bluuebunny/crossref_metadata_2025 huggingface dataset:
Requirement for asparagine in the aquaporin NPA sequence signature motifs for cation exclusion
Authors: Wree Dorothea , Wu Binghua , Zeuthen Thomas , Beitz Eric
Published: December 2010

Two highly conserved NPA motifs are a hallmark of the aquaporin (AQP) family. The NPA triplets form N‐terminal helix capping structures with the Asn side chains located in the centre of the water or solute‐conducting channel, and are considered to play an important role in AQP selectivity. Although another AQP selectivity filter site, the aromatic/Arg (ar/R) constriction, has been well characterized by mutational analysis, experimental data concerning the NPA region – in particular, the Asn position – is missing. Here, we report on the cloning and mutational analysis of a novel aquaglyceroporin carrying one SPA motif instead of the NPA motif from Burkholderia cenocepacia, an epidemic pathogen of cystic fibrosis patients. Of 1357 AQP sequences deposited in RefSeq, we identified only 15 with an Asn exchange. Using direct and phenotypic permeability assays, we found that Asn and Ser are freely interchangeable at both NPA sites without affecting protein expression or water, glycerol and methylamine permeability. However, other mutations in the NPA region led to reduced permeability (S186C and S186D), to nonfunctional channels (N64D), or even to lack of protein expression (S186A and S186T). Using electrophysiology, we found that an analogous mammalian AQP1 N76S mutant excluded protons and potassium ions, but leaked sodium ions, providing an argument for the overwhelming prevalence of Asn over other amino acids. We conclude that, at the first position in the NPA motifs, only Asn provides efficient helix cap stabilization and cation exclusion, whereas other small residues compromise structural stability or cation exclusion but not necessarily water and solute permeability.
Monitoring of Tumor Growth and Post‐Irradiation Recurrence in a Diffuse Intrinsic Pontine Glioma Mouse Model
Authors: Caretti Viola , Zondervan Ilse , Meijer Dimphna H. , Idema Sander , Vos Wim , Hamans Bob , Bugiani Marianna , Hulleman Esther , Wesseling Pieter , Vandertop W. Peter , Noske David P. , Kaspers Gertjan , Molthoff Carla F.M. , Wurdinger Thomas
Published: December 2010

Diffuse intrinsic pontine glioma (DIPG) is a fatal malignancy because of its diffuse infiltrative growth pattern. Translational research suffers from the lack of a representative DIPG animal model. Hence, human E98 glioma cells were stereotactically injected into the pons of nude mice. The E98 DIPG tumors presented a strikingly similar histhopathology to autopsy material of a DIPG patient, including diffuse and perivascular growth, brainstem‐ and supratentorial invasiveness and leptomeningeal growth. Magnetic resonance imaging (MRI) was effectively employed to image the E98 DIPG tumor. [18F] 3′‐deoxy‐3′‐[18F]fluorothymidine (FLT) positron emission tomography (PET) imaging was applied to assess the subcutaneous (s.c.) E98 tumor proliferation status but no orthotopic DIPG activity could be visualized. Next, E98 cells were cultured in vitro and engineered to express firefly luciferase and mCherry (E98‐Fluc‐mCherry). These cultured E98‐Fluc‐mCherry cells developed focal pontine glioma when injected into the pons directly. However, the diffuse E98 DIPG infiltrative phenotype was restored when cells were injected into the pons immediately after an intermediate s.c. passage. The diffuse E98‐Fluc‐mCherry model was subsequently used to test escalating doses of irradiation, applying the bioluminescent Fluc signal to monitor tumor recurrence over time. Altogether, we here describe an accurate DIPG mouse model that can be of clinical relevance for testing experimental therapeutics in vivo.
Deposition of Hyperphosphorylated Tau in Cerebellum of PS1 E280A Alzheimer's Disease
Authors: Sepulveda‐Falla Diego , Matschke Jakob , Bernreuther Christian , Hagel Christian , Puig Berta , Villegas Andres , Garcia Gloria , Zea Julian , Gomez‐Mancilla Baltazar , Ferrer Isidre , Lopera Francisco , Glatzel Markus
Published: December 2010

Early‐onset familial Alzheimer's disease (AD) caused by presenilin‐1 mutation E280A (PS1‐E280A) presents wide clinical and neuropathological variabilities. We characterized clinically and neuropathologically PS1‐E280A focusing in cerebellar involvement and compared it with early‐onset sporadic Alzheimer's disease (EOSAD). Twelve E280A brains and 12 matched EOSAD brains were analyzed for beta‐amyloid and hyperphosphorylated tau (pTau) morphology, beta‐amyloid subspecies 1–40, 1–42 levels, pTau levels, and expression of stress kinases in frontal cortex and cerebellum. The data were correlated to clinical and genetic findings. We observed higher beta‐amyloid load, beta‐amyloid 1–42 and pTau concentrations in frontal cortex of PS1‐E280A compared with EOSAD. High beta‐amyloid load was found in the cerebellum of PS1‐E280A and EOSAD patients. In PS1‐E280A, beta‐amyloid localized to the molecular and Purkinje cell layers, whereas EOSAD showed them in Purkinje and granular cell layers. Surprisingly, 11 out of 12 PS1‐E280A patients showed deposition of pTau in the cerebellum. Also, seven out of 12 PS1‐E280A patients presented cerebellar ataxia. We conclude that deposition of beta‐amyloid in the cerebellum is prominent in early‐onset AD irrespective of genetic or sporadic origin. The presence of pTau in cerebellum in PS1‐E280A underscores the relevance of cerebellar involvement in AD and might be correlated to clinical phenotype.
Bidirectional visible‐NIR and biconical FT‐IR reflectance spectra of Almahata Sitta meteorite samples
Authors: HIROI Takahiro , JENNISKENS Peter , BISHOP Janice L. , SHATIR Tahani S. M. , KUDODA Ayman M. , SHADDAD Muawia H.
Published: December 2010

