bluuebunny/crossref_metadata_2025 huggingface dataset:
Discovery and Characterization of Atropisomer PH‐797804, a p38 MAP Kinase Inhibitor, as a Clinical Drug Candidate
Authors: Xing Li , Devadas Balekudru , Devraj Rajesh V. , Selness Shaun R. , Shieh Huey , Walker John K. , Mao Michael , Messing Dean , Samas Brian , Yang Jerry Z. , Anderson Gary D. , Webb Elizabeth G. , Monahan Joseph B.
Published: December 2011

PH‐797804 ((aS)‐3‐{3‐bromo‐4‐[(2,4‐difluorobenzyl)oxy]‐6‐methyl‐2‐oxopyridin‐1(2H)‐yl}‐N,4‐dimethylbenzamde) is a diarylpyridinone inhibitor of p38 mitogen‐activated protein (MAP) kinase derived from a racemic mixture as the more potent atropisomer (aS), first proposed by molecular modeling and subsequently confirmed by experiments. Due to steric constraints imposed by the pyridinone carbonyl group and the 6‐ and 6′‐methyl substituents of PH‐797804, rotation around the connecting bond of the pyridinone and the N‐phenyl ring is restricted. Density functional theory predicts a remarkably high rotational energy barrier of >30 kcal mol−1, corresponding to a half‐life of more than one hundred years at room temperature. This gives rise to discrete conformational spaces for the N‐phenylpyridinone group, and as a result, two atropic isomers that do not interconvert under ambient conditions. Molecular modeling studies predict that the two isomers should differ in their binding affinity for p38α kinase; whereas the atropic S (aS) isomer binds favorably, the opposite aR isomer incurs significant steric interference with p38α kinase. The two isomers were subsequently identified and separated by chiral chromatography. IC50 values from p38α kinase assays confirm that one atropisomer is >100‐fold more potent than the other. It was ultimately confirmed by small‐molecule X‐ray diffraction that the more potent atropisomer, PH‐797804, is the aS isomer of the racemic pair. Extensive pharmacological characterization supports that PH‐797804 carries most activity both in vitro and in vivo, and it has a stability profile compatible with oral formulation and delivery options.
Developmental expression of cell recognition molecules in the mushroom body and antennal lobe of the locust Locusta migratoria
Authors: Eickhoff René , Bicker Gerd
Published: December 2011

We examined the development of olfactory neuropils in the hemimetabolous insect Locusta migratoria with an emphasis on the mushroom bodies, protocerebral integration centers implicated in memory formation. Using a marker of the cyclic adenosine monophosphate (cAMP) signaling cascade and lipophilic dye labeling, we obtained new insights into mushroom body organization by resolving previously unrecognized accessory lobelets arising from Class III Kenyon cells. We utilized antibodies against axonal guidance cues, such as the cell surface glycoproteins Semaphorin 1a (Sema 1a) and Fasciclin I (Fas I), as embryonic markers to compile a comprehensive atlas of mushroom body development. During embryogenesis, all neuropils of the olfactory pathway transiently expressed Sema 1a. The immunoreactivity was particularly strong in developing mushroom bodies. During late embryonic stages, Sema 1a expression in the mushroom bodies became restricted to a subset of Kenyon cells in the core region of the peduncle. Sema 1a was differentially sorted to the Kenyon cell axons and absent in the dendrites. In contrast to Drosophila, locust mushroom bodies and antennal lobes expressed Fas I, but not Fas II. While Fas I immunoreactivity was widely distributed in the midbrain during embryogenesis, labeling persisted into adulthood only in the mushroom bodies and antennal lobes. Kenyon cells proliferated throughout the larval stages. Their neurites retained the embryonic expression pattern of Sema 1a and Fas I, suggesting a role for these molecules in developmental mushroom body plasticity. Our study serves as an initial step toward functional analyses of Sema 1a and Fas I expression during locust mushroom body formation. J. Comp. Neurol. 520:2021–2040, 2012. © 2011 Wiley Periodicals, Inc.
Compensatory redistribution of neuroligins and N‐cadherin following deletion of synaptic β1‐integrin
Authors: Mortillo Steven , Elste Alice , Ge Yongchao , Patil Shekhar B. , Hsiao Kuangfu , Huntley George W. , Davis Ronald L. , Benson Deanna L.
Published: December 2011

β1‐containing integrins are required for persistent synaptic potentiation in hippocampus and regulate hippocampal‐dependent learning. Based largely on indirect evidence, there is a prevailing assumption that β1‐integrins are localized at synapses, where they contribute to synapse adhesion and signaling, but this has not been examined directly. Here we investigate the fine localization of β1‐integrin in adult mouse hippocampus using high‐resolution immunogold labeling, with a particular emphasis on synaptic labeling patterns. We find that β1‐integrins localize to synapses in CA1 and are concentrated postsynaptically. At the postsynaptic membrane, β1‐integrins are found more commonly clustered near active zone centers rather than at the peripheral edges. In mice harboring a conditional deletion of β1‐integrins, labeling for N‐cadherin and neuroligins increases. Western blots show increased levels of N‐cadherin in total lysates and neuroligins increase selectively in synaptosomes. These data suggest there is a dynamic, compensatory adjustment of synaptic adhesion. Such adjustment is specific only for certain cell adhesion molecules (CAMs), because labeling for SynCAM is unchanged. Together, our findings demonstrate unequivocally that β1‐integrin is an integral synaptic adhesion protein, and suggest that adhesive function at the synapse reflects a cooperative and dynamic network of multiple CAM families. J. Comp. Neurol. 520:2041–;2052, 2012. © 2011 Wiley Periodicals, Inc.
Accumulated caveolae constitute subcellular compartments for glial calcium signaling in lanceolate sensory endings innervating rat vibrissae
Authors: Takahashi‐Iwanaga Hiromi , Iwanaga Toshihiko
Published: December 2011

