bluuebunny/crossref_metadata_2025 huggingface dataset:
Explosion at dormant Alaskan volcano
Authors: Zielinki Sarah
Published: October 2006

The Fourpeaked volcano, which is located in a remote part of Alaska, and which has had no known activity in the last 10,000 years, released ash, gas, and steam on 17 September, according to the Alaska Volcano Observatory (AVO). The volcano has continued to release sulfur dioxide at a rate that is similar to that measured before the January 2006 eruptions of Alaska's Augustine volcano. This indicates there is abundant, new magma within a few kilometers of the surface, said AVO research geophysicist Peter Cervelli of the U.S. Geological Survey. AVO has issued a hazard concern level of ‘yellow’ for the volcano (the volcano previously had no level of concern), warning that the volcano could erupt within the next days, months, or years. The Fourpeaked volcano had been unmonitored. Weather‐permitting, AVO plans to soon install on the mountain a web camera, short‐period seismometer, and pressure sensor to detect explosions, said Cervelli. Fourpeaked Mountain is located 320 kilometers southwest of Anchorage on the Alaska Peninsula.
Spatial Layout and Face-to-Face Interaction in Offices—A Study of the Mechanisms of Spatial Effects on Face-to-Face Interaction
Authors: Rashid Mahbub , Kampschroer Kevin , Wineman Jean , Zimring Craig
Published: October 2006

In this paper we report a study that uses space-syntax theories and techniques to develop a model explaining how spatial layouts, through their effects on movement and visible copresence, may affect face-to-face interaction in offices. Though several previous space-syntax studies have shown that spatial layouts have significant effects on movement and face-to-face interaction in offices, none has investigated the relations among movement, visible copresence, and face-to-face interaction in offices with significantly different layouts. On the basis of statistical analyses of the spatial and behavioral data collected at four moderately large offices, this study shows that spatial layouts have consistent effects on movement, but inconsistent effects on visible copresence and face-to-face interaction; that visible copresence, not movement, is an important predictor of face-to-face interaction; that movement has negligible effects on the relationship between visible copresence and face-to-face interaction; and that functional programs have little or no effect on the culture of face-to-face interaction in these offices. Limitations of the research design for workplace study and implications of the research findings for workplace design and management are discussed.
Adjusting Spatial-Entropy Measures for Scale and Resolution Effects
Authors: Heikkila Eric J , Hu Lingqian
Published: October 2006

In this paper we revisit the concept of entropy as it manifests itself in spatial terms. We focus specifically on the question of how entropy measures applied to different urban contexts can be adjusted to allow for meaningful comparisons between cities with differing geographic dimensions. It is well known that entropy is affected by the number of geographic units over which it is computed. As a result, the size and number of census tracts in an urban area constitute an intervening factor in making direct comparisons. Some authors advocate addressing this problem by normalizing entropy to its maximum value to derive a ‘relative entropy’ measure. We prove that this conventional normalization procedure does not suffice, and we show further that Theil's decomposition method does provide the proper solution. We then demonstrate how to apply this technique through the use of census data for US cities in 2000, with the empirical results clearly underlying the importance of making these adjustments.
Potentials for Planning Support: A Planning-Conceptual Approach
Authors: Geertman Stan
Published: October 2006

Over the course of many years, professional planners have used a plethora of methods and tools to support their planning activities. Nevertheless, it can be argued that planning practioners have never fully embraced the much wider diversity of available methods, techniques, and models developed in the research laboratories. On the basis of this observation, this study poses several questions about why there is an apparent mismatch in planning practice between supply, demand, and applications of planning-support instruments (including ‘planning support systems’) and their outcomes (dedicated information and knowledge), and how this mismatch can be solved. In order to arrive at an answer, a conceptual framework is constructed, which constitutes crucial factors that influence the potential planning support roles of information, knowledge, and instruments. With the help of this framework, a developmental overview is interpreted of the theoretical planning traditions that exerted an influence on planning practice during the last half millennium in the Western world. From this interpretation, some lessons can be learned about the improvement of the planning-support role in factual planning practice, and moreover, it opens up some new questions and discussion points.
Land-Use Optimization for Controlling Peak Flow Discharge and Nonpoint Source Water Pollution
Authors: Yeo In-Young , Guldmann Jean-Michel
Published: October 2006

In this paper we present and apply a modeling methodology to reduce stormwater runoff through land-use planning, in order to mitigate the impact of nonpoint source pollution. A stormwater-runoff simulation model is used to generate peak discharge pseudodata, that are inputted into a regression analysis, in which the functional relationship between peak discharge and land-use variables is approximated as a quadratic function ( R2 = 0.98). This function is then used in an optimization model to allocate future land uses (urban, conservation, and agriculture) at the subwatershed level, in a way that minimizes the resulting peak discharge at the watershed outlet. A discharge reduction of 44% is achieved, compared with the discharge resulting from the present (actual) land-use pattern. The most downstream and upstream areas are to be protected with more conservation, and most urban activities are allocated to the minimal impact subwatershed. Sensitivity analyses are performed and suggest maintaining at least 25% of the land in a conservation state, developing no more than 12% for urban purposes, and no more than 70% for agricultural purposes.
Space Syntax Analysis of Colonial Houses in India
Authors: Bandyopadhyay Abir , Merchant Arif N
Published: October 2006

