bluuebunny/crossref_metadata_2025 huggingface dataset:
Pseudopodium-enriched atypical kinase 1 regulates the cytoskeleton and cancer progression
Authors: Wang Yingchun , Kelber Jonathan A. , Cao Hop S. Tran , Cantin Greg T. , Lin Rui , Wang Wei , Kaushal Sharmeela , Bristow Jeanne M. , Edgington Thomas S. , Hoffman Robert M. , Bouvet Michael , Yates John R. , Klemke Richard L.
Published: June 2010

Regulation of the actin-myosin cytoskeleton plays a central role in cell migration and cancer progression. Here, we report the discovery of a cytoskeleton-associated kinase, pseudopodium-enriched atypical kinase 1 (PEAK1). PEAK1 is a 190-kDa nonreceptor tyrosine kinase that localizes to actin filaments and focal adhesions. PEAK1 undergoes Src-induced tyrosine phosphorylation, regulates the p130Cas-Crk-paxillin and Erk signaling pathways, and operates downstream of integrin and epidermal growth factor receptors (EGFR) to control cell spreading, migration, and proliferation. Perturbation of PEAK1 levels in cancer cells alters anchorage-independent growth and tumor progression in mice. Notably, primary and metastatic samples from colon cancer patients display amplified PEAK1 levels in 81% of the cases. Our findings indicate that PEAK1 is an important cytoskeletal regulatory kinase and possible target for anticancer therapy.
Folding of a transcriptionally acting PreQ
1
riboswitch
Authors: Rieder Ulrike , Kreutz Christoph , Micura Ronald
Published: June 2010

7-Aminomethyl-7-deazaguanine (preQ
1
) sensitive mRNA domains belong to the smallest riboswitches known to date. Although recent efforts have revealed the three-dimensional architecture of the ligand–aptamer complex less is known about the molecular details of the ligand-induced response mechanism that modulates gene expression. We present an in vitro investigation on the ligand-induced folding process of the preQ
1
responsive RNA element from
Fusobacterium nucleatum
using biophysical methods, including fluorescence and NMR spectroscopy of site-specifically labeled riboswitch variants. We provide evidence that the full-length riboswitch domain adopts two different coexisting stem-loop structures in the expression platform. Upon addition of preQ
1
, the equilibrium of the competing hairpins is significantly shifted. This system therefore, represents a finely tunable antiterminator/terminator interplay that impacts the in vivo cellular response mechanism. A model is presented how a riboswitch that provides no obvious overlap between aptamer and terminator stem-loop solves this communication problem by involving bistable sequence determinants.
Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus
Authors: Sheline Yvette I. , Price Joseph L. , Yan Zhizi , Mintun Mark A.
Published: June 2010

To better understand intrinsic brain connections in major depression, we used a neuroimaging technique that measures resting state functional connectivity using functional MRI (fMRI). Three different brain networks—the cognitive control network, default mode network, and affective network—were investigated. Compared with controls, in depressed subjects each of these three networks had increased connectivity to the same bilateral dorsal medial prefrontal cortex region, an area that we term the dorsal nexus. The dorsal nexus demonstrated dramatically increased depression-associated fMRI connectivity with large portions of each of the three networks. The discovery that these regions are linked together through the dorsal nexus provides a potential mechanism to explain how symptoms of major depression thought to arise in distinct networks—decreased ability to focus on cognitive tasks, rumination, excessive self-focus, increased vigilance, and emotional, visceral, and autonomic dysregulation—could occur concurrently and behave synergistically. It suggests that the newly identified dorsal nexus plays a critical role in depressive symptomatology, in effect “hot wiring” networks together; it further suggests that reducing increased connectivity of the dorsal nexus presents a potential therapeutic target.
Evolution of multicomponent pheromone signals in small ermine moths involves a single fatty-acyl reductase gene
Authors: Liénard Marjorie A. , Hagström Åsa K. , Lassance Jean-Marc , Löfstedt Christer
Published: June 2010

Fatty-acyl CoA reductases (FAR) convert fatty acids into fatty alcohols in pro- and eukaryotic organisms. In the Lepidoptera, members of the
FAR
gene family serve in the biosynthesis of sex pheromones involved in mate communication. We used a group of closely related species, the small ermine moths (Lepidoptera: Yponomeutidae) as a model to investigate the role of FARs in the biosynthesis of complex pheromone blends. Homology-based molecular cloning in three
Yponomeuta
species led to the identification of multiple putative FAR transcripts homologous to
FAR
genes from the
Bombyx mori
genome. The expression of one transcript was restricted to the female pheromone-gland tissue, suggesting a role in pheromone biosynthesis, and the encoded protein belonged to a recently identified Lepidoptera-specific
pgFAR
gene subfamily. The
Yponomeuta evonymellus pgFAR
mRNA was up-regulated in sexually mature females and exhibited a 24-h cyclic fluctuation pattern peaking in the pheromone production period. Heterologous expression confirmed that the
Yponomeuta pgFAR
orthologs in all three species investigated [
Y. evonymellus
(L.),
Yponomeuta padellus
(L.), and
Yponomeuta rorellus
(Hübner)] encode a functional FAR with a broad substrate range that efficiently promoted accumulation of primary alcohols in recombinant yeast supplied with a series of biologically relevant C14- or C16-acyl precursors. Taken together, our data evidence that a single alcohol-producing pgFAR played a critical function in the production of the multicomponent pheromones of yponomeutids and support the hypothesis of moth pheromone-biosynthetic FARs belonging to a
FAR
gene subfamily unique to Lepidoptera.
Unconscious inhibition separates two forms of cognitive control
Authors: Boy Frederic , Husain Masud , Sumner Petroc
Published: June 2010

