through SOCs and stimulated IEC migration after wounding. STIM1 interacted with TRPC1 and formed STIM1/TRPC1 complex, whereas inactivation of STIM1 by STIM1 silencing decreased SOC-mediated Ca2+ influx and inhibited epithelial restitution. In cells overexpressing EF-hand mutant STIM1, TRPC1 silencing also decreased STIM1/TRPC1 complex, reduced SOC-mediated Ca2+ influx, and repressed cell migration after wounding. Our findings demonstrate that induced STIM1 translocation to the plasma membrane promotes IEC migration after wounding by enhancing TRPC1-mediated Ca2+ signaling and provide new insight into the mechanism of intestinal epithelial restitution.
Sex differences in intracellular Ca2+ accumulation following eccentric contractions of rat skeletal muscle in vivo
Authors: Sonobe Takashi , Inagaki Tadakatsu , Sudo Mizuki , Poole David C. , Kano Yutaka
Published: July 2010

It is commonly believed that estrogen and sex influences play significant effects in skeletal muscle damage following eccentric exercise. The mechanistic bases for this sex-specific phenomenon remain to be resolved. The muscle damage has been linked to loss of Ca2+ homeostasis and resultant intramyocyte Ca2+ ([Ca2+]i) accumulation; therefore, we tested the hypothesis that the greater eccentric exercise-induced muscle damage in males would be associated with more pronounced [Ca2+]i accumulation. The intact spinotrapezius muscle of adult Wistar rats [male, female, and ovariectomized (OVX)—to investigate the effects of estrogen] was exteriorized. Tetanic eccentric contractions (100 Hz, 700-ms duration, 20 contractions/min for a total of 10 sets of 50 contractions) were elicited by electrical stimulation during synchronized muscle stretch of 10% resting muscle length. The fluorescence ratio (F340/F380 nm) was determined from images captured following each set of contractions, and fura-2 AM was used to estimate [Ca2+]i and changes thereof. Following eccentric contractions, [Ca2+]i increased significantly in male (42.8 ± 5.3%, P < 0.01) but not in female (9.4 ± 3.5%) rats. OVX evidenced an intermediate response (17.0 ± 1.2%) that remained significantly reduced compared with males. These results demonstrate that females maintain [Ca2+]i homeostasis following novel eccentric contractions, whereas males do not, which is consistent with a role for elevated [Ca2+]i in eccentric exercise-induced muscle damage. The presence of normal estrogen levels is not obligatory for the difference between the sexes.
Regulation of skeletal muscle regeneration by CCR2-activating chemokines is directly related to macrophage recruitment
Authors: Martinez Carlo O. , McHale Matthew J. , Wells Jason T. , Ochoa Oscar , Michalek Joel E. , McManus Linda M. , Shireman Paula K.
Published: July 2010

Muscle regeneration requires CC chemokine receptor 2 (CCR2) expression on bone marrow-derived cells; macrophages are a prominent CCR2-expressing cell in this process. CCR2−/− mice have severe impairments in angiogenesis, macrophage recruitment, and skeletal muscle regeneration following cardiotoxin (CTX)-induced injury. However, multiple chemokines activate CCR2, including monocyte chemotactic proteins (MCP)-1, -3, and -5. We hypothesized that MCP-1 is the chemokine ligand that mediates the impairments present in CCR2−/− mice. We examined muscle regeneration, capillary density, and cellular recruitment in MCP-1−/− and CCR2−/− mice following injury. Muscle regeneration and adipocyte accumulation, but not capillary density, were significantly impaired in MCP-1−/− compared with wild-type (WT) mice; however, muscle regeneration and adipocyte accumulation impairments were not as severe as observed in CCR2−/− mice. Although tissue levels of MCP-5 were elevated in MCP-1−/− mice compared with WT, the administration of MCP-5 neutralizing antibody did not alter muscle regeneration in MCP-1−/− mice. While neutrophil accumulation after injury was similar in all three mouse strains, macrophage recruitment was highest in WT mice, intermediate in MCP-1−/− mice, and severely impaired in CCR2−/− mice. In conclusion, while the absence of MCP-1 resulted in impaired macrophage recruitment and muscle regeneration, MCP-1−/− mice exhibit an intermediate phenotype compared with CCR2−/− mice. Intermediate macrophage recruitment in MCP-1−/− mice was associated with similar capillary density to WT, suggesting that fewer macrophages may be needed to restore angiogenesis vs. muscle regeneration. Finally, other chemokines, in addition to MCP-1 and MCP-5, may activate CCR2-dependent regenerative processes resulting in an intermediate phenotype in MCP-1−/− mice.
Critical role of Nox4-based NADPH oxidase in glucose-induced oxidative stress in the kidney: implications in type 2 diabetic nephropathy
Authors: Sedeek M. , Callera G. , Montezano A. , Gutsol A. , Heitz F. , Szyndralewiez C. , Page P. , Kennedy C. R. J. , Burns K. D. , Touyz R. M. , Hébert R. L.
Published: July 2010