Abstract–Bidirectional visible and near‐infrared and off‐axis biconical Fourier transform infrared reflectance spectra of Almahata Sitta meteorite stone samples, fragments of asteroid 2008 TC3, have been measured. These meteorites represent the first freshly fallen polymict ureilites available for such studies. Although the chip samples show varying degrees of terrestrial weathering depending on their environment on Earth, many of them are much fresher than other ureilites known to date. The majority of the Almahata Sitta chips studied here show only a weak near‐UV absorption, a flat spectrum at visible and near‐IR wavelengths, and varying depths of the 1 and 2 μm pyroxene and olivine bands. The astronomical reflectance observations of the asteroid 2008 TC3over the range 0.55–1.0 μm provide a constraint on what a combination of the measured spectra can represent in the surface reflectance of the asteroid over the 0.32–2.55 μm range measured in this study. Most of the recovered samples of Almahata Sitta have textures and albedos similar to stones #27 (largest recovered fragment), #4, and #47. Results of linear least‐square fits of the asteroid 2008 TC3spectrum with two sets of the meteorite spectra suggest that the asteroid had 10–12% albedo and no fine regolith on its surface. We note that other lithologies may be at the surface of other fragments of the asteroid family from which 2008 TC3originated. In that case, reflectance spectra could vary significantly among family members.
Thermal and fragmentation history of ureilitic asteroids: Insights from the Almahata Sitta fall
Authors: HERRIN Jason S. , ZOLENSKY Michael E. , ITO Motoo , LE Loan , MITTLEFEHLDT David W. , JENNISKENS Peter , ROSS Aidan J. , SHADDAD Muawia H.
Published: December 2010

Abstract–The Almahata Sitta fall event provides a unique opportunity to gain insight into the nature of ureilitic objects in space and the delivery of ureilite meteorites to Earth. From thermal events recorded in the mineralogy, petrology, and chemistry of ureilites recovered from the fall area, we reconstruct a timeline of events that led to their genesis. This history is similar to that of other known ureilites and supportive of a disrupted ureilite parent body hypothesis. Temperatures of final mantle equilibrium were 1200–1300 °C, but this high‐temperature history was abruptly terminated by rapid cooling and reduction associated with pressure loss. The onset of late reduction reactions and onset of rapid cooling must have been essentially simultaneous, most likely engendered by the same event. Cooling rates of 0.05–2 °C h−1determined from reversely zoned olivines and pyroxenes in Almahata Sitta imply rapid disassembly into fragments tens meters in size or smaller. This phenomenon seems to have affected all known portions of the ureilite parent body mantle, implying an event of global significance rather than localized unroofing. Reaccretion of one or more daughter asteroids occurred only after significant heat loss at minimum time scales of weeks to months, during which time the debris cloud surrounding the disrupted parent was inefficient at retaining heat. Fragments initially dislodged from the ureilite parent body mantle underwent subsequent size reduction and mixed with various chondritic bodies, giving rise to polylithologic aggregate objects such as asteroid 2008 TC3.
Estimation of Multibody Kinematics Using Position Measurements
Authors: Lee Jenchieh , Flashner Henryk , McNitt-Gray Jill L.
Published: December 2010

A method for the estimation of kinematics of a system of rigid bodies connected by three degrees of freedom rotational joints using position measurements is introduced. In the proposed approach, system kinematics are computed from experimental measurements while preserving important physical and kinematic properties. These properties include system integrity, i.e., preserving interconnections between the bodies, and the entire system dynamic properties, namely, center of mass kinematics and its angular momentum. The computational procedure consists in solving a sequence of optimizations of appropriately formulated objective functions that incorporate the preservation of physical and kinematic properties by employing the penalty function approach. The configuration of the segment kinematics of the system is computed via a quaternion parametrization of orientation that leads to an efficient computation procedure. The sequence of optimization problems is solved using an embedded iteration process. Two studies are presented to demonstrate the performance of the proposed approach: estimations of the kinematics of a simulated three-link model and of an experimentally measured 3D motion of human body during flight phase of a jump. The results of the two studies indicate fast convergence of the algorithm to an optimal solution while accurately satisfying the imposed the constraints.
Adhesion, proliferation, and gene expression profile of human umbilical vein endothelial cells cultured on bilayered polyelectrolyte coatings composed of glycosaminoglycans
Authors: Heng Boon Chin , Bezerra Paula Porto , Meng Qing Rui , Chin Desmond Wai-Loon , Koh Li Buay , Li Hai , Zhang Hua , Preiser Peter Rainer , Boey Freddy Yin-Chiang , Venkatraman Subbu S.
Published: December 2010

