bluuebunny/crossref_metadata_2025 huggingface dataset:
Solar Energy to Biofuels
Authors: Agrawal Rakesh , Singh Navneet R.
Published: June 2010

In a solar economy, sustainably available biomass holds the potential to be an excellent nonfossil source of high energy density transportation fuel. However, if sustainably available biomass cannot supply the liquid fuel need for the entire transport sector, alternatives must be sought. This article reviews biomass to liquid fuel conversion processes that treat biomass primarily as a carbon source and boost liquid fuel production substantially by using supplementary energy that is recovered from solar energy at much higher efficiencies than the biomass itself. The need to develop technologies for an energy-efficient future sustainable transport sector infrastructure that will use different forms of energy, such as electricity, H2, and heat, in a synergistic interaction with each other is emphasized. An enabling template for such a future transport infrastructure is presented. An advantage of the use of such a template is that it reduces the land area needed to propel an entire transport sector. Also, some solutions for the transition period that synergistically combine biomass with fossil fuels are briefly discussed.
Controlling Order in Block Copolymer Thin Films for Nanopatterning Applications
Authors: Marencic Andrew P. , Register Richard A.
Published: June 2010

An attractive “unconventional” lithographic technique to pattern periodic, sub-100 nm features uses self-assembled block copolymer thin films as etch masks. Unfortunately, as-cast films lack the orientational and positional order of the microphase-separated domains that are necessary for many desired applications. Reviewed herein are techniques developed to guide the self-assembly process in thin films, which permit varying degrees of control over the patterns formed by the microdomains. Techniques that can control the out-of-plane order of the microdomains are first summarized. Then, techniques that control the lateral ordering are reviewed, beginning with those that generate large defect-free grains, then those that impart orientational order to the microdomains, and finally those that can control both the orientation and position of individual microdomains. Each technique is summarized with experimental examples and discussions regarding the mechanism of the guided self-assembly process.
Moving Beyond Mass-Based Parameters for Conductivity Analysis of Sulfonated Polymers
Authors: Kim Yu Seung , Pivovar Bryan S.
Published: June 2010

The proton conductivity of polymer electrolytes is critical for fuel cells and has therefore been studied in significant detail. The conductivity of sulfonated polymers has been linked to material characteristics to elucidate trends. Mass-based measurements based on water uptake and ion exchange capacity are two of the most common material characteristics used to make comparisons between polymer electrolytes, but they have significant limitations when correlated to proton conductivity. These limitations arise in part because different polymers can have significantly different densities and because conduction occurs over length scales more appropriately represented by volume measurements rather than mass. Herein we establish and review volume-related parameters that can be used to compare the proton conductivity of different polymer electrolytes. Morphological effects on proton conductivity are also considered. Finally, the impact of these phenomena on designing next-generation sulfonated polymers for polymer electrolyte membrane fuel cells is discussed.
Applications of Supercritical Fluids
Authors: Brunner Gerd
Published: June 2010

This review discusses supercritical fluids in industrial and near-to-industry applications. Supercritical fluids are flexible tools for processing materials. Supercritical fluids have been applied to mass-transfer processes, phase-transition processes, reactive systems, materials-related processes, and nanostructured materials. Some applications are already at industrial capacity, whereas others remain under development. In addition to extraction, application areas include impregnation and cleaning, multistage countercurrent separation, particle formation, coating, and reactive systems such as hydrogenation, biomass gasification, and supercritical water oxidation. Polymers are modified with supercritical fluids, and colloids and emulsions as well as nanostructured materials exhibit interesting phenomena when in contact with supercritical fluids that can be industrially exploited. For these applications to succeed, the properties of supercritical fluids in combination with the materials processed must be clearly determined and fundamental knowledge of the complex behavior must be made readily available.
Protein kinase C induces endocytosis of the sodium taurocholate cotransporting polypeptide
Authors: Stross Claudia , Helmer Angelika , Weissenberger Katrin , Görg Boris , Keitel Verena , Häussinger Dieter , Kubitz Ralf
Published: June 2010

Bile salts influence signaling and metabolic pathways. In hepatocytes, the sodium taurocholate cotransporting polypeptide (Ntcp) is a major determinant of intracellular bile salt levels. Short-term downregulation of Ntcp is not well characterized to date. FLAG and enhanced green fluorescent protein (EGFP) tags were cloned to the extra- and intracellular termini of Ntcp. Endocytosis of Ntcp in transfected HepG2 cells was visualized by fluorescence of EGFP, and membrane surface expression of Ntcp was quantified by flow cytometry with fluorochrome-labeled FLAG antibodies. Activation of protein kinase C (PKC) by phorbolester or thymeleatoxin an activator of Ca2+-dependent conventional PKCs (cPKCs), induced endocytosis of Ntcp, whereas the Na+-K+-ATPase remained in the plasma membrane. The PKC inhibitor BIM I and the cPKC-selective inhibitor Gö6976 abolished PMA-induced endocytosis. Because of this internalization, cell surface expression of Ntcp was reduced by 36 ± 7%, bile salt uptake was decreased by 25%, and taurolithocholate sulfate-induced cell toxicity was prevented. In conclusion, Ca2+-dependent PKCs induce vesicular retrieval of Ntcp, thereby reducing bile salt uptake. This mechanism may protect hepatocytes from toxic intracellular bile salt concentrations.
Contraction-induced secretion of VEGF from skeletal muscle cells is mediated by adenosine
Authors: Høier Birgitte , Olsen Karina , Nyberg Michael , Bangsbo Jens , Hellsten Ylva
Published: June 2010