Molecular mechanisms underlying renal complications of diabetes remain unclear. We tested whether renal NADPH oxidase (Nox) 4 contributes to increased reactive oxygen species (ROS) generation and hyperactivation of redox-sensitive signaling pathways in diabetic nephropathy. Diabetic mice ( db/ db) (20 wk) and cultured mouse proximal tubule (MPT) cells exposed to high glucose (25 mmol/l, d-glucose) were studied. Expression (gene and protein) of Nox4, p22phox, and p47phox, but not Nox1 or Nox2, was increased in kidney cortex, but not medulla, from db/ db vs. control mice ( db/ m) ( P < 0.05). ROS generation, p38 mitogen-activated protein (MAP) kinase phosphorylation, and content of fibronectin and transforming growth factor (TGF)-β1/2 were increased in db/ db vs. db/ m ( P < 0.01). High glucose increased expression of Nox4, but not other Noxes vs. normal glucose ( P < 0.05). This was associated with increased NADPH oxidase activation and enhanced ROS production. Nox4 downregulation by small-interfering RNA and inhibition of Nox4 activity by GK-136901 (Nox1/4 inhibitor) attenuated d-glucose-induced NADPH oxidase-derived ROS generation. High d-glucose, but not l-glucose, stimulated phosphorylation of p38MAP kinase and increased expression of TGF-β1/2 and fibronectin, effects that were inhibited by SB-203580 (p38MAP kinase inhibitor). GK-136901 inhibited d-glucose-induced actions. Our data indicate that, in diabetic conditions: 1) renal Nox4 is upregulated in a cortex-specific manner, 2) MPT cells possess functionally active Nox4-based NADPH, 3) Nox4 is a major source of renal ROS, and 4) activation of profibrotic processes is mediated via Nox4-sensitive, p38MAP kinase-dependent pathways. These findings implicate Nox4-based NADPH oxidase in molecular mechanisms underlying fibrosis in type 2 diabetic nephropathy.
Dose- and time-dependent glucocorticoid receptor signaling in podocytes
Authors: Guess Adam , Agrawal Shipra , Wei Chang-Ching , Ransom Richard F. , Benndorf Rainer , Smoyer William E.
Published: July 2010

Glucocorticoids (GC) are the primary therapy for idiopathic nephrotic syndrome (NS). Recent evidence has identified glomerular podocytes as a potential site of GC action in this disease. The objectives of this study were to determine the presence of key components of the glucocorticoid receptor (GR) complex and the functionality of this signaling pathway in podocytes and to explore potential opportunities for manipulation of GC responsiveness. Here, we show that cultured murine podocytes express key components of the GR complex, including the GR, heat shock protein 90, and the immunophilins FKBP51 and FKBP52. The functionality of GR-mediated signaling was verified by measuring several GC (dexamethasone)-induced responses, including 1) increases in mRNA and protein levels of selected GC-regulated genes (FKBP51, phenol sulfotransferase 1, αB-crystallin); 2) downregulation of the GR protein; 3) increased phosphorylation of the GR; and 4) translocation of the GR into the nuclear fraction. Dexamethasone-induced phosphorylation and downregulation of GR protein were also demonstrated in isolated rat glomeruli. Podocyte gene expression in response to dexamethasone was regulated at both the transcriptional and posttranscriptional levels, the latter also including protein degradation. Short-term, high-dose GC treatment resulted in similar changes in gene expression and GR phosphorylation to that of long-term, low-dose GC treatment, thus providing a molecular rationale for the known efficacy of pulse GC therapy in NS. Induction of FKBP51 and downregulation of the GR represent negative feedback mechanisms that can potentially be exploited to improve clinical GC efficacy. Collectively, these findings demonstrate the presence of key molecular components of the GR signaling pathway and its functionality in podocytes and identify novel opportunities for improving clinical GC efficacy in the treatment of NS.
Defining an inhibitory domain in the gamma subunit of the epithelial sodium channel
Authors: Passero Christopher J. , Carattino Marcelo D. , Kashlan Ossama B. , Myerburg Mike M. , Hughey Rebecca P. , Kleyman Thomas R.
Published: July 2010

Proteases activate the epithelial sodium channel (ENaC) by cleaving the large extracellular domains of the α- and γ-subunits and releasing peptides with inhibitory properties. Furin and prostasin activate mouse ENaC by cleaving the γ-subunit at sites flanking a 43 residue inhibitory tract (γE144-K186). To determine whether there is a minimal inhibitory region within this 43 residue tract, we generated serial deletions in the inhibitory tract of the γ-subunit in channels resistant to cleavage by furin and prostasin. We found that partial or complete deletion of a short segment in the γ-subunit, R158-N171, enhanced channel activity. Synthetic peptides overlapping this segment in the γ-subunit further identified a key 11-mer tract, R158-F168 (RFLNLIPLLVF), which inhibited wild-type ENaC expressed in Xenopus laevis oocytes, and endogenous channels in mpkCCD cells and human airway epithelia. Further studies with amino acid-substituted peptides defined residues that are required for inhibition in this key 11-mer tract. The presence of the native γ inhibitory tract in ENaC weakened the intrinsic binding constant of the 11-mer peptide inhibitor, suggesting that the γ inhibitory tract and the 11-mer peptide interact at overlapping sites within the channel.
Voltage-gated divalent currents in descending vasa recta pericytes
Authors: Zhang Zhong , Lin Hai , Cao Chunhua , Khurana Sandeep , Pallone Thomas L.
Published: July 2010