This study characterized human umbilical vein endothelial cell HUVEC adhesion, proliferation, and gene expression on bilayered polyelectrolyte coatings composed of an outermost layer of glycosaminoglycans hyaluronan, heparin, or chondroitin sulfate, with an underlying layer of poly-l-lysine or chitosan. The proportion of cells that adhered to the various polyelectrolyte coatings after 1 and 2 h incubations was quantified by the WST-8 assay. Interchanging poly-l-lysine with chitosan resulted in significant differences in cellular adhesion to the outermost glycosaminoglycan layer after 1 h, but these differences became insignificant after 2 h. The proliferation of HUVEC on the various bilayered polyelectrolyte coatings over 10 days was characterized using the WST-8 assay. Regardless of whether the underlying layer was poly-l-lysine or chitosan, HUVEC proliferation on the hyaluronan outermost layer was significantly less than on heparin or chondroitin sulfate. Additionally, it was observed that there was more proliferation with poly-l-lysine as the underlying layer, compared to chitosan. Subsequently, real-time polymerase chain reaction was used to analyze the expression of seven genes related to adhesion, migration, and endothelial function (VWF, VEGFR, VEGFA, endoglin, integrin-α5, ICAM1, and ICAM2 by HUVEC cultured on the various bilayered polyelectrolyte coatings for 3 days. With poly-l-lysine as the underlying layer, biologically significant differences greater than twofold in the expression of VWF, VEGFR, VEGFA, endoglin, and ICAM1 were observed among the three glycosaminoglycans. With chitosan as the underlying layer, all three glycosaminoglycans displayed biologically significant differences in the expression of VWF and VEGFR compared to the chitosan control. CT-HA displayed the highest level of expression of VWF, whereas expression levels of VEGFR were almost similar among the three glycosaminoglycans.
Impact of vitronectin concentration and surface properties on the stable propagation of human embryonic stem cells
Authors: Li Jian , Bardy Jo'an , Yap Lynn Y. W. , Chen Allen , Victor Nurcombe , Cool Simon M. , Oh Steve K. W. , Birch William R.
Published: December 2010

The standard method for culturing human embryonic stem cells (hESC) uses supporting feeder layers of cells or an undefined substrate, MatrigelTM, which is a basement membrane extracted from murine sarcoma. For stem cell therapeutic applications, a superior alternative would be a defined, artificial surface that is based on immobilized human plasma vitronectin (VN), which is an adhesion-mediating protein. Therefore, VN adsorbed to diverse polymer surfaces was explored for the continuous propagation of hESC. Cells propagated on VN-coated tissue culture polystyrene (TCPS) are karyotypically normal after >10 passages of continuous culture, and are able to differentiate into embryoid bodies containing all three germ layers. Expansion rates and pluripotent marker expression verified that a minimal VN surface density threshold is required on TCPS. Further exploration of adsorbed VN was conducted on polymer substrates with different properties, ranging from hydrophilic to hydrophobic and including cationic and anionic polyelectrolyte coatings. Despite differing surface properties, these substrates adsorbed VN above the required surface density threshold and were capable of supporting hESC expansion for >10 passages. Correlating wettability of the VN-coated surfaces with the response of cultured hESC, higher cell expansion rates and OCT-4 expression levels were found for VN-coated TCPS, which exhibits a water contact angle close to 65°. Importantly, this simple, defined surface matches the performance of the benchmark Matrigel, which is a hydrogel with highly complex composition.
Personalized Prostate Cancer Screening: Improving PSA Tests with Genomic Information
Authors: Witte John S.
Published: December 2010

Incorporation of genetic markers into prostate-specific antigen screening may ultimately yield a more predictive screening tool for prostate cancer.
A Therapeutic Target for Smoking-Associated Lung Cancer
Authors: Turner Nicholas C. , Seckl Michael J.
Published: December 2010

A new oncogenic aberration in smoking-associated lung cancer may be the disease's first relatively high-frequency therapeutic target.
Therapeutic Targeting for the Long Term
Authors: Bremer Andrew A.
Published: December 2010

The liver X receptor–β may be required for the adverse metabolic effects of exogenously administered glucocorticoids.
THE MASS-CRITICAL FOURTH-ORDER SCHRÖDINGER EQUATION IN HIGH DIMENSIONS
Authors: PAUSADER BENOIT , SHAO SHUANGLIN
Published: December 2010

We prove global wellposedness and scattering for the Mass-critical homogeneous fourth-order Schrödinger equation in high dimensions n ≥ 5, for general L2initial data in the defocusing case, and for general initial data with Mass less than certain fraction of the Mass of the ground state in the focusing case.
FORMATION OF TRAPPED SURFACES FOR THE SPHERICALLY SYMMETRIC EINSTEIN–VLASOV SYSTEM
Authors: ANDRÉASSON HÅKAN , REIN GERHARD
Published: December 2010

We consider the spherically symmetric, asymptotically flat, non-vacuum Einstein equations, using as matter model a collisionless gas as described by the Vlasov equation. We find explicit conditions on the initial data which guarantee the formation of a trapped surface in the evolution which in particular implies that weak cosmic censorship holds for these data. We also analyze the evolution of solutions after a trapped surface has formed and we show that the event horizon is future complete. Furthermore we find that the apparent horizon and the event horizon do not coincide. This behavior is analogous to what is found in certain Vaidya spacetimes. The analysis is carried out in Eddington–Finkelstein coordinates.
LARGE-DATA SOLUTION OF A MODEL SYSTEM FOR SINGULAR SHOCKS
Authors: SEVER MICHAEL
Published: December 2010

A suitably modified front-tracking algorithm is used to solve a class of Cauchy problems for a pair of conservation laws known as the model system for singular shocks or as the Keyfitz–Kranzer system. Initial data of large oscillation and including a finite number of positive Dirac masses in one of the dependent variables is permitted.