The influence of colonial (British) rule on native (Indian) culture and vice versa has resulted in the development of ‘hybrid’ architectural styles, which are seen in the external ‘form’ of the buildings. The development of a hybrid style is an important phase in the evolution of domestic architecture in India. In this paper we explore whether such hybrid nature is also reflected in the spatial organizations of some colonial houses of eastern India. For this, a suitable methodology was evolved to analyze the spatial organizations. The compositional rules in the generation of spatial layout in these houses are analyzed through the use of space syntax analysis, with some modifications, in order to type them spatially. Typically, space syntax analysis deciphers the spatial organization by the formation of ‘inequality genotypes’, which describe only the integration (and segregation) of spaces as per the access relations. To understand more about the Indian social and cultural norms that might have influenced the spatial organizations of the houses, the accessibility, adjacency, and orientation of the spaces also need to be studied. In this paper we explain the methodology used to generate ‘genotype strings’, incorporate the aforementioned information, and help to understand and document the ingrained social and cultural factors in spatial organizations of the houses more explicitly.
The dynamics of Machiavellian intelligence
Authors: Gavrilets Sergey , Vose Aaron
Published: October 2006

The “Machiavellian intelligence” hypothesis (or the “social brain” hypothesis) posits that large brains and distinctive cognitive abilities of humans have evolved via intense social competition in which social competitors developed increasingly sophisticated “Machiavellian” strategies as a means to achieve higher social and reproductive success. Here we build a mathematical model aiming to explore this hypothesis. In the model, genes control brains which invent and learn strategies (memes) which are used by males to gain advantage in competition for mates. We show that the dynamics of intelligence has three distinct phases. During the dormant phase only newly invented memes are present in the population. During the cognitive explosion phase the population's meme count and the learning ability, cerebral capacity (controlling the number of different memes that the brain can learn and use), and Machiavellian fitness of individuals increase in a runaway fashion. During the saturation phase natural selection resulting from the costs of having large brains checks further increases in cognitive abilities. Overall, our results suggest that the mechanisms underlying the “Machiavellian intelligence” hypothesis can indeed result in the evolution of significant cognitive abilities on the time scale of 10 to 20 thousand generations. We show that cerebral capacity evolves faster and to a larger degree than learning ability. Our model suggests that there may be a tendency toward a reduction in cognitive abilities (driven by the costs of having a large brain) as the reproductive advantage of having a large brain decreases and the exposure to memes increases in modern societies.
Phase knowledge enables rational screens for protein crystallization
Authors: Anderson Megan J. , Hansen Carl L. , Quake Stephen R.
Published: October 2006

We show that knowledge of the phase behavior of a protein allows one to create a rational screen that increases the success rate of crystallizing challenging proteins. The strategy is based on using microfluidics to perform large numbers of protein solubility experiments across many different chemical conditions to identify reagents for crystallization experiments. Phase diagrams were generated for the identified reagents and used to design customized crystallization screens for every protein. This strategy was applied with a 75% success rate to the crystallization of 12 diverse proteins, most of which failed to crystallize when using traditional techniques. The overall diffraction success rate was 33%, about double what was achieved with conventional automation in large-scale protein structure consortia. The higher diffraction success rates are achieved by designing customized crystallization screens using the phase behavior information for each target. The identification of reagents based on an understanding of protein solubility and the use of phase diagrams in the design of individualized crystallization screens therefore promotes high crystallization rates and the production of diffraction-quality crystals.
A gender- and sexual orientation-dependent spatial attentional effect of invisible images
Authors: Jiang Yi , Costello Patricia , Fang Fang , Huang Miner , He Sheng
Published: October 2006

Human observers are constantly bombarded with a vast amount of information. Selective attention helps us to quickly process what is important while ignoring the irrelevant. In this study, we demonstrate that information that has not entered observers' consciousness, such as interocularly suppressed (invisible) erotic pictures, can direct the distribution of spatial attention. Furthermore, invisible erotic information can either attract or repel observers' spatial attention depending on their gender and sexual orientation. While unaware of the suppressed pictures, heterosexual males' attention was attracted to invisible female nudes, heterosexual females' attention was attracted to invisible male nudes, gay males behaved similarly to heterosexual females, and gay/bisexual females performed in-between heterosexual males and females.
Photoprotection of human retinal pigment epithelium cells against blue light-induced apoptosis by melanin free radicals from
Sepia officinalis
Authors: Seagle Brandon-Luke L. , Gasyna Elzbieta M. , Mieler William F. , Norris James R.
Published: October 2006

Cultured retinal pigment epithelium (RPE) cells can phagocytize large foreign particles. Heterogeneous melanin aggregates from
Sepia officinalis
, a species of cuttlefish, were fed to cultured human RPE cells to produce cells laden with
Sepia
melanin. Blue light-induced apoptosis (BLIA) assays were performed by flow cytometry on parallel cultures consisting of RPE cells isolated from independent eyes and evenly divided into two cultures, one fed
Sepia
melanin and one containing only native melanin. After culturing and growth of the cells under blue light illumination for 7 days, the apoptosis percentage of all cultures indicated that
Sepia
feeding significantly reduced BLIA. To account for
Sepia
photoprotection, continuous-wave EPR and time-resolved EPR experiments were performed with parallel RPE cultures by using UV (355 nm) and green (532 nm) laser irradiation. Continuous-wave EPR spectra prove that the concentrations of intrinsic and extrinsic melanin free radicals in the
Sepia
–RPE culture are large compared with those concentrations in the RPE culture. Time-resolved EPR spectra indicate that both UV and green light produced extrinsic melanin radicals as radical pairs from the triplet manifold with a linear dependence on the number of photons per second. These experiments conclusively demonstrate that decreased RPE susceptibility to BLIA correlates with increased intracellular melanin free radical concentrations and that nonnative melanin can supplement native melanin photoprotection of RPE cells.
Cardiac myosin binding protein c phosphorylation is cardioprotective
Authors: Sadayappan Sakthivel , Osinska Hanna , Klevitsky Raisa , Lorenz John N. , Sargent Michelle , Molkentin Jeffrey D. , Seidman Christine E. , Seidman Jonathan G. , Robbins Jeffrey
Published: October 2006