Multiple voltage-gated Ca2+channel (CaV) subtypes have been reported to participate in control of the juxtamedullary glomerular arterioles of the kidney. Using the patch-clamp technique, we examined whole cell CaVcurrents of pericytes that contract descending vasa recta (DVR). The dihydropyridine CaVagonist FPL64176 (FPL) stimulated inward Ca2+and Ba2+currents that activated with threshold depolarizations to −40 mV and maximized between −20 and −10 mV. These currents were blocked by nifedipine (1 μM) and Ni2+(100 and 1,000 μM), exhibited slow inactivation, and conducted Ba2+> Ca2+at a ratio of 2.3:1, consistent with “long-lasting” L-type CaV. In FPL, with 1 mM Ca2+as charge carrier, Boltzmann fits yielded half-maximal activation potential ( V1/2) and slope factors of −57.9 mV and 11.0 for inactivation and −33.3 mV and 4.4 for activation. In the absence of FPL stimulation, higher concentrations of divalent charge carriers were needed to measure basal currents. In 10 mM Ba2+, pericyte CaVcurrents activated with threshold depolarizations to −30 mV, were blocked by nifedipine, exhibited voltage-dependent block by diltiazem (10 μM), and conducted Ba2+> Ca2+at a ratio of ∼2:1. In Ca2+, Boltzmann fits to the data yielded V1/2and slope factors of −39.6 mV and 10.0 for inactivation and 2.8 mV and 7.7 for activation. In Ba2+, V1/2and slope factors were −29.2 mV and 9.2 for inactivation and −5.6 mV and 6.1 for activation. Neither calciseptine (10 nM), mibefradil (1 μM), nor ω-agatoxin IVA (20 and 100 nM) blocked basal Ba2+currents. Calciseptine (10 nM) and mibefradil (1 μM) also failed to reverse ANG II-induced DVR vasoconstriction, although raising mibefradil concentration to 10 μM was partially effective. We conclude that DVR pericytes predominantly express voltage-gated divalent currents that are carried by L-type channels.
Proteomic analysis identifies insulin-like growth factor-binding protein-related protein-1 as a podocyte product
Authors: Matsumoto Takayuki , Hess Sonja , Kajiyama Hiroshi , Sakairi Toru , Saleem Moin A. , Mathieson Peter W. , Nojima Yoshihisa , Kopp Jeffrey B.
Published: July 2010

The podocyte secretory proteome may influence the phenotype of adjacent podocytes, endothelial cells, parietal epithelial cells, and tubular epithelial cells but has not been systematically characterized. We have initiated studies to characterize this proteome, with the goal of further understanding the podocyte cell biology. We cultured differentiated conditionally immortalized human podocytes and subjected the proteins in conditioned medium to mass spectrometry. At a false discovery rate of <3%, we identified 111 candidates from conditioned medium, including 44 proteins that have signal peptides or are described as secreted proteins in the UniProt database. As validation, we confirmed that one of these proteins, insulin-like growth factor-binding protein-related protein-1 (IGFBP-rP1), was expressed in mRNA and protein of cultured podocytes. In addition, transforming growth factor-β1 stimulation increased IGFBP-rP1 in conditioned medium. We analyzed IGFBP-rP1 glomerular expression in a mouse model of human immunodeficiency virus-associated nephropathy. IGFBP-rP1 was absent from podocytes of normal mice and was expressed in podocytes and pseudocrescents of transgenic mice, where it was coexpressed with desmin, a podocyte injury marker. We conclude that IGFBP-rP1 may be a product of injured podocytes. Further analysis of the podocyte secretory proteome may identify biomarkers of podocyte injury.
Immersion before dry simulated dive reduces cardiomyocyte function and increases mortality after decompression
Authors: Gaustad Svein Erik , Brubakk Alf O. , Høydal Morten , Catalucci Daniele , Condorelli Gianluigi , Dujic Zeljko , Marinovic Jasna , Ljubkovic Marko , Møllerløkken Andreas , Wisløff Ulrik
Published: July 2010

Diving and decompression performed under immersed conditions have been shown to reduce cardiac function. The mechanisms for these changes are not known. The effect of immersion before a simulated hyperbaric dive on cardiomyocyte function was studied. Twenty-three rats were assigned to four groups: control, 1 h thermoneutral immersion, dry dive, and 1 h thermoneutral immersion before a dive (preimmersion dive). Rats exposed to a dive were compressed to 700 kPa, maintained for 45 min breathing air, and decompressed linearly to the surface at a rate of 50 kPa/min. Postdive, the animals were anesthetized and the right ventricle insonated for bubble detection using ultrasound. Isolation of cardiomyocytes from the left ventricle was performed and studied using an inverted fluorescence microscope with video-based sarcomere spacing. Compared with a dry dive, preimmersion dive significantly increased bubble production and decreased the survival time (bubble grade 1 vs. 5, and survival time 60 vs. 17 min, respectively). Preimmersion dive lead to 18% decreased cardiomyocyte shortening, 20% slower diastolic relengthening, and 22% higher calcium amplitudes compared with controls. The protein levels of the sarco-endoplasmic reticulum calcium ATPase (SERCA2a), Na+/Ca2+ exchanger (NCX), and phospholamban phosphorylation in the left ventricular tissue were significantly reduced after both dry and preimmersion dive compared with control and immersed animals. The data suggest that immersion before a dive results in impaired cardiomyocyte and Ca2+ handling and may be a cellular explanation to reduced cardiac function observed in humans after a dive.
Severe and Progressive Neurotransmitter Release Aberrations in Familial Hemiplegic Migraine Type 1 Cacna1a S218L Knock-in Mice
Authors: Kaja Simon , Van de Ven Rob C. G. , Broos Ludo A. M. , Frants Rune R. , Ferrari Michel D. , Van den Maagdenberg Arn M.J.M. , Plomp Jaap J.
Published: July 2010

