bluuebunny/crossref_metadata_2025 huggingface dataset:
Nucleoporin Phosphorylation Triggered by the Encephalomyocarditis Virus Leader Protein Is Mediated by Mitogen-Activated Protein Kinases
Authors: Porter Frederick W. , Brown Bradley , Palmenberg Ann C.
Published: September 2010

Cardioviruses disrupt nucleocytoplasmic transport through the activity of their leader (L) protein. We have shown that hyperphosphorylation of nuclear pore proteins (nucleoporins or Nups), including Nup62, Nup153, and Nup214, is central to this L protein function and requires one or more cytosolic kinases. In this study, potential cellular enzymes involved in encephalomyocarditis virus (EMCV) L-directed Nup phosphorylation were screened with a panel of specific, cell-permeating kinase inhibitors. Extracellular signal-regulated receptor kinase (ERK) and p38 mitogen-activated protein kinase inhibitors (U0126 and SB203580) were sufficient to block Nup hyperphosphorylation in EMCV-infected or L-expressing cells. Recombinant L alone, in the absence of infection, triggered activation of ERK and p38, independent of their upstream signaling cascades. Conserved residues within the L zinc finger (Cys
19
) and acidic domain (Asp
48
,
51
,
52
,
55
) were essential for this activation and for the phosphorylation of Nups, suggesting that the phenomena are linked. Analysis of the hyperphosphorylated Nup species revealed only phosphoserine and phosphothreonine residues. The sizes of the tryptic phosphopeptides derived from Nup62 were compatible with sites in the Phe/Gly repeat domain which display common consensus sequences for ERK and p38 substrates. The results provide strong evidence that ERK and p38 are the probable effector kinases required for L-dependent inhibition of nuclear trafficking.
Impairment of Hepatitis B Virus Virion Secretion by Single-Amino-Acid Substitutions in the Small Envelope Protein and Rescue by a Novel Glycosylation Site
Authors: Ito Kiyoaki , Qin Yanli , Guarnieri Michael , Garcia Tamako , Kwei Karen , Mizokami Masashi , Zhang Jiming , Li Jisu , Wands Jack R. , Tong Shuping
Published: September 2010

Mutations in the S region of the hepatitis B virus (HBV) envelope gene are associated with immune escape, occult infection, and resistance to therapy. We previously identified naturally occurring mutations in the S gene that alter HBV virion secretion. Here we used transcomplementation assay to confirm that the I110M, G119E, and R169P mutations in the S domain of viral envelope proteins impair virion secretion and that an M133T mutation rescues virion secretion of the I110M and G119E mutants. The G119E mutation impaired detection of secreted hepatitis B surface antigen (HBsAg), suggesting immune escape. The R169P mutant protein is defective in HBsAg secretion as well and has a dominant negative effect when it is coexpressed with wild-type envelope proteins. Although the S domain is present in all three envelope proteins, the I110M, G119E, and R169P mutations impair virion secretion through the small envelope protein. Conversely, coexpression of just the small envelope protein of the M133T mutant could rescue virion secretion. The M133T mutation could also overcome the secretion defect caused by the G145R immune-escape mutation or mutation at N146, the site of N-linked glycosylation. In fact, the M133T mutation creates a novel N-linked glycosylation site (131NST133). Destroying this site by N131Q/T mutation or preventing glycosylation by tunicamycin treatment of transfected cells abrogated the effect of the M133T mutation. Our findings demonstrate that N-linked glycosylation of HBV envelope proteins is critical for virion secretion and that the secretion defect caused by mutations in the S protein can be rescued by an extra glycosylation site.
Genetic Identity and Biological Phenotype of a Transmitted/Founder Virus Representative of Nonpathogenic Simian Immunodeficiency Virus Infection in African Green Monkeys
Authors: Gnanadurai Clement Wesley , Pandrea Ivona , Parrish Nicholas F. , Kraus Matthias H. , Learn Gerald H. , Salazar Maria G. , Sauermann Ulrike , Töpfer Katharina , Gautam Rajeev , Münch Jan , Stahl-Hennig Christiane , Apetrei Christian , Hahn Beatrice H. , Kirchhoff Frank
Published: September 2010

Understanding the lack of disease progression in nonpathogenic simian immunodeficiency virus (SIV) infections is essential for deciphering the immunopathogenesis of human AIDS. Yet,
in vivo
studies have been hampered by a paucity of infectious molecular clones (IMCs) of SIV suitable to dissect the viral and host factors responsible for the nonpathogenic phenotype. Here, we describe the identification, cloning, and biological analysis of the first transmitted/founder (T/F) virus representing a nonpathogenic SIV infection. Blood was collected at peak viremia from an acutely infected sabaeus monkey (
Chlorocebus sabaeus
) inoculated intravenously with an African green monkey SIV (SIVagm) strain (Sab92018) that had never been propagated
in vitro
. To generate IMCs, we first used conventional (bulk) PCR to amplify full-length viral genomes from peripheral blood mononuclear cell (PBMC) DNA. Although this yielded two intact SIVagmSab genomes, biological characterization revealed that both were replication defective. We then performed single-genome amplification (SGA) to generate partially overlapping 5′ (
n
= 10) and 3′ (
n
= 13) half genomes from plasma viral RNA. Analysis of these amplicons revealed clusters of nearly identical viral sequences representing the progeny of T/F viruses. Synthesis of the consensus sequence of one of these generated an IMC (Sab92018ivTF) that produced infectious CCR5-tropic virions and replicated to high titers in Molt-4 clone 8 cells and African green monkey PBMCs. Sab92018ivTF also initiated productive infection in sabaeus monkeys and faithfully recapitulated the replication kinetics and nonpathogenic phenotype of the parental Sab92018 strain. These results thus extend the T/F virus concept to nonpathogenic SIV infections and provide an important new tool to define viral determinants of disease nonprogression.
How to teach moral theories in applied ethics
Authors: Saunders Ben
Published: September 2010

