bluuebunny/crossref_metadata_2025 huggingface dataset:
Discrete Cationic Zinc and Magnesium Complexes for Dual Organic/Organometallic‐Catalyzed Ring‐Opening Polymerization of Trimethylene Carbonate
Authors: Brignou Pierre , Guillaume Sophie M. , Roisnel Thierry , Bourissou Didier , Carpentier Jean‐François
Published: June 2012

We describe herein an original approach for the efficient immortal ring‐opening polymerization (iROP) of trimethylene carbonate (TMC) under mild conditions using dual‐catalyst systems combining a discrete cationic metal complex with a tertiary amine. A series of new zinc and magnesium cationic complexes of the type [{NNO}M]+[anion]− ({NNO}−=2,4‐di‐tert‐butyl‐6‐{[(2′‐dimethylaminoethyl)methylamino]methyl}phenolate; M=Zn, [anion]−=[B(C6F5)4]− (2), [H2N‐ {B(C6F5)3}2]− (3), and [EtB(C6F5)3]− (4); M=Mg, [anion]−=[H2N{B(C6F5)3}2]− (7)) have been prepared from the corresponding neutral compounds [{NNO}ZnEt] (1) and [{NNO}‐ Mg(nBu)] (6). Compounds 2–4 and 7 exist as free ion pairs, as revealed by 1H, 13C, 19F, and 11B NMR spectroscopy in THF solution, and an X‐ray crystallographic analysis of the bis(THF) adduct of compound 7, 7⋅(THF)2. The neutral complexes 1 and 6, in combination with one equivalent or an excess of benzyl alcohol (BnOH), initiate the rapid iROP of TMC, in bulk or in toluene solution, at 45–60 °C (turnover frequency, TOF, up to 25–30 000 mol(TMC)⋅mol(Zn)⋅h−1 for 1 and 220–240 000 mol(TMC)⋅mol(Mg)⋅h−1 for 6), to afford H‐PTMC‐OBn with controlled macromolecular features. ROP reactions mediated by the cationic systems 2/BnOH and 7/BnOH proceeded much more slowly (TOF up to 500 and 3 000 mol(TMC)⋅mol(Zn or Mg)⋅h−1 at 110 °C) than those based on the parent neutral compounds 1/BnOH and 6/BnOH, respectively. Use of original dual organic/organometallic catalyst systems, obtained by adding 0.2–5 equiv of a tertiary amine such as NEt3 to zinc cationic complexes [{NNO}Zn]+[anion]− (2–4), promoted high activities (TOF up to 18 300 mol(TMC)⋅mol(Zn)⋅h−1 at 45 °C) giving H‐PTMC‐OBn with good control over the Mn and Mw/Mn values. Variation of the nature of the anion in 2–4 did not significantly affect the performance of these catalyst systems. On the other hand, the dual magnesium‐based catalyst system 7/NEt3 proved to be poorly effective.
Enantioselective Synthesis of AG‐041R by using N‐Heteroarenesulfonyl Cinchona Alkaloid Amides as Organocatalysts
Authors: Hara Noriyuki , Nakamura Shuichi , Sano Masahide , Tamura Ryota , Funahashi Yasuhiro , Shibata Norio
Published: June 2012

The organocatalytic enantioselective decarboxylative addition of malonic acid half thioesters to ketimines derived from isatins by using N‐heteroarenesulfonyl cinchona alkaloid amides afforded products with high enantioselectivity. The products could be converted into optically active AG‐041R. X‐ray crystallographic analysis revealed that the hydrogen bonding between the sulfonimide proton and the 8‐quinolyl nitrogen atom plays an important role in exerting the enantioselectivity of the reaction.
Ensemble‐Averaged QM/MM Kinetic Isotope Effects for the SN2 Reaction of Cyanide Anions with Chloroethane in DMSO Solution
Authors: Ruiz Pernía J. Javier , Williams Ian H.
Published: June 2012

The existence of solvent fluctuations leads to populations of reactant‐state (RS) and transition‐state (TS) configurations and implies that property calculations must include appropriate averaging over distributions of values for individual configurations. Average kinetic isotope effects 〈KIE〉 for NC−+EtCl→NCEt+Cl− in DMSO solution at 30 °C are best obtained as the ratio 〈fRS〉/〈fTS〉 of isotopic partition function ratios separately averaged over all RS and TS configurations. In this way the hybrid AM1/OPLS‐AA potential yields 〈KIE〉 values for all six isotopic substitutions (2° α‐2H2, 2° β‐2H3, α‐11C/14C, leaving group 37Cl, and nucleophile 13C and 15N) for this reaction in the correct direction as measured experimentally. These thermally‐averaged calculated KIEs may be compared meaningfully with experiment, and only one of them differs in magnitude from the experimental value by more than one standard deviation from the mean. This success contrasts with previous KIE calculations based upon traditional methods without averaging. The isotopic partition function ratios are best evaluated using all (internal) vibrational and (external) librational frequencies obtained from Hessians determined for subsets of atoms, relaxed to local minima or saddle points, within frozen solvent environments of structures sampled along molecular dynamics trajectories for RS and TS. The current method may perfectly well be implemented with other QM or QM/MM methods, and thus provides a useful tool for investigating KIEs in relation to studies of chemical reaction mechanisms in solution or catalyzed by enzymes.
Synthesis, Characterization, and Application of Two Al(ORF)3 Lewis Superacids
Authors: Kraft Anne , Trapp Nils , Himmel Daniel , Böhrer Hannes , Schlüter Peter , Scherer Harald , Krossing Ingo
Published: June 2012

