bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2
Authors: Krintel Christian , Frydenvang Karla , Olsen Lars , Kristensen Maria T. , de Barrios Oriol , Naur Peter , Francotte Pierre , Pirotte Bernard , Gajhede Michael , Kastrup Jette S.
Published: September 2011

Positive allosteric modulators of the ionotropic glutamate receptor-2 (GluA2) are promising compounds for the treatment of cognitive disorders, e.g. Alzheimer's disease. These modulators bind within the dimer interface of the LBD (ligand-binding domain) and stabilize the agonist-bound conformation slowing receptor desensitization and/or deactivation. In the present study, we employ isothermal titration calorimetry to determine binding affinities and thermodynamic details of binding of modulators of GluA2. A mutant of the LBD of GluA2 (LBD-L483Y-N754S) that forms a stable dimer in solution was used. The potent GluA2 modulator BPAM-97 was used as a reference compound. Evidence that BPAM-97 binds in the same pocket as the well-known GluA2 modulator cyclothiazide was obtained from X-ray structures. The LBD-L483Y-N754S:BPAM-97 complex has a Kd of 5.6 μM (ΔH=−4.9 kcal/mol, −TΔS=−2.3 kcal/mol; where 1 kcal≈4.187 kJ). BPAM-97 was used in a displacement assay to determine a Kd of 0.46 mM (ΔH=−1.2 kcal/mol, −TΔS=−3.3 kcal/mol) for the LBD-L483Y-N754S:IDRA-21 complex. The major structural factors increasing the potency of BPAM-97 over IDRA-21 are the increased van der Waals contacts to, primarily, Met496 in GluA2 imposed by the ethyl substituent of BPAM-97. These results add important information on binding affinities and thermodynamic details, and provide a new tool in the development of drugs against cognitive disorders.
Intracellular curvature-generating proteins in cell-to-cell fusion
Authors: Richard Jean-Philippe , Leikina Evgenia , Langen Ralf , Henne William Mike , Popova Margarita , Balla Tamas , McMahon Harvey T. , Kozlov Michael M. , Chernomordik Leonid V.
Published: September 2011

Cell-to-cell fusion plays an important role in normal physiology and in different pathological conditions. Early fusion stages mediated by specialized proteins and yielding fusion pores are followed by a pore expansion stage that is dependent on cell metabolism and yet unidentified machinery. Because of a similarity of membrane bending in the fusion pore rim and in highly curved intracellular membrane compartments, in the present study we explored whether changes in the activity of the proteins that generate these compartments affect cell fusion initiated by protein fusogens of influenza virus and baculovirus. We raised the intracellular concentration of curvature-generating proteins in cells by either expressing or microinjecting the ENTH (epsin N-terminal homology) domain of epsin or by expressing the GRAF1 (GTPase regulator associated with focal adhesion kinase 1) BAR (Bin/amphiphysin/Rvs) domain or the FCHo2 (FCH domain-only protein 2) F-BAR domain. Each of these treatments promoted syncytium formation. Cell fusion extents were also influenced by treatments targeting the function of another curvature-generating protein, dynamin. Cell-membrane-permeant inhibitors of dynamin GTPase blocked expansion of fusion pores and dominant-negative mutants of dynamin influenced the syncytium formation extents. We also report that syncytium formation is inhibited by reagents lowering the content and accessibility of PtdIns(4,5)P2, an important regulator of intracellular membrane remodelling. Our findings indicate that fusion pore expansion at late stages of cell-to-cell fusion is mediated, directly or indirectly, by intracellular membrane-shaping proteins.
Insights into the mechanisms underlying CFTR channel activity, the molecular basis for cystic fibrosis and strategies for therapy
Authors: Chiaw Patrick Kim , Eckford Paul D.W. , Bear Christine E.
Published: September 2011

Mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) cause CF (cystic fibrosis), a fatal genetic disease commonly leading to airway obstruction with recurrent airway inflammation and infection. Pulmonary obstruction in CF has been linked to the loss of CFTR function as a regulated Cl− channel on the lumen-facing membrane of the epithelium lining the airways. We have learned much about the molecular basis for nucleotide- and phosphorylation-dependent regulation of channel activity of the normal (wild-type) version of the CFTR protein through electrophysiological studies. The major CF-causing mutation, F508del-CFTR, causes the protein to misfold and be retained in the ER (endoplasmic reticulum). Importantly, recent studies in cell culture have shown that retention in the ER can be ‘corrected’ through the application of certain small-molecule modulators and, once at the surface, the altered channel function of the major mutant can be ‘potentiated’, pharmacologically. Importantly, two such small molecules, a ‘corrector’ (VX-809) and a ‘potentiator’ (VX-770) compound are undergoing clinical trial for the treatment of CF. In this chapter, we describe recent discoveries regarding the wild-type CFTR and F508del-CFTR protein, in the context of molecular models based on X-ray structures of prokaryotic ABC (ATP-binding cassette) proteins. Finally, we discuss the promise of small-molecule modulators to probe the relationship between structure and function in the wild-type protein, the molecular defects caused by the most common mutation and the structural changes required to correct these defects.
The TAP translocation machinery in adaptive immunity and viral escape mechanisms
Authors: Abele Rupert , Tampé Robert
Published: September 2011