In the human brain, cognitive-control processes are generally considered distinct from the unconscious mechanisms elicited by subliminal priming. Here, we show that cognitive control engaged in situations of response conflict interacts with the negative (inhibitory) phase of subliminal priming. Thus, cognitive control may surprisingly share common processes with nonconscious brain mechanisms. In contrast, our findings reveal that subliminal inhibition does not, however, interact with control adaptation—the supposed modulation of current control settings by previous experience of conflict. Therefore, although influential models have grouped immediate cognitive control and control adaptation together as products of the same conflict detection and control network, their relationship to subliminal inhibition separates them. Overall, these results suggest that the important distinction lies not between cognitive or top-down processes on the one hand and nonconscious priming mechanisms on the other hand but between responsive (poststimulus) mechanisms that deal with sensorimotor activation after it has occurred and preparatory (prestimulus) mechanisms that are modulated before stimulus arrival.
Imaging of enzyme replacement therapy using PET
Authors: Phenix Christopher P. , Rempel Brian P. , Colobong Karen , Doudet Doris J. , Adam Michael J. , Clarke Lorne A. , Withers Stephen G.
Published: June 2010

Direct enzyme replacement therapy (ERT) has been introduced as a means to treat a number of rare, complex genetic conditions associated with lysosomal dysfunction. Gaucher disease was the first for which this therapy was applied and remains the prototypical example. Although ERT using recombinant lysosomal enzymes has been shown to be effective in altering the clinical course of Gaucher disease, Fabry disease, Hurler syndrome, Hunter syndrome, Maroteaux-Lamy syndrome, and Pompe disease, the recalcitrance of certain disease manifestations underscores important unanswered questions related to dosing regimes, tissue half-life of the recombinant enzyme and the ability of intravenously administered enzyme to reach critical sites of known disease pathology. We have developed an innovative method for tagging acid β-glucocerebrosidase (GCase), the recombinant enzyme formulated in Cerezyme® used to treat Gaucher disease, using an
18
F-labeled substrate analogue that becomes trapped within the active site of the enzyme. Using micro-PET we show that the tissue distribution of injected enzyme can be imaged in a murine model and that the PET data correlate with tissue
18
F counts. Further we show that PET imaging readily monitors pharmacokinetic changes effected by receptor blocking. The ability to
18
F-label GCase to monitor the enzyme distribution and tissue half-life in vivo by PET provides a powerful research tool with an immediate clinical application to Gaucher disease and a clear path for application to other ERTs.
Protein complexing in a methanogen suggests electron bifurcation and electron delivery from formate to heterodisulfide reductase
Authors: Costa Kyle C. , Wong Phoebe M. , Wang Tiansong , Lie Thomas J. , Dodsworth Jeremy A. , Swanson Ingrid , Burn June A. , Hackett Murray , Leigh John A.
Published: June 2010

In methanogenic Archaea, the final step of methanogenesis generates methane and a heterodisulfide of coenzyme M and coenzyme B (CoM-S-S-CoB). Reduction of this heterodisulfide by heterodisulfide reductase to regenerate HS-CoM and HS-CoB is an exergonic process. Thauer et al. [Thauer, et al. 2008
Nat Rev Microbiol
6:579–591] recently suggested that in hydrogenotrophic methanogens the energy of heterodisulfide reduction powers the most endergonic reaction in the pathway, catalyzed by the formylmethanofuran dehydrogenase, via flavin-based electron bifurcation. Here we present evidence that these two steps in methanogenesis are physically linked. We identify a protein complex from the hydrogenotrophic methanogen,
Methanococcus maripaludis
, that contains heterodisulfide reductase, formylmethanofuran dehydrogenase, F
420
-nonreducing hydrogenase, and formate dehydrogenase. In addition to establishing a physical basis for the electron-bifurcation model of energy conservation, the composition of the complex also suggests that either H
2
or formate (two alternative electron donors for methanogenesis) can donate electrons to the heterodisulfide-H
2
via F
420
-nonreducing hydrogenase or formate via formate dehydrogenase. Electron flow from formate to the heterodisulfide rather than the use of H
2
as an intermediate represents a previously unknown path of electron flow in methanogenesis. We further tested whether this path occurs by constructing a mutant lacking F
420
-nonreducing hydrogenase. The mutant displayed growth equal to wild-type with formate but markedly slower growth with hydrogen. The results support the model of electron bifurcation and suggest that formate, like H
2
, is closely integrated into the methanogenic pathway.
Crystal structure of soluble MD-1 and its interaction with lipid IVa
Authors: Yoon Sung-il , Hong Minsun , Han Gye Won , Wilson Ian A.
Published: June 2010