We report herein the synthesis and full characterization of the donor‐free Lewis superacids Al(ORF)3 with ORF=OC(CF3)3 (1) and OC(C5F10)C6F5 (2), the stabilization of 1 as adducts with the very weak Lewis bases PhF, 1,2‐F2C6H4, and SO2, as well as the internal CF activation pathway of 1 leading to Al2(F)(ORF)5 (4) and trimeric [FAl(ORF)2]3 (5, ORF=OC(CF3)3). Insights have been gained from NMR studies, single‐crystal structure determinations, and DFT calculations. The usefulness of these Lewis acids for halide abstractions has been demonstrated by reactions with trityl chloride (NMR; crystal structures). The trityl salts allow the introduction of new, heteroleptic weakly coordinating [Cl‐Al(ORF)3]− anions, for example, by hydride or alkyl abstraction reactions.
Fluorescent Microporous Organic Polymers: Potential Testbed for Optical Applications
Authors: Patra Abhijit , Scherf Ullrich
Published: June 2012

Fluorescent microporous organic polymers (MOPs) are an emerging class of porous organic materials with considerable technological relevance due to great promise in a range of applications, in addition to typical usage in gas storage and catalysis. In this respect, innovative optical materials have been developed based on MOPs. In this Concept article, a brief appraisal of the fabrication methodologies of fluorescent MOPs in the form of bulk solid as well as in nanoparticles, their optical attributes, and promising application potentials are presented.
From lin‐Benzoguanines to lin‐Benzohypoxanthines as Ligands for Zymomonas mobilis tRNA–Guanine Transglycosylase: Replacement of Protein–Ligand Hydrogen Bonding by Importing Water Clusters
Authors: Barandun Luzi Jakob , Immekus Florian , Kohler Philipp C. , Tonazzi Sandro , Wagner Björn , Wendelspiess Severin , Ritschel Tina , Heine Andreas , Kansy Manfred , Klebe Gerhard , Diederich François
Published: June 2012

The foodborne illness shigellosis is caused by Shigella bacteria that secrete the highly cytotoxic Shiga toxin, which is also formed by the closely related enterohemorrhagic Escherichia coli (EHEC). It has been shown that tRNA–guanine transglycosylase (TGT) is essential for the pathogenicity of Shigella flexneri. Herein, the molecular recognition properties of a guanine binding pocket in Zymomonas mobilis TGT are investigated with a series of lin‐benzohypoxanthine‐ and lin‐benzoguanine‐based inhibitors that bear substituents to occupy either the ribose‐33 or the ribose‐34 pocket. The three inhibitor scaffolds differ by the substituent at C(6) being H, NH2, or NHalkyl. These differences lead to major changes in the inhibition constants, pKa values, and binding modes. Compared to the lin‐benzoguanines, with an exocyclic NH2 at C(6), the lin‐benzohypoxanthines without an exocyclic NH2 group have a weaker affinity as several ionic protein–ligand hydrogen bonds are lost. X‐ray cocrystal structure analysis reveals that a new water cluster is imported into the space vacated by the lacking NH2 group and by a conformational shift of the side chain of catalytic Asp102. In the presence of an N‐alkyl group at C(6) in lin‐benzoguanine ligands, this water cluster is largely maintained but replacement of one of the water molecules in the cluster leads to a substantial loss in binding affinity. This study provides new insight into the role of water clusters at enzyme active sites and their challenging substitution by ligand parts, a topic of general interest in contemporary structure‐based drug design.
Capturing the Antiaromatic #6094C68 Carbon Cage in the Radio‐Frequency Furnace
Authors: Amsharov Konstantin Yu. , Ziegler Karolin , Mueller Andreas , Jansen Martin
Published: June 2012

Although all fullerenes do not satisfy the classical aromaticity condition, as a result of their nonplanar nature, they experience effective stabilization due to extensive cyclic π‐electron delocalization and exhibit pronounced “spherical aromaticity”. This feature has raised the question of the opposite phenomenon, that is, the existence of antiaromatic carbon cages. Here the first experimental evidence of the existence of antiaromatic fullerenes is reported. The elusive #6094C68 was effectively captured as C68Cl8 by in situ chlorination in the gas phase during radio‐frequency synthesis. The chlorinated cage was separated by means of multistage HPLC, and its connectivity unambiguously determined by single‐crystal X‐ray analysis. Halogen‐stripped pristine #6094C68 was monitored by mass spectrometry of the chlorinated C68Cl8 cage. Quantum chemical calculations reveal the highly antiaromatic character of #6094C68, in accordance with all geometric, energetic, and magnetic criteria of aromaticity. Chlorine addition leads to substantial stabilization of the cage owing to aromatization in the resulting C68Cl8, which explains its high abundance in the primary fullerene soot. This work provides new insights into the process of fullerene formation and better understanding of aromaticity phenomena in general.
A Substrate‐Driven Approach to Determine Reactivities of α,β‐Unsaturated Carboxylic Esters Towards Asymmetric Bioreduction
Authors: Tasnádi Gábor , Winkler Christoph K. , Clay Dorina , Sultana Nargis , Fabian Walter M. F. , Hall Mélanie , Ditrich Klaus , Faber Kurt
Published: June 2012

