bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic polymorphisms of CYP2C9 and CYP2C19 are not related to drug‐induced idiosyncratic liver injury (DILI)
Authors: Pachkoria K , Lucena M I , Ruiz‐Cabello F , Crespo E , Cabello M R , Andrade R J ,   on behalf of the Spanish Group for the Study of Drug‐Induced Liver Disease (Grupo de Estudio para las Hepatopatías Asociadas a Medicamentos (GEHAM)
Published: February 2007

Background and purpose:

The general view on the pathogenesis of drug‐induced idiosyncratic liver injury (DILI) is that parent compounds are rendered hepatotoxic by metabolism, mainly by cytochrome (CYP) 450, although other metabolic pathways can contribute. Anecdotal reports suggest a role of CYP 450 polymorphisms in DILI. We aimed to assess in a series of Spanish DILI patients the prevalence of important allelic variants of CYP2C9 and CYP2C19, known to be involved in the metabolism of several hepatotoxic drugs.

Experimental approach:

Genotyping of CYP2C9 (*2, *3) and CYP2C19 (*2 and *3), was carried out in a total of 28 and 32 patients with a well established diagnosis of DILI. CYP2C9 and CYP2C19 variants were analysed in genomic DNA by means of PCR‐FRET and compared with previous findings in other Caucasian populations.

Key results:

CYP2C9 and CYP2C19 allele and genotype frequencies were in agreement with Hardy‐Weinberg equilibrium. Fourteen patients (50%) were heterozygous and 1(4%) found to be compound heterozygous for the CYP2C9 allele. Seven (22%) were found to carry one and 1(3%) carried two CYP2C19 mutated alleles. No patients were homozygous for *3 allele. The distribution of both CYP2C9 and CYP2C19 allelic variants in DILI patients were similar to those in other Caucasian populations. Patients with variant and those with wild‐type alleles did not differ in regard to clinical presentation of DILI, type of injury and outcome.

Conclusions and Implications:

We find no evidence to support CYP2C9 and CYP2C19 genetic polymorphisms as predictable potential risk factors for DILI.

British Journal of Pharmacology (2007) 150, 808–815. doi:10.1038/sj.bjp.0707122
Phosphorylation of sodium channels mediated by protein kinase‐C modulates inhibition by topiramate of tetrodotoxin‐sensitive transient sodium current
Authors: Curia G , Aracri P , Colombo E , Scalmani P , Mantegazza M , Avanzini G , Franceschetti S
Published: February 2007

Background and purpose:

Topiramate is a novel anticonvulsant known to modulate the activity of several ligand‐ and voltage‐gated ion channels in neurons. The mechanism of action of topiramate, at a molecular level, is still unclear, but the phosphorylation state of the channel/receptor seems to be a factor that is able to influence its activity. We investigated the consequences of phosphorylation of the sodium channel on the effect of topiramate on tetrodotoxin (TTX)‐sensitive transient Na+current (INaT).

Experimental approach:

INaTwas recorded in dissociated neurons of rat sensorimotor cortex using whole‐cell patch‐clamp configuration.

Key results:

We found that topiramate (100 μM) significantly shifted the steady‐state INaTinactivation curve in a hyperpolarized direction. In neurons pre‐treated with a PKC‐activator, 1‐oleoyl‐2‐acetyl‐sn‐glycerol (OAG; 2 μM), the net effect of topiramate on steady‐state INaTinactivation was significantly decreased. In addition, OAG also slightly shifted the INaTactivation curve in a hyperpolarized direction, while perfusion with topiramate had no effect on the parameters of INaTactivation.

Conclusions and Implications:

These data show that PKC‐activation can modulate the effect of topiramate on INaT. This suggests that channel phosphorylation in physiological or pathological conditions (such as epiliepsy), can alter the action of topiramate on sodium currents.

British Journal of Pharmacology(2007)150, 792–797. doi:10.1038/sj.bjp.0707144
Study on the method of controlling chaos in an Er-doped fiber dual-ring laser via external optical injection and shifting optical feedback light
Authors: Senlin Yan
Published: February 2007

Controlling chaos in an erbium-doped fiber dual-ring laser is studied by injecting an external light and shifting the phase of an optical feedback light. First, the parameters of the externally injected optical signal are adjusted to bring the chaotic laser into a single-period state and a multiperiod state, respectively. In addition, the single-mode locking in a single ring of the laser as well as the dual-mode locking in dual ring of the laser are found. Secondly, the method of optical feedback is used to stabilize chaos by controlling the parameters of the optical devices in an external optical path. We show that the optical negative feedback can stabilize the chaotic laser into a single-period state, while the optical positive feedback can stabilize the chaotic laser into another single-period state and a period-doubling state. Lastly, various dynamical states are produced in the laser by shifting the phase of the optical feedback light.
Electron-ion-coincidence spectra of K-shell excited Ne, Ar, and Kr clusters
Authors: Murakami H. , Nagaya K. , Ohmasa Y. , Iwayama H. , Yao M.
Published: February 2007

Electron-ion-coincidence spectra were recorded for K-shell excited krypton, argon, and neon clusters covering the size range from 1 atom to about 3000 atoms by utilizing hard x-ray undulator beamlines. Multiply charged ions Rz+(z⩾2) and singly charged ions Rn+(n⩾1) are observed as cluster fragments, and their relative abundance exhibits a characteristic dependence on the average cluster size ⟨N⟩. It is expected from these results that the charges generated on the cluster surface are strongly localized while those in the cluster core are more delocalized. The estimated charge separation distance increases with ⟨N⟩, and it is longer for lighter elements.
Photoelectrochemical reaction and H2 generation at zero bias optimized by carrier concentration of n-type GaN
Authors: Ono Masato , Fujii Katsushi , Ito Takashi , Iwaki Yasuhiro , Hirako Akira , Yao Takafumi , Ohkawa Kazuhiro
Published: February 2007

