bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment with lenalidomide modulates T‐cell immunophenotype and cytokine production in patients with chronic lymphocytic leukemia
Authors: Lee Bang‐Ning , Gao Hui , Cohen Evan N. , Badoux Xavier , Wierda William G. , Estrov Zeev , Faderl Stefan H. , Keating Michael J. , Ferrajoli Alessandra , Reuben James M.
Published: February 2011

BACKGROUND:

Lenalidomide, an immunomodulatory agent, has activity in lymphoproliferative disorders. The authors, therefore, evaluated its effects on T‐cell immunophenotype and cytokine production in patients with chronic lymphocytic leukemia (CLL).

METHODS:

To study the immunomodulatory effects of lenalidomide in CLL, the authors recruited 24 patients with untreated CLL enrolled in a phase 2 clinical trial of lenalidomide and obtained peripheral blood specimens for immunologic studies consisting of enumeration of T cells and assessing their ability to synthesize cytokines after activation through T‐cell receptor (TCR).

RESULTS:

After 3 cycles of therapy, patients had a significant reduction in percentage (%) and absolute lymphocyte count (ALC) and an increase in percentage of T cells, percentage of activated CD8+ T cells producing IFN‐γ, and percentage of regulatory T (TR) cells when compared with their respective levels before treatment. After 15 cycles of treatment, responder patients had significant reduction in percentage of lymphocytes and ALC, percentage of activated CD4+ T cells producing IL‐2, IFN‐γ, or TNF‐α, and percentage of TR cells when compared with their perspective levels after 3 cycles of treatment. Furthermore, the numbers of activated CD4+ T cells producing IL‐2, IFN‐γ, or TNF‐α, activated CD8+ T cells producing IFN‐γ, and TR cells normalized to the range of healthy subjects.

CONCLUSIONS:

Treatment with lenalidomide resulted in the normalization of functional T‐cell subsets in responders, suggesting that lenalidomide may modulate cell‐mediated immunity in patients with CLL. Cancer 2011;. © 2011 American Cancer Society.
Distribution of the auxiliary GABAB receptor subunits KCTD8, 12, 12b, and 16 in the mouse brain
Authors: Metz Michaela , Gassmann Martin , Fakler Bernd , Schaeren‐Wiemers Nicole , Bettler Bernhard
Published: February 2011

GABAB receptors are the G‐protein‐coupled receptors for γ‐aminobutyric acid (GABA). KCTD8, 12, 12b, and 16 were recently identified as auxiliary GABAB receptor subunits and distinctly influence biophysical and pharmacological properties of the receptor response. Here we examined the expression patterns of the KCTDs in the mouse brain. Using in situ hybridization analysis, we found that most neurons express KCTD transcripts, supporting biochemical data showing that most GABAB receptors in the brain incorporate KCTD proteins. In the adult brain, KCTD12 and 16 have a widespread and KCTD8 and 12b a restricted expression pattern. Individual neurons can coexpress multiple KCTDs, as shown for granule cells and CA1/CA3 pyramidal cells in the hippocampus that coexpress KCTD12 and 16. In contrast, granule, Purkinje, and Golgi cells in the cerebellum selectively express one KCTD at a time. The expression levels of individual KCTD transcripts vary during postnatal brain development. Immunohistochemistry reveals that individual KCTD proteins can exhibit distinct axonal or dendritic localizations in neuronal populations. KCTDs are also detectable in nonneuronal tissues not expected to express GABAB receptors, suggesting that the role of KCTD proteins extends beyond GABAB receptors. In summary, our findings support that most brain GABAB receptors associate with KCTD proteins, but that the repertoire and abundance of KCTDs varies during development, among brain areas, neuronal populations, and at subcellular sites. We propose that the distinct spatial and temporal KCTD distribution patterns underlie functional differences in native GABAB responses. J. Comp. Neurol. 519:1435–1454, 2011. © 2011 Wiley‐Liss, Inc.
Complex neural architecture in the diploblastic larva of Clava multicornis (Hydrozoa, Cnidaria)
Authors: Piraino Stefano , Zega Giuliana , Di Benedetto Cristiano , Leone Antonella , Dell'Anna Alessandro , Pennati Roberta , Candia Carnevali Daniela , Schmid Volker , Reichert Heinrich
Published: February 2011

The organization of the cnidarian nervous system has been widely documented in polyps and medusae, but little is known about the nervous system of planula larvae, which give rise to adult forms after settling and metamorphosis. We describe histological and cytological features of the nervous system in planulae of the hydrozoan Clava multicornis. These planulae do not swim freely in the water column but rather crawl on the substrate by means of directional, coordinated ciliary movement coupled to lateral muscular bending movements associated with positive phototaxis. Histological analysis shows pronounced anteroposterior regionalization of the planula's nervous system, with different neural cell types highly concentrated at the anterior pole. Transmission electron microscopy of planulae shows the nervous system to be unusually complex, with a large, orderly array of sensory cells at the anterior pole. In the anterior half of the planula, the basiectodermal plexus of neurites forms an extensive orthogonal network, whereas more posteriorly neurites extend longitudinally along the body axis. Additional levels of nervous system complexity are uncovered by neuropeptide‐specific immunocytochemistry, which reveals distinct neural subsets having specific molecular phenotypes. Together these observations imply that the nervous system of the planula of Clava multicornis manifests a remarkable level of histological, cytological, and functional organization, the features of which may be reminiscent of those present in early bilaterian animals. J. Comp. Neurol. 519:1931–1951, 2011. © 2011 Wiley‐Liss, Inc.
Reelin inhibits migration of sympathetic preganglionic neurons in the spinal cord of the chick
Authors: Yip Yee Ping , Zhou Guangdou , Kubo Ken‐Ichiro , Nakajima Kazunori , Yip Joseph W.
Published: February 2011