Lipopolysaccharide (LPS) of Gram-negative bacteria is a common pathogen-associated molecular pattern (PAMP) that induces potent innate immune responses. The host immune response against LPS is triggered by myeloid differentiation factor 2 (MD-2) in association with Toll-like receptor 4 (TLR4) on the cell surface. The MD-2/TLR4-mediated LPS response is regulated by the evolutionarily related complex of MD-1 and Toll-like receptor homolog RP105. Here, we report crystallographic and biophysical data that demonstrate a previously unidentified direct interaction of MD-1 with LPS. The crystal structure of chicken MD-1 (cMD-1) at 2.0 Å resolution exhibits a β-cup-like fold, similar to MD-2, that encloses a hydrophobic cavity between the two β-sheets. A lipid-like moiety was observed inside the cavity, suggesting the possibility of a direct MD-1/LPS interaction. LPS was subsequently identified as an MD-1 ligand by native gel electrophoresis and gel filtration analyses. The crystal structure of cMD-1 with lipid IVa, an LPS precursor, at 2.4 Å resolution revealed that the lipid inserts into the deep hydrophobic cavity of the β-cup-like structure, but with some important differences compared with MD-2. These findings suggest that soluble MD-1 alone, in addition to its complex with RP105, can regulate host LPS sensitivity.
Altered ultrasonic vocalizations in a tuberous sclerosis mouse model of autism
Authors: Young David M. , Schenk A. Katrin , Yang Shi-Bing , Jan Yuh Nung , Jan Lily Yeh
Published: June 2010

Tuberous sclerosis (TSC) is an autosomally dominant neurocutaneous disease notable for its high comorbidity with autism in human patients. Studies of murine models of tuberous sclerosis have found defects in cognition and learning, but thus far have not uncovered deficits in social behaviors relevant to autism. To explore social communication and interaction in TSC2 heterozygous mice, we recorded ultrasonic vocalizations (USV) and found that although both wild-type (WT) and heterozygous pups born to WT dams showed similar call rates and patterns, baseline vocalization rates were elevated in pups born to heterozygous dams. Further analysis revealed several robust features of maternal potentiation in all but WT pups born to heterozygous dams. This lack of potentiation is suggestive of defects in mother–pup social interaction during or before the reunion period between WT pups and heterozygous dams. Intriguingly, male pups of both genotypes born to heterozygous dams showed particularly heightened call rates and burst patterns. Because our maternal retrieval experiments revealed that TSC2
+/−
dams exhibited improved defensive reactions against intruders and highly efficient pup retrieval performance, the alterations in their pups’ USVs and maternal potentiation do not appear to result from poor maternal care. These findings suggest that a pup's interaction with its mother strongly influences the pup's vocal communication, revealing an intriguing dependence of this social behavior on TSC2 gene dosage of both parties involved. Our study of this murine model thus uncovers social abnormalities that arise from TSC haploinsufficiency and are suggestive of autism.
A constitutively activated form of the p110β isoform of PI3-kinase induces prostatic intraepithelial neoplasia in mice
Authors: Lee Sang Hyun , Poulogiannis George , Pyne Saumyadipta , Jia Shidong , Zou Lihua , Signoretti Sabina , Loda Massimo , Cantley Lewis Clayton , Roberts Thomas M.
Published: June 2010

Recent work has shown that ablation of p110β, but not p110α, markedly impairs tumorigenesis driven by loss of phosphatase and tensin homolog (PTEN) in the mouse prostate. Other laboratories have reported complementary data in human prostate tumor lines, suggesting that p110β activation is necessary for tumorigenesis driven by PTEN loss. Given the multiple functions of PTEN, we wondered if p110β activation also is sufficient for tumorigenesis. Here, we report that transgenic expression of a constitutively activated p110β allele in the prostate drives prostate intraepithelial neoplasia formation. The resulting lesions are similar to, but are clearly distinct from, the ones arising from PTEN loss or Akt activation. Array analyses of transcription in multiple murine prostate tumor models featuring PI3K/AKT pathway activation allowed construction of a pathway signature that may be useful in predicting the prognosis of human prostate tumors.
Mixed T cell receptor dimers harbor potentially harmful neoreactivity
Authors: van Loenen Marleen M. , de Boer Renate , Amir Avital L. , Hagedoorn Renate S. , Volbeda Gerdien L. , Willemze Roelof , van Rood Johannes J. , Falkenburg J. H. Frederik , Heemskerk Mirjam H. M.
Published: June 2010

Adoptive transfer of T cell receptor (TCR)-transduced T cells may be an attractive strategy to target both hematological malignancies and solid tumors. By introducing a TCR, large numbers of T cells with defined antigen (Ag) specificity can be obtained. However, by introduction of a TCR, mixed TCR dimers can be formed. Besides the decrease in TCR expression of the introduced and endogenous TCR, these mixed TCR dimers could harbor potentially harmful specificities. In this study, we demonstrate that introduction of TCRs resulted in formation of neoreactive mixed TCR dimers, composed of the introduced TCR chains pairing with either the endogenous TCR α or β chain. Neoreactivities observed were HLA class I or class II restricted. Most neoreactive mixed TCR dimers were allo-HLA reactive; however, neoreactive mixed TCR dimers with autoreactive activity were also observed. We demonstrate that inclusion of an extra disulfide bond between the constant domains of the introduced TCR markedly reduced neoreactivity, whereas enhanced effectiveness of the introduced TCR was observed. In conclusion, TCR transfer results in the formation of neoreactive mixed TCR dimers with the potential to generate off-target effects, underlining the importance of searching for techniques to facilitate preferential pairing.
Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndrome
Authors: Quintana Albert , Kruse Shane E. , Kapur Raj P. , Sanz Elisenda , Palmiter Richard D.
Published: June 2010