The authors studied the photoelectrochemical properties dependent on carrier concentration of n-type GaN. The photocurrent at zero bias became the maximum value at the carrier concentration of 1.7×1017cm−3. Using the sample optimized carrier concentration, the authors achieved H2 gas generation at a Pt counterelectrode without extra bias for the first time. The authors also discussed the mechanism of the dependence of photocurrent on the carrier concentration of GaN.
Nucleation and growth of single crystals with uniform crystallographic orientation inside alumina nanopores
Authors: Yadlovker D. , Berger S.
Published: February 2007

Single crystal rods, having nanometer-size diameter, were grown with uniform crystallographic orientation inside a matrix of alumina nanopores. The fabrication process of this nanocomposite structure consists of several stages. First, a highly dense array of alumina pores (about 1011cm−2 and an average diameter of about 35nm) is prepared by an electrochemical anodization process of pure Al substrate. Then, the pores are filled with a liquid solution aided by the pores’ capillary forces. Finally, the temperature of the liquid solution is slightly decreased to a supersaturated state where precipitation starts only at the pore bottom. The nucleation preference at the pore bottom is explained thermodynamically based on the contact angle, geometrical parameters of the nucleus, surface curvature, and pore diameter. In each pore the nucleus is grown to a single crystal that completely fills its volume. The crystallographic orientation of the single crystals inside the pores can be controlled by temperature and composition during growth. The nucleation and growth processes in the alumina nanopores are demonstrated with Rochelle salt (NaKC4H4O6∙4H2O) and potassium nitrate (KNO3).
Optical emission study of nonthermal plasma confirms reaction mechanisms involving neutral rather than charged species
Authors: Zhao Gui-Bing , Argyle Morris D. , Radosz Maciej
Published: February 2007

Charge transfer reactions are commonly used to explain NOx conversion in nonthermal plasma. An analysis of optical emission spectra induced by pulsed corona discharge in NOx-containing argon suggests that, in fact, the contribution of charge transfer reactions to NOx conversion in nonthermal plasma is negligible. During electrical discharge in such gas mixtures, NO(B), an electronic excited state of NO formed due to the dissociative recombination reactions of NO2+ and N2O+ and the optical emission of NO(B) could be a proof that cations are responsible for NOx conversion. However, the optical emission of NO(B) is not observed, leading to the conclusion that cations are not involved to any measurable degree. Therefore, charge transfer reactions cannot play a significant role in nonthermal plasma largely because the cations are neutralized with electrons before any charge transfer reactions can occur and concentrations of radicals are far higher than those of cations, which inhibits charged particle reactions. Instead, neutral active species, such as atoms, molecular fragments, and excited molecules, are the major active species contributing to nonthermal plasma reactions.
Structure of shock waves in glass fiber reinforced polymer matrix composites
Authors: Tsai Liren , Prakash Vikas , Rajendran A. M. , Dandekar Dattatraya P.
Published: February 2007

Glass fiber reinforced polymer (GRP) composites are attractive candidates for future combat vehicle armor systems. Due to their complex architecture, shock waves in GRP undergo geometric and material dispersion as well as attenuation with distance of shock wave propagation. In the present study a series of plate impact experiments is conducted to investigate the structure of shock waves in the GRP. The effects of material and geometric dispersion as well as the GRP’s hydrodynamic response on the attenuation of the shock waves are considered. It is observed that the hydrodynamic effects dictate the structure of shock waves in the GRP.
Growth and structure of PbVO3 thin films
Authors: Martin Lane W. , Zhan Qian , Suzuki Yuri , Ramesh R. , Chi Miaofang , Browning Nigel , Mizoguchi Teruyasu , Kreisel Jens
Published: February 2007

Multifunctional materials promise to provide the foundation for a new class of devices in which functional properties are coupled to one another. Examples include magnetoelectric materials in which magnetic and ferroelectric properties are coupled. Here the authors report the successful growth of single phase, fully epitaxial thin films of the multifunctional material, PbVO3, using pulsed laser deposition. This growth offers an alternative means for the production of PbVO3 outside of high-temperature and high-pressure techniques through growth of epitaxial thin films on various substrates. The structure of this highly distorted perovskite is examined using x-ray diffraction, Raman spectroscopy, and transmission electron microscopy.
Experimental studies of direct-drive, low-intensity, low-adiabat spherical implosions on OMEGA
Authors: Smalyuk V. A. , Betti R. , Delettrez J. A. , Glebov V. Yu. , Goncharov V. N. , Li D. Y. , Meyerhofer D. D. , Regan S. P. , Roberts S. , Sangster T. C. , Stoeckl C. , Seka W. , Frenje J. A. , Li C. K. , Petrasso R. D. , Séguin F. H.
Published: February 2007

Low-adiabat (high-compressibility) implosions were performed with ∼860μmdiam, 24- and 35-μm-thick shells filled with 15atm of D2 gas driven with ∼12.5 kJ, 3-ns-square pulse shapes, and a laser intensity of ∼2×1014W∕cm2. Initial target modulations, imprinted on the target surface by laser nonuniformities, were varied by using drive with and without smoothing by spectral dispersion. The performance of the spherical implosions (with a gas fuel convergence of ∼16) was correlated with measured target modulations at the end of the acceleration phase performed in a planar target with similar conditions using through-foil radiography. The neutron yield decreases sharply when target modulations become comparable with the target thickness at the end of the acceleration phase. The measured target areal densities are less sensitive to target modulations. Implosions with 35-μm-thick shells produced neutron-averaged areal densities that are among the highest on OMEGA [T. R. Boehly et al., Opt. Commun. 133, 495 (1997)].
Variant of ADHMN construction associated with q-analysis
Authors: Nakamula Atsushi
Published: February 2007