The present study examined the effects of Reelin in the migration of sympathetic preganglionic neurons (SPN) in the spinal cord of the chick. SPN in the chick first migrate from the neuroepithelium to the ventrolateral spinal cord. They then undergo a secondary migration to cluster adjacent to the central canal, forming the column of Terni (CT). During secondary migration, abundant Reelin is found in large areas of the ventral spinal cord; the only areas devoid of Reelin are areas occupied by SPN or somatic motor neurons and the pathway along which SPN migrate. Ectopic expression of Reelin in the pathway of SPN through electroporation of full‐length Reelin DNA stopped SPN migration toward their destination. The spatiotemporal pattern of Reelin expression, along with the inhibition of SPN migration by exogenous Reelin, suggests that Reelin functions as a barrier to SPN migration during normal development of the spinal cord. J. Comp. Neurol. 519:1970–1978, 2011. © 2011 Wiley‐Liss, Inc.
Axon cap morphology of the sea robin (Prionotus carolinus): mauthner cell is correlated with the presence of “signature” field potentials and a C‐Type startle response
Authors: Zottoli Steven J. , Wong Tina W. , Agostini Mark A. , Meyers Jason R.
Published: February 2011

Studies on the Mauthner cell (M‐cell) of goldfish, Carassius auratus, have facilitated our understanding of how sensory information is integrated in the hindbrain to initiate C‐type fast startle responses (C‐starts). The goldfish M‐cell initial segment/axon hillock is surrounded by a composite axon cap consisting of a central core and a peripheral zone covered by a glial cell layer. The high resistivity of the axon cap results in “signature” field potentials recorded on activation of the M‐cell, allowing unequivocal physiological identification of the M‐cell and of its feedback and reciprocal inhibitory networks that are crucial in ensuring that only one M‐cell is active and that it fires only once. Phylogenetic mapping of axon cap morphology to muscle activity patterns and behavior predicts that teleost fishes that have a composite axon cap, like that of the goldfish, will perform C‐start behavior with primarily unilateral muscle activity. We have chosen to study these predictions in the northern sea robin, Prionotus carolinus, a percomorph fish. Although sea robins have a very different phylogenetic position, body form, and habitat compared with the goldfish, they display the correlation of axon cap morphology to physiology and C‐start behavior. Differences in response parameters suggest some evolutionary trade‐offs in sea robin C‐start behavior compared with that of the goldfish, but the correlations in morphology, physiology, and behavior are common features of both otophysan and nonotophysan teleosts. The M‐cell will continue to provide an unprecedented opportunity to study the evolution of a neural circuit in the context of behavior. J. Comp. Neurol. 519:1979–1998, 2011. © 2011 Wiley‐Liss, Inc.
Olfactory projections in the white sturgeon, Acipenser transmontanus: An experimental study
Authors: Northcutt R. Glenn
Published: February 2011

Telencephalic evolution in ray‐finned fishes shows increasing complexity from polypteriform fishes through sturgeons to teleosts. Telencephalic organization in sturgeons is thus critical to our understanding of ray‐finned fish evolution, but it is poorly understood, particularly as regards the roof or pallium. Two major hypotheses exist regarding the medial part of area dorsalis (Dm): that Dm is extended; and that Dm is restricted. The extent and topography of secondary olfactory projections to the pallium are critical in evaluating these hypotheses, but there is little agreement regarding these projections. Olfactory projections in the white sturgeon were therefore examined by using the carbocyanine probe DiI, biocytin, and biotinylated dextrin amine (BDA). Both DiI and BDA revealed primary olfactory projections to the olfactory bulb and primary extrabulbar projections widely in the telencephalon and to more restricted regions of the diencephalon. Myelinated secondary olfactory fibers caused DiI to be less effective in labeling secondary olfactory projections, which terminate in all subpallial nuclei and in the pallium: sparsely in the medial pallial division (Dm); heavily in the posterior pallial division (Dp); and more lightly in the lateral pallial division (Dl). In the diencephalon, substantial secondary olfactory projections were seen to the habenular nuclei, the rostral pole of the inferior lobe, and several nuclei of the posterior tubercle. All secondary olfactory projections were bilateral but heavier ipsilaterally. Bulbopetal neurons were located in both pallial and subpallial centers and were more numerous ipsilaterally. These results corroborate an earlier experimental study on the shovelnose sturgeon and indicate a restricted Dm in sturgeons. J. Comp. Neurol. 519:1999–2022, 2011. © 2011 Wiley‐Liss, Inc.
Zorilla: a peer‐to‐peer middleware for real‐world distributed systems
Authors: Drost Niels , van Nieuwpoort Rob V. , Maassen Jason , Seinstra Frank J. , Bal Henri E.
Published: February 2011

The inherent complex nature of current distributed computing architectures hinders the widespread adoption of these systems for mainstream use. In general, users have access to a highly heterogeneous set of compute resources, which may include clusters, grids, desktop grids, clouds, and other compute platforms. This heterogeneity is especially problematic when running parallel and distributed applications. Software is needed which easily combines as many resources as possible into one coherent computing platform.

In this paper, we introduce Zorilla: peer‐to‐peer (P2P) middleware that creates a single distributed environment from any available set of compute resources. Zorilla imposes minimal requirements on the resource used, is platform independent, and does not rely on central components. In addition to providing functionality on bare resources, Zorilla can exploit locally available middleware. Zorilla explicitly supports distributed and parallel applications, and allows resources from multiple sites to cooperate in a single computation.

