bluuebunny/crossref_metadata_2025 huggingface dataset:
Measurement of interfacial area and intensity of mass transfer in the gas phase in a packing with significant dependence of the interfacial area on the density of irrigation
Authors: Červenka Jan , Brož Zdeněk , Kolář Václav
Published: February 2011

The dependence has been measured of the interfacial area and the number of transfer units for gas side resistance controlled absorption on the flow rate of gas and liquid at counter- and cocurrent flow arrangement. The measurements have been carried out for a vertical expanded metal sheet packing exhibiting a strong dependence of the interfacial area on the density of irrigation. The interfacial area has been measured by absorption of carbon dioxide into a solution of sodium hydroxide under the conditions of the pseudo first order reaction. The number of transfer units has been measured by absorption of sulphur dioxide also into a solution of sodium hydroxide. In addition, the pressure drop has been correlated against the flow rate of gas and liquid.
Preparation of pyridinium salts of 2-furane derivatives
Authors: Kríž Miroslav , Kováč Jaroslav , Mlynárik Vladimír
Published: February 2011

Pyridinium salts have been prepared by nucleophilic substitution reaction of 5-halogeno-2-furane derivatives with pyridine and its 3- and 4-substituted derivatives, where R = 3-methyl, 3-ethyl, 3-amino, 3-methoxycarbonyl, 3-aminocarbonyl, 4-amino, 4-aminocarbonyl, 4-phenoxy, and 3,4-dimethyl, and structure of the derivatives prepared has been confirmed by their 1H NMR and 13C NMR spectra.
Spatial arrangement of 1-(2-furyl)-2-methoxycarbonyl-4-(5-X-2-furyl)butadienes
Authors: Žvak Vladimír , Dandárová Miloslava , Kováč Jaroslav , Špirková Katarína
Published: February 2011

The *1( NMR spectrometry of 1-(2-furyl)-2-methoxycarbonyl-4-(5-X-2-furyl)butadienes showed the double bonds of the butadiene backbone to have E, E, or E, Z configurations and s-trans conformation. The unsubstituted furan ring is in an s-cis conformation with respect to the double bond of the butadiene chain. The E, E isomers and the E, Z isomers have the substituted furan ring out of the butadiene backbone plane.
Potential antipsychotic agents: 2-Chloro- and 2-methyl-11-(2-piperazinoethoxy)-6,11-dihydrodibenzo[b,e]thiepins and some related compounds; Synthesis and pharmacology
Authors: Bártl Václav , Šindelář Karel , Valenta Vladimír , Holubek Jiří , Svátek Emil , Schlanger Jiří , Dlabač Antonín , Metyšová Jiřina , Protiva Miroslav
Published: February 2011

Reactions of 2-chloro- and 2-methyl-6,11-dihydrodibenzo[b,e]thiepin-11-ol with 2-bromoethanol in the presence of sulfuric acid in boiling benzene afforded the 2-bromoethyl ethers VIa and VIb which were transformed by substitution reactions with 1-methylpiperazine, 1-(2-hydroxyethyl)-piperazine and 1-(ethoxycarbonyl)piperazine to the title compounds. Alkaline hydrolysis of the carbamate IVa gave the secondary amine IIIa. Treatment of the bromo ether VIa with 4-(4-chloro-3-trifluoromethylphenyl)piperidin-4-ol resulted in the piperidine derivative VIIa. Substitution reaction of 11-chloro-6,11-dihydrodibenzo[b,e]thiepin with 1-(2-methoxyethyl)piperazine and 1-(2-ethoxyethyl)piperazine led to the amino ethers VIII and IX. Reaction of 11-chloro-11-phenyl-6,11-dihydrodibenzo[b,e]thiepin with 2-dimethylaminoethanethiol in dimethylformamide at 90°C gave a mixture of two isomeric bases which was separated to the expected sulfide X and the base XII, resulting evidently after the rearrangement of the primary carbocation. A similar reaction of 3-dimethylaminopropanethiol afforded a single product of structure XI. Out of the compounds prepared, the ether VIII was found most interesting: it is little toxic and has significant antireserpine activity in two tests (is considered a potential antidepressant). The ethers Iab, Iab, IIIa and VIIa did not reveal the expected neuroleptic activity.
Inhibition of nucleic acid synthesis in L1210 cells by nucleoside analogs
Authors: Beránek Jiří , Acton Edward M.
Published: February 2011

Series of pyrimidine nucleoside analogs were tested for inhibition of DNA and/or RNA synthesis at L1210 cells. The structure-activity relationship was studied at the analogs of cancerostatic agents 5-fluorouracil and arabinosylcytosine. Out of them the 5'-chloro derivatives give some promise. The inhibitory activity of cyclocytidine vs DNA and RNA synthesis approaches the activity of cancerostatic antibotics.
Enzymatic resolution of γ-carboxy-DL-glutamic acid
Authors: Čeřovský Václav , Jošt Karel
Published: February 2011

Optically active γ-carboxy-L-glutamic acid was prepared by enantioselective reaction of benzyloxycarbonyl-γ-carboxy-DL-glutamic acid with phenylhydrazine, catalyzed by papain (E.C.3.4.22.2), and subsequent removal of the protecting groups from the obtained benzyloxycarbonyl-γ-carboxy-L-glutamic acid α-phenylhydrazide.
Intensification of cooling in a batch reactor with an exothermic reaction by nonisothermal control in stable pseudostationary states
Authors: Horák Josef , Beránek Petr , Maršálková Dagmar
Published: February 2011