A q-deformation of the ADHMN caloron construction is considered, under which the anti-self-dual (ASD) conditions of the gauge fields are preserved. It is shown that the q-dependent Nahm data with certain constraints are crucial to determine the ASD gauge fields, as in the case of ordinary caloron construction. As an application of the q-deformed ADHMN construction, we give a q-deformed caloron of Harrington-Shepard type. Some limits of the parameters are also considered.
CuTCNQ resistive nonvolatile memories with a noble metal bottom electrode
Authors: Müller R. , Naulaerts R. , Billen J. , Genoe J. , Heremans P.
Published: February 2007

Resistive electrical switching of the organic semiconductor Cu-tetracyanoquinodimethane (CuTCNQ) was investigated between gold bottom and aluminum top contacts. Corresponding Au∕CuTCNQ∕Al crossbar memories achieved several thousand write/erase cycles. The switching process was further studied by current-time measurements, and temperature-dependent measurements of the on state conductivity.
Room temperature generation of terahertz radiation from a grating-bicoupled plasmon-resonant emitter: Size effect
Authors: Meziani Yahya Moubarak , Otsuji Taiichi , Hanabe Mitsuhiro , Ishibashi Takuma , Uno Tomohiro , Sano Eiichi
Published: February 2007

A doubly interdigitated grating gates structure was incorporated into a GaAs-based high-electron mobility transistor to configure a plasmon-resonant emitter. Two dimensional electrons are then periodically confined in 100nm regions. The devices exhibit a plasma-wave signature under 1.5μm cw laser illumination. Two devices with different geometries have been subjected to an impulsive laser at room temperature. The authors observed clear generation of terahertz radiation from both devices.
Three-color polymeric light-emitting devices using selective photo-oxidation of multilayered conjugated polymers
Authors: Deng X. Y. , Wong K. Y. , Mo Y. Q.
Published: February 2007

The authors present a method for fabricating three-color polymer light-emitting devices by low-cost spin-coating and dry photopatterning processes. This method employed two emissive polymer layers in tandem, with each layer separately patterned by a photo-oxidation process. Different combinations of the two patterned layers give rise to the three primary colors, with the emission spectrum of each color essentially the same as that from individual constituent red-, green-, or blue-emitting polymers, and with luminous efficiencies comparable to that from the corresponding standard single-color devices. This method may provide a low-cost, high throughput procedure to manufacture polymeric flat-panel display devices.
Trapping and manipulation of a single micro-object in solution with femtosecond laser-induced mechanical force
Authors: Jiang Yuqiang , Matsumoto Yoshitaka , Hosokawa Yoichiroh , Masuhara Hiroshi , Oh Isamu
Published: February 2007

A nondestructive and noncontact method to trap and manipulate a microparticle in solution is proposed by utilizing femtosecond laser-induced nonlinear phenomena. A 90μm diameter polystyrene bead in solution was trapped and manipulated by scanning femtosecond laser pulses around it, which was ascribed to shockwave, cavitation bubble, and jet flow. The maximum mechanical force exerted by laser irradiation was estimated to be over 1μN. In comparison with conventional optical tweezers, this method provides not only a much larger trapping force but also a noninvasive advantage.
You Could Truly Be Yourself If You Just Weren't You: Sexuality, Disabled Body Space, and the (Neo)Liberal Politics of Self-Help
Authors: Sothern Matthew
Published: February 2007

Recent work in disability studies has drawn attention to the changing relationship between the visual representations of disability and contemporary US capitalism. One change identified is a newfound cultural recognition of disabled sexuality. In this paper I extend these arguments by considering the kinds of sexuality projected onto the disabled body at the intersection of regimes of disability, sexuality, and neoliberalism. I provide a governmentality/queer reading of visual representations of disabled sexuality and of two self-help disabled sex manuals to argue that interest in disabled sex may witness an investment in the ongoing production of normative sexualities, what Foucault called a ‘truth of the self, within the context of neoliberal spatialities of disability. Based on dominant cultural understandings of sex as ‘natural’, ‘predictable’, and ‘representable’, these self-help manuals serve to produce a framework that depoliticizes the claims of disability culture movements. These manuals render the project of disabled sexual liberation a personal project of self-governance that scarcely challenges contemporary structures of (neo)liberalism.
Identity, Place, and the Political Mobilization of Urban Minorities: Comparative Perspectives on Irish Catholics in Buffalo and Toronto 1880–1910
Authors: Jenkins William
Published: February 2007

In this paper the political fortunes and identities of Irish Catholics in US and Canadian cities are explored through a comparative study of Buffalo and Toronto. Local spaces of political administration in the urban arena, such as wards, were significant in affecting the generation of sociopolitical networks of power which in turn had implications for the sense of political identity and involvement felt by Irish Catholics within these two places. The importance of such spaces, however, was also contingent on the interaction between these cities' Irish Catholic populations and wider geographies of social, economic, and ethnoreligious relations over time as well as on the topographies and traditions of political power that extended beyond the municipal scale in both societies.
Too Close for Comfort: Loving Thy Neighbour and the Management of Multicultural Intimacies
Authors: Fortier Anne-Marie
Published: February 2007