Zorilla makes extensive use of both virtualization and P2P techniques. We will demonstrate how virtualization and P2P combine into a simple design, while enhancing functionality and ease of use. Together, these techniques bring our goal a step closer: transparent, easy use of resources, even on very heterogeneous distributed systems. Copyright © 2011 John Wiley & Sons, Ltd.
On systematic wave digital modeling of passive hyperbolic partial differential equations
Authors: Leuer Christiane , Ochs Karlheinz
Published: February 2011

Wave digital models are known to be most suitable for the digital emulation of passive physical systems. Starting from a system description in the form of a suited partial differential equation (PDE), a reference circuit having a one‐to‐one corresponding wave digital structure has to be synthesized. This synthesis transfers the principle of action at proximity and the passivity of the physical system into algorithms, which offer full parallelism, passivity, and robustness against signal and coefficient quantizations. Finding a reference circuit to a given PDE is an open problem, which has only partially been solved. In this paper, we present a schematic reference circuit synthesis for a special class of hyperbolic PDEs. In order to cut down the complexity of the synthesis, we introduce additional design parameters and decompose the PDE into an ordinary differential equation (ODE) and hyperbolic PDE subsystems. The parameters can be exploited to optimize the reference circuit and its corresponding wave digital structure. The method is applied to the Sine‐Gordon equation from the soliton theory and verified by simulation. Copyright © 2011 John Wiley & Sons, Ltd.
All‐MOS implementation of RC networks for time‐controlled Gaussian spatial filtering
Authors: Fernández‐Berni J. , Carmona‐Galán R.
Published: February 2011

This paper addresses the design and VLSI implementation of MOS‐based RC networks capable of performing time‐controlled Gaussian filtering. In these networks, all the resistors are substituted one by one by a single MOS transistor biased in the ohmic region. The design of this elementary transistor is carefully realized according to the value of the ideal resistor to be emulated. For a prescribed signal range, the MOSFET in triode region delivers an interval of instantaneous resistance values. We demonstrate that, for the elementary 2‐node network, establishing the design equation at a particular point within this interval guarantees minimum error. This equation is then corroborated for networks of arbitrary size by analyzing them from a stochastic point of view. Following the design methodology proposed, the error committed by an MOS‐based grid when compared with its equivalent ideal RC network is, despite the intrinsic nonlinearities of the transistors, below 1% even under mismatch conditions of 10%. In terms of image processing, this error hardly affects the outcome, which is perceptually equivalent to that of the ideal network. These results, extracted from simulation, are verified in a prototype vision chip with QCIF resolution manufactured in the AMS 0.35µm CMOS‐OPTO process. This prototype incorporates a focal‐plane MOS‐based RC network that performs fully programmable Gaussian filtering. Copyright © 2011 John Wiley & Sons, Ltd.
Growth of Few‐Layer Graphene on a Thin Cobalt Film on a Si/SiO2 Substrate
Authors: Kim Eunho , An Hyosub , Jang Hyunchul , Cho Won‐Ju , Lee Naesung , Lee Wan‐Gyu , Jung Jongwan
Published: February 2011

Few‐layered sheets of graphene were synthesized on polycrystalline thin Co and Ni films by low pressure chemical vapor deposition. On average, thinner layers of graphene were synthesized on Co than on the conventional Ni at the same process conditions, but slightly higher defects were detected on Co‐grown graphene layers than on Ni‐grown ones. Possible explanations for this are suggested.
Aerosol‐Assisted CVD of Titanium Dioxide Thin Films from Methanolic Solutions of Titanium Tetraisopropoxide; Substrate and Aerosol‐Selective Deposition of Rutile or Anatase
Authors: Edusi Cynthia , Hyett Geoffrey , Sankar Gopinathan , Parkin Ivan P.
Published: February 2011

Titanium dioxide (TiO2) thin films are synthesized using aerosol‐assisted (AA)CVD of titanium (IV) isopropoxide (TTIP) in methanol. Deposition is carried out on glass, steel, and titanium substrates at 400–550°C. The films produce morphologies that are radically different to those from typical aerosol‐assisted processes, and from the use of TTIP in low or atmospheric pressure (AP)CVD. The films show some substrate‐dependent morphology and properties. In particular at 550°C the films on steel show needle‐ and rod‐like particles. X‐ray diffraction (XRD) and Raman spectroscopy of the TiO2 films show that on steel or titanium substrates only the rutile form can be obtained, whereas on glass either anatase, anatase/rutile mixtures, or rutile can be obtained, depending on substrate temperature. The TiO2 films formed at 550°C on all substrates are hydrophobic to water droplets, with contact angles in the range 101–110°. These films become hydrophilic on heating to above 100°C in air, or superhydrophillic when irradiated under 254 nm radiation generating water‐contact angles less than 5°. Surprisingly, use of TTIP under APCVD on steel substrates without an aerosol form exclusively the anatase form of TiO2 at 400–550°C, whereas use of a methanolic aerosol delivery system for the TTIP forms rutile. Hence use of the methanol aerosol has a controlling influence on the deposition chemistry. The TiO2 thin films are shown to be active photocatalysts using a dye‐ink test, and are also shown to be able to photo‐split water in a sacrificial system to evolve oxygen.
Curauá Fiber Microimaging, Atomic Layer Deposition of Metal Oxide Films, and Obtaining of Nanowalled Microtubes
Authors: Grafova Iryna , Kemell Marianna , Lunz Juliana N. , Marques Maria de Fátima V. , Grafov Andriy , Leskelä Markku
Published: February 2011

