bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection and Genetic Characterization of Enteroviruses Circulating among Wild Populations of Chimpanzees in Cameroon: Relationship with Human and Simian Enteroviruses
Authors: Harvala Heli , Sharp Colin P. , Ngole Eitel Mpoudi , Delaporte Eric , Peeters Martine , Simmonds Peter
Published: February 2011

Enteroviruses (EVs), members of the family
Picornaviridae
, are a genetically and antigenically diverse range of viruses causing acute infections in humans and several Old World monkey (OWM) species. Despite their known wide distribution in primates, nothing is currently known about the occurrence, frequency, and genetic diversity of enteroviruses infecting apes. To investigate this, 27 chimpanzee and 27 gorilla fecal samples collected from undisturbed jungle areas with minimal human contact in Cameroon were screened for EVs. Four chimpanzee samples were positive, but none of the gorilla samples were positive. Genetic characterization of the VP1, VP4, and partial VP2 genes, the 5′ untranslated region, and partial 3Dpol sequences enabled chimpanzee-derived EVs to be identified as (i) the species A type, EV76, (ii) a new species D type assigned as EV111, along with a human isolate from the Democratic Republic of Congo previously described by the International Committee on the Taxonomy of Viruses, and (iii) a new species B type (assigned as EV110) most closely related to, although a distinct type from, the SA5 isolate recovered from a vervet monkey. The identification of EVs infecting chimpanzees related to those circulating in human and OWM populations provides evidence for cross-species transmission of EVs between primates. However, the direction of transfer and the existence of primate sources of zoonotic enterovirus infections in humans require further investigation of population exposure and more extensive characterization of EVs circulating in wild ape populations.
Effects of Receptor Binding Specificity of Avian Influenza Virus on the Human Innate Immune Response
Authors: Ramos Irene , Bernal-Rubio Dabeiba , Durham Natasha , Belicha-Villanueva Alan , Lowen Anice C. , Steel John , Fernandez-Sesma Ana
Published: February 2011

Humans infected by the highly pathogenic H5N1 avian influenza viruses (HPAIV) present unusually high concentrations in serum of proinflammatory cytokines and chemokines, which are believed to contribute to the high pathogenicity of these viruses. The hemagglutinins (HAs) of avian influenza viruses preferentially bind to sialic acids attached through α2,3 linkages (SAα2,3) to the terminal galactose of carbohydrates on the host cell surface, while the HAs from human strains bind to α2,6-linked SA (SAα2,6). To evaluate the role of the viral receptor specificity in promoting innate immune responses in humans, we generated recombinant influenza viruses, one bearing the HA and neuraminidase (NA) genes from the A/Vietnam/1203/2004 H5N1 HPAIV in an influenza A/Puerto Rico/8/1934 (A/PR/8/34) backbone with specificity for SAα2,3 and the other a mutant virus (with Q226L and G228S in the HA) with preferential receptor specificity for SAα2,6. Viruses with preferential affinity for SAα2,3 induced higher levels of proinflammatory cytokines and interferon (IFN)-inducible genes in primary human dendritic cells (DCs) than viruses with SAα2,6 binding specificity, and these differences were independent of viral replication, as shown by infections with UV-inactivated viruses. Moreover, human primary macrophages and respiratory epithelial cells showed higher expression of proinflammatory genes after infection with the virus with SAα2,3 affinity than after infection with the virus with SAα2,6 affinity. These data indicate that binding to SAα2,3 by H5N1 HPAIV may be sensed by human cells differently than binding to SAα2,6, inducing an exacerbated innate proinflammatory response in infected individuals.
Analysis of Poliovirus Protein 3A Interactions with Viral and Cellular Proteins in Infected Cells
Authors: Teterina Natalya L. , Pinto Yuval , Weaver Joseph D. , Jensen Kenneth S. , Ehrenfeld Ellie
Published: February 2011

Poliovirus proteins 3A and 3AB are small, membrane-binding proteins that play multiple roles in viral RNA replication complex formation and function. In the infected cell, these proteins associate with other viral and cellular proteins as part of a supramolecular complex whose structure and composition are unknown. We isolated viable viruses with three different epitope tags (FLAG, hemagglutinin [HA], and c-myc) inserted into the N-terminal region of protein 3A. These viruses exhibited growth properties and characteristics very similar to those of the wild-type, untagged virus. Extracts prepared from the infected cells were subjected to immunoaffinity purification of the tagged proteins by adsorption to commercial antibody-linked beads and examined after elution for cellular and other viral proteins that remained bound to 3A sequences during purification. Viral proteins 2C, 2BC, 3D, and 3CD were detected in all three immunopurified 3A samples. Among the cellular proteins previously reported to interact with 3A either directly or indirectly, neither LIS1 nor phosphoinositol-4 kinase (PI4K) were detected in any of the purified tagged 3A samples. However, the guanine nucleotide exchange factor GBF1, which is a key regulator of membrane trafficking in the cellular protein secretory pathway and which has been shown previously to bind enteroviral protein 3A and to be required for viral RNA replication, was readily recovered along with immunoaffinity-purified 3A-FLAG. Surprisingly, we failed to cocapture GBF1 with 3A-HA or 3A-myc proteins. A model for variable binding of these 3A mutant proteins to GBF1 based on amino acid sequence motifs and the resulting practical and functional consequences thereof are discussed.
Transcriptional Repression of C4 Complement by Hepatitis C Virus Proteins
Authors: Banerjee Arup , Mazumdar Budhaditya , Meyer Keith , Di Bisceglie Adrian M. , Ray Ratna B. , Ray Ranjit
Published: February 2011