The adaptive immune system plays an essential role in protecting vertebrates against a broad range of pathogens and cancer. The MHC class I-dependent pathway of antigen presentation represents a sophisticated cellular machinery to recognize and eliminate infected or malignantly transformed cells, taking advantage of the proteasomal turnover of the cell's proteome. TAP (transporter associated with antigen processing) 1/2 (ABCB2/3, where ABC is ATP-binding cassette) is the principal component in the recognition, translocation, chaperoning, editing and final loading of antigenic peptides on to MHC I complexes in the ER (endoplasmic reticulum) lumen. These different tasks are co-ordinated within a dynamic macromolecular peptide-loading complex consisting of TAP1/2 and various auxiliary factors, such as the adapter protein tapasin, the oxidoreductase ERp57, the lectin chaperone calreticulin, and the final peptide acceptor the MHC I heavy chain associated with β2-microglobulin. In this chapter, we summarize the structural organization and molecular mechanism of the antigen-translocation machinery as well as various modes of regulation by viral factors and in genetic diseases and tumour development.
Zero-β modeling of coaxial helicity injection in the HIT-II spherical torus
Authors: Bayliss R. A. , Sovinec C. R. , Redd A. J.
Published: September 2011

Coaxial helicity injection in the HIT-II [A. J. Redd et al., Phys. Plasmas 9, 2006 (2002)] spherical torus is modeled with time-dependent resistive magnetohydrodynamics computations run to steady state for conditions without strong relaxation. Laboratory and computed results on injector current and plasma current agree reasonably well as toroidal magnetic field and injector flux are scaled. The scalings are consistent with a dimensional estimate from the Grad-Shafranov equation that provides a new perspective on a previously published model based on a current-sheet equilibrium and the magnetic pressure required for the “bubble-burst” criterion. Numerical solutions of the Grad-Shafranov equation with an assumed current profile also indicate large qualitative changes as the predicted criterion is crossed.
Towards a fully kinetic 3D electromagnetic particle-in-cell model of streamer formation and dynamics in high-pressure electronegative gases
Authors: Rose D. V. , Welch D. R. , Clark R. E. , Thoma C. , Zimmerman W. R. , Bruner N. , Rambo P. K. , Atherton B. W.
Published: September 2011

Streamer and leader formation in high pressure devices is dynamic process involving a broad range of physical phenomena. These include elastic and inelastic particle collisions in the gas, radiation generation, transport and absorption, and electrode interactions. Accurate modeling of these physical processes is essential for a number of applications, including high-current, laser-triggered gas switches. Towards this end, we present a new 3D implicit particle-in-cell simulation model of gas breakdown leading to streamer formation in electronegative gases. The model uses a Monte Carlo treatment for all particle interactions and includes discrete photon generation, transport, and absorption for ultra-violet and soft x-ray radiation. Central to the realization of this fully kinetic particle treatment is an algorithm that manages the total particle count by species while preserving the local momentum distribution functions and conserving charge [D. R. Welch, T. C. Genoni, R. E. Clark, and D. V. Rose, J. Comput. Phys. 227, 143 (2007)]. The simulation model is fully electromagnetic, making it capable of following, for example, the evolution of a gas switch from the point of laser-induced localized breakdown of the gas between electrodes through the successive stages of streamer propagation, initial electrode current connection, and high-current conduction channel evolution, where self-magnetic field effects are likely to be important. We describe the model details and underlying assumptions used and present sample results from 3D simulations of streamer formation and propagation in SF6.
Theory of reversible associative-dissociative diffusion-influenced chemical reaction. I. Geminate reaction
Authors: Doktorov Alexander B. , Kipriyanov Alexey A.
Published: September 2011

A many-particle, in the general case, inhomogeneous reacting system of independent pairs of reactants, where geminate reversible reaction \documentclass[12pt]{minimal}\begin{document}$A+B\rightleftarrows C$\end{document}A+B⇄C takes place, is considered in the framework of the kinetic theory approach. The kinetic equations in the thermodynamic limit are obtained, and important relations between kinetic coefficients characterizing the reaction course are established, as well as the relations between the kinetic dependencies under different initial conditions including the relations that extend the familiar literature results to the case of rather realistic model of the reacting system. Universal long-term kinetic laws of the reaction course are determined.
Computer simulations of thermo-shrinking polyelectrolyte gels
Authors: Quesada-Pérez Manuel , Guadalupe Ibarra-Armenta José , Martín-Molina Alberto
Published: September 2011

In this work, thermo-responsive polyelectrolyte gels have been simulated using polymer networks of diamond-like topology in the framework of the primitive model. Monte Carlo simulations were performed in the canonical ensemble and a wide collection of situations has been systematically analysed. Unlike previous studies, our model includes an effective solvent-mediated potential for the hydrophobic interaction between non-bonded polymer beads. This model predicts that the strength of the attractive hydrophobic forces increases with temperature, which plays a key role in the explanation of the thermo-shrinking behaviour of many real gels. Although this hydrophobic model is simple (and it could overestimate the interactions at high temperature), our simulation results qualitatively reproduce several features of the swelling behaviour of real gels and microgels reported by experimentalists. This agreement suggests that the effective solvent-mediated polymer-polymer interaction used here is a good candidate for hydrophobic interaction. In addition, our work shows that the functional form of the hydrophobic interaction has a profound influence on the swelling behaviour of polyelectrolyte gels. In particular, systems with weak hydrophobic forces exhibit discontinuous volume changes, whereas gels with strong hydrophobic forces do not show hallmarks of phase transitions, even for highly charged polyelectrolyte chains.
Analysis of Ce3+ luminescence quenching in solid solutions between Y3Al5O12 and Y3Ga5O12 by temperature dependence of photoconductivity measurement
Authors: Ueda Jumpei , Tanabe Setsuhisa , Nakanishi Takayuki
Published: September 2011

