bluuebunny/crossref_metadata_2025 huggingface dataset:
Reversible resistive switching of SrTiOx thin films for nonvolatile memory applications
Authors: Choi Dooho , Lee Dongsoo , Sim Hyunjun , Chang Man , Hwang Hyunsang
Published: February 2006

Nonvolatile and reversible bistable and multistable resistance states of polycrystalline SrTiOx thin film were studied. The pulse-laser-deposition method was employed to grow the film, and the clear resistance switching was observed under dc bias sweep and voltage pulses. More than two controllable resistance states were observed by applying voltage pulses. These reversible states have a resistance difference by nearly two orders of magnitude, and we verified that this sharp resistance switching takes place at the metal-oxide interface. Excellent reliability characteristics, such as endurance cycles of up to 105 times and data retention time of up to 106s at 125°C demonstrate the promise of SrTiOx film for future nonvolatile random access memory applications.
Jahn-Teller effect in spinel manganites probed by soft x-ray absorption spectroscopy
Authors: Noh Han-Jin , Yeo S. , Kang J.-S. , Zhang C. L. , Cheong S.-W. , Oh S.-J. , Johnson P. D.
Published: February 2006

We present soft x-ray absorption spectroscopy (XAS) on spinel manganites and show it can be used as a powerful tool to directly probe the Jahn-Teller (JT) splitting energy in transition metal oxides. The MnL2,3-edge XAS spectra of the spinel ZnMnxGa2−xO4(x=0.5,1.0,1.4,and2.0) and AMn2O4(A=MgandCd) change very systematically with the structural distortion of JT active octahedral sublattices. The XAS spectra are well reproduced by the configuration interaction cluster model including full ionic multiplet structure, and the spectral evolution is explained by JT energy splitting due to the elongation of the MnO6 octahedra in the model. In the OK-edge XAS spectra, the JT distortion produces a weak effect, less distinctive than in L2,3-edge spectra.
Gate-controlled spin splitting in GaN∕AlN quantum wells
Authors: Lo Ikai , Wang W. T. , Gau M. H. , Tsai J. K. , Tsay S. F. , Chiang J. C.
Published: February 2006

The spin splitting of wurtzite GaN was calculated by 32×32 Hamiltonian with spin-orbital interaction. The band-folding effect generates two conduction bands ΔC1 and ΔC3 in which the p-wave probability shows a tremendous change when kz approaches the anticrossing zone. We found that a large spin plitting in GaN∕AlN quantum wells is produced due to ΔC1-ΔC3 coupling, and is effectively controlled by electric field. Based on the mechanism and gate-controllable spin splitting, we proposed a p-wave-enhanced quantum well, InxGa1-xN∕InyAl1−yN, for the application of the spin-polarized field effect transistor designed by Datta and Das [Appl. Phys. Lett. 56, 665 (1990)].
Organic light-emitting devices with a hole-blocking layer inserted between the hole-injection layer and hole-transporting layer
Authors: Divayana Y. , Chen B. J. , Sun X. W. , Sarma K. S.
Published: February 2006

A hole-blocking layer (HBL), 2,9-dimethyl-4, 7-diphenylphenanthroline (BCP), was incorporated between the hole-transporting layer (HTL) and hole-injection layer for a tris-(8-hydroxyqunoline) aluminum-based organic light-emitting device. Such a structure helps to reduce the hole-leakage to the cathode resulting in improved current efficiency. Optimum BCP thickness of around 3nm was observed to produce a current efficiency of 3.25cd∕A, which corresponds to a 30% improvement compared to that of the standard device without BCP (2.5cd∕A). Low operating voltage was also achieved by minimizing the thickness of the HTL. Both operating voltage and efficiency can be tuned by varying the thickness of HTL and HBL, respectively.
Fabrication and thermoelectric properties of layered cobaltite, γ-Sr0.32Na0.21CoO2 epitaxial films
Authors: Sugiura Kenji , Ohta Hiromichi , Nomura Kenji , Hirano Masahiro , Hosono Hideo , Koumoto Kunihito
Published: February 2006

Thermoelectric properties of γ-Sr0.32Na0.21CoO2 epitaxial films, which were fabricated on the (0001)-face of α-Al2O3 substrates by ion exchange processes between Na+ and Sr2+ ions with γ-Na0.8CoO2 epitaxial films, were measured to clarify the effect of Sr2+-ion exchange of γ-Na0.8CoO2 on the thermoelectric properties. Electrical conductivity (σ), Seebeck coefficient (S), and thermoelectric power factor (PF=S2σ) of the γ-Sr0.32Na0.21CoO2 film (300K) were 8.9×102Scm−1, +120μVK−1, and 1.2×10−3Wm−1K−2, respectively. These values were relatively large compared to those of γ-Na0.8CoO2 epitaxial films (σ=1.2×103Scm−1, S=+95μVK−1, and PF=1.1×10−3Wm−1K−2). The γ-Sr0.32Na0.21CoO2 epitaxial film exhibited much improved chemical stability against moisture compared to the γ-Na0.8CoO2 epitaxial film. The Sr2+-ion exchange of γ-Na0.8CoO2 is vital for practical thermoelectric applications.
Photoluminescence from single InSb quantum wells
Authors: Smith S. J. , Nash G. R. , Fearn M. , Buckle L. , Emeny M. T. , Ashley T.
Published: February 2006