The degree of CC bond activation in the asymmetric bioreduction of α,β‐unsaturated carboxylic esters by ene‐reductases was studied, and general recommendations to render these “borderline‐substrates” more reactive towards enzymatic reduction are proposed. The concept of “supported substrate activation” was developed. In general, an additional α‐halogenated substituent proved to be beneficial for enzymatic activity, whereas β‐alkyl or β‐aryl substituents were detrimental for the reactivity of nonhalogenated substrates, and α‐cyano groups showed little effect. The alcohol moiety of the ester functionality was found to have a strong influence on the reaction rate. Overall, activities were determined by both steric and electronic effects.
Controlled Synthesis of Gold Nanostars by Using a Zwitterionic Surfactant
Authors: Casu Alberto , Cabrini Elisa , Donà Alice , Falqui Andrea , Diaz‐Fernandez Yuri , Milanese Chiara , Taglietti Angelo , Pallavicini Piersandro
Published: June 2012

By replacing cetyltrimethylammonium bromide (CTAB) with the zwitterionic lauryl sulfobetaine (LSB) surfactant in the classical seed‐growth synthesis, monocrystalline gold nanostars (m‐NS) and pentatwinned gold asymmetric nanostars (a‐NS) were obtained instead of nanorods. The main product under all synthetic conditions was a‐NS, which have branches with high aspect ratios (AR), thus leading to LSPR absorptions in the 750–1150 nm range. The percentage of m‐NS versus a‐NS, the aspect ratio of the a‐NS branches, and consequently the position of their LSPR absorption can be finely tuned simply by regulating the concentration of reductant, the concentration of surfactant, or the concentration of the “catalytic” Ag+ cation. The m‐NS have instead shorter and larger branches, the AR of which is poorly influenced by synthetic conditions and displays an LSPR positioned around 700 nm. A growth mechanism that involves the direct contact of the sulfate moiety of LSB on the surface of the nano‐object is proposed, thereby implying preferential coating of the {111} Au faces with weak interactions. Consistent with this, we also observed the straightforward complete displacement of the LSB surfactant from the surface of the nanostars. This was obtained by the simple addition of thiols in aqueous solution to yield extremely stable coated a‐NS and m‐NS that are resistant to highly acidic, basic, and in similar to in vivo conditions.
Enhanced Magnetic Hardness in a Nanoscale Metal–Organic Hybrid Ferrimagnet
Authors: Guo Li‐Rong , Bao Song‐Song , Liu Bin , Zeng Dai , Zhao Jie , Du Jun , Zheng Li‐Min
Published: June 2012

A new layered metal–organic hybrid compound, namely, [Co3(μ3‐OH)2(BTP)2] (1; BTP=4‐(3‐bromothienyl)phosphonate), is reported. The inorganic layer can be viewed as a pseudo‐Kagomé lattice composed of corner‐sharing irregular triangles of Co3(μ3‐OH), with the cavities filled with the PO3 groups. The interlayer space is occupied by the 3‐bromothienyl groups of BTP2−. The bulk sample of compound 1 experiences a long‐range ferromagnetic ordering below 30.5 K, with a coercivity (Hc) of 5.04 kOe at 5 K. A systematic study on the size‐dependent magnetic coercivity of 1 reveals that the coercivity of 1 increases with reduced particle size from the micrometer to the nanometer scale. When the particle size is about 50–200 nm, the coercivity reaches 24.2 kOe at 5 K. The results demonstrate that compound 1 can vary from a soft magnet to one of the hardest molecule‐based magnets, simply by reducing the particle size to nanoscale region.
Origin of Selectivity of Tsuji–Trost Allylic Alkylation of Lactones: Highly Ordered Transition States with Lithium‐Containing Enolates
Authors: Patil Mahendra , Thiel Walter
Published: June 2012

We report computational investigations on the mechanism and the selectivity of Pd‐catalyzed allylic alkylation of γ‐valerolactone. Density functional calculations using the B3LYP functional are performed on the selectivity‐determining nucleophilic addition step of this reaction. The B3LYP results of commonly assumed pathways fail to reproduce the observed selectivity of the reaction. Therefore, alternative pathways are considered for the nucleophilic addition step, to explain the experimentally established role of the additives LiCl and lithium diisopropyl amide (LDA) in the Pd‐catalyzed reaction. These pathways involve different approaches of the enolate toward the η3‐allylpalladium complex that are mainly guided by stabilizing Clδ−⋅⋅⋅Liδ+⋅⋅⋅O(enolate) interactions in the transition state. In the calculations, the experimentally observed trans‐product selectivity for the prototypical reaction with (S)‐BINAP ligands is found only when assuming the addition of a “mixed” Li‐enolate/LiCl adduct to the η3‐allylpalladium complex. This mechanism provides a reasonable explanation for the experimental results and sheds light on the role of LiCl in the reaction. The analysis of the different transition‐state models allows us to identify steric and electronic factors that stabilize or destabilize the relevant diastereomeric transition states. Calculations for different combinations of substrates (γ‐valerolactone and δ‐caprolactone) and catalysts (with (R)‐ and (S)‐BINAP ligands) reproduce the experimentally observed selectivities well and thus provide further support for the proposed mechanism.
CH Activation: A Complementary Tool in the Total Synthesis of Complex Natural Products
Authors: Chen David Y.‐K. , Youn So Won
Published: June 2012

The recent advent of transition‐metal mediated CH activation is revolutionizing the synthetic field and gradually infusing a “CH activation mind‐set” in both students and practitioners of organic synthesis. As a powerful testament of this emerging synthetic tool, applications of CH activation in the context of total synthesis of complex natural products are beginning to blossom. Herein, recently completed total syntheses showcasing creative and ingenious incorporation of CH activation as a strategic manoeuver are compared with their “non‐CH activation” counterparts, illuminating a new paradigm in strategic synthetic design.
Hot Gas Filtration in Biomass‐Based Synthesis Gas
Authors: Grove Anne Kristin , Vodegel Stefan
Published: June 2012