To explore the lethal, ataxic phenotype of complex I deficiency in Ndufs4 knockout (KO) mice, we inactivated Ndufs4 selectively in neurons and glia (NesKO mice). NesKO mice manifested the same symptoms as KO mice including retarded growth, loss of motor ability, breathing abnormalities, and death by ~7 wk. Progressive neuronal deterioration and gliosis in specific brain areas corresponded to behavioral changes as the disease advanced, with early involvement of the olfactory bulb, cerebellum, and vestibular nuclei. Neurons, particularly in these brain regions, had aberrant mitochondrial morphology. Activation of caspase 8, but not caspase 9, in affected brain regions implicate the initiation of the extrinsic apoptotic pathway. Limited caspase 3 activation and the predominance of ultrastructural features of necrotic cell death suggest a switch from apoptosis to necrosis in affected neurons. These data suggest that dysfunctional complex I in specific brain regions results in progressive glial activation that promotes neuronal death that ultimately results in mortality.
Ribosome recycling step in yeast cytoplasmic protein synthesis is catalyzed by eEF3 and ATP
Authors: Kurata Shinya , Nielsen Klaus H. , Mitchell Sarah F. , Lorsch Jon R. , Kaji Akira , Kaji Hideko
Published: June 2010

After each round of protein biosynthesis, the posttermination complex (PoTC) consisting of a ribosome, mRNA, and tRNA must be disassembled into its components for a new round of translation. Here, we show that a
Saccharomyces cerevisiae
model PoTC was disassembled by ATP and eukaryotic elongation factor 3 (eEF3). GTP or ITP functioned with less efficiency and adenosine 5γ′-(β,γ-imido)triphosphate did not function at all. The
k
cat
of eEF3 was 1.12 min
-1
, which is comparable to that of the in vitro initiation step. The disassembly reaction was inhibited by aminoglycosides and cycloheximide. The subunits formed from the yeast model PoTC remained separated under ionic conditions close to those existing in vivo, suggesting that they are ready to enter the initiation process. Based on our experimental techniques used in this paper, the release of mRNA and tRNA and ribosome dissociation took place simultaneously. No 40S•mRNA complex was observed, indicating that eEF3 action promotes ribosome recycling, not reinitiation.
Stereodynamics of O(3P) +H2 at Scattering Energies of 0.5, 0.75, and 1.0 eV
Authors: Wei-keh Wu Victor
Published: June 2010

Quasiclassical trajectory calculation of the title reaction O(3P)+H2→OH+H at three different scattering energies of 0.5, 0.75, and 1.0 eV on the lowest electronic potential energy surface 13A" has been done. Distribution P(θr) of polar angles between the relative velocity k of the reactant and rotational angular momentum vector j' of the product, distribution (P∈r) of the azimuthal as well as dihedral angles correlating k-k'-j', 3-dimensional distribution, and polarization-dependent differential cross sections (PDDCSs) dependent upon the scattering angle of the product molecule OH between the relative velocity k of the reactant and k' of the product at different scattering energies of 0.5, 0.75, and 1.0 eV are presented and discussed.
Improved Calculation of Vibrational Energy Levels in F2 Molecule using the RKR Method
Authors: Wang Jian-kun , Wu Zhen-sen
Published: June 2010

The potential energy curves of the ground state X2Σ+g of the fluorine molecule have been accurately reconstructed employing the Ryderg-Klein-Rees (RKR) method extrapolated by a Hulburt and Hirschfeler potential function for longer internuclear distances. Solving the corresponding radial one-dimensional Schrödinger equation of nuclear motion yields 22 bound vibrational levels above v = 0. The comparison of these theoretical levels with the experimental data yields a mean absolute deviation of about 7.6 cm−1 over the 23 levels. The highest vibrational level energy obtained using this method is 13308.16 cm−1 and the relative deviation compared with the experimental datum of 13408.49 cm−1 is only 0.74%. The value from our method is much closer and more accurate than the value obtained by the quantum mechanical ab initio method by Bytautas. The reported agreement of the vibrational levels and dissociation energy with experiment is contingent upon the potential energy curve of the F2 ground state.
Statistical Thermodynamic Properties of Linear Protein Solutions
Authors: Li Li-fen , Liang Xi-xia , Li Qian-zhong
Published: June 2010

The thermodynamic properties of linear protein solutions are discussed by a statistical mechanics theory with a lattice model. The numerical results show that the Gibbs function of the solution decreases, and the protein chemical potential is enhanced with increase of the protein concentration for dilute solutions. The influences of chain length and temperature on the Gibbs function of the solution as well as the protein chemical potential are analyzed. As an application of the theory, the chemical potentials of some mutants of type I antifreeze proteins are computed and discussed.
Ag Deposition Forms and Uniformity on Porous Silicon by Electrochemical Method
Authors: Song Xiao-lan , Xu Da-yu , Yang Hai-ping , Yu Zhen-xing , Qiu Guan-zhou
Published: June 2010

The electrochemical deposition technique was applied to achieve porous silicon (PS) surface passivated with Ag deposition for improving the properties of PS photoluminescence. The relation of Ag depositing forms to current density and the effect of PS hydrophilic surface on deposition uniformity were investigated. The experimental results indicated that there were two critical current densities (maximum and minimum) in which Ag was absent and electroplated on PS surface correspondingly, and the range of current density for deposition of Ag on porous silicon was from 50 μA/cm2 to 400 μA/cm2. The process of changing PS surface from hydrophobic into hydrophilic had positive effect on Ag deposition uniformity. Under the same experimental conditions, PS hydrophobic surface presented uneven Ag deposition. However, hydrophilic surface treated with SC-1 solution was even. Finally, the effect of PS surface passivation with Ag even deposition on photoluminescence intensity and stabilization of PS was studied. It was discovered that Ag passivation inhibited the degradation of PL intensity effectively. In addition, excessive Ag deposition had a quenching effect on room-temperature visible photoluminescence of PS.
Effect of Cyclic Deformation on Magnetorheological Elastomers
Authors: Zhang Wei , Gong Xing-long , Sun Tao-lin , Fan Yan-ceng , Jiang Wan-quan
Published: June 2010