An algorithm is set up and tested for the temperature control of a batch reactor consisting in jump changes in the inlet temperature of entering coolant. This temperature is so chosen that its difference from the temperature of the reaction mixture is near the highest difference at which the stable pseudostationary state of the system still exists. For the prediction of the new coolant inlet temperature, a zero-order reaction model is used with an adaptive parameter estimated from the experimentally established value of the maximum of the reaction mixture overheating at the previous coolant temperature.
Synthesis of benzylidenemalonaldehydes
Authors: Arnold Zdeněk , Král Vladimír , Dvořák Dalimil
Published: February 2011

A general two-step synthesis of benzylidenemalonaldehydes (V), based on condensation of substituted benzaldehydes with 1,3-bis(dimethylamino)trimethinium perchlorate, is described. The course of this reaction, character of the intermediate and spectral characteristics of the products are discussed. The obtained dialdehydes are classified as new organic Lewis acids.
Vinylogues and heterocyclic analogues of benzylidenemalonaldehydes
Authors: Arnold Zdeněk , Dvořák Dalimil , Král Vladimír
Published: February 2011

Nine analogues of benzylidenemalonaldehyde (IV) were prepared by condensation of bis(dimethylamino)trimethinium perchlorate with two vinylogues of benzaldehyde and a series of heterocyclic aldehydes. The reaction intermediate was isolated and shown by 1H NMR spectroscopy to be the bis-iminium salt III. The conformation of 3-phenylprop-2-enylidenemalonaldehyde (IVa), determined by its 1H NMR spectrum, may serve as a more general model of arylmethylenemalonaldehydes.
Synthesis of 1,2,4-triazino[5,6-b]- and imidazo[4,5-b]quinoline derivatives
Authors: Slouka Jan , Bekárek Vojtěch , Nálepa Karel , Lyčka Antonín
Published: February 2011

o-Nitrophenylpyruvic acid thiosemicarbazone (I) has been cyclized to 2-thio-5-(o-nitrobenzyl)-6-azauracil (II) which has been transformed in 5-(o-nitrobenzyl)-6-azauracil (III) by both oxidation, and methylation and hydrolysis of the 3-methylmercapto-6-(o-nitrobenzyl)-2,5-dihydro-1,2,4-triazin-5-one (V) formed. Reduction of derivative III with iron(II) hydroxide and cyclization of the amino derivative IV formed gives 2,3,4,10-tetrahydro-1,2,4-triazino[5,6-b]quinolin-3-one (VI). Compound VI is transformed in acid medium to 1-amino-1,2-dihydroimidazo[4,5-b]quinolin-2-one (VIII) via the tautomer VII, and in boiling acetic acid it gives the acetylamino derivative IX. The N-amino derivative VIII reacts with carbonyl compounds to give the corresponding hydrazones X - XII, and its nitrosation gives 1,2-dihydroimidazo[4,5-b]quinolin-2-one (XIII).
Analysis of the pore structure of adsorbents and its characterization by a numerical method
Authors: Kadlec Ondřej , Choma Jerzy , Jankowska Helena , Swiatkowski Andrzej
Published: February 2011

This paper describes the algorithm of numerical evaluation of the parameters of the pore structure of adsorbents ( the micro, mezo and macropores). The structure of individual types of pores is described with the equation proposed by one of the present authors and giving the total distribution function of the pores with respect to their radii. The reliability of the suggested algorithm was verified in a number of calculations using a specially developed program. The results of the analysis and characterization of three different specimens of active carbon are shown as an example.
Spectrophotometric and paper chromatographic analysis of mixtures of 4-nitrotoluene-2-sulphonic acid and 4,4'-dinitrostilbene-2,2'-disulphonic acid
Authors: Barek Jiří , Daňhel Ivo
Published: February 2011

Mixtures of 4-nitrotoluene-2-sulphonic and 4,4'-dinitrostilbene-2,2'-disulphonic acids were analyzed by a direct spectrophotometric method and by a method consisting of their paper chromatographic separation and d.c. polarographic determination.
Potential uses of metallocarborane sandwich anions for analysis, characterization and isolation of various cations and organic bases
Authors: Plešek Jaromír , Baše Karel , Mareš František , Hanousek František , Štíbr Bohumil , Heřmánek Stanislav
Published: February 2011

Unique properties of metallocarborane sandwich anions of the type [(C2B9H11)2M(III)]- as chemical stability, specific reactivity, very strong acidity of conjugated acids along with an extreme organophility of their salts and a very limited solubility of the salts with organic cations in water are discussed. The application of metallocarboranes to analysis, characterization and isolation of organic bases, including alkaloids, amino acids, amides, etc., from very diluted water solutions is suggested and demonstrated on some examples.
Stereostructure of slovanolides: X-ray crystallography of the 3-oxo-4αH,8α-benzoyloxy-10β,11α-diacetoxyslovanolide
Authors: Rychłewska Urszula , Holub Miroslav , Buděšínský Miloš , Smítalová Zdenka
Published: February 2011

X-Ray structural analysis of 3-oxo-4αH,8α-benzoyloxy-10β,11α-diacetoxyslovanolide (XII) confirmed the correctness of the previously proposed structure of slovanolides. A comparison of the X-ray and 1H NMR data of lactone XII showed that the confirmation of this substance in crystals and in chloroform or benzene solutions is very similar. The structure of the lactone from Laserpitium marginatum has been corrected to formula XIa.
Kinetic analysis of reactions of phenylhydrazonopropanedinitriles with thiols
Authors: Antalík Marián , Šturdík Ernest , Pytela Oldřich , Drobnica Ľudovít , Sulo Pavol
Published: February 2011