Familial hemiplegic migraine type 1 (FHM1) is caused by mutations in the CACNA1A gene, encoding neuronal presynaptic CaV2.1 (P/Q-type) Ca2+ channels. These channels mediate neurotransmitter release at many central synapses and at the neuromuscular junction (NMJ). Mutation S218L causes a severe neurological phenotype of FHM and, additionally, ataxia and susceptibility to seizures, delayed brain edema, and fatal coma after minor head trauma. Recently, we generated a Cacna1a S218L knock-in mutant mouse, displaying these features and reduced survival. A first electrophysiological study showed high susceptibility for cortical spreading depression, enhanced neuronal soma Ca2+ influx, and at diaphragm NMJs, a considerable increase of neurotransmitter release. We here assessed the function of S218L knock-in NMJs at several muscle types in great detail. Pharmacological analyses using specific CaV subtype-blocking toxins excluded compensatory contribution of non-CaV2.1 channels. Endplate potentials were considerably broadened at many NMJs. High rate (40 Hz)–evoked acetylcholine release was slightly reduced; however, it was not associated with block of neurotransmission causing weakness, as assessed with grip strength measurements and in vitro muscle contraction experiments. The synaptopathy clearly progressed with age, including development of an increased acetylcholine release at low-rate nerve stimulation at physiological extracellular Ca2+ concentration and further endplate potential broadening. Our results suggest enhanced Ca2+ influx into motor nerve terminals through S218L-mutated presynaptic CaV2.1 channels, likely because of the earlier reported negative shift of activation potential and reduced inactivation. Similar severe aberrations at central synapses of S218L mutant mice and humans may underlie or contribute to the drastic neurological phenotype.
Excitatory Input Onto Hilar Somatostatin Interneurons Is Increased in a Chronic Model of Epilepsy
Authors: Halabisky Brian , Parada Isabel , Buckmaster Paul S. , Prince David A.
Published: July 2010

The density of somatostatin (SOM)-containing GABAergic interneurons in the hilus of the dentate gyrus is significantly decreased in both human and experimental temporal lobe epilepsy. We used the pilocarpine model of status epilepticus and temporal lobe epilepsy in mice to study anatomical and electrophysiological properties of surviving somatostatin interneurons and determine whether compensatory functional changes occur that might offset loss of other inhibitory neurons. Using standard patch-clamp techniques and pipettes containing biocytin, whole cell recordings were obtained in hippocampal slices maintained in vitro. Hilar SOM cells containing enhanced green fluorescent protein (EGFP) were identified with fluorescent and infrared differential interference contrast video microscopy in epileptic and control GIN (E GFP-expressing Inhibitory Neurons) mice. Results showed that SOM cells from epileptic mice had 1) significant increases in somatic area and dendritic length; 2) changes in membrane properties, including a small but significant decrease in resting membrane potential, and increases in time constant and whole cell capacitance; 3) increased frequency of slowly rising spontaneous excitatory postsynaptic currents (sEPSCs) due primarily to increased mEPSC frequency, without changes in the probability of release; 4) increased evoked EPSC amplitude; and 5) increased spontaneous action potential generation in cell-attached recordings. Results suggest an increase in excitatory innervation, perhaps on distal dendrites, considering the slower rising EPSCs and increased output of hilar SOM cells in this model of epilepsy. In sum, these changes would be expected to increase the inhibitory output of surviving SOM interneurons and in part compensate for interneuronal loss in the epileptogenic hippocampus.
Putative Pyramidal Neurons and Interneurons in the Monkey Parietal Cortex Make Different Contributions to the Performance of a Visual Grouping Task
Authors: Yokoi Isao , Komatsu Hidehiko
Published: July 2010

Visual grouping of discrete elements is an important function for object recognition. We recently conducted an experiment to study neural correlates of visual grouping. We recorded neuronal activities while monkeys performed a grouping detection task in which they discriminated visual patterns composed of discrete dots arranged in a cross and detected targets in which dots with the same contrast were aligned horizontally or vertically. We found that some neurons in the lateral bank of the intraparietal sulcus exhibit activity related to visual grouping. In the present study, we analyzed how different types of neurons contribute to visual grouping. We classified the recorded neurons as putative pyramidal neurons or putative interneurons, depending on the duration of their action potentials. We found that putative pyramidal neurons exhibited selectivity for the orientation of the target, and this selectivity was enhanced by attention to a particular target orientation. By contrast, putative interneurons responded more strongly to the target stimuli than to the nontargets, regardless of the orientation of the target. These results suggest that different classes of parietal neurons contribute differently to the grouping of discrete elements.
Feasible Modified Subgradient Method for Solving the Thermal Unit Commitment Problem as a New Approach
Authors: Filik Ummuhan Basaran , Kurban Mehmet
Published: July 2010