Fatigue properties of magnetorheological elastomer (MRE) samples were investigated based on cis-polybutadiene rubber by using a fatigue test machine. Three MRE samples with iron particles mass fraction of 60%, 70%, and 80% were fabricated, and their properties dependence of three strain amplitudes (50%, 75%, and 100%) were measured. The absolute magnetorheological (MR) effect, storage modulus, and loss modulus of MRE samples after fatigue were evaluated by a modified dynamic mechanical analyzer. The results revealed that MR effect, storage modulus, and loss modulus of MREs containing 80% iron particles depended strongly on the strain amplitudes and the number of cycles, while storage modulus and loss modulus of MREs containing 70% iron particles also depended on the strain amplitudes and the number of cycles but not as strongly as sample which contains 80% iron particles, but the properties of MREs containing 60% iron particles after cyclic deformation were almost independent of the fatigued conditions. In order to investigate the fatigue mechanism of MREs, the sample was carried out with a quasi-static tensile testing and its surface morphology during testing was observed in situ by scanning electron microscopy.
TiO2 Nanoparticles Produced by Electric-Discharge-Nanofluid-Process as Photoelectrode of DSSC
Authors: Chen Sih-li , Su Hung-ting , Chang Ho , Jwo Ching-song , Ju Feng Hsiao
Published: June 2010

Self-made TiO2 nanoparticles were used as photoelectrode material of dye sensitized solar cell. The TiO2 thin film coats through spreading nanoparticles evenly onto the ITO glass via self-made spin-heat platform, and then TiO2 thin film is soaked in the dye N-719 more than 12 h to prepare the photoelectrode device. The TiO2 nanoparticles produced by electric-discharge-nanofluid-process have premium anatase crystal property, and its diameter can be controlled within a range of 20–50 nm. The surface energy zeta potential of nanofluid is from −22 mV to −28.8 mV, it is a stable particle suspension in the deionized water. A trace of surfactant Triton X-100 put upon the surface of ITO glass can produce a uniform and dense TiO2 thin film and heating up the spin platform to 200 °C is able to eliminate mixed surfactant. Self-made TiO2 film presents excellent dye absorption performance and even doesn't need heat treatment procedure to enhance essential property. Results of energy analysis show the thicker film structure will increase the short-circuit current density that causes higher conversion efficiency. But, as the film structure is large and thick, both the open-circuit voltage and fill factor will decline gradually to lead bad efficiency of dye-sensitized solar cell.
CSPP Is a Ciliary Protein Interacting with Nephrocystin 8 and Required for Cilia Formation
Authors: Patzke Sebastian , Redick Sambra , Warsame Abdirashid , Murga-Zamalloa Carlos A. , Khanna Hemant , Doxsey Stephen , Stokke Trond
Published: June 2010

We described previously the cell cycle- and microtubule-related functions of two splice isoforms of the centrosome spindle pole-associated protein (CSPP and CSPP-L). Here, we show that endogenous CSPP isoforms not only localize to centrosomes and the midbody in cycling cells but also extend to the cilia axoneme in postmitotic resting cells. They are required for ciliogenesis in hTERT-RPE1 cells in vitro and are expressed in ciliated renal, retinal, and respiratory cells in vivo. We report that CSPP isoforms require their common C-terminal domain to interact with Nephrocystin 8 (NPHP8/RPGRIP1L) and to form a ternary complex with NPHP8 and NPHP4. We find CSPP-L to be required for the efficient localization of NPHP8 but not NPHP4 to the basal body. The ciliogenesis defect in hTERT-RPE1 cells is, however, not mediated through loss of NPHP8. Similar to the effects of ectopical expression of CSPP-L, cilia length increased in NPHP8-depleted cells. Our results thus suggest that CSPP proteins may be involved in further cytoskeletal organization of the basal body and its primary cilium. To conclude, we have identified a novel, nonmitotic function of CSPP proteins placing them into a ciliary protein network crucial for normal renal and retinal tissue architecture and physiology.
Oxford Handbook of Neurology
Authors: Manji Hadi , Wills Adrian , Kitchen Neil , Dorward Neil , Connelly Sean , Mehta Amrish
Published: June 2010

The Oxford Handbook of Neurology is a practical and concise, quick reference guide for use on the ward and in clinical settings. It includes a wealth of information and invaluable clinical guidance passed down by generations of neurologists, but not often available in textbooks.
Population genomic sequencing of Coccidioides fungi reveals recent hybridization and transposon control
Authors: Neafsey Daniel E. , Barker Bridget M. , Sharpton Thomas J. , Stajich Jason E. , Park Daniel J. , Whiston Emily , Hung Chiung-Yu , McMahan Cody , White Jared , Sykes Sean , Heiman David , Young Sarah , Zeng Qiandong , Abouelleil Amr , Aftuck Lynne , Bessette Daniel , Brown Adam , FitzGerald Michael , Lui Annie , Macdonald J. Pendexter , Priest Margaret , Orbach Marc J. , Galgiani John N. , Kirkland Theo N. , Cole Garry T. , Birren Bruce W. , Henn Matthew R. , Taylor John W. , Rounsley Steven D.
Published: June 2010