The terminal Schwann cells that accompany lanceolate sensory endings in the rat vibrissal follicle are known to display the small plasma membrane invaginations termed caveolae, which concentrate Ca2+ signaling molecules. We have previously shown that these cells generate Ca2+ signals at the lamellar processes covering the receptor axons through activation of the metabotropic purinoceptor P2Y2. To investigate the roles of caveolae in the spatiotemporal organization of Ca2+ signals, terminal Schwann cells were observed by immunohistochemistry for the caveola protein caveolin‐1, and by transmission and scanning electron microscopy. In addition, immunohistochemical detection of P2Y2 and its coupling partner Gq/11 along with confocal image analysis of the purinergically induced glial Ca2+ responses was performed in isolated tissue preparations either treated or untreated with the caveolae eliminator methyl‐β‐cyclodextrin. Results showed the Schwann lamellae to be characterized by the presence of dense caveolae accompanying a fine tubular network of the endoplasmic reticulum Ca2+ store and by intense expression of the signaling molecules P2Y2 and Gq/11. Loss of caveolae diffusely redistributed these molecules throughout the entire cell and impaired the lamellar Ca2+ signals, both in chronological priority (preceding the global cell response) and in spatial integrity (involving the entire length of the processes). To our knowledge, this is the first report of a subcellular accumulation of caveolae underlying compartmentalized glial Ca2+ signals that can couple with local effects on the accompanying axon terminals. J. Comp. Neurol. 520:2053–2066, 2012. © 2011 Wiley Periodicals, Inc.
Density gradients of vesicular glutamate‐ and GABA transporter‐immunoreactive boutons in calbindin‐ and μ‐opioid receptor‐defined compartments in the rat striatum
Authors: Wouterlood Floris G. , Härtig Wolfgang , Groenewegen Henk J. , Voorn Pieter
Published: December 2011

Cortical and subcortical inputs to the striatum are functionally highly organized and they obey to some extent striatal patch‐matrix topography. Whether this organization is reflected in the density of various glutamatergic endings is unknown. We therefore mapped boutons expressing the vesicular glutamate transporters VGluT1 and VGluT2, together with boutons immunoreactive for vesicular γ‐aminobutyric acid (GABA) transporter (VGAT) in patch and matrix throughout the striatum. We used triple‐immunofluorescence staining followed by multichannel, high‐magnification confocal laser scanning and 3D object recognition. Densities of VGluT1 and VGluT2 boutons were on average higher in matrix than in patches in all striatal sectors. The dorsal one‐third of the striatum contained the highest densities of VGluT1 boutons. Subsequent 3D surface plotting revealed patterns of density “valleys” in the dorsomedial striatum coinciding with patch locations in the patch‐matrix mapping. The density of VGluT1 boutons increased along three axes: ventrolateral‐to‐dorsomedial, ventral‐to‐dorsal, and lateral‐to‐medial. In contrast, VGluT2 showed a global increase in density from lateral to medial and a relatively high density in the ventral striatum. VGAT appeared more evenly distributed in the striatal patch‐matrix than the VGluTs, with a tendency of bouton density to increase from medial to lateral. We noted a good correlation between the high VGluT1 bouton density dorsomedially with inputs from dorsal medial prefrontal cortex and related thalamic regions, and the enhanced VGluT2 input ventromedially with input from ventral medial prefrontal cortex and thalamic, amygdaloid, and hippocampal sources. J. Comp. Neurol. 520:2123–2142, 2012. © 2011 Wiley Periodicals, Inc.
Are Unsaturated Isocyanides so Different from the Corresponding Nitriles?
Authors: Chrostowska Anna , Matrane Abdellatif , Maki Daisuke , Khayar Said , Ushiki Hideharu , Graciaa Alain , Belachemi Larbi , Guillemin Jean‐Claude
Published: December 2011

Simple unsaturated and cyclopropylic isocyanides are synthesized by an efficient and simple approach. These compounds with gradually increasing distance between the unsaturated moiety and the isonitrile group are studied by UV photoelectron spectroscopy and quantum chemical calculations, and also compared to the corresponding nitriles. The first photoelectron band of the unsaturated compounds is linked to removal of an electron from the HOMO, which corresponds to CC multiple‐bond ionization in antibonding interaction with the π‐isocyanide bond (in the same plane) for conjugated systems, or in antibonding interaction with the pseudo‐π‐CH2 group for isolated systems. For the 1‐ethenyl derivatives, both cyano and isocyano groups act as a π‐electron acceptor from the vinyl group, but the isocyano π system is much more strongly destabilized (ionization energies (IEs) shift to smaller values) by vinyl (3.12 eV) than the cyano π system is (2.70 eV). In comparison with the 1‐ethynyl derivatives, a less pronounced destabilization (2.69 eV) of πNC by the ethynyl system (1.86 eV for πCN), and nearly the same order of magnitude of the energetic gap between the total antibonding (πCC−πNC) and the total bonding (πCC+πNC) IEs for ethenyl and ethynyl compounds are noted. The huge values of these last‐named data for H2CCHNC (3.85 eV) and for HCCNC (4.04 eV) reflect the strong interaction between the unsaturated carbon–carbon moiety and the isocyanide group, and thus more efficient conjugation than for the corresponding nitriles.
Parity violation and parity conservation in unstirred crystallization: Effect of first crystals
Authors: Szurgot M.
Published: December 2011