Cardiac myosin binding protein C (cMyBP-C) has three phosphorylatable serines at its N terminus (Ser-273, Ser-282, and Ser-302), and the residues' phosphorylation states may alter thick filament structure and function. To examine the effects of cMyBP-C phosphorylation, we generated transgenic mice with cardiac-specific expression of a cMyBP-C in which the three phosphorylation sites were mutated to aspartic acid, mimicking constitutive phosphorylation (cMyBP-C
AllP+
). The allele was bred into a cMyBP-C null background (cMyBP-C
(t/t)
) to ensure the absence of endogenous dephosphorylated cMyBP-C. cMyBP-C
AllP+
was incorporated normally into the cardiac sarcomere and restored normal cardiac function in the null background. However, subtle changes in sarcomere ultrastructure, characterized by increased distances between the thick filaments, indicated that phosphomimetic cMyBP-C affects thick–thin filament relationships, and yeast two-hybrid data and pull-down studies both showed that charged residues in these positions effectively prevented interaction with the myosin heavy chain. Confirming the physiological relevance of these data, the cMyBP-C
AllP+:(t/t)
hearts were resistant to ischemia–reperfusion injury. These data demonstrate that cMyBP-C phosphorylation functions in maintaining thick filament spacing and structure and can help protect the myocardium from ischemic injury.
A single dose of doxorubicin-functionalized bow-tie dendrimer cures mice bearing C-26 colon carcinomas
Authors: Lee Cameron C. , Gillies Elizabeth R. , Fox Megan E. , Guillaudeu Steven J. , Fréchet Jean M. J. , Dy Edward E. , Szoka Francis C.
Published: October 2006

The antitumor effect of doxorubicin (DOX) conjugated to a biodegradable dendrimer was evaluated in mice bearing C-26 colon carcinomas. An asymmetric biodegradable polyester dendrimer containing 8–10 wt % DOX was prepared. The design of the dendrimer carrier optimized blood circulation time through size and molecular architecture, drug loading through multiple attachment sites, solubility through PEGylation, and drug release through the use of pH-sensitive hydrazone linkages. In culture, dendrimer–DOX was >10 times less toxic than free DOX toward C-26 colon carcinoma cells after exposure for 72 h. Upon i.v. administration to BALB/c mice with s.c. C-26 tumors, dendrimer–DOX was eliminated from the serum with a half-life of 16 ± 1 h, and its tumor uptake was ninefold higher than i.v. administered free DOX at 48 h. In efficacy studies performed with BALB/c mice bearing s.c. C-26 tumors, a single i.v. injection of dendrimer–DOX at 20 mg/kg DOX equivalents 8 days after tumor implantation caused complete tumor regression and 100% survival of the mice over the 60-day experiment. No cures were achieved in tumor-implanted mice treated with free DOX at its maximum tolerated dose (6 mg/kg), drug-free dendrimer, or dendrimer–DOX in which the DOX was attached by means of a stable carbamate bond. The antitumor effect of dendrimer–DOX was similar to that of an equimolar dose of liposomal DOX (Doxil). The remarkable antitumor activity of dendrimer–DOX results from the ability of the dendrimer to favorably modulate the pharmacokinetics of attached DOX.
Use of polysialic acid in repair of the central nervous system
Authors: El Maarouf Abderrahman , Petridis Athanasios K. , Rutishauser Urs
Published: October 2006

Polysialic acid (PSA), a large cell-surface carbohydrate that regulates cell interactions, is used during vertebrate development to promote precursor cell migration and axon path-finding. The induction of PSA expression in damaged adult CNS tissues could help them to rebuild by creating conditions permissive for architectural remodeling. This possibility has been explored in two contexts, the regeneration of axons and the recruitment of endogenous neural precursors to a lesion. Glial scars that form at CNS injury sites block axon regeneration. It has been found that transfection of scar astrocytes by a viral vector encoding polysialyltransferase leads to sustained expression of high levels of PSA. With this treatment, a substantial portion of severed corticospinal tract axon processes were able to grow through a spinal injury site. In the studies of precursor cell migration to a cortical lesion, it was found that induced PSA expression in a path extending from the subventricular zone to a lesion near the cortical surface increased recruitment of BrdU/nestin-positive cells along the path and into the injury site. These displaced precursors were able to differentiate in a regionally appropriate manner. These findings suggest that induced PSA expression can be used as a strategy for promoting tissue repair involving both replacement of cells and rebuilding of neural connections.
The role of platelet adhesion receptor GPIbα far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis
Authors: Bergmeier Wolfgang , Piffath Crystal L. , Goerge Tobias , Cifuni Stephen M. , Ruggeri Zaverio M. , Ware Jerry , Wagner Denisa D.
Published: October 2006