The fourth component of human complement (C4) plays an important role in innate immune function. C4 activity has been observed to be significantly lower in patients with chronic hepatitis C virus (HCV) infections, although the mechanism remains unknown. In this study, we have examined the mechanisms of C4 regulation by HCV. Liver biopsy specimens from patients with chronic HCV infections displayed significantly lower C4 mRNA levels than liver tissue samples from patients with unrelated liver disease. Further, C4 mRNA levels of the two isoforms (C4A and C4B) were significantly reduced in hepatocytes transfected with RNA from HCV genotype 1a or 2a. Subsequently, a significant C4 regulatory role of HCV core or NS5A upon C4 promoter activity was observed. HCV core or NS5A transgenic mice displayed a reduction in C4 mRNA. Gamma interferon (IFN-γ)-induced C4 promoter activation was also impaired in the presence of HCV proteins. We further demonstrated that HCV core reduced the expression of upstream stimulating factor 1 (USF-1), a transcription factor important for basal C4 expression. On the other hand, the expression of interferon regulatory factor 1 (IRF-1), which is important for IFN-γ-induced C4 expression, was inhibited by hepatocytes expressing HCV NS5A. These results underscore the roles of HCV proteins in innate immune regulation in establishing a chronic infection.
Mutagenesis of Varicella-Zoster Virus Glycoprotein I (gI) Identifies a Cysteine Residue Critical for gE/gI Heterodimer Formation, gI Structure, and Virulence in Skin Cells
Authors: Oliver Stefan L. , Sommer Marvin H. , Reichelt Mike , Rajamani Jaya , Vlaycheva-Beisheim Leonssia , Stamatis Shaye , Cheng Jason , Jones Carol , Zehnder James , Arvin Ann M.
Published: February 2011

Varicella-zoster virus (VZV) is the alphaherpesvirus that causes chicken pox (varicella) and shingles (zoster). The two VZV glycoproteins gE and gI form a heterodimer that mediates efficient cell-to-cell spread. Deletion of gI yields a small-plaque-phenotype virus, ΔgI virus, which is avirulent in human skin using the xenograft model of VZV pathogenesis. In the present study, 10 mutant viruses were generated to determine which residues were required for the typical function of gI. Three phosphorylation sites in the cytoplasmic domain of gI were not required for VZV virulence
in vivo
. Two deletion mutants mapped a gE binding region in gI to residues 105 to 125. A glycosylation site, N116, in this region did not affect virulence. Substitution of four cysteine residues highly conserved in the
Alphaherpesvirinae
established that C95 is required for gE/gI heterodimer formation. The C95A and Δ105–125 (with residues 105 to 125 deleted) viruses had small-plaque phenotypes with reduced replication kinetics
in vitro
similar to those of the ΔgI virus. The Δ105–125 virus was avirulent for human skin
in vivo
. In contrast, the C95A mutant replicated
in vivo
but with significantly reduced kinetics compared to those of the wild-type virus. In addition to abolished gE/gI heterodimer formation, gI from the C95A or the Δ105–125 mutant was not recognized by monoclonal antibodies that detect the canonical conformation of gI, demonstrating structural disruption of gI in these viruses. This alteration prevented gI incorporation into virus particles. Thus, residues C95 and 105 to 125 are critical for gI structure required for gE/gI heterodimer formation, virion incorporation, and ultimately, effective viral spread in human skin.
A NOTE ON THE COMPUTATION OF THE SHAPLEY VALUE FOR VON NEUMANN–MORGENSTERN MARKET GAMES
Authors: FRAGNELLI VITO , MECA ANA
Published: February 2011

We consider a von Neumann–Morgenstern market game and present a simple expression for the Shapley value via decomposition as the difference of an airport game and an extended airport game. The resulting formula has a useful interpretation for designing an allocation procedure among the agents.
Timing of uplift of the Troodos Massif (Cyprus) constrained by sedimentary and magnetic polarity evidence
Authors: Kinnaird Tim C. , Robertson Alastair H.F. , Morris Antony
Published: February 2011

Plio-Pleistocene sediments exposed around the ophiolitic Troodos Massif document spectacular uplift from below sea level to a maximum height of
c
. 2000 m. Sedimentation reflects a dominant control of focused tectonic uplift, modified by the effects of glacio-eustatic sea-level change and climatic change. Understanding the uplift and controls on deposition has been hindered by an inadequate age model. Here, we present a preliminary investigation of the polarity of remanent magnetizations recorded within the upper part of the Pliocene succession in the Pissouri and Mesaoria basins and from the Pleistocene marine terrace deposits that border the Troodos Massif. When integrated with available lithostatigraphic and biostratigraphic data, the main results are as follows. Focused uplift of the Troodos Massif began during the Late Pliocene, either between 2.14 and 1.95 Ma or immediately prior to 1.77 Ma. Shallow-marine, ophiolite-derived clastic and bioclastic sediments accumulated in both the Mesaoria and Pissouri basins, implying that the Troodos Massif was uplifted as a single tectonic entity. Non-marine, deltaic and fluvial facies prograded into both of the basins during the Pleistocene (1.77 Ma–recent). Marine terraces in SW and south Cyprus were cut and covered by littoral sediments from <0.78 Ma, suggesting that high rates of uplift of the Troodos Massif persisted into mid- and late Pleistocene time.
Radiation and extinction patterns in Permian floras from North China as indicators for environmental and climate change
Authors: Stevens Liadan G. , Hilton Jason , Bond David P.G. , Glasspool Ian J. , Jardine Phillip E.
Published: February 2011