The Lagrangian relaxation‐ (LR‐) based methods are commonly used to solve the thermal unit commitment (UC) problem which is an important subject in power system engineering. The main drawback of this group of methods is the difference between the dual and the primal solutions which gives some significant problems on the quality of the feasible solutions. In this paper, a new approach, feasible modified subgradient (F‐MSG) method which does not require finding an unconstrained global minimum of the Lagrangian function and knowing an optimal value of the problem under consideration in order to update dual variables at the each iteration, is firstly used for solving the thermal UC problem. The major advantage of the proposed approach is that it guarantees the zero duality gap and convergence independently from the size of the problem. In order to discuss the advantages of this method, the four‐unit Tuncbilek thermal plant, which is located in Kutahya region in Turkey, is chosen as a small test system. The numerical results show that F‐MSG gives better solutions as compared to the standard LR method.
The LH/hCG Axis in Endometrial Cancer: A New Target in the Treatment of Recurrent or Metastatic Disease
Authors: Arcangeli A. , Noci I. , Fortunato A. , Scarselli G. F.
Published: July 2010

Endometrial cancer (EC) is a hormone‐dependent cancer that currently represents the most frequent malignancy of the female reproductive tract. The involvement of steroid hormones in EC etiology and progression has been reported. More recently, gonadotropins, and, in particular LH/hCG, are emerging as novel regulators of tumor progression. In the present review, we discuss the role of the LH/hCG axis (i.e. LH/hCG and its receptors, LH/hCG‐R) in both gonadal and nongonadal tissues, in physiological and neoplastic conditions. In cancer cells, LH/hCG mainly controls cell proliferation and apoptosis. In particular, in EC LH/hCG improves cell invasiveness, through a mechanism which involves the LH/hCG‐R, which in turn activate protein kinase A and modulate integrin adhesion receptors. Indeed, the LH/hCG‐R mRNA is expressed in primary ECs and this expression correlates with LH/hCG‐induced cell invasiveness in vitro. These results lead to hypothesize that recurrent and metastatic ECs, which express LH/hCG‐R, could benefit from therapies aimed at decreasing LH levels, through Gn‐RH analogues. Hence, the LH/hCG axis could represent a prognostic factor and a new therapeutic target in EC.
Additions to the Known Distribution ofEpipompilus aztecus(Cresson, 1869) andE. excelsus(Bradley, 1944) (Hymenoptera: Pompilidae)
Authors: dos Santos Eduardo Fernando , Noll Fernando Barbosa
Published: July 2010

Knowledge about the species distribution ofEpipompilusKohl, 1884, is largely based on the records from the species description. Recent efforts in South American bodiversity studies indicate that knowledge about the distribution ofEpipompilusspecies in the region is in an early stage. Two new records ofE. aztecuswere obtained for the semideciduous Atlantic Forest, in central Brazil, and one record for the Amazonian Forest in northern Brazil, indicating that its distribution extends between Central and South America. The new records ofE. excelsuswere obtained mainly from the Atlantic Forest highlands, indicating that this species is commonly found in the southeastern South American Central Plateau and restricted to forest ecosystem of this region.
New Three-Level Resource Management Enhancing Quality of Offline Hardware Task Placement on FPGA
Authors: Belaid Ikbel , Muller Fabrice , Benjemaa Maher
Published: July 2010

Currently, reconfigurable hardware devices feature a high density of heterogeneous resources to enable multitasking and offer flexibility in application needs. These concepts raise the need for efficient management of hardware tasks and hardware resources. The scheduling of hardware tasks is highly dependent on placement. Placement focuses on allocation of hardware resources required by the scheduled hardware tasks. In this paper, we propose novel three-level resource management that investigates enhancement of placement quality by reducing task rejection, configuration overheads, and by optimizing resource utilization. Improving placement quality will produce significant enhancement of performance for scheduling and overall execution time of the application in FPGA. Hence, the placement problem is formulated into a constrained optimization problem and resolved with powerful solvers using the Branch and Bound method. The obtained results of an application of heterogeneous hardware tasks show an average resource utilization of 36% of the available resources on the reconfigurable region and an overall overhead of 11% of total application running time, and we have eliminated the issue of task rejection. Compared to static implementation, the gain in resource utilization within the reconfigurable region achieves up to 43%.
The Epidermal Growth Factor Receptor Antibody Cetuximab Induces Autophagy in Cancer Cells by Downregulating HIF-1α and Bcl-2 and Activating the Beclin 1/hVps34 Complex
Authors: Li Xinqun , Fan Zhen
Published: July 2010