Phenylhydrazonopropanedinitriles react with aliphatic thiols in aqueous solutions to give 2-phenylhydrazono-3-imino-3-alkylthiopropanedinitriles. The observed first-order rate constants kobs (s-1) depend on pH value of the reaction medium and on the thiol concentration. Kinetic analysis showed that the reactions are nucleophilic additions of bimolecular type involving non-dissociated phenylhydrazonopropanedinitriles and thiolate anions as the electrophilic and nucleophilic partners, respectively. A relation is given enabling transformation of the found kobs constants into the second-order rate constants k (1 mol-1 s-1) independent on the pH value of medium and of the thiol concentration.
Anomalous mass spectra of some aporphine methiodides
Authors: Dolejš Ladislav
Published: February 2011

Methiodides of corydine, isocorydine and isothebaine are O-demethylated in the ionic source of the mass spectrometer by hydrogen iodide formed on pyrolysis of the sample. The reaction is common in aporphine methiodides substituted in positions 1 and 11 by one hydroxyl and one methoxyl group. The behaviour can be explained by the combined action of the hydrogen bridge and steric strain.
MO study of Td-D4h equilibrium in complexes of transition metals. II. Equilibrium in tetrafluoro and tetrabromo complexes of atoms of the first transition row
Authors: Pelikán Peter , Liška Marek
Published: February 2011

The CNDO method for transition metals in the UHF version has been used to study the equilibrium of configuration isomers of tetrahedral and square-planar tetrafluoro and tetrabromo complexes of the first transition row atoms in the oxidation degree II (Mn(II), Fe(II), Co(II), Ni(II), Cu(II) both in low-spin and in high-spin states. The results show that the ability (given by electronic structure of the central atom) to form the square-planar complexes decreases monotonously in the series: Mn(II) > Fe(II) > Co(II) > Ni(II) > Cu(II). With respect to the effect of the electronic structure of ligands, the same ability decreases in the series: F- > Cl- > Br-.
Contribution to the study of the kinetics of redox reactions proceeding via electrode processes. Verification of the theory
Authors: Macenauer Jaroslav
Published: February 2011

The kinetics of redox reactions of the type n2 Ox1 + n1 Red2 → n1 Ox2 + n2 Red1 proceeding via electrode processes was studied on seven practical examples. The reaction time was measured as function of experimental parameters (resistance, concentration, volume of solution, electrode surface area), and the theoretical equation for the reaction time was verified.
Transport characteristics of a mechanically agitated aerated vessel
Authors: Holeček Oldřich , Linek Václav , Hovorka František , Beneš Petr
Published: February 2011

The gas holdup and impeller power input in a mechanically agitated aerated vessel were measured for aqueous solutions of ten inorganic salts as functions of the type and concentration of the electrolyte present, the impeller speed, and the gas flow rate. The dependence of the holdup on the physical properties of batch is best described by relations including the quantity X = c(dσ/dc)2F, where F = (1 + d ln f/d ln c)-1. The best fit to experimental holdup data is given by the empirical equation Z = 5.0 . 10-4 Re-0.226 Kp0.25 We1.09 Y1.16, where Kp = Vg/nd3, Y = 2 - exp (-X+), X+ = X/Xcrit, Xcrit = 3. 10-6 k mol-1 kg2 m3 s-4, with mean and maximum deviations between calculated and experimental values of 12% and 20%, respectively. Incorporation of quantities that improve the ability of holdup correlations to account for the dependence of gas holdup on the physical properties of electrolyte solutions fails to produce the same effect in correlations for impeller power input to aerated batch. The best estimate of the power input (within 20%) is obtained by using the equation PaPo = 0.226 We-0.0081 Kp-0.294.
Correlation between the structure of aromatic compounds and the rate of their biological degradation
Authors: Pitter Pavel
Published: February 2011

Linear relations have been obtained between the logarithms of the biological degradation rate of phenol and aniline derivatives and the substituent constants σ accounting for their electronic effects. The reaction constant in the Hammett equation is negative; the biological degradation rate is negatively affected by electron-withdrawing substituents. Of the OH, CH3, Cl, NO2, and NH2 substituents tested, only amino group led to deviations from the linear correlations for monosubstituted phenols. The rate of degradation of the aromatic system seems to be controlled by electronic effects, the limiting stage being the electrophilic substitution; correlations using the steric or lipophilic constants failed.
29Si (and 13C) NMR spectra of modified silatranyl derivatives of some monosaccharides
Authors: Schraml Jan , Krapivin Aleksandr Mikhailovich , Luzin Aleksandr Petrovich , Kilesso Vladimir Mikhailovich , Pestunovich Vadim Aleksandrovich
Published: February 2011

29Si (and 13C) NMR chemical shifts are reported for several 2-carba-3-oxahomosilatranyl (3,9,10-trioxa-6-aza-1-silabicyclo[3.3.4]dodecane-1-yl) and silatranyl (2,8,9-trioxa-5-aza-1-silabicyclo[3.3.3]undecane-1-yl) derivatives of some monosaccharides and other alcohols. The limited data suggest somewhat larger sensitivity of the silicon chemical shifts to molecular structure in 2-carba-3-oxahomosilatranyl derivatives than in silatranyl derivatives. In comparison with trimethylsilyl derivatives homosilatranyl derivatives show lower structural sensitivity of the silicon chemical shift. In some cases, however, larger stability of the silatranyl or 2-carba-3-oxahomosilatranyl derivatives than that of trimethylsilyl derivatives might be a distinct advantage.
Monomethyl and dimethyl ethers of methyl β-D-xylopyranoside
Authors: Staněk Jan , Jeřábková Jana , Jarý Jiří
Published: February 2011