The luminescent properties of single InSb quantum wells have been investigated as a function of temperature and incident laser power. A large peak was observed in the photoluminescence, corresponding to emission from the quantum well, which moves to lower energy with increasing temperature and tracks the bulk InSb band gap with a constant energy up-shift of ∼50meV. The integrated photoluminescence intensity was observed to fall with increasing temperature, with a well defined activation energy of 17meV at high temperatures, and to be proportional to the square of the excitation intensity.
Pollen treatment for mutation induction in Eucalyptus globulus ssp. globulus (Myrtaceae)
Authors: McManus L. J. , Sasse J. , Blomstedt C. K. , Bossinger G.
Published: February 2006

Mutation induction has played an integral role in the improvement of most commercially important crop species but has not been successfully applied to tree species because of their long reproductive cycles which hinder the use of the traditional seed-treatment approaches. Treatment of pollen with a chemical mutagen prior to pollination will, theoretically, allow stable, heterozygous mutant trees to be produced in a relatively short time and might facilitate mutagenesis of tree species. As the first step in testing this hypothesis, a controlled-pollination trial with chemically treated pollen was conducted in Eucalyptus globulus ssp. globulus (Labill.). Assessment of fruit, seed and seedlings from more than 500 pollinations associated mutagenic treatment of pollen with a significant reduction in seed set. Non-significant increases in capsule (fruit) abortion, the inhibition of seed germination and the incidence of aberration in seedlings were also noted. We argue that pollen treatment may be a useful means of producing Eucalyptus mutants with variation in flowering time, salinity and frost tolerance, lignification and other traits of scientific and economic importance.
A short isoform of NOD2/CARD15, NOD2-S, is an endogenous inhibitor of NOD2/receptor-interacting protein kinase 2-induced signaling pathways
Authors: Rosenstiel Philip , Huse Klaus , Till Andreas , Hampe Jochen , Hellmig Stephan , Sina Christian , Billmann Susanne , von Kampen Oliver , Waetzig Georg H. , Platzer Matthias , Seegert Dirk , Schreiber Stefan
Published: February 2006

Alterations in splicing patterns of genes contribute to the regulation of gene function by generating endogenous inhibitor or activator molecules. Nucleotide-binding and oligomerization domain (NOD) 2 is an intracellular receptor for bacterial cell wall components and plays an important role in initiating immune responses against cytoinvasive pathogens. NOD2 overexpression sensitizes intestinal epithelial cells toward bacterial cell wall components, activates the proinflammatory transcription factor NF-κB, and induces the subsequent release of the chemotactic cytokine IL-8. Here, we have assessed the regulation and function of a transcript isoform of NOD2, NOD2-S, generated by the skipping of the third exon, which encodes for a protein that is truncated within the second caspase recruitment (CARD) domain. NOD2-S is preferentially expressed in the human colon and is up-regulated by the antiinflammatory cytokine IL-10. Overexpression of NOD2-S down-regulates NOD2-induced NF-κB activation and IL-8 release. Moreover, NOD2-S also interferes with the maturation and secretion of pro-IL-1β downstream of NOD2 and its adaptor molecule receptor-interacting protein kinase 2. We provide a molecular basis for these effects, as we show that NOD2-S interacts with both, NOD2 and receptor-interacting protein kinase 2 and inhibits the “nodosome” assembly by interfering with the oligomerization of NOD2. These data unveil another level of complexicity in the regulation of intracellular innate immunity and may have important implications for the molecular understanding of NOD/NALP protein-driven disease pathophysiology.
Myo1c binds tightly and specifically to phosphatidylinositol 4,5-bisphosphate and inositol 1,4,5-trisphosphate
Authors: Hokanson David E. , Ostap E. Michael
Published: February 2006

Myosin-I is the single-headed member of the myosin superfamily that associates with acidic phospholipids through its basic tail domain. Membrane association is essential for proper myosin-I localization and function. However, little is known about the physiological relevance of the direct association of myosin-I with phospholipids or about phospholipid headgroup-binding specificity. To better understand the mechanism of myosin-I–membrane association, we measured effective dissociation constants for the binding of a recombinant myo1c tail construct (which includes three IQ domains and bound calmodulins) to large unilamellar vesicles (LUVs) composed of phosphatidylcholine and various concentrations of phosphatidylserine (PS) or phosphatidylinositol 4,5-bisphosphate (PIP2). We found that the myo1c-tail binds tightly to LUVs containing >60% PS but very weakly to LUVs containing physiological PS concentrations (<40%). The myo1c tail and not the IQ motifs bind tightly to LUVs containing 2% PIP2. Additionally, we found that the myo1c tail binds to soluble inositol-1,4,5-trisphosphate with nearly the same affinity as to PIP2in LUVs, suggesting that myo1c binds specifically to the headgroup of PIP2. We also show that a GFP-myosin-I-tail chimera expressed in epithelial cells is transiently localized to regions known to be enriched in PIP2. Our results suggest that myo1c does not bind to physiological concentrations of PS but rather binds tightly to PIP2.
Ecological functions of tetrodotoxin in a deadly polyclad flatworm
Authors: Ritson-Williams Raphael , Yotsu-Yamashita Mari , Paul Valerie J.
Published: February 2006

The deadly neurotoxin tetrodotoxin (TTX) is found in a variety of animal phyla and, because of its toxicity, is most often assumed to deter predation. On the tropical Pacific island of Guam, we found an undescribed flatworm (planocerid sp. 1) that contains high levels of TTX and its analogs. Through ecological experiments, we show that TTXs do not protect these flatworms from some predators but instead are used to capture mobile prey. TTX is known to have multiple ecological functions, which has probably led to its widespread presence among prokaryotes and at least 10 metazoan phyla.
Depth sectioning with the aberration-corrected scanning transmission electron microscope
Authors: Borisevich Albina Y. , Lupini Andrew R. , Pennycook Stephen J.
Published: February 2006