Recent discussion has focused on whether or not to teach moral theories, and, if yes, to what extent. In this piece the author argues that the criticisms of teaching moral theories raised by Rob Lawlor should lead us to reconsider not whether but how to teach moral theories. It seems that most of the problems Lawlor identifies derive from an uncritical, theory-led approach to teaching. It is suggested that we might instead start by discussing practical cases or the desiderata of a successful moral theory, and then build up to comparing theories such as consequentialism, deontology, and so on. In this way, theories are taught but students do not take them to be the alpha and omega of moral thinking.
Stenting of a symptomatic long-segment extracranial vertebral artery occlusion
Authors: Gupta Rishi , Sivapatham Thinesh , Moskowitz Shaye I , Srivastava Sunita
Published: September 2010

We present a 56-year-old man who presented with bilateral vertebral artery occlusions and recurrent transient ischemic attacks and strokes despite maximal medical therapy. A long-segment extracranial right vertebral occlusion was noted and successfully reconstructed with four drug-eluting stents. The patient has been symptom free for 3 months and does not exhibit restenosis on follow-up angiography. Stenting and angioplasty of a long-segment vertebral artery occlusion is technically feasible in select cases.
SOME CRITERIA FOR EXISTENCE OF SUPPLEMENTS TO NORMAL SUBGROUPS AND THEIR APPLICATIONS
Authors: KURDACHENKO LEONID A. , OTAL JAVIER , SUBBOTIN IGOR YA.
Published: September 2010

We established several new criteria for existence of complements and supplements to some normal abelian subgroups in groups. In passing, as one of the many useful applications and corollaries of these results, we obtained a description of some finitely generated soluble groups of finite Hirsch–Zaitsev rank. As another application of our results, we obtained a D.J.S. Robinson's theorem on structure of finitely generated soluble groups of finite section rank. The original proof of this theorem was homological, but all proofs in this paper, including this one, are purely group-theoretical.
Solvent-free synthesis of meso- tetraarylporphyrins in air: product diversity and yield optimization
Authors: Nia Shabnam , Gong Xianchang , Drain Charles Michael , Jurow Matthew , Rizvi Waqar , Qureshy Meroz
Published: September 2010

The scope and optimization of a solvent-free method for the rapid preparation and facile purification of technologically important meso-substituted aryl porphyrins, such as 5,10,15,20-tetraphenylporphyrin is presented. This one-step method involves heating the aromatic aldehyde to ~200°C in a vial fitted with a septum-lined cap, followed by addition of the pyrrole and maintaining the temperature for about 20 minutes. The dioxygen in air serves as the oxidant. Present results show that the addition of benzoic acid as a catalyst improves the yield of 5,10,15,20-tetraphenylporphyrin from 22% to 32% and of para halogenated phenylporphyrins from 10% to ~25%. Herein is also presented an examination of the many factors that influence the yield, the ease of purification, and the ability to scale up the reaction. Since the tarry by-products from this method are much less soluble than in most other synthetic strategies, much less solvent is required for purification; simple extraction is often sufficient. This method can be scaled in the lab to > 300 mg, and provides an attractive route to many meso-substituted porphyrins because of its minimal waste generation in terms of both solvent and chromatography support.
Photooxygenation of alkenes by molecular oxygen in the presence of porphyrins and chlorin sensitizers under visible light irradiation
Authors: Hajimohammadi Mahdi , Safari Nasser
Published: September 2010

Photooxidation of alkenes by molecular oxygen and visible light in the presence of tetraphenylporphyrin (H2TPP) , tetramesitylporphyrin (H2TMP) , tetrakis pentafluorophenylporphyrin (H2TPFPP) and tetrakis(2,3-dimetoxyphenyl)porphyrin T(2,3-OMeP)P and metalloporphyrins such as ClFeTPP , ClMnTMP , ClMnTPP , ClMnTPFPP , ClCoTPP and ZnTPP has been performed. Photooxidation of alkenes with tetraphenylchlorin (H2TPC) as the sensitizer with visible light has also been studied. The conversion rates for alkene oxidation were in the order of free-base porphyrins > chlorin > metalloporphyrins. In the presence of NaN3/Na2SO3 the yield of oxidation products and conversion percentage is considerably reduced, confirming involvement of 1O2 in the mechanism.
Influence of protonation of peripheral substituents on photophysical and photochemical properties of tetrapyrazinoporphyrazines
Authors: Novakova Veronika , Mørkved Eva H. , Miletin Miroslav , Zimcik Petr
Published: September 2010