For such initial data, a distribution solution is constructed up to an arbitrary given finite time T. At any given time up to T, the constructed solution is uniformly bounded in space except possibly at a finite number of points. With respect to time, our solutions are weakly Lipshitz in the space of measures on ℝ. However, our solutions are not traditional weak solutions, because of the unavoidable appearance of singular shocks carrying finite Dirac mass. Furthermore, the bounded parts of our solutions are of lower than customary regularity, being of bounded 2-variation in space, pointwise but not uniformly with respect to time.
Photon Science at Accelerator-Based Light Sources
Authors: Schneider Jochen R.
Published: December 2010

Accelerator-based light sources stimulated progress in photon science in a truly extraordinary manner. The spectral brightness of storage-ring-based facilities increased by three orders of magnitude every 10 years since the 1960s. The extreme peak brightness at single-pass free electron X-ray lasers with pulse durations variable between about 1 and 300 femtoseconds will allow transformative experiments in many areas of science. This article is an attempt to show how progress in accelerator science and technology stimulated advancement in photon science, by discussing a limited number of examples of work at third generation storage ring facilities and free electron lasers. Hopes for further improvements in specific beam properties are expressed.
Accelerator-Based Sources of Infrared and Terahertz Radiation
Authors: Müller Anke-Susanne
Published: December 2010

Infrared radiation from the near- to the far-infrared (terahertz) region of the electromagnetic spectrum is extensively used for many different purposes. Accelerator-based sources of infrared and terahertz radiation have become well-accepted research tools. This article introduces the physics processes underlying the generation of infrared radiation by different methods. Special emphasis is put on the interesting properties of coherent radiation, and the corresponding accelerator requirements are discussed. Finally, the various available accelerator-based sources are compared in view of different figures of merit.
DNA Barcoding of Marine Metazoa
Authors: Bucklin Ann , Steinke Dirk , Blanco-Bercial Leocadio
Published: December 2010

More than 230,000 known species representing 31 metazoan phyla populate the world's oceans. Perhaps another 1,000,000 or more species remain to be discovered. There is reason for concern that species extinctions may outpace discovery, especially in diverse and endangered marine habitats such as coral reefs. DNA barcodes (i.e., short DNA sequences for species recognition and discrimination) are useful tools to accelerate species-level analysis of marine biodiversity and to facilitate conservation efforts. This review focuses on the usual barcode region for metazoans: a ∼648 base-pair region of the mitochondrial cytochrome c oxidase subunit I (COI) gene. Barcodes have also been used for population genetic and phylogeographic analysis, identification of prey in gut contents, detection of invasive species, forensics, and seafood safety. More controversially, barcodes have been used to delimit species boundaries, reveal cryptic species, and discover new species. Emerging frontiers are the use of barcodes for rapid and increasingly automated biodiversity assessment by high-throughput sequencing, including environmental barcoding and the use of barcodes to detect species for which formal identification or scientific naming may never be possible.
Microbial Extracellular Enzymes and the Marine Carbon Cycle
Authors: Arnosti Carol
Published: December 2010

Extracellular enzymes initiate microbial remineralization of organic matter by hydrolyzing substrates to sizes sufficiently small to be transported across cell membranes. As much of marine primary productivity is processed by heterotrophic microbes, the substrate specificities of extracellular enzymes, the rates at which they function in seawater and sediments, and factors controlling their production, distribution, and active lifetimes, are central to carbon cycling in marine systems. In this review, these topics are considered from biochemical, microbial/molecular biological, and geochemical perspectives. Our understanding of the capabilities and limitations of heterotrophic microbial communities has been greatly advanced in recent years, in part through genetic and genomic approaches. New methods to measure enzyme activities in the field are needed to keep pace with these advances and to pursue intriguing evidence that patterns of enzyme activities in different environments are linked to differences in microbial community composition that may profoundly affect the marine carbon cycle.
Modeling the Dynamics of Continental Shelf Carbon
Authors: Hofmann Eileen E. , Cahill Bronwyn , Fennel Katja , Friedrichs Marjorie A.M. , Hyde Kimberly , Lee Cindy , Mannino Antonio , Najjar Raymond G. , O'Reilly John E. , Wilkin John , Xue Jianhong
Published: December 2010

Continental margin systems are important contributors to global nutrient and carbon budgets. Effort is needed to quantify this contribution and how it will be modified under changing patterns of climate and land use. Coupled models will be used to provide projections of future states of continental margin systems. Thus, it is appropriate to consider the limitations that impede the development of realistic models. Here, we provide an overview of the current state of modeling carbon cycling on continental margins as well as the processes and issues that provide the next challenges to such models. Our overview is done within the context of a coupled circulation-biogeochemical model developed for the northeastern North American continental shelf region. Particular choices of forcing and initial fields and process parameterizations are used to illustrate the consequences for simulated distributions, as revealed by comparisons to observations using quantitative statistical metrics.
Biofilms and Marine Invertebrate Larvae: What Bacteria Produce That Larvae Use to Choose Settlement Sites
Authors: Hadfield Michael G.
Published: December 2010