The preparative advantages of partial methylation with subsequent separation of isomers over standard syntheses of individual derivatives are presented on the case of the methylation of methyl β-D-xylopyranoside (I). All seven possible methyl ethers were isolated in reasonable yields from a single reaction. Literature data concerning methyl 2,3-di-O-methyl-β-D-xylopyranoside (V) and methyl 2,4-di-O-methyl-β-D-xylopyranoside (VI) have been revised.
Preparation and synandrogenic activity of 17β-hydroxy-4,5-seco-5-androsten-3-one
Authors: Stárka Luboslav , Kasal Alexander , Bičíková Marie , Hampl Richard
Published: February 2011

Acylation of the sodium salt of dimethyl sulfoxide with methyl 17β-benzoyloxy-A-nor-3,5-seco-5-androsten-3-oate (I) gave the corresponding sulfoxide II which was desulfurated with aluminium amalgam to 17β-hydroxy-4,5-seco-5-androsten-3-one (IV). In vitro and in vivo assays of compound IV have shown that in contrast to antiandrogenic 4,5-seco derivatives V - VIII it has a synandrogenic activity.
Impact of intracranial self-expanding stents in the treatment of acute ischemic stroke: efficacy and limitations: Table 1
Authors: Ansari Saeed , McConnell Douglas J , Azari Hassan , Levy Elad I , Hoh Brian L , Waters Michael F , Mocco J
Published: February 2011

In recent years, endovascular self-expanding stents have become a viable option for neurointerventionalists treating acute ischemic stroke. Timely intervention for stroke could mean the difference between complete recovery and significant morbidity or death. Since 2006, a handful of clinical trials have demonstrated the potential of self-expanding stents in dependably achieving quick revascularization. These devices are expanding in utilization as new designs offer greater procedural flexibility and better clinical results. We discuss these clinical investigations, focusing on the procedural capabilities and limitations of each self-expanding stent design.
Endovascular management of a giant aneurysm through saphenous vein graft after extracranial–intracranial bypass: case report and literature review
Authors: Pandey Paritosh , Rayes Mahmoud , Hong David , Guthikonda Murali , Xavier Andrew
Published: February 2011

It is known that giant intracerebral aneurysms have a high rupture and mortality rate. Furthermore, their optimal treatment method is not straightforward. While traditionally they have been managed with surgical clipping, it is not always possible. A unique case is presented in which a patient with multiple intracranial aneurysms was treated using a multimodality approach. After an intracranial–extracranial bypass, the left internal carotid artery ophthalmic aneurysm continued to grow on follow-up angiogram. Thus it was decided to go ahead with coiling of the aneurysm. The coils were delivered through the saphenous vein graft. The patient tolerated the procedure well and there were no procedural complications.
Heart Valve Structure and Function in Development and Disease
Authors: Hinton Robert B. , Yutzey Katherine E.
Published: February 2011

The mature heart valves are made up of highly organized extracellular matrix (ECM) and valve interstitial cells (VICs) surrounded by an endothelial cell layer. The ECM of the valves is stratified into elastin-, proteoglycan-, and collagen-rich layers that confer distinct biomechanical properties to the leaflets and supporting structures. Signaling pathways have critical functions in primary valvulogenesis as well as the maintenance of valve structure and function over time. Animal models provide powerful tools to study valve development and disease processes. Valve disease is a significant public health problem, and increasing evidence implicates aberrant developmental mechanisms underlying pathogenesis. Further studies are necessary to determine regulatory pathway interactions underlying valve pathogenesis in order to generate new avenues for novel therapeutics.
Tight Junction Pore and Leak Pathways: A Dynamic Duo
Authors: Shen Le , Weber Christopher R. , Raleigh David R. , Yu Dan , Turner Jerrold R.
Published: February 2011

Tissue barriers that restrict passage of liquids, ions, and larger solutes are essential for the development of multicellular organisms. In simple organisms this allows distinct cell types to interface with the external environment. In more complex species, the diversity of cell types capable of forming barriers increases dramatically. Although the plasma membranes of these barrier-forming cells prevent flux of most hydrophilic solutes, the paracellular, or shunt, pathway between cells must also be sealed. This function is accomplished in vertebrates by the zonula occludens, or tight junction. The tight junction barrier is not absolute but is selectively permeable and is able to discriminate between solutes on the basis of size and charge. Many tight junction components have been identified over the past 20 years, and recent progress has provided new insights into the proteins and interactions that regulate structure and function. This review presents these data in a historical context and proposes an integrated model in which dynamic regulation of tight junction protein interactions determines barrier function.
Effects of Oxygen on Growth and Size: Synthesis of Molecular, Organismal, and Evolutionary Studies withDrosophila melanogaster
Authors: Harrison Jon F. , Haddad Gabriel G.
Published: February 2011