Bei der thermochemischen Konversion von biologischen Stoffen zu Synthesegas im Wirbelschichtreaktor gehen Nährstoffe als Staub ins Produktgas. Mit der Heißgasfiltration besteht die Möglichkeit, diese Mineralien zurückzugewinnen. Die Besonderheiten des Gases stellen neue technische Aufgaben. Der folgende Artikel schildert jahrelange Betriebs‐ und Optimierungserfahrungen in einer Technikumsanlage.
Characterization of a human βV‐tubulin antibody and expression of this isotype in normal and malignant human tissue
Authors: Chao Suzan K. , Wang Yihong , Verdier‐Pinard Pascal , Yang Chia‐Ping H. , Liu Lingling , Rodriguez‐Gabin Alicia , McDaid Hayley M. , Horwitz Susan Band
Published: July 2012

There are seven distinct β‐tubulin isotypes and eight α‐tubulin isotypes in mammals that are hypothesized to have tissue‐ and cell‐specific functions. There is an interest in the use of tubulin isotypes as prognostic markers of malignancy. βV‐tubulin, like βIII‐tubulin, has been implicated in malignant transformation and drug resistance, however little is known about its localization and function. Thus, we generated for the first time, a rabbit polyclonal antibody specific for human βV‐tubulin. The antibody did not cross‐react with mouse βV‐tubulin or other human β‐tubulin isotypes and specifically labeled βV‐tubulin by immunoblotting, immunofluorescence and immunohistochemistry. Immunohistochemistry of various human normal tissues revealed that βV‐tubulin was expressed in endothelial cells, myocytes and cells with muscle differentiation, structures with transport and/or secretory function such as renal tubules, pancreatic ducts and bile ducts, and epithelium with secretory function such as prostate. βV‐tubulin was also specifically expressed in pancreatic islets and intratubular germ cell neoplasia, where it may have diagnostic utility. Initial studies in breast, lung and ovarian cancers indicated aberrant expression of βV‐tubulin, suggesting that this isoform may be associated with tumorigenesis. Thus, βV‐tubulin expression is a potentially promising prognostic marker of malignancy. © 2012 Wiley Periodicals, Inc
Ground‐State and Excitation Spectra of a Strongly Correlated Lattice by the Coupled Cluster Method
Authors: Mirone Alessandro
Published: June 2012

The coupled cluster method is applied to a strongly correlated lattice Hamiltonian, and the coupled cluster linear response method is extended to the calculation of electronic spectra by finding an approximation to a resolvent operator which describes the spectral response of the coupled cluster solution to excitation operators. In this spectral coupled cluster method, the ground and excited states appear as resonances in the spectra, and the resolvent can be iteratively improved in selected spectral regions. The method is applied to a MnO2 plane model which corresponds to previous experimental works.
Gas Exchange in the Respiratory Distress Syndromes
Authors: Albert Richard K. , Jobe Alan
Published: June 2012

This article describes the gas exchange abnormalities occurring in the acute respiratory distress syndrome seen in adults and children and in the respiratory distress syndrome that occurs in neonates. Evidence is presented indicating that the major gas exchange abnormality accounting for the hypoxemia in both conditions is shunt, and that approximately 50% of patients also have lungs regions in which low ventilation‐to‐perfusion ratios contribute to the venous admixture. The various mechanisms by which hypercarbia may develop and by which positive end‐expiratory pressure improves gas exchange are reviewed, as are the effects of vascular tone and airway narrowing. The mechanisms by which surfactant abnormalities occur in the two conditions are described, as are the histological findings that have been associated with shunt and low ventilation‐to‐perfusion. © 2012 American Physiological Society.Compr Physiol2:1585‐1617, 2012.
Genetic Diseases: Congenital Central Hypoventilation, Rett, and Prader‐Willi Syndromes
Authors: Gallego Jorge
Published: June 2012

The present review summarizes current knowledge on three rare genetic disorders of respiratory control, congenital central hypoventilation syndrome (CCHS), Rett syndrome (RTT), and Prader‐Willi syndrome (PWS). CCHS is characterized by lack of ventilatory chemosensitivity caused byPHOX2Bgene abnormalities consisting mainly of alanine expansions. RTT is associated with episodes of tachypneic and irregular breathing intermixed with breathholds and apneas and is caused by mutations in the X‐linkedMECP2gene encoding methyl‐CpG‐binding protein. PWS manifests as sleep‐disordered breathing with apneas and episodes of hypoventilation and is caused by the loss of a group of paternally inherited genes on chromosome 15. CCHS is the most specific disorder of respiratory control, whereas the breathing disorders in RTT and PWS are components of a more general developmental disorder. The main clinical features of these three disorders are reviewed with special emphasis on the associated brain abnormalities. In all three syndromes, disease‐causing genetic defects have been identified, allowing the development of genetically engineered mouse models. New directions for future therapies based on these models or, in some cases, on clinical experience are delineated. Studies of CCHS, RTT, and PWS extend our knowledge of the molecular and cellular aspects of respiratory rhythm generation and suggest possible pharmacological approaches to respiratory control disorders. This knowledge is relevant for the clinical management of many respiratory disorders that are far more prevalent than the rare diseases discussed here. © 2012 American Physiological Society.Compr Physiol2:2255‐2279, 2012.
Control of Breathing in Invertebrate Model Systems
Authors: Bell Harold J. , Syed Naweed I.
Published: June 2012