In this paper I examine how new forms of multicultural intimacy are imagined in contemporary Britain, and how they are invested with particular ideals of mixing, loving thy neighbour, and feelings for the nation. I trace these discursive themes in a myriad of social locations and forms—a television documentary titled The Last White Kids, reviews of the documentary in the press, and government policies on community cohesion. A key point of this paper is that racial, ethnic, and cultural relations are not only negotiated and ‘managed’ in literal spatial locations, but also imagined through specific emotional and ethical injunctions, such as ‘embracing the other’ and loving they neighbour. Moreover, these injunctions are imagined in the ambivalent spatial terms of obligations to, and dangers of, proximity—an ambivalence that is inflected with articulations of ‘race’, class, and gender. The analysis thus explores how the imperative of neighbourly love refers to both the desires for and anxieties about what the intimacy stems from and fosters. Who gets close to whom, and under what circumstances, is not left to chance.
Utopia, Performativity, and the Unhomely
Authors: Kraftl Peter
Published: February 2007

In this paper I discuss how a differently conceived performative and architectural understanding of Utopia can help us to rework and extend notions of utopianism that have received renewed attention in recent times. In developing this point, I argue that, although notions of dwelling and comfort are key to Utopia and architecture, the ‘unhomely’ and ‘unsettling’, which also appear in aspects of thought on performativity, are a crucial and as-yet greatly underscrutinised part of thinking about Utopia. I attempt to question what we consider ‘good’ or desirable, and hence to enlarge the frame of what we consider ‘utopian’. Through this, I consider the potential beginnings of an extended uncanny Utopian ethics.
Ectopic brown adipose tissue in muscle provides a mechanism for differences in risk of metabolic syndrome in mice
Authors: Almind Katrine , Manieri Monia , Sivitz William I. , Cinti Saverio , Kahn C. Ronald
Published: February 2007

C57BL/6 (B6) mice subjected to a high-fat diet develop metabolic syndrome with obesity, hyperglycemia, and insulin resistance, whereas 129S6/SvEvTac (129) mice are relatively protected from this disorder because of differences in higher basal energy expenditure in 129 mice, leading to lower weight gain. At a molecular level, this difference correlates with a marked higher expression of uncoupling protein 1 (UCP1) and a higher degree of uncoupling
in vitro
in mitochondria isolated from muscle of 129 versus B6 mice. Detailed histological examination, however, reveals that this UCP1 is in mitochondria of brown adipocytes interspersed between muscle bundles. Indeed, the number of UCP1-positive brown fat cells in intermuscular fat in 129 mice is >700-fold higher than in B6 mice. These brown fat cells are subject to further up-regulation of UCP1 after stimulation with a β
3
-adrenergic receptor agonist. Thus, ectopic deposits of brown adipose tissue in intermuscular depots with regulatable expression of UCP1 provide a genetically based mechanism of protection from weight gain and metabolic syndrome between strains of mice.
Identification of prostate cancer mRNA markers by averaged differential expression and their detection in biopsies, blood, and urine
Authors: Bai V. Uma , Kaseb Ahmed , Tejwani Sheela , Divine George W. , Barrack Evelyn R. , Menon Mani , Pardee Arthur B. , Reddy G. Prem-Veer
Published: February 2007

The advent of serum prostate-specific antigen (PSA) as a biomarker has enabled early detection of prostate cancer and, hence, improved clinical outcome. However, a low PSA is not a guarantee of disease-free status, and an elevated PSA is frequently associated with a negative biopsy. Therefore, our goal is to identify molecular markers that can detect prostate cancer with greater specificity in body fluids such as urine or blood. We used the RT-PCR differential display method to first identify mRNA transcripts differentially expressed in tumor vs. patient-matched nontumor prostate tissue. This analysis led to the identification of 44 mRNA transcripts that were expressed differentially in some but not all tumor specimens examined. To identify mRNA transcripts that are differentially expressed in most tumor specimens, we turned to differential display of pooled tissue samples, a technique we name averaged differential expression (ADE). We performed differential display of mRNA from patient-matched nontumor vs. tumor tissue, each pooled from 10 patients with various Gleason scores. Differentially expressed mRNA transcripts identified by ADE were fewer in number, but were expressed in a greater percentage of tumors (>75%) than those identified by differential display of mRNA from individual patient samples. Differential expression of these mRNA transcripts was also detected by RT-PCR in mRNA isolated from urine and blood samples of prostate cancer patients. Our findings demonstrate the principle that specific cDNA probes of frequently differentially expressed mRNA transcripts identified by ADE can be used for the detection of prostate cancer in urine and blood samples.
Discovery of growth hormone-releasing hormones and receptors in nonmammalian vertebrates
Authors: Lee Leo T. O. , Siu Francis K. Y. , Tam Janice K. V. , Lau Ivy T. Y. , Wong Anderson O. L. , Lin Marie C. M. , Vaudry Hubert , Chow Billy K. C.
Published: February 2007