Photocurrent excitation spectra were measured to investigate the quenching in the garnet solid solutions. Intense photocurrent excitation bands attributed to the lowest 5d1 and the second lowest 5d2 levels were observed in the Ce-doped Y3Al2Ga3O12 (Ce:YAGG) and Y3Ga5O12 (Ce:YGG). Based on the results of temperature dependence of photoconductivity, the 5d1 and 5d2 levels in the Ce:YAGG are found to be located below and within the conduction band, respectively, while both levels in the Ce:YGG are found to be located within its conduction band located at lower energy levels. In addition, the threshold of photoionization from the 4f level of Ce3+ to the conduction band in the Ce:YAGG and Ce:YGG were estimated to be 3.2, and 2.8 eV, respectively. We conclude that the main quenching process in the Ce:YAGG is caused by the thermally stimulated ionization process with activation energy of 90 meV from the 5d1 to the conduction band, and that in the Ce:YGG is caused by the direct ionization process from the 5d levels to the conduction band.
Nitrogen nuclear spin flips in nitroxide spin probes of different sizes in glassy o-terphenyl: Possible relation with α- and β-relaxations
Authors: Isaev N. P. , Dzuba S. A.
Published: September 2011

The pulsed electron-electron double resonance (ELDOR) technique was employed to study nitroxide spin probes of three different sizes dissolved in glassy o-terphenyl. A microwave pulse applied to the central hyperfine structure (hfs) component of the nitroxide electron paramagnetic resonance spectrum was followed by two echo-detecting pulses of different microwave frequency to probe the magnetization transfer (MT) to the low-field hfs component. The MT between hfs components is readily related to flips in the nitrogen nuclear spin, which in turn are induced by molecular motion. The MT on the time scale of tens of microseconds was observed over a wide temperature range, including temperatures near and well below the glass transition. For a bulky nitroxide, it was found that MT rates approach dielectric α (primary) relaxation frequencies reported for o-terphenyl in the literature. For small nitroxides, MT rates were found to match the frequencies of dielectric β (secondary) Johari-Goldstein relaxation. The most probable motional mechanism inducing the nitrogen nuclear spin flips is large-angle angular jumps, between some orientations of unequal occupation probabilities. The pulsed ELDOR of nitroxide spin probes may provide additional insight into the nature of Johari-Goldstein relaxation in glassy media and may serve as a tool for studying this relaxation in substances consisting of non-rigid molecules (such as branched polymers) and in heterogeneous and non-polar systems (such as a core of biological membranes).
Note: Cluster temperatures in non-isothermal nucleation
Authors: Barrett Jonathan C.
Published: September 2011

An analytical approximation for the mean cluster energy and, hence, cluster “temperature” is derived for homogeneous nucleation in pure vapor, where latent heat release leads to the cluster temperature differing from that of the surrounding vapor. It is shown that both supercritical and subcritical clusters are warmer than the surrounding vapor. The temperature of large supercritical growing clusters is also considered.
Acoustic reflections on marine populations
Authors: Jaffe Jules S. , Roberts Paul L. D.
Published: September 2011

Armed with a simple diffraction-based model, an acoustic oceanographer can bounce sound off marine animals to learn important information about their size and orientation.
The Place of Zeno's Paradox
Authors: Hemming Laurence Paul
Published: September 2011

This paper begins by examining the recent history of interpretations of one of Zeno's paradoxes of motion, the paradox of dichotomy. It then returns to the record of antiquity to ask how Aristotle ‘solved’ the paradox and what decisions about place and motion were assumed in that solution. After appealing to Heidegger's readings of the Aristotelian text, the paper then proceeds to offer an entirely original interpretation of Zeno's paradox of dichotomy, which has important implications for a contemporary understanding of motion and place (rather than space). Instead, the paradox is read as a provocation to ‘see’ something which Zeno, it would appear, believed was ‘missing’, or had been forgotten and had disappeared, and to review all over again what Parmenides might have meant in his claim that being is one, singular, and indivisible.
MicroRNA-149*, a p53-responsive microRNA, functions as an oncogenic regulator in human melanoma
Authors: Jin Lei , Hu Wang Lai , Jiang Chen Chen , Wang Jia Xu , Han Chuan Chun , Chu Ping , Zhang Lin Jie , Thorne Rick F. , Wilmott James , Scolyer Richard A. , Hersey Peter , Zhang Xu Dong , Wu Mian
Published: September 2011