Statistics of nucleation of chiral forms was studied to establish the effect of the number of first crystals and their handedness on distributions of enantiomers. Various bimodal, trimodal and unimodal distributions are obtained in unstirred crystallization, depending on the number of initial crystals and growth conditions. The binomial distribution satisfactorily describes experimental distributions of enantiomeric excess and may be used to predict distributions and probabilities of nucleation of enantiomers. The first nucleated crystals determine the handedness of secondary crystals, and number of initial crystals governs statistics of chiral nucleation. According to the binomial distribution if single crystals nucleate as the first, the bimodal distributions result with D and L peaks. If LD, LL, and DD pairs are nucleated as first, trimodal distributions with D, R, and L peaks are created, and if groups of crystals of various handedness nucleate as the first the unimodal distributions of enantiomeric excess with racemate R peaks are formed. Chiral nucleation experiments on sodium bromate were the basis for the theoretical considerations and verifications of predictions resulting from binomial distributions on probabilities of the creation of L and D crystals, and racemates, and the presence of D, L, and R peaks in the distributions. Growth conditions affect the number of the first crystals and effectiveness of cloning, and as a result, the distributions of enantiomers. Formation of pure enantiomers and/or racemates proves that the conservation of chiral symmetry, and the breakage of chiral symmetry can occur in unstirred crystallization. (© 2012 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Fundamentals and practice of metal contacts to wide band gap semiconductor devices
Authors: Borysiewicz M. A. , Kamińska E. , Myśliwiec M. , Wzorek M. , Kuchuk A. , Barcz A. , Dynowska E. , di Forte‐Poisson M.‐A. , Giesen C. , Piotrowska A.
Published: December 2011

Presented are the theoretical and experimental fundamentals of the fabrication of ohmic contacts to n‐ and p‐type wide band gap semiconductors such as SiC and GaN. In particular, the Ni‐Si/n‐SiC, Al‐Ti/p‐SiC, Ti‐Al/n‐GaN and Ni‐Au/p‐GaN systems are discussed with the focus on the thermally activated chemical reactions taking place at the metal‐semiconductor interface, that lead to the appearance of ohmic behaviour in the contact. Examples of reactions at very intimate interfaces are shown, which are irresolvable using even such sophisticated characterisation methods as high‐resolution transmission electron microscopy and can only be explained using modelling. The issue of thermal stability of the contacts is discussed and the introduction of specifically designed diffusion barriers (eg. Ta‐Si‐N) into the contact metallisation stack is presented as a solution improving drastically the thermal stability of the contacts without degrading their electrical properties. (© 2012 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Highly Stable Noble‐Metal Nanoparticles in Tetraalkylphosphonium Ionic Liquids for in situ Catalysis
Authors: Banerjee Abhinandan , Theron Robin , Scott Robert W. J.
Published: December 2011

Gold and palladium nanoparticles were prepared by lithium borohydride reduction of the metal salt precursors in tetraalkylphosphonium halide ionic liquids in the absence of any organic solvents or external nanoparticle stabilizers. These colloidal suspensions remained stable and showed no nanoparticle agglomeration over many months. A combination of electrostatic interactions between the coordinatively unsaturated metal nanoparticle surface and the ionic‐liquid anions, bolstered by steric protection offered by the bulky alkylated phosphonium cations, is likely to be the reason behind such stabilization. The halide anion strongly absorbs to the nanoparticle surface, leading to exceptional nanoparticle stability in halide ionic liquids; other tetraalkylphosphonium ionic liquids with non‐coordinating anions, such as tosylate and hexafluorophosphate, show considerably lower affinities towards the stabilization of nanoparticles. Palladium nanoparticles stabilized in the tetraalkylphosphonium halide ionic liquid were stable, efficient, and recyclable catalysts for a variety of hydrogenation reactions at ambient pressures with sustained activity. Aerial oxidation of the metal nanoparticles occurred over time and was readily reversed by re‐reduction of oxidized metal salts.
Developments of TaN ALD Process for 3D Conformal Coatings
Authors: Brizé Virginie , Prieur Thomas , Violet Perrine , Artaud Laurent , Berthomé Grégory , Blanquet Elisabeth , Boichot Raphaël , Coindeau Stéphane , Doisneau Béatrice , Farcy Alexis , Mantoux Arnaud , Nuta Ioana , Pons Michel , Volpi Fabien
Published: December 2011

There is a growing interest in producing tantalum nitride (TaN) thin films for various industrial applications. For example, in microelectronics, the development of IC technology is driven by the need to increase both performance and functionality while reducing power and cost. This goal can be achieved by several solutions among which the introduction of architecture enhancements such as 3D integration. The most challenging step is the deposition of a conformal, continuous, and adherent diffusion barrier. In this work, atomic layer deposition (ALD) of TaN thin films is explored using the combination between the thermodynamical behavior of the precursor, mass transfer in the reactor, and the operating conditions. TaN thin film deposition on very complex shape substrates, such as nanodots, TSV, silicon nanowires, and carbon nanotubes, has been evaluated.
In vitro and in vivo efficacy of PEGylated diisopropyl fluorophosphatase (DFPase)
Authors: Melzer Marco , Heidenreich Anne , Dorandeu Frederic , Gäb Jürgen , Kehe Kai , Thiermann Horst , Letzel Thomas , Blum Marc‐Michael
Published: December 2011