Autophagy is a regulated catabolic process triggered in cells deprived of nutrients or growth factors that govern nutrient uptake. Here, we report that autophagy is induced by cetuximab, a therapeutic antibody that blocks epidermal growth factor receptor function. Cancer cell treatment with cetuximab triggered autophagosome formation, conversion of microtubule-associated protein 1 light chain 3 from its cytoplasmic to membrane-associated form, and increased acidic vesicular organelle formation. Autophagy occurred when cetuximab inhibited the class I phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin pathway, but not when it inhibited only the mitogen-activated protein/extracellular signal-regulated kinase kinase/Erk pathway, and it was accompanied by decreased levels of hypoxia inducible factor-1 α (HIF-1α) and Bcl-2. Stable overexpression of a HIF-1α mutant prevented cetuximab-induced autophagy and decrease in Bcl-2 levels. Knockdown of autophagy regulator beclin 1 or cell treatment with autophagy inhibitor 3-methyladenine, a class III PI3K (hVps34) inhibitor, also inhibited cetuximab-induced autophagy. Furthermore, knockdown of beclin 1 or Atg7 or treatment with the lysosome inhibitor chloroquine sensitized cancer cells to cetuximab-induced apoptosis. Mechanistic analysis argued that cetuximab acted by promoting an association between beclin 1 and hVps34, which was inhibited by overexpression of Bcl-2. Our findings suggest that the autophagy protects cancer cells from the proapoptotic effects of cetuximab. Cancer Res; 70(14); 5942–52. ©2010 AACR.
Transplanting Normal Vascular Proangiogenic Cells to Tumor-Bearing Mice Triggers Vascular Remodeling and Reduces Hypoxia in Tumors
Authors: Sasajima Junpei , Mizukami Yusuke , Sugiyama Yoshiaki , Nakamura Kazumasa , Kawamoto Toru , Koizumi Kazuya , Fujii Rie , Motomura Wataru , Sato Kazuya , Suzuki Yasuaki , Tanno Satoshi , Fujiya Mikihiro , Sasaki Katsunori , Shimizu Norihiko , Karasaki Hidenori , Kono Toru , Kawabe Jun-ichi , Ii Masaaki , Yoshiara Hiroki , Kamiyama Naohisa , Ashida Toshifumi , Bardeesy Nabeel , Chung Daniel C. , Kohgo Yutaka
Published: July 2010

Blood vessels deliver oxygen and nutrients to tissues, and vascular networks are spatially organized to meet the metabolic needs for maintaining homeostasis. In contrast, the vasculature of tumors is immature and leaky, resulting in insufficient delivery of nutrients and oxygen. Vasculogenic processes occur normally in adult tissues to repair “injured” blood vessels, leading us to hypothesize that bone marrow mononuclear cells (BMMNC) may be able to restore appropriate vessel function in the tumor vasculature. Culturing BMMNCs in endothelial growth medium resulted in the early outgrowth of spindle-shaped attached cells expressing CD11b/Flt1/Tie2/c-Kit/CXCR4 with proangiogenic activity. Intravenous administration of these cultured vascular proangiogenic cells (VPC) into nude mice bearing pancreatic cancer xenografts and Pdx1-Cre;LSL-KrasG12D;p53lox/+ genetically engineered mice that develop pancreatic ductal adenocarcinoma significantly reduced areas of hypoxia without enhancing tumor growth. The resulting vasculature structurally mimicked normal vessels with intensive pericyte coverage. Increases in vascularized areas within VPC-injected xenografts were visualized with an ultrasound diagnostic system during injection of a microbubble-based contrast agent (Sonazoid), indicating a functional “normalization” of the tumor vasculature. In addition, gene expression profiles in the VPC-transplanted xenografts revealed a marked reduction in major factors involved in drug resistance and “stemness” of cancer cells. Together, our findings identify a novel alternate approach to regulate abnormal tumor vessels, offering the potential to improve the delivery and efficacy of anticancer drugs to hypoxic tumors. Cancer Res; 70(15); 6283–92. ©2010 AACR.
Gr-1+CD11b+ Myeloid Cells Tip the Balance of Immune Protection to Tumor Promotion in the Premetastatic Lung
Authors: Yan Hannah H. , Pickup Michael , Pang Yanli , Gorska Agnieszka E. , Li Zhaoyang , Chytil Anna , Geng Yipeng , Gray Jerome W. , Moses Harold L. , Yang Li
Published: July 2010

The mechanisms by which a primary tumor affects a selected distant organ before tumor cell arrival remain to be elucidated. This report shows that Gr-1+CD11b+ cells are significantly increased in lungs of mice bearing mammary adenocarcinomas before tumor cell arrival. In the premetastatic lungs, these immature myeloid cells significantly decrease IFN-γ production and increase proinflammatory cytokines. In addition, they produce large quantities of matrix metalloproteinase 9 (MMP9) and promote vascular remodeling. Deletion of MMP9 normalizes aberrant vasculature in the premetastatic lung and diminishes lung metastasis. The production and activity of MMP9 is selectively restricted to lungs and organs with a large number of Gr-1+CD11b+ cells. Our work reveals a novel protumor mechanism for Gr-1+CD11b+ cells that changes the premetastatic lung into an inflammatory and proliferative environment, diminishes immune protection, and promotes metastasis through aberrant vasculature formation. Thus, inhibition of Gr-1+CD11b+ cells could normalize the premetastatic lung environment, improve host immunosurveillance, and inhibit tumor metastasis. Cancer Res; 70(15); 6139–49. ©2010 AACR.
Bisphosphonates Induce Apoptosis of Circulating Endothelial Cells in Multiple Myeloma Patients and in Subjects with Bisphosphonate-Induced Osteonecrosis of the Jaws
Authors: Allegra Alessandro , Alonci Andrea , Penna Giuseppa , Granata Angela , Nastro Siniscalchi Enrico , Oteri Giacomo , Loddo Saverio , Teti Diana , Cicciù Domenico , De Ponte Francesco Saverio , Musolino Caterina
Published: July 2010

