bluuebunny/crossref_metadata_2025 huggingface dataset:
Transverse tubular system depolarization reduces tetanic force in rat skeletal muscle fibers by impairing action potential repriming
Authors: Dutka T. L. , Lamb G. D.
Published: March 2007

When muscle fibers are repeatedly stimulated, they may become depolarized and force output decline. Excitation of the transverse tubular system (T-system) is critical for activation, but its role in muscle fatigue is poorly understood. Here, mechanically skinned fibers from rat fast-twitch muscle were used, because the sarcolemma is absent but the T-system retains normal excitability and its properties can be studied in isolation. The T-system membrane was fully polarized by bathing the skinned fiber in an internal solution with 126 mM K+ (control solution) or set at partially depolarized levels (approximately −63 and −58 mV) in solutions with 66 or 55 mM K+, respectively, and action potentials (APs) were triggered in the sealed T-system by field stimulation. Prolonged depolarization of the T-system reduced tetanic force proportionately more than twitch force, with greater effect at higher stimulation frequency (responses at 20 and 100 Hz reduced to 71 and 62% in 66 mM K+ and to 54 and 35% in 55 mM K+, respectively). Double-pulse stimulation showed that depolarization increased the repriming period (estimated minimum time before a second AP can be produced) from ∼4 ms to ∼7.5 and 15 ms in the 66 and 55 mM K+ solutions, respectively. These results demonstrate that T-system depolarization reduces tetanic force by impairing AP repriming, rather than by preventing AP generation per se or by inactivating the T-system voltage sensors. The findings also explain why it is advantageous to reduce the rate of motoneuron stimulation to muscles during repeated or prolonged periods of activity.
Interaction of Pyk2 and PTP-PEST with leupaxin in prostate cancer cells
Authors: Sahu Surasri Nandan , Nunez Stephanie , Bai Guang , Gupta Anandarup
Published: March 2007

We have identified the presence of leupaxin (LPXN), which belongs to the paxillin extended family of focal adhesion-associated adaptor proteins, in prostate cancer cells. Previous studies have demonstrated that LPXN is a component of the podosomal signaling complex found in osteoclasts, where LPXN was found to associate with the protein tyrosine kinases Pyk2 and c-Src and the cytosolic protein tyrosine phosphatase-proline-, glutamate-, serine-, and threonine-rich sequence (PTP-PEST). In the current study, LPXN was detectable as a 50-kDa protein in PC-3 cells, a bone-derived metastatic prostate cancer cell line. In PC-3 cells, LPXN was also found to associate with Pyk2, c-Src, and PTP-PEST. A siRNA-mediated inhibition of LPXN resulted in decreased in vitro PC-3 cell migration. A recombinant adenoviral-mediated overexpression of LPXN resulted in an increased association of Pyk2 with LPXN, whereas a similar adenoviral-mediated overexpression of PTP-PEST resulted in decreased association of Pyk2 and c-Src with LPXN. The overexpression of LPXN in PC-3 cells resulted in increased migration, as assessed by in vitro Transwell migration assays. On the contrary, the overexpression of PTP-PEST in PC-3 cells resulted in decreased migration. The overexpression of LPXN resulted in increased activity of Rho GTPase, which was decreased in PTP-PEST-overexpressing cells. The increase in Rho GTPase activity following overexpression of LPXN was inhibited in the presence of Y27632, a selective inhibitor of Rho GTPase. In conclusion, our data demonstrate that LPXN forms a signaling complex with Pyk2, c-Src, and PTP-PEST to regulate migration of prostate cancer cells.
Suppression of endotoxin-induced fever in near-term pregnant rats is mediated by brain nitric oxide
Authors: Begg Denovan P. , Kent Stephen , McKinley Michael J. , Mathai Michael L.
Published: March 2007

Over the last three decades, experiments in several mammalian species have shown that the febrile response to bacterial endotoxin is attenuated late in pregnancy. More recent evidence has established that the expression of nitric oxide synthase (NOS) enzymes is increased in the brain late in pregnancy. The current study investigated the possible role of brain nitric oxide in mediating the phenomenon of fever suppression. Core body temperature (Tb) of near-term pregnant rats ( day 19 and 20) was measured following inhibition of brain NOS and intraperitoneal injection of LPS (50 μg/kg); they were compared with both day 15 pregnant and virgin animals. Intracerebroventricular injection with an inhibitor of NOS, NG-monomethyl-l-arginine citrate (l-NMMA; 280 μg), in near-term pregnant rats restored the febrile response to LPS. As expected, near-term dams that received intracerebroventricular vehicle + IP LPS did not increase Tb, in contrast to the 1.0 ± 0.2°C rise in Tb in dams treated with ICV l-NMMA + IP LPS ( P < 0.01). In virgin females and day 15 pregnant controls receiving this treatment, the increases in Tb were 1.5 ± 0.3°C and 1.6 ± 0.4°C, respectively. Thus, blockade of brain NOS restored the febrile response to LPS in near-term dams; at 5 h postinjection, Tb was 60–70% of that observed in virgins and day 15 pregnant animals. Intracerebroventricular l-NMMA alone did not induce a significant change in Tb in any group. These results suggest that the mechanism underlying the suppression of the febrile response in near-term pregnancy is mediated by nitric oxide signaling in the brain.
Adrenomedullin insufficiency increases allergen-induced airway hyperresponsiveness in mice
Authors: Yamamoto Hiroshi , Nagase Takahide , Shindo Takayuki , Teramoto Shinji , Aoki-Nagase Tomoko , Yamaguchi Yasuhiro , Hanaoka Yoko , Kurihara Hiroki , Ouchi Yasuyoshi
Published: March 2007