Highly toxic organophosphorus compounds that irreversibly inhibit the enzyme acetycholinesterase (AChE), including nerve agents like tabun, sarin, or soman, still pose a credible threat to civilian populations and military personnel. New therapeutics that can be used as a pretreatment or after poisoning with these compounds, complementing existing treatment schemes such as the use of atropine and AChE reactivating oximes, are currently the subject of intense research. A prominent role among potential candidates is taken by enzymes that can detoxify nerve agents by hydrolysis. Diisopropyl fluorophosphatase (DFPase) from the squid Loligo vulgaris is known to effectively hydrolyze DFP and the range of G‐type nerve agents including sarin and soman. In the present work, DFPase was PEGylated to increase biological half‐life, and to lower or avoid an immunogenic reaction and proteolytic digest. Addition of linear polyethylene glycol (PEG) chains was achieved using mPEG‐NHS esters and conjugates were characterized by electrospray ionization – time of flight – mass specrometry (ESI‐ToF‐MS). PEGylated wildtype DFPase and a mutant selective for the more toxic stereoisomers of the agents were tested in vivo with rats that were challenged with a subcutaneous 3x LD50 dose of soman. While wildtype DFPase prevented death only at extremely high doses, the mutant was able keep the animals alive and to minimize or totally avoid symptoms of poisoning. The results serve as a proof of principle that engineered variants of DFPase are potential candidates for in vivo use if substrate affinity can be improved or the turnover rate enhanced to lower the required enzyme dose. Copyright © 2011 John Wiley & Sons, Ltd.
The MicroRNA miR‐8 is a positive regulator of pigmentation and eclosion in Drosophila
Authors: Kennell Jennifer A. , Cadigan Ken M. , Shakhmantsir Iryna , Waldron Evan J.
Published: December 2011

Background: MicroRNAs (miRNAs) are short, non‐coding RNAs that post‐transcriptionally silence gene expression by binding to target mRNAs. Previous studies have identified the miRNA miR‐8 as a pleiotropic regulator of Drosophila development, controlling body size and neuronal survival by targeting multiple mRNAs. In this study we demonstrate that miR‐8 is also required for proper spatial patterning of pigment on the adult abdominal cuticle in females but not males. Results: Female adult flies lacking miR‐8 exhibit decreased pigmentation of the dorsal abdomen, with a pattern of pigmentation similar to wild type flies grown at higher temperatures. This pigmentation defect in miR‐8 mutants is independent of the previously reported body size defect, and miR‐8 acts directly in the developing cuticle to regulate pigmentation patterning. The decrease in pigmentation in miR‐8 mutants was more pronounced in flies grown at higher temperatures. We also found that loss of miR‐8 dramatically affected the ability to eclose at higher temperatures. Conclusion: Loss of miR‐8 increased the sensitivity of Drosophila to higher temperatures for both pigmentation patterning and the ability to eclose. Together, these data suggest that miR‐8 acts as a buffer to stabilize gene expression patterns in the midst of environmental variation. Developmental Dynamics 241:161–168, 2012. © 2011 Wiley Periodicals, Inc.
Sox10‐iCreERT2: A mouse line to inducibly trace the neural crest and oligodendrocyte lineage
Authors: Simon Christiane , Lickert Heiko , Götz Magdalena , Dimou Leda
Published: December 2011

SOX10 is a well‐conserved and widely expressed transcription factor involved in the regulation of embryonic development and in the determination of cell fate. As it is expressed in neural crest cells, their derivatives and the oligodendrocyte lineage, mutations of the protein contribute to a variety of diseases like neurocristopathies, peripheral demyelinating neuropathies, and melanoma. Here, we report the generation of an inducible Sox10‐iCreERT2 BAC transgenic mouse line that labels, depending on the timepoint of induction, distinct derivatives of the otic placode and the neural crest as well as cells of the oligodendrocyte lineage. Surprisingly, we could show a neural crest origin of pericytes in the brain. Besides its use for fate‐mapping, the Sox10‐iCreERT2 mouse line is a powerful tool to conditionally inactivate genes in the neural crest cells, their progeny and/or the oligodendrocyte lineage in a time‐dependent fashion to gain further insights into their function and contribution to diseases. genesis 50:506–515, 2012. © 2011 Wiley Periodicals, Inc.
Oocyte destruction is activated during viral infection
Authors: Thomson Travis C. , Schneemann Anette , Johnson Joshua
Published: December 2011

Viral infection has been associated with a starvation‐like state in Drosophila melanogaster. Because starvation and inhibiting TOR kinase activity in vivo result in blocked oocyte production, we hypothesized that viral infection would also result in compromised oogenesis. Wild‐type flies were injected with flock house virus (FHV) and survival and embryo production were monitored. Infected flies had a dose‐responsive loss of fecundity that corresponded to a global reduction in Akt/TOR signaling. Highly penetrant egg chamber destruction mid‐way through oogenesis was noted and FHV coat protein was detected within developing egg chambers. As seen with in vivo TOR inhibition, oogenesis was partially rescued in loss of function discs large and merlin mutants. As expected, mutants in genes known to be involved in virus internalization and trafficking [Clathrin heavy chain (chc) and synaptotagmin] survive longer during infection. However, oogenesis was rescued only in chc mutants. This suggests that viral response mechanisms that control fly survival and egg chamber survival are separable. The genetic and signaling requirements for oocyte destruction delineated here represent a novel host–virus interaction with implications for the control of both fly and virus populations. genesis 50:453–465, 2012. © 2012 Wiley Periodicals, Inc.
Mountain pine beetle infestation impacts: modeling water and energy budgets at the hill‐slope scale
Authors: Mikkelson K. M. , Maxwell R. M. , Ferguson I. , Stednick J. D. , McCray J. E. , Sharp J. O.
Published: December 2011