Bisphosphonates (BPs) are the current standard of care for bone lesions in patients with multiple myeloma (MM) but they are associated with a number of side effects such as osteonecrosis of the jaw. The exact mechanisms of osteonecrosis are not elucidated, and its physiopathology is based on several hypotheses such as a decrease in bone remodeling or an inhibitory effect on angiogenesis. The aim of our study was to investigate the mechanism involved in the pathogenesis of osteonecrosis. We examined the apoptosis of circulating endothelial progenitor cells in MM subjects before and after BP treatment and in osteonecrosis patients using a flow-cytometric analysis. Our data showed an increase in endothelial cell apoptosis in MM patients after BP administration and in osteonecrosis subjects. Our study seems in agreement with the hypothesis that BPs can inhibit angiogenesis interfering with endothelial cell proliferation and survival, leading to loss of blood vessels and avascular necrosis.
Education of Logopedists or Speech-Language Pathologists in Bulgaria, Greece, Macedonia, Poland and Russia
Authors: Georgieva Dobrinka
Published: July 2010

This article provides an overview of student training programs in logopedics in Bulgaria, Greece, Macedonia, Poland and the Russian Federation. The data were collected using a special questionnaire developed by Söderpalm in 2006 and supplemented by the author. Bachelor’s, master’s and PhD programs in the field of pure logopedics no longer exist in some countries. In other locations, logopedics is included as a part of special education student training. In all cases, student education in logopedics is centralized in the universities. Educational programs are accredited by national agencies for accreditation or evaluation or by the respective Ministries of Education.
Emerging Issues in Health and Education in Asia-Pacific: A Focus on Speech-Language Pathology
Authors: Cheng Li-Rong Lilly
Published: July 2010

The purpose of this paper is to present some emerging issues in health and education in the Asia-Pacific region. Special attention will be given to the education of speech-language pathologists (SLP) and to service provision for the people with communicative disorders whenever possible. Information on the education of SLP in Asia-Pacific is not easy to gather because of the geographical distances between areas, language differences in the data compiled and the lack of consistent collaboration and information exchanges. In this article, a case study from Singapore is also presented. Implications for clinical services and education are discussed at the end of this paper.
Communication in the Migrant Community in Malta
Authors: Grech Helen , Cheng Li-Rong Lilly
Published: July 2010

Aims: The study aimed to obtain information about communication in the migrant community in Malta. The objectives were to identify the communication skills of the migrants in terms of language use and exposure; to verify whether members of the migrant community have access to participation, education, socialization and opportunities for gainful employment, and to identify if the migrant community is willing to share insights. Method: A questionnaire was specifically devised to collect data via structured interviews. The project targeted candidates seeking refugee status. Forty immigrants consented to participate and were interviewed with the help of interpreters and carers. Results: Results indicate that migrants seem to experience different levels of adaptation and assimilation into the host cultural and social network. Some feel marginalized, while others seem to be adjusting to the new culture; these individuals also reported minimal to no difficulties with communicating with the local people. Communication among themselves was reported to be difficult for some, even though most of the migrants hailed from North Africa. Conclusion: The study provides an overview of challenges identified and highlights the need for service providers to identify cultural and linguistic characteristics to optimize their interpretation of behaviour.
Predation and Predation Attempts on Red Titi Monkeys (Callicebus discolor) and Equatorial Sakis (Pithecia aequatorialis) in Amazonian Ecuador
Authors: de Luna Ana Gabriela , Sanmiguel Ramiro , Fiore Anthony Di , Fernandez-Duque Eduardo
Published: July 2010

Anecdotal reports of predation as well as observed predation attempts and rates of animal disappearance provide some of the most relevant data for evaluating the influence that predation risk may have on primate behavioural ecology. Here, we report rates of disappearance from six groups of red titi monkeys (Callicebus discolor) and two groups of equatorial sakis (Pithecia aequatorialis) followed over a period of four and a half years at a lowland site in Amazonian Ecuador. We also describe the first direct observation of a harpy eagle (Harpia harpyja) preying upon a titi monkey, as well as 3 unsuccessful attacks by tayras (Eira barbara) on titi monkeys and 4 unsuccessful attacks by various raptors on sakis. Our data indicate that pitheciid primates may face a wider array of possible predators than previously recognized, and that titi monkeys and sakis are susceptible to different major classes of predators. Our observations also suggest differences in the sex role during predator defence that could be related to the evolution and maintenance of monogamous systems.
A Single-Center Experience of Antimicrobial Resistance Patterns in Pediatric Urinary Tract Infection
Authors: Senel Saliha , Karacan Candemir , Erkek Nilgun , Gol Nese
Published: July 2010