The tumor suppressor p53 is activated in response to cellular stress to prevent malignant transformation by activation of the DNA repair machinery to preserve the cell, or by induction of apoptosis to eliminate the cell should the damage prove irrevocable. The gene encoding p53 frequently undergoes inactivating mutations in many human cancers, but WT p53 is often expressed at high levels in melanoma, which, as judged from the malignant nature of the disease, fails to act as an effective tumor suppressor. Here we show that p53 directly up-regulates microRNA-149* (miR-149*) that in turn targets glycogen synthase kinase-3α, resulting in increased expression of Mcl-1 and resistance to apoptosis in melanoma cells. Although deficiency in miR-149* undermined survival of melanoma cells and inhibited melanoma growth in a mouse xenograft model, elevated expression of miR-149* was found in fresh human metastatic melanoma isolates, which was associated with decreased glycogen synthase kinase-3α and increased Mcl-1. These results reveal a p53-dependent, miR-149*–mediated pathway that contributes to survival of melanoma cells, provides a rational explanation for the ineffectiveness of p53 to suppress melanoma, and identifies the expression of miR-149* as a mechanism involved in the increased expression of Mcl-1 in melanoma cells.
Kinetically inhibited order in a diamond-lattice antiferromagnet
Authors: MacDougall Gregory J. , Gout Delphine , Zarestky Jerel L. , Ehlers Georg , Podlesnyak Andrey , McGuire Michael A. , Mandrus David , Nagler Stephen E.
Published: September 2011

Frustrated magnetic systems exhibit highly degenerate ground states and strong fluctuations, often leading to new physics. An intriguing example of current interest is the antiferromagnet on a diamond lattice, realized physically in A-site spinel materials. This is a prototypical system in three dimensions where frustration arises from competing interactions rather than purely geometric constraints, and theory suggests the possibility of unusual magnetic order at low temperature. Here, we present a comprehensive single-crystal neutron scattering study of CoAl
2
O
4
, a highly frustrated A-site spinel. We observe strong diffuse scattering that peaks at wavevectors associated with Néel ordering. Below the temperature
T
∗
 = 6.5 K, there is a dramatic change in the elastic scattering lineshape accompanied by the emergence of well-defined spin-wave excitations.
T
∗
had previously been associated with the onset of glassy behavior. Our new results suggest instead that
T
∗
signifies a first-order phase transition, but with true long-range order inhibited by the kinetic freezing of domain walls. This scenario might be expected to occur widely in frustrated systems containing first-order phase transitions and is a natural explanation for existing reports of anomalous glassy behavior in other materials.
Extracellular reduction of uranium via
Geobacter
conductive pili as a protective cellular mechanism
Authors: Cologgi Dena L. , Lampa-Pastirk Sanela , Speers Allison M. , Kelly Shelly D. , Reguera Gemma
Published: September 2011

The in situ stimulation of Fe(III) oxide reduction by
Geobacter
bacteria leads to the concomitant precipitation of hexavalent uranium [U(VI)] from groundwater. Despite its promise for the bioremediation of uranium contaminants, the biological mechanism behind this reaction remains elusive. Because Fe(III) oxide reduction requires the expression of
Geobacter
's conductive pili, we evaluated their contribution to uranium reduction in
Geobacter sulfurreducens
grown under pili-inducing or noninducing conditions. A pilin-deficient mutant and a genetically complemented strain with reduced outer membrane
c
-cytochrome content were used as controls. Pili expression significantly enhanced the rate and extent of uranium immobilization per cell and prevented periplasmic mineralization. As a result, pili expression also preserved the vital respiratory activities of the cell envelope and the cell's viability. Uranium preferentially precipitated along the pili and, to a lesser extent, on outer membrane redox-active foci. In contrast, the pilus-defective strains had different degrees of periplasmic mineralization matching well with their outer membrane
c
-cytochrome content. X-ray absorption spectroscopy analyses demonstrated the extracellular reduction of U(VI) by the pili to mononuclear tetravalent uranium U(IV) complexed by carbon-containing ligands, consistent with a biological reduction. In contrast, the U(IV) in the pilin-deficient mutant cells also required an additional phosphorous ligand, in agreement with the predominantly periplasmic mineralization of uranium observed in this strain. These findings demonstrate a previously unrecognized role for
Geobacter
conductive pili in the extracellular reduction of uranium, and highlight its essential function as a catalytic and protective cellular mechanism that is of interest for the bioremediation of uranium-contaminated groundwater.
Sensing cooperativity in ATP hydrolysis for single multisubunit enzymes in solution
Authors: Jiang Yan , Douglas Nicholai R. , Conley Nicholas R. , Miller Erik J. , Frydman Judith , Moerner W. E.
Published: September 2011