Communities of microorganisms form thin coats across solid surfaces in the sea. Larvae of many marine invertebrates use biofilm components as cues to appropriate settlement sites. Research on the tube-dwelling polychaete worm Hydroides elegans, a globally common member of biofouling communities, is described to exemplify approaches to understanding biofilm bacteria as a source of settlement cues and larvae as bearers of receptors for bacterial cues. The association of species of the bacterial genus Pseudoalteromonas with larval settlement in many phyla is described, and the question of whether cues are soluble or surface-bound is reviewed, concluding that most evidence points to surface-bound cues. Seemingly contradictory data for stimulation of barnacle settlement are discussed; possibly both explanations are true. Paleontological evidence reveals a relationship between metazoans and biofilms very early in metazoan evolution, and thus the receptors for bacterial cues of invertebrate larvae are very old and possibly unique. Finally, despite more than 60 years of intense investigation, we still know very little about either the bacterial ligands that stimulate larval settlement or the cellular basis of their detection by larvae.
Local Adaptation in Marine Invertebrates
Authors: Sanford Eric , Kelly Morgan W.
Published: December 2010

Local adaptation in the sea was regarded historically as a rare phenomenon that was limited to a handful of species with exceptionally low dispersal potential. However, a growing body of experimental studies indicates that adaptive differentiation occurs in numerous marine invertebrates in response to selection imposed by strong gradients (and more complex mosaics) of abiotic and biotic conditions. Moreover, a surprisingly high proportion of the marine invertebrates known or suspected of exhibiting local adaptation are species with planktonic dispersal. Adaptive divergence among populations can occur over a range of spatial scales, including those that are fine-grained (i.e., meters to kilometers), reflecting a balance between scales of gene flow and selection. Addressing the causes and consequences of adaptive genetic differentiation among invertebrate populations promises to advance community ecology, climate change research, and the effective management of marine ecosystems.
Microbial Nitrogen Cycling Processes in Oxygen Minimum Zones
Authors: Lam Phyllis , Kuypers Marcel M.M.
Published: December 2010

Oxygen minimum zones (OMZs) harbor unique microbial communities that rely on alternative electron acceptors for respiration. Conditions therein enable an almost complete nitrogen (N) cycle and substantial N-loss. N-loss in OMZs is attributable to anammox and heterotrophic denitrification, whereas nitrate reduction to nitrite along with dissimilatory nitrate reduction to ammonium are major remineralization pathways. Despite virtually anoxic conditions, nitrification also occurs in OMZs, converting remineralized ammonium to N-oxides. The concurrence of all these processes provides a direct channel from organic N to the ultimate N-loss, whereas most individual processes are likely controlled by organic matter. Many microorganisms inhabiting the OMZs are capable of multiple functions in the N- and other elemental cycles. Their versatile metabolic potentials versus actual activities present a challenge to ecophysiological and biogeochemical measurements. These challenges need to be tackled before we can realistically predict how N-cycling in OMZs, and thus oceanic N-balance, will respond to future global perturbations.
Nitrogen Cycle of the Open Ocean: From Genes to Ecosystems
Authors: Zehr Jonathan P. , Kudela Raphael M.
Published: December 2010

The marine nitrogen (N) cycle controls the productivity of the oceans. This cycle is driven by complex biogeochemical transformations, including nitrogen fixation, denitrification, and assimilation and anaerobic ammonia oxidation, mediated by microorganisms. New processes and organisms continue to be discovered, complicating the already complex picture of oceanic N cycling. Genomics research has uncovered the diversity of nitrogen metabolism strategies in phytoplankton and bacterioplankton. The elemental ratios of nutrients in biological material are more flexible than previously believed, with implications for vertical export of carbon and associated nutrients to the deep ocean. Estimates of nitrogen fixation and denitrification continue to be modified, and anaerobic ammonia oxidation has been identified as a new process involved in denitrification in oxygen minimum zones. The nitrogen cycle in the oceans is an integral feature of the function of ocean ecosystems and will be a central player in how oceans respond during global environmental change.
Geologist at Sea: Aspects of Ocean History
Authors: Berger Wolfgang H.
Published: December 2010

Ocean history is largely read from deep-sea sediments, using microscopic fossils, notably foraminifers. Ice age fluctuations in the ocean's sediments provided for a new geologic understanding of climate change. The discovery of rapid decay of ice masses at the end of glacial periods was especially important, yielding rates of sea level rise reaching values of 1 to 2 m per century for millennia. Thanks to deep-ocean drilling, the overall planetary cooling trend in the Cenozoic was recognized as occurring in three large steps. The first step is at the Eocene–Oligocene boundary and is marked by a great change in sedimentation patterns; the second is in the middle Miocene, associated with a major pulse in the buildup of Antarctic ice masses and the intensification of upwelling regimes; and the third is within the late Pliocene and led into the northern ice ages. Evolution in the sea is linked to these various steps.
Marine Primary Production in Relation to Climate Variability and Change
Authors: Chavez Francisco P. , Messié Monique , Pennington J. Timothy
Published: December 2010

Marine photosynthetic plankton are responsible for approximately 50 petagrams (1015) of carbon per year of net primary production, an amount equivalent to that on land. This primary production supports essentially all life in the oceans and profoundly affects global biogeochemical cycles and climate. This review discusses the general distribution of primary production in the sea, the processes that regulate this distribution, and how marine primary production is sensitive to climate variability and change. Statistical modes of ocean variability and their characteristic interannual to multi-decadal timescales over the last century are described. Recent in situ and satellite time-series of primary production can be clearly linked to interannual ocean variability. Global marine primary production appears to have increased over the past several decades in association with multi-decadal variations. A paleoclimate record extends discussion to the centennial scale, providing contrasting insights into how marine primary production might vary in the future.
Recurrent Antitopographic Inhibition Mediates Competitive Stimulus Selection in an Attention Network
Authors: Lai Dihui , Brandt Sebastian , Luksch Harald , Wessel Ralf
Published: December 2010