The ability to correct the aberrations of the probe-forming lens in the scanning transmission electron microscope provides not only a significant improvement in transverse resolution but in addition brings depth resolution at the nanometer scale. Aberration correction therefore opens up the possibility of 3D imaging by optical sectioning. Here we develop a definition for the depth resolution for scanning transmission electron microscope depth sectioning and present initial results from this method. Objects such as catalytic metal clusters and single atoms on various support materials are imaged in three dimensions with a resolution of several nanometers. Effective focal depth is determined by statistical analysis and the contributing factors are discussed. Finally, current challenges and future capabilities available through new instruments are discussed.
Base-tetrad swapping results in dimerization of RNA quadruplexes: Implications for formation of thei-motif RNA octaplex
Authors: Pan Baocheng , Shi Ke , Sundaralingam Muttaiya
Published: February 2006

Nucleic acids adopt different multistranded helical architectures to perform various biological functions. Here, we report a crystal structure of an RNA quadruplex containing “base-tetrad swapping” and bulged nucleotide at 2.1-Å resolution. The base-tetrad swapping results in a dimer of quadruplexes with an intercalated octaplex fragment at the 5′ end junction. The intercalated base tetrads provide the basic repeat unit for constructing a model of intercalated RNA octaplex. The model we obtained shows fundamentally different characteristics from duplex, triplex, and quadruplex. We also observed two different orientations of bulged uridine residues that are related to the interaction with surroundings. This structural evidence reflects the conformational flexibility of bulged nucleotides in RNA quadruplexes and implies the potential roles of bulged nucleotides as recognition and interaction sites in RNA–protein and RNA–RNA interactions.
Cooperativity in the self-assembly of porphyrin ladders
Authors: Camara-Campos Amaya , Hunter Christopher A. , Tomas Salvador
Published: February 2006

Cooperativity is a general feature of intermolecular interactions in biomolecular systems, but there are many different facets of the phenomenon that are not well understood. Positive cooperativity stabilizes a system as progressively more interactions are added, and the origin of the beneficial free energy may be entropic or enthalpic in origin. An “enthalpic chelate effect” has been proposed to operate through structural tightening that improves all of the functional group interactions in a complex, when it is more strongly bound. Here, we present direct calorimetric evidence that no such enthalpic effects exist in the cooperative assembly of supramolecular ladder complexes composed of metalloporphyrin oligomers coordinated to bipyridine ligands. The enthalpic contributions of the individual coordination interactions are 35 kJ·mol
−1
and constant over a range of free energies of self-assembly of −35 to −111 kJ·mol
−1
. In rigid well defined systems of this type, the enthalpies of individual interactions are additive, and no enthalpic cooperative effects are apparent. The implication is that in more flexible, less well defined systems such as biomolecular assemblies, the enthalpy contributions available from specific functional group interactions are well defined and constant parameters.
Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers
Authors: Singh Ravi , Pantarotto Davide , Lacerda Lara , Pastorin Giorgia , Klumpp Cédric , Prato Maurizio , Bianco Alberto , Kostarelos Kostas
Published: February 2006

Carbon nanotubes (CNT) are intensively being developed for biomedical applications including drug and gene delivery. Although all possible clinical applications will require compatibility of CNT with the biological milieu, theirin vivocapabilities and limitations have not yet been explored. In this work, water-soluble, single-walled CNT (SWNT) have been functionalized with the chelating molecule diethylentriaminepentaacetic (DTPA) and labeled with indium (111In) for imaging purposes. Intravenous (i.v.) administration of these functionalized SWNT (f-SWNT) followed by radioactivity tracing using gamma scintigraphy indicated thatf-SWNT are not retained in any of the reticuloendothelial system organs (liver or spleen) and are rapidly cleared from systemic blood circulation through the renal excretion route. The observed rapid blood clearance and half-life (3 h) off-SWNT has major implications for all potential clinical uses of CNT. Moreover, urine excretion studies using bothf-SWNT and functionalized multiwalled CNT followed by electron microscopy analysis of urine samples revealed that both types of nanotubes were excreted as intact nanotubes. This work describes the pharmacokinetic parameters of i.v. administered functionalized CNT relevant for various therapeutic and diagnostic applications.
Cyclic GMP-independent mechanisms contribute to the inhibition of platelet adhesion by nitric oxide donor: A role for α-actinin nitration
Authors: Marcondes Sisi , Cardoso Marcia H. M. , Morganti Rafael P. , Thomazzi Sara M. , Lilla Sergio , Murad Ferid , De Nucci Gilberto , Antunes Edson
Published: February 2006