Octasubstituted zinc tetrapyrazinoporphyrazines with four N,N-dimethylaminophenyls and four phenyl or pyridin-3-yl substituents were synthesized and fully characterized. Their fluorescence quantum yields in DMF or pyridine were very low, almost undetectable, as a consequence of ultrafast intramolecular charge transfer. Titration of their DMF solutions with sulfuric acid led to increase of the fluorescence quantum yields by two orders of magnitude when the full protonation of peripheral substituents was achieved. Intramolecular charge transfer is no longer a favorable way of excited-state relaxation at full protonation of N,N-dimethylaminophenyl substituents because of loss of donor centers (free electron pair on its nitrogen). Similarly, singlet oxygen quantum yields also increased by two orders of magnitude when sulfuric acid was added to tetrapyrazinoporphyrazine solutions in DMF. Protonation at azomethine nitrogens of tetrapyrazinoporphyrazine macrocycle was observed at higher acid concentrations and it led to considerable decrease of fluorescence quantum yields. Octaphenyl zinc tetrapyrazinoporphyrazine and octa(pyridin-3-yl) zinc tetrapyrazinoporphyrazine were used as controls without intramolecular charge transfer. Their fluorescence and singlet oxygen quantum yields were high in DMF and decreased at higher concentrations of sulfuric acid due to protonation of azomethine nitrogens. The results suggest that the photophysical and photochemical properties of studied compounds may be controlled by changes of pH of medium.
STRESS–STRAIN EVOLUTION IN CAST IN-738 SUPERALLOY SINGLE FUSION WELDS
Authors: BONIFAZ E. A. , RICHARDS N. L.
Published: September 2010

A three-dimensional finite element elastic–plastic model was developed to study localized plastic strains and residual stresses that exist in a body that has previously been subjected to nonuniform temperature changes. The mechanical model was used to compute the evolution of plastic strains and residual stresses of welded material. The thermal gradient histories calculated during the GTA welding of cast IN-738LC alloys were imposed as load conditions on structural calculations. It can be clearly seen that at constant heat input, the level of plastic strains and the level of residual (Mises) stresses increase with welding speed. The model predicts highest residual stresses in regions of highest elastic strains, in agreement with conventional phenomenological material models where the macroscopic residual stress is always directly related to the macroscopic elastic strain. The highest residual stresses are located at the fusion line (where coarser dendrite secondary arm spacing exist); and the highest plastic strains are located at centerline (where finer dendrite secondary arm spacing exist). The calculations were performed using ABAQUS®FE code on the basis of a time-increment Lagrangian formulation.
ON THE DENSITY OF DISCRIMINANTS OF ABELIAN EXTENSIONS OF A NUMBER FIELD
Authors: MAMMO BEHAILU
Published: September 2010

Let G = Cℓ × Cℓ denote the product of two cyclic groups of prime order ℓ, and let k be an algebraic number field. Let N(k, G, m) denote the number of abelian extensions K of k with Galois group G(K/k) isomorphic to G, and the relative discriminant 𝒟(K/k) of norm equal to m. In this paper, we derive an asymptotic formula for ∑m≤XN(k, G; m). This extends the result previously obtained by Datskovsky and Mammo.
EVALUATIONS OF CUBIC TWISTED KLOOSTERMAN SHEAF SUMS
Authors: BOOHER JEREMY , ETROPOLSKI ANASTASSIA , HITTSON AMANDA
Published: September 2010

We prove some conjectures of Evans and Katz presented in a paper by Evans regarding twisted Kloosterman sheaf sums Tn. These conjectures give explicit evaluations of the sums Tn where the character is cubic and n = 4. There are also conjectured relationships between evaluations of Tn and the coefficients of certain modular forms. For three of these modular forms, each of weight 3, it is conjectured that the coefficients are related to the squares of the coefficients of weight 2 modular forms. We prove these relationships using the theory of complex multiplication.
LUCIFERASES FOR THE STUDY OF PROTEIN–PROTEIN INTERACTIONS IN LIVE CELLS AND ANIMALS
Authors: KAFI A. K. M. , HATTORI MITSURU , OZAWA TAKEAKI
Published: September 2010

Many imaging technologies based on luminescent proteins have proven useful for detecting protein–protein interactions, tracking cells in mice, and monitoring transcriptional regulation of specific genes. Especially, novel bioluminescent proteins have advanced the study of induced protein interactions and protein modification in live cells and animals. This review focuses on recent developments of bioluminescent probes for quantitative evaluation of specific protein–protein interactions and their spatio-temporal imaging by means of split luciferase complementation techniques. From the comparison between fluorescent and bioluminescent proteins, advantages and drawbacks of the bioluminescence techniques are described.
TOTAL OSSICULAR REPLACEMENT PROSTHESES: MATERIALS AND DESIGNS
Authors: MILLER P. R. , GITTARD S. D. , ADUNKA O. , PILLSBURY H. C. , LEE Y. S. , NARAYAN R. J.
Published: September 2010

Surgeons and patients are demanding improved replacements for dysfunctional ossicular bones. Replacement of the entire ossicular chain and positioning the prosthesis between the stapes footplate and the tympanic membrane are of particular challenges. Many materials have been used since the first ossicular replacement; at the present time, the two most widely used materials are titanium and hydroxyapatite. Studies have indicated little difference between these two materials. A variety of novel additions have been added to total ossicular replacement prostheses to overcome limitations associated with conventional prostheses. Testing of novel prosthesis materials and designs over long time intervals is needed in order to validate and expand their usage.
CYTOTOXICITY EVALUATIONS OF FLUORESCENT CARBON NANOPARTICLES
Authors: LIU JIA-HUI , ANILKUMAR PARAMBATH , CAO LI , WANG XIN , YANG SHENG-TAO , LUO PENGJU G. , WANG HAIFANG , LU FUSHEN , MEZIANI MOHAMMED J. , LIU YUANFANG , KORCH KATERINA , SUN YA-PING
Published: September 2010