The role of adenosine and contraction for secretion of vascular endothelial growth factor (VEGF) in skeletal muscle was investigated in human subjects and rat primary skeletal muscle cells. Microdialysis probes were inserted in the thigh muscle of seven male subjects, and dialysate was collected at rest, during infusion of adenosine, and during knee extensor exercise. The dialysate was analyzed for content of VEGF protein and adenosine. The mechanism of VEGF secretion from muscle cells in culture was examined in resting and electrostimulated cells and in response to the adenosine analog NECA and the adenosine A2A receptor specific analog CGS-21680. Adenosine receptors A1, A2A, and A2B were blocked with DPCPX, ZM-241385, and enprofylline, respectively. cAMP-dependent protein kinase A (PKA) and mitogen-activated protein kinase (MAPK) were inhibited by H-89 and PD-98509, respectively. The human experiment showed that adenosine infusion enhanced ( P < 0.05) the interstitial concentration of VEGF protein approximately fourfold above baseline. Exercise increased ( P < 0.05) the interstitial VEGF concentration approximately sixfold above rest in parallel with an approximately threefold increase in adenosine concentration. In accordance, in cultured muscle cells, NECA and contraction caused secretion of VEGF ( P < 0.05). The contraction-induced secretion of VEGF was abolished by the A2B antagonist enprofylline and by inhibition of PKA or MAPK. The results demonstrate that adenosine causes secretion of VEGF from human skeletal muscle cells and that the contraction-induced secretion of VEGF protein is partially mediated via adenosine acting on A2B adenosine receptors. Moreover, the contraction-induced secretion of VEGF protein from muscle is dependent on both PKA and MAPK activation, but only the MAPK pathway appears to be adenosine dependent, revealing involvement of additional pathways in VEGF secretion.
AP-1 overexpression impairs corticosteroid inhibition of collagen production by fibroblasts isolated from asthmatic subjects
Authors: Jacques Eric , Semlali Abdelhabib , Boulet Louis Philippe , Chakir Jamila
Published: June 2010

Asthma is characterized by airway remodeling associated with an increase in the deposition of ECM proteins such as type I collagen. These components are mainly produced by fibroblasts. Inhaled corticosteroids are considered the cornerstone of asthma therapy. Despite substantial evidence as to the anti-inflammatory action of corticosteroids, their effect on controlling ECM protein deposition in the airways is not completely understood. This study determined the effect of dexamethasone (Dex) on collagen production by bronchial fibroblasts derived from asthmatic and healthy subjects. Expression of procollagen mRNA in fibroblasts from asthmatics and normal controls was determined by quantitative PCR. Regulation of the procollagen-α1I promoter was evaluated by transient transfections. Transforming growth factor-β (TGF-β) protein expression was determined by ELISA. Protein expression of glucocorticoid receptor (GR) and interaction with activator protein-1 (AP-1), a collagen regulatory transcription factor, was assessed by Western blots, coimmunoprecipitations, and EMSA. AP-1 overexpression was performed by transient transfection using c-Fos/c-Jun expression plasmids. Dex significantly downregulated procollagen production and promoter activity in normal fibroblasts but had no effect on asthmatic fibroblasts. AP-1 and GR interaction increased after Dex stimulation in asthmatic fibroblasts. AP-1 overexpression in control fibroblasts abrogated collagen gene response to Dex. These results show that Dex failed to reduce collagen production in fibroblasts from asthmatic subjects. This impaired response may be related to AP-1 overexpression in these cells.
Inhibitory effects of carbocisteine on type A seasonal influenza virus infection in human airway epithelial cells
Authors: Yamaya Mutsuo , Nishimura Hidekazu , Shinya Kyoko , Hatachi Yukimasa , Sasaki Takahiko , Yasuda Hiroyasu , Yoshida Motoki , Asada Masanori , Fujino Naoya , Suzuki Takaya , Deng Xue , Kubo Hiroshi , Nagatomi Ryoichi
Published: June 2010

Type A human seasonal influenza (FluA) virus infection causes exacerbations of bronchial asthma and chronic obstructive pulmonary disease (COPD). l-carbocisteine, a mucolytic agent, reduces the frequency of common colds and exacerbations in COPD. However, the inhibitory effects of l-carbocisteine on FluA virus infection are uncertain. We studied the effects of l-carbocisteine on FluA virus infection in airway epithelial cells. Human tracheal epithelial cells were pretreated with l-carbocisteine and infected with FluA virus (H3N2). Viral titers in supernatant fluids, RNA of FluA virus in the cells, and concentrations of proinflammatory cytokines in supernatant fluids, including IL-6, increased with time after infection. l-carbocisteine reduced viral titers in supernatant fluids, RNA of FluA virus in the cells, the susceptibility to FluA virus infection, and concentrations of cytokines induced by virus infection. The epithelial cells expressed sialic acid with an α2,6-linkage (SAα2,6Gal), a receptor for human influenza virus on the cells, and l-carbocisteine reduced the expression of SAα2,6Gal. l-carbocisteine reduced the number of acidic endosomes from which FluA viral RNA enters into the cytoplasm and reduced the fluorescence intensity from acidic endosomes. Furthermore, l-carbocisteine reduced NF-κB proteins including p50 and p65 in the nuclear extracts of the cells. These findings suggest that l-carbocisteine may inhibit FluA virus infection, partly through the reduced expression of the receptor for human influenza virus in the human airway epithelial cells via the inhibition of NF-κB and through increasing pH in endosomes. l-carbocisteine may reduce airway inflammation in influenza virus infection.
Novel plasminogen activator inhibitor-1-derived peptide protects against impairment of cerebrovasodilation after photothrombosis through inhibition of JNK MAPK
Authors: Armstead William M. , Riley John , Kiessling J. Willis , Cines Douglas B. , Higazi Abd Al-Roof
Published: June 2010