In order to operate in a coordinated fashion, multisubunit enzymes use cooperative interactions intrinsic to their enzymatic cycle, but this process remains poorly understood. Accordingly, ATP number distributions in various hydrolyzed states have been obtained for single copies of the mammalian double-ring multisubunit chaperonin TRiC/CCT in free solution using the emission from chaperonin-bound fluorescent nucleotides and closed-loop feedback trapping provided by an Anti-Brownian ELectrokinetic trap. Observations of the 16-subunit complexes as ADP molecules are dissociating shows a peak in the bound ADP number distribution at 8 ADP, whose height falls over time with little shift in the position of the peak, indicating a highly cooperative ADP release process which would be difficult to observe by ensemble-averaged methods. When AlFx is added to produce ATP hydrolysis transition state mimics (ADP·AlFx) locked to the complex, the peak at 8 nucleotides dominates for all but the lowest incubation concentrations. Although ensemble averages of the single-molecule data show agreement with standard cooperativity models, surprisingly, the observed number distributions depart from standard models, illustrating the value of these single-molecule observations in constraining the mechanism of cooperativity. While a complete alternative microscopic model cannot be defined at present, the addition of subunit-occupancy-dependent cooperativity in hydrolysis yields distributions consistent with the data.
Interplay between spontaneous and induced brain activity during human non-rapid eye movement sleep
Authors: Dang-Vu Thien Thanh , Bonjean Maxime , Schabus Manuel , Boly Mélanie , Darsaud Annabelle , Desseilles Martin , Degueldre Christian , Balteau Evelyne , Phillips Christophe , Luxen André , Sejnowski Terrence J. , Maquet Pierre
Published: September 2011

Humans are less responsive to the surrounding environment during sleep. However, the extent to which the human brain responds to external stimuli during sleep is uncertain. We used simultaneous EEG and functional MRI to characterize brain responses to tones during wakefulness and non-rapid eye movement (NREM) sleep. Sounds during wakefulness elicited responses in the thalamus and primary auditory cortex. These responses persisted in NREM sleep, except throughout spindles, during which they became less consistent. When sounds induced a K complex, activity in the auditory cortex was enhanced and responses in distant frontal areas were elicited, similar to the stereotypical pattern associated with slow oscillations. These data show that sound processing during NREM sleep is constrained by fundamental brain oscillatory modes (slow oscillations and spindles), which result in a complex interplay between spontaneous and induced brain activity. The distortion of sensory information at the thalamic level, especially during spindles, functionally isolates the cortex from the environment and might provide unique conditions favorable for off-line memory processing.
A 5-methylcytosine DNA glycosylase/lyase demethylates the retrotransposon
Tos17
and promotes its transposition in rice
Authors: La Honggui , Ding Bo , Mishra Gyan P. , Zhou Bo , Yang Hongmei , Bellizzi Maria del Rosario , Chen Songbiao , Meyers Blake C. , Peng Zhaohua , Zhu Jian-Kang , Wang Guo-Liang
Published: September 2011

DNA 5-methylcytosine (5-meC) is an important epigenetic mark for transcriptional gene silencing in many eukaryotes. In
Arabidopsis
, 5-meC DNA glycosylase/lyases actively remove 5-meC to counteract transcriptional gene silencing in a locus-specific manner, and have been suggested to maintain the expression of transposons. However, it is unclear whether plant DNA demethylases can promote the transposition of transposons. Here we report the functional characterization of the DNA glycosylase/lyase DNG701 in rice.
DNG701
encodes a large (1,812 amino acid residues) DNA glycosylase domain protein. Recombinant DNG701 protein showed 5-meC DNA glycosylase and lyase activities in vitro. Knockout or knockdown of
DNG701
in rice plants led to DNA hypermethylation and reduced expression of the retrotransposon
Tos17
.
Tos17
showed less transposition in calli derived from
dng701
knockout mutant seeds compared with that in wild-type calli. Overexpression of
DNG701
in both rice calli and transgenic plants substantially reduced DNA methylation levels of
Tos17
and enhanced its expression. The overexpression also led to more frequent transposition of
Tos17
in calli. Our results demonstrate that rice DNG701 is a 5-meC DNA glycosylase/lyase responsible for the demethylation of
Tos17
and this DNA demethylase plays a critical role in promoting
Tos17
transposition in rice calli.
Reproductive strategy of the jellyfish Aurelia aurita (Cnidaria Scyphomedusae) in the Suez Canal and its migration between the Red Sea and Mediterranean
Authors: El-Serehy Hamed A. , Al-Rasheid Khaled A.
Published: September 2011

The life history of the common jellyfish A. aurita (Linnaeus) in the Suez Canal was investigated by monthly sampling over a 28 month period from September 2006 to December 2008. Young medusae of 2–3 cm diameter appeared during February/March. Growth was rapid. Some specimens of this cohort reached 16 cm and spawned by March/May and then decreased in size or died. Others reached a maximal size of 10 cm by September, after which spawning took place. A few mature individuals remained after spawning in the next year but decreased in size. Release of ephyrae seems to be induced by a lowering of ambient environmental temperature to below 16°C, with peak of release occurring in December–February. A drop in temperature may be the primary cue for strobilation in the Suez Canal. A. aurita seems to be an immigrant plankter to the Suez Canal, and much interest was focused on determining from which end of the canal these organisms were invading the opposite sea. However, the canal itself, along with its lakes, should also be considered as a substantial permanent habitat in its own right. The canal cannot be considered only as a funnel or corridor through which animals pass like ships from one sea to the other.