GPIbα binding to von Willebrand factor (VWF) exposed at a site of vascular injury is thought to be the first step in the formation of a hemostatic plug. However, our previous studies in VWF-deficient mice demonstrated delayed but not absent arterial thrombus formation, suggesting that, under these conditions, GPIbα may bind other ligands or that a receptor other than GPIbα can mediate platelet adhesion. Here, we studied thrombus formation in transgenic mice expressing GPIbα in which the extracellular domain was replaced by that of the human IL-4 receptor (IL4Rα/GPIbα-tg mice). Platelet adhesion to ferric chloride-treated mesenteric arterioles in IL4Rα/GPIbα-tg mice was virtually absent in contrast to avid adhesion in WT mice. As a consequence, arterial thrombus formation was inhibited completely in the mutant mice. Our studies further show that, when infused into WT recipient mice, IL4Rα/GPIbα-tg platelets or WT platelets lacking the 45-kDa N-terminal domain of GPIbα failed to incorporate into growing arterial thrombi, even if the platelets were activated before infusion. Surprisingly, platelets lacking β3 integrins, which are unable to form thrombi on their own, incorporated efficiently into WT thrombi. Our studies provide
in vivo
evidence that GPIbα absolutely is required for recruitment of platelets to both exposed subendothelium and thrombi under arterial flow conditions. Thus, GPIbα contributes to arterial thrombosis by important adhesion mechanisms independent of the binding to VWF.
Book Review
Authors: Abildgaard Andreas
Published: October 2006

Magnetic Resonance Angiography. Techniques, Indications and Practical Applications. Edited by G. Schneider, M. R. Prince, J. F. M. Meaney, and V. B. Ho. Berlin, Heidelberg, New York: Springer-Verlag, 2005. ISBN 8847002664. 358 pages. 333 figures. Price hardcover: 199
Quantitative assessment of regional emphysema distribution in patients with chronic obstructive pulmonary disease (COPD)
Authors: Stavngaard T. , Shaker S. B. , Bach K. S. , Stoel B. C. , Dirksen A.
Published: October 2006

Purpose: To compare objective and subjective assessment of the distribution of emphysema in unselected patients with chronic obstructive pulmonary disease (COPD).

Material and Methods: 167 patients were computed tomography (CT) scanned, and the relative area (RA-910) of emphysema in each CT slice was plotted against table position. The craniocaudal distribution was calculated as the slope of the regression line, and grouped as upper-lung-zone predominance (ULP), lower-lung-zone predominance (LLP), or mild/homogeneous distribution (MHE). CT scans were also classified as ULP, LLP, and MHE based on visual assessment of three high-resolution CT (HRCT) slices, and the leading pattern of emphysema was classified as centrilobular (CLE), paraseptal (PSE), panlobular (PLE), or no emphysema (NE).

Results: By objective classification, scans were divided into almost equal numbers of ULP, LLP, and MHE, whereas visual evaluation classified more scans as ULP ( P<0.001) and very few as LLP ( P<0.0001). In patients with CLE, 49% had ULP by objective classification, whereas LLP was the commonest leading pattern in PSE, PLE, and NE.

Conclusion: We found significant discrepancies between the objective and subjective distributions of emphysema in various morphological patterns, which may be of clinical importance in, for instance, lung-volume-reduction surgery.
Differential activation and function of Rho GTPases duringSalmonella–host cell interactions
Authors: Patel Jayesh C. , Galán Jorge E.
Published: October 2006

Salmonella enterica, the cause of food poisoning and typhoid fever, has evolved sophisticated mechanisms to modulate Rho family guanosine triphosphatases (GTPases) to mediate specific cellular responses such as actin remodeling, macropinocytosis, and nuclear responses. These responses are largely the result of the activity of a set of bacterial proteins (SopE, SopE2, and SopB) that, upon delivery into host cells via a type III secretion system, activate specific Rho family GTPases either directly (SopE and SopE2) or indirectly (SopB) through the stimulation of an endogenous exchange factor. We show that different Rho family GTPases play a distinct role in Salmonella-induced cellular responses. In addition, we report that SopB stimulates cellular responses by activating SH3-containing guanine nucleotide exchange factor (SGEF), an exchange factor for RhoG, which we found plays a central role in the actin cytoskeleton remodeling stimulated by Salmonella. These results reveal a remarkable level of complexity in the manipulation of Rho family GTPases by a bacterial pathogen.
Phage display selection of efficient glutamine‐donor substrate peptides for transglutaminase 2
Authors: Keresztessy Zsolt , Csősz Éva , Hársfalvi Jolán , Csomós Krisztián , Gray Joe , Lightowlers Robert N. , Lakey Jeremy H. , Balajthy Zoltán , Fésüs László
Published: October 2006