Curauá (Ananas erectifolius) is a new lignocellulosic material possessing valuable properties. Scanning electron microscopy (SEM) studies of natural and delignified fibers reveal their dense structure and nanoveinlets of cellulose agglomerates. Thin Al2O3 and Ta2O5 coatings of various thicknesses (30 − 130 nm) are grown on the fiber surface by atomic layer deposition (ALD). Nanowalled microtubes of Al2O3 and Ta2O5 are prepared by annealing the coated fibers in an oxidative atmosphere to verify compactness, homogeneity, and continuity of the coatings obtained. The suitability of curauá fiber for ALD applications is shown. Both ALD coatings and the nanowalled microtubes replicate well the irregular fiber relief, they are resistant and homogeneous.
Cell cycle dependent TN‐C promoter activity determined by live cell imaging
Authors: Halter Michael , Sisan Daniel R. , Chalfoun Joe , Stottrup Benjamin L. , Cardone Antonio , Dima Alden A. , Tona Alessandro , Plant Anne L. , Elliott John T.
Published: February 2011

The extracellular matrix protein tenascin‐C plays a critical role in development, wound healing, and cancer progression, but how it is controlled and how it exerts its physiological responses remain unclear. By quantifying the behavior of live cells with phase contrast and fluorescence microscopy, the dynamic regulation of TN‐C promoter activity is examined. We employ an NIH 3T3 cell line stably transfected with the TN‐C promoter ligated to the gene sequence for destabilized green fluorescent protein (GFP). Fully automated image analysis routines, validated by comparison with data derived from manual segmentation and tracking of single cells, are used to quantify changes in the cellular GFP in hundreds of individual cells throughout their cell cycle during live cell imaging experiments lasting 62 h. We find that individual cells vary substantially in their expression patterns over the cell cycle, but that on average TN‐C promoter activity increases during the last 40% of the cell cycle. We also find that the increase in promoter activity is proportional to the activity earlier in the cell cycle. This work illustrates the application of live cell microscopy and automated image analysis of a promoter‐driven GFP reporter cell line to identify subtle gene regulatory mechanisms that are difficult to uncover using population averaged measurements. Published 2011 Wiley‐Liss, Inc.
Providing reliable and link stability‐based geocasting model in underwater environment
Authors: Dhurandher Sanjay K. , Obaidat Mohammad S. , Gupta Megha
Published: February 2011

This paper presents a geocast technique for underwater sensor networks. The model named as Routing and Multicast Tree based Geocasting (RMTG) (TRACE'10, Bhopal, India, 2010; ICWET'10, Mumbai, India, 2010) has been designed for underwater sensor networks. In our previous work (TRACE'10, Bhopal, India, 2010; ICWET'10, Mumbai, India, 2010) we proposed only a theoretical model for underwater geocasting. The RMTG technique uses greedy forwarding and previous hop handshaking to route the packets towards the geocast region and further disseminates the data within the geocast region by creating a multicast shortest path tree. We also presented various link broken scenarios along with their solutions. The proposed model does not use the flooding technique to deliver the packets inside the geocast region that is used in most of the geocasting techniques. In this paper, we present the simulated RMTG model. The simulation results show that the proposed model provides an efficient distribution of data in the geocast region in terms of node mobility handling, packet delivery ratio and a better end‐to‐end latency. Most of the work on geocasting has been done for mobile and vehicular ad hoc networks; hence we present in this paper a novel simulated model for underwater environment. Copyright © 2011 John Wiley & Sons, Ltd.
Predictors of associated autoimmune diseases in families with type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium
Authors: Wägner Ana M. , Santana Ángelo , Herńndez Marta , Wiebe Julia C. , Nóvoa Javier , Mauricio Dídac ,   The T1DGC6
Published: February 2011

Background

Type 1 diabetes (T1D) is a clinically heterogeneous disease. The presence of associated autoimmune diseases (AAIDs) may represent a distinct form of autoimmune diabetes, with involvement of specific mechanisms. The aim of this study was to find predictors of AAIDs in the Type 1 Diabetes Genetics Consortium data set.

Methods

Three thousand two hundred and sixty‐three families with at least two siblings with T1D were included. Clinical information was obtained using questionnaires, anti‐GAD (glutamic acid decarboxylase) and anti‐protein tyrosine phosphatase (IA‐2) were measured and human leukocyte antigen (HLA) genotyping was performed. Siblings with T1D with and without AAIDs were compared and a multivariate regression analysis was performed to find predictors of AAIDs. T1D‐associated HLA haplotypes were defined as the four most susceptible and protective, respectively.

Results

One or more AAIDs were present in 14.4% of the T1D affected siblings. Age of diabetes onset, current age and time since diagnosis were higher, there was a female predominance and more family history of AAIDs in the group with AAIDs, as well as more frequent anti‐GAD and less frequent anti‐IA‐2 antibodies. Risk and protective HLA haplotype distributions were similar, though DRB1*0301‐DQA1*0501‐DQB1*0201 was more frequent in the group with AAIDs. In the multivariate analysis, female gender, age of onset, family history of AAID, time since diagnosis and anti‐GAD positivity were significantly associated with AAIDs.

Conclusions

In patients with T1D, the presence of AAIDs is associated with female predominance, more frequent family history of AAIDs, later onset of T1D and more anti‐GAD antibodies, despite longer duration of the disease. The predominance of certain HLA haplotypes suggests that specific mechanisms of disease may be involved. Copyright © 2011 John Wiley & Sons, Ltd.
Simultaneous diffuse reflectance infrared determination of clavulanic acid and amoxicillin using multivariate calibration techniques
Authors: Müller Aline Lima Hermes , Picoloto Rochele Sogari , Ferrão Marco Flores , da Silva Fabiana Ernestina Barcellos , Müller Edson Irineu , de Moraes Flores Érico Marlon
Published: February 2011