Adrenomedullin (ADM), a newly identified vasodilating peptide, is reported to be expressed in lungs and have a bronchodilating effect. We hypothesized whether ADM could be involved in the pathogenesis of bronchial asthma. We examined the role of ADM in airway responsiveness using heterozygous ADM-deficient mice ( AM+/−) and their littermate control ( AM+/+). Here, we show that airway responsiveness is enhanced in ADM mutant mice after sensitization and challenge with ovalbumin (OVA). The immunoreactive ADM level in the lung tissue after methacholine challenge was significantly greater in the wild-type mice than that in the mutant. However, the impairment of ADM gene function did not affect immunoglobulins (OVA-specific IgE and IgG1), T helper 1 and 2 cytokines, and leukotrenes. Thus the conventional mechanism of allergen-induced airway responsiveness is not relevant to this model. Furthermore, morphometric analysis revealed that eosinophilia and airway hypersecretion were similarly found in both the OVA-treated ADM mutant mice and the OVA-treated wild-type mice. On the other hand, the area of the airway smooth muscle layer of the OVA-treated mutant mice was significantly greater than that of the OVA-treated wild-type mice. These results suggest that ADM gene disruption may be associated with airway smooth muscle hyperplasia as well as enhanced airway hyperresponsiveness. ADM mutant mice might provide novel insights to study the pathophysiological role of ADM in vivo.
Standard Treatments Induce Antigen-Specific Immune Responses in Prostate Cancer
Authors: Nesslinger Nancy J. , Sahota Robert A. , Stone Brad , Johnson Kayli , Chima Navraj , King Caitlin , Rasmussen Devon , Bishop Darcy , Rennie Paul S. , Gleave Martin , Blood Paul , Pai Howard , Ludgate Charles , Nelson Brad H.
Published: March 2007

Purpose: Prostate tumors express antigens that are recognized by the immune system in a significant proportion of patients; however, little is known about the effect of standard treatments on tumor-specific immunity. Radiation therapy induces expression of inflammatory and immune-stimulatory molecules, and neoadjuvant hormone therapy causes prominent T-cell infiltration of prostate tumors. We therefore hypothesized that radiation therapy and hormone therapy may initiate tumor-specific immune responses.

Experimental Design: Pretreatment and posttreatment serum samples from 73 men with nonmetastatic prostate cancer and 50 cancer-free controls were evaluated by Western blotting and SEREX (serological identification of antigens by recombinant cDNA expression cloning) antigen arrays to examine whether autoantibody responses to tumor proteins arose during the course of standard treatment.

Results: Western blotting revealed the development of treatment-associated autoantibody responses in patients undergoing neoadjuvant hormone therapy (7 of 24, 29.2%), external beam radiation therapy (4 of 29, 13.8%), and brachytherapy (5 of 20, 25%), compared with 0 of 14 patients undergoing radical prostatectomy and 2 of 36 (5.6%) controls. Responses were seen within 4 to 9 months of initiation of treatment and were equally prevalent across different disease risk groups. Similarly, in the murine Shionogi tumor model, hormone therapy induced tumor-associated autoantibody responses in 5 of 10 animals. In four patients, SEREX immunoscreening of a prostate cancer cDNA expression library identified several antigens recognized by treatment-associated autoantibodies, including PARP1, ZNF707 + PTMA, CEP78, SDCCAG1, and ODF2.

Conclusion: We show for the first time that standard treatments induce antigen-specific immune responses in prostate cancer patients. Thus, immunologic mechanisms may contribute to clinical outcomes after hormone and radiation therapy, an effect that could potentially be exploited as a practical, personalized form of immunotherapy.
The Association Between Measures of Progression and Survival in Castrate-Metastatic Prostate Cancer
Authors: Scher Howard I. , Warren Mary , Heller Glenn
Published: March 2007

Purpose: To explore the association between progression-free survival and overall survival time in patients with castration-resistant prostate cancer treated with microtubule-targeted therapies.

Experimental Design: We retrospectively studied patients treated in three trials evaluating a taxane or an epothilone for progressive castration-resistant prostate cancer. Study subjects were 98 patients with bone metastases; 63 of them also had soft tissue lesions. All scans were reviewed independently. Associations of radiographic progression-free survival and prostate-specific antigen (PSA) progression-free survival with survival time were measured using Kendall's τ, adjusted for right censoring. A smoothing procedure was applied to estimate Kendall's τ within each neighborhood of the follow-up process.

Results: The overall associations between progression-free survival time and overall survival time were moderate: 0.4 for radiographic progression-free survival and 0.33 for PSA progression-free survival. The association between radiographic progression-free survival and overall survival was weakest early in the follow-up process, whereas the PSA association was weakest when the progression-free survival–related event (PSA progression, death, or censoring) occurred after 6 months from the start of treatment.