Understanding substrate specificity and identification of natural targets of transglutaminase 2 (TG2), the ubiquitous multifunctional cross‐linking enzyme, which forms isopeptide bonds between protein‐linked glutamine and lysine residues, is crucial in the elucidation of its physiological role. As a novel means of specificity analysis, we adapted the phage display technique to select glutamine‐donor substrates from a random heptapeptide library via binding to recombinant TG2 and elution with a synthetic amine‐donor substrate. Twenty‐six Gln‐containing sequences from the second and third biopanning rounds were susceptible for TG2‐mediated incorporation of 5‐(biotinamido)penthylamine, and the peptides GQQQTPY, GLQQASV, and WQTPMNS were modified most efficiently. A consensus around glutamines was established as pQX(P,T,S)l, which is consistent with identified substrates listed in the TRANSDAB database. Database searches showed that several proteins contain peptides similar to the phage‐selected sequences, and the N‐terminal glutamine‐rich domain of SWI1/SNF1‐related chromatin remodeling proteins was chosen for detailed analysis. MALDI/TOF and tandem mass spectrometry‐based studies of a representative part of the domain, SGYGQQGQTPYYNQQSPHPQQQQPPYS (SnQ1), revealed that Q6, Q8, and Q22 are modified by TG2. Kinetic parameters of SnQ1 transamidation (KMapp = 250 μM, kcat = 18.3 sec−1, and kcat/KMapp = 73,200) classify it as an efficient TG2 substrate. Circular dichroism spectra indicated that SnQ1 has a random coil conformation, supporting its accessibility in the full‐length parental protein. Added together, here we report a novel use of the phage display technology with great potential in transglutaminase research.
Catalytic mechanism of cyclophilin as observed in molecular dynamics simulations: Pathway prediction and reconciliation of X‐ray crystallographic and NMR solution data
Authors: Trzesniak Daniel , van Gunsteren Wilfred F.
Published: October 2006

Cyclophilins are proteins that catalyze X‐proline cis–trans interconversion, where X represents any amino acid. Its mechanism of action has been investigated over the past years but still generates discussion, especially because until recently structures of the ligand in the cis and trans conformations for the same system were lacking. X‐ray crystallographic structures for the complex cyclophilin A and HIV‐1 capsid mutants with ligands in the cis and trans conformations suggest a mechanism where the N‐terminal portion of the ligand rotates during the cis–trans isomerization. However, a few years before, a C‐terminal rotating ligand was proposed to explain NMR solution data. In the present study we use molecular dynamics (MD) simulations to generate a trans structure starting from the cis structure. From simulations starting from the cis and trans structures obtained through the rotational pathways, the seeming contradiction between the two sets of experimental data could be resolved. The simulated N‐terminal rotated trans structure shows good agreement with the equivalent crystal structure and, moreover, is consistent with the NMR data. These results illustrate the use of MD simulation at atomic resolution to model structural transitions and to interpret experimental data.
Characterization of two potentially universal turn motifs that shape the repeated five‐residues fold—Crystal structure of a lumenal pentapeptide repeat protein from Cyanothece 51142
Authors: Buchko Garry W. , Ni Shuisong , Robinson Howard , Welsh Eric A. , Pakrasi Himadri B. , Kennedy Michael A.
Published: October 2006

The genome of the diurnal cyanobacterium Cyanothece sp. PCC 51142 has recently been sequenced and observed to contain 35 pentapeptide repeat proteins (PRPs). These proteins, while present throughout the prokaryotic and eukaryotic kingdoms, are most abundant in cyanobacteria. The sheer number of PRPs in cyanobacteria coupled with their predicted location in every cellular compartment argues for important, yet unknown, physiological and biochemical functions. To gain biochemical insights, the crystal structure for Rfr32, a 167‐residue PRP with an N‐terminal 29‐residue signal peptide, was determined at 2.1 Å resolution. The structure is dominated by 21 tandem pentapeptide repeats that fold into a right‐handed quadrilateral β‐helix, or Rfr‐fold, as observed for the tandem pentapeptide repeats in the only other PRP structure, the mycobacterial fluoroquinoline resistance protein MfpA from Mycobacterium tuberculosis. Sitting on top of the Rfr‐fold are two short, antiparallel α‐helices, bridged with a disulfide bond, that perhaps prevent edge‐to‐edge aggregation at the C terminus. Analysis of the main‐chain (Φ,Ψ) dihedral orientations for the pentapeptide repeats in Rfr32 and MfpA makes it possible to recognize the structural details for the two distinct types of four‐residue turns adopted by the pentapeptide repeats in the Rfr‐fold. These turns, labeled type II and type IV β‐turns, may be universal motifs that shape the Rfr‐fold in all PRPs.
Statistical potential for assessment and prediction of protein structures
Authors: Shen Min‐yi , Sali Andrej
Published: October 2006

Protein structures in the Protein Data Bank provide a wealth of data about the interactions that determine the native states of proteins. Using the probability theory, we derive an atomic distance‐dependent statistical potential from a sample of native structures that does not depend on any adjustable parameters (Discrete Optimized Protein Energy, or DOPE). DOPE is based on an improved reference state that corresponds to noninteracting atoms in a homogeneous sphere with the radius dependent on a sample native structure; it thus accounts for the finite and spherical shape of the native structures. The DOPE potential was extracted from a nonredundant set of 1472 crystallographic structures. We tested DOPE and five other scoring functions by the detection of the native state among six multiple target decoy sets, the correlation between the score and model error, and the identification of the most accurate non‐native structure in the decoy set. For all decoy sets, DOPE is the best performing function in terms of all criteria, except for a tie in one criterion for one decoy set. To facilitate its use in various applications, such as model assessment, loop modeling, and fitting into cryo‐electron microscopy mass density maps combined with comparative protein structure modeling, DOPE was incorporated into the modeling package MODELLER‐8.
Predicting and testing resource partitioning in a tropical fish assemblage of zooplanktivorous ‘barbs’: an ecomorphological approach
Authors: Dejen E. , Vijverberg J. , De Graaf M. , Sibbing F. A.
Published: October 2006