Permian continental sequences from North China contain previously unrecognized episodes of plant radiation and elevated extinction. The earliest extinction, in the Lower Shihhotse Formation (Roadian, Guadalupian), records a 45% floral species loss and is tentatively correlated with global extinctions amongst dinocephalian reptiles. Two younger extinctions are dated by correlating the Illawara Reversal and palaeomagnetic polarity sequences from Shanxi Province against global palaeomagnetic history. Missing data from the Shanxi sequence are evaluated using a novel approach estimating likely maximum and minimum sequence changes that provide age estimates for post-Illawara events in North China. The second extinction in the middle Upper Shihhotse Formation is more significant and is dated to the mid-Capitanian, with a loss of 56% of plant species coinciding with two phases of volcanism of the Emeishan Large Igneous Province in South China, previously linked to the mid-Capitanian marine mass extinction. The youngest extinction in the upper Upper Shihhotse Formation (late Capitanian to mid-Wuchapingian) is catastrophic and represents the end of range in the sequence. Changes in sedimentary facies suggest it to be related to global climatic warming and drying. Other viable causal mechanisms for the extinction episodes include plate motion and collision, global climate change, volcanism and biological competition.
Transcriptional regulation of the Menkes copper ATPase (Atp7a) gene by hypoxia-inducible factor (HIF2α) in intestinal epithelial cells
Authors: Xie Liwei , Collins James F.
Published: February 2011

Iron homeostasis-related genes (e.g., Dmt1 and Dcytb) are upregulated by hypoxia-inducible factor 2α (HIF2α) during iron deficiency in the mammalian intestine. Menkes copper ATPase ( Atp7a) gene expression is also strongly induced in the duodenum of iron-deficient rats. The current study was thus designed to test the hypothesis that Atp7a is regulated by HIF2α. Rat intestinal epithelial (IEC-6) cells were utilized to model the intestinal epithelium, and CoCl2 and 1% O2 were applied to mimic hypoxia in vitro. Both treatments significantly increased endogenous Atp7a mRNA levels; mRNA induction with CoCl2 treatment was blunted by a transcriptional inhibitor. The rat Atp7a promoter was thus cloned and studied. Various sized promoter constructs were inserted into a luciferase reporter vector and transfected into cells. A −224/+88 bp construct had full activity and was induced by CoCl2; this promoter fragment was thus utilized for subsequent analyses. Interestingly, this region contains three phylogenetically conserved, putative hypoxia response elements (HRE; 5′-NCGTGN-3′). It was further noted that HIF2α overexpression caused a significant upregulation of promoter activity while HIF1α overexpression had little effect. To determine whether Atp7a is a direct HIF target, three putative HREs were deleted individually or in combination; all were shown to be essential for transcriptional induction. Chromatin immunoprecipitation studies also demonstrated that HIF2α binds to the Atp7a promoter region. Lastly, Atp7a and HIF2α protein levels were shown to be increased by both treatments. In conclusion, the Atp7a gene is upregulated by direct interaction with HIF2α, demonstrating coordinate regulation with genes related to intestinal iron homeostasis.
Intracellular targeting of peroxiredoxin 6 to lysosomal organelles requires MAPK activity and binding to 14-3-3ε
Authors: Sorokina Elena M. , Feinstein Sheldon I. , Zhou Suiping , Fisher Aron B.
Published: February 2011

Peroxiredoxin 6 (Prdx6), a bifunctional protein with GSH peroxidase and lysosomal-type phospholipase A2 activities, has been localized to both cytosolic and acidic compartments (lamellar bodies and lysosomes) in lung alveolar epithelium. We postulate that Prdx6 subcellular localization affects the balance between the two activities. Immunostaining localized Prdx6 to lysosome-related organelles in the MLE12 and A549 alveolar epithelial cell lines. Inhibition of trafficking by brefeldin A indicated processing of the protein through the vesicular pathway. Trafficking of Prdx6 was decreased by inhibitors of PKC, ERK, and p38 MAPK. Immunocytochemistry, immunoprecipitation, and an in situ proximity ligation assay (Duolink) showed that binding of the lysosomal targeting sequence of Prdx6 ( amino acids 31–40) to 14-3-3ε was dependent on activity of PKC, ERK, and p38 MAPK. Knockdown of 14-3-3ε with siRNA inhibited the lysosomal targeting of Prdx6. In vitro study with recombinant proteins by pull-down assay and surface plasmon resonance confirmed the interaction of Prdx6 and 14-3-3ε. These findings suggest that ERK and p38 MAPK regulate subcellular localization of Prdx6 by activation of 14-3-3ε as a chaperone protein, resulting in its translocation to acidic organelles.
Lipophilicity as a determinant of thiazolidinedione action in vitro: findings from BLX-1002, a novel compound without affinity to PPARs
Authors: Brunmair Barbara , Staniek Katrin , Lehner Zsuzsanna , Dey Debendranath , Bolten Charles W. , Stadlbauer Karin , Luger Anton , Fürnsinn Clemens
Published: February 2011