The sole FDA-approved treatment for acute stroke is recombinant tissue-type plasminogen activator (rtPA). However, rtPA aggravates the impairment of cerebrovasodilation induced by global hypoxia/ischemia; this impairment is attenuated by the preinjury treatment with the plasminogen activator inhibitor derivative EEIIMD. MAPK (a family of kinases, p38, and JNK) is upregulated after cerebral ischemia. In this study, we determined whether the novel plasminogen activator inhibitor-derived peptide, Ac-RMAPEEIIMDRPFLYVVR-amide, (PAI-1-DP) given 30 min before or 2 h after, focal central nervous system injury induced by photothrombosis would preserve responses to cerebrovasodilators and the role of p38 and JNK MAPK in such effects. Cerebrospinal fluid JNK and p38 levels were elevated by photothrombotic injury, an effect potentiated by rtPA. Cerebrovasodilation was blunted by photothrombosis and reversed to vasoconstriction by rtPA but restored to dilation by PAI-1-DP pre- and posttreatment. PAI-1-DP blocked JNK, but preserved p38 MAPK upregulation after photothrombosis. The JNK MAPK antagonist SP600125 prevented, and the p38 antagonist SB203580 potentiated, impaired cerebrovasodilation after photothrombosis. These data indicate that rtPA impairs cerebrovasodilation after injury by activating JNK, while p38 MAPK is protective, and that the novel peptide PAI-1-DP protects by inhibiting activation of JNK by rtPA. JNK MAPK inhibitors, including PAI-1-DP, may offer a novel approach to increase the benefit-to-risk ratio of thrombolytic therapy and enable its use in central nervous system ischemic disorders.
Oral administration of a PPAR-δ agonist to rodents worsens, not improves, maximal insulin-stimulated glucose transport in skeletal muscle of different fibers
Authors: Cresser Justin , Bonen Arend , Chabowski Adrian , Stefanyk Leslie E. , Gulli Roberto , Ritchie Ian , Dyck David J.
Published: June 2010

Agonists targeting the nuclear receptor peroxisome proliferator-activated receptors (PPAR)-δ may be potential therapeutic agents for insulin-resistant related conditions, as they may be able to stimulate fatty acid (FA) oxidation and attenuate the accumulation of harmful lipid species in skeletal muscle. Several reports have demonstrated that PPAR-δ agonists improve whole body insulin sensitivity. However, whether these agonists exert their direct effects on glucose and FA metabolism in skeletal muscle, and specifically with different fiber types, is unknown. This study was undertaken to determine the effects of oral treatment with the PPAR-δ agonist, GW 501516, in conjunction with the administration of a high-saturated-fat diet on insulin-stimulated glucose transport in isolated oxidative (soleus) and glycolytic (epitrochlearis) rodent skeletal muscle in vitro. High-fat feeding significantly decreased maximal insulin-stimulated glucose transport in soleus, but not epitrochlearis muscle, and was associated with increased skeletal muscle diacylglycerol and ceramide content. Unexpectedly, treatment with the PPAR-δ agonist significantly reduced insulin-stimulated glucose transport in both soleus and epitrochlearis muscles, regardless of dietary fat content. The reduction in insulin-stimulated glucose transport induced by the agonist was associated with large increases in total muscle fatty acid translocase (FAT)/CD36protein content, but not diacylglycerol or ceramide contents. Agonist treatment did not alter the protein content of PPAR-δ, GLUT4, or insulin-signaling proteins (IRS-1, p85 PI3-K, Akt). Agonist treatment led to a small, but significant increase, in the oxidative capacity of glycolytic but not oxidative muscle. We propose that chronic treatment with the PPAR-δ agonist GW 501516 may induce or worsen insulin resistance in rodent skeletal muscle by increasing the capacity for FA transport across the sarcolemma without a sufficient compensatory increase in FA oxidation. However, an accumulation of diacylglycerol and ceramide, while associated with diet-induced insulin resistance, does not appear to be responsible for the agonist-induced reduction in insulin-stimulated glucose transport.
Sepsis and glucocorticoids upregulate p300 and downregulate HDAC6 expression and activity in skeletal muscle
Authors: Alamdari Nima , Smith Ira J. , Aversa Zaira , Hasselgren Per-Olof
Published: June 2010