Morphometrics on 25 critical feeding structures predicted conspicuous specializations in Barbus tanapelagius (pursuit hunting for zooplankton), Labeobarbus brevicephalus (surface dwelling pump‐filter‐feeder on zooplankton) and Barbus pleurogramma (particulate feeding on tough, benthic food), whereas for Barbus humilis intermediate values predicted few constraints and specializations in feeding. These potential niches, set by fish size and structural constraints, were tested by comparing gut contents collected during a 24 months sampling programme on Lake Tana, Ethiopia. Zooplankton dominated the diet of B. tanapelagius (75% of gut volume) and L. brevicephalus (39%). The guts of B. pleurogramma and juveniles of the large labeobarbs showed an array of benthic food types, whereas B. humilis had the widest food niche, both zooplankton (40% of gut volume) and benthic invertebrates. Although the pelagic species showed the largest spatial overlap, their size, feeding modes and utilization of zooplankters differed: L. brevicephalus preyed predominantly on the larger zooplankton (Daphnia sp.) and B. tanapelagius also on smaller species (e.g. Bosmina sp. and cyclopoid copepods). The spatial segregation between B. tanapelagius (pelagic) and the juvenile labeobarbs (littoral) indicated the possibility for a small pelagic barb fishery without negative effects on the labeobarb stocks. The ecomorphological approach using the ‘Food‐Fish Model’ appeared to predict competitive positions and resource partitioning appropriately, and is of major importance to evaluate food web interactions.
Gape morphology of cod Gadus morhua L., haddock Melanogrammus aeglefinus (L.) and whiting Merlangius merlangus (L.) through metamorphosis from larvae to juveniles in the western Irish Sea
Authors: Rowlands W. Ll. , Dickey‐Collas M. , Geffen A. J. , Nash R. D. M.
Published: October 2006

Variations in standard length (LS), gape size (SG) and jaw length (LJ) were studied in larval and juvenile gadoids (cod Gadus morhua, haddock Melanogrammus aeglefinus and whiting Merlangius merlangus) from 4 to 70 mm. The increase in SG and LJ was not linear with respect to LS. The relationship was best described by segmented regression lines in all three species, with an inflection point at c. 10·5 mm. The SG and LJ increased more rapidly in relation to larval LS for individuals smaller than this inflection point size. The rates of increase slowed significantly post‐inflection, an effect more noticeable in SG data compared to LJ data. In each case, the inflection point fell in the intermediate period of development between the larval and juvenile stages, which could be considered as metamorphosis. Published equations that have been used to predict SG from LJ lead to the overestimation of gape. New relationships are presented, which may be used to predict SG from measurements of either LS or upper jaw length in cod, haddock and whiting.
Induced sex change in black sea bass
Authors: Benton C. B. , Berlinsky D. L.
Published: October 2006

Experiments were conducted to identify factors involved in sex change in the protogynous black sea bass Centropristis striata. Black sea bass maintained in the ratio of 8 females (F):0 males (M) for 9 months reversed sex while those kept at the ratios of 6F:2M or 4F:4M did not. Female black sea bass implanted with 1·0 mg 11‐ketotestosterone (11‐KT) or 10 mg fadrozole (FAD) changed sex and began spermiating while those implanted with 0·1 mg 11‐KT or 1·0 mg FAD underwent incomplete sex reversal. One fish implanted with 1·0 mg FAD initiated sex change but was not spermiating at the end of the study. One fish in the control group, the largest fish in the study, initiated sex change. These results suggest that the presence of males may restrict sex reversal in black sea bass and that high 17β‐oestradiol:11‐KT is required for maintaining ovarian function.
Pharmacokinetics and safety assessments of high‐dose and 4‐week treatment with S‐3304, a novel matrix metalloproteinase inhibitor, in healthy volunteers
Authors: Mant Timothy G. K. , Bradford Daniel , Amin Dipti M. , Pisupati Jaya , Kambayashi Yoshikazu , Yano Yoshitaka , Tanaka Kazushige , Yamada‐Sawada Takuko
Published: October 2006

Aims

To investigate the tolerability, safety and pharmacokinetics of S‐3304 in healthy volunteers treated with high doses of S‐3304 for 28 days.

Methods

Thirty‐two healthy volunteers were recruited. Four male and four female subjects were allocated to one of four doses (800 mg, 1600 mg, 2400 mg and 3200 mg). At each dose six volunteers took active medication and two volunteers took placebo in a double‐blind fashion. Volunteers took a single dose on days 1 and 28 for pharmacokinetic purposes, and took twice daily doses from day 3–27. The pharmacokinetics of S‐3304 and its hydroxy metabolites were evaluated. Tolerance was based on subjective adverse events, clinical examination, vital signs, ECG and laboratory tests including haematology and biochemistry profiles using CTC grading.

Results

Doses up to 2400 mg twice daily were generally well tolerated. At 3200 mg twice daily, five volunteers including one randomized to placebo were withdrawn from treatment mainly due to alanine aminotransferase (ALT) elevation. Cmax of S‐3304 on day 1, whose geometric mean and 95% confidence interval were 66.3 µg ml−1 (48.8, 90.0) for 800 mg, 82.6 µg ml−1 (69.3, 98.6) for 1600 mg, 89.5 µg ml−1 (79.5, 100.7) for 2400 mg, and 110.5 µg ml−1 (88.9, 137.7) for 3200 mg, respectively, was correlated with the log‐transformed peak ALT (P < 0.0001 for male and P = 0.048 for female volunteers).