A. aurita appears to enter the Suez Canal from the south via water currents; to do so it needs to be carried over a distance of 20 km along the canal from the Gulf of Suez into the Bitter Lakes, then pass across the Bitter Lakes before being carried a further 12 km along the canal into Lake Timsah. Transport of A. aurita southward along the canal from the Mediterranean is unlikely to take place during most seasons of the year because it would require transport against the dominant-water flow; it is possible only during a brief period (July–September) of reversed flow. Because the main part of the 80 km from the Red Sea is canalized, passive transport of A. aurita by water currents from the north could occur within a week during the brief period of reversed flow even at the low speed of 0.5 km hour−1. Moreover, conditions (barriers, obstacles and/or links) along the migratory route of the Suez Canal, in either direction, are likely to determine the success of passive transport of A. aurita.
Influence of land use patterns on some limnological characteristics in the south-eastern part of Lake Victoria, Tanzania
Authors: Shayo Salome D. , Lugomela Charles , Machiwa John F.
Published: September 2011

To investigate the influence of human activities on limnological characteristics of Lake Victoria, we analyzed inorganic nutrient concentrations, phytoplankton diversity and biomass at three locations with different land use patterns: Mwanza (urban/industrial), Magu (agricultural) and Kayenze (sparsely populated). Mwanza had significantly higher ammonia concentration compared to Kayenze and Magu. At the shoreline stations, significantly higher nitrate concentration was observed at Mwanza compared to Kayenze and Magu. Similarly, Mwanza had significantly higher concentrations of soluble reactive phosphorous in the shoreline stations compared to Magu and Kayenze, but not in the open waters stations. Shoreline stations also showed significant differences in phytoplankton diversity among sites. The shoreline station at Mwanza also showed significantly higher levels of Chl. a compared to those at Magu and Kayenze. However, in the open water stations Chl. a concentrations did not differ significantly among sites. The results suggested that urban pollution in Mwanza and agricultural activities in River Simiyu catchment strongly influence the limnology of Lake Victoria and that the nearshore waters, which are the receiving points, were highly impacted compared to the waters outside bays. Thus, proper urban waste management and sustainable land management practices are critical for reducing point and non-point sources of pollution into Lake Victoria.
Novel function of keratins 5 and 14 in proliferation and differentiation of stratified epithelial cells
Authors: Alam Hunain , Sehgal Lalit , Kundu Samrat T. , Dalal Sorab N. , Vaidya Milind M.
Published: September 2011

Keratins are cytoplasmic intermediate filament proteins preferentially expressed by epithelial tissues in a site-specific and differentiation-dependent manner. The complex network of keratin filaments in stratified epithelia is tightly regulated during squamous cell differentiation. Keratin 14 (K14) is expressed in mitotically active basal layer cells, along with its partner keratin 5 (K5), and their expression is down-regulated as cells differentiate. Apart from the cytoprotective functions of K14, very little is known about K14 regulatory functions, since the K14 knockout mice show postnatal lethality. In this study, K14 expression was inhibited using RNA interference in cell lines derived from stratified epithelia to study the K14 functions in epithelial homeostasis. The K14 knockdown clones demonstrated substantial decreases in the levels of the K14 partner K5. These cells showed reduction in cell proliferation and delay in cell cycle progression, along with decreased phosphorylated Akt levels. K14 knockdown cells also exhibited enhanced levels of activated Notch1, involucrin, and K1. In addition, K14 knockdown AW13516 cells showed significant reduction in tumorigenicity. Our results suggest that K5 and K14 may have a role in maintenance of cell proliferation potential in the basal layer of stratified epithelia, modulating phosphatidylinositol 3-kinase/Akt–mediated cell proliferation and/or Notch1-dependent cell differentiation.
Coupling of T161 and T14 phosphorylations protects cyclin B–CDK1 from premature activation
Authors: Coulonval Katia , Kooken Hugues , Roger Pierre P.
Published: September 2011

Mitosis is triggered by the abrupt dephosphorylation of inhibitory Y15 and T14 residues of cyclin B1–bound cyclin-dependent kinase (CDK)1 that is also phosphorylated at T161 in its activation loop. The sequence of events leading to the accumulation of fully phosphorylated cyclin B1–CDK1 complexes remains unclear. Two-dimensional gel electrophoresis allowed us to determine whether T14, Y15, and T161 phosphorylations occur on same CDK1 molecules and to characterize the physiological occurrence of their seven phosphorylation combinations. Intriguingly, in cyclin B1–CDK1, the activating T161 phosphorylation never occurred without the T14 phosphorylation. This strict association could not be uncoupled by a substantial reduction of T14 phosphorylation in response to Myt1 knockdown, suggesting some causal relationship. However, T14 phosphorylation was not directly required for T161 phosphorylation, because Myt1 knockdown did uncouple these phosphorylations when leptomycin B prevented cyclin B1–CDK1 complexes from accumulating in cytoplasm. The coupling mechanism therefore depended on unperturbed cyclin B1–CDK1 traffic. The unexpected observation that the activating phosphorylation of cyclin B1–CDK1 was tightly coupled to its T14 phosphorylation, but not Y15 phosphorylation, suggests a mechanism that prevents premature activation by constitutively active CDK-activating kinase. This explained the opposite effects of reduced expression of Myt1 and Wee1, with only the latter inducing catastrophic mitoses.
Dual roles of Munc18-1 rely on distinct binding modes of the central cavity with Stx1A and SNARE complex
Authors: Shi Lei , Kümmel Daniel , Coleman Jeff , Melia Thomas J. , Giraudo Claudio G.
Published: September 2011