Drosophila melanogaster is a model genetic organism with an exceptional hypoxia tolerance relative to mammals. Forward genetic, microarray, and P-element manipulations and selection experiments have revealed multiple mechanisms of severe hypoxia tolerance, including RNA editing, downregulation of metabolism, and prevention of protein unfolding. Drosophila live in microbe-rich, semiliquid food in which hypoxia likely indicates deteriorating environments. Hypoxia reduces growth and size by multiple mechanisms, influencing larval feeding rates, protein synthesis, imaginal cell size, and control of molting. In moderate hypoxia, these effects appear to occur without ATP limitation and are instead mediated by signaling systems, including hypoxia-inducible factor and atypical guanyl cyclase sensing of oxygen, with downstream actions on behavior, anabolism, and the cell cycle. In hypoxia, flies develop smaller sizes, but size does not evolve, whereas in hyperoxia, flies evolve larger sizes without exhibiting developmental size plasticity, suggesting differential evolutionary responses to natural versus novel directions of oxygen change.
Endometriosis: The Role of Neuroangiogenesis
Authors: Asante Albert , Taylor Robert N.
Published: February 2011

Endometriosis is a common cause of pelvic pain and infertility, affecting ∼10% of reproductive-age women. Annual costs for medical and surgical care in the United States exceed $20 billion. The disorder is characterized by implants of endometrial tissue outside the uterine cavity. Endometriotic lesions induce a state of chronic peritoneal inflammation, accompanied by elevated prostaglandin, cytokine, and growth factor concentrations. The current therapy is surgical ablation of ectopic implants and hormones that block the hypothalamic-pituitary-ovarian axis, but these approaches are expensive, carry perioperative risks, or have unpleasant side effects of hypoestrogenism. Recent evidence indicates that ectopic endometriotic implants recruit their own unique neural and vascular supplies through neuroangiogenesis. It is believed that these nascent nerve fibers in endometriosis implants influence dorsal root neurons within the central nervous system, increasing pain perception in patients. We consider the mechanisms and therapeutic implications of neuroangiogenesis in these lesions and propose potential treatments for the control or elimination of endometriosis-associated pain.
LEA Proteins During Water Stress: Not Just for Plants Anymore
Authors: Hand Steven C. , Menze Michael A. , Toner Mehmet , Boswell Leaf , Moore Daniel
Published: February 2011

Late embryogenesis abundant (LEA) proteins are extremely hydrophilic proteins that were first identified in land plants. Intracellular accumulation is tightly correlated with acquisition of desiccation tolerance, and data support their capacity to stabilize other proteins and membranes during drying, especially in the presence of sugars like trehalose. Exciting reports now show that LEA proteins are not restricted to plants; multiple forms are expressed in desiccation-tolerant animals from at least four phyla. We evaluate here the expression, subcellular localization, biochemical properties, and potential functions of LEA proteins in animal species during water stress. LEA proteins are intrinsically unstructured in aqueous solution, but surprisingly, many assume their native conformation during drying. They are targeted to multiple cellular locations, including mitochondria, and evidence supports that LEA proteins stabilize vitrified sugar glasses thought to be important in the dried state. More in vivo experimentation will be necessary to fully unravel the multiple functional properties of these macromolecules during water stress.
Interaction of Cigarette Exposure and Airway Epithelial Cell Gene Expression
Authors: Brody Jerome S. , Steiling Katrina
Published: February 2011

Cigarette smoking is responsible for lung cancer and chronic obstructive pulmonary disease (COPD), the leading cause of death from cancer and the second-leading cause of death in the United States. In the United States, 46 million people smoke, with an equal number of former smokers. Moreover, 20–25% of current or former smokers will develop either disease, and smokers with one disease are at increased risk for developing the other. There are no tools for predicting risk of developing either disease; no accepted tools for early diagnosis of potentially curable lung cancer; and no tools for defining molecular pathways or molecular subtypes of these diseases, for predicting rate of progression, or for assessing response to therapy at a biochemical or molecular level. This review discusses current studies and the future potential of measuring global gene expression in epithelial cells that are in the airway field of injury and of using the genomic information derived to begin to answer some of the above questions.
How the Genetics of Deafness Illuminates Auditory Physiology
Authors: Richardson Guy P. , de Monvel Jacques Boutet , Petit Christine
Published: February 2011

Although the basic principles underlying the function of the peripheral auditory system have been known for many years, the molecules required for hearing have hitherto remained elusive. Genetic approaches have recently provided unparalleled molecular insight into how the hair bundle, the hair cell's mechanosensory organelle, forms and functions. We discuss how the proteins encoded by the Usher syndrome type 1 genes form molecular complexes required for hair-bundle development and for gating the mechanotransducer channel. We show how mouse models for nonsyndromic forms of deafness involving genes encoding Triobp and stereocilin reveal, respectively, the way stereocilia rootlets contribute to the hair bundle's mechanical properties and how the hair bundle produces suppressive masking, a property that contributes to speech intelligibility. Finally, we examine how mutations in the genes encoding α- and β-tectorin reveal multiple roles for the tectorial membrane, an extracellular matrix unique to the cochlea, in stimulating hair bundles.
A Long Affair with Renal Tubules
Authors: Giebisch Gerhard H.
Published: February 2011

This essay provides a summary of my professional activities. My interest in renal physiology started as a medical student in Vienna, when I became acquainted with Homer Smith's essays on kidney function. After moving to the United States in 1951, I was fortunate to be mentored by Robert Pitts, in whose Department of Physiology at Cornell Medical College in New York I was given early independence, intellectual stimulation, and the opportunity to pursue experiments on single renal tubules. The problem of how the nephron manages its myriad of transport functions has never lost its fascination for me, and I am profoundly grateful to the many colleagues at Cornell Medical College and at Yale University School of Medicine who shared my passion for the kidney.
Regulation of Renal NaCl Transport by Nitric Oxide, Endothelin, and ATP: Clinical Implications
Authors: Garvin Jeffrey L. , Herrera Marcela , Ortiz Pablo A.
Published: February 2011