Fluorescent nanoparticles have received much attention for their potential applications in biology and medicine, such as uses as fluorescence markers or imaging agents. Recently, surface-passivated carbon nanoparticles or "carbon dots" were demonstrated to be brightly fluorescent, thus representing a new platform for nanoscale fluorescent agents. For targeted bioapplications of carbon dots, an understanding of their toxicity behavior is necessary, including issues on potential defunctionalization of the dots in biological systems that might result in the exposure of the nanoscale carbon core. In this work, we performed cytotoxicity evaluations on both precursor carbon nanoparticles and carbon dots, from which the results suggested no significant cytotoxic effects.
RNA-binding protein HuR regulates RGS4 mRNA stability in rabbit colonic smooth muscle cells
Authors: Li Fang , Hu Danielle Y. , Liu Shu , Mahavadi Sunila , Yen William , Murthy Karnam S. , Khalili Kamel , Hu Wenhui
Published: September 2010

Regulator of G protein signaling 4 (RGS4) regulates the strength and duration of G protein signaling and plays an important role in smooth muscle contraction, cardiac development, and psychiatric disorders. Little is known about the posttranscriptional regulation of RGS4 expression. We cloned the full-length cDNA of rabbit RGS4, which contains a long 3′-untranslated region (UTR) with several AU-rich elements (AREs). We determined whether RGS4 mRNA stability is mediated by the RNA-binding protein human antigen R (HuR) and contributes to IL-1β-induced upregulation of RGS4 expression. We show that IL-1β treatment in colonic smooth muscle cells doubled the half-life of RGS4 mRNA. Addition of RGS4 3′-UTR to the downstream of Renilla luciferase reporter induced dramatic reduction in the enzyme activity and mRNA expression of luciferase, which was attenuated by the site-directed mutation of the two 3′-most ARE sites. IL-1β increased luciferase mRNA stability in a UTR-dependent manner. Knockdown of HuR significantly aggravated UTR-mediated instability of luciferase and inhibited IL-1β-induced upregulation of RGS4 mRNA. In addition, IL-1β increased cytosolic translocation and RGS4 mRNA binding of HuR. These findings suggest that 3′-most ARE sites within RGS4 3′-UTR are essential for the instability of RGS4 mRNA and IL-1β promotes the stability of RGS4 mRNA through HuR.
Nitrosative modifications of protein and lipid signaling molecules by reactive nitrogen species
Authors: White Phillip J. , Charbonneau Alexandre , Cooney Gregory J. , Marette André
Published: September 2010

This review is the last of four review articles addressing covalent modifications of proteins and lipids. Two of the reviews in this series were previously published ( 15 , 28 ) and dealt with modifications of signaling proteins by GlcNAcylation and serine phosphorylation. In the current issue of the Journal, we complete this series with two reviews, one by Riahi et al. (102a) on the signaling and cellular functions of 4-hydroxyalkenals, key products of lipid peroxidation processes, and our present review on the effects of nitrosative modifications of protein and lipid signaling molecules by reactive nitrogen species. The aim of this Perspectives review is to highlight the significant role that reactive nitrogen species may play in the regulation of cellular metabolism through this important class of posttranslational modification. The potential role of nitrosative modifications in the regulation of insulin signal transduction, mitochondrial energy metabolism, mRNA transcription, stress signaling, and endoplasmic reticulum function will each be discussed. Since nitrosative modifications are not restricted to proteins, the current understanding of a recently described genus of “nitro-fatty acids” will also be addressed.
Long-term exposure to high-altitude chronic hypoxia during gestation induces neonatal pulmonary hypertension at sea level
Authors: Herrera Emilio A. , Riquelme Raquel A. , Ebensperger Germán , Reyes Roberto V. , Ulloa César E. , Cabello Gertrudis , Krause Bernardo J. , Parer Julian T. , Giussani Dino A. , Llanos Aníbal J.
Published: September 2010

We determined whether postnatal pulmonary hypertension induced by 70% of pregnancy at high altitude (HA) persists once the offspring return to sea level and investigated pulmonary vascular mechanisms operating under these circumstances. Pregnant ewes were divided into two groups: conception, pregnancy, and delivery at low altitude (580 m, LLL) and conception at low altitude, pregnancy at HA (3,600 m) from 30% of gestation until delivery, and return to lowland (LHL). Pulmonary arterial pressure (PAP) was measured in vivo. Vascular reactivity and morphometry were assessed in small pulmonary arteries (SPA). Protein expression of vascular mediators was determined. LHL lambs had higher basal PAP and a greater increment in PAP after NG-nitro-l-arginine methyl ester (20.9 ± 1.1 vs. 13.7 ± 0.5 mmHg; 39.9 ± 5.0 vs. 18.3 ± 1.3 mmHg, respectively). SPA from LHL had a greater maximal contraction to K+ (1.34 ± 0.05 vs. 1.16 ± 0.05 N/m), higher sensitivity to endothelin-1 and nitroprusside, and persistence of dilatation following blockade of soluble guanylate cyclase. The heart ratio of the right ventricle-to-left ventricle plus septum was higher in the LHL relative to LLL. The muscle area of SPA (29.3 ± 2.9 vs. 21.1 ± 1.7%) and the protein expression of endothelial nitric oxide synthase (1.7 ± 0.1 vs. 1.1 ± 0.2), phosphodiesterase (1.4 ± 0.1 vs. 0.7 ± 0.1), and Ca2+-activated K+ channel (0.76 ± 0.16 vs. 0.30 ± 0.01) were greater in LHL compared with LLL lambs. In contrast, LHL had decreased heme oxygenase-1 expression (0.82 ± 0.26 vs. 2.22 ± 0.44) and carbon monoxide production (all P < 0.05). Postnatal pulmonary hypertension induced by 70% of pregnancy at HA promotes cardiopulmonary remodeling that persists at sea level.
Renal cortical and medullary blood flow responses to altered NO availability in humans
Authors: Damkjær Mads , Vafaee Manoucher , Møller Michael L. , Braad Poul Erik , Petersen Henrik , Høilund-Carlsen Poul Flemming , Bie Peter
Published: September 2010