The mountain pine beetle (MPB) epidemic in western North America is generating growing concern associated with aesthetics, ecology, and forest and water resources. Given the substantial acreage of prematurely dying forests within Colorado and Wyoming (~two million acres in 2008), MPB infestations have the potential to significantly alter forest canopy, impacting several aspects of the local water and land‐energy cycle. Hydrologic processes that may be influenced include canopy interception of precipitation and radiation, snow accumulation, melt and sublimation, soil infiltration and evapotranspiration. To investigate the changing hydrologic and energy regimes associated with MPB infestations, we used an integrated hydrologic model coupled with a land surface model to incorporate physical processes related to energy at the land surface. This platform was used to model hillslope‐scale hydrology and land‐energy changes throughout the phases of MPB infestation through modification of the physical parameterisation that accounts for alteration of stomatal resistance and leaf area indices. Our results demonstrate that MPB infested watersheds will experience a decrease in evapotranspiration, an increase in snow accumulation accompanied by earlier and faster snowmelt and associated increases in runoff volume and timing. Impacts are similar to those projected under climate change, yet with a systematically higher snowpack. These results have implications for water resource management because of higher tendencies for flooding in the spring and drought in the summer. Copyright © 2011 John Wiley & Sons, Ltd.
Non‐Innocent Ligands: New Opportunities in Iron Catalysis
Authors: Blanchard Sébastien , Derat Etienne , Desage‐El Murr Marine , Fensterbank Louis , Malacria Max , Mouriès‐Mansuy Virginie
Published: December 2011

Introduced in the late sixties, non‐innocent (or redox) ligands have been extensively studied for their unusual and intriguing chemical behavior. Their ability to delocalize and/or provide electrons to the metal center of organometallic complexes confers them undisputable chemical interest and has proved valuable in the development of novel synthetic methodologies. This review will focus on the chemistry and applications of low‐valent iron complexes bearing potentially non‐innocent ligands. Because of the elusive nature of these ligands, and whenever possible, theoretical calculations and analysis of spectroscopic data will be presented in an effort to provide insights into the catalytic activity of the complexes.
A Chiral‐Pool‐Based Approach to the Core Structure of (+)‐Hyperforin
Authors: Richard Jean‐Alexandre , Chen David Y.‐K.
Published: December 2011

Asymmetric entry to the bicyclic core structure of (+)‐hyperforin is presented. The developed synthetic strategy features a carefully orchestrated stereochemical relay from the single chiral center residing within (–)‐Wieland–Miescher ketone and an intramolecular aldol reaction to cast the [3.3.1] bicyclic scaffold found in a diverse array of polycyclic polyprenylated acylphloroglucinols.
Dantrolene rescues arrhythmogenic RYR2 defect in a patient‐specific stem cell model of catecholaminergic polymorphic ventricular tachycardia
Authors: Jung Christian B. , Moretti Alessandra , Mederos y Schnitzler Michael , Iop Laura , Storch Ursula , Bellin Milena , Dorn Tatjana , Ruppenthal Sandra , Pfeiffer Sarah , Goedel Alexander , Dirschinger Ralf J. , Seyfarth Melchior , Lam Jason T. , Sinnecker Daniel , Gudermann Thomas , Lipp Peter , Laugwitz Karl‐Ludwig
Published: December 2011

Coordinated release of calcium (Ca2+) from the sarcoplasmic reticulum (SR) through cardiac ryanodine receptor (RYR2) channels is essential for cardiomyocyte function. In catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited disease characterized by stress‐induced ventricular arrhythmias in young patients with structurally normal hearts, autosomal dominant mutations in RYR2 or recessive mutations in calsequestrin lead to aberrant diastolic Ca2+ release from the SR causing arrhythmogenic delayed after depolarizations (DADs). Here, we report the generation of induced pluripotent stem cells (iPSCs) from a CPVT patient carrying a novel RYR2 S406L mutation. In patient iPSC‐derived cardiomyocytes, catecholaminergic stress led to elevated diastolic Ca2+ concentrations, a reduced SR Ca2+ content and an increased susceptibility to DADs and arrhythmia as compared to control myocytes. This was due to increased frequency and duration of elementary Ca2+ release events (Ca2+ sparks). Dantrolene, a drug effective on malignant hyperthermia, restored normal Ca2+ spark properties and rescued the arrhythmogenic phenotype. This suggests defective inter‐domain interactions within the RYR2 channel as the pathomechanism of the S406L mutation. Our work provides a new in vitro model to study the pathogenesis of human cardiac arrhythmias and develop novel therapies for CPVT.
The response of braided planform configuration to flow variations, bed reworking and vegetation: the case of the Tagliamento River, Italy
Authors: Welber Matilde , Bertoldi Walter , Tubino Marco
Published: December 2011

Morphological features of braided rivers (bars, channels and pools) experience major changes in area, shape and spatial distribution as a response to (i) the pulsation of discharge during a flood and (ii) the bed evolution induced by floods. In this work, at‐a‐station relationships between water level and planform configuration were investigated on the Tagliamento River, a large gravel‐bed braided river in northeast Italy, over a 2‐year study period comprising three bankfull events and several small‐to‐medium floods. The analysis was performed on two 1‐km‐long reaches, characterized by different riparian vegetation cover. Ground‐based images with an hourly temporal resolution were acquired using software‐controlled, digital cameras. Bars, channels, pools and vegetated patches were manually digitized on more than 100 rectified images. Sequences of constant‐level images spanning the study period were used to quantify the impact of floods on the stability of at‐a‐station relationships and on the turnover rate of water bodies.