The nitric oxide-mediated actions are mostly due to cyclic GMP (cGMP) formation, but cGMP-independent mechanisms, such as tyrosine nitration, have been suggested as potential signaling pathways modulating the NO-induced responses. However, the mechanisms that lead to tyrosine nitration in platelets are poorly studied, and the protein targets of nitration have not been identified in these cells. Therefore, we have used the model of platelet adhesion to fibrinogen-coated plates to investigate the cGMP-independent mechanisms of the NO-donor sodium nitroprusside (SNP) that leads to inhibition of platelet adhesion. SNP concentration-dependently inhibited platelet adhesion, as observed at 15-min and 60-min adhesion. Additionally, SNP markedly increased the cGMP levels, and the soluble guanylate inhibitor ODQ nearly abolished the SNP-mediated cGMP elevations in all experimental conditions used. Nevertheless, ODQ failed to affect the adhesion inhibition obtained with 1.0 mM SNP at 15 min. On the other hand, superoxide dismutase or peroxynitrite (ONOO−) scavenger epigallocatechin gallate significantly reversed the inhibition of platelet adhesion by SNP (1 mM, 15 min). Western blot analysis in SNP (1 mM, 15 min)-treated platelets showed a single tyrosine-nitrated protein with an apparent mass of ≈105 kDa. Nanospray LC-MS/MS identified the human α-actinin 1 cytoskeletal isoform (P12814) as the protein contained in the nitrated SDS gel band. Thus, tyrosine nitration of α-actinin, through ONOO−formation, may be a key modulatory mechanism to control platelet adhesion.
Opsin is present as dimers in COS1 cells: Identification of amino acids at the dimeric interface
Authors: Kota Parvathi , Reeves Philip J. , RajBhandary Uttam L. , Khorana H. Gobind
Published: February 2006

Rhodopsin in the disk membranes of rod outer segments serves as the dim-light photoreceptor and is a prototypic member of a G protein-coupled receptor family. Electron and atomic-force microscopy indicate that rhodopsin is present as dimers in the native membranes. Here, we have expressed the protein, opsin, in COS1 cells and have studied its molecular state by using FRET and by intermolecular cross-linking after site-directed cysteine mutagenesis. To observe FRET, the ends of the genes corresponding to the N termini of the cyan or yellow fluorescent proteins were fused to the ends of the genes corresponding to the C terminus of the opsin and the resulting fused genes were expressed in COS1 cells. The emission spectra
in situ
of the expressed proteins were recorded, and FRET was then calculated. The result indicated intermolecular interaction between opsin molecules in COS1 cells. To identify the amino acids involved in the interaction, those predicted by molecular modeling to be at the dimer interface were mutated one at a time to cysteine, and dimer formation was measured by the rate of disulfide bond formation in the presence of cupric orthophenanthroline. The mutants W175C and Y206C formed the dimers most rapidly, showing that the two amino acids were at the dimer interface.
Rhodopsin self-associates in asolectin liposomes
Authors: Mansoor Steven E. , Palczewski Krzysztof , Farrens David L.
Published: February 2006

We show that the photoreceptor rhodopsin (Rh) can exist in the membrane as a dimer or multimer using luminescence resonance energy transfer and FRET methods. Our approach looked for interactions between Rh molecules reconstituted into asolectin liposomes. The low receptor density used in the measurements ensured minimal receptor crowding and artifactual association. The fluorescently labeled Rh molecules were fully functional, as measured by their ability to activate the G protein transducin. The luminescence resonance energy transfer measurements revealed a distance of 47–50 Å between Rh molecules. The measured efficiency of FRET between receptors was close to the theoretical maximum possible, indicating nearly quantitative Rh–Rh association. Together, these results provide compelling evidence that Rh spontaneously self-associates in membranes.
Chromatin remodeling by nucleosome disassembly
in vitro
Authors: Lorch Yahli , Maier-Davis Barbara , Kornberg Roger D.
Published: February 2006

The RSC chromatin-remodeling complex completely disassembles a nucleosome in the presence of the histone chaperone Nap1 and ATP. Disassembly occurs in a stepwise manner, with the removal of H2A/H2B dimers, followed by the rest of the histones and the release of naked DNA. RSC and related chromatin-remodeling complexes may be responsible for the removal of promoter nucleosomes during transcriptional activation
in vivo
.
Differential effects of aging on fluid intake in response to hypovolemia, hypertonicity, and hormonal stimuli in Munich Wistar rats
Authors: McKinley M. J. , Denton D. A. , Thomas C. J. , Woods R. L. , Mathai M. L.
Published: February 2006

A significant proportion of aged humans may have impaired thirst and inadequate fluid intake after a period of fluid deprivation. We have studied the water drinking responses, relative to body weight, of Munich Wistar (MW) rats in response to osmotic, hypovolemic, dehydrational, and angiotensin (Ang)-related stimuli as they aged from 3 to 24 months. Young 3-months-old (m.o.) rats had the largest daily fluid intakes and drinking responses to hypertonic and dehydrational stimuli, suggesting that they have accentuated thirst in comparison with older age groups. There were no differences in daily fluid intake from 6–24 m.o.; however, drinking responses to i.p. injection of hypertonic 0.4 mol/liter NaCl gradually declined over this period so that in 24-m.o. rats the response was only half that of 6-m.o. rats. Water intake after 24-h water deprivation also declined gradually over 24 months. Drinking responses to hypovolemia induced by s.c. injection of colloid (polyethylene glycol) were unchanged in 6- to 15-m.o. rats, then declined precipitously in 18- to 24-m.o. rats. Drinking responses to s.c. Ang II or s.c. isoproterenol were not reduced in 24-m.o. rats, nor was the drinking associated with feeding. Therefore, there are specific impairments of water intake in response to hypertonicity and hypovolemia in aged MW rats, but Ang-related drinking is not reduced. Like aged humans, aged MW rats exhibit high plasma atrial natriuretic peptide levels and impaired cardiovascular reflexes that could contribute to the impairment of thirst with age.
IL-32, a proinflammatory cytokine in rheumatoid arthritis
Authors: Joosten Leo A. B. , Netea Mihai G. , Kim Soo-Hyun , Yoon Do-Young , Oppers-Walgreen Birgitte , Radstake Timothy R. D. , Barrera Pilar , van de Loo Fons A. J. , Dinarello Charles A. , van den Berg Wim B.
Published: February 2006