The objective of this study was to quantify regional renal blood flow in humans. In nine young volunteers on a controlled diet, the lower abdomen was CT-scanned, and regional renal blood flow was determined by positron emission tomography (PET) scanning using H215O as tracer. Measurements were performed at baseline, during constant intravenous infusion of nitric oxide (NO) donor glyceryl nitrate and after intravenous injection of NO synthase inhibitor Nω-monomethyl-l-arginine (l-NMMA). Using the CT image, the kidney pole areas were delineated as volumes of interest (VOI). In the data analysis, tissue layers with a thickness of one voxel were eliminated stepwise from the external surface of the VOI (voxel peeling), and the blood flow subsequently was determined in each new, reduced VOI. Blood flow in the shrinking VOIs decreased as the number of cycles of voxel peeling increased. After 4–5 cycles, blood flow was not reduced further by additional voxel peeling. This volume-insensitive flow was measured to be 2.30 ± 0.17 ml·g tissue−1·min−1during the control period; it increased during infusion of glyceryl nitrate to 2.97 ± 0.18 ml·g tissue−1·min−1( P < 0.05) and decreased after l-NMMA injection to 1.57 ± 0.17 ml·g tissue−1·min−1( P < 0.05). Cortical blood flow was 4.67 ± 0.31 ml·g tissue−1·min−1during control, unchanged by glyceryl nitrate, and decreased after l-NMMA [3.48 ± 0.23 ml·(g·min)−1, P < 0.05]. PET/CT scanning allows identification of a renal medullary region in which the measured blood flow is 1) low, 2) independent of reduction in the VOI, and 3) reactive to changes in systemic NO supply. The technique seems to provide indices of renal medullary blood flow in humans.
PP2A contributes to endothelial death in high glucose: inhibition by benfotiamine
Authors: Du Y. , Kowluru A. , Kern T. S.
Published: September 2010

Endothelial death is critical in diabetic vascular diseases, but regulating factors have been only partially elucidated. Phosphatases play important regulatory roles in cell metabolism, but have not previously been implicated in hyperglycemia-induced cell death. We investigated the role of the phosphatase, type 2A protein phosphatase (PP2A), in hyperglycemia-induced changes in signaling and death in bovine aortic endothelial cells (BAEC). We explored also the influence of benfotiamine on this phosphatase. Activation of PP2A was assessed in BAEC by the extent of methylation and measurement of activity, and the enzyme was inhibited using selective pharmacological (okadaic acid, sodium fostriecin) and molecular (small interfering RNA) approaches. BAECs cultured in 30 mM glucose significantly increased PP2A methylation and activity, and PP2A inhibitors blocked these abnormalities. PP2A activity was increased also in aorta and retina from diabetic rats. NF-κB activity and cell death in BAEC were significantly increased in 30 mM glucose and inhibited by PP2A inhibition. NF-κB played a role in the hyperglycemia-induced death of BAEC, since blocking its translocation with SN50 also inhibited cell death. Inhibition of PP2A blocked the hyperglycemia-induced dephosphorylation of NF-κB and Bad, thus favoring cell survival. Incubation of benfotiamine with BAEC inhibited the high glucose-induced activation of PP2A and NF-κB and cell death, as well as several other metabolic defects, which likewise were inhibited by inhibitors of PP2A. Activation of PP2A contributes to endothelial cell death in high glucose, and beneficial actions of benfotiamine are due, at least in part, to inhibition of PP2A activation.
Renal protection in chronic kidney disease: hypoxia-inducible factor activation vs. angiotensin II blockade
Authors: Deng Aihua , Arndt Mary Ann K. , Satriano Joseph , Singh Prabhleen , Rieg Timo , Thomson Scott , Tang Tong , Blantz Roland C.
Published: September 2010

The 5/6thnephrectomy or ablation/infarction (A/I) preparation has been used as a classic model of chronic kidney disease (CKD). We observed increased kidney oxygen consumption (QO2) and altered renal hemodynamics in the A/I kidney that were normalized after combined angiotensin II (ANG II) blockade. Studies suggest hypoxia inducible factor as a protective influence in A/I. We induced hypoxia-inducible factor (HIF) and HIF target proteins by two different methods, cobalt chloride (CoCl2) and dimethyloxalyglycine (DMOG), for the first week after creation of A/I and compared the metabolic and renal hemodynamic outcomes to combined ANG II blockade. We also examined the HIF target proteins expressed by using Western blots and real-time PCR. Treatment with DMOG, CoCl2, and ANG II blockade normalized kidney oxygen consumption factored by Na reabsorption and increased both renal blood flow and glomerular filtration rate. At 1 wk, CoCl2and DMOG increased kidney expression of HIF by Western blot. In the untreated A/I kidney, VEGF, heme oxygenase-1, and GLUT1 were all modestly increased. Both ANG II blockade and CoCl2therapy increased VEGF and GLUT1 but the cobalt markedly so. ANG II blockade decreased heme oxygenase-1 expression while CoCl2increased it. By real-time PCR, erythropoietin and GLUT1 were only increased by CoCl2therapy. Cell proliferation was modestly increased by ANG II blockade but markedly after cobalt therapy. Metabolic and hemodynamic abnormalities were corrected equally by ANG II blockade and HIF therapies. However, the molecular patterns differed significantly between ANG II blockade and cobalt therapy. HIF induction may prove to be protective in this model of CKD.
Pudendal nerve injury reduces urethral outlet resistance in diabetic rats
Authors: Pan Hui Q. , Lin Dan L. , Strauch Christopher , Butler Robert S. , Monnier Vincent M. , Daneshgari Firouz , Damaser Margot S.
Published: September 2010