The pharmacology of thiazolidinediones (TZDs) seems to be driven not only by activation of peroxisome proliferator-activated receptor-γ (PPARγ), but also by PPARγ-independent effects on mitochondrial function and cellular fuel handling. This study portrayed such actions of the novel hydrophilic TZD compound BLX-1002 and compared them to those of conventional TZDs. Mitochondrial function and fuel handling were examined in disrupted rat muscle mitochondria, intact rat liver mitochondria, and specimens of rat skeletal muscle. BLX-1002 was superior to most other TZDs as an inhibitor of respiratory complex 1 in disrupted mitochondria, but had less effect than any other TZD on oxygen consumption by intact mitochondria and on fuel metabolism by intact tissue. The latter finding was obviously related to the hydrophilic properties of BLX-1002, because high potentials of individual TZDs to shift muscle fuel metabolism from the aerobic into the anaerobic pathway were associated with high ClogP values indicative of high lipophilicity and low hydrophilicity (e.g., % increase in lactate release induced by 10 μmol/l of respective compound: BLX-1002, ClogP 0.39, +10 ± 8%, not significant; pioglitazone, ClogP 3.53, +68 ± 12%, P < 0.001; troglitazone, ClogP 5.58, +157 ± 14%, P < 0.001). The observed specific properties of BLX-1002 could result from relatively strong direct affinity to an unknown mitochondrial target, but limited access to this target. Results suggest 1) that impairment of mitochondrial function and increased anaerobic fuel metabolism are unlikely to account for PPARγ-independent glucose lowering by BLX-1002, and 2) that higher lipophilicity of an individual TZD is associated with stronger acceleration of anaerobic glycolysis.
Evaluation of gravimetric techniques to estimate the microvascular filtration coefficient
Authors: Dongaonkar R. M. , Laine G. A. , Stewart R. H. , Quick C. M.
Published: February 2011

Microvascular permeability to water is characterized by the microvascular filtration coefficient ( K f). Conventional gravimetric techniques to estimate K f rely on data obtained from either transient or steady-state increases in organ weight in response to increases in microvascular pressure. Both techniques result in considerably different estimates and neither account for interstitial fluid storage and lymphatic return. We therefore developed a theoretical framework to evaluate K f estimation techniques by 1) comparing conventional techniques to a novel technique that includes effects of interstitial fluid storage and lymphatic return, 2) evaluating the ability of conventional techniques to reproduce K f from simulated gravimetric data generated by a realistic interstitial fluid balance model, 3) analyzing new data collected from rat intestine, and 4) analyzing previously reported data. These approaches revealed that the steady-state gravimetric technique yields estimates that are not directly related to K f and are in some cases directly proportional to interstitial compliance. However, the transient gravimetric technique yields accurate estimates in some organs, because the typical experimental duration minimizes the effects of interstitial fluid storage and lymphatic return. Furthermore, our analytical framework reveals that the supposed requirement of tying off all draining lymphatic vessels for the transient technique is unnecessary. Finally, our numerical simulations indicate that our comprehensive technique accurately reproduces the value of K f in all organs, is not confounded by interstitial storage and lymphatic return, and provides corroboration of the estimate from the transient technique.
Differential activation of adrenal, renal, and lumbar sympathetic nerves following stimulation of the rostral ventrolateral medulla of the rat
Authors: Mueller Patrick J. , Mischel Nicholas A. , Scislo Tadeusz J.
Published: February 2011

Under acute and chronic conditions, the sympathetic nervous system can be activated in a differential and even selective manner. Activation of the rostral ventrolateral medulla (RVLM) has been implicated in differential control of sympathetic outputs based on evidence primarily in the cat. Although several studies indicate that differential control of sympathetic outflow occurs in other species, only a few studies have addressed whether the RVLM is capable of producing varying patterns of sympathetic activation in the rat. Therefore, the purpose of the present study was to determine whether activation of the RVLM results in simultaneous and differential increases in preganglionic adrenal (pre-ASNA), renal (RSNA), and lumbar (LSNA) sympathetic nerve activities. In urethane-chloralose anesthetized rats, pre-ASNA, RSNA, and LSNA were recorded simultaneously in all animals. Microinjections of selected concentrations and volumes of glutamate increased pre-ASNA, RSNA, and LSNA concurrently and differentially. Pre-ASNA and RSNA (in most cases) exhibited greater increases compared with LSNA on a percentage basis. By varying the volume or location of the glutamate microinjections, we also identified individual examples of differential and selective activation of these nerves. Decreases in arterial pressure or bilateral blockade of RVLM GABAA receptors also revealed differential activation, with the latter having a 3- to 4-fold greater effect on sympathetic activity. Our data provide evidence that activation of the rat RVLM increases renal, lumbar, and preganglionic adrenal sympathetic nerve activities concurrently, differentially, and, in some cases, selectively.
CCAAT/enhancer binding protein β-deficiency enhances type 1 diabetic bone phenotype by increasing marrow adiposity and bone resorption
Authors: Motyl Katherine J. , Raetz Michelle , Tekalur Srinivasan Arjun , Schwartz Richard C. , McCabe Laura R.
Published: February 2011