Muscle wasting during sepsis is in part regulated by glucocorticoids. In recent studies, treatment of cultured muscle cells in vitro with dexamethasone upregulated expression and activity of p300, a histone acetyl transferase (HAT), and reduced expression and activity of the histone deacetylases-3 (HDAC3) and -6, changes that favor hyperacetylation. Here, we tested the hypothesis that sepsis and glucocorticoids regulate p300 and HDAC3 and -6 in skeletal muscle in vivo. Because sepsis-induced metabolic changes are particularly pronounced in white, fast-twitch skeletal muscle, most experiments were performed in extensor digitorum longus muscles. Sepsis in rats upregulated p300 mRNA and protein levels, stimulated HAT activity, and reduced HDAC6 expression and HDAC activity. The sepsis-induced changes in p300 and HDAC expression were prevented by the glucocorticoid receptor antagonist RU38486. Treatment of rats with dexamethasone increased expression of p300 and HAT activity, reduced expression of HDAC3 and -6, and inhibited HDAC activity. Finally, treatment with the HDAC inhibitor trichostatin A resulted in increased muscle proteolysis and expression of the ubiquitin ligase atrogin-1. Taken together, our results suggest for the first time that sepsis-induced muscle wasting may be regulated by glucocorticoid-dependent hyperacetylation caused by increased p300 and reduced HDAC expression and activity. The recent development of pharmacological HDAC activators may provide a novel avenue to prevent and treat muscle wasting in sepsis and other catabolic conditions.
Effects of 3 days unloading on molecular regulators of muscle size in humans
Authors: Gustafsson T. , Osterlund T. , Flanagan J. N. , von Waldén F. , Trappe T. A. , Linnehan R. M. , Tesch P. A.
Published: June 2010

Changes in skeletal muscle mass are controlled by mechanisms that dictate protein synthesis or degradation. The current human study explored whether changes in activation of the phosphoinositide 3-kinase (PI3K)-Akt1, p38, myostatin, and mRNA expression of markers of protein degradation and synthesis occur soon after withdrawal of weight bearing. Biopsies of the vastus lateralis muscle (VL) and soleus muscle (Sol) were obtained from eight healthy men before and following 3 days of unilateral lower limb suspension (ULLS). Akt1, Forkhead box class O (FOXO)-1A, FOXO-3A, p38, and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) phosphorylation and protein levels and myostatin protein level were analyzed by Western blot. Levels of mRNA of IGF1, FOXO-1A, FOXO-3A, atrogin-1, MuRF-1, caspase-3, calpain-2, calpain-3, 4E-BP1, and myostatin were measured using real-time PCR. The amounts of phosphorylated Akt1, FOXO-1A, FOXO-3A, and p38 were unaltered ( P > 0.05) after ULLS. Similarly, mRNA levels of IGF1, FOXO-1A, FOXO-3A, caspase-3, calpain-2, and calpain-3 showed no changes ( P > 0.05). The mRNA levels of atrogin-1 and MuRF-1, as well as the mRNA and protein phosphorylation of 4E-BP1, increased ( P < 0.05) in VL but not in Sol. Both muscles showed increased ( P < 0.05) myostatin mRNA and protein following ULLS. These results suggest that pathways other than PI3K-Akt stimulate atrogin-1 and MuRF-1 expression within 3 days of ULLS. Alternatively, transient changes in these pathways occurred in the early phase of ULLS. The increased myostatin mRNA and protein expression also indicate that multiple processes are involved in the early phase of muscle wasting. Further, the reported difference in gene expression pattern across muscles suggests that mechanisms regulating protein content in human skeletal muscle are influenced by phenotype and/or function.
Strain screen and haplotype association mapping of wheel running in inbred mouse strains
Authors: Lightfoot J. Timothy , Leamy Larry , Pomp Daniel , Turner Michael J. , Fodor Anthony A. , Knab Amy , Bowen Robert S. , Ferguson David , Moore-Harrison Trudy , Hamilton Alicia
Published: June 2010

Previous genetic association studies of physical activity, in both animal and human models, have been limited in number of subjects and genetically homozygous strains used as well as number of genomic markers available for analysis. Expansion of the available mouse physical activity strain screens and the recently published dense single-nucleotide polymorphism (SNP) map of the mouse genome (≈8.3 million SNPs) and associated statistical methods allowed us to construct a more generalizable map of the quantitative trait loci (QTL) associated with physical activity. Specifically, we measured wheel running activity in male and female mice (average age 9 wk) in 41 inbred strains and used activity data from 38 of these strains in a haplotype association mapping analysis to determine QTL associated with activity. As seen previously, there was a large range of activity patterns among the strains, with the highest and lowest strains differing significantly in daily distance run (27.4-fold), duration of activity (23.6-fold), and speed (2.9-fold). On a daily basis, female mice ran further (24%), longer (13%), and faster (11%). Twelve QTL were identified, with three (on Chr. 12, 18, and 19) in both male and female mice, five specific to males, and four specific to females. Eight of the 12 QTL, including the 3 general QTL found for both sexes, fell into intergenic areas. The results of this study further support the findings of a moderate to high heritability of physical activity and add general genomic areas applicable to a large number of mouse strains that can be further mined for candidate genes associated with regulation of physical activity. Additionally, results suggest that potential genetic mechanisms arising from traditional noncoding regions of the genome may be involved in regulation of physical activity.
Concomitant administration of nitric oxide and glucocorticoids improves protection against bronchoconstriction in a murine model of asthma
Authors: Jonasson Sofia , Hedenstierna Göran , Hjoberg Josephine
Published: June 2010