Diabetics have voiding and continence dysfunction to which elevated levels of advanced glycation end products (AGE) may contribute. In addition, pudendal nerve injury is correlated with voiding dysfunction and stress incontinence in rats. The aim of this study was to investigate whether pudendal nerve crush (PNC) in diabetic rats alters urinary function. Female virgin Sprague-Dawley rats (144) were divided equally into diabetic, diuretic, and control groups. Half of the animals in each group were subjected to PNC, and the other half to sham PNC. Diabetes was induced 8 wk before PNC or sham PNC by streptozotocin injection (35 mg/kg). Animals underwent conscious cystometry and leak point pressure (LPP) testing 4 or 13 days after PNC or sham PNC. Tissues of half the animals were tested for levels of AGEs. Qualitative histological assessment was performed in the remaining animals. Diabetic rats 4 days after PNC voided significantly greater volume in a shorter time and with significantly less pressure than after sham PNC, suggesting that diabetic rats have a functional outlet obstruction that is relieved by PNC. LPP was significantly reduced 4 days after PNC in diabetic and diuretic animals and returned to normal 13 days after PNC. Diabetic rats with PNC demonstrated increased muscle fiber disruption and atrophy of the external urethral sphincter. AGEs were significantly elevated in diabetic rats. PNC relieves a functional outlet obstruction in diabetic rats. AGEs are elevated in diabetic rats and could play a role in urinary dysfunction and recovery from PNC.
Tinnitus, Diminished Sound-Level Tolerance, and Elevated Auditory Activity in Humans With Clinically Normal Hearing Sensitivity
Authors: Gu Jianwen Wendy , Halpin Christopher F. , Nam Eui-Cheol , Levine Robert A. , Melcher Jennifer R.
Published: September 2010

Phantom sensations and sensory hypersensitivity are disordered perceptions that characterize a variety of intractable conditions involving the somatosensory, visual, and auditory modalities. We report physiological correlates of two perceptual abnormalities in the auditory domain: tinnitus, the phantom perception of sound, and hyperacusis, a decreased tolerance of sound based on loudness. Here, subjects with and without tinnitus, all with clinically normal hearing thresholds, underwent 1) behavioral testing to assess sound-level tolerance and 2) functional MRI to measure sound-evoked activation of central auditory centers. Despite receiving identical sound stimulation levels, subjects with diminished sound-level tolerance (i.e., hyperacusis) showed elevated activation in the auditory midbrain, thalamus, and primary auditory cortex compared with subjects with normal tolerance. Primary auditory cortex, but not subcortical centers, showed elevated activation specifically related to tinnitus. The results directly link hyperacusis and tinnitus to hyperactivity within the central auditory system. We hypothesize that the tinnitus-related elevations in cortical activation may reflect undue attention drawn to the auditory domain, an interpretation consistent with the lack of tinnitus-related effects subcortically where activation is less potently modulated by attentional state. The data strengthen, at a mechanistic level, analogies drawn previously between tinnitus/hyperacusis and other, nonauditory disordered perceptions thought to arise from neural hyperactivity such as chronic neuropathic pain and photophobia.
Electrical Stimulation of the Frontal Eye Fields in the Head-Free Macaque Evokes Kinematically Normal 3D Gaze Shifts
Authors: Monteon Jachin A. , Constantin Alina G. , Wang Hongying , Martinez-Trujillo Julio , Crawford J. Douglas
Published: September 2010

The frontal eye field (FEF) is a region of the primate prefrontal cortex that is central to eye-movement generation and target selection. It has been shown that neurons in this area encode commands for saccadic eye movements. Furthermore, it has been suggested that the FEF may be involved in the generation of gaze commands for the eye and the head. To test this suggestion, we systematically stimulated (with pulses of 300 Hz frequency, 200 ms duration, 30–100 μA intensity) the FEF of two macaques, with the head unrestrained, while recording three-dimensional (3D) eye and head rotations. In a total of 95 sites, the stimulation consistently elicited gaze-orienting movements ranging in amplitude from 2 to 172°, directed contralateral to the stimulation site, and with variable vertical components. These movements were typically a combination of eye-in-head saccades and head-in-space movements. We then performed a comparison between the stimulation-evoked movements and gaze shifts voluntarily made by the animal. The kinematics of the stimulation-evoked movements (i.e., their spatiotemporal properties, their velocity–amplitude relationships, and the relative contributions of the eye and the head as a function of movement amplitude) were very similar to those of natural gaze shifts. Moreover, they obeyed the same 3D constraints as the natural gaze shifts (i.e., modified Listing's law for eye-in-head movements). As in natural gaze shifts, saccade and vestibuloocular reflex torsion during stimulation-evoked movements were coordinated so that at the end of the head movement the eye-in-head ended up in Listing's plane. In summary, movements evoked by stimulation of the FEF closely resembled those of naturally occurring eye–head gaze shifts. Thus we conclude that the FEF explicitly encodes gaze commands and that the kinematic aspects of eye–head coordination are likely specified by downstream mechanisms.
Aging and microRNA expression in human skeletal muscle: a microarray and bioinformatics analysis
Authors: Drummond Micah J. , McCarthy John J. , Sinha Mala , Spratt Heidi M. , Volpi Elena , Esser Karyn A. , Rasmussen Blake B.
Published: September 2010