Sec1/Munc18 proteins play a fundamental role in multiple steps of intracellular membrane trafficking. Dual functions have been attributed to Munc18-1: it can act as a chaperone when it interacts with monomeric syntaxin 1A, and it can activate soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) for membrane fusion when it binds to SNARE complexes. Although both modes of binding involve the central cavity of Munc18-1, their precise molecular mechanisms of action are not fully understood. In this paper, we describe a novel Munc18-1 mutant in the central cavity that showed a reduced interaction with syntaxin 1A and impaired chaperone function, but still bound to assembled SNARE complexes and promoted liposome fusion and secretion in neuroendocrine cells. Soluble syntaxin 1A H3 domain partially blocks Munc18-1 activation of liposome fusion by occupying the Munc18-1 central cavity. Our findings lead us to propose a transition model between the two distinct binding modes by which Munc18 can control and assist in SNARE-complex assembly during neurotransmitter release.
Clinical Governance
Authors: Jaggs-Fowler Robert M.
Published: September 2011

Clinical governance is central to the modern day practice of medicine. However, despite its importance, it remains a concept that is commonly cited but rarely explained. This article looks at the origins of the term ‘clinical governance’, attempts to elucidate its meaning and identify the various components which underpin it as a process imperative to the attainment of quality health care.
Primary Prevention of Cardiovascular Disease
Authors: Shah Sachil
Published: September 2011

Cardiovascular disease (CVD) is a spectrum of disorders that includes stroke, coronary heart disease (CHD) and peripheral vascular disease (PVD). CVD is the UK's biggest cause of death, with over 191 000 deaths a year. The extent to which CVD affects the health of the population and the financial burden this places on the National Health Service (NHS) makes it an important modifiable disease. Preventing CVD is now a significant role of the general practice team.
Construction of energy landscapes can clarify the movement and distribution of foraging animals
Authors: Wilson Rory P. , Quintana Flavio , Hobson Victoria J.
Published: September 2011

Variation in the physical characteristics of the environment should impact the movement energetics of animals. Although cognizance of this may help interpret movement ecology, determination of the landscape-dependent energy expenditure of wild animals is problematic. We used accelerometers in animal-attached tags to derive energy expenditure in 54 free-living imperial cormorants
Phalacrocorax atriceps
and construct an energy landscape of the area around a breeding colony. Examination of the space use of a further 74 birds over 4 years showed that foraging areas selected varied considerably in distance from the colony and water depth, but were characterized by minimal power requirements compared with other areas in the available landscape. This accords with classic optimal foraging concepts, which state that animals should maximize net energy gain by minimizing costs where possible and show how deriving energy landscapes can help understand how and why animals distribute themselves in space.
The role of matrix proteins in the control of nacreous layer deposition during pearl formation
Authors: Liu Xiaojun , Li Jiale , Xiang Liang , Sun Juan , Zheng Guilan , Zhang Guiyou , Wang Hongzhong , Xie Liping , Zhang Rongqing
Published: September 2011

To study the function of pearl oyster matrix proteins in nacreous layer biomineralizationin vivo, we examined the deposition on pearl nuclei and the expression of matrix protein genes in the pearl sac during the early stage of pearl formation. We found that the process of pearl formation involves two consecutive stages: (i) irregular calcium carbonate (CaCO3) deposition on the bare nucleus and (ii) CaCO3deposition that becomes more and more regular until the mature nacreous layer has formed on the nucleus. The low-expression level of matrix proteins in the pearl sac during periods of irregular CaCO3deposition suggests that deposition may not be controlled by the organic matrix during this stage of the process. However, significant expression of matrix proteins in the pearl sac was detected by day 30–35 after implantation. On day 30, a thin layer of CaCO3, which we believe was amorphous CaCO3, covered large aragonites. By day 35, the nacreous layer had formed. The whole process is similar to that observed in shells, and the temporal expression of matrix protein genes indicated that their bioactivities were crucial for pearl development. Matrix proteins controlled the crystal phase, shape, size, nucleation and aggregation of CaCO3crystals.
The van Niel International Prize for Studies in Bacterial Systematics, awarded by The University of Queensland Awarded in 2011 to George M. Garrity
Authors:   International Committee on Systematics of Prokaryotes
Published: September 2011

The Senate of The University of Queensland, on the recommendation of a panel of experts of the International Committee on Systematics of Prokaryotes, is pleased to present the van Niel International Prize for Studies in Bacterial Systematics for the triennium 2009–2011 to Professor George M. Garrity in recognition of his contribution made to the field of bacterial systematics. The award, established in 1986 by Professor V. B. D. Skerman of The University of Queensland, honours the contribution of scholarship in the field of microbiology by Professor Cornelis Bernardus van Niel.
How do plant viruses induce disease? Interactions and interference with host components
Authors: Pallas Vicente , García Juan Antonio
Published: September 2011

Plant viruses are biotrophic pathogens that need living tissue for their multiplication and thus, in the infection–defence equilibrium, they do not normally cause plant death. In some instances virus infection may have no apparent pathological effect or may even provide a selective advantage to the host, but in many cases it causes the symptomatic phenotypes of disease. These pathological phenotypes are the result of interference and/or competition for a substantial amount of host resources, which can disrupt host physiology to cause disease. This interference/competition affects a number of genes, which seems to be greater the more severe the symptoms that they cause. Induced or repressed genes belong to a broad range of cellular processes, such as hormonal regulation, cell cycle control and endogenous transport of macromolecules, among others. In addition, recent evidence indicates the existence of interplay between plant development and antiviral defence processes, and that interference among the common points of their signalling pathways can trigger pathological manifestations. This review provides an update on the latest advances in understanding how viruses affect substantial cellular processes, and how plant antiviral defences contribute to pathological phenotypes.
Generation and characterization of a recombinant Rift Valley fever virus expressing a V5 epitope-tagged RNA-dependent RNA polymerase
Authors: Brennan Benjamin , Li Ping , Elliott Richard M.
Published: September 2011