Conclusions: Current measures of progression-free survival time for men with castration-resistant prostate cancer are not strongly concordant with survival time. Factors that attenuate the association include interval censoring and the discontinuation of therapy early in the follow-up due to imaging changes that may not reflect true failure of the treatment. For radiographic progression-free survival, the association may be increased by requiring confirmation of progression with a second scan, as is routinely done when assessing response.
Enhanced Stretch-Induced Myogenic Tone in the Basilar Artery of Spontaneously Hypertensive Rats
Authors: Ahn Duck-Sun , Choi Soo-Kyoung , Kim Young-Hwan , Cho Young-Eun , Shin Heung Mook , Morgan Kathleen G. , Lee Young-Ho
Published: March 2007

We investigated if the magnitude of myogenic tone in the basilar artery of SHR differs from that in WKY and, if so, whether RhoA- or PKC-dependent mechanisms were involved. Myogenic tone was developed in response to stretch. Stretch-induced myogenic contraction was significantly greater in the SHR than WKY in the presence of external Ca2+. However, in the absence of external Ca2+, stretch did not evoke a myogenic tone. The [Ca2+]i-induced contraction was larger in SHR than WKY and the [Ca2+]i-force curve was significantly shifted to the left in SHR compared to WKY. Y-27632 significantly inhibited stretch-induced myogenic tone, but the inhibitory effect was larger in the SHR than WKY. However, PKC inhibitors had no significant effect on the myogenic tone. RhoA and PKCΕ were expressed at higher levels in the SHR compared to the WKY. RhoA and PKCα translocated from the cytosol to the cell membrane in response to stretch in both animals, but PKCΕ was translocated only in SHR. Our results strongly suggest that stretch-induced myogenic tone is enhanced in SHR, and the activation of RhoA/Rho kinase plays an important role in the enhanced myogenic tone in SHR.
Transglutaminase 1 Stabilizes β-Actin in Endothelial Cells Correlating with a Stabilization of Intercellular Junctions
Authors: Baumgartner Werner , Weth Agnes
Published: March 2007

Microvascular endothelial monolayers from mouse myocardium become resistant to various barrier-compromising stimuli correlating with the expression of transglutaminase 1 (TGase1) and its translocation towards cellular junctions. In contrast, endothelial monolayers from mouse lung microvessels do not express TGase1 and remain sensitive to barrier-compromising stimuli corresponding to the known in vivo sensitivity of the lung microvasculature. Using the TGase-substrate 5-(biotinamido)-pentylamine, specific TGase inhibitors and RNAi, one target protein of TGase1 in endothelial cells was found to be β-actin, suggesting that tissue-specific stabilization of the cortical actin filament network by intracellular TGase1 activity may play a role in controlling barrier properties of endothelial monolayers.
Pravastatin Decreases Wall Shear Stress and Blood Velocity in the Internal Carotid Artery Without Affecting Flow Volume
Authors: Box Frieke M.A. , van der Grond Jeroen , de Craen Anton J.M. , Palm-Meinders Inge H. , van der Geest Rob J. , Jukema J. Wouter , Reiber Johan H.C. , van Buchem Mark A. , Blauw Gerard J.
Published: March 2007

Background and Purpose—

Despite speculations, it is unknown whether statins affect wall shear stress (WSS). Therefore, the effect of pravastatin on WSS was investigated.

Methods—

In 355 elderly individuals participating in the PROSPER study (follow up after 3 years), the effect of 40 mg pravastatin on WSS was assessed in the internal carotid artery using magnetic resonance imaging.

Results—

WSS and blood velocity decreased both in the pravastatin group and in the placebo group but decreased faster in the pravastatin group (
P
<0.04,
P
<0.02). Blood volume flow did not differ between the groups.

Conclusions—

In elderly subjects, the WSS and blood velocity of the internal carotid artery declines significantly over time and this decline is more pronounced in subjects treated with 40 mg pravastatin compared with the placebo group.
Smooth Muscle–Targeted Knockout of Connexin43 Enhances Neointimal Formation in Response to Vascular Injury
Authors: Liao Yongbo , Regan Christopher P. , Manabe Ichiro , Owens Gary K. , Day Kathy H. , Damon Dave N. , Duling Brian R.
Published: March 2007

Objective—

Vascular disease alters and reduces connexin expression and a reduction in connexin 43 (Cx43) expression diminishes the extent of atherosclerosis observed in a high-cholesterol diet murine model. We hypothesized that connexins might play a role in the smooth muscle cell response to vascular injury.

Methods and Results—

We therefore studied a line of smooth muscle cell-specific, Cx43 gene knockout mice (SM Cx43 KO) in which the carotid arteries were injured, either by vascular occlusion or by a wire injury. In the SM Cx43 KO mice both types of injury manifested accelerated growth of the neointima and of the adventitia. Isolated vascular smooth muscle cells from the SM Cx43 KO mice grew at a slightly faster rate in culture, and to marginally higher saturation densities than those of control mice, but these changes were not adequate to explain the large changes in the injured vessels.