Conclusions

In healthy volunteers the maximum tolerated dose of S‐3304 was 2400 mg twice daily. ALT elevation was the most frequent dose‐limiting factor and was correlated with Cmax on day 1.
Current management of follicular lymphomas
Authors: Hiddemann Wolfgang , Buske Christian , Dreyling Martin , Weigert Oliver , Lenz Georg , Unterhalt Michael
Published: October 2006

After decades of stagnation, the prognosis of patients with follicular lymphomas (FL) has changed substantially within the last few years due to new and effective therapeutic modalities. These include myeloablative therapy followed by autologous stem cell transplantation (ASCT) in younger patients in first remission, which showed a significant prolongation of remission duration in three prospective randomised trials while the impact on overall survival still needs to be determined. Adding the anti‐CD 20 antibody Rituximab to conventional chemotherapy resulted in a significant increase in remission rate, remission duration and, in two of four currently available prospective randomised studies, even in a longer overall survival. A prolongation of remission duration was also seen when Rituximab was given as maintenance after cytoreductive therapy including Rituximab. Radio‐immunotherapy (RIT) with radioisotopes coupled to monoclonal antibodies produced encouraging data in several phase II studies. New therapeutic perspectives have also emerged from increasing insights into the biology of the disease that unravel molecular targets for novel agents, some of which have entered clinical evaluation already.
A novel beta‐delta globin gene fusion, anti‐Lepore Hong Kong, leads to overexpression of delta globin chain and a mild thalassaemia intermedia phenotype when co‐inherited with β0‐thalassaemia
Authors: So Chi‐Chiu , Chan Amy Y. Y. , Tsang Stella T. Y. , Lee Anselm C. W. , Au Wing‐Yan , Ma Edmond S. K. , Chan Li‐Chong
Published: October 2006

Anti‐Lepore haemoglobins (Hb) are rare βδ fusion variants that arise from non‐homologous crossover during meiosis, resulting in a δ–βδ–β configuration. A novel anti‐Lepore mutation (anti‐Lepore Hong Kong) was found in two Chinese families with raised Hb A2. Direct sequencing revealed a crossover within a 54‐bp region spanning the junction of cap site (CAP) and exon 1, which predicted the production of normal δ‐globin. Determination of α/β‐mRNA ratios by quantitative real‐time polymerase chain reaction demonstrated downregulation of the β gene in cis due to the interposed βδ fusion gene. Although heterozygotes have normal red cell indices and are clinically silent, compound heterozygotes with β0 mutation in trans produce a mild thalassaemia intermedia phenotype with a markedly raised Hb A2 level that may mimic clinically mild Hb E‐β+‐thalassaemia. Awareness of the presence of anti‐Lepore Hong Kong will help to resolve diagnostic problems in regions with significant prevalence of globin disorders.
Smooth muscle cell proliferation but not neointimal formation is dependent on alloantibody in a murine model of intimal hyperplasia
Authors: Soleimani B , Katopodis A , Wieczorek G , George A J T , Hornick P I , Heusser C
Published: October 2006

Transplant coronary artery disease is the pre-eminent cause of late cardiac allograft failure. It is primarily characterized by a concentric intimal hyperplasia, which we designate transplant intimal hyperplasia (TIH). Although the pathogenesis of TIH is predominately immune driven, the specific role of alloantibodies in the disease process remains undefined. In this study we investigated the contribution of alloantibodies to the development of TIH in a murine model. Orthotopic, carotid artery transplantation was performed between B10A(2R) (H-2h2) donor mice and B-cell deficient μMT–/– knockout or wild-type C57BL/6 (H-2b) recipients in the absence of immunosuppression. Grafts were harvested at 35 days and subjected to planimetry and immunohistochemistry. Alloantibodies were detectable in wild-type recipients within 7 days of transplantation and recipients developed marked TIH at 35 days. Allografts harvested from B-cell deficient recipient mice also developed TIH, which was comparable in severity with wild-type recipients. However, whereas allografts from wild-type recipients showed marked intimal smooth muscle cell (SMC) proliferation, the neointima in B-cell deficient recipients lacked SMCs. Post-transplantation administration of anti-donor serum to μMT–/– recipients restored neointimal SMC population but did not influence the severity of TIH. Significant neointimal formation occurs in the absence of alloantibodies but lacks a SMC component. Therefore, SMC migration and proliferation is antibody dependent.
A diurnal variation in testicular hormone production is maintained following gonadotrophin suppression in normal men
Authors: Walton Melanie J. , Anderson Richard A. , Kicman Andrew T. , Elton Rob A. , Ossowska Karolina , Baird David T.
Published: October 2006

Objective  A diurnal variation in serum testosterone in adult men is well recognized, but whether this occurs during exogenous testosterone administration and the degree to which it is endogenous to the testis is unclear.

Design  A clinical research centre investigation of testicular function in normal men.

Patients  Twenty normal men were recruited, 10 of whom were investigated during administration of testosterone with etonogestrel to suppress gonadotrophin secretion.

Measurements  Hourly blood samples were taken over 24 h for measurement of testosterone, inhibin B, LH, FSH and cortisol. Urinary excretion of testosterone and the testicular steroid epitestosterone was also measured.