In mammals, growth hormone-releasing hormone (GHRH) is the most important neuroendocrine factor that stimulates the release of growth hormone (GH) from the anterior pituitary. In nonmammalian vertebrates, however, the previously named GHRH-like peptides were unable to demonstrate robust GH-releasing activities. In this article, we provide evidence that these GHRH-like peptides are homologues of mammalian PACAP-related peptides (PRP). Instead, GHRH peptides encoded in cDNAs isolated from goldfish, zebrafish, and African clawed frog were identified. Moreover, receptors specific for these GHRHs were characterized from goldfish and zebrafish. These GHRHs and GHRH receptors (GHRH-Rs) are phylogenetically and structurally more similar to their mammalian counterparts than the previously named GHRH-like peptides and GHRH-like receptors. Information regarding their chromosomal locations and organization of neighboring genes confirmed that they share the same origins as the mammalian genes. Functionally, the goldfish GHRH dose-dependently activates cAMP production in receptor-transfected CHO cells as well as GH release from goldfish pituitary cells. Tissue distribution studies showed that the goldfish GHRH is expressed almost exclusively in the brain, whereas the goldfish GHRH-R is actively expressed in brain and pituitary. Taken together, these results provide evidence for a previously uncharacterized GHRH-GHRH-R axis in nonmammalian vertebrates. Based on these data, a comprehensive evolutionary scheme for GHRH, PRP-PACAP, and PHI-VIP genes in relation to three rounds of genome duplication early on in vertebrate evolution is proposed. These GHRHs, also found in flounder,
Fugu
, medaka, stickleback,
Tetraodon
, and rainbow trout, provide research directions regarding the neuroendocrine control of growth in vertebrates.
Death-effector domain-containing protein DEDD is an inhibitor of mitotic Cdk1/cyclin B1
Authors: Arai Satoko , Miyake Katsuhisa , Voit Renate , Nemoto Shino , Wakeland Edward K. , Grummt Ingrid , Miyazaki Toru
Published: February 2007

Accumulating evidence has shown that many molecules, including some cyclin-dependent kinases (Cdks) and cyclins, as well as the death-effector domain (DED)-containing FADD, function for both apoptosis and cell cycle. Here we identified that DEDD, which also possesses the DED domain, acts as a novel inhibitor of the mitotic Cdk1/cyclin B1 complex. DEDD associates with mitotic Cdk1/cyclin B1 complexes via direct binding to cyclin B1 and reduces their function. In agreement, kinase activity of nuclear Cdk1/cyclin B1 in DEDD-null (DEDD
−/−
) embryonic fibroblasts is increased compared with that in DEDD
+/+
cells, which results in accelerated mitotic progression, thus exhibiting a shortened G
2
/M stage. Interestingly, DEDD
−/−
cells also demonstrated decreased G
1
duration, which perhaps enhanced the overall reduction in rRNA amounts and cell volume, primarily caused by the rapid termination of rRNA synthesis before cell division. Likewise, DEDD
−/−
mice show decreased body and organ weights relative to DEDD
+/+
mice. Thus, DEDD is an impeder of cell mitosis, and its absence critically influences cell and body size via modulation of rRNA synthesis.
Vaccinia virus D10 protein has mRNA decapping activity, providing a mechanism for control of host and viral gene expression
Authors: Parrish Susan , Resch Wolfgang , Moss Bernard
Published: February 2007

Previous studies indicated that the vaccinia virus D10 protein, which is conserved in all sequenced poxviruses, participates in the rapid turnover of host and viral mRNAs. D10 contains a motif present in the family of Nudix/MutT enzymes, a subset of which has been shown to enhance mRNA turnover in eukaryotic cells through cleavage of the 5′ cap (m
7
GpppNm-). Here, we demonstrate that a purified recombinant D10 fusion protein possesses an intrinsic activity that liberates m
7
GDP from capped RNA substrates. Furthermore, point mutations in the Nudix/MutT motif abolished decapping activity. D10 has a strong affinity for capped RNA substrates (
K
m
≈ 3 nm). RNAs of 24–309 nt were decapped to comparable extents, whereas the cap of a 12-nt RNA was uncleaved. At large molar ratios relative to capped RNA substrate, competitor m
7
GpppG, m
7
GTP, or m
7
GDP inhibited decapping, whereas even higher concentrations of unmethylated analogs did not. High concentrations of uncapped RNA were also inhibitory, suggesting that D10 recognizes its substrate through interaction with both cap and RNA moieties. Thus far, poxviruses represent the only virus family shown to encode a Nudix hydrolase-decapping enzyme. Although it may seem self-destructive for a virus to encode a decapping and a capping enzyme, accelerated mRNA turnover helps eliminate competing host mRNAs and allows stage-specific synthesis of viral proteins.
Activation of endosomal dynein motors by stepwise assembly of Rab7–RILP–p150Glued, ORP1L, and the receptor βlll spectrin
Authors: Johansson Marie , Rocha Nuno , Zwart Wilbert , Jordens Ingrid , Janssen Lennert , Kuijl Coenraad , Olkkonen Vesa M. , Neefjes Jacques
Published: February 2007

The small GTPase Rab7 controls late endocytic transport by the minus end–directed motor protein complex dynein–dynactin, but how it does this is unclear. Rab7-interacting lysosomal protein (RILP) and oxysterol-binding protein–related protein 1L (ORP1L) are two effectors of Rab7. We show that GTP-bound Rab7 simultaneously binds RILP and ORP1L to form a RILP–Rab7–ORP1L complex. RILP interacts directly with the C-terminal 25-kD region of the dynactin projecting arm p150Glued, which is required for dynein motor recruitment to late endocytic compartments (LEs). Still, p150Glued recruitment by Rab7–RILP does not suffice to induce dynein-driven minus-end transport of LEs. ORP1L, as well as βIII spectrin, which is the general receptor for dynactin on vesicles, are essential for dynein motor activity. Our results illustrate that the assembly of microtubule motors on endosomes involves a cascade of linked events. First, Rab7 recruits two effectors, RILP and ORP1L, to form a tripartite complex. Next, RILP directly binds to the p150Glued dynactin subunit to recruit the dynein motor. Finally, the specific dynein motor receptor Rab7–RILP is transferred by ORP1L to βIII spectrin. Dynein will initiate translocation of late endosomes to microtubule minus ends only after interacting with βIII spectrin, which requires the activities of Rab7–RILP and ORP1L.
Formation of microtubule-based traps controls the sorting and concentration of vesicles to restricted sites of regenerating neurons after axotomy
Authors: Erez Hadas , Malkinson Guy , Prager-Khoutorsky Masha , De Zeeuw Chris I. , Hoogenraad Casper C. , Spira Micha E.
Published: February 2007