The invertebrates have adopted a myriad of breathing strategies to facilitate the extraction of adequate quantities of oxygen from their surrounding environments. Their respiratory structures can take a wide variety of forms, including integumentary surfaces, lungs, gills, tracheal systems, and even parallel combinations of these same gas exchange structures. Like their vertebrate counterparts, the invertebrates have evolved elaborate control strategies to regulate their breathing activity. Our goal in this article is to present the reader with a description of what is known regarding the control of breathing in some of the specific invertebrate species that have been used as model systems to study different mechanistic aspects of the control of breathing. We will examine how several species have been used to study fundamental principles of respiratory rhythm generation, central and peripheral chemosensory modulation of breathing, and plasticity in the control of breathing. We will also present the reader with an overview of some of the behavioral and neuronal adaptability that has been extensively documented in these animals. By presenting explicit invertebrate species as model organisms, we will illustrate mechanistic principles that form the neuronal foundation of respiratory control, and moreover appear likely to be conserved across not only invertebrates, but vertebrate species as well. © 2012 American Physiological Society.Compr Physiol2:1745‐1766, 2012.
Effects of Gas Exchange on Acid‐Base Balance
Authors: Lindinger Michael I. , Heigenhauser George J.F.
Published: June 2012

This paper describes the interactions between ventilation and acid‐base balance under a variety of conditions including rest, exercise, altitude, pregnancy, and various muscle, respiratory, cardiac, and renal pathologies. We introduce the physicochemical approach to assessing acid‐base status and demonstrate how this approach can be used to quantify the origins of acid‐base disorders using examples from the literature. The relationships between chemoreceptor and metaboreceptor control of ventilation and acid‐base balance summarized here for adults, youth, and in various pathological conditions. There is a dynamic interplay between disturbances in acid‐base balance, that is, exercise, that affect ventilation as well as imposed or pathological disturbances of ventilation that affect acid‐base balance. Interactions between ventilation and acid‐base balance are highlighted for moderate‐ to high‐intensity exercise, altitude, induced acidosis and alkalosis, pregnancy, obesity, and some pathological conditions. In many situations, complete acid‐base data are lacking, indicating a need for further research aimed at elucidating mechanistic bases for relationships between alterations in acid‐base state and the ventilatory responses. © 2012 American Physiological Society.Compr Physiol2:2203‐2254, 2012.
Pathological Consequences of Intermittent Hypoxia in the Central Nervous System
Authors: Zhang Shelley X.L. , Wang Yang , Gozal David
Published: June 2012

Intermittent hypoxia (IH) is a frequent occurrence in clinical settings. In the last decades, evidence has emerged implicating the gas exchange alterations and sleep disruption associated with those disorders in the high prevalence of cognitive and behavioral deficits afflicting these patients. In an effort to better characterize the role of IH, and to identify potential mechanisms of IH‐induced central nervous system (CNS) dysfunction, a large number of rodent models have been recently developed. The cumulative evidence confirms that IH indeed induces a heterotopic pattern of injury in the brain, particularly affecting cortical, subcortical, and hippocampal regions, ultimately leading to neuronal apoptosis and activation of microglia. These IH‐induced deleterious processes exhibit substantial variability across the lifespan, are under substantial modulatory influences of diet, physical or intellectual activity, and genetic factors, and preferentially recruit oxidative stress and inflammatory pathways. © 2012 American Physiological Society.Compr Physiol2:1767‐1777, 2012.
Biophysics of Glomerular Filtration
Authors: Thomson Scott C. , Blantz Roland C.
Published: June 2012

Enlightened by William Bowman's depiction of the anatomy in 1842, Carl Ludwig immediately proposed glomerular filtration as a physical process. Nuances of this process have come to light in a rather orderly progression over the past 150 years with essential contributions from clearance methods, renal micropuncture, physical theories of nonequilibrium thermodynamics and electrical double layers, morphometry, and mathematics. Herein, we describe that progression of knowledge. Ongoing work pertains to the nature, location, and efficiency of the barrier to protein sieving, induction of endothelial fenestrae by growth factors from the podocyte, and potential resistance faced by filtrate exiting the subpodocyte space. Published 2012.Compr Physiol2:1671‐1699, 2012.
Life Under Water: Physiological Adaptations to Diving and Living at Sea
Authors: Castellini Michael
Published: June 2012

This review covers the field of diving physiology by following a chronological approach and focusing heavily on marine mammals. Because the study of modern diving physiology can be traced almost entirely to the work of Laurence Irving in the 1930s, this particular field of physiology is different than most in that it did not derive from multiple laboratories working at many locations or on different aspects of a similar problem. Because most of the physiology principles still used today were first formulated by Irving, it is important to the study of this field that the sequence of thought is examined as a progression of theory. The review covers the field in roughly decadal blocks and traces ideas as they were first suggested, tested, modified and in some cases, abandoned. Because diving physiology has also been extremely dependent on new technologies used in the development of diving recorders, a chronological approach fits well with advances in electronics and mechanical innovation. There are many species that dive underwater as part of their natural behavior, but it is mainly the marine mammals (seals, sea lions, and whales) that demonstrate both long duration and dives to great depth. There have been many studies on other diving species including birds, snakes, small aquatic mammals, and humans. This work examines these other diving species as appropriate and a listing of reviews and relevant literature on these groups is included at the end. © 2012 American Physiological Society.Compr Physiol2:1889‐1919, 2012.
Factors Limiting Exercise Tolerance in Chronic Lung Diseases
Authors: Vogiatzis Ioannis , Zakynthinos Spyros
Published: June 2012