NaCl absorption along the nephron is regulated not just by humoral factors but also by factors that do not circulate or act on the cells where they are produced. Generally, nitric oxide (NO) inhibits NaCl absorption along the nephron. However, the effects of NO in the proximal tubule are controversial and may be biphasic. Similarly, the effects of endothelin on proximal tubule transport are biphasic. In more distal segments, endothelin inhibits NaCl absorption and may be mediated by NO. Adenosine triphosphate (ATP) inhibits sodium bicarbonate absorption in the proximal tubule, NaCl absorption in thick ascending limbs via NO, and water reabsorption in collecting ducts. Defects in the effects of NO, endothelin, and ATP increase blood pressure, especially in a NaCl-sensitive manner. In diabetes, disruption of NO-induced inhibition of transport may contribute to increased blood pressure and renal damage. However, our understanding of how NO, endothelin, and ATP work, and of their role in pathology, is rudimentary at best.
Role of Chitin and Chitinase/Chitinase-Like Proteins in Inflammation, Tissue Remodeling, and Injury
Authors: Lee Chun Geun , Da Silva Carla A. , Dela Cruz Charles S. , Ahangari Farida , Ma Bing , Kang Min-Jong , He Chuan-Hua , Takyar Seyedtaghi , Elias Jack A.
Published: February 2011

The 18 glycosyl hydrolase family of chitinases is an ancient gene family that is widely expressed from prokaryotes to eukaryotes. In mammals, despite the absence of endogenous chitin, a number of chitinases and chitinase-like proteins (C/CLPs) have been identified. However, their roles have only recently begun to be elucidated. Acidic mammalian chitinase (AMCase) inhibits chitin-induced innate inflammation; augments chitin-free, allergen-induced Th2 inflammation; and mediates effector functions of IL-13. The CLPs BRP-39/YKL-40 (also termed chitinase 3-like 1) inhibit oxidant-induced lung injury, augments adaptive Th2 immunity, regulates apoptosis, stimulates alternative macrophage activation, and contributes to fibrosis and wound healing. In accord with these findings, levels of YKL-40 in the lung and serum are increased in asthma and other inflammatory and remodeling disorders and often correlate with disease severity. Our understanding of the roles of C/CLPs in inflammation, tissue remodeling, and tissue injury in health and disease is reviewed below.
The Link Between Vascular Features and Thrombosis
Authors: Esmon Charles T. , Esmon Naomi L.
Published: February 2011

The mechanisms of vascular control of thrombotic events remain unclear. The vasculature possesses essential anticoagulant factors that regulate coagulation. Because the endothelium-to-blood ratios are much higher in the microcirculation, it is likely that stasis contributes to thrombotic risk, due in large part to failure to rapidly access the microcirculation and to gain access to this highly anticoagulant environment. Inflammation can potentiate thrombosis in part through downregulation of the vascular anticoagulants, a process that appears to be exacerbated in aging, a well-known risk factor for thrombosis. Surgery and trauma, two major risk factors for thrombosis, result in the release of a variety of cellular components that trigger coagulation through separate mechanisms.
The functional −374T/A polymorphism of the receptor for advanced glycation end products may modulate Crohn's disease
Authors: Däbritz Jan , Friedrichs Frauke , Weinhage Toni , Hampe Jochen , Kucharzik Torsten , Lügering Andreas , Broeckel Ulrich , Schreiber Stefan , Spieker Tilmann , Stoll Monika , Foell Dirk
Published: February 2011

The receptor for advanced glycation end products (RAGE) is involved in innate immune mechanisms. Polymorphisms of the RAGE gene have been described as a factor amplifying inflammation in susceptible patients, but the association with Crohn's disease (CD) is not known. The coding RAGE polymorphism G82S (rs2070600) and two promoter polymorphisms, −374T/A (rs1800624) and −429T/C (rs1800625), were studied in two samples from Germany and the United States consisting of 421 and 317 CD patients and 549 and 218 controls, respectively. To test the functional relevance, additional data on serum soluble RAGE (sRAGE), tissue RNA, and protein levels were collected and immunohistochemical stainings of bowel tissue of CD patients and healthy controls as well as models of experimental (dextran sodium sulfate-induced) colitis in RAGE knockout and wild-type mice were performed. The −374T/A RAGE promotor single nucleotide polymorphism (SNP) was negatively associated with CD (odds ratio = 0.708, 95% confidence interval = 0.535–0.938, P = 0.016) and with stenosis (OR = 0.627, P = 0.04) in the German sample. Transmission disequilibrium testing confirmed an undertransmission of the −374A allele. Serum sRAGE levels were higher in patients in complete remission of the −374AA/TA group (1,975 ± 299 pg/ml; −374TT group: 1,310 ± 153 pg/ml SE, P < 0.05) and showed a trend toward decreased levels in CD patients with active disease compared with CD patients in remission. Further in vitro and in vivo studies indicated that an increase of sRAGE ameliorates inflammation. The −429T/C and the G82S polymorphism were not associated with CD. The −374T/A RAGE polymorphism leading to facilitated RAGE gene transcription may to some degree protect from developing a stricturing subphenotype of CD, most likely by increasing levels of sRAGE, which neutralizes proinflammatory mediators.
SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β1and PDGF
Authors: Atorrasagasti Catalina , Aquino Jorge B. , Hofman Leonardo , Alaniz Laura , Malvicini Mariana , Garcia Mariana , Benedetti Lorena , Friedman Scott L. , Podhajcer Osvaldo , Mazzolini Guillermo
Published: February 2011