We have sequenced the genomes of 18 isolates of the closely related human pathogenic fungi Coccidioides immitis and Coccidioides posadasii to more clearly elucidate population genomic structure, bringing the total number of sequenced genomes for each species to 10. Our data confirm earlier microsatellite-based findings that these species are genetically differentiated, but our population genomics approach reveals that hybridization and genetic introgression have recently occurred between the two species. The directionality of introgression is primarily from C. posadasii to C. immitis, and we find more than 800 genes exhibiting strong evidence of introgression in one or more sequenced isolates. We performed PCR-based sequencing of one region exhibiting introgression in 40 C. immitis isolates to confirm and better define the extent of gene flow between the species. We find more coding sequence than expected by chance in the introgressed regions, suggesting that natural selection may play a role in the observed genetic exchange. We find notable heterogeneity in repetitive sequence composition among the sequenced genomes and present the first detailed genome-wide profile of a repeat-induced point mutation (RIP) process distinctly different from what has been observed in Neurospora. We identify promiscuous HLA-I and HLA-II epitopes in both proteomes and discuss the possible implications of introgression and population genomic data for public health and vaccine candidate prioritization. This study highlights the importance of population genomic data for detecting subtle but potentially important phenomena such as introgression.
Protection of Telomeres 1 Is Required for Telomere Integrity in the Moss Physcomitrella patens
Authors: Shakirov Eugene V. , Perroud Pierre-François , Nelson Andrew D. , Cannell Maren E. , Quatrano Ralph S. , Shippen Dorothy E.
Published: June 2010

In vertebrates, the single-stranded telomeric DNA binding protein Protection of Telomeres 1 (POT1) shields chromosome ends and prevents them from eliciting a DNA damage response. By contrast, Arabidopsis thaliana encodes two divergent full-length POT1 paralogs that do not exhibit telomeric DNA binding in vitro and have evolved to mediate telomerase regulation instead of chromosome end protection. To further investigate the role of POT1 in plants, we established the moss Physcomitrella patens as a new model for telomere biology and a counterpoint to Arabidopsis. The sequence and architecture of the telomere tract is similar in P. patens and Arabidopsis, but P. patens harbors only a single-copy POT1 gene. Unlike At POT1 proteins, Pp POT1 efficiently bound single-stranded telomeric DNA in vitro. Deletion of the P. patens POT1 gene resulted in the rapid onset of severe developmental defects and sterility. Although telomerase activity levels were unperturbed, telomeres were substantially shortened, harbored extended G-overhangs, and engaged in end-to-end fusions. We conclude that the telomere capping function of POT1 is conserved in early diverging land plants but is subsequently lost in Arabidopsis.
Hand dermatitis/eczema: Current management strategy
Authors: SEHGAL Virendra N. , SRIVASTAVA Govind , AGGARWAL Ashok K. , SHARMA Alpna D.
Published: June 2010

Ever since its inception a couple of centuries ago, hand dermatitis/eczema has been in the reckoning. Idiosyncrasies continued to loom large thereafter, till it acquired its appropriate position. Dermatitis/eczema are synonymous, often used to indicate a polymorphic pattern of the inflammation of the skin, characterized by pruritus, erythema and vesiculation. A spectrum delineated into acute sub‐acute and chronic dermatitis of the hands. Pompholyx, recurrent focal palmer peeling, ring, wear and tear and fingertip eczema, apron, discoid eczema, chronic acral dermatitis, gut and patchy papulosquamous eczema are its clinical variants. Occupational dermatitis/eczema may be contributory. Etiological definitions are clinched by detailed history of exogenous and endogenous factors. However, scientific confirmation of the entity is through patch testing by using available antigens.
Increased carbonyl protein level in the stratum corneum of inflammatory skin disorders: A non‐invasive approach
Authors: IWAI Ichiro , SHIMADZU Kiyo , KOBAYASHI Yusuke , HIRAO Tetsuji , ETOU Takafumi
Published: June 2010

The stratum corneum (SC) is the interface of body and environment, and is continuously exposed to oxidative stress, resulting in carbonyl modification of proteins. We have developed a simple and non‐invasive method to assess carbonyl protein (CP) level in the SC, applied it to various kinds of skin, and revealed a link between the stratum corneum carbonylated protein (SCCP) level and water content in the SC. The purpose of the present study is to examine the SCCP level in inflammatory skin disorders associated with xerosis. Psoriasis vulgaris (PV) and atopic dermatitis (AD) are typical inflammatory skin disorders, of which the stratum corneum shows markedly low water content. SC samples were non‐invasively collected from the lesional and non‐lesional areas of PV and AD by adhesive tape stripping, and their carbonyl groups were determined by reaction with fluorescein‐5‐thiosemicarbazide. The average fluorescence intensity of the SC was calculated as SCCP level. Higher SCCP level was observed in the lesional area of PV as compared with non‐lesional area or healthy control. Lesional area of AD also exhibited higher SCCP level than corresponding non‐lesional area, of which SCCP level was slightly higher than the healthy control. These data suggest the involvement of oxidative modification of the SC protein, at least in part, in generation of xerotic skin in inflammatory skin disorders as well as dry skin in healthy subjects.
Serum interleukin‐6 level is reflected in elevated high‐sensitivity C‐reactive protein level in patients with systemic sclerosis
Authors: OHTSUKA Tsutomu
Published: June 2010