Transformation of a transected axonal tip into a growth cone (GC) is a critical step in the cascade leading to neuronal regeneration. Critical to the regrowth is the supply and concentration of vesicles at restricted sites along the cut axon. The mechanisms underlying these processes are largely unknown. Using online confocal imaging of transected, cultured Aplysia californica neurons, we report that axotomy leads to reorientation of the microtubule (MT) polarities and formation of two distinct MT-based vesicle traps at the cut axonal end. Approximately 100 μm proximal to the cut end, a selective trap for anterogradely transported vesicles is formed, which is the plus end trap. Distally, a minus end trap is formed that exclusively captures retrogradely transported vesicles. The concentration of anterogradely transported vesicles in the former trap optimizes the formation of a GC after axotomy.
Ultraviolet radiation triggers apoptosis of fibroblasts and skin keratinocytes mainly via the BH3-only protein Noxa
Authors: Naik Edwina , Michalak Ewa M. , Villunger Andreas , Adams Jerry M. , Strasser Andreas
Published: February 2007

To identify the mechanisms of ultraviolet radiation (UVR)–induced cell death, for which the tumor suppressor p53 is essential, we have analyzed mouse embryonic fibroblasts (MEFs) and keratinocytes in mouse skin that have specific apoptotic pathways blocked genetically. Blocking the death receptor pathway provided no protection to MEFs, whereas UVR-induced apoptosis was potently inhibited by Bcl-2 overexpression, implicating the mitochondrial pathway. Indeed, Bcl-2 overexpression boosted cell survival more than p53 loss, revealing a p53-independent pathway controlled by the Bcl-2 family. Analysis of primary MEFs lacking individual members of its BH3-only subfamily identified major initiating roles for the p53 targets Noxa and Puma. In the transformed derivatives, where Puma, unexpectedly, was not induced by UVR, Noxa had the dominant role and Bim a minor role. Furthermore, loss of Noxa suppressed the formation of apoptotic keratinocytes in the skin of UV-irradiated mice. Collectively, these results demonstrate that UVR activates the Bcl-2–regulated apoptotic pathway predominantly through activation of Noxa and, depending on cellular context, Puma.
Residual active granzyme B in cathepsin C–null lymphocytes is sufficient for perforin-dependent target cell apoptosis
Authors: Sutton Vivien R. , Waterhouse Nigel J. , Browne Kylie A. , Sedelies Karin , Ciccone Annette , Anthony Desiree , Koskinen Aulikki , Mullbacher Arno , Trapani Joseph A.
Published: February 2007

Cathepsin C activates serine proteases expressed in hematopoietic cells by cleaving an N-terminal dipeptide from the proenzyme upon granule packaging. The lymphocytes of cathepsin C–null mice are therefore proposed to totally lack granzyme B activity and perforin-dependent cytotoxicity. Surprisingly, we show, using live cell microscopy and other methodologies, that cells targeted by allogenic CD8+ cytotoxic T lymphocyte (CTL) raised in cathepsin C–null mice die through perforin-dependent apoptosis indistinguishable from that induced by wild-type CTL. The cathepsin C–null CTL expressed reduced but still appreciable granzyme B activity, but minimal granzyme A activity. Also, in contrast to mice with inactivation of both their granzyme A/B genes, cathepsin C deficiency did not confer susceptibility to ectromelia virus infection in vivo. Overall, our results indicate that although cathepsin C clearly generates the majority of granzyme B activity, some is still generated in its absence, pointing to alternative mechanisms for granzyme B processing and activation. Cathepsin C deficiency also results in considerably milder immune deficiency than perforin or granzyme A/B deficiency.
Human and murine granzyme B exhibit divergent substrate preferences
Authors: Cullen Sean P. , Adrain Colin , Lüthi Alexander U. , Duriez Patrick J. , Martin Seamus J.
Published: February 2007

The cytotoxic lymphocyte protease granzyme B (GzmB) can promote apoptosis through direct processing and activation of members of the caspase family. GzmB can also cleave the BH3-only protein, BID, to promote caspase-independent mitochondrial permeabilization. Although human and mouse forms of GzmB exhibit extensive homology, these proteases diverge at residues predicted to influence substrate binding. We show that human and mouse GzmB exhibit radical differences in their ability to cleave BID, as well as several other key substrates, such as ICAD and caspase-8. Moreover, pharmacological inhibition of caspases clonogenically rescued human and mouse target cells from apoptosis initiated by mouse GzmB, but failed to do so in response to human GzmB. These data demonstrate that human and murine GzmB are distinct enzymes with different substrate preferences. Our observations also illustrate how subtle differences in enzyme structure can radically affect substrate selection.
Activation of the D prostanoid 1 receptor suppresses asthma by modulation of lung dendritic cell function and induction of regulatory T cells
Authors: Hammad Hamida , Kool Mirjam , Soullié Thomas , Narumiya Shuh , Trottein François , Hoogsteden Henk C. , Lambrecht Bart N.
Published: February 2007