The major limitation to exercise performance in patients with chronic lung diseases is an issue of great importance since identifying the factors that prevent these patients from carrying out activities of daily living provides an important perspective for the choice of the appropriate therapeutic strategy. The factors that limit exercise capacity may be different in patients with different disease entities (i.e., chronic obstructive, restrictive or pulmonary vascular lung disease) or disease severity and ultimately depend on the degree of malfunction or miss coordination between the different physiological systems (i.e., respiratory, cardiovascular and peripheral muscles). This review focuses on patients with chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD) and pulmonary vascular disease (PVD). ILD and PVD are included because there is sufficient experimental evidence for the factors that limit exercise capacity and because these disorders are representative of restrictive and pulmonary vascular disorders, respectively. A great deal of emphasis is given, however, to causes of exercise intolerance in COPD mainly because of the plethora of research findings that have been published in this area and also because exercise intolerance in COPD has been used as a model for understanding the interactions of different pathophysiologic mechanisms in exercise limitation. As exercise intolerance in COPD is recognized as being multifactorial, the impacts of the following factors on patients’ exercise capacity are explored from an integrative physiological perspective: (i) imbalance between the ventilatory capacity and requirement; (ii) imbalance between energy demands and supplies to working respiratory and peripheral muscles; and (iii) peripheral muscle intrinsic dysfunction/weakness. © 2012 American Physiological Society.Compr Physiol2:1779‐1817, 2012.
Computational Models and Emergent Properties of Respiratory Neural Networks
Authors: Lindsey Bruce G. , Rybak Ilya A. , Smith Jeffrey C.
Published: June 2012

Computational models of the neural control system for breathing in mammals provide a theoretical and computational framework bringing together experimental data obtained from different animal preparations under various experimental conditions. Many of these models were developed in parallel and iteratively with experimental studies and provided predictions guiding new experiments. This data‐driven modeling approach has advanced our understanding of respiratory network architecture and neural mechanisms underlying generation of the respiratory rhythm and pattern, including their functional reorganization under different physiological conditions. Models reviewed here vary in neurobiological details and computational complexity and span multiple spatiotemporal scales of respiratory control mechanisms. Recent models describe interacting populations of respiratory neurons spatially distributed within the Bötzinger and pre‐Bötzinger complexes and rostral ventrolateral medulla that contain core circuits of the respiratory central pattern generator (CPG). Network interactions within these circuits along with intrinsic rhythmogenic properties of neurons form a hierarchy of multiple rhythm generation mechanisms. The functional expression of these mechanisms is controlled by input drives from other brainstem components, including the retrotrapezoid nucleus and pons, which regulate the dynamic behavior of the core circuitry. The emerging view is that the brainstem respiratory network has rhythmogenic capabilities at multiple levels of circuit organization. This allows flexible, state‐dependent expression of different neural pattern‐generation mechanisms under various physiological conditions, enabling a wide repertoire of respiratory behaviors. Some models consider control of the respiratory CPG by pulmonary feedback and network reconfiguration during defensive behaviors such as cough. Future directions in modeling of the respiratory CPG are considered. Published 2012.Compr Physiol2:1619‐1670, 2012.
Structure and Function of the Thin Limbs of the Loop of Henle
Authors: Pannabecker Thomas L.
Published: June 2012

The thin limbs of the loop of Henle, which comprise the intermediate segment, connect the proximal tubule to the distal tubule and lie entirely within the renal medulla. The descending thin limb consists of at least two or three morphologically and functionally distinct subsegments and participates in transepithelial transport of NaCl, urea, and water. Only one functionally distinct segment is recognized for the ascending thin limb, which carries out transepithelial transport of NaCl and urea in the reabsorptive and/or secretory directions. Membrane transporters involved with passive transcellular Cl, urea, and water fluxes have been characterized for thin limbs; however, these pathways do not account for all transepithelial fluid and solute fluxes that have been measuredin vivo. The paracellular pathway has been proposed to play an important role in transepithelial Na and urea fluxes in defined thin‐limb subsegments. As the transport pathways become clearer, the overall function of the thin limbs is becoming better understood. Primary and secondary signaling pathways and protein‐protein interactions are increasingly recognized as important modulators of thin‐limb cell function and cell metabolism. These functions must be investigated under diverse extracellular conditions, particularly for those cells of the deep inner medulla that function in an environment of wide variation in hyperosmolality. Transgenic mouse models of several key water and solute transport proteins have provided significant insights into thin‐limb function. An understanding of the overall architecture of the medulla, including juxtapositions of thin limbs with collecting ducts, thick ascending limbs, and vasa recta, is essential for understanding the role of the kidney in maintaining Na and water homeostasis, and for understanding the urine concentrating mechanism. © 2012 American Physiological Society.Compr Physiol2:2063‐2086, 2012.
Exercise Limitation Following Transplantation
Authors: Williams Trevor J. , McKenna Michael J.
Published: June 2012