Systemic sclerosis (SSc) is a systemic connective tissue disease of unknown etiology which presents immunological, vascular and connective tissue abnormalities. Serum interleukin (IL)‐6 has been reported to be elevated in patients with SSc. Clinical and laboratory findings affecting the elevated level of high‐sensitivity C‐reactive protein (hs‐CRP) were studied in patients with SSc. Clinical and laboratory findings also included serum IL‐6 level. Thirty‐nine SSc patients (male : female = 7:32, age 19–84 years, mean 62.6 years) were studied. hs‐CRP was measured with a nephelometric assay. Serum IL‐6 level was measured by enzyme‐linked immunosorbent assay. The distributions of hs‐CRP showed that 18 cases (46.2%) were not elevated (<0.07 mg/dL), but 21 cases (53.8%) were (≥0.07 mg/dL). Alkaline phosphatase and IL‐6 in SSc patients with elevated hs‐CRP (291 ± 95 U/L, 3.23 ± 2.74 pg/mL) were significantly more elevated than those in not elevated patients (221 ± 75 U/L, 1.53 ± 1.12 pg/mL) (P < 0.02, P < 0.01). The correlation between hs‐CRP level and IL‐6 level in SSc patients was 0.687 (P < 0.001). In conclusion, elevated serum IL‐6 levels are reflected in elevated hs‐CRP levels in SSc patients.
Analysis of clinical, radiological and laboratory variables in psoriatic arthritis with 25 Japanese patients
Authors: MAEJIMA Hideki , TANIGUCHI Tomonori , WATARAI Akira , AKI Ryouichi , KATSUOKA Kensei
Published: June 2010

Psoriatic arthritis (PsA) has many clinical and radiological manifestations but lacks a specific laboratory marker. The aim of the present study was to identify noteworthy features in PsA patients on routine clinical examinations. The subjects were 25 PsA patients who were classified based on the Classification of Psoriatic Arthritis (CASPAR) criteria. The clinical and radiological findings and laboratory parameters were analyzed by retrospective chart review. On clinical examination, dactylitis was present in 13 (52%) of 25 patients, swollen and/or tender Achilles tendons were present in nine (36%), and sacroiliitis was present in eight (32%). Of the radiological features, juxta‐articular new bone formation (JANF) was seen in 12 (48%), extra‐articular new bone formation was seen in nine (36%) and sacroiliitis was seen in six (24%). Dactylitis and JANF had the highest prevalence rates. The Psoriasis Area and Severity Index score, swollen and/or tender joint count, erythrocyte sedimentation rate, C‐reactive protein, and matrix metalloproteinase‐3 were higher in patients with sacroiliitis than in those without sacroiliitis (P < 0.05). Dactylitis, JANF and sacroiliitis may be noteworthy manifestations in Japanese patients with PsA.
Hakai acts as a coregulator of estrogen receptor alpha in breast cancer cells
Authors: Gong Eun‐Yeung , Park Eunsook , Lee Keesook
Published: June 2010

Estrogen receptors play a key role in breast cancer development. One of the current therapeutic strategies for the treatment of estrogen receptor (ER)‐α‐positive breast cancers relies on the blockade of ERα transcriptional activity. In the present study, we characterized Hakai, originally characterized as an E‐cadherin binding protein, as a strong blockade of ERα in breast cancer cells. We showed that Hakai inhibited the transcriptional activity of ERα by binding directly to ERα. The DNA‐binding domain of ERα was found to be responsible for its interaction with Hakai. Hakai competed with ERα coactivators, such as steroid receptor coactivator‐1 (SRC‐1) and glucocoriticord receptor interacting protein‐1 (GRIP‐1), for the modulation of ERα transactivation, while its ubiquitin‐ligase activity was not required. Further, overexpression of Hakai inhibited the proliferation and migration of breast cancer cells. Taken together, these results suggest that Hakai is a novel corepressor of ERα and may play a negative role in the development and progression of breast cancers. (Cancer Sci 2010)
Interpleural analgesia for attenuation of postoperative pain after hepatic resection*
Authors: Weinberg L. , Scurrah N. , Parker F. , Story D. , McNicol L.
Published: June 2010

We performed a prospective randomised trial to evaluate the analgesic efficacy of interpleural analgesia in patients undergoing hepatic resection. The control group (n = 25) received multimodal analgesia with intravenous morphine patient‐controlled analgesia; in addition, the interventional group (n = 25) received interpleural analgesia with a 20‐ml loading dose of levo bupivacaine 0.5% followed by a continuous infusion of levobupivacaine 0.125%. Outcome measures included pain intensity on movement using a visual analogue scale over 24 h, cumulative morphine and rescue analgesia requirements, patient satisfaction, hospital stay and all adverse events. Patients in the interpleural group were less sedated and none required treatment for respiratory depression compared to 6 (24%) in the control group (p< 0.01). Patients in the interpleural group also had lower pain scores during movement in the first 24 h. Patients’ satisfaction, opioid requirements and duration of hospital stay were similar. We conclude that continuous interpleural analgesia augments intravenous morphine analgesia, decreases postoperative sedation and reduces respiratory depression after hepatic resection.
A comparison of the Glidescope® and Karl Storz DCI® videolaryngoscopes in a paediatric manikin*
Authors: Hurford D. M. , White M. C.
Published: June 2010