Conclusions—

These observations provide direct evidence that smooth muscle Cx43 gap junctions play a multi-faceted role in modulating the in vivo growth response of vascular smooth muscle cells to vascular injury.
Friendship through Fourteenth-Century Fissures: Dai Liang, Wu Sidao and Ding Henian
Authors: Gerritsen Anne
Published: March 2007

This essay analyzes one set of male bonds—the relationships between three men in the Yuan-Ming transition—to understand the range of meanings assigned to the practice of friendship in the fourteenth century. Through the exchange of writings, the three men constructed a friendship based on shared cultural ideas that was more valuable to them than the ethnic, regional, and political differences between them. At a time when the violence and disruptions associated with the Yuan-Ming transition and the lack of access to examinations and the civil service created a crisis in masculinity, these friendships allowed them to create a space where masculine values could be shared and expressed.
Male Friendship and Jiangxue (Philosophical Debates) in Sixteenth-Century China
Authors: Huang Martin
Published: March 2007

This article focuses on the significant rise of the status of friendship in sixteenth-century Chinese cultural discourses and the relevant roles played by the jiangxue (philosophical debating) activities on the part of many members of the popular neo-Confucian movement of the School of the Mind. It seeks to demonstrate how the practices of jiangxue helped construct a special cultural and social sphere where male friendships could flourish with great freedom and where friendship was granted the kind of Confucian legitimacy it had never enjoyed before. The article also explores the resultant tensions within the important Confucian ethical concept of wulun (the five cardinal human relationships) as it was being contested and re/negotiated during that time.
Why Is the Sophist a Sequel to the Theaetetus?
Authors: Kahn Charles
Published: March 2007

The Theaetetus and the Sophist both stand in the shadow of the Parmenides, to which they refer. I propose to interpret these two dialogues as Plato's first move in the project of reshaping his metaphysics with the double aim of avoiding problems raised in the Parmenides and applying his general theory to the philosophy of nature. The classical doctrine of Forms is subject to revision, but Plato's fundamental metaphysics is preserved in the Philebus as well as in the Timaeus. The most important change is the explicit enlargement of the notion of Being to include the nature of things that change.This reshaping of the metaphysics is prepared in the Theaetetus and Sophist by an analysis of sensory phenomena in the former and, in the latter, a new account of Forms as a network of mutual connections and exclusions. The division of labor between the two dialogues is symbolized by the role of Heraclitus in the former and that of Parmenides in the latter. Theaetetus asks for a discussion of Parmenides as well, but Socrates will not undertake it. For that we need the visitor from Elea. Hence the Theaetetus deals with becoming and flux but not with being; that topic is reserved for Eleatic treatment in the Sophist. But the problems of falsity and Not-Being, formulated in the first dialogue, cannot be resolved without the considerations of truth and Being, reserved for the later dialogue. That is why there must be a sequel to the Theaetetus.
Animal Agendas: Conflict over Productive Animals in Twentieth-Century Australian Cities
Authors: Gaynor Andrea
Published: March 2007

Over the course of the twentieth century, the number of productive nonhuman animals (livestock and poultry) in Australian cities declined dramatically. This decline resulted—at least in part—from an imaginative geography, in which productive animals were deemed inappropriate occupants of urban spaces. A class-based prioritization of amenity, privacy, order, and the protection of real property values—as well as a gender order within which animal-keeping was not recognized as a legitimate economic activity for women—shaped this imaginative geography of animals that found its most critical expression in local government regulations. However, there were different imaginative geographies among women and men—mostly those from the working class—whose emotional and economic relationships with productive animals led them to advocate for those animals as legitimate and desirable urban inhabitants.
The Cunning Dingo
Authors: Parker Merryl
Published: March 2007

The Australian dingo, like the dog, descends from the wolf. However, although dogs have undergone a lengthy taming process that allows them to fit into human society, dingoes retain many wolf characteristics. Like the wolf and unlike the dog, dingoes do not bark. Dingoes howl; they come into season once a year, and they can dislocate their powerful jaws to seize prey. Since the arrival of settlers and their farming practices in Australia 200 years ago, dingoes have killed sheep, and dogs have learned to protect and control those sheep. Medieval texts admire dogs for their intelligence while denigrating wolves as "cunning"—a word defined as deceitful, crafty, and treacherous. A study of Australian colonial texts reveals a popular representation of the dingo as cowardly, promiscuous, vicious—and cunning. This study compares the representation of dingoes (who by killing sheep worked against the settlers) with the representation of dogs (who protected the farmers' economic interests). Finally, the paper examines those colonial writers who, either deliberately or unintentionally, allowed the dingo to escape the denigrating representation of cunning.
Regulation of protein C inhibitor (PCI) activity by specific oxidized and negatively charged phospholipids
Authors: Malleier Julia M. , Oskolkova Olga , Bochkov Valery , Jerabek Ingrid , Sokolikova Barbora , Perkmann Thomas , Breuss Johannes , Binder Bernd R. , Geiger Margarethe
Published: March 2007

Protein C inhibitor (PCI) is a serpin with affinity for heparin and phosphatidylethanolamine (PE). We analyzed the interaction of PCI with different phospholipids and their oxidized forms. PCI bound to oxidized PE (OxPE), and oxidized and unoxidized phosphatidylserine (PS) immobilized on microtiter plates and in aqueous suspension. Binding to OxPE and PS was competed by heparin, but not by the aminophospholipid-binding protein annexin V or the PCI-binding lipid retinoic acid. PS and OxPE stimulated the inhibition of activated protein C (aPC) by PCI in a Ca++-dependent manner, indicating that binding of both, aPC (Ca++ dependent) and PCI (Ca++ independent), to phospholipids is necessary. A peptide corresponding to the heparin-binding site of PCI abolished the stimulatory effect of PS on aPC inhibition. No stimulatory effect of phospholipids on aPC inhibition was seen with a PCI mutant lacking the heparin-binding site. A heparin-like effect of phospholipids (OxPE) was not seen with antithrombin III, another heparin-binding serpin, suggesting that it is specific for PCI. PCI and annexin V were found to be endogenously colocalized in atherosclerotic plaques, supporting the hypothesis that exposure of oxidized PE and/or PS may be important for the local regulation of PCI activity in vivo.
Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma
Authors: Trudel Suzanne , Li Zhi Hua , Rauw Jennifer , Tiedemann Rodger E. , Wen Xiao Yan , Stewart A. Keith
Published: March 2007