A common characteristic of aging is loss of skeletal muscle (sarcopenia), which can lead to falls and fractures. MicroRNAs (miRNAs) are novel posttranscriptional modulators of gene expression with potential roles as regulators of skeletal muscle mass and function. The purpose of this study was to profile miRNA expression patterns in aging human skeletal muscle with a miRNA array followed by in-depth functional and network analysis. Muscle biopsy samples from 36 men [young: 31 ± 2 ( n = 19); older: 73 ± 3 ( n = 17)] were 1) analyzed for expression of miRNAs with a miRNA array, 2) validated with TaqMan quantitative real-time PCR assays, and 3) identified (and later validated) for potential gene targets with the bioinformatics knowledge base software Ingenuity Pathways Analysis. Eighteen miRNAs were differentially expressed in older humans ( P < 0.05 and >500 expression level). Let-7 family members Let-7b and Let-7e were significantly elevated and further validated in older subjects ( P < 0.05). Functional and network analysis from Ingenuity determined that gene targets of the Let-7s were associated with molecular networks involved in cell cycle control such as cellular proliferation and differentiation. We confirmed with real-time PCR that mRNA expression of cell cycle regulators CDK6, CDC25A, and CDC34 were downregulated in older compared with young subjects ( P < 0.05). In addition, PAX7 mRNA expression was lower in older subjects ( P < 0.05). These data suggest that aging is characterized by a higher expression of Let-7 family members that may downregulate genes related to cellular proliferation. We propose that higher Let-7 expression may be an indicator of impaired cell cycle function possibly contributing to reduced muscle cell renewal and regeneration in older human muscle.
Heat Shock Protein: Hard Worker or Bad Offender for Gastric Diseases
Authors: Lee Ho-Jae , Ock Chan Young , Kim Seong-Jin , Hahm Ki-Baik
Published: September 2010

Heat shock proteins (HSPs) have core housekeeping functions in the cells where they are built-in components of folding, signal transduction pathways, and quality control functions for which they proofread the structure of proteins and repair misfolded conformers. Helicobacter pylori (H. pylori) infection leads to significant inflammations in the gastric mucosa, which is closely associated with development of either precancerous lesion including chronic atrophic gastritis or gastric cancer in addition to, peptic ulcer disease, and mucosa-associated lymphoid tissue (MALT) lymphoma. Therefore, the association between H. pylori infection and role of HSP has been focused as an important issue because there had been rather conflicting publications showing that HSPs as a good worker for defense against H. pylori infection, whereas HSPs as a bad offender contributing to the progression of H. pylori-associated gastric carcinogenesis in addition to aggravation of gastric inflammation. In this paper regarding proteomic discovery of HSPs related to H. pylori-associated gastric diseases, we introduce several evidences obtained from proteomic analysis dealing with friend or foe role of HSP in H. pylori infection from a cellular level to human diseases. The implication of HSPs in alcoholic or NSAIDs-induced gastritis and the intervening of HSPs in biological changes exemplified with TGF-β signaling, key tumor suppressor growth factors regulating inflammation, immune function, and carcinogenesis were further introduced.
Humanoid Walking Robot: Modeling, Inverse Dynamics, and Gain Scheduling Control
Authors: Kljuno Elvedin , Williams Robert L.
Published: September 2010

This article presents reference-model-based control design for a 10 degree-of-freedom bipedal walking robot, using nonlinear gain scheduling. The main goal is to show concentrated mass models can be used for prediction of the required joint torques for a bipedal walking robot. Relatively complicated architecture, high DOF, and balancing requirements make the control task of these robots difficult. Although linear control techniques can be used to control bipedal robots, nonlinear control is necessary for better performance. The emphasis of this work is to show that the reference model can be a bipedal walking model with concentrated mass at the center of gravity, which removes the problems related to design of a pseudo-inverse system. Another significance of this approach is the reduced calculation requirements due to the simplified procedure of nominal joint torques calculation. Kinematic and dynamic analysis is discussed including results for joint torques and ground force necessary to implement a prescribed walking motion. This analysis is accompanied by a comparison with experimental data. An inverse plant and a tracking error linearization-based controller design approach is described. We propose a novel combination of a nonlinear gain scheduling with a concentrated mass model for the MIMO bipedal robot system.
Conservative Management of Placenta Accreta in a Multiparous Woman
Authors: Hunt Jennifer C.
Published: September 2010

Placenta accreta refers to any abnormally invasive placental implantation. Diagnosis is suspected postpartum with failed delivery of a retained placenta. Massive obstetrical hemorrhage is a known complication, often requiring peripartum hysterectomy. We report a case of presumed placenta accreta in a patient following failed manual removal of a retained placenta. We describe an attempt at conservative management with methotrexate in a stable patient desiring future fertility. Treatment was unsuccessful and led to the development of a disseminated intrauterine infection complicated by a bowel obstruction, requiring both a hysterectomy and small bowel resection. In hemodynamically stable patients, conservative management of placenta accreta may involve leaving placental tissuein situwith subsequent administration of methotrexate. However, ongoing close observation is required to identify complications.
Dynamic Determinants of Longevity and Exceptional Health
Authors: Yashin Anatoli I. , Arbeev Konstantin G. , Akushevich Igor , Arbeeva Liubov , Kravchenko Julia , Il'yasova Dora , Kulminski Alexander , Akushevich Lucy , Culminskaya Irina , Wu Deqing , Ukraintseva Svetlana V.
Published: September 2010