A method for simultaneous determination of clavulanic acid (CA) and amoxicillin (AMO) in commercial tablets was developed using diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) and multivariate calibration. Twenty‐five samples (10 commercial and 15 synthetic) were used as a calibration set and 15 samples (10 commercial and 5 synthetic) were used for a prediction set. Calibration models were developed using partial least squares (PLS), interval PLS (iPLS), and synergy interval PLS (siPLS) algorithms. The best algorithm for CA determination was siPLS model with spectra divided in 30 intervals and combinations of 2 intervals. This model showed a root mean square error of prediction (RMSEP) of 5.1 mg g−1. For AMO determination, the best siPLS model was obtained with spectra divided in 10 intervals and combinations of 4 intervals. This model showed a RMSEP of 22.3 mg g−1. The proposed method was considered as a suitable for the simultaneous determination of CA and AMO in commercial pharmaceuticals products. Copyright © 2011 John Wiley & Sons, Ltd.
Synphilin suppresses α‐synuclein neurotoxicity in a Parkinson's disease Drosophila model
Authors: Vargas René Hernández‐ , Ornelas Luis Fonseca‐ , González Ignacio López‐ , Escovar Juan Riesgo‐ , Zurita Mario , Reynaud Enrique
Published: February 2011

Parkinson's disease (PD) is the second most common neurodegenerative disorder in humans. It affects 1% of the population over 65‐years old. Its causes are environmental and genetic. As the world population ages, there is an urgent need for better and more detailed animal models for this kind of disease. In this work we show that the use of transgenic Drosophila is comparable to more complicated and costly animal models such as mice. The Drosophila model behaves very similar to the equivalent transgenic mice model. We show that both Synphilin‐1 and α‐synuclein are toxic by themselves, but when co‐expressed, they suppress their toxicity reciprocally. Importantly, the symptoms induced in the fly can be treated and partially reverted using standard PD pharmacological treatments. This work showcases Drosophila as a detailed and multifaceted model for Parkinson's disease, providing a convenient platform in which to study and find new genetic modifiers of PD. genesis 49:392–402, 2011. © 2011 Wiley‐Liss, Inc.
Stella‐Cre mice are highly efficient Cre deleters
Authors: Liu Hui , Wang Wei , Chew Su‐Kit , Lee Song‐Choon , Li Juan , Vassiliou George S. , Green Tony , Futreal P. Andrew , Bradley Allan , Zhang Shujun , Liu Pentao
Published: February 2011

Cre‐loxP recombination is widely used for genetic manipulation of the mouse genome. Here, we report generation and characterization of a new Cre line, Stella‐Cre, where Cre expression cassette was targeted to the 3′ UTR of the Stella locus. Stella is specifically expressed in preimplantation embryos and in the germline. Cre‐loxP recombination efficiency in Stella‐Cre mice was investigated at several genomic loci including Rosa26, Jak2, and Npm1. At all the loci examined, we observed 100% Cre‐loxP recombination efficiency in the embryos and in the germline. Thus, Stella‐Cre mice serve as a very efficient deleter line. genesis 49:689–695, 2011. © 2011 Wiley‐Liss, Inc.
C‐type lectin SIGNR1 enhances cellular oxidative burst response against C. albicans in cooperation with Dectin‐1
Authors: Takahara Kazuhiko , Tokieda Sumika , Nagaoka Koji , Takeda Tatsuki , Kimura Yukino , Inaba Kayo
Published: February 2011

We investigated the role of SIGNR1 in the recognition of Candida albicans and the subsequent cellular oxidative burst response. Soluble SIGNR1 (sSIGNR1) tetramer bound equally to zymosan and both heat‐killed (HK) and live C. albicans in an EDTA‐sensitive manner, whereas sDectin‐1 tetramer predominantly bound to zymosan and HK‐microbes in an EDTA‐independent manner. In cellular response, enhanced oxidative burst was observed in RAW264.7 cells expressing SIGNR1 (RAW‐SIGNR1) compared with RAW‐control cells upon stimulation with HK‐C. albicans and zymosan. This response was independent of TLR2 and the cytosolic portion of SIGNR1 but dependent on the recognition by SIGNR1 via carbohydrate recognition domain. Antagonistic laminarin and anti‐Dectin‐1 mAb cooperatively reduced the response with mannan and anti‐SIGNR1 mAb, respectively, although they had no effect by themselves. Moreover, oxidative response and bactericidal activity largely relied on Syk‐mediated signaling. RAW‐SIGNR1 cells not only captured microbes more efficiently but also showed higher responses than RAW‐control cells. Similar enhanced responses were observed in SIGNR‐1‐expressing resident peritoneal Mϕ. Interestingly, Dectin‐1 was recruited to the phagosomal membrane upon the stimulation and physically associated with SIGNR1. These results suggest that SIGNR1 plays a significant role in inducing oxidative response to C. albicans by Syk‐dependent signaling, possibly through Dectin‐1.
Reduced IL‐2 expression in NOD mice leads to a temporal increase in CD62LloFoxP3+CD4+ T cells with limited suppressor activity
Authors: Goudy Kevin S. , Johnson Mark C. , Garland Alaina , Li Chengwen , Samulski Richard J. , Wang Bo , Tisch Roland
Published: February 2011