Topographically organized neurons represent multiple stimuli within complex visual scenes and compete for subsequent processing in higher visual centers. The underlying neural mechanisms of this process have long been elusive. We investigate an experimentally constrained model of a midbrain structure: the optic tectum and the reciprocally connected nucleus isthmi. We show that a recurrent antitopographic inhibition mediates the competitive stimulus selection between distant sensory inputs in this visual pathway. This recurrent antitopographic inhibition is fundamentally different from surround inhibition in that it projects on all locations of its input layer, except to the locus from which it receives input. At a larger scale, the model shows how a focal top-down input from a forebrain region, the arcopallial gaze field, biases the competitive stimulus selection via the combined activation of a local excitation and the recurrent antitopographic inhibition. Our findings reveal circuit mechanisms of competitive stimulus selection and should motivate a search for anatomical implementations of these mechanisms in a range of vertebrate attentional systems.
Exercise, weight loss, and changes in body composition in mice: phenotypic relationships and genetic architecture
Authors: Kelly Scott A. , Nehrenberg Derrick L. , Hua Kunjie , Garland Theodore , Pomp Daniel
Published: December 2010

The regulation of body weight and composition is complex, simultaneously affected by genetic architecture, the environment, and their interactions. We sought to analyze the complex phenotypic relationships between voluntary exercise, food consumption, and changes in body weight and composition and simultaneously localize quantitative trait loci (QTL) controlling these traits. A large ( n = 815) murine advanced intercross line (G4) was created from a reciprocal cross between a high-running line and the inbred strain C57BL/6J. Body weight and composition (% fat, % lean) were measured at 4, 6, and 8 wk of age. After measurements at 8 wk of age, mice were given access to running wheels, during which food consumption was quantified and after which body weight and composition were assessed to evaluate exercise-induced changes. Phenotypic correlations indicated that the relationship between exercise and overall change in weight and adiposity depended on body composition before the initiation of exercise. Interval mapping revealed QTL for body weight, % fat, and % lean at 4, 6, and 8 wk of age. Furthermore, QTL were observed for food consumption and changes in weight, % fat, and % lean in response to short-term exercise. Here we provide some clarity for the relationship between weight loss, reduction in adiposity, food consumption, and exercise. Simultaneously, we reinforce the genetic basis for body weight and composition with some independent loci controlling growth at different ages. Finally, we present unique QTL providing insight regarding variation in weight loss and reduction in adiposity in response to exercise.
Global Stability and Oscillation of a Discrete Annual Plants Model
Authors: Saker S. H.
Published: December 2010

The objective of this paper is to systematically study the stability and
oscillation of the discrete delay annual plants model. In particular, we establish
some sufficient conditions for global stability of the unique positive fixed point and
establish an explicit sufficient condition for oscillation of the positive solutions about
the fixed point. Some illustrative examples and numerical simulations are included
to demonstrate the validity and applicability of the results.
Intraoperative PTH Assay during Minimally Invasive Parathyroidectomy May Be Helpful in the Detection of Double Adenomas and May Minimise the Risk of Recurrent Surgery
Authors: Ypsilantis E. , Charfare H. , Wassif W. S.
Published: December 2010

Background. Minimally invasive parathyroidectomy (MIP) is increasingly replacing the traditional bilateral neck exploration in the treatment of primary hyperparathyroidism (PHP). Intraoperative PTH (IOPTH) measurement has recently been introduced as a useful adjunct in confirming successful excision of abnormal parathyroid gland.Aims. We evaluate the safety, efficacy, and clinical usefulness of IOPTH measurement during MIP in a district general hospital.Methods. Retrospective review of eleven consecutive patients with PHP who underwent MIP with IOPTH, following preoperative assessment with ultrasound and sestamibi scans.Results. All patients had successful removal of the abnormal parathyroid gland. The concordance rate between ultrasound and sestamibi scan in localising the parathyroid adenoma was 82%. IOPTH measurement confirmed the removal of adenoma in all cases and, in one case, led to identification of a second adenoma, not localised preoperatively. The median hospital stay was 2 days (range 1–7 days). All patients remained normocalcaemic after a median of 6 months (range 1–10 months).Conclusions. Minimally invasive parathyroidectomy is a feasible, safe, and effective method for treatment of PHP. The use of IOPTH monitoring potentially offers increased sensitivity in detecting multiglandular disease, can minimise the need and risk associated with recurrent operations, and may facilitate cost-effective minimally invasive surgery.
Synthesis of Peptides fromα- andβ-Tubulin Containing Glutamic Acid Side-Chain Linked Oligo-Glu with Defined Length
Authors: Tegge Werner , Bonafe Carlos F. S. , Teichmann Aileen , Erck Christian
Published: December 2010