Bone loss in type 1 diabetes is accompanied by increased marrow fat, which could directly reduce osteoblast activity or result from altered bone marrow mesenchymal cell lineage selection (adipocyte vs. osteoblast). CCAAT/enhancer binding protein beta (C/EBPβ) is an important regulator of both adipocyte and osteoblast differentiation. C/EBPβ-null mice have delayed bone formation and defective lipid accumulation in brown adipose tissue. To examine the balance of C/EBPβ functions in the diabetic context, we induced type 1 diabetes in C/EBPβ-null (knockout, KO) mice. We found that C/EBPβ deficiency actually enhanced the diabetic bone phenotype. While KO mice had reduced peripheral fat mass compared with wild-type mice, they had 5-fold more marrow adipocytes than diabetic wild-type mice. The enhanced marrow adiposity may be attributed to compensation by C/EBPδ, peroxisome proliferator-activated receptor-γ2, and C/EBPα. Concurrently, we observed reduced bone density. Relative to genotype controls, trabecular bone volume fraction loss was escalated in diabetic KO mice (−48%) compared with changes in diabetic wild-type mice (−22%). Despite greater bone loss, osteoblast markers were not further suppressed in diabetic KO mice. Instead, osteoclast markers were increased in the KO diabetic mice. Thus, C/EBPβ deficiency increases diabetes-induced bone marrow (not peripheral) adipose depot mass, and promotes additional bone loss through stimulating bone resorption. C/EBPβ-deficiency also reduced bone stiffness and diabetes exacerbated this (two-way ANOVA P < 0.02). We conclude that C/EBPβ alone is not responsible for the bone vs. fat phenotype switch observed in T1 diabetes and that suppression of CEBPβ levels may further bone loss and decrease bone stiffness by increasing bone resorption.
The lighter side of BDNF
Authors: Noble Emily E. , Billington Charles J. , Kotz Catherine M. , Wang ChuanFeng
Published: February 2011

Brain-derived neurotrophic factor (BDNF) mediates energy metabolism and feeding behavior. As a neurotrophin, BDNF promotes neuronal differentiation, survival during early development, adult neurogenesis, and neural plasticity; thus, there is the potential that BDNF could modify circuits important to eating behavior and energy expenditure. The possibility that “faulty” circuits could be remodeled by BDNF is an exciting concept for new therapies for obesity and eating disorders. In the hypothalamus, BDNF and its receptor, tropomyosin-related kinase B (TrkB), are extensively expressed in areas associated with feeding and metabolism. Hypothalamic BDNF and TrkB appear to inhibit food intake and increase energy expenditure, leading to negative energy balance. In the hippocampus, the involvement of BDNF in neural plasticity and neurogenesis is important to learning and memory, but less is known about how BDNF participates in energy homeostasis. We review current research about BDNF in specific brain locations related to energy balance, environmental, and behavioral influences on BDNF expression and the possibility that BDNF may influence energy homeostasis via its role in neurogenesis and neural plasticity.
The endoplasmic reticulum stress response and diabetic kidney disease
Authors: Cunard Robyn , Sharma Kumar
Published: February 2011

The endoplasmic reticulum (ER) folds and modifies proteins; however, during conditions of cellular stress, unfolded proteins accumulate in the ER and activate the unfolded protein response (UPR). The UPR, also referred to as the ER stress response, activates three distinct signaling cascades that are designed to globally reduce transcription and translation. The three major arms of the mammalian UPR include 1) protein kinase RNA (PKR)-like ER kinase (PERK), 2) inositol-requiring protein-1 (IRE1α), and 3) activating transcription factor-6 (ATF6) pathways. The PERK pathway rapidly attenuates protein translation, whereas the ATF6 and IRE1α cascades transcriptionally upregulate ER chaperone genes that promote proper folding and ER-associated degradation (ERAD) of proteins. This integrated response in turn allows the folding machinery of the ER to catch up with the backlog of unfolded proteins. The ER stress response plays a role in a number of pathophysiological processes, including pancreatic β-cell failure and apoptosis. The goals of the current review are to familiarize investigators with cellular and tissue activation of this response in the rodent and human diabetic kidney. Additionally, we will review therapeutic modulators of the ER stress response and discuss their efficacy in models of diabetic kidney disease. The ER stress response has both protective and deleterious features. A better understanding of the molecular pathways regulated during this process in a cell- and disease-specific manner could reveal novel therapeutic strategies in chronic renal diseases, including diabetic kidney disease.
Contextual cuing contributes to the independent modification of multiple internal models for vocal control
Authors: Keough Dwayne , Jones Jeffery A.
Published: February 2011

Research on the control of visually guided limb movements indicates that the brain learns and continuously updates an internal model that maps the relationship between motor commands and sensory feedback. A growing body of work suggests that an internal model that relates motor commands to sensory feedback also supports vocal control. There is evidence from arm-reaching studies that shows that when provided with a contextual cue, the motor system can acquire multiple internal models, which allows an animal to adapt to different perturbations in diverse contexts. In this study we show that trained singers can rapidly acquire multiple internal models regarding voice fundamental frequency ( F0). These models accommodate different perturbations to ongoing auditory feedback. Participants heard three musical notes and reproduced each one in succession. The musical targets could serve as a contextual cue to indicate which direction (up or down) feedback would be altered on each trial; however, participants were not explicitly instructed to use this strategy. When participants were gradually exposed to altered feedback adaptation was observed immediately following vocal onset. Aftereffects were target specific and did not influence vocal productions on subsequent trials. When target notes were no longer a contextual cue, adaptation occurred during altered feedback trials and evidence for trial-by-trial adaptation was found. These findings indicate that the brain is exceptionally sensitive to the deviations between auditory feedback and the predicted consequence of a motor command during vocalization. Moreover, these results indicate that, with contextual cues, the vocal control system may maintain multiple internal models that are capable of independent modification during different tasks or environments.
Processing of species-specific auditory patterns in the cricket brain by ascending, local, and descending neurons during standing and walking
Authors: Zorović M. , Hedwig B.
Published: February 2011