Bcl family members Bcl-2, Bcl-xL, and Mcl-1, are frequently expressed and implicated in the survival of myeloma cells. Obatoclax (GX015-070) is a novel, small-molecule antagonist of the BH3-binding groove of the Bcl family of proteins. We show that GX015-070 inhibits the binding of Bak to Mcl-1, up-regulates Bim, induces cytochrome c release, and activates capase-3 in human myeloma cell lines (HMCLs), confirming the predicted mechanism of action. Consequently, GX015-070 potently inhibited the viability of 15 of 16 HMCLs (mean IC50 of 246 nM), including those resistant to melphalan and dexamethasone. In combination studies, GX015-070 enhanced the antimyeloma activity induced by melphalan, dexamethasone, or bortezomib. Sensitivity to GX015-070 correlated with the absence or near absence of Bcl-xL. Coculture with interleukin-6 or adherence to bone marrow stroma conferred modest resistance; however, it did not overcome GX015-070–induced cytotoxicity. Of importance, GX015-070 as a single agent induced potent cytotoxic responses against patient-derived tumor cells. GX015-070 inhibited normal bone marrow–derived colony formation; however, cytotoxicity to human blood lymphocytes was not observed. Taken together, these studies describe a novel BH3 mimic with selectivity for Mcl-1, and support the therapeutic application of GX015-070 for diverse neoplasias including multiple myeloma.
Intercenter reliability and validity of the rhesus macaque GeneChip
Authors: Duan Fenghai , Spindel Eliot R , Li Yu-Hua , Norgren Robert B
Published: March 2007

Background

The non-human primate (NHP) research community has been intensely interested in obtaining whole-genome expression arrays for their work. Recently, novel approaches were used to generate the DNA sequence information for a rhesus GeneChip. To test the reliability of the rhesus GeneChip across different centers, RNA was isolated from five sources: cerebral cortex, pancreas, thymus, testis, and an immortalized fibroblast cell line. Aliquots of this RNA were sent to each of three centers: Yerkes National Primate Research Center, Oregon National Primate Research Center and the University of Nebraska Medical Center. Each center labeled the samples and hybridized them with two rhesus macaque GeneChips. In addition, rhesus samples were hybridzed with human GeneChips to compare with samples hybridized with the rhesus GeneChip.

Results

The results indicate that center effects were minimal and the rhesus GeneChip appears highly reliable. To test the validity of the rhesus GeneChip, five of the most differentially expressed genes among tissues identified in the reliability experiments were chosen for analysis with Quantitative PCR. For all 5 genes, the qPCR and GeneChip results were in agreement with regard to differential expression between tissues. Significantly more probesets were called present when rhesus samples were hybridized with the rhesus GeneChip than when these same samples were hybridized with a human GeneChip.

Conclusion

The rhesus GeneChip is both a reliable and a valid tool for examining gene expression and represents a significant improvement over the use of the human GeneChip for rhesus macaque gene expression studies.
Gene expression profiles in asbestos-exposed epithelial and mesothelial lung cell lines
Authors: Nymark Penny , Lindholm Pamela M , Korpela Mikko V , Lahti Leo , Ruosaari Salla , Kaski Samuel , Hollmén Jaakko , Anttila Sisko , Kinnula Vuokko L , Knuutila Sakari
Published: March 2007

Background

Asbestos has been shown to cause chromosomal damage and DNA aberrations. Exposure to asbestos causes many lung diseases e.g. asbestosis, malignant mesothelioma, and lung cancer, but the disease-related processes are still largely unknown. We exposed the human cell lines A549, Beas-2B and Met5A to crocidolite asbestos and determined time-dependent gene expression profiles by using Affymetrix arrays. The hybridization data was analyzed by using an algorithm specifically designed for clustering of short time series expression data. A canonical correlation analysis was applied to identify correlations between the cell lines, and a Gene Ontology analysis method for the identification of enriched, differentially expressed biological processes.

Results

We recognized a large number of previously known as well as new potential asbestos-associated genes and biological processes, and identified chromosomal regions enriched with genes potentially contributing to common responses to asbestos in these cell lines. These include genes such as the thioredoxin domain containing gene (TXNDC) and the potential tumor suppressor, BCL2/adenovirus E1B 19kD-interacting protein gene (BNIP3L), GO-terms such as "positive regulation of I-kappaB kinase/NF-kappaB cascade" and "positive regulation of transcription, DNA-dependent", and chromosomal regions such as 2p22, 9p13, and 14q21. We present the complete data sets as Additional files.