Side-chain oligo- and polyglutamylation represents an important posttranslational modification in tubulin physiology. The particular number of glutamate units is related to specific regulatory functions. In this work, we present a method for the synthesis of building blocks for the Fmoc synthesis of peptides containing main chain glutamic acid residues that carry side-chain branching with oligo-glutamic acid. The two model peptide sequences CYEEVGVDSVEGEG-E()-EEGEEY and CQDATADEQG-E()-FEEEEGEDEA from the C-termini of mammalianα1- andβ1-tubulin, respectively, containing oligo-glutamic acid side-chain branching with lengths of 1 to 5 amino acids were assembled in good yield and purity. The products may lead to the generation of specific antibodies which should be important tools for a more detailed investigation of polyglutamylation processes.
Novel HeterogenousCHS1Mutations Identified in Five Japanese Patients with Chediak-Higashi Syndrome
Authors: Tanabe Fuminori , Kasai Hirotake , Morimoto Michiko , Oh Shigeharu , Takada Hidetoshi , Hara Toshiro , Ito Masahiko
Published: December 2010

Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder characterized by oculocutaneous albinism, recurrent bacterial infections and progressive neurological dysfunction. We demonstrate novel heterogenous mutations ofCHS1, the responsive gene of CHS, identified in five Japanese patients with CHS. Patients 1, 2, and 3 were siblings, and they had albinism of the skin and hair. They all had a heterogenous two-base deletion (c.5541-5542 del AA, p.Q1847fsX1850) in exon 18. Patient 4 had a heterogenous single-base insertion (c.3944-3945 ins C, p.T1315fsX1331) in exon 10. The patient exhibited severe early-onset phenotype and suffered from hemophagocytic lymphohistiocytosis. Patient 5 had two heterogenous nonsense mutations; c.7982C>G, p.S2661X in exon 30 and c.8281A>T, p.R2761X in exon 31. The patient suffered from infections in childhood and had visual disturbance and albinism of the skin and hair. TheCHS1mutations described here have not been reported previously.
Breast Cancer in Low- and Middle-Income Countries: An Emerging and Challenging Epidemic
Authors: Tfayli Arafat , Temraz Sally , Abou Mrad Rachel , Shamseddine Ali
Published: December 2010

Breast cancer is a major health care problem that affects more than one million women yearly. While it is traditionally thought of as a disease of the industrialized world, around 45% of breast cancer cases and 55% of breast cancer deaths occur in low and middle income countries. Managing breast cancer in low income countries poses a different set of challenges including access to screening, stage at presentation, adequacy of management and availability of therapeutic interventions. In this paper, we will review the challenges faced in the management of breast cancer in low and middle income countries.
Effects of Polyethylene Glycol Spacer Length and Ligand Density on Folate Receptor Targeting of Liposomal Doxorubicin In Vitro
Authors: Kawano Kumi , Maitani Yoshie
Published: December 2010

The folate receptor is an attractive target for selective tumor delivery of liposomal doxorubicin (DXR) because it is abundantly expressed in a large percentage of tumors. This study examined the effect of polyethylene glycol (PEG) spacer length and folate ligand density on the targeting ability of folate-modified liposomes. Liposomes were modified with folate-derivatized PEG-distearoylphosphatidylethanolamine with PEG molecular weights of 2000, 3400, or 5000. The association of DXR-loaded liposomes with KB cells, which overexpress the folate receptor, was evaluated by flow cytometry at various ratios of folate modification. A low ratio of folate modification with a sufficiently long PEG chain showed the highest folate receptor-mediated association with the cells, but did not show the highest in vitro cytotoxicity. DXR release from folate-modified liposomes in endosomes might be different. These findings will be useful for designing folate receptor-targeting carriers.
Guillain‐Barré Syndrome Animal Model: The First Proof of Molecular Mimicry in Human Autoimmune Disorder
Authors: Shahrizaila Nortina , Yuki Nobuhiro
Published: December 2010

Molecular mimicry between self and microbial components has been proposed as the pathogenic mechanism of autoimmune diseases, and this hypothesis is proven in Guillain‐Barré syndrome. Guillain‐Barré syndrome, the most frequent cause of acute neuromuscular paralysis, sometimes occurs after Campylobacter jejuni enteritis. Gangliosides are predominantly cell‐surface glycolipids highly expressed in nervous tissue, whilst lipo‐oligosaccharides are major components of the Gram‐negative bacterium C. jejuni outer membrane. IgG autoantibodies to GM1 ganglioside were found in the sera from patients with Guillain‐Barré syndrome. Molecular mimicry was demonstrated between GM1 and lipo‐oligosaccharide of C. jejuni isolated from the patients. Disease models by sensitization of rabbits with GM1 and C. jejuni lipo‐oligosaccharide were established. Guillain‐Barré syndrome provided the first verification that an autoimmune disease is triggered by molecular mimicry. Its disease models are helpful to further understand the molecular pathogenesis as well as to develop new treatments in Guillain‐Barré syndrome.
Pharmacological Treatment of Obesity in Children and Adolescents: Present and Future
Authors: Iughetti Lorenzo , China Mariachiara , Berri Rossella , Predieri Barbara
Published: December 2010