The analysis shows that wetted area increased almost linearly with water level in both reaches. The average number of branches per cross‐section peaked at intermediate flow levels, increasing from 2 at low flow up to 6–7. The number of branches displayed the largest fluctuations over time, with significant changes produced also by moderate floods. Turnover rates were high in both reaches, with more than 30% of wetted areas at low flow converting into bare gravel in less than 2 months. Vegetation colonization was found to limit the mobility of the low flow channels over time by concentrating the flow in fewer, deeper anabranches. The number of channels per cross‐section was 30–40% less in the vegetated reach and the proportion of low flow water bodies in the same position after 12 months increased from 3% to 14%. Copyright © 2012 John Wiley & Sons, Ltd.
Multiple metals exposure and neurotoxic risk in bald eagles (Haliaeetus leucocephalus) from two Great Lakes states
Authors: Nam Dong-Ha , Rutkiewicz Jennifer , Basu Niladri
Published: December 2011

In the present study, the authors determined concentrations of several elements (As, Cd, Co, Cu, Cr, Mn, Pb, Sb, Zn) in the brains and livers of 46 bald eagles (Haliaeetus leucocephalus) from two Great Lakes states, Michigan and Minnesota. To explore whether exposures are of neurological concern, the authors assessed their associations with neurochemical receptors (N-methyl-D-aspartate [NMDA] and γ-aminobutyric acid A [GABA(A)]) and enzymes (glutamine synthetase [GS] and glutamic acid decarboxylase [GAD]) that play critical roles in vertebrate neurobehavior and reproduction. For most elements, levels in the livers and brains did not differ between region and gender. Hepatic Pb levels averaged 33.1 ppm (dry wt), 30.4% of all carcasses exceeded proposed avian Pb thresholds (>26.4 ppm), and in 30.8% of the birds examined evidence of Pb pellets or fragments was found. Significant changes in the activities of GS and GAD were related to brain concentrations of several metals (Pb, Cd, Co, Cu, Zn). No relationships were found among any of the nine elements and NMDA or GABA(A) receptor levels. When combined with the authors' previous study on these same eagles that showed Hg-associated alterations in GS, GAD, and NMDA receptor levels, the present research suggests that bald eagles are exposed to various elements, especially Pb and Hg, that are capable of causing changes in GABAergic and glutamatergic neurotransmission. The functional significance of these neurochemical changes warrants attention. Environ. Toxicol. Chem. 2012;31:623–631. © 2011 SETAC
Acute toxicity of poly- and perfluorinated compounds to two cladocerans, Daphnia magna and Chydorus sphaericus
Authors: Ding Guang-Hui , Frömel Tobias , van den Brandhof Evert-Jan , Baerselman Rob , Peijnenburg Willie J.G.M.
Published: December 2011

With their global distribution, environmental persistence, and potential risk to human beings and ecosystems, poly- and perfluorinated compounds (PFCs) are of particular concern for research and regulatory communities. However, insufficient toxicity data are available for most poly- and perfluorinated compounds to assess their possible environmental hazards accurately. Therefore, the acute toxicity of seven poly- and perfluorinated carboxylic acids and alcohols on two cladocerans, Daphnia magna and Chydorus sphaericus, was evaluated in the present study. The adverse effects of these PFCs on these two cladocerans decreased with increasing fluorinated carbon chain length (nC) and quantitative structure–activity relationships were developed to quantify this observation. Because the 50% inhibition effects (EC50) values obtained are far above concentrations typically found in surface water, acute harmful effects of these chemicals to D. magna and C. sphaericus are not expected in the real environment. Environ. Toxicol. Chem. 2012;31:605–610. © 2011 SETAC
Gastrointestinal absorption, metabolic debromination, and hydroxylation of three commercial polybrominated diphenyl ether mixtures by common carp
Authors: Zeng Yan-Hong , Luo Xiao-Jun , Chen Hua-Shan , Yu Le-Huan , Chen She-Jun , Mai Bi-Xian
Published: December 2011

The gastrointestinal absorption, metabolic debromination, and hydroxylation of three commercial brominated diphenyl ether (BDE) mixtures were separately studied in juvenile common carp. The absorption rate of penta-BDE was higher than that of octa- and deca-BDE, likely because of the lower molecular volumes of its major congeners. However, no significantly positive relationships were found between the number of bromine atoms and the absorption rate, especially for congeners with a bromine atom number larger than six. The major congeners in fish carcass were, respectively, BDE-47 and BDE-100 in the penta-BDE exposure; BDE-154, -155, -149, and BDE-153 in the octa-BDE exposure; and BDE-154, -155, -149, -188, -179, and BDE-202 in the deca-BDE exposure. Congeners with at least one meta- or para- doubly flanked bromine atom easily undergo metabolic debromination in fish. None of the targeted MeO-polybrominated diphenyl ether (PBDE) congeners were detected in serum samples, implying that the methylation of OH-PBDE is not likely occurring in fish. Eleven OH-PBDEs and several unidentified OH-PBDE congeners were found in penta-BDE-exposed fish. The similar level among three mono-OH-BDE47 congeners suggested that the position of OH in the phenyl ring is not selective. The hydroxylation is not a significant metabolic pathway compared with debromination. No OH-PBDE congeners were found in the serum samples from deca-BDE-exposed fish, which may attributable to the low level of PBDE precursors in fish. Environ. Toxicol. Chem. 2012;31:731–738. © 2011 SETAC
Inhibition of poly(ADP‐ribose) polymerase (PARP) and ataxia telangiectasia mutated (ATM) on the chemosensitivity of mantle cell lymphoma to agents that induce DNA strand breaks
Authors: Golla Radha M. , Li Min , Shen Yulei , Ji Ming , Yan Ying , Fu Kai , Greiner Timothy C. , McKeithan Timothy W. , Chan Wing C.
Published: December 2011