IL-32 is a recently discovered cytokine that induces TNFα, IL-1β, IL-6, and chemokines. We investigated whether IL-32 is expressed in the synovia of patients with rheumatoid arthritis (RA) and studied associations with disease severity and the presence of other cytokines. Immunohistochemistry revealed that IL-32 is highly expressed in RA synovial tissue biopsies, whereas IL-32 was not observed in synovial tissues from patients with osteoarthritis. Moreover, in synovial biopsies from 29 RA patients with active disease, the level of IL-32 staining correlated with erythrocyte sedimentation rate, a marker of systemic inflammation (
R
= 0.63 and
P
< 0.0003). Synovial staining of IL-32 also correlated with indices of synovial inflammation (
R
= 0.80 and
P
< 0.0001) as well as synovial presence of TNFα (
R
= 0.68 and
P
< 0.004), IL-1β (
R
= 0.79 and
P
< 0.0001), and IL-18 (
R
= 0.82 and
P
< 0.001). IL-32 was a potent inducer of prostaglandin E
2
release in mouse macrophages and human blood monocytes, an important property for inflammation. After the injection of human IL-32γ into the knee joints of naïve mice, joint swelling, with pronounced influx of inflammatory cells and cartilage damage, was observed. In TNFα-deficient mice, IL-32-driven joint swelling was absent and cell influx was markedly reduced, but loss of proteoglycan was unaffected, suggesting that IL-32 activity is, in part, TNFα-dependent. IL-32, strongly associated with TNFα, IL-1β, and IL-18, appears to play a role in human RA and may be a novel target in autoimmune diseases.
Heterogeneous but conserved natural killer receptor gene complexes in four major orders of mammals
Authors: Hao Li , Klein Jan , Nei Masatoshi
Published: February 2006

The natural killer (NK) receptor gene complex (NKC) encodes a large number of C-type lectin-like receptors, which are expressed on NK and other immune-related cells. These receptors play an important role in regulating NK-cell cytolytic activity, protecting cells against virus infection and tumorigenesis. To understand the evolutionary history of the NKC, we characterized the C-type lectin-like NKC genes and their organization from four major orders of placental mammals, primates (human), rodents (mouse and rat), carnivores (dog), and artiodactyls (cattle) and then conducted phylogenetic analysis of these genes. The results indicate that the NKC of placental mammals is highly heterogeneous in terms of the gene content and rates of birth and death of different gene lineages, but the NKC is also remarkably conserved in its gene organization and persistence of orthologous gene lineages. Among the 28 identified NKC gene lineages, 4,
KLRA1
,
KLRB1
,
CLEC2D
, and
CLEC4A/B/C
, have expanded rapidly in rodents only. The high birth and death rate of these 4 gene families might be due to functional differentiation driven by positive selection. Identification of putative NKC sequences in opossum and chicken genomes implies that the expansion of the NKC gene families might have occurred before the radiation of placental mammals but after the divergence of birds from mammals.
Functional analyses of GB virus B p13 protein: Development of a recombinant GB virus B hepatitis virus with a p7 protein
Authors: Takikawa Shingo , Engle Ronald E. , Emerson Suzanne U. , Purcell Robert H. , St. Claire Marisa , Bukh Jens
Published: February 2006

GB virus B (GBV-B), which infects tamarins, is the virus most closely related to hepatitis C virus (HCV). HCV has a protein (p7) that is believed to form an ion channel. It is critical for viability.
In vitro
studies suggest that GBV-B has an analogous but larger protein (p13). We found that substitutions of the −1 and/or −3 residues of the putative cleavage sites (amino acid 613/614 and 732/733) abolished processing
in vitro
and rendered an infectious GBV-B clone nonviable in tamarins. Internal cleavage was predicted at two sites (amino acid 669/670 and 681/682), and
in vitro
analysis indicated processing at both sites, suggesting that p13 is processed into two components (p6 and p7). Mutants with substitution at amino acid 669 or 681 were viable
in vivo
, but the recovered viruses had changes at amino acid 669 and 681, respectively, which restored cleavage. A mutant lacking amino acid 614–681 (p6 plus part of p7) was nonviable. However, a mutant lacking amino acid 614–669 (p6) produced high titer viremia and acute resolving hepatitis; viruses recovered from both animals lacked the deleted sequence and had no other mutations. Thus, p6 was dispensable but p7 was essential for infectivity. The availability of a recombinant GBV-B virus containing a p7 protein with similarities to the HCV p7 will enhance the relevance of this model and will be of importance for identifying compounds that inhibit p7 function as additional therapeutic agents.
Wnt signaling in the thymus is regulated by differential expression of intracellular signaling molecules
Authors: Weerkamp Floor , Baert Miranda R. M. , Naber Brigitta A. E. , Koster Esther E. L. , de Haas Edwin F. E. , Atkuri Kondala R. , van Dongen Jacques J. M. , Herzenberg Leonard A. , Staal Frank J. T.
Published: February 2006