Conclusion

This study identifies several interesting targets for further investigation in relation to asbestos-associated diseases.
De novo C16- and C24-ceramide generation contributes to spontaneous neutrophil apoptosis
Authors: Seumois Grégory , Fillet Marianne , Gillet Laurent , Faccinetto Céline , Desmet Christophe , François Cédric , Dewals Benjamin , Oury Cécile , Vanderplasschen Alain , Lekeux Pierre , Bureau Fabrice
Published: March 2007

Neutrophils rapidly undergo spontaneous apoptosis following their release from the bone marrow. Although central to leukocyte homeostasis, the mechanisms that regulate neutrophil apoptosis remain poorly understood. We show here that apoptosis of cultured neutrophils is preceded by a substantial increase in the intracellular levels of 16 and 24 carbon atom (C16- and C24)-ceramides, which are lipid second messengers of apoptosis and stress signaling. Treatment of neutrophils with fumonisin B2, a selective inhibitor of the de novo pathway of ceramide synthesis, prevented accumulation of C16- and C24-ceramides. Moreover, fumonisin B2 significantly reduced caspase-3, -8, and -9 activation and apoptosis in these cells. Conversely, 3-O-methylsphingomyelin and fantofarone, which are specific inhibitors of neutral and acid sphingomyelinases, respectively, neither inhibited C16- and C24-ceramide production nor decreased the apoptosis rate in neutrophils, indicating that in these cells, ceramides are not generated from membrane sphingomyelin. Further experiments showed that increasing endogenous C16- and C24-ceramide levels by using DL-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol and (1S,2R)-D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol, two inhibitors of ceramide metabolism, enhances caspase-3, -8, and -9 activity and increases neutrophil apoptosis. Similarly, apoptosis was induced rapidly when synthetic C16- and/or C24-ceramides were added to neutrophil cultures. Finally, GM-CSF, a cytokine that delays neutrophil apoptosis, abrogated C16- and C24-ceramide accumulation totally in cultured neutrophils, whereas Fas ligation accelerated apoptosis in these cells without affecting de novo ceramide production. We conclude that de novo generation of C16- and C24-ceramides contributes to spontaneous neutrophil apoptosis via caspase activation and that GM-CSF exerts its antiapoptotic effects on neutrophils, at least partly through inhibition of ceramide accumulation.
Chemokine regulation of atherosclerosis
Authors: Barlic Jana , Murphy Philip M
Published: March 2007

Oxidative stress and inflammation are accepted as major factors in the pathogenesis of atherosclerosis, but how they interact to produce a plaque has not been delineated clearly. Recent data suggest that oxidized lipids may act in part by regulating production of chemokines and chemokine receptors, which in turn, may direct monocytes and other blood leukocytes to the vessel wall, where they may interact with endothelial cells and smooth muscle cells. The receptors may act at the level of recruitment, retention, and egress, not only through classic, chemotactic mechanisms but also through direct, intercellular adhesion. The results suggest a coordinated mechanism for inflammatory cell accumulation in plaque and identify novel targets, such as CCR2 and CX3CR1, for potential drug development in coronary artery disease.
Effect of antidepressant therapy on executive function after stroke
Authors: Narushima Kenji , Paradiso Sergio , Moser David J. , Jorge Ricardo , Robinson Robert G.
Published: March 2007

Background

Executive dysfunction is common after stroke and may impair long-term outcome. Remedies for this condition are limited.

Aims

To examine the effect of antidepressants on executive function after stroke.

Method

Forty-seven patients who had had a stroke during the prior 6 months received 12 weeks of antidepressant treatment in double-blind placebo-controlled fashion, followed by assessment of executive function at the end of treatment and after 2 years.

Results

No significant group effect was found at the end of treatment. However, 21 months after the end of treatment the placebo group showed deterioration of executive function, whereas the active treatment group showed clear and significant improvement independent of depressive symptoms (F=12.1, d.f.=1,45,P= 0.001).

Conclusions

Antidepressant treatment fosters long-term improvement of executive function following stroke. This phenomenon is consistent with a reorganisation of neuronal networks associated with prefrontal functions based on modulation of monoaminergic neurotransmission and the activity of neurotrophins.
Bias in psychiatric case–control studies
Authors: Lee William , Bindman Jonathan , Ford Tamsin , Glozier Nick , Moran Paul , Stewart Robert , Hotopf Matthew
Published: March 2007

Background

Case–control studies are vulnerable to selection and information biases
which may generate misleading findings.

Aims

To assess the quality of methodological reporting of case–control studies
published in general psychiatric journals.

Method

All the case–control studies published over a 2-year period in the six
general psychiatric journals with impact factors of more than 3 were
assessed by a group of psychiatrists with training in epidemiology using
a structured assessment devised for the purpose. The measured study
quality was compared across type of exposure and journal.

Results

The reporting of methods in the 408 identified papers was generally poor,
with basic information about recruitment of participants often absent.
Reduction of selection bias was described best in the ‘pencil and paper’
studies and worst in the genetic studies. Neuroimaging studies reported
the most safeguards against information bias. Measurement of exposure was
reported least well in studies determining the exposure with a biological
test.