Glucocorticoids (GC) remain the first choice of treatment in asthma, but GC therapy is not always effective and is associated with side effects. In a porcine study in our laboratory, simultaneous administration of GC and nitric oxide (NO) attenuated the endotoxin-induced inflammatory response and made GC treatment more effective than inhaled NO or steroids alone. In the present study, we aimed to further investigate the interactions between NO and GC treatment in two murine models of asthma. Inflammation was induced by endotoxin, ovalbumin, or a combination of both. With an animal ventilator and a forced oscillation method (FlexiVent), lung mechanics and airway reactivity to methacholine in response to various treatments were assessed. We also describe histology and glucocorticoid receptor (GR) protein expression in response to inhaled NO treatment [40 ppm NO gas or NO donors sodium nitroprusside (SNP) or diethylamine NONOate (DEA/NO)]. SNP and GC provided protection against bronchoconstriction to a similar degree in the model of severe asthma. When GC-treated mice were given SNP, maximum airway reactivity was further reduced. Similar effects were seen after DEA/NO delivery to GC-treated animals. Using 1- H-[1,2,4]-oxadiazolo-[4,3- a]-quinoxalin-1-one (ODQ), a soluble guanylate cyclase inhibitor, we found this effect of NO donors to be mediated through a cGMP-independent mechanism. In the severe model, prolonged NO treatment restored or even increased the nuclear levels of GR. In conclusion, in our murine model of severe asthma GC treatment provided protection to only a limited degree against bronchoconstriction, while concomitant treatment with a NO donor was markedly more potent than the use of either NO or GC alone.
Substance P Modulation of Hypoglossal Motoneuron Excitability During Development: Changing Balance Between Conductances
Authors: Adachi Tadafumi , Huxtable Adrianne G. , Fang X. , Funk Gregory D.
Published: June 2010

Although Substance P (SP) acts primarily through neurokinin 1 (NK1) receptors to increase the excitability of virtually all motoneurons (MNs) tested, the ontogeny of this transmitter system is not known for any MN pool. Hypoglossal (XII) MNs innervate tongue protruder muscles and participate in several behaviors that must be functional from birth including swallowing, suckling and breathing. We used immunohistochemistry, Western immunoblotting, and whole cell recording of XII MNs in brain stem slices from rats ranging in age from postnatal day zero (P0) to P23 to explore developmental changes in: NK1 receptor expression; currents evoked by SPNK1(an NK1-selective SP receptor agonist) and; the efficacy of transduction pathways transforming ligand binding into channel modulation. Despite developmental reductions in XII MN NK1 receptor expression, SPNK1current density remained constant at 6.1 ± 1.0 (SE) pA/pF. SPNK1activated at least two conductances. Activation of a pH-insensitive Na+conductance dominated in neonates (P0–P5), but its contribution fell from ∼80 to ∼55% in juveniles (P14–P23). SPNK1also inhibited a pH-sensitive, two-pore domain K+(TASK)-like K+current. Its contribution increased developmentally. First, the density of this pH-sensitive K+current doubled between P0 and P23. Second, SPNK1did not affect this current in neonates, but reduced it by 20% at P7–P10 and 80% in juveniles. In addition, potentiation of repetitive firing was greatest in juveniles. These data establish that despite apparent reductions in NK1 receptor density, SP remains an important modulator of XII MN excitability throughout postnatal development due, in part, to increased expression of a pH-sensitive, TASK-like conductance.
A Pallidus-Habenula-Dopamine Pathway Signals Inferred Stimulus Values
Authors: Bromberg-Martin Ethan S. , Matsumoto Masayuki , Hong Simon , Hikosaka Okihide
Published: June 2010

The reward value of a stimulus can be learned through two distinct mechanisms: reinforcement learning through repeated stimulus-reward pairings and abstract inference based on knowledge of the task at hand. The reinforcement mechanism is often identified with midbrain dopamine neurons. Here we show that a neural pathway controlling the dopamine system does not rely exclusively on either stimulus-reward pairings or abstract inference but instead uses a combination of the two. We trained monkeys to perform a reward-biased saccade task in which the reward values of two saccade targets were related in a systematic manner. Animals used each trial's reward outcome to learn the values of both targets: the target that had been presented and whose reward outcome had been experienced (experienced value) and the target that had not been presented but whose value could be inferred from the reward statistics of the task (inferred value). We then recorded from three populations of reward-coding neurons: substantia nigra dopamine neurons; a major input to dopamine neurons, the lateral habenula; and neurons that project to the lateral habenula, located in the globus pallidus. All three populations encoded both experienced values and inferred values. In some animals, neurons encoded experienced values more strongly than inferred values, and the animals showed behavioral evidence of learning faster from experience than from inference. Our data indicate that the pallidus-habenula-dopamine pathway signals reward values estimated through both experience and inference.
Active Control of Bias for the Control of Posture and Movement
Authors: Guigon Emmanuel
Published: June 2010

Posture and movement are fundamental, intermixed components of motor coordination. Current approaches consider either that 1) movement is an active, anticipatory process and posture is a passive feedback process or 2) movement and posture result from a common passive process. In both cases, the presence of a passive component renders control scarcely robust and stable in the face of transmission delays and low feedback gains. Here we show in a model that posture and movement could result from the same active process: an optimal feedback control that drives the body from its estimated state to its goal in a given (planning) time by acting through muscles on the insertion position (bias) of compliant linkages (tendons). Computer simulations show that iteration of this process in the presence of noise indifferently produces realistic postural sway, fast goal-directed movements, and natural transitions between posture and movement.
The Roles of Somatostatin-Expressing (GIN) and Fast-Spiking Inhibitory Interneurons inup-downStates of Mouse Neocortex
Authors: Fanselow Erika E. , Connors Barry W.
Published: June 2010