The recognition of the male calling song is essential for phonotaxis in female crickets. We investigated the responses toward different models of song patterns by ascending, local, and descending neurons in the brain of standing and walking crickets. We describe results for two ascending, three local, and two descending interneurons. Characteristic dendritic and axonal arborizations of the local and descending neurons indicate a flow of auditory information from the ascending interneurons toward the lateral accessory lobes and point toward the relevance of this brain region for cricket phonotaxis. Two aspects of auditory processing were studied: the tuning of interneuron activity to pulse repetition rate and the precision of pattern copying. Whereas ascending neurons exhibited weak, low-pass properties, local neurons showed both low- and band-pass properties, and descending neurons represented clear band-pass filters. Accurate copying of single pulses was found at all three levels of the auditory pathway. Animals were walking on a trackball, which allowed an assessment of the effect that walking has on auditory processing. During walking, all neurons were additionally activated, and in most neurons, the spike rate was correlated to walking velocity. The number of spikes elicited by a chirp increased with walking only in ascending neurons, whereas the peak instantaneous spike rate of the auditory responses increased on all levels of the processing pathway. Extra spiking activity resulted in a somewhat degraded copying of the pulse pattern in most neurons.
Developmental profile of slow hand movement oscillation coupling in humans
Authors: Deutsch Katherine M. , Stephens John A. , Farmer Simon F.
Published: February 2011

In adults, slow hand and finger movements are characterized by 6- to 12-Hz discontinuities visible in the raw records and spectra of motion signals such as acceleration. This pulsitile behavior is correlated with motor unit synchronization at 6–12 Hz as shown by significant coherence at these frequencies between pairs of motor units and between the motor units and the acceleration recorded from the limb part controlled by the muscle, suggesting that it has a central origin. In this study, we examined the correlation between this 6- to 12-Hz pulsatile behavior and muscle activity as a function of childhood development. Sixty-eight participants (ages 4–25 yr) performed static wrist extensions against gravity or slow wrist extension and flexion movements while extensor carpi radialis muscle electromyographic (EMG) and wrist acceleration signals were simultaneously recorded. Coherence between EMG and acceleration within the 6- to 12-Hz frequency band was used as an index of the strength of the relation between central drive and the motor output. The main findings of the study are 1) EMG-acceleration coherence increased with increases in age, with the age differences being greater under movement conditions and the difference between conditions increasing with age; 2) the EMG signal showed increases in normalized power with increases in age under both conditions; and 3) coherence under movement conditions was moderately positively correlated with manual dexterity. These findings indicate that the strength of the 6- to 12-Hz central oscillatory drive to the motor output increases through childhood development and may contribute to age-related improvements in motor skills.
Human primary visual cortex (V1) is selective for second-order spatial frequency
Authors: Hallum Luke E. , Landy Michael S. , Heeger David J.
Published: February 2011

A variety of cues can differentiate objects from their surrounds. These include “first-order” cues such as luminance modulations and “second-order” cues involving modulations of orientation and contrast. Human sensitivity to first-order modulations is well described by a computational model involving spatially localized filters that are selective for orientation and spatial frequency (SF). It is widely held that first-order modulations are represented by the firing rates of simple and complex cells (“first-order” neurons) in primary visual cortex (V1) that, likewise, have spatially localized receptive fields that are selective for orientation- and SF. Human sensitivity to second-order modulations is well described by a filter-rectify-filter (FRF) model, with first- and second-order filters selective for orientation and SF. However, little is known about how neuronal activity in visual cortex represents second-order modulations. We tested the FRF model by using an functional (f)MRI-adaptation protocol to characterize the selectivity of activity in visual cortex to second-order, orientation-defined gratings of two different SFs. fMRI responses throughout early visual cortex exhibited selective adaptation to these stimuli. The low-SF grating was a more effective adapter than the high-SF grating, incompatible with the FRF model. To explain the results, we extended the FRF model by incorporating normalization, yielding a filter-rectify-normalize-filter model, in which normalization enhances selectivity for second-order SF but only for low spatial frequencies. We conclude that neurons in human visual cortex are selective for second-order SF, that normalization (surround suppression) contributes to this selectivity, and that the selectivity in higher visual areas is simply fed forward from V1.
The Modified Negative Decision Number in Graphs
Authors: Wang Changping
Published: February 2011

A mapping x : V → {−1,1} is called negative if ∑u∈N[v]x(u) ≤ 1 for every v ∈ V. The maximum of the values of ∑v∈Vx(v) taken over all negative mappings x, is called the modified negative decision number and is denoted by βD ′(G). In this paper, several sharp upper bounds of this number for a general graph are presented. Exact values of these numbers for cycles, paths, cliques and bicliques are found.
Harmonic Deformation of Planar Curves
Authors: Symeonidis Eleutherius
Published: February 2011

We establish a principle of deformation of an arbitrary planar curve, so that the
integral of a harmonic function over this curve does not change. The equations of deformation
can be derived from a specific “potential.” Several applications are presented.
Effect of Hachimijiogan against Renal Dysfunction and Involvement of Hypoxia‐Inducible Factor‐1α in the Remnant Kidney Model
Authors: Oka Hiroshi , Goto Hirozo , Koizumi Keiichi , Nakamura Shin , Tsuneyama Koichi , Zhou Yue , Jo Michiko , Fujimoto Takako , Sakurai Hiroaki , Shibahara Naotoshi , Saiki Ikuo , Shimada Yutaka
Published: February 2011