IL‐2 plays a critical role in the induction and maintenance of FoxP3‐expressing regulatory T cells (FoxP3+Tregs). Reduced expression of IL‐2 is linked to T‐cell‐mediated autoimmune diseases such as type 1 diabetes (T1D), in which an imbalance between FoxP3+Tregs and pathogenic T effectors exists. We investigated the contribution of IL‐2 to dysregulation of FoxP3+Tregs by comparing wildtype NOD mice with animals congenic for a C57BL/6‐derived disease‐resistant Il2 allele and in which T‐cell secretion of IL‐2 is increased (NOD.B6Idd3). Although NOD mice exhibited a progressive decline in the frequency of CD62LhiFoxP3+Tregs due to an increase in CD62LloFoxP3+Tregs, CD62LhiFoxP3+Tregs were maintained in the pancreatic lymph nodes and islets of NOD.B6Idd3 mice. Notably, the frequency of proliferating CD62LhiFoxP3+Tregs was elevated in the islets of NOD.B6Idd3 versus NOD mice. Increasing levels of IL‐2 in vivo also resulted in larger numbers of CD62LhiFoxP3+Tregs in NOD mice. These results demonstrate that IL‐2 influences the suppressor activity of the FoxP3+Tregs pool by regulating the balance between CD62Llo and CD62Lhi FoxP3+Tregs. In NOD mice, reduced IL‐2 expression leads to an increase in nonsuppressive CD62LloFoxP3+Tregs, which in turn correlates with a pool of CD62LhiFoxP3+Tregs with limited proliferation.
Integrated T‐cell receptor and costimulatory signals determine TGF‐β‐dependent differentiation and maintenance of Foxp3+ regulatory T cells
Authors: Gabryšová Leona , Christensen Jillian R. , Wu Xuemei , Kissenpfennig Adrien , Malissen Bernard , O'Garra Anne
Published: February 2011

Foxp3‐expressing Tregs play a non‐redundant role in protecting against immune pathologies. Foxp3+ Tregs can arise intra‐ and extra‐thymically, however, the signals directing their differentiation and maintenance in the periphery are not well understood. We show that stimulation of mouse naïve CD4+ T cells in vitro with optimal doses of anti‐CD3/anti‐CD28 resulted in high frequencies of Foxp3+ T cells via a TGF‐β‐dependent mechanism. Addition of TGF‐β and retinoic acid overcame the inhibition of Foxp3 expression observed during high‐strength anti‐CD3/anti‐CD28 stimulation. Reducing the strength of TCR or costimulatory signals with inhibitors of mammalian target of rapamycin (mTOR) or MEK/ERK signalling also enhanced expression of Foxp3 in a TGF‐β‐dependent manner. Addition of TGF‐β was further required to maintain Foxp3 expression in ex vivo derived Foxp3+ Tregs upon prolonged anti‐CD3/anti‐CD28 signalling. Thus, induction/maintenance of Foxp3 expression by TGF‐β is modulated by the integrated strength of TCR/costimulatory signals.
Notch signaling regulates the development of a novel type of Thy1‐expressing dendritic cell in the thymus
Authors: Ishifune Chieko , Maekawa Yoichi , Nishida Jun , Kitamura Akiko , Tanigaki Kenji , Yagita Hideo , Yasutomo Koji
Published: February 2011

Dendritic cells (DCs) are specialized antigen‐presenting cells (APCs) required for T‐cell activation and are classified into several subtypes by phenotypic and functional characteristics. However, it remains unclear if distinct transcription factors control the development of each DC subpopulation. In this report, we demonstrate that Notch signaling controls the development of a novel DC subtype that expresses Thy1 (Thy1+DCs). Overstimulation of bone marrow cells with the Notch ligand Delta‐like 1 promoted the development of Thy1+DCs. Thy1+DCs are characterized as CD11c+MHC class II+NK1.1−B220−CD8α+, and are present in the thymus but not in the spleen and lymph nodes. Thymic Thy1+DCs are able to capture exogenous proteins and delete CD4+CD8+ T cells. Transplantation experiments demonstrated that CD44+CD25− and CD44+CD25+ thymocytes can differentiate into Thy1+DCs. Recombination signal binding protein for immunoglobulin kappa J region (RBP‐J) deficiency in lineage‐negative bone marrow cells, but not CD11c+ cells, disrupted Thy1+DC development in the thymus. Our data indicate that Notch signaling controls the development of a novel type of Thy1‐expressing DC in the thymus that possibly controls negative selection, and indicates that there may be highly regulated, differential transcriptional control of DC development. Furthermore, our findings suggest that Notch signaling regulates T‐cell development not only by intrinsically inducing T‐cell lineage‐specific gene programs, but also by regulating negative selection through Thy1+DCs.
Facile Access to Homo‐ and Heteroleptic, Triply Bonded Dimolybdenum Hexaalkoxides with Unsaturated Alkoxide Ligands
Authors: Krackl Sebastian , Ma Jian‐Gong , Aksu Yilmaz , Driess Matthias
Published: February 2011

A series of monodentate, triply bonded Mo2(OR)6 complexes [R = MBE (1) (MBE = 2‐methylbut‐3‐ene‐2‐yl), MMP (2) (MMP = 1‐methoxy‐2‐methylpropane‐2‐yl), Terp (3) [Terp = 2‐(4‐methylcyclohex‐3‐enyl)propane‐2‐yl], which exhibit C–C double bonds or an ether function in the ligand sphere, were synthesized and characterized by multinuclear (1H, 13C and 95Mo) NMR studies. The partial alcoholysis of the latter complexes with neopentyl alcohol (neopentOH) led to the heteroleptic alkoxides Mo2(OR)n(Oneopent)6–n (4–7) {n = 2 [for R = tBu (4), MBE (5), MMP (6)], 4 [for R = Terp (7)]}. This concept was further applied to the synthesis of Mo2(O2DMH)2(OtBu)2 (8) (DMH = 2,5 dimethylhexyl) by starting from the Mo2(OtBu)6 precursor. The 1H NMR spectra for the heteroleptic complexes 4–8 show signals that are significantly shifted to a higher field for the RO ligand protons compared to those of their homoleptic analogues. This is the result of a change in the spatial position of the alkoxide ligands (RO) in the homoleptic compared to the heteroleptic complexes that leads to a different magnetic environment for the alkoxide ligands due to the magnetic anisotropy of the Mo–Mo triple bond. 95Mo NMR studies of the complexes 1–8 show that the resonance strongly depends on the substitution pattern of the alkoxide and that a shift to higher field is observed when going from the tertiary to the primary alkoxides. The molecular structures for 4–8 were determined by single‐crystal X‐ray diffraction, and all of the complexes show a staggered conformation as well as an asymmetric ligand distribution, which results in unequal Mo–O bond lengths. For the heteroleptic complexes 4–7, the RO ligands (R = tBu, MBE, MMP and Terp, respectively) exhibit the longest bond lengths, which suggests that the position of the ligand strongly depends on the steric congestion of the α‐carbon atom of the alkoxide ligand. In 6, the methoxy function enables an intramolecular O→Mo coordination as is indicated by a Mo–O distance of 2.2464(7) Å. This fact is supported by a lengthening of the Mo–Mo triple bond.
Tandem 1,5‐Hydride Shift/6π Electrocyclization of Ketenimines and Carbodiimides Substituted with Cyclic Acetal and Dithioacetal Functions: Experiments and Computations
Authors: Alajarin Mateo , Bonillo Baltasar , Ortin Maria‐Mar , Sanchez‐Andrada Pilar , Vidal Angel
Published: February 2011