Organ transplantation is one of the medical miracles or the 20th century. It has the capacity to substantially improve exercise performance and quality of life in patients who are severely limited with chronic organ failure. We focus on the most commonly performed solid‐organ transplants and describe peak exercise performance following recovery from transplantation. Across all of the common transplants, evaluated significant reduction ino2peakis seen (typically renal and liver 65%‐80% with heart and/or lung 50%‐60% of predicted). Those with the lowesto2peakpretransplant have the lowesto2peakposttransplant. Overall very few patients have ao2peakin the normal range. Investigation of the cause of the reduction ofo2peakhas identified many factors pre‐ and posttransplant that may contribute. These include organ‐specific factors in the otherwise well‐functioning allograft (e.g., chronotropic incompetence in heart transplantation) as well as allograft dysfunction itself (e.g., chronic lung allograft dysfunction). However, looking across all transplants, a pattern emerges. A low muscle mass with qualitative change in large exercising skeletal muscle groups is seen pretransplant. Many factor posttransplant aggravate these changes or prevent them recovering, especially calcineurin antagonist drugs which are key immunosuppressing agents. This results in the reduction ofo2peakdespite restoration of near normal function of the initially failing organ system. As such organ transplantation has provided an experiment of nature that has focused our attention on an important confounder of chronic organ failure‐skeletal muscle dysfunction. © 2012 American Physiological Society.Compr Physiol2:1937‐1979, 2012.
Cell Biology and Physiology of CLC Chloride Channels and Transporters
Authors: Stauber Tobias , Weinert Stefanie , Jentsch Thomas J.
Published: June 2012

Proteins of the CLC gene family assemble to homo‐ or sometimes heterodimers and either function as Cl–channels or as Cl–/H+‐exchangers. CLC proteins are present in all phyla. Detailed structural information is available from crystal structures of bacterial and algal CLCs. Mammals express nine CLC genes, four of which encode Cl–channels and five 2Cl–/H+‐exchangers. Two accessory β‐subunits are known: (1) barttin and (2) Ostm1. ClC‐Ka and ClC‐Kb Cl–channels need barttin, whereas Ostm1 is required for the function of the lysosomal ClC‐7 2Cl–/H+‐exchanger. ClC‐1, ‐2, ‐Ka and ‐Kb Cl–channels reside in the plasma membrane and function in the control of electrical excitability of muscles or neurons, in extra‐ and intracellular ion homeostasis, and in transepithelial transport. The mainly endosomal/lysosomal Cl–/H+‐exchangers ClC‐3 to ClC‐7 may facilitate vesicular acidification by shunting currents of proton pumps and increase vesicular Cl–concentration. ClC‐3 is also present on synaptic vesicles, whereas ClC‐4 and ‐5 can reach the plasma membrane to some extent. ClC‐7/Ostm1 is coinserted with the vesicular H+‐ATPase into the acid‐secreting ruffled border membrane of osteoclasts. Mice or humans lacking ClC‐7 or Ostm1 display osteopetrosis and lysosomal storage disease. Disruption of the endosomal ClC‐5 Cl–/H+‐exchanger leads to proteinuria and Dent's disease. Mouse models in which ClC‐5 or ClC‐7 is converted to uncoupled Cl–conductors suggest an important role of vesicular Cl–accumulation in these pathologies. The important functions of CLC Cl–channels were also revealed by human diseases and mouse models, with phenotypes including myotonia, renal loss of salt and water, deafness, blindness, leukodystrophy, and male infertility. © 2012 American Physiological Society.Compr Physiol2:1701‐1744, 2012.
Airway‐Parenchymal Interdependence
Authors: Paré Peter D. , Mitzner Wayne
Published: June 2012

In this article, we discuss the interaction of the lung parenchyma and the airways as well as the physiological and pathophysiological significance of this interaction. These two components of the respiratory organ can be thought of as two independent elastic structures but in fact the mechanical properties of one influence the behavior of the other. Traditionally, the interaction has focused on the effects of the lung on the airways but there is good evidence that the opposite is also true, that is, that the mechanical properties of the airways influence the elastic properties of the parenchyma. The interplay between components of the respiratory system including the airways, parenchyma, and vasculature is often referred to as “interdependence.” This interdependence transmits the elastic recoil of the lung to create an effective pressure that dilates the airways as transpulmonary pressure and lung volume increase. By using a continuum mechanics analysis of the lung parenchyma, it is possible to predict the effective pressure between the airways and parenchyma, and these predictions can be empirically evaluated. Normal airway caliber is maintained by this pressure in the adventitial interstitium of the airway, and it attenuates the ability of airway smooth muscle to narrow airways. Interdependence has physiological and pathophysiological significance. Weakening of the forces of interdependence contributes to airway dysfunction and gas exchange impairment in acute and chronic airway diseases including asthma and emphysema. © 2012 American Physiological Society.Compr Physiol2:1921‐1935, 2012.
Claudins and Other Tight Junction Proteins
Authors: Günzel Dorothee , Fromm Michael
Published: June 2012