In chronic renal failure, hypoxia of renal tissue is thought to be the common final pathway leading to end‐stage renal failure. In this study the effects of hachimijiogan, a Kampo formula, were studied with respect to hypoxia‐inducible factor (HIF). Using remnant kidney rats, we studied the effects of hachimijiogan on renal function in comparison with angiotensin II receptor blocker. The result showed that oral administration of hachimijiogan for seven days suppressed urinary protein excretion and urinary 8‐OHdG, a marker of antioxidant activity, equally as well as oral administration of candesartan cilexetil. In contrast, the protein volume of HIF‐1α in the renal cortex was not increased in the candesartan cilexetil group, but that in the hachimijiogan group was increased. In immunohistochemical studies as well, the expression of HIF‐1α of the high‐dose hachimijiogan group increased compared to that of the control group. Vascular endothelial growth factor and glucose transporter 1, target genes of HIF‐1α, were also increased in the hachimijiogan group. These results suggest that hachimijiogan produces a protective effect by a mechanism different from that of candesartan cilexetil.
Frequency Monitoring and Control during Power System Restoration Based on Wide Area Measurement System
Authors: Nourizadeh Saber , Yari Vahid , Ranjbar Ali Mohammad
Published: February 2011

Frequency control during power system restoration has not been strongly addressed. Operators are often concerned with the offline sizing of load and generation steps, but, nowadays, the introduction of Wide Area Measurement System (WAMS) makes it possible to monitor the stability of power system online. The constraints of WAMS operation result in some changes in power system frequency control. This paper proposes a novel methodology for frequency control and monitoring during the early steps of power system restoration based on WAMS. Detailed load modeling is achieved based on the static load modeling approach. Power generators′ modeling is also accomplished utilizing the single machine equivalent of the power system based on PMU measurements. Simulation results of the presented methodology on the 39 bus New England power system clearly show the effectiveness and applicability of the proposed method. The simulation results show that the presented approach has a completely acceptable precision and an outstanding speed with less than 0.05% error. The outstanding speed of the presented approach along with the result precision will result in a great promotion in power system restoration methodologies.
Lower Confidence Bounds for the Probabilities of Correct Selection
Authors: Singh Radhey S. , Kumar Narinder
Published: February 2011

We extend the results of Gupta and Liang (1998), derived for location parameters, to obtain lower confidence bounds for the probability of correctly selecting the t best populations (PCSt) simultaneously for all t = 1, …, k − 1 for the general scale parameter models, where k is the number of populations involved in the selection problem. The application of the results to the exponential and normal probability models is discussed. The implementation of the simultaneous lower confidence bounds for PCSt is illustrated through real‐life datasets.
Enhanced Safety Profiles of the Telomerase-Specific Replication-Competent Adenovirus by Incorporation of Normal Cell-Specific microRNA-Targeted Sequences
Authors: Sugio Kumiko , Sakurai Fuminori , Katayama Kazufumi , Tashiro Katsuhisa , Matsui Hayato , Kawabata Kenji , Kawase Atsushi , Iwaki Masahiro , Hayakawa Takao , Fujiwara Toshiyoshi , Mizuguchi Hiroyuki
Published: February 2011

Purpose: Oncolytic adenoviruses (Ad) have been actively pursued as potential agents for cancer treatment. Among the various types of oncolytic Ads, the telomerase-specific replication-competent Ad (TRAD), which possesses an E1 gene expression cassette driven by the human telomerase reverse transcriptase promoter, has shown promising results in human clinical trials; however, the E1 gene is also slightly expressed in normal cells, leading to replication of TRAD and cellular toxicity in normal cells.

Experimental Design: To overcome this problem, we utilized a microRNA (miRNA)-regulated gene expression system. Four copies of complementary sequences for miR-143, -145, -199a, or let-7a, which have been reported to be exclusively downregulated in tumor cells, were incorporated into the 3′-untranslated region of the E1 gene expression cassette.

Results: Among the TRAD variants (herein called TRADs) constructed, TRADs containing the sequences complementary to miR-143, -145, or -199a showed efficient oncolytic activity comparable to the parental TRAD in the tumor cells. On the other hand, replication of the TRADs containing the miRNA complementary sequences was at most 1,000-fold suppressed in the normal cells, including primary normal cells. In addition, to suppress the replication of the TRADs in hepatocytes as well as other normal cells, we constructed a TRAD containing 2 distinct complementary sequences for miR-199a and liver-specific miR-122a (TRAD-122a/199aT). TRAD-122a/199aT exhibited more than 10-fold reduction in viral replication in all the normal cells examined, including primary hepatocytes.

Conclusions: This study showed that oncolytic Ads containing the sequences complementary to normal cell-specific miRNAs showed significantly improved safety profiles without altering tumor cell lysis activity. Clin Cancer Res; 17(9); 2807–18. ©2011 AACR.
Phase I Pharmacokinetic and Pharmacodynamic Study of SJG-136, a Novel DNA Sequence Selective Minor Groove Cross-linking Agent, in Advanced Solid Tumors
Authors: Puzanov Igor , Lee Wooin , Chen Alice P. , Calcutt M. Wade , Hachey David L. , Vermeulen Wendy L. , Spanswick Victoria J. , Liao Chih-Yi , Hartley John A. , Berlin Jordan D. , Rothenberg Mace L.
Published: February 2011

Purpose: This phase I study assessed the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of SJG-136, a sequence-specific DNA cross-linking agent, in patients with advanced cancer.