N‐Aryl ketenimines bearing five‐ and six‐membered cyclic acetal functions – such as 1,3‐dioxolane, 1,3‐dithiolane, 1,3‐dioxane, and 1,3‐dithiane systems – at the ortho position of the N‐aryl substituent transform on mild thermal treatment into quinolines, through a tandem sequence consisting of a [1,5]‐H shift followed by a 6π electrocyclic ring closure. Structurally analogous N‐aryl carbodiimides are converted into quinazolines in comparable tandem processes. Similar sequences can be successfully applied to N‐thienyl and N‐pyrazolyl ketenimines. DFT calculations have established a two‐step mechanism for those conversions, consisting of an initial 1,5‐hydride shift and subsequent 6π electrocyclization, and confirm the beneficial effect of the acetal function, which gives hydride character to the migrating hydrogen atom. The capability to promote the H shift depends on the type of acetal function (acetal better than dithioacetal), its ring size (five‐membered better than six‐membered) and the heterocumulenic fragment (ketenimine better than carbodiimide). Changing the benzene ring connecting the acetal and ketenimine functions for a heterocyclic ring has pronounced consequences for the magnitude of the energy barriers.
Studies towards the Synthesis of Pentalenene: Mechanistic Insights into the Isomerization Phenomenon During RCM of Medium‐Sized Rings
Authors: De Bo Guillaume , Markó István E.
Published: February 2011

Isomerization issues have been encountered during the ring‐closing metathesis (RCM) step of a new approach towards pentalenene. This paper describes the mechanistic insights gained during the study of this side reaction from a substrate perspective. Isomerization issues have been encountered during the RCM step of a new approach towards pentalenene.
Betti Reaction of Cyclic Imines with Naphthols and Phenols – Preparation of New Derivatives of Betti's Bases
Authors: Cimarelli Cristina , Fratoni Davide , Mazzanti Andrea , Palmieri Gianni
Published: February 2011

A large library of aminocycloalkylphenols and ‐naphthols is obtained by the Betti reaction between activated phenols and naphthols and five‐ and six‐membered cyclic imines. Due to the formation of an intramolecular hydrogen bond in the transition state, the attack takes place regioselectively at the position adjacent to the hydroxy group of the aromatic compounds. X‐ray crystallography and chirooptical methods (electronic circular dichroism) were used to ascertain the absolute configuration of two aminoalkylnaphthols obtained, after resolution of the corresponding racemates with (R,R)‐tartaric acid. In addition, some aminoalkylnaphthols and‐phenols were alkylated at the nitrogen atom to obtain N‐methylated products in good yields.
A General, Diastereoselective Synthesis of Highly Functionalized Bicyclo[n.3.1]alkane Systems Based on an Anionic Domino Reaction of α‐Nitrocycloalkanones
Authors: Giorgi Giorgio , Miranda Sonia , Ruiz Miriam , Rodriguez Jean , López‐Alvarado Pilar , Menéndez J. Carlos
Published: February 2011

The base‐promoted Michael–aldol anionic domino reactions of cyclic α‐nitro ketones and α,β‐unsaturated aldehydes afforded bicyclo[n.3.1]alkanone systems of seven different ring sizes (n = 3–9), normally in excellent yields. This can be considered the first general method for the synthesis of this type of carbocycle. Furthermore, up to four stereocentres are generated, three of which are contiguous and include a functionalized quaternary bridgehead carbon atom. The diastereoselectivity was often complete, was much higher than in less general reactions based on related domino processes, and involved the generation of a different major diastereomer due to the control of the Michael and aldol individual steps of the reaction by the nitro group.
Diastereoselective Synthesis of Lincosamine Precursors
Authors: Serra Fiona , Coutrot Philippe , Estève‐Quelquejeu Mélanie , Herson Patrick , Olszewski Tomasz K. , Grison Claude
Published: February 2011

The stereoselective syntheses of the four aminodiol precursors of the diastereomers of lincosamine are reported. The procedure is based on the initial two‐carbon elongationof 1,2;3,4‐di‐O‐isopropylidene‐α‐D‐galactohexodialdo‐1,5‐pyranose, followed by the stereocontrolled introduction of the amino group by nucleophilic amination. Two complementary approaches have been investigated and compared: The first one is the direct transformation of α‐chloroglycidic ester into β‐amino‐α‐keto ester. The second strategy is a three‐step synthesis that is based on the treatment of the β‐iodo‐α‐keto ester with dibenzylamine. Subsequent reduction of the β‐amino‐α‐keto ester provides the pure D‐erythro, L‐threo, L‐erythro, and D‐threo aminodiols after chromatographic purification. Further classical transformations afford the N‐acetyl derivatives, which are key precursors of the lincosamine diastereomers.
Gold nanoparticles deposited capillaries for in‐capillary microextraction capillary zone electrophoresis of monohydroxy‐polycyclic aromatic hydrocarbons
Authors: Wang Huiyong , Knobel Gaston , Wilson Walter B. , Calimag‐Williams Korina , Campiglia Andres D.
Published: February 2011