The viral RNA-dependent RNA polymerase (RdRp; L protein) of Rift Valley fever virus (RVFV; family Bunyaviridae) is a 238 kDa protein that is crucial for the life cycle of the virus, as it catalyses both transcription of viral mRNAs and replication of the tripartite genome. Despite its importance, little is known about the intracellular distribution of the polymerase or its other roles during infection, primarily because of lack of specific antibodies that recognize L protein. To begin to address these questions we investigated whether the RVFV (MP12 strain) polymerase could tolerate insertion of the V5 epitope, as has been previously demonstrated for the Bunyamwera virus L protein. Insertion of the 14 aa epitope into the polymerase sequence at aa 1852 resulted in a polymerase that retained functionality in a minigenome assay, and we were able to rescue recombinant viruses that expressed the modified L protein by reverse genetics. The L protein could be detected in infected cells by Western blotting with anti-V5 antibodies. Examination of recombinant virus-infected cells by immunofluorescence revealed a punctate perinuclear or cytoplasmic distribution of the polymerase that co-localized with the nucleocapsid protein. The generation of RVFV expressing a tagged RdRp will allow detailed examination of the role of the viral polymerase in the virus life cycle.
EDIFF: a program for automated unit-cell determination and indexing of electron diffraction data
Authors: Jiang Linhua , Georgieva Dilyana , Abrahams Jan Pieter
Published: September 2011

EDIFFis a new user-friendly software suite for unit-cell determination of three-dimensional nanocrystals from randomly oriented electron diffraction patterns with unknown independent orientations. It can also be used for three-dimensional cell reconstruction from diffraction tilt series. In neither case is exact knowledge of the angular relationship between the patterns required. The unit cell can be validated and the crystal system assigned.EDIFFcan index the reflections in electron diffraction patterns. Thus,EDIFFcan be employed as a first step in reconstructing the three-dimensional atomic structure of organic and inorganic molecules and of proteins from diffraction data. An example illustrates the viability of theEDIFFapproach.
Application of a theory for particle statistics to structure refinement from powder diffraction data
Authors: Ida T. , Izumi F.
Published: September 2011

A new methodology is proposed for structure refinement using powder diffraction data, from which models for particle statistics and any other statistical errors can be formally optimized. This method is nothing but a straightforward implementation of the maximum-likelihood method, extended to the error estimation. Structure parameters refined by the method for fluorapatite [Ca5(PO4)3F], anglesite (PbSO4) and barite (BaSO4) become significantly closer to those obtained by single-crystal structure analyses in comparison with the results of the conventional Rietveld method.
The effect of gravity on the resolution of small-angle neutron diffraction peaks
Authors: Mildner D. F. R. , Barker J. G. , Kline S. R.
Published: September 2011

The resolution ellipses for neutron diffraction peaks at small scattering vectors lie along lines that point to a position vertically above the beam center on the small-angle scattering detector. This gravity effect is only noticeable for neutron beams at long wavelengths and with large wavelength spreads.
The influence of prophylactic factor VIII in severe haemophilia A
Authors: GISSEL M. , WHELIHAN M. F. , FERRIS L. A. , MANN K. G. , RIVARD G. E. , BRUMMEL‐ZIEDINS K. E.
Published: September 2011

Summary.  Haemophilia A individuals displaying a similar genetic defect have heterogeneous clinical phenotypes. Our objective was to evaluate the underlying effect of exogenous factor (f)VIII on tissue factor (Tf)‐initiated blood coagulation in severe haemophilia utilizing both empirical and computational models. We investigated twenty‐five clinically severe haemophilia A patients. All individuals were on fVIII prophylaxis and had not received fVIII from 0.25 to 4 days prior to phlebotomy. Coagulation was initiated by the addition of Tf to contact‐pathway inhibited whole blood ± an anti‐fVIII antibody. Aliquots were quenched over 20 min and analyzed for thrombin generation and fibrin formation. Coagulation factor levels were obtained and used to computationally predict thrombin generation with fVIII set to either zero or its value at the time of the draw. As a result of prophylactic fVIII, at the time of the blood draw, the individuals had fVIII levels that ranged from <1% to 22%. Thrombin generation (maximum level and rate) in both empirical and computational systems increased as the level of fVIII increased. FXIII activation rates also increased as the fVIII level increased. Upon suppression of fVIII, thrombin generation became comparable in both systems. Plasma composition analysis showed a negative correlation between bleeding history and computational thrombin generation in the absence of fVIII. Residual prophylactic fVIII directly causes an increase in thrombin generation and fibrin cross‐linking in individuals with clinically severe haemophilia A. The combination of each individual’s coagulation factors (outside of fVIII) determine each individual’s baseline thrombin potential and may affect bleeding risk.