Liver fibrosis is an active process that involves changes in cell-cell and cell-extracellular matrix (ECM) interaction. Secreted protein, acidic and rich in cysteine (SPARC) is an ECM protein with many biological functions that is overexpressed in cirrhotic livers and upregulated in activated hepatic stellate cells (aHSCs). We have recently shown that SPARC downregulation ameliorates liver fibrosis in vivo. To uncover the cellular mechanisms involved, we have specifically knocked down SPARC in two aHSC lines [the CFSC-2G (rat) and the LX-2 (human)] and in primary cultured rat aHSCs. Transient downregulation of SPARC in hepatic stellate cells (HSCs) did not affect their proliferation and had only minor effects on apoptosis. However, SPARC knockdown increased HSC adhesion to fibronectin and significantly decreased their migration toward PDFG-BB and TGF-β1. Interestingly, TGF-β1secretion by HSCs was reduced following SPARC small interfering RNA (siRNA) treatment, and preincubation with TGF-β1restored the migratory capacity of SPARC siRNA-treated cells through mechanisms partially independent from TGF-β1-mediated induction of SPARC expression; thus SPARC knockdown seems to exert its effects on HSCs partially through modulation of TGF-β1expression levels. Importantly, collagen-I mRNA expression was reduced in SPARC siRNA-transfected HSCs. Consistent with previous results, SPARC knockdown in aHSCs was associated with altered F-actin expression patterns and deregulation of key ECM and cell adhesion molecules, i.e., downregulation of N-cadherin and upregulation of E-cadherin. Our data together suggest that the upregulation of SPARC previously reported for aHSCs partially mediates profibrogenic activities of TGF-β1and PDGF-BB and identify SPARC as a potential therapeutic target for liver fibrosis.
Proliferation modulates intestinal smooth muscle phenotype in vitro and in colitis in vivo
Authors: Nair Dileep G. , Han T. Y. , Lourenssen S. , Blennerhassett Michael G.
Published: February 2011

Intestinal inflammation causes an increased intestinal wall thickness, in part, due to the proliferation of smooth muscle cells, which impairs the contractile phenotype elsewhere. To study this, cells from the circular muscle layer of the rat colon (CSMC) were isolated and studied, both in primary culture and after extended passage, using quantitative PCR, Western blot analysis, and immunocytochemistry. By 4 days in vitro, both mRNA and protein for the smooth muscle marker proteins α-smooth muscle actin, desmin, and SM22-α were reduced by >50%, and mRNA for cyclin D1 was increased threefold, evidence for modulation to a proliferative phenotype. Continued growth caused significant further decrease in expression, evidence that phenotypic loss in CSMC was proportional to the extent of proliferation. In CSMC isolated at day 2 of trinitrobenzene sulfonic acid-induced colitis, flow cytometry and Western blotting showed that these differentiated markers were reduced in mitotic CSMC, while similar to control in nonmitotic CSMC. By day 35 post-trinitrobenzene sulfonic acid, when inflammation has resolved, CSMC were hypertrophic, but, nonetheless, showed markedly decreased expression of smooth muscle protein markers per cell. In vitro, day 35 CSMC displayed an accelerated loss of phenotype and increased thymidine uptake in response to serum or PDGF-BB. Furthermore, carbachol-induced expression of phospho-AKT (a marker of cholinergic response) was lost from day 35 CSMC in vitro, while retained in control cells. Therefore, proliferation reduces the expression of smooth-muscle-specific markers in CSMC, possibly leading to altered contractility. However, inflammation-induced proliferation in vivo also causes lasting changes that include unexpected priming for an exaggerated response to proliferative stimuli. Identification of the molecular mechanisms of intestinal smooth muscle cell phenotypic modulation will be helpful in reducing the detrimental effects of inflammation.
Mechanics of left ventricular relaxation, early diastolic lengthening, and suction investigated in a mathematical model
Authors: Remme Espen W. , Opdahl Anders , Smiseth Otto A.
Published: February 2011

We investigated the determinants of ventricular early diastolic lengthening and mechanics of suction using a mathematical model of the left ventricle (LV). The model was based on a force balance between the force represented by LV pressure (LVP) and active and passive myocardial forces. The predicted lengthening velocity ( e′) from the model agreed well with measurements from 10 dogs during 5 different interventions ( R = 0.69, P < 0.001). The model showed that e′ was increased when relaxation rate and systolic shortening increased, when passive stiffness was decreased, and when the rate of fall of LVP during early filling was decreased relative to the rate of fall of active stress. We first defined suction as the work the myocardium performed to pull blood into the ventricle. This occurred when contractile active forces decayed below and became weaker than restoring forces, producing a negative LVP. An alternative definition of suction is filling during falling pressure, commonly believed to be caused by release of restoring forces. However, the model showed that this phenomenon also occurred when there had been no systolic compression below unstressed length and therefore in the absence of restoring forces. In conclusion, relaxation rate, LVP, systolic shortening, and passive stiffness were all independent determinants of e′. The model generated a suction effect seen as lengthening occurring during falling pressure. However, this was not equivalent with the myocardium performing pulling work on the blood, which was performed only when restoring forces were higher than remaining active fiber force, corresponding to a negative transmural pressure.
Differential vulnerability of skeletal muscle feed arteries to dysfunction in insulin resistance: impact of fiber type and daily activity
Authors: Bender Shawn B. , Newcomer Sean C. , Harold Laughlin M.
Published: February 2011