Conclusions

Poor reporting of recruitment strategies threatens the validity of
reported results and reduces the generalisability of studies.
The Hes gene family: repressors and oscillators that orchestrate embryogenesis
Authors: Kageyama Ryoichiro , Ohtsuka Toshiyuki , Kobayashi Taeko
Published: March 2007

Embryogenesis involves orchestrated processes of cell proliferation and differentiation. The mammalian Hes basic helix-loop-helix repressor genes play central roles in these processes by maintaining progenitor cells in an undifferentiated state and by regulating binary cell fate decisions. Hes genes also display an oscillatory expression pattern and control the timing of biological events, such as somite segmentation. Many aspects of Hes expression are regulated by Notch signaling, which mediates cell-cell communication. This primer describes these pleiotropic roles of Hes genes in some developmental processes and aims to clarify the basic mechanism of how gene networks operate in vertebrate embryogenesis.
TheO-fucosyltransferase O-fut1 is an extracellular component that is essential for the constitutive endocytic trafficking of Notch inDrosophila
Authors: Sasamura Takeshi , Ishikawa Hiroyuki O. , Sasaki Nobuo , Higashi Syunsuke , Kanai Maiko , Nakao Shiho , Ayukawa Tomonori , Aigaki Toshiro , Noda Katsuhisa , Miyoshi Eiji , Taniguchi Naoyuki , Matsuno Kenji
Published: March 2007

Notch is a transmembrane receptor that mediates the cell-cell interactions necessary for many cell-fate decisions. Endocytic trafficking of Notch plays important roles in the activation and downregulation of this receptor. A Drosophila O-FucT-1 homolog, encoded by O-fut1, catalyzes the O-fucosylation of Notch, a modification essential for Notch signaling and ligand binding. It was recently proposed that O-fut1 acts as a chaperon for Notch in the endoplasmic reticulum and is required for Notch to exit the endoplasmic reticulum. Here, we report that O-fut1 has additional functions in the endocytic transportation of Notch. O-fut1 was indispensable for the constitutive transportation of Notch from the plasma membrane to the early endosome, which we show was independent of the O-fucosyltransferase activity of O-fut1. We also found that O-fut1 promoted the turnover of Notch, which consequently downregulated Notch signaling. O-fut1 formed a stable complex with the extracellular domain of Notch. In addition, O-fut1 protein added to conditioned medium and endocytosed was sufficient to rescue normal Notch transportation to the early endosome in O-fut1 knockdown cells. Thus, an extracellular interaction between Notch and O-fut1 is essential for the normal endocytic transportation of Notch. We propose that O-fut1 is the first example, except for ligands, of a molecule that is required extracellularly for receptor transportation by endocytosis.
The nuclear envelope protein MAN1 regulates TGFβ signaling and vasculogenesis in the embryonic yolk sac
Authors: Cohen Tatiana V. , Kosti Ourania , Stewart Colin L.
Published: March 2007

MAN1 is an integral protein of the inner nuclear membrane of the nuclear envelope (NE). MAN1 interacts with SMAD transcription factors, which in turn are regulated by the Transforming growth factor beta (TGFβ) superfamily of signaling molecules. To determine the role of MAN1 in mouse development, we used a gene-trap embryonic stem cell clone to derive mice with a functional mutation in MAN1 (Man1GT/GT). Expression of Man1during early development is initially low but increases at embryonic day 9.5(E9.5). Coincident with this increase, homozygous gene-trapped Man1(Man1GT/GT) embryos die by E10.5. Examination of mutant embryos and tetraploid rescue experiments reveals that abnormal yolk-sac vascularization is the probable cause of lethality. We also established embryonic stem cell lines and their differentiated derivatives that are homozygous for the Man1GT allele. Using these lines, we show that the Man1GT allele results in increased phosphorylation, nuclear localization and elevated levels of SMAD transcriptional activity, predominantly of SMAD2/3, which are regulated by the ALK5 signaling pathway. Our studies identify a previously uncharacterized role for an integral nuclear envelope protein in the regulation of yolk-sac angiogenesis by TGFβ signaling and reveal that the NE has an essential role in regulating transcription factor activity during mouse development.
Homocysteine, 5,10-Methylenetetrahydrofolate Reductase 677C>T Polymorphism, Nutrient Intake, and Incident Cardiovascular Disease in 24 968 Initially Healthy Women
Authors: Zee Robert YL , Mora Samia , Cheng Suzanne , Erlich Henry A , Lindpaintner Klaus , Rifai Nader , Buring Julie E , Ridker Paul M
Published: March 2007

Background: Hyperhomocysteinemia has been associated with a higher risk of cardiovascular disease (CVD) in epidemiological studies, but recent trials have failed to show a benefit of lowering homocysteine. To address this apparent paradox, we explored whether interaction between genetic and dietary factors related to homocysteine metabolism contributes to CVD risk.

Methods: We evaluated the associations of homocysteine, methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype, and dietary intake of folate/B-vitamins with subsequent CVD events in 24 968 apparently healthy white American women followed for 10 years. Plasma homocysteine was measured using an enzymatic assay. MTHFR genotype was determined with a multiplex PCR using biotinylated primers.

Results: In unadjusted analyses, homocysteine showed moderately strong linear associations with CVD, with hazard ratios (95% CI) comparing top with bottom quintiles for total CVD of 1.92 (1.55–2.37), myocardial infarction 2.32 (1.52–3.54), and ischemic stroke 2.25 (1.45–3.50), all Ptrend <0.001. These ratios were markedly attenuated after adjusting for traditional risk factors and socioeconomic status to 1.08 (0.86–1.36), Ptrend = 0.12; 1.20 (0.76–1.87), Ptrend = 0.14; and 1.21 (0.75–1.94), Ptrend = 0.50, respectively. Homocysteine was associated with MTHFR genotype (1.4 μmol/L higher homocysteine for TT vs CC, P <0.001) and inversely with intake of folate, vitamin B2, B6, and B12, all Ptrend <0.001. However, there was no association of MTHFR genotype or dietary folate/B-vitamins with CVD. In addition, there were no gene–diet or gene–homocysteine interactions in relation to CVD.