A new paediatric Glidescope® (Cobalt GVL® Stat) has recently become available. This varies in design from the Karl Storz DCI® videolaryngoscope, as it possesses a short curved disposable blade compared with the narrower straighter blade of the Storz®. We compared the time taken for tracheal intubation under normal and difficult intubation conditions in a paediatric manikin. A total of 32 anaesthetists completed four intubations in a random order, with each participant blinded to the airway condition. We hypothesised there would be no difference between the devices. The results showed no difference in tracheal intubation time between the Glidescope and the Storz videolaryngoscope. The mean (SD) times under normal conditions were 18.8 (5.2) s vs 19.9 (6.1) s, (p = 0.16), respectively. Under difficult conditions the times were 22.6 (10.5) vs 27.0 (14.2) s, (p = 0.13), respectively. There were no differences in the visual analogue scores for field of view, ease of use, willingness to use in an emergency, and overall satisfaction.
Deep pore pressures and seafloor venting in the Auger Basin, Gulf of Mexico
Authors: Reilly Matthew J. , Flemings Peter B.
Published: June 2010

Pore fluid overpressures in four reservoir sandstones in the Auger Basin, deepwater Gulf of Mexico, are similar across the basin, suggesting that these sandstones are hydraulically connected over distances >20 km. Small overpressure gradients within them suggest upward flow rates between 1 and 20 mm year−1. At the crest of these sandstones, pore pressure equals or exceeds the least principal stress, and we interpret that high fluid pressure is fracturing the caprock and driving flow vertically. A well drilled into the crest of the Auger sandstones confirmed the presence of extreme overpressures that converge on both the least principal stress and the overburden stress. Above these zones, spectacular mud volcanoes are venting fluids today. Overpressured aquifers with significant structural relief may drive fluid vents and mud volcanoes around the world.
Impaired irinotecan biotransformation in hepatic microsomal fractions from patients with chronic liver disease
Authors: D'Esposito Fabrizio , Nebot Noelia , Edwards Robert J. , Murray Michael
Published: June 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The anticancer agent irinotecan is a prodrug that is hydrolyzed by hepatic carboxylesterase to its active and toxic metabolite SN‐38 and oxidized by CYP3A4 to its inactive metabolite APC.

• Irinotecan therapy is complicated by co‐administered drugs that inhibit CYP3A4 and decrease APC formation and that indirectly increase SN‐38 formation.

• Dose adjustment in cancer patients with liver disease has been recommended.

WHAT THIS STUDY ADDS

• In microsomal fractions from patients with severe hepatic dysfunction both APC and SN‐38 formation were decreased due to down‐regulation of CYP3A4 and carboxylesterase enzymes. Thus relative SN‐38 : APC formation was preserved.

• In some fractions the SN‐38 : APC ratio was increased, thus providing a possible explanation for clinical reports of increased SN‐38 exposure in some patients with liver dysfunction.

• Close monitoring of SN‐38 formation in patients with severe liver disease is warranted.

AIMS

Dose modification with the anticancer agent irinotecan is recommended in patients with severe liver dysfunction. This study evaluated the impact of liver disease on the relative formation of phase I products of irinotecan biotransformation in human microsomesin vitro.

METHODS

Microsomes from subjects with normal liver function and liver dysfunction (n = 20) were assessed for irinotecan biotransformation and the expression of cytochrome P450 (CYP) 3A4 and carboxylesterase (CES) enzymes.

RESULTS

Liver disease down‐regulated CYP3A4 expression (median 33% of control, range 0–126%,P < 0.05) and impaired CYP3A4‐dependent oxidation of irinotecan to the inactive 7‐ethyl‐10‐[4‐N‐(5‐aminopentanoic acid)‐1‐piperidino]carbonyloxycamptothecin (APC) (median 0.2, range 0–1.21 pmol mg protein−1 min−1compared with median 0.66, range 0–2.35 in control,P < 0.01). CES‐mediated hydrolysis of irinotecan to 7‐ethyl‐10‐hydroxycamptothecin (SN‐38) was also impaired in liver disease (median 8.38, range 0–20.7 pmol mg protein−1 min−1compared with median 13.3, range 0–28.9 in control,P < 0.05). In seven of 20 liver disease microsomes neither metabolite was detected but in three the SN‐38 : APC ratio was high (41–68) compared with the remaining 10 samples (ratio 11–36).

CONCLUSIONS

Down‐regulation of CYP3A4 in liver disease decreased APC formation from irinotecan. SN‐38 production was decreased and CES1 and 2 were down‐regulated in most samples. However, in a subset of disease samples SN‐38 production was relatively high because CYP3A4 activity was markedly impaired. This may account for clinical reports of increased SN‐38 exposure in some patients with liver disease. Dose adjustments in cancer patients with liver disease who receive irinotecan are important and circulating SN‐38 concentrations should be monitored closely.
Predictors of parents seeking help or advice about children's communication development in the early years
Authors: Skeat J. , Eadie P. , Ukoumunne O. , Reilly S.
Published: June 2010

Background  Children's access to services for communication disorders is often determined by parental decisions to seek help or advice. The factors that predict whether parents seek help/advice about their child's communication development were explored in this study.

Methods  Parents of children in a large, community cohort of children (the Early Language in Victoria Study) were asked whether they had sought help or advice about speech and language development at 1, 2, 3 and 4 years. Child, family and environmental variables, as well as parental concern and children's communication status, were used to predict help/advice seeking. The communication abilities of those in the help‐seeking group were also evaluated.

Results  Gender, age, children's communication status and parental concern were consistent predictors of help/advice seeking. Significant over and under‐identification was evident, and there was preliminary evidence that children with overt communication difficulties (such as unintelligible speech) were more likely to receive help.

Conclusions  Parental support and education, as well as education of professionals who regularly have contact with young children, is necessary to support appropriate early identification of communication problems. Further research into service level factors such as availability and accessibility which may support or inhibit help/advice seeking is also indicated.