It is well known from epidemiology that values of indices describing physiological state in a given age may influence human morbidity and mortality risks. Studies of connection between aging and life span suggest a possibility that dynamic properties of age trajectories of the physiological indices could also be important contributors to morbidity and mortality risks. In this paper we use data on longitudinal changes in body mass index, diastolic blood pressure, pulse pressure, pulse rate, blood glucose, hematocrit, and serum cholesterol in the Framingham Heart Study participants, to investigate this possibility in depth. We found that some of the variables describing individual dynamics of the age-associated changes in physiological indices influence human longevity and exceptional health more substantially than the variables describing physiological state. These newly identified variables are promising targets for prevention aiming to postpone onsets of common elderly diseases and increase longevity.
Experimental Bleaching of a Reef-Building Coral Using a Simplified Recirculating Laboratory Exposure System
Authors: Barron Mace G. , McGill Cheryl J. , Courtney Lee A. , Marcovich Dragoslav T.
Published: September 2010

Determining stressor-response relationships in reef building corals continues to be a critical research need due to global declines in coral reef ecosystems and projected declines for the future. A simplified recirculating coral exposure system was coupled to a solar simulator to allow laboratory testing of a diversity of species and morphologies of reef building corals under ecologically relevant conditions of temperature and solar radiation. Combinations of lamps and attenuating filters allowed for assignment of solar radiation treatments in experimental bleaching studies. Three bleaching experiments were performed using the reef building coral,Pocillopora damicornis, to assess the reproducibility of system performance and coral responses under control and stress conditions. Experiments showed consistent temperature- and solar radiation dependent-changes in pigment, numbers of symbiotic algae, photosystem II quantum yield, and tissue loss during exposure and recovery. The laboratory exposure system is recommended for use in experimental bleaching studies with reef building corals.
Characteristics of Interstitial Fibrosis and Inflammatory Cell Infiltration in Right Ventricles of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension
Authors: Overbeek Maria J. , Mouchaers Koen T. B. , Niessen Hans M. , Hadi Awal M. , Kupreishvili Koba , Boonstra Anco , Voskuyl Alexandre E. , Belien Jeroen A. M. , Smit Egbert F. , Dijkmans Ben C. , Vonk-Noordegraaf Anton , Grünberg Katrien
Published: September 2010

Objective. Systemic sclerosis-associated pulmonary arterial hypertension (SScPAH) has a disturbed function of the right ventricle (RV) when compared to idiopathic PAH (IPAH). Systemic sclerosis may also affect the heart. We hypothesize that RV differences may occur at the level of interstitial inflammation and—fibrosis and compared inflammatory cell infiltrate and fibrosis between the RV of SScPAH, IPAH, and healthy controls.Methods. Paraffin-embedded tissue samples of RV and left ventricle (LV) from SScPAH (n=5) and IPAH (n=9) patients and controls (n=4) were picrosirius red stained for detection of interstitial fibrosis, which was quantified semiautomatically. Neutrophilic granulocytes (MPO), macrophages (CD68), and lymphocytes (CD45) were immunohistochemically stained and only interstitial leukocytes were counted. Presence of epi- or endocardial inflammation, and of perivascular or intimal fibrosis of coronary arteries was assessed semiquantitatively (0–3: absent to extensive).Results. RV's of SScPAH showed significantly more inflammatory cells than of IPAH (cells/mm2, mean±sd MPO11±3versus6±1; CD68 11±3versus6±1; CD45 11±1versus5±1,P<.05) and than of controls. RV interstitial fibrosis was similar in SScPAH and IPAH (4±1versus5±1%,P=.9), and did not differ from controls (5±1%,P=.8). In 4 SScPAH and 5 IPAH RV's foci of replacement fibrosis were found. No differences were found on epi- or endocardial inflammation or on perivascular or intimal fibrosis of coronary arteries.Conclusion. SScPAH RVs display denser inflammatory infiltrates than IPAH, while they do not differ with respect to interstitial fibrosis. Whether increased inflammatory status is a contributor to altered RV function in SScPAH warrants further research.
Modeling and Characterization for Microstrip Filters in the Manufacturing Process through the Unscented Transform and Use of Electromagnetic Simulators
Authors: Ortega Paredes Abraham E. , de Menezes Leonardo R. A. X. , Abdalla Humberto , Romani Ivan N. A.
Published: September 2010

This paper presents the unscented transform (UT) applied to uncertainty modeling of manufacturing tolerances at the design stage of microwave passive devices. The process combines the UT with electromagnetic simulations and assumes that the numerical sources of error are negligible in comparison to the imperfections due to the manufacturing process. The technique was validated with the simulation, construction, and test of several sets of identical microstrip filters with very good results. Although the combination of UT and electromagnetic simulators was presented for microstrip filters, it can also be used for different types of microwave devices.
Using Genetic Algorithms to Represent Higher-Level Planning in Simulation Models of Conflict
Authors: Moffat James , Fellows Susan
Published: September 2010

The focus of warfare has shifted from the Industrial Age to the Information Age, as encapsulated by the term Network Enabled Capability. This emphasises information sharing, command decision-making, and the resultant plans made by commanders on the basis of that information. Planning by a higher level military commander is, in most cases, regarded as such a difficult process to emulate, that it is performed by a real commander during wargaming or during an experimental session based on a Synthetic Environment. Such an approach gives a rich representation of a small number of data points. However, a more complete analysis should allow search across a wider set of alternatives. This requires a closed-form version of such a simulation. In this paper, we discuss an approach to this problem, based on emulating the higher command process using a combination of game theory and genetic algorithms. This process was initially implemented in an exploratory research initiative, described here, and now forms the basis of the development of a “Mission Planner,” potentially applicable to all of our higher level closed-form simulation models.