Wnt signaling is essential for T cell development in the thymus, but the stages in which it occurs and the molecular mechanisms underlying Wnt responsiveness have remained elusive. Here we examined Wnt signaling activity in both human and murine thymocyte populations by determining β-catenin levels, Tcf-reporter activation and expression of Wnt-target genes. We demonstrate that Wnt signaling occurs in all thymocyte subsets, including the more mature populations, but most prominently in the double negative (DN) subsets. This differential sensitivity to Wnt signaling was not caused by differences in the presence of Wnts or Wnt receptors, as these appeared to be expressed at comparable levels in all thymocyte subsets. Rather, it can be explained by high expression of activating signaling molecules in DN cells, e.g., β-catenin, plakoglobin, and long forms of Tcf-1, and by low levels of inhibitory molecules. By blocking Wnt signaling from the earliest stage onwards using overexpression of Dickkopf, we show that inhibition of the canonical Wnt pathway blocks development at the most immature DN1 stage. Thus, responsiveness to developmental signals can be regulated by differential expression of intracellular mediators rather than by abundance of receptors or ligands.
Monovalent ligation of the B cell receptor induces receptor activation but fails to promote antigen presentation
Authors: Kim You-Me , Pan Jennifer Yi-Jiun , Korbel Gregory A. , Peperzak Victor , Boes Marianne , Ploegh Hidde L.
Published: February 2006

We explored the role of antigen valency in B cell receptor (BCR) activation and rearrangement of intracellular MHC class II compartments as factors that contribute to the efficacy of antigen presentation. Using primary B cells that express a hen egg lysozyme (HEL)-specific BCR, we found that oligomeric HEL more efficiently promoted both BCR activation and internalization than did monovalent HEL, although monovalent HEL, unlike monovalent Fab fragments of anti-Ig, readily triggered the BCR. Nonetheless, oligovalent ligation positions the BCR in a membrane microdomain that is distinct from one engaged in the course of monovalent ligation, as judged by detergent extraction of the BCR. Furthermore, oligovalent HEL induced more pronounced rearrangement of MHC class II-containing antigen-processing compartments. Using videomicroscopy we observed in real time the rearrangement of MHC class II compartments as well as delivery of antigen in primary B cells. The observed increase in rearrangement of MHC class II-positive compartments and the disposition of antigen-bound BCRs therein correlates with improved presentation of a HEL-derived epitope. Although monomeric HEL efficiently engages the BCR, presentation of HEL-derived epitopes is impaired compared to oligovalent antigens. This trait may help explain the known ability of soluble, disaggregated antigen to induce a state of B cell tolerance.
Mutant Huntingtin: Nuclear translocation and cytotoxicity mediated by GAPDH
Authors: Bae Byoung-Il , Hara Makoto R. , Cascio Matthew B. , Wellington Cheryl L. , Hayden Michael R. , Ross Christopher A. , Ha Hyo Chol , Li Xiao-Jiang , Snyder Solomon H. , Sawa Akira
Published: February 2006

The pathophysiology of Huntington’s disease reflects actions of mutant Huntingtin (Htt) (mHtt) protein with polyglutamine repeats, whose N-terminal fragment translocates to the nucleus to elicit neurotoxicity. We establish that the nuclear translocation and associated cytotoxicity of mHtt reflect a ternary complex of mHtt with GAPDH and Siah1, a ubiquitin-E3-ligase. Overexpression of GAPDH or Siah1 enhances nuclear translocation of mHtt and cytotoxicity, whereas GAPDH mutants that cannot bind Siah1 prevent translocation. Depletion of GAPDH or Siah1 by RNA interference diminishes nuclear translocation of mHtt.
Gene expression patterns in dendritic cells infected with measles virus compared with other pathogens
Authors: Zilliox Michael J. , Parmigiani Giovanni , Griffin Diane E.
Published: February 2006

Gene expression patterns supply insight into complex biological networks that provide the organization in which viruses and host cells interact. Measles virus (MV) is an important human pathogen that induces transient immunosuppression followed by life-long immunity in infected individuals. Dendritic cells (DCs) are potent antigen-presenting cells that initiate the immune response to pathogens and are postulated to play a role in MV-induced immunosuppression. To better understand the interaction of MV with DCs, we examined the gene expression changes that occur over the first 24 h after infection and compared these changes to those induced by other viral, bacterial, and fungal pathogens. There were 1,553 significantly regulated genes with nearly 60% of them down-regulated. MV-infected DCs up-regulated a core of genes associated with maturation of antigen-presenting function and migration to lymph nodes but also included genes for IFN-regulatory factors 1 and 7, 2′5′ oligoadenylate synthetase, Mx, and TNF superfamily proteins 2, 7, 9, and 10 (TNF-related apoptosis-inducing ligand). MV induced genes for IFNs, ILs, chemokines, antiviral proteins, histones, and metallothioneins, many of which were also induced by influenza virus, whereas genes for protein synthesis and oxidative phosphorylation were down-regulated. Unique to MV were the induction of genes for a broad array of IFN-αs and the failure to up-regulate dsRNA-dependent protein kinase. These results provide a modular view of common and unique DC responses after infection and suggest mechanisms by which MV may modulate the immune response.
IL-7 promotes T cell proliferation through destabilization of p27Kip1
Authors: Li Wen Qing , Jiang Qiong , Aleem Eiman , Kaldis Philipp , Khaled Annette R. , Durum Scott K.
Published: February 2006