There is a high incidence of genomic aberration of ataxia telangiectasia mutated (ATM) and genes encoding proteins involved in the ATM pathway in mantle cell lymphoma (MCL). It has been shown that poly(ADP‐ribose) polymerase inhibitor (PARPi) strongly enhances the cytotoxicity of agents, causing single‐strand DNA breaks in cells with impaired homologous recombination repair. Here, we show that PARPi AG14361 potentiates the cytotoxicity induced by topotecan treatment in MCL cell lines, which was not dependent on either TP53 or CHEK2 status. Inhibition and/or knockdown of ATM and BRCA2 did not potentiate the cytotoxic effect of treatment with PARPi and topotecan. With loss of function of ATM, other kinases can still mediate activation of ATM substrates as demonstrated by continued phosphorylation of CHEK2 (Thr‐68), although attenuated and delayed. These results suggest that PARPi may enhance the therapeutic efficacy of DNA damaging agents on MCL through TP53‐independent mechanisms without requiring the inhibition of either ATM or BRCA2. Copyright © 2011 John Wiley & Sons, Ltd.
Characterization of hydraulic suitability of Chinese sturgeon (Acipenser sinensis) spawning habitat in the Yangtze River
Authors: Wang Yuankun , Xia Ziqiang , Wang Dong
Published: December 2011

Hydrodynamic flow fields affect the ecological processes such as the water diversity and the distribution of organisms. Understanding the hydrodynamic and ecological processes is critical for the restoration and protection of especially fragile ecological habitats in river systems. This study uses turbulent flow to characterize the ecological behaviour of Chinese Sturgeon (Acipenser sinensis) in the Yangtze River. The Delft3D‐Flow model, which is first validated with field‐measured data, is used to simulate the flow field within spawning habitats of Chinese Sturgeon, downstream of Gezhouba Dam. The model‐simulated turbulent kinetic energy (TKE) and its distribution pattern are then used to characterize the hydraulic environment of the fish's spawning habitat. For the spawning habitat, downstream of Gezhouba Dam, the lower limit of TKE for the Chinese Sturgeon egg mass field is 0.025 m2/s2, which occurs at a velocity less than 1.7 m/s. Chinese Sturgeon prefers habitats with TKE range of 0.010 ~ 0.015 m2/s2 for resting. This suggests that discharge regimes provide the basis for ecological regulation of the Three Gorges Reservoir and the scientific reference for river management. Copyright © 2011 John Wiley & Sons, Ltd.
The drying up of Britain? A national estimate of changes in seasonal river flows from 11 Regional Climate Model simulations
Authors: Prudhomme Christel , Young Andy , Watts Glenn , Haxton Tracey , Crooks Sue , Williamson Jennifer , Davies Helen , Dadson Simon , Allen Stuart
Published: December 2011

As climate change may modify the hydrological cycle significantly, understanding the impact on river flow is important because it affects long‐term water resources planning. Here, we describe a high‐resolution British assessment of changes in river flows in the 2050s under 11 different realisations of HadRM3. In winter, river flows may either increase or decrease, with a wide range of possible decreases in summer flow. These results should encourage adaptation that copes with a broad range of future hydrological conditions. Copyright © 2011 John Wiley & Sons, Ltd.
An analysis of the impact of spatial variability in rainfall on runoff and sediment predictions from a distributed model
Authors: Adams Russell , Western Andrew W. , Seed Alan W.
Published: December 2011

This paper investigates the effect of introducing spatially varying rainfall fields to a hydrological model simulating runoff and erosion. Pairs of model simulations were run using either spatially uniform (i.e. spatially averaged) or spatially varying rainfall fields on a 500‐m grid. The hydrological model used was a simplified version of Thales which enabled runoff generation processes to be isolated from hillslope averaging processes. Both saturation excess and infiltration excess generation mechanisms were considered, as simplifications of actual hillslope processes. A 5‐year average recurrence interval synthetic rainfall event typical of temperate climates (Melbourne, Australia) was used. The erosion model was based on the WEPP interrill equation, modified to allow nonlinear terms relating the erosion rate to rainfall or runoff‐squared. The model results were extracted at different scales to investigate whether the effects of spatially varying rainfall were scale dependent. A series of statistical metrics were developed to assess the variability due to introducing the spatially varying rainfall field. At the catchment (approximately 150 km2) scale, it was found that particularly for saturation excess runoff, model predictions of runoff were insensitive to the spatial resolution of the rainfall data. Generally, erosion processes at smaller sub‐catchment scales, particularly when the sediment generation equation had non linearity, were more sensitive to spatial rainfall variability. Introducing runon infiltration reduced the total runoff and sediment yield at all scales, and this process was also most sensitive to the rainfall resolution. Copyright © 2011 John Wiley & Sons, Ltd.
Sensitivity of cervical carcinoma cells to vesicular stomatitis virus‐induced oncolysis: Potential role of human papilloma virus infection
Authors: Le Boeuf Fabrice , Niknejad Nima , Wang Jiahu , Auer Rebecca , Weberpals Johanne I. , Bell John C. , Dimitroulakos Jim
Published: December 2011