The neocortex contains multiple types of inhibitory neurons whose properties suggest they may play different roles within the cortical circuit. By recording from three cell types during two distinct network states (up and down states) in vitro, we were able to quantify differences in firing characteristics between these cells during different network regimes. We recorded from regular-spiking (RS) excitatory cells and two types of inhibitory neurons, the fast-spiking (FS) neurons and GFP- (and somatostatin-) expressing inhibitory neurons (GIN), in layer 2/3 of slices from mouse somatosensory neocortex. Comparisons of firing characteristics between these cells during up- and down-states showed several patterns. First, of these cell types, only GIN cells fired persistently during down-states, whereas all three cell types fired readily during up-states. Second, the onset of firing and distribution of action potentials throughout up-states differed by cell type, showing that FS cell up-state firing occurred preferentially near the beginning of the up-state, whereas the firing of RS cells was slower to develop at the start of the up-state, and GIN cell firing was sustained throughout the duration of the up-state. Finally, membrane potential and spike correlations between heterogeneous cell types were more pronounced during up-states and, in the case of RS synapses onto GIN cells, varied throughout the up-state. These results suggest that there is a division of labor between FS and GIN cells as the up-state progresses and suggest that GIN cells could be important in the termination of up-states.
Motor Learning Without Doing: Trial-by-Trial Improvement in Motor Performance During Mental Training
Authors: Gentili Rodolphe , Han Cheol E. , Schweighofer Nicolas , Papaxanthis Charalambos
Published: June 2010

Although there is converging experimental and clinical evidences suggesting that mental training with motor imagery can improve motor performance, it is unclear how humans can learn movements through mental training despite the lack of sensory feedback from the body and the environment. In a first experiment, we measured the trial-by-trial decrease in durations of executed movements (physical training group) and mentally simulated movements (motor-imagery training group), by means of training on a multiple-target arm-pointing task requiring high accuracy and speed. Movement durations were significantly lower in posttest compared with pretest after both physical and motor-imagery training. Although both the posttraining performance and the rate of learning were smaller in motor-imagery training group than in physical training group, the change in movement duration and the asymptotic movement duration after a hypothetical large number of trials were identical. The two control groups (eye-movement training and rest groups) did not show change in movement duration. In the second experiment, additional kinematic analyses revealed that arm movements were straighter and faster both immediately and 24 h after physical and motor-imagery training. No such improvements were observed in the eye-movement training group. Our results suggest that the brain uses state estimation, provided by internal forward model predictions, to improve motor performance during mental training. Furthermore, our results suggest that mental practice can, at least in young healthy subjects and if given after a short bout of physical practice, be successfully substituted to physical practice to improve motor performance.
Neural and Temporal Dynamics Underlying Visual Selection for Action
Authors: van Elk M. , van Schie H. T. , Neggers S.F.W. , Bekkering H.
Published: June 2010

The present study investigated the selection for action hypothesis, according to which a subject's action intention to perform a movement influences the way in which visual information is being processed. Subjects were instructed in separate blocks either to grasp or to point to a three-dimensional target-object and event-related potentials were recorded relative to stimulus onset. It was found that grasping compared with pointing resulted in a stronger N1 component and a subsequent selection negativity, which were localized to the lateral occipital complex. These effects suggest that the intention to grasp influences the processing of action-relevant features in ventral stream areas already at an early stage (e.g., enhanced processing of object orientation for grasping). These findings provide new insight in the neural and temporal dynamics underlying perception–action coupling and provide neural evidence for a selection for action principle in early human visual processing.
Targeted Gene Silencing Using RGD-Labeled Chitosan Nanoparticles
Authors: Han Hee Dong , Mangala Lingegowda S. , Lee Jeong Won , Shahzad Mian M.K. , Kim Hye Sun , Shen Deyu , Nam Eun Ji , Mora Edna M. , Stone Rebecca L. , Lu Chunhua , Lee Sun Joo , Roh Ju Won , Nick Alpa M. , Lopez-Berestein Gabriel , Sood Anil K.
Published: June 2010

Purpose: This study aimed to develop an Arg-Gly-Asp (RGD) peptide-labeled chitosan nanoparticle (RGD-CH-NP) as a novel tumor targeted delivery system for short interfering RNA (siRNA).

Experimental Design: RGD peptide conjugated with chitosan by thiolation reaction was confirmed by proton-NMR (H-NMR). Binding of RGD-CH-NP with ανβ3 integrin was examined by flow cytometry and fluorescence microscopy. Antitumor efficacy was examined in orthotopic mouse models of ovarian carcinoma.

Results: We show that RGD-CH-NP loaded with siRNA significantly increased selective intratumoral delivery in orthotopic animal models of ovarian cancer. In addition, we show targeted silencing of multiple growth-promoting genes (POSTN, FAK, and PLXDC1) along with therapeutic efficacy in the SKOV3ip1, HeyA8, and A2780 models using siRNA incorporated into RGD-CH-NP (siRNA/RGD-CH-NP). Furthermore, we show in vivo tumor vascular targeting using RGD-CH-NP by delivering PLXDC1-targeted siRNA into the ανβ3 integrin–positive tumor endothelial cells in the A2780 tumor-bearing mice. This approach resulted in significant inhibition of tumor growth compared with controls.