Interleukin (IL)-7 is required for survival and homeostatic proliferation of T lymphocytes. The survival effect of IL-7 is primarily through regulation of Bcl-2 family members; however, the proliferative mechanism is unclear. It has not been determined whether the IL-7 receptor actually delivers a proliferative signal or whether, by promoting survival, proliferation results from signals other than the IL-7 receptor. We show that in an IL-7–dependent T cell line, cells protected from apoptosis nevertheless underwent cell cycle arrest after IL-7 withdrawal. This arrest was accompanied by up-regulation of the cyclin-dependent kinase inhibitor p27Kip1 through a posttranslational mechanism. Overexpression of p27Kip1 induced G1 arrest in the presence of IL-7, whereas knockdown of p27Kip1 by small interfering RNA promoted S phase entry after IL-7 withdrawal. CD4 or CD8 T cells transferred into IL-7–deficient hosts underwent G1 arrest, whereas 27Kip1-deficient T cells underwent proliferation. We observed that IL-7 withdrawal activated protein kinase C (PKC)θ and that inhibition of PKCθ with a pharmacological inhibitor completely blocked the rise of p27Kip1 and rescued cells from G1 arrest. The conventional pathway to breakdown of p27Kip1 is mediated by S phase kinase-associated protein 2; however, our evidence suggests that PKCθ acts via a distinct, unknown pathway inducing G1 arrest after IL-7 withdrawal from T cells. Hence, IL-7 maintains T cell proliferation through a novel pathway of p27Kip1 regulation.
Functional Estrogen Receptors in the Mitochondria of Breast Cancer Cells
Authors: Pedram Ali , Razandi Mahnaz , Wallace Douglas C. , Levin Ellis R.
Published: February 2006

Steroid hormones have been reported to indirectly impact mitochondrial functions, attributed to nuclear receptor-induced production of proteins that localize in this cytoplasmic organelle. Here we show high-affinity estrogen receptors in the mitochondria of MCF-7 breast cancer cells and endothelial cells, compatible with classical estrogen receptors ERα and ERβ. We report that in MCF-7, estrogen inhibits UV radiation-induced cytochrome C release, the decrease of the mitochondrial membrane potential, and apoptotic cell death. UV stimulated the formation of mitochondrial reactive oxygen species (mROS), and mROS were essential to inducing mitochondrial events of cell death. mROS mediated the UV activation of c-jun N-terminal kinase (JNK), and protein kinase C (PKC) δ, underlying the subsequent translocation of Bax to the mitochondria where oligomerization was promoted. E2 (estradiol) inhibited all these events, directly acting in mitochondria to inhibit mROS by rapidly up-regulating manganese superoxide dismutase activity. We implicate novel functions of ER in the mitochondria of breast cancer that lead to the survival of the tumor cells.
The Moral Limits of the Criminal Law: Volume 2: Offense to Others
Authors: Feinberg Joel
Published: February 2006

This book is the second in a four-volume work entitled The Moral Limits of Criminal Law, which examines the acts that the state may make criminal. It focuses on the issue of offense, presenting a detailed analysis of offensive behavior and how it is more a nuisance than a menace. It identifies the different kinds of offenses and the standards for evaluating their seriousness. The issue of obscenity is analyzed within the context of pornography and the Constitution. Obscene words, their functions, and social and legal implications are also discussed.
Offensive Nuisances
Authors: Feinberg Joel
Published: February 2006

The offense principle requires that an unpleasant state of mind or offense be produced wrongfully by another party, but not that it be an offense in the strict sense of ordinary language. The legislative problem of determining when offensive conduct is a public or criminal nuisance could be expressed, with equal accuracy, as a problem about determining the extent of personal privacy or autonomy. The former way of describing the matter lends itself to talk of balancing the independent value or reasonableness of the offending conduct against the seriousness of the offense cause, whereas the latter way lends itself to talk of drawing boundaries between the various private domains of persons, and between private domains of a person and the public world.
Mediating the Offense Principle
Authors: Feinberg Joel
Published: February 2006

The legitimacy of criminal law’s concern with offensiveness even in the absence of harm or danger must rest on the intuitive force of the examples given, most of which have been made as extreme as possible and depicted with uncompromising vividness. The seriousness of an offense is determined by four standards: the magnitude of the offense, the standard of reasonable avoidability, the Volenti maxim, and the discounting of abnormal susceptibilities. Having determined the seriousness of a given category of offense based on these standards, the legislator will proceed to balance that seriousness against the reasonableness of various kinds of conduct that can produce it.
The Idea of the Obscene
Authors: Feinberg Joel
Published: February 2006

Obscenity is an extreme form of offensiveness producing repugnance, shock, or disgust, although the offending materials can, at the same time, be alluring to some degree. The main feature that distinguishes obscene things from other repellant or offensive things is their blatancy: their massive obtrusiveness, their extreme and unvarnished bluntness, their brazenly naked exhibition. The three classes of objects that can be termed as “obscene” are: obscene natural objects, obscene persons, and obscene created things. There are three ways in which these objects can be offensive to the point of obscenity: by direct offense to the senses, by offense to lower order sensibilities, by offense to higher sensibilities.
Pornography and the Constitution
Authors: Feinberg Joel
Published: February 2006

The Supreme Court views the word “obscene” as akin to word “pornographic”. Nothing is “obscene” unless it tends to cause erotic states in the mind of the beholder, and anything that produces this kind of “psychic stimulation” is a likely candidate for the obscenity label whether or not the induced states are offensive to the person who has them or anyone else aware of them. Recent Supreme Court decisions on the permissibility of pornography, particularly the various judicial formulae the court has produced to deal with the problem, are reviewed. It is shown that the Court has vacillated between different legitimizing principles, applying either a liberal offense principle mediated by balancing tests or a thinly disguised moralism.
Obscene Words and their Functions, I
Authors: Feinberg Joel
Published: February 2006