High‐risk carcinogenic subtypes of human papilloma virus (HPV) are associated with the development of squamous cell carcinomas of the cervix (CC) and a subset of head and neck (HNSCC). Recurrent metastatic diseases of these sites display a dismal prognosis. Therefore, there is an urgent need to uncover innovative therapeutic strategies in this clinical setting. Oncolytic viruses, including vesicular stomatitis virus (VSV), were identified due to their ability to specifically target tumor cells that generally display defects in interferon (IFN) signaling. HPV expressed proteins can inhibit IFN signaling; therefore, HPV‐infected cells may be particularly sensitive to VSV oncolysis. In this study, we evaluated the sensitivity of four CC (HPV+) and four HNSCC (HPV−) derived cell lines to VSV oncolysis. Interestingly, the CC cell lines were consistently more sensitive to VSV cytotoxicity than the HNSCC cell lines tested. Exogenous IFN addition or infection with two attenuated VSV variants that are more susceptible to IFN inhibition failed to attenuate VSV oncolysis in hypersensitive CC cell lines. Furthermore, the expression of HPV‐E6, that inhibits IFN receptor signaling, in the VSV‐resistant HNSCC cell line SCC25 attenuated VSV‐induced IFN response and significantly enhanced VSV cytotoxicity. Finally, differential VSV infection and replication was confirmed in xenograft murine tumor models and explant tumor tissues from two patients with CC. Taken together, these results demonstrate that HPV‐infected cells are susceptible to oncolytic virus therapy and that this approach may represent a novel therapeutic approach in HPV positive CC and HNSCC patients.
Vitamin or mineral supplement intake and the risk of head and neck cancer: pooled analysis in the INHANCE consortium
Authors: Li Qian , Chuang Shu‐Chun , Eluf‐Neto Jose , Menezes Ana , Matos Elena , Koifman Sergio , Wünsch‐Filho Victor , Fernandez Leticia , Daudt Alexander W. , Curado Maria Paula , Winn Deborah M. , Franceschi Silvia , Herrero Rolando , Castellsague Xavier , Morgenstern Hal , Zhang Zuo‐Feng , Lazarus Philip , Muscat Joshua , McClean Michael , Kelsey Karl T. , Hayes Richard B. , Purdue Mark P. , Schwartz Stephen M. , Chen Chu , Benhamou Simone , Olshan Andrew F. , Yu Guopei , Schantz Stimson , Ferro Gilles , Brennan Paul , Boffetta Paolo , Hashibe Mia
Published: December 2011

To investigate the potential role of vitamin or mineral supplementation on the risk of head and neck cancer (HNC), we analyzed individual‐level pooled data from 12 case–control studies (7,002 HNC cases and 8,383 controls) participating in the International Head and Neck Cancer Epidemiology consortium. There were a total of 2,028 oral cavity cancer, 2,465 pharyngeal cancer, 874 unspecified oral/pharynx cancer, 1,329 laryngeal cancer and 306 overlapping HNC cases. Odds ratios (OR) and 95% confidence intervals (CIs) for self reported ever use of any vitamins, multivitamins, vitamin A, vitamin C, vitamin E, and calcium, beta‐carotene, iron, selenium and zinc supplements were assessed. We further examined frequency, duration and cumulative exposure of each vitamin or mineral when possible and stratified by smoking and drinking status. All ORs were adjusted for age, sex, race/ethnicity, study center, education level, pack‐years of smoking, frequency of alcohol drinking and fruit/vegetable intake. A decreased risk of HNC was observed with ever use of vitamin C (OR = 0.76, 95% CI = 0.59–0.96) and with ever use of calcium supplement (OR = 0.64, 95% CI = 0.42–0.97). The inverse association with HNC risk was also observed for 10 or more years of vitamin C use (OR = 0.72, 95% CI = 0.54–0.97) and more than 365 tablets of cumulative calcium intake (OR = 0.36, 95% CI = 0.16–0.83), but linear trends were not observed for the frequency or duration of any supplement intake. We did not observe any strong associations between vitamin or mineral supplement intake and the risk of HNC.
Chemical Bonding in Al5Co2: The Electron Localizability–Electron Density Approach
Authors: Ormeci Alim , Grin Yuri
Published: December 2011

Al5Co2 is an intermetallic compound which can be considered as an approximant of the quasicrystalline decagonal phases. Chemical bonding in Al5Co2 is investigated by using the electron localizability–electron density approach. The analysis reveals that two atomic clusters, one three dimensional, the other planar, can be identified on the basis of two‐centre bonds that are formed around the shortest Al–Co distances. These clusters and one of the Al types interact through multi‐centre bonds, indicating that both covalent and metallic interactions coexist in Al5Co2.
IMPACTS OF DIRECT SEEDING INTO MULCH ON THE YIELD, WATER USE EFFICIENCY AND NITROGEN DYNAMICS OF CORN, SORGHUM AND DURUM WHEAT
Authors: Khaledian M. R. , Mailhol J. C. , Ruelle P. , Mubarak I.
Published: December 2011

Direct seeding into mulch (DSM) is a cropping system that is increasingly used in the world. The major concern among producers is the possible yield penalties associated with DSM compared to conventional tillage (CT). The aim of our study was to assess the effects of DSM on the yields of corn, sorghum and durum wheat, as well as water use efficiency (WUE) and nitrogen dynamics. An experimental study was carried out at the Lavalette experimental station from 2001 to 2007. Corn, sorghum and durum wheat were sown in two tillage treatments (CT and DSM). Yield and some yield components, nitrogen dynamics and WUE were determined. The results showed that DSM could maintain the crop production of corn and sorghum, however, for durum wheat, CT performed better. DSM improved WUE and irrigation water use efficiency (IWUE) of corn and sorghum and decreased crop evapotranspiration from 5 to 27%. These results suggest that DSM is a relevant alternative to the CT system for corn and sorghum in the SE of France. Adopting DSM with a relevant crop rotation and cover crop resulting in a better IWUE for this system compared with CT can effectively address water scarcity issues in this region. Copyright © 2011 John Wiley & Sons, Ltd.