Objective: To assess the prevalence of urinary tract pathogens and their resistance patterns against antimicrobial agents in a single center. Patients and Methods: In children <16 years of age admitted for urinary tract infection (UTI) to the Dr. Sami Ulus Teaching and Training Hospital from January 2004 to December 2008, positive urine cultures were reviewed. Results: A total of 3,485 positive urine cultures were identified, of which 2,379 (68%) were from females and 106 (32%) from males. Their mean age was 63.5 ± 40.7 months. Escherichia coli was the most common causative agent both in total and among different age groups. Ampicillin had the highest resistance rate from all the pathogens isolated (63.8%), followed by piperacillin (51.8%) and trimethoprim-sulfamethoxazole (TMP-SMX; 48.6%). Cephalotin also had a high resistance rate (32.7%). The least resistance was for imipenem, amikacin, netilmicin and ciprofloxacin (0.13, 1.7, 2.4 and 7.5%, respectively). None of the Klebsiella and Pseudomonas isolates were resistant to imipenem. None of the Staphylococcus aureus isolates were resistant to teicoplanin and vancomycin. Vancomycin-resistant Enterococcus spp. were isolated from two cultures. Conclusion:E. coli was the most common causative agent of UTI in children. Ampicillin, TMP-SMX or cephalothin and piperacillin had the highest resistance rates against urinary tract pathogens in our center.
In silico Binding Predictions for Identification of HLA-DR-Promiscuous Regions and Epitopes of Mycobacterium tuberculosis Protein MPT64 (Rv1980c) and Their Recognition by Human Th1 Cells
Authors: Mustafa Abu Salim
Published: July 2010

Objective: To identify HLA-promiscuous regions and epitopes of MPT64 (Rv1980c), a major secreted antigen of Mycobacterium tuberculosis, by in silico analysis for binding to HLA-DR molecules. Materials and Methods: The sequence of mature MPT64 protein (aa 1–205) was analyzed in silico for HLA-DR binding regions and T cell epitopes using ProPred, a web-based prediction server. The prediction results were experimentally verified by testing 20-mer synthetic peptides corresponding to the predicted HLA-DR binding regions and epitopes with T cell lines established from peripheral blood mononuclear cells of PPD-positive and HLA-heterogeneous healthy subjects in Th1 cell assays (antigen-induced proliferation and IFN-γ secretion). Results: The in silico analysis for binding of the mature MPT64 sequence to HLA-DR molecules suggested that it could bind to molecules expressed from all HLA-DR alleles (n = 51) included in ProPred. Furthermore, ProPred identified 26 epitopes and 8 nonoverlapping HLA-DR binding regions (9–35 aa in length) in the Rv1980c sequence, with 5 regions (aa 20–44, aa 68–102, aa 132–146, aa 164–186 and aa 194–202) being HLA-DR-promiscuous. By using synthetic peptides and T cell lines in Th1 cell assays, 4 peptides of MPT64 (aa 21–40, aa 81–100, aa 171–190 and aa 191–20), from 4 of the 5 HLA-DR-promiscuous regions predicted by ProPred, were experimentally verified to be HLA-DR-promiscuous and to have immunodominant epitopes. Conclusion: The in silico method (ProPred) suggested promiscuous HLA-DR-binding of mature MPT64 and identified HLA-promiscuous and immunodominant regions and epitopes of this protein.
Relative Frequency of Staphylococcal Carriage and Antibiotic Sensitivity of Isolated Staphylococci in Hemodialysis Patients in Shiraz, Iran
Authors: Motamedifar Mohammad , Hassanzadeh Parvin , Ghafari Narjes
Published: July 2010

Objective: The purpose of this study was to determine the nasal carriage rate of Staphylococcus aureus in hemodialysis patients and the antibiogram of all isolated S. aureus from carriers. Subjects and Methods: A cross-sectional study was carried out from May to September 2007. 130 patients (49 females, 81 males; mean age 55.6 ± 15.2 years) with chronic renal failure were included in the study. The patients had undergone hemodialysis for at least 12 months in the dialysis ward of Faghihi Hospital, a referral center in Shiraz, Iran. Swab specimens were taken from the anterior nares and skin of the patients and cultured microbiologically. Next, antibiotic susceptibility tests were performed for all of the isolated S. aureus. Results: 32 (24.6%) patients (95% CI 17.5–32.9%) were nasal carriers of S. aureus versus 98 (75.4%) non-carriers. S. aureus was also isolated from skin of 5 (3.8%) patients who were nasal carriers as well. The isolated S. aureus were 100, 97.3, 73.0, 70.3, 40.5 and 21.6% sensitive to vancomycin, rifampin, ciprofloxacin, tetracycline, methicillin and erythromycin, respectively. Conclusion: Because the nasal carriage rate of S. aureus observed in dialysis patients in this study was relatively high, we recommend screening for S. aureus in hemodialysis patients to enable prompt prevention strategies.