Obscene words have the capacity to offend and shock listeners, and in some cases even fill with dread and horror. The class of words that are either obscene, totally disreputable, or naughty enough to be forbidden, is diverse and heterogeneous. These include sexual vulgarities, other “dirty words”, political labels, ethnic slurs, insulting terms, and religious blasphemies. Obscene-to-naughty words and phrases can be classified into two main categories: profanities and vulgarities. Derivative uses of obscenity are discussed.
Obscene Words and their Functions, II
Authors: Feinberg Joel
Published: February 2006

Invective has various uses including expressive intensification, bandinage, calumny, insult, challenge, and provocation. For many of these uses, obscene words can advance the purposes of the speaker, but are inessential and self-defeating in many cases. The relation between some of the most common styles of invective and older forms of malediction, the uses of invective, the doctrine of fighting words and its difficulties, the role of obscenity in invective, and derivative uses of obscenity are discussed.
Obscene Words and Social Policy
Authors: Feinberg Joel
Published: February 2006

Obscenity is the language of impiety, irreverence, and disrespect. Some use it to convey a disrespectful attitude towards a person or platitude, while others use it to reject the prevailing norms of propriety. The meanings of the terms euphemism, cacophemism, prophemism, and disphemism are explained. The reaction to excessive euphemization, two strategies for ridding the language of obscene words, the phenomenon of dirty-mindedness, and the case for retaining the obscene vocabulary are discussed.
Obscene Words and the Law
Authors: Feinberg Joel
Published: February 2006

A wholesale ban on uttering or writing obscene words cannot be justified even by the principle of legal moralism. Moreover, the offense principle cannot justify the criminal prohibition of the utterance of obscenities in public places even when these are intentionally used to cause offense. The use of obscene words can only be made criminal when it is an unjustified, deliberately imposed nuisance. This form of nuisance is a kind of harassment, and the fact that it employs obscene words is by no means essential to its moral gravamen. Obscenity in the media is discussed.
Introduction
Authors: Stern David G.
Published: February 2006

Unlike most books on Wittgenstein, Wittgenstein on Mind and Language begins from the initial articulation of his thoughts in his first drafts, conversations, and lectures, and attends closely to the process of revision that led to the Tractatus and Philosophical Investigations. This introductory chapter provides information about the nature of the Wittgenstein papers, summarizes the rationale for reading his work in this way, and outlines the reading of the development of Wittgenstein’s philosophy that this approach yields. This discussion on the development of Wittgenstein’s thought emphasizes the role of his changing conception of the nature of experience and its relationship to the world, the closely related problem of the relationship between ordinary language and its analysis, his later conception of the role of analogies in generating — and dissolving — philosophical problems, the parallels with psychoanalysis, and the variety of philosophical methods employed in his later philosophical writing. There is also an overview of a central theme of the book as a whole: the contrast Wittgenstein drew between “ordinary” and “philosophical” ways of looking at things when he wrote the Tractatus, and how that contrast was transformed in his subsequent writing, focusing on his contrast between “primary” and “secondary” worlds and his notion of a “phenomenological language”.
From Logical Atomism to Practical Holism
Authors: Stern David G.
Published: February 2006

This chapter examines the developments that led from Wittgenstein’s early logical atomist view that all meaningful discourse can be analyzed into logically independent elementary propositions to his later philosophy. In 1929, Wittgenstein rejected logical atomism for a “logical holist” conception of language as composed of calculi, formal systems characterized by their constitutive rules. By the mid-1930s, he had rejected the model of a calculus, emphasizing that language is action within a social and natural context — more like a game than a calculus — and that rule-governed behavior is dependent on a background of practices which cannot themselves be explicitly formulated as rules. The discussion of these central developments for the emergence of his later “practical holism” focuses on changes in his conception of the nature of measurement and the role of mind and mental processes in linguistic meaning.
The Description of Immediate Experience
Authors: Stern David G.
Published: February 2006

The first section of this chapter presents a close reading of Wittgenstein’s “Remarks on Logical Form”, focusing on the conception of the relationship between language and experience, and the nature of the analysis of immediate experience that are set out there. Section two sets out an interpretation of what Wittgenstein meant when he said that he had rejected “phenomenological language” or “primary language” as his goal. Distinguishing between a weak and a strong sense of these terms shows how he could have given up the goal of formulating a language that would amount to a complete analysis of immediate experience, yet retain the goal of finding ways of clarifying what we say about experience. Section three discusses Wittgenstein’s use of the analogy of the pictures on a roll of film in a movie projector and the pictures on a cinema screen for the relationship between world and experience. The final section analyzes how and why the analogy leads Wittgenstein to a paradoxical conception of immediate experience as a separate realm, “timeless” and “neighborless”, a conception of the “world as idea” that is supposedly inexpressible.
The Flow of Life
Authors: Stern David G.
Published: February 2006

In 1929, Wittgenstein made use of river imagery to convey the supposedly inexpressible thesis that all is in flux (“Alles fliesst”). However, he rejects this extreme thesis in manuscripts from the early 1930s and drafts of the Philosophical Investigations, affirming that one can step twice into the same river. His later discussion of the “stream of life” involves a return, in certain respects, to the river analogy, albeit in a very different key. Examining Wittgenstein’s changing use of this image casts light on the continuities and discontinuities in the development of his philosophy. Wittgenstein’s argument that a private definition is impossible because ostension always depends on a “technique of use”, and his rejection of a positive theory of mind is clarified by examining some unusually explicit notes for a public lecture on private language. This material shows how the treatment of training and practice in the opening sections of the Philosophical Investigations is the basis for the subsequent discussion of both rule-following and privacy.