Prostaglandins (PGs) can enhance or suppress inflammation by acting on different receptors expressed by hematopoietic and nonhematopoietic cells. Prostaglandin D2 binds to the D prostanoid (DP)1 and DP2 receptor and is seen as a critical mediator of asthma causing vasodilation, bronchoconstriction, and inflammatory cell influx. Here we show that inhalation of a selective DP1 agonist suppresses the cardinal features of asthma by targeting the function of lung dendritic cells (DCs). In mice treated with DP1 agonist or receiving DP1 agonist-treated DCs, there was an increase in Foxp3+ CD4+ regulatory T cells that suppressed inflammation in an interleukin 10–dependent way. These effects of DP1 agonist on DCs were mediated by cyclic AMP–dependent protein kinase A. We furthermore show that activation of DP1 by an endogenous ligand inhibits airway inflammation as chimeric mice with selective hematopoietic loss of DP1 had strongly enhanced airway inflammation and antigen-pulsed DCs lacking DP1 were better at inducing airway T helper 2 responses in the lung. Triggering DP1 on DCs is an important mechanism to induce regulatory T cells and to control the extent of airway inflammation. This pathway could be exploited to design novel treatments for asthma.
Cardiopoietic programming of embryonic stem cells for tumor-free heart repair
Authors: Behfar Atta , Perez-Terzic Carmen , Faustino Randolph S. , Arrell D. Kent , Hodgson Denice M. , Yamada Satsuki , Puceat Michel , Niederländer Nicolas , Alekseev Alexey E , Zingman Leonid V. , Terzic Andre
Published: February 2007

Embryonic stem cells have the distinct potential for tissue regeneration, including cardiac repair. Their propensity for multilineage differentiation carries, however, the liability of neoplastic growth, impeding therapeutic application. Here, the tumorigenic threat associated with embryonic stem cell transplantation was suppressed by cardiac-restricted transgenic expression of the reprogramming cytokine TNF-α, enhancing the cardiogenic competence of recipient heart. The in vivo aptitude of TNF-α to promote cardiac differentiation was recapitulated in embryoid bodies in vitro. The procardiogenic action required an intact endoderm and was mediated by secreted cardio-inductive signals. Resolved TNF-α–induced endoderm-derived factors, combined in a cocktail, secured guided differentiation of embryonic stem cells in monolayers produce cardiac progenitors termed cardiopoietic cells. Characterized by a down-regulation of oncogenic markers, up-regulation, and nuclear translocation of cardiac transcription factors, this predetermined population yielded functional cardiomyocyte progeny. Recruited cardiopoietic cells delivered in infarcted hearts generated cardiomyocytes that proliferated into scar tissue, integrating with host myocardium for tumor-free repair. Thus, cardiopoietic programming establishes a strategy to hone stem cell pluripotency, offering a tumor-resistant approach for regeneration.
Rotational Analysis of two Mutually Interacting Electronic States of1Π Character in Th0
Authors: A von Bornstedt  , G Edvinsson
Published: February 2007

Two new electronic states of1Π character have been found for the Th0 molecule. Rotational analysis shows that there are homogeneous perturbations between the two states, and these perturbations have been analysed by computer methods. Some derived molecular constants are given below.

StateT0BecBedΔG1/2M21 734.320.3258570.325754850.87K22 635.650.3186360.318642795.5
NetPhosYeast: prediction of protein phosphorylation sites in yeast
Authors: Ingrell Christian R. , Miller Martin L. , Jensen Ole N. , Blom Nikolaj
Published: February 2007

Summary: We here present a neural network-based method for the prediction of protein phosphorylation sites in yeast—an important model organism for basic research. Existing protein phosphorylation site predictors are primarily based on mammalian data and show reduced sensitivity on yeast phosphorylation sites compared to those in humans, suggesting the need for an yeast-specific phosphorylation site predictor. NetPhosYeast achieves a correlation coefficient close to 0.75 with a sensitivity of 0.84 and specificity of 0.90 and outperforms existing predictors in the identification of phosphorylation sites in yeast.

Availability: The NetPhosYeast prediction service is available as a public web server at http://www.cbs.dtu.dk/services/NetPhosYeast/

Contact:  nikob@cbs.dtu.dk
Effectiveness of Massage Therapy for Chronic, Non‐Malignant Pain: A Review
Authors: Tsao Jennie C. I.
Published: February 2007

Previous reviews of massage therapy for chronic, non‐malignant pain have focused on discrete pain conditions. This article aims to provide a broad overview of the literature on the effectiveness of massage for a variety of chronic, non‐malignant pain complaints to identify gaps in the research and to inform future clinical trials. Computerized databases were searched for relevant studies including prior reviews and primary trials of massage therapy for chronic, non‐malignant pain. Existing research provides fairly robust support for the analgesic effects of massage for non‐specific low back pain, but only moderate support for such effects on shoulder pain and headache pain. There is only modest, preliminary support for massage in the treatment of fibromyalgia, mixed chronic pain conditions, neck pain and carpal tunnel syndrome. Thus, research to date provides varying levels of evidence for the benefits of massage therapy for different chronic pain conditions. Future studies should employ rigorous study designs and include follow‐up assessments for additional quantification of the longer‐term effects of massage on chronic pain.
Immunology and Homeopathy. 5. The Rationale of the ‘Simile’
Authors: Bellavite Paolo , Ortolani Riccardo , Pontarollo Francesco , Pitari Giuseppina , Conforti Anita
Published: February 2007