Conclusions: This study shows that RGD-CH-NP is a novel and highly selective delivery system for siRNA with the potential for broad applications in human disease. Clin Cancer Res; 16(15); 3910–22. ©2010 AACR.
Preservation of Kidney Function with Combined Inhibition of NADPH Oxidase and Angiotensin-Converting Enzyme in Diabetic Nephropathy
Authors: Thallas-Bonke Vicki , Coughlan Melinda T. , Bach Leon A. , Cooper Mark E. , Forbes Josephine M.
Published: June 2010

Background/Aims: Antihypertensive therapies such as angiotensin-converting enzyme-1 inhibitors (ACEi) slow the decline in renal function seen with diabetic nephropathy, although there is still progression ultimately to end-stage renal disease. The aim of this study was to determine if there were added renoprotective benefits seen by combining ACEi with blockade of NADPH oxidase. Methods: Sprague-Dawley diabetic and non-diabetic rats were randomized to receive intervention therapy with apocynin (15 mg/kg/day, weeks 16–32), apocynin + the ACEi ramipril (1 mg/kg/day, weeks 16–32), or ramipril alone (1 mg/kg). Results: All three treatments retarded the development of albuminuria in the diabetic rats. Apocynin conferred its benefit either as a monotherapy or in combination with ramipril without affecting blood pressure per se. Renal morphological injury was attenuated by all three treatment strategies. Diabetes was associated with increasing renal fibronectin and type IV collagen protein expression, with the combination regimen resulting in the highest decrease in extracellular matrix accumulation. All three treatments prevented the diabetes-associated increases in renal cytosolic superoxide generation as well as urinary isoprostanes. While renal TGF-β1 activation was reduced by ramipril treatment but not by apocynin as a monotherapy, kidney cortical membranous VEGF was reduced by apocynin as monotherapy and dual therapy but not by ramipril alone. Conclusions: Combination of NADPH oxidase blockade with ACE inhibitors is a promising regimen which warrants further investigation as a way to confer additional renoprotection in diabetes.
Emergence of Proteus mirabilis Isolates Producing TEM-52 Extended-Spectrum β-Lactamases in Croatia
Authors: Sardelić Sanda , Bedenić Branka , Šijak Dubravko , Colinon Celine , Kalenić Smilja
Published: June 2010

Background: An increased frequency of extended-spectrum β-lactamase (ESBL)-positive Proteus mirabilis isolates was observed recently in the Clinical Hospital Center Split in Croatia. The aim of this study was the molecular characterization of ESBLs in P. mirabilis isolates from this hospital. Material and Methods: Seven strains showing reduced susceptibility to ceftazidime were investigated. Antimicrobial susceptibility was determined using the broth microdilution method. ESBLs were characterized by PCR and sequencing of blaESBL genes. Quinolone resistance determinants (qnr genes) were characterized by PCR. Genotyping of strains was performed by pulsed-field gel electrophoresis (PFGE). Results: The presence of an ESBL was confirmed in all strains by a double-disk synergy test. All strains were resistant to amoxicillin, piperacillin, gentamicin, ciprofloxacin, chloramphenicol, sulfamethoxazole and trimethoprim, but susceptible to ceftazidime/clavulanic acid, piperacillin/tazobactam, cefoxitin, imipenem and meropenem; PCR sequencing using primers targeting blaESBL genes revealed TEM-52 β-lactamase. PFGE genotyping demonstrated the clonal relatedness of TEM-52-producing P. mirabilis strains isolated from different clinical samples and wards within the hospital. BlaTEM-52 in 3 isolates was carried by a 70-kb conjugative plasmid. Conclusions: Our findings indicate the emergence of the TEM-52 enzyme among P. mirabilis in Croatia.
TLR9 Signaling Failure Renders Peyer’s Patch Regulatory B Cells Unresponsive to Stimulation with CpG Oligodeoxynucleotides
Authors: Booth Jayaum S. , Arsenault Ryan , Napper Scott , Griebel Philip J. , Potter Andrew A. , Babiuk Lorne A. , Mutwiri George K.
Published: June 2010

Intestinal Peyer’s patch (PP) regulatory CD21+ B cells (Bregs) suppress TLR9-induced innate immune responses. However, it is not known whether TLR9 activation is regulated in PP Bregs. Here, we investigated the responses of PP Bregs to stimulation with the TLR9 agonist CpG oligodeoxynucleotides (ODN). We observed that PP CD21+ Bregs express high levels of TLR9 mRNA, but fail to proliferate when stimulated with CpG ODN. Furthermore, unlike CD21+ B cells from blood, PP CD21+ Bregs do not secrete IgM or IL-12 following CpG ODN stimulation. We hypothesized that the unresponsiveness of PP Bregs to CpG stimulation was due to an inability of the TLR9 agonist to activate the TLR9 signaling pathway in these cells. This was confirmed by kinome analysis which demonstrated dynamic patterns of phosphorylation of key TLR adaptor proteins such as IRAK1, TAK1, IKK and NF-ĸB-p65 in CpG-stimulated blood CD21+ B cells, consistent with activation of the TLR9 pathway. In contrast, stimulation of PP CD21+ Bregs with CpG ODN resulted in phosphorylation patterns of these adaptor proteins suggestive of inactivation of the TLR9 pathway. The absence of apparent TLR9 signaling events immediately following stimulation indicated that signaling is blocked close to the receptor. Our observations suggest a novel mechanism by which the host regulates TLR responses in TLR-expressing cells with regulatory functions.
Food Allergy: An Increasing Problem for the Elderly
Authors: Möhrenschlager Matthias , Ring Johannes
Published: June 2010