The prevalence of overweight and obesity is increasing in children and adolescents worldwide raising the question on the approach to this condition because of the potential morbidity, mortality, and economic tolls. Dietetic and behavioral treatments alone have only limited success; consequently, discussion on strategies for treating childhood and adolescent obesity has been promoted. Considering that our knowledge on the physiological systems regulating food intake and body weight is considerably increased, many studies have underlined the scientific and clinical relevance of potential treatments based on management of peripheral or central neuropeptides signals by drugs. In this paper, we analyze the data on the currently approved obesity pharmacological treatment suggesting the new potential drugs.
Expression of Snail in Epidermal Keratinocytes Promotes Cutaneous Inflammation and Hyperplasia Conducive to Tumor Formation
Authors: Du Fei , Nakamura Yoshikazu , Tan Tuan-Lin , Lee Pedro , Lee Robert , Yu Benjamin , Jamora Colin
Published: December 2010

Although metastasis is the most lethal consequence of tumor progression, comparatively little is known regarding the molecular machinery governing this process. In many carcinomas, there is a robust correlation between the expression of the transcription factor Snail and a poor prognosis, but the contribution of this protein to the metastatic process remains unresolved. Interestingly, the prolonged expression of Snail in epidermal keratinocytes is sufficient to recapitulate early features of metastasis. However, it does so without inducing a complete epithelial-mesenchymal transition (EMT), a developmental phenomenon mediated by Snail that is extensively invoked as the mechanism fueling tumorigenesis. Instead, we found that the local invasiveness of keratinocytes is the consequence of the recruitment and activity of macrophages. Moreover, keratinocyte proliferation is the product of an IL-17/IL-6/Stat3 signaling module initiated by activated resident γδT cells in the transgenic skin. Together, these phenotypes prime the transgenic skin for the formation and metastasis of tumors in response to chemically induced carcinogenesis. Thus, the contribution of Snail to the progression of carcinomas is largely through the creation of a hyperproliferative and inflammatory niche that facilitates tumor development and dissemination. Cancer Res; 70(24); 10080–9. ©2010 AACR.
Active Immunotherapy Induces Antibody Responses That Target Tumor Angiogenesis
Authors: Schoenfeld Jonathan , Jinushi Masahisa , Nakazaki Yukoh , Wiener Daniel , Park Joosang , Soiffer Robert , Neuberg Donna , Mihm Martin , Hodi F. Stephen , Dranoff Glenn
Published: December 2010

The inhibition of VEGF signaling with antibodies or small molecules achieves clinical benefits in diverse solid malignancies. Nonetheless, therapeutic effects are usually not sustained, and most patients eventually succumb to progressive disease, indicating that antiangiogenic strategies require additional optimization. Vaccination with lethally irradiated, autologous tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF) and antibody blockade of cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) trigger a tumor vasculopathy in some long-term responding subjects. These reactions are characterized by disrupted tumor blood vessels in association with lymphocyte and granulocyte infiltrates and zonal areas of ischemic tumor necrosis. However, the mechanisms underlying this immune-mediated destruction of the tumor vasculature remain to be clarified. Here, we show that GM-CSF–secreting tumor cell vaccines and CTLA-4 blockade elicit a functionally important humoral reaction against multiple angiogenic cytokines. Antibodies to angiopoietin-1 and angiopoietin-2 block Tie-2 binding, downstream signaling, endothelial cell tube formation, and macrophage chemotaxis. Antibodies to macrophage inhibitory factor (MIF) attenuate macrophage Tie-2 expression and matrix metalloproteinase-9 (MMP-9) production. Together, these results delineate an immunotherapy-induced host response that broadly targets the angiogenic network in the tumor microenvironment. Cancer Res; 70(24); 10150–60. ©2010 AACR.
Pemetrexed Indirectly Activates the Metabolic Kinase AMPK in Human Carcinomas
Authors: Rothbart Scott B. , Racanelli Alexandra C. , Moran Richard G.
Published: December 2010

The chemotherapeutic drug pemetrexed, an inhibitor of thymidylate synthase, has an important secondary target in human leukemic cells, aminoimidazolecarboxamide ribonucleotide formyltransferase (AICART), the second folate-dependent enzyme of purine biosynthesis. The purine intermediate aminoimidazolecarboxamide ribonucleotide (ZMP), which accumulates behind this block, transmits an inhibitory signal to the mTORC1 complex via activation of the cellular energy sensor AMP-activated kinase (AMPK). Given that the PI3K-AKT-mTOR pathway is frequently deregulated during carcinogenesis, we asked whether the indirect activation of AMPK by pemetrexed offers an effective therapeutic strategy for carcinomas with defects in this pathway. Activation of AMPK by ZMP in pemetrexed-treated colon and lung carcinoma cells and the downstream consequences of this activation were strikingly more robust than previously seen in leukemic cells. Genetic experiments demonstrated the intermediacy of AICART inhibition and the centrality of AMPK activation in these effects. Whereas AMPK activation resulted in marked inhibition of mTORC1, other targets of AMPK were phosphorylated that were not mTORC1-dependent. Whereas AMPK activation is thought to require AMPKα T172 phosphorylation, pemetrexed also activated AMPK in carcinoma cells null for LKB1, the predominant AMPKα T172 kinase whose deficiency is common in lung adenocarcinomas. Like rapamycin analogs, pemetrexed relieved feedback suppression of PI3K and AKT, but the prolonged accumulation of unphosphorylated 4E-BP1, a tight-binding inhibitor of cap-dependent translation, was seen following AMPK activation. Our findings indicate that AMPK activation by pemetrexed inhibits mTORC1-dependent and -independent processes that control translation and lipid metabolism, identifying pemetrexed as a targeted therapeutic agent for this pathway that differs significantly from rapamycin analogs. Cancer Res; 70(24); 10299–309. ©2010 AACR.