The foundation of homeopathic medicine is the ‘Similia Principle’, also known as the ‘Principle of Similarity’ or also as the ‘Simile’, which reflects the inversion of pharmacological effects in healthy subjects as compared with sick ones. This article describes the inversion of effects, a widespread medical phenomenon, through three possible mechanisms: non‐linearity of dose–response relationship, different initial pathophysiological states of the organism, and pharmacodynamics of body response to the medicine. Based on the systemic networks which play an important role in response to stress, a unitary and general model is designed: homeopathic medicines could interact with sensitive (primed) regulation systems through complex information, which simulate the disorders of natural disease. Reorganization of regulation systems, through a coherent response to the medicine, could pave the way to the healing of the cellular, tissue and neuro‐immuno‐endocrine homeodynamics. Preliminary evidence is suggesting that even ultra‐low doses and high‐dilutions of drugs may incorporate structural or frequency information and interact with chaotic dynamics and physical‐electromagnetic levels of regulation. From the clinical standpoint, the ‘simile’ can be regarded as a heuristic principle, according to which the detailed knowledge of pathogenic effects of drugs, associated with careful analysis of signs and symptoms of the ill subject, could assist in identifying homeopathic remedies with high grade of specificity for the individual case.
Interleukin‐4 induces human hepatocyte apoptosis through a Fas‐independent pathway
Authors: Aoudjehane Lynda , Podevin Philippe , Scatton Olivier , Jaffray Patrick , Dusanter-Fourt Isabelle , Feldmann Gérard , Massault Pierre-Philippe , Grira Lilia , Bringuier Annie , Dousset Bertrand , Chouzenoux Sandrine , Soubrane Olivier , Calmus Yvon , Conti Filomena
Published: February 2007

IL‐4 is overexpressed in liver grafts during severe recurrent hepatitis C and rejection. Hepatocyte apoptosis is involved in both these phenomena. We therefore examined the proapoptotic effect of IL‐4 on HepG2 cells and human hepatocytes in vitro, together with the underlying mechanisms. We first measured IL‐4 receptor expression, STAT6 activation by IL‐4, and STAT6 inhibition by an anti‐IL‐4 antibody or by STAT6 siRNA transfection. We then focused on the pathways involved in IL‐4‐mediated apoptosis and the role of STAT6 activation in apoptosis initiation. The IL‐4 receptor was expressed on both cell types, and STAT6 was activated by IL‐4. Both anti‐IL‐4 and STAT‐6 siRNA inhibited this activation. IL‐4 induced apoptosis of both HepG2 cells (P= 0.008 vs. untreated control) and human hepatocytes (P<0.001 vs. untreated control). IL‐4 reduced the mitochondrial membrane potential, activated Bid and Bax, and augmented caspase 3, 8, and 9 activity. STAT6 blockade inhibited IL‐4‐induced apoptosis. Expression of Fas and Fas ligand was unaffected when HepG2 cells and hepatocytes were cultured with IL‐4, and Fas/FasL pathway blockade failed to inhibit IL‐4‐induced apoptosis. These results show that IL‐4 induces apoptosis of human hepatocytes through IL‐4 receptor binding, STAT6 activation, decreased mitochondrial membrane potential, and increased caspase activation, independently of the Fas pathway. IL‐4 might thus contribute to the progression of severe liver graft damage.—Aoudjehane, L., Podevin, P., Scatton, O., Jaffray, P., Dusanter‐Fourt, I., Feldmann, G., Massault, P. P., Grira, L., Bringuier, A., Dousset, B., Chouzenoux, S., Soubrane, O., Calmus, Y., Conti, F. Interleukin‐4 induces human hepatocyte apoptosis through a Fas‐independent pathway. FASEB J. 21, 1433–1444 (2007)
Behavioural interventions for preventing and treating obesity in adults
Authors: Sharma M.
Published: February 2007

The purpose of this study was to review existing behavioural interventions for preventing and treating obesity in adult population that were published between 2000 and September 2006. A total of 23 interventions were found. Most of these interventions targeted both physical activity and nutrition behaviours. Majority of the interventions were not based on any explicit behavioural theory. In terms of duration, the interventions ranged from 3 weeks to 9 years. Approximately half of the interventions were less than 6 months in duration. Most of the interventions were implemented by the researchers themselves. However, some interventions were implemented by nurse educators, nutritionists, trained public health nurses, dietitians, healthcare providers, fitness workers and certified diabetic educators. Most of the interventions used group sessions as the predominant method to deliver the programme. Three of the interventions used media. Majority of the interventions were implemented in patient care settings with some in community settings. The most common determinant for measuring impact of the interventions has been body mass index. Fifteen interventions showed positive change in adiposity indices while six showed no change in adiposity indices. Recommendations for enhancing the effectiveness of behavioural interventions for prevention of obesity are presented.
FACTOR PRICES AND INCOME DISTRIBUTION IN LESS INDUSTRIALISED ECONOMIES 1870–1939
Authors: Greasley David , Inwood Kris , Singleton John
Published: February 2007

Global trade expansion after 1870 had potentially powerful effects on income distribution, especially in land‐abundant less industrialised economies, by increasing land prices relative to wages. The papers in this issue add evidence on wage–rentals for a range of countries, specifically Australia, Canada, Ghana, India, and Sweden. These new data offer partial support for Jeffrey Williamson’s view that the distributional effects of booming global trade to 1914 were powerful and ubiquitous, but they highlight that more attention might be given to geographical boundaries and to other distribution forces including technology and wage bargaining conditions.
HECKSHER‐OHLIN IN CANADA: NEW ESTIMATES OF REGIONAL WAGES AND LAND PRICES
Authors: Emery J. C. Herbert , Inwood Kris , Thille Henry
Published: February 2007

Many immigrant‐receiving and land‐abundant countries experienced a diminishing ratio of wages to land prices during the globalisation era from 1870 to 1910. Factor price evidence suggests that Canada does not fit the pattern. We present the first Canadian estimates of region‐specific wages and land prices that span the period from 1871 to 1925. Our evidence indicates that while Canada as a nation looks like an anomaly in the era of convergence, this is largely an artefact of aggregating the experience of the labour‐abundant eastern provinces with the late‐settling and land‐abundant western provinces.