As populations become older all over the world, allergic reactions in elderly persons will be encountered more often in the future. Up to now, there has been much more literature on allergy prevalence in childhood than on allergy diseases in adults. As a challenge to epidemiology, allergic disorders in elderly persons may be masked by various symptoms corresponding with a general age-induced decline of physiological functions, including vitamin D deficiency and gastric pH increase. How much structural and functional changes (e.g. low calcitriol level) or effects caused by drugs (e.g. acid-suppression medications) in addition to immunological alterations encountered at old age are responsible for this development is a matter of debate. In the years ahead, the problem of allergy in adulthood and especially in the elderly will become more pronounced.
The mechanism of stem cell differentiation into smooth muscle cells
Authors: Wang Gang , Luo Zhenling , Xu Qingbo , Xiao Qingzhong
Published: June 2010

Stem cells represent one of the most promising areas in biological and medical research. All stem cells are defined as having two basic properties: unlimited self-renewal and the broad potential to differentiate in vitro, via ″progenitor cells″, into somatic cells of many tissue types, in which smooth muscle cell (SMC) differentiation is a complicated and not well defined process. It is known that serum response factors (SRF) and co-activator myocardin are essential transcription factors in SMC differentiation. Upstream activators or regulators for the transcription factors have been recently identified, such as reactive oxygen species, histone deacetylases, microRNAs and extracellular matrix (ECM) proteins and integrins. In this review we, therefore, aim to briefly summarise recent progress in the mechanism of stem cell differentiation into SMCs to highlight the potential targets for promoting/inhibiting SMC differentiation useful for vessel-tissue engineering and treatment of vascular disease.
Metabolic Syndrome and Carotid Intima-Media Thickness in Young Adults: Roles of Apolipoprotein B, Apolipoprotein A-I, C-Reactive Protein, and Secretory Phospholipase A2: The Cardiovascular Risk in Young Finns Study
Authors: Mattsson Noora , Magnussen Costan G. , Rönnemaa Tapani , Mallat Ziad , Benessiano Joelle , Jula Antti , Taittonen Leena , Kähönen Mika , Juonala Markus , Viikari Jorma S.A. , Raitakari Olli T.
Published: June 2010

Objective—

Aberrations in apolipoprotein (apo) metabolism and increased systemic inflammation associate with the metabolic syndrome (MetS) and may contribute to its atherogenicity. We examined whether the association between carotid atherosclerosis and MetS in a population of young adults is mediated by apoB and apoA-I and/or by inflammatory markers C-reactive protein and type II secretory phospholipase A2.

Methods and Results—

We used cross-sectional and 6-year prospective data from the cardiovascular risk in young Finns study. In young adults (aged 24 to 39 years), apoB, C-reactive protein, and type II secretory phospholipase A2 enzyme activity were significantly higher and apoA-I lower in subjects with MetS (N=325) than in subjects without MetS (N=1858). In prospective analysis (N=1587), both MetS and high apoB predicted (
P
<0.0001) incident high carotid intima-media thickness, defined as carotid intima-media thickness >90th percentile and/or plaque. The association between MetS and incident high carotid intima-media thickness was attenuated by ≈40% after adjustment with apoB. Adjustments with apoA-I, C-reactive protein, or type II secretory phospholipase A2 did not diminish the association.

Conclusion—

High levels of apoB, C-reactive protein, and type II secretory phospholipase A2 and low levels of apoA-I associate with MetS in young adults. The atherogenicity of MetS in this population assessed by incident high carotid intima-media thickness appears to be substantially mediated by elevated apoB but not inflammatory markers.
Development of Spontaneous Anergy in Invariant Natural Killer T Cells in a Mouse Model of Dyslipidemia
Authors: Braun Nicole A. , Mendez-Fernandez Yanice V. , Covarrubias Roman , Porcelli Steven A. , Savage Paul B. , Yagita Hideo , Van Kaer Luc , Major Amy S.
Published: June 2010

Objective—

In this study, we investigated whether dyslipidemia-associated perturbed invariant natural killer T (iNKT) cell function is due to intrinsic changes in iNKT cells or defects in the ability of antigen-presenting cells to activate iNKT cells.

Methods and Results—

We compared iNKT cell expansion and cytokine production in C57BL/6J (B6) and apolipoprotein E-deficient (apoE
−/−
) mice. In response to in vivo stimulation with α-galactosylceramide, a prototypic iNKT cell glycolipid antigen, apoE
−/−
mice showed significantly decreased splenic iNKT cell expansion at 3 days after injection, a profile associated with iNKT cell anergy due to chronic stimulation. This decrease in expansion and cytokine production was accompanied by a 2-fold increase in percentage of iNKT cells expressing the inhibitory marker programmed death-1 in apoE
−/−
mice compared with controls. However, in vivo and in vitro blockade of programmed death-1 using monoclonal antibody was not able to restore functions of iNKT cells from apoE
−/−
mice to B6 levels. iNKT cells from apoE
−/−
mice also had increased intracellular T cell receptor and Ly49 expression, a phenotype associated with previous activation. Changes in iNKT cell functions were cell autonomous, because dendritic cells from apoE
−/−
mice were able to activate B6 iNKT cells, but iNKT cells from apoE
−/−
mice were not able to respond to B6 dendritic cells.

Conclusion—

These data suggest that chronic dyslipidemia induces an iNKT cell phenotype that is unresponsive to further simulation by exogenous glycolipid and that sustained unresponsiveness is iNKT cell intrinsic.