Epithelial transport relies on the proper function and regulation of the tight junction (TJ), other‐wise uncontrolled paracellular leakage of solutes and water would occur. They also act as a fence against mixing of membrane proteins of the apical and basolateral side. The proteins determining paracellular transport consist of four transmembrane regions, intracellular N and C terminals, one intracellular and two extracellular loops (ECLs). The ECLs interact laterally and with counterparts of the neighboring cell and by this achieve a general sealing function. Two TJ protein families can be distinguished, claudins, comprising 27 members in mammals, and TJ‐associated MARVEL proteins (TAMP), comprising occludin, tricellulin, and MarvelD3. They are linked to a multitude of TJ‐associated regulatory and scaffolding proteins. The major TJ proteins are classified according to the physiological role they play in enabling or preventing paracellular transport. Many TJ proteins have sealing functions (claudins 1, 3, 5, 11, 14, 19, and tricellulin). In contrast, a significant number of claudins form channels across TJs which feature selectivity for cations (claudins 2, 10b, and 15), anions (claudin‐10a and ‐17), or are permeable to water (claudin‐2). For several TJ proteins, function is yet unclear as their effects on epithelial barriers are inconsistent (claudins 4, 7, 8, 16, and occludin). TJs undergo physiological and pathophysiological regulation by altering protein composition or abundance. Major pathophysiological conditions which involve changes in TJ protein composition are (1) effects of pathogens binding to TJ proteins, (2) altered TJ protein composition during inflammation and infection, and (3) altered TJ protein expression in cancers. © 2012 American Physiological Society.Compr Physiol2:1819‐1852, 2012.
Role of Ion Transport in Control of Apoptotic Cell Death
Authors: Lang Florian , Hoffmann Else K.
Published: June 2012

Cell shrinkage is a hallmark and contributes to signaling of apoptosis. Apoptotic cell shrinkage requires ion transport across the cell membrane involving K+channels, Cl−or anion channels, Na+/H+exchange, Na+,K+,Cl−cotransport, and Na+/K+ATPase. Activation of K+channels fosters K+exit with decrease of cytosolic K+concentration, activation of anion channels triggers exit of Cl−, organic osmolytes, and HCO3−. Cellular loss of K+and organic osmolytes as well as cytosolic acidification favor apoptosis. Ca2+entry through Ca2+‐permeable cation channels may result in apoptosis by affecting mitochondrial integrity, stimulating proteinases, inducing cell shrinkage due to activation of Ca2+‐sensitive K+channels, and triggering cell‐membrane scrambling. Signaling involved in the modification of cell‐volume regulatory ion transport during apoptosis include mitogen‐activated kinases p38, JNK, ERK1/2, MEKK1, MKK4, the small G proteins Cdc42, and/or Rac and the transcription factor p53. Osmosensing involves integrin receptors, focal adhesion kinases, and tyrosine kinase receptors. Hyperosmotic shock leads to vesicular acidification followed by activation of acid sphingomyelinase, ceramide formation, release of reactive oxygen species, activation of the tyrosine kinase Yes with subsequent stimulation of CD95 trafficking to the cell membrane. Apoptosis is counteracted by mechanisms involved in regulatory volume increase (RVI), by organic osmolytes, by focal adhesion kinase, and by heat‐shock proteins. Clearly, our knowledge on the interplay between cell‐volume regulatory mechanisms and suicidal cell death is still far from complete and substantial additional experimental effort is needed to elucidate the role of cell‐volume regulatory mechanisms in suicidal cell death. © 2012 American Physiological Society.Compr Physiol2:2037‐2061, 2012.
K+Channels: Function‐Structural Overview
Authors: González Carlos , Baez‐Nieto David , Valencia Ignacio , Oyarzún Ingrid , Rojas Patricio , Naranjo David , Latorre Ramón
Published: June 2012

Potassium channels are particularly important in determining the shape and duration of the action potential, controlling the membrane potential, modulating hormone secretion, epithelial function and, in the case of those K+channels activated by Ca2+, damping excitatory signals. The multiplicity of roles played by K+channels is only possible to their mammoth diversity that includes at present 70 K+channels encoding genes in mammals. Today, thanks to the use of cloning, mutagenesis, and the more recent structural studies using x‐ray crystallography, we are in a unique position to understand the origins of the enormous diversity of this superfamily of ion channels, the roles they play in different cell types, and the relations that exist between structure and function. With the exception of two‐pore K+channels that are dimers, voltage‐dependent K+channels are tetrameric assemblies and share an extremely well conserved pore region, in which the ion‐selectivity filter resides. In the present overview, we discuss in the function, localization, and the relations between function and structure of the five different subfamilies of K+channels: (a) inward rectifiers, Kir; (b) four transmembrane segments‐2 pores, K2P; (c) voltage‐gated, Kv; (d) the Slo family; and (e) Ca2+‐activated SK family, SKCa. © 2012 American Physiological Society.Compr Physiol2:2087‐2149, 2012.
Gap Junctions
Authors: Nielsen Morten Schak , Nygaard Axelsen Lene , Sorgen Paul L. , Verma Vandana , Delmar Mario , Holstein‐Rathlou Niels‐Henrik
Published: June 2012

Gap junctions are essential to the function of multicellular animals, which require a high degree of coordination between cells. In vertebrates, gap junctions comprise connexins and currently 21 connexins are known in humans. The functions of gap junctions are highly diverse and include exchange of metabolites and electrical signals between cells, as well as functions, which are apparently unrelated to intercellular communication. Given the diversity of gap junction physiology, regulation of gap junction activity is complex. The structure of the various connexins is known to some extent; and structural rearrangements and intramolecular interactions are important for regulation of channel function. Intercellular coupling is further regulated by the number and activity of channels present in gap junctional plaques. The number of connexins in cell‐cell channels is regulated by controlling transcription, translation, trafficking, and degradation; and all of these processes are under strict control. Once in the membrane, channel activity is determined by the conductive properties of the connexin involved, which can be regulated by voltage and chemical gating, as well as a large number of posttranslational modifications. The aim of the present article is to review our current knowledge on the structure, regulation, function, and pharmacology of gap junctions. This will be supported by examples of how different connexins and their regulation act in concert to achieve appropriate physiological control, and how disturbances of connexin function can lead to disease. © 2012 American Physiological Society.Compr Physiol2:1981‐2035, 2012.