Results  In the controls, a diurnal variation in serum testosterone and LH but not FSH was detected. The treated group had similar testosterone concentrations but showed no diurnal variation. Periodicity was also detected in inhibin B concentrations in 5 of the controls and in 9 of the treated group, who also showed synchrony not seen in the controls. Both groups showed diurnal variation in cortisol. Urinary testosterone excretion did not show a diurnal variation in either group, but this was apparent for epitestosterone with a morning peak in both groups despite the markedly lower excretion in the treated men.

Conclusions  The diurnal variation of testosterone in normal men is due to a change in secretion rather than in clearance and is largely LH driven. An endogenous rhythm in both testicular steroidogenesis (epitestosterone) and Sertoli cell function (inhibin B) is also present.
Genetic profiling of dendritic cells exposed to live‐ or ultraviolet‐irradiated Chlamydia muridarum reveals marked differences in CXC chemokine profiles
Authors: Zaharik Michelle L. , Nayar Tarun , White Rick , Ma Caixia , Vallance Bruce A. , Straka Nadine , Jiang Xiaozhou , Rey‐Ladino Jose , Shen Caixia , Brunham Robert C.
Published: October 2006

Chlamydia trachomatis is a major cause of sexually transmitted disease worldwide for which an effective vaccine is being actively pursued. Current vaccine efforts will be aided by elucidating the interaction between Chlamydia and dendritic cells (DCs). Protective immunity appears to develop slowly following natural infection in humans, and early vaccine trials using inactivated C. trachomatis resulted in partial, short‐lived protection with possible enhanced inflammatory pathology during re‐infection. Thus, immunity following natural infection with live chlamydia may differ fundamentally from immune responses induced by immunization with inactivated chlamydia. We explored this conjecture by studying the response of DCs exposed to either viable or inactivated [ultraviolet (UV) –irradiated] chlamydia elementary bodies (EBs; designated as Live‐EB and UV‐EB, respectively) using Affymetrix GeneChip microarrays. Thirty‐one immunologically characterized genes were differentially expressed by DCs following exposure to Live‐EB or UV‐EB, including two glutamic acid–leucine–arginine cysteine–X–cysteine (ELR CXC) neutrophil chemoattractant chemokines, Cxcl1 (KC), and Cxcl2 (MIP‐2). Up‐regulation of these genes by Live‐EB as compared to UV‐EB was verified by quantitative reverse transcription–polymerase chain reaction and increased chemokine secretion was confirmed by enzyme‐linked immunosorbent assay both in vitro and in vivo. Immunofluorescence and fluorescence‐activated cell sorter analysis of chlamydia‐infected lung tissue confirmed that Live‐EB but not UV‐EB induced significant DC and neutrophil infiltration during infection. These observations demonstrate that the development of an antichlamydial immune response is dramatically influenced by chlamydial viability. This has implications as to why early inactivated chlamydial vaccines were ineffective and suggests that new vaccine design efforts may benefit from in vitro DC screening for ELR chemokine expression profiles.
Unexpected development of autoimmunity in BAFF‐R‐mutant MRL‐lprmice
Authors: Ju Zhong L. , Shi Gui Y. , Zuo Jin X. , Zhang Jing W. ,   Jian Sun
Published: October 2006

BAFF‐R is the predominant receptor that mediates B‐cell activating factor (BAFF)‐dependent B‐cell signalling and plays a critical role in late‐stage B‐cell maturation and survival. BAFF has been implicated in the development of autoimmunity and systemic lupus erythematosus (SLE). To define the role of BAFF‐R in autoimmunity and SLE, we crossed A/WySnJ mice with MRL‐lprmice and generated BAFF‐R‐mutant MRL‐lprmice. The BAFF‐R mutation markedly impaired the development of immature, mature and marginal zone B cells in the spleens of MRL‐lprmice. Unexpectedly, the BAFF‐R mutation in MRL‐lprmice did not result in decreased autoantibody production, hypergammaglobulinaemia or immune complex‐mediated glomerulonephritis. Rather, the ability of BAFF‐R‐mutantlprsplenic B cells to produce immunoglobulinsin vitrowas not decreased, although germinal centre formation, antibody response and B‐cell proliferation were impaired. Further studies found increased numbers of B cells in the bone marrow of BAFF‐R‐mutant MRL‐lprmice compared to the BAFF‐R‐intact lupus mice. ELISPOT analysis revealed that BAFF‐R‐mutant MRL‐lprmice had more antibody‐secreting cells in their bone marrow than the control mice. Thus, these findings could explain the development of autoimmunity and hypergammaglobulinaemia observed in BAFF‐R‐mutant MRL‐lprmice.
Physico‐chemical properties of protein‐bound polysaccharide from Agaricus blazei Murill prepared by ultrafiltration and spray drying process
Authors: Hong Joo Heon , Choi Yong Hee
Published: October 2006

This study was conducted to develop the powder material and investigate the various physico‐chemical properties of protein‐bound polysaccharide with different molecular weight from Agaricus blazei Murill using ultrafiltration and spray‐drying process. Powder properties of the three spray‐dried powders were very different based on their molecular weights. The inlet temperature had less influence than pump rate on particle size of spray‐dried powders. The moisture content of powders was increased with increasing pump rate and decreasing inlet temperature. Among these powders, SD‐1, the molecular weight of which is below 10 kDa, was less flowable by internal cohesion. The decomposition temperature for the powders was in the range of 200–400 °C and showed relatively good enough for their thermal stabilities.