This article presents the first application of gold nanoparticles deposited capillaries as pre‐concentration devices for in‐capillary microextraction CZE and their use for the analysis of monohydroxy‐polycyclic aromatic hydrocarbons in synthetic urine samples. The successful separation of 1‐hydroxypyrene, 9‐hydroxyphenanthrene, 3‐hydroxybenzo[a]pyrene (3‐OHbap), 4‐hydroxybenzo[a]pyrene and 5‐hydroxybenzo[a]pyrene under a single set of electrophoretic conditions is demonstrated as well as the feasibility to obtain competitive ultraviolet absorption LOD with commercial instrumentation. Enrichment factors ranging from 87 (9‐OHphe) to 100 (3‐OHbap) made it possible to obtain LOD ranging from 9 ng/mL (9‐OHphe and 3‐OHbap) to 14 ng/mL (4‐hydroxybenzo[a]pyrene).
Return of the Trojan horse: intracellular phenotype switching and immune evasion by Staphylococcus aureus
Authors: Garzoni Christian , Kelley William L.
Published: February 2011

Staphylococcus aureus small colony variants (SCVs), which are characterized by slow growth and a range of morphological and metabolic changes including altered antibiotic resistance profiles, have been studied for several decades. This Closeup highlights findings described in this issue of EMBO Molecular Medicine by Tuchscherr et al (2011), who present strong evidence that SCVs can arise in chronic infection models when S. aureus is internalized in non‐professional phagocytes and survives intracellularly. As the intracellular residency time increases, the proportion of SCVs grows and the host cell inflammatory response diminishes. The study suggests that this mode of phenotype switching is an essential feature of the S. aureus infection process and can explain an underlying cause of chronic and relapsing infections.

See related article in EMBO Mol Med (Tuchscherr et al (2011) EMBO Mol Med 3: 129‐141)
Interlaboratory comparison of measurements of acid-volatile sulfide and simultaneously extracted nickel in spiked sediments
Authors: Brumbaugh William G , Hammerschmidt Chad R , Zanella Luciana , Rogevich Emily , Salata Gregory , Bolek Radoslaw
Published: February 2011

An interlaboratory comparison of acid-volatile sulfide (AVS) and simultaneously extracted nickel (SEM_Ni) measurements of sediments was conducted among five independent laboratories. Relative standard deviations for the seven test samples ranged from 5.6 to 71% (mean = 25%) for AVS and from 5.5 to 15% (mean = 10%) for SEM_Ni. These results are in stark contrast to a recently published study that indicated AVS and SEM analyses were highly variable among laboratories. Environ. Toxicol. Chem. 2011; 30:1306–1309. © 2011 SETAC
Development of a microarray for Enchytraeus albidus (Oligochaeta): preliminary tool with diverse applications
Authors: Amorim Mónica J.B , Novais Sara C , Van Der Ven Karlijn , Vandenbrouck Tine , Soares Amadeu M.V.M , De Coen Wim
Published: February 2011

Standard bioassays allow hazard assessment at the population level, but much remains to be learned about the molecular level response of organisms to stressors. The main aim of this study was the development of a DNA microarray for Enchytraeus albidus, a common soil worm species. Further, this microarray was tested using worms exposed to Cu, phenmedipham, and different soil types. Hybridization onto the developed microarray revealed several genes with homology to known sequences. Genes of interest were confirmed through real-time polymerase chain reaction. It was possible to discriminate between natural and chemical stressors and chemical concentrations. Gene responses were detected under conditions known to have effects in the reproduction of individuals. It was confirmed that the integration of different endpoints improves the assessment process and enhances the understanding of the modes of action of stressors. The chemical stress-induced genes were related to factors such as immune response, stress response, metabolic processes, and/or signal transduction. The present study represents the first step of a gene-level study in the ecologically relevant and standard test species E. albidus. It demonstrates the usefulness of cDNA normalization in the production of cDNA libraries of ecotoxicological standard organisms that are not genome models like E. albidus. Environ. Toxicol. Chem. 2011; 30:1395–1402. © 2011 SETAC
A Single Layer Glucose Fuel Cell Intended as Power Supplying Coating for Medical Implants
Authors: Kloke A. , Biller B. , Kräling U. , Kerzenmacher S. , Zengerle R. , von Stetten F.
Published: February 2011

We present a novel type of abiotically catalysed implantable glucose fuel cell with anode and cathode placed side by side, using a Raney‐platinum glucose oxidation anode with high tolerance towards oxygen. In contrast to conventional assembly designs used for implantable glucose fuel cells, no permeable cathode mounted in front of the anode to effect oxygen depletion is required. At 2.2 ± 0.1 μW cm–2 the single layer fuel cell exhibits only half the maximum power density of the conventional fuel cell, which solely stems from the doubled total fuel cell area demand. Nevertheless, the novel single layer design is advantageous in terms of simplified fabrication and reduced overall thickness, facilitating implementation of the fuel cell as a power supplying coating directly on the surface of medical implants. Furthermore, the single layer design offers an attractive possibility to diminish the reduction of power density by limited oxygen mass transfer to the cathode by increasing the cathode to anode area proportion. With doubled cathode area proportion a by 36% higher power density can be reached. To calculate the optimum cathode to anode area proportions, we introduced an analytical model based on the experimentally determined polarisation resistances of the individual electrodes.