Functional and structural heterogeneity exists among skeletal muscle vascular beds related, in part, to muscle fiber type composition. This study was designed to delineate whether the vulnerability to vascular dysfunction in insulin resistance is uniformly distributed among skeletal muscle vasculatures and whether physical activity modifies this vulnerability. Obese, hyperphagic Otsuka Long-Evans Tokushima fatty rats (20 wk old) were sedentary (OSED) or physically active (OPA; access to running wheels) and compared with age-matched sedentary Long-Evans Tokushima Otsuka (LSED) rats. Vascular responses were determined in isolated, pressurized feed arteries from fast-twitch gastrocnemius (GFAs) and slow-twitch soleus (SFAs) muscles. OSED animals were obese, insulin resistant, and hypertriglyceridemic, traits absent in LSED and OPA rats. GFAs from OSED animals exhibited depressed dilation to ACh, but not sodium nitroprusside, and enhanced vasoconstriction to endothelin-1 (ET-1), but not phenylephrine, compared with those in LSED. Immunoblot analysis suggests reduced endothelial nitric oxide synthase phosphorylation at Ser1177 and endothelin subtype A receptor expression in OSED GFAs. Physical activity prevented reduced nitric oxide-dependent dilation to ACh, but not enhanced ET-1 vasoconstriction, in GFA from OPA animals. Conversely, vasoreactivity of SFAs to ACh and ET-1 were principally similar in all groups, whereas dilation to sodium nitroprusside was enhanced in OSED and OPA rats. These data demonstrate, for the first time, that SFAs from insulin-resistant rats exhibit reduced vulnerability to dysfunction versus GFAs and that physical activity largely prevents GFA dysfunction. We conclude that these results demonstrate that vascular dysfunction associated with insulin resistance is heterogeneously distributed across skeletal muscle vasculatures related, in part, to muscle fiber type and activity level.
Responsiveness of the human airway in vitro during deep inspiration and tidal oscillation
Authors: Noble Peter B. , Jones Robyn L. , Needi Elangovan Thaya , Cairncross Alvenia , Mitchell Howard W. , James Alan L. , McFawn Peter K.
Published: February 2011

In healthy individuals, deep inspiration produces bronchodilation and reduced airway responsiveness, which may be a response of the airway wall to mechanical stretch. The aim of this study was to examine the in vitro response of isolated human airways to the dynamic mechanical stretch associated with normal breathing. Human bronchial segments ( n = 6) were acquired from patients without airflow obstruction undergoing lung resection for pulmonary neoplasms. The side branches were ligated and the airways were mounted in an organ bath chamber. Airway narrowing to cumulative concentrations of acetylcholine (3 × 10−6 M to 3 × 10−3 M) was measured under static conditions and in the presence of “tidal” oscillations with intermittent “deep inspiration.” Respiratory maneuvers were simulated by varying transmural pressure using a motor-controlled syringe pump (tidal 5 to 10 cmH2O at 0.25 Hz, deep inspiration 5 to 30 cmH2O). Airway narrowing was determined from decreases in lumen volume. Tidal oscillation had no effect on airway responses to acetylcholine which was similar to those under static conditions. Deep inspiration in tidally oscillating, acetylcholine-contracted airways produced potent, transient (<1 min) bronchodilation, ranging from full reversal in airway narrowing at low acetylcholine concentrations to ∼50% reversal at the highest concentration. This resulted in a temporary reduction in maximal airway response ( P < 0.001), without a change in sensitivity to acetylcholine. Our findings are that the mechanical stretch of human airways produced by physiological transmural pressures generated during deep inspiration produces bronchodilation and a transient reduction in airway responsiveness, which can explain the beneficial effects of deep inspiration in bronchial provocation testing in vivo.
Absence of Class II–Associated Invariant Chain Peptide on Leukemic Blasts of Patients Promotes Activation of Autologous Leukemia-Reactive CD4+ T Cells
Authors: van Luijn Marvin M. , van den Ancker Willemijn , Chamuleau Martine E.D. , Zevenbergen Adri , Westers Theresia M. , Ossenkoppele Gert J. , van Ham S. Marieke , van de Loosdrecht Arjan A.
Published: February 2011

Immune escape in cancer poses a substantial obstacle to successful cancer immunotherapy. Multiple defects in HLA class I antigen presentation exist in cancer that may contribute to immune escape, but less is known about roles for HLA class II antigen presentation. On class II+ leukemic blasts, the presence of class II–associated invariant chain peptide (CLIP) is known to be correlated with poor survival in acute myeloid leukemia (AML). In this study, we evaluated the functional significance of CLIP expression on leukemic blasts of AML patients. CD4+ T cells from patients were cocultured with autologous CLIP− and CLIP+ primary leukemic blasts and analyzed for several functional parameters by flow cytometry. Increased HLA-DR and IFN-γ expression was observed for CD4+ T cells stimulated with CLIP− leukemic blasts, in contrast to CLIP+ leukemic blasts, which indicated an activation and polarization of the CD4+ T cells toward T-helper 1 cells. In addition, CLIP− leukemic blasts induced greater outgrowth of effector memory CD4+ T cells (with HLA-DR–restricted T-cell receptor Vβ repertoires) that were associated with better leukemia-specific reactivity than with CLIP+ leukemic blasts. Our findings offer a clinical rationale to downmodulate CLIP on leukemic blasts as a strategy to degrade immune escape and improve leukemia-specific T-cell immunity in AML patients. Cancer Res; 71(7); 2507–17. ©2011 AACR.