Experimental Design: In schedule A, seven patients received escalating doses of SJG-136 (6, 12, 24, and 48 μg/m2) daily for 5 of 21 days. Blood samples were collected for PK analysis on days 1 and 5 of cycle 1. In schedule B, SJG-136 was given daily for 3 of 21 days (N = 17; doses 20, 25, 30, and 35 μg/m2). Blood samples were collected on days 1 and 3 of cycles 1 and 2 for PK and PD analysis. Patients in schedule B received dexamethasone and early diuretic care.

Results: Schedule A—dose-limiting toxicities included grade 3 edema, dyspnea, fatigue, and delayed liver toxicity (grade 3–4). PK analysis revealed dose-dependent increases in AUC and Cmax. Substantial changes in volume of distribution at steady-state occurred after repeated dosing in some patients prior to the onset of edema. Schedule B—the same toxicities were manageable with steroid premedication and diuretic support. No significant myelosuppression occurred on either schedule. DNA interstrand cross-links correlated with systemic exposure of SJG-136 following the second dose in cycle 1 and were still detectable immediately before cycle 2.

Conclusions: The MTD of SJG-136 in this study was 30 μg/m2 administered on a daily 3× basis with no myelosuppression effects. Coupled with supportive management, SJG-136 is now advancing to a phase II trial in ovarian cancer. Clin Cancer Res; 17(11); 3794–802. ©2011 AACR.
Yes-Associated Protein 1 Exhibits Oncogenic Property in Gastric Cancer and Its Nuclear Accumulation Associates with Poor Prognosis
Authors: Kang Wei , Tong Joanna H.M. , Chan Anthony W.H. , Lee Tin-Lap , Lung Raymond W.M. , Leung Patrick P.S. , So Ken K.Y. , Wu Kaichun , Fan Daiming , Yu Jun , Sung Joseph J.Y. , To Ka-Fai
Published: February 2011

Purpose: Yes-associated protein 1 (YAP1) is a multifunctional protein that can interact with different transcription factors to activate gene expression. The role of YAP1 in tumorigenesis is unclear. We aimed to investigate the functional role of YAP1 in tumorigenesis of gastric cancer.

Experimental Design: YAP1 expresson in gastric adenocarcinoma was evaluated. The biological function was determined by proliferation assay, colony formation, cell invasion, and flow cytometric analysis through knocking down or ectopic expressing YAP1 in gastric cancer cell lines coupled with in vivo study. The possible downstream effectors of YAP1 were investigated by expression microarray.

Results: YAP1 protein expression was upregulated in gastric cancer. Nuclear accumulation of YAP1 was associated with poor disease-specific survival (P = 0.021), especially in patients with early-stage diseases (P < 0.001). Knockdown YAP1 resulted in a significant reduction in proliferation, anchorage-dependent colony formation, cell invasion, and cell motility. Ectopic YAP1 expression promoted anchorage-independent colony formation, induced a more invasive phenotype, and accelerated cell growth both in vitro and in vivo. Microarray analysis highlighted the alteration of MAPK (mitogen-activated protein kinase) pathway by YAP1. We confirmed a constitutive activation of RAF/MEK/ERK (extracellular signal-regulated kinase) in YAP1-expressing MKN45 cells and further showed that YAP1 enhanced serum/epidermal growth factor–induced c-Fos expression in gastric cancer cells.

Conclusions: Our findings supported that YAP1 exhibits oncogenic property in gastric cancer. We provided the first evidence that YAP1 exerted the oncogenic function by enhancing the capacity to activate the early-response gene pathway. YAP1 could be a prognostic biomarker and potential therapeutic target for gastric cancer. Clin Cancer Res; 17(8); 2130–9. ©2011 AACR.
Reduction of Alzheimer’s Disease Amyloid-β in Plasma by Hemodialysis and Its Relation to Cognitive Functions
Authors: Kitaguchi N. , Kawaguchi K. , Nakai S. , Murakami K. , Ito S. , Hoshino H. , Hori H. , Ohashi A. , Shimano Y. , Suzuki N. , Yuzawa Y. , Mutoh T. , Sugiyama S.
Published: February 2011

Background/Aims: Rapid removal of plasma amyloid-β (Aβ) by blood purification may serve as a peripheral Aβ sink from the brain for Alzheimer’s disease therapy. We investigated the reduction of plasma Aβ during hemodialysis and cognitive states. Methods: Aβ concentrations and Mini-Mental State Examinations (MMSE) were investigated in 37 hemodialysis patients (68.9 ± 4.1 years). Results: The dialyzers effectively removed Aβ1–40 and Aβ1–42, 63.9 ± 14.4 and 51.6 ± 17.0% at 4 h dialysis, resulting in the reduction of Aβs in whole-body circulation by 51.1 ± 8.9 and 32.7 ± 12.0%, respectively. Although the plasma Aβs before dialysis (750.8 ± 171.3 pg/ml for Aβ1–40) were higher than those reported for Alzheimer’s disease patients, the cognitive states of hemodialysis patients were relatively normal, especially of longer dialysis vintages. Conclusions: Dialyzers effectively reduced Aβs in whole-body circulation. Repeated rapid decrease of plasma Aβs might maintain cognitive state.