Conclusions: In this large-scale prospective study, the association of homocysteine with CVD was markedly attenuated after adjusting for risk factors and was not modified by MTHFR 677C>T or intake of folate or B-vitamins.
Zum fünfundzwanzigsten Jahrgang der Zeitschrift für Sprachwissenschaft
Authors: Thümmel Wolf
Published: March 2007

Schon bei den informellen Vorbereitungen zur Gründung der Deutschen Gesellschaft für Sprachwissenschaft (DGfS) im Jahre 1977 wurde die Etablierung einer Zeitschrift als Publikationsorgan der Gesellschaft erwogen und zur Beratung auf die Tagesordnung der Gründungsversammlung am 4. 2. 1978 gesetzt. Drei Jahre später hat dann die Mitgliederversammlung in Regensburg beschlossen, die Zeitschrift für Sprachwissenschaft als verbandseigene Zeitschrift zu gründen und auf diese effektive und außerhalb der DGfS erkennbare Weise satzungsgemäß den wissenschaftlichen Austausch auf dem Gebiet der BRD und West-Berlin zu fördern.
Der Vistembor brehlte dem Luhr Knotten auf den bänken Leuster – Wie sich die Fähigkeit zur satzinternen Großschreibung entwickelt
Authors: Günther Hartmut
Published: March 2007

Using capital letters within sentences not only for proper names but also for nouns is a specific feature of the German writing system. A short sketch of the historical development and two different approaches to the description of this phenomenon is given. Data using the dictation of pseudoword texts show that the ability to master this feature of German orthography develops independently of the way the rule of capitalizing nouns is taught at school.
Assessment of Bone Acquisition in Childhood and Adolescence
Authors: Gilsanz Vicente , Wren Tishya
Published: March 2007

Availability, ease of use, relative low cost, and minimal radiation exposure have made dual-energy x-ray absorptiometry the most widely used technique worldwide to obtain bone measurements for both research and clinical purposes in pediatric populations. However, errors related to growth and maturity significantly diminish the accuracy of dual-energy x-ray absorptiometry bone measurements. Several investigators have found that dual-energy x-ray absorptiometry in children frequently leads to a misdiagnosis of osteoporosis and an underestimation of the amount of bone. In this regard, a recent official position paper by the International Society for Clinical Densitometry states that subjects <20 years of age should not be given a diagnosis of osteoporosis on the basis of dual-energy x-ray absorptiometry criteria. Nevertheless, the increased awareness that osteoporosis has its antecedents in childhood and the demand for examinations of bone acquisition and response to therapy stress the urgent need to improve the value of dual-energy x-ray absorptiometry measurements for children.
Hierarchical modeling of nanoindentation and microstructural evolution of face-centered cubic gold aggregates
Authors: Ma Jeong Beom , Zikry M.A. , Ashamwi W.M. , Brenner D.W.
Published: March 2007

A hierarchical computational method has been developed and used with a finite-element microstructurally based dislocation density multiple-slip crystalline formulation to predict how nanoindentation affects behavior in face-centered cubic crystalline aggregates at scales that span the molecular to the continuum level. Displacement profiles from molecular dynamics simulations of nanoindentation were used to obtain scaling relations, which are based on indented depths, grain-sizes, and grain aggregate distributions. These scaling relations are then used to coarsen grains in a microstructurally based finite-element formulation that accounts for dislocation density evolution, crystalline structures, and grain-sizes. This computational approach was validated with a number of experimental measurements pertaining to single gold crystals. This hierarchical model provides a methodology to link molecular level simulations with a microstructurally based finite element method formulation that can be used to ascertain inelastic effects, such as shear-slip distribution, pressure accumulation, and dislocation density and slip-rate evolution at physical scales that are commensurate with ductile behavior at the microstructural scale.
Low-temperature plasma-enhanced atomic layer deposition growth of WNxCy from a novel precursor for barrier applications in nanoscale devices
Authors: Zeng Wanxue , Wang Xiaodong , Kumar Sumit , Peters David W. , Eisenbraun Eric T.
Published: March 2007

A low-temperature plasma-enhanced atomic layer deposition (PEALD) process has been developed for the growth of ultrathin WNxCy films, using a halide-free W precursor. A 32-nm-thick PEALD WNxCy film deposited using this process at 250 °C possesses a composition of W72C20N5, resistivity of ∼250 μΩ·cm, a root-mean-square (rms) surface roughness of 0.23 nm, and a thickness conformality of more than 80% on trench structures with a width of 120 nm and an aspect ratio of 11. The WNxCy films exhibited excellent thermal stability, whereby resistivity, thickness, surface roughness, and crystal structure were stable after 30 min anneals in 700 Torr, forming gas ambient at temperatures up to 700 °C. Copper diffusion barrier performance measurements show that a 9 nm thick WNxCy film could prevent copper diffusion after a 30 min anneal at 700 °C, while a 2-nm-thick film could prevent copper diffusion after a 30 min anneal at 500 °C.
Pulsed laser characterization of multicomponent polymer acoustic and mechanical properties in the sub-GHz regime
Authors: Saini G. , Pezeril T. , Torchinsky D.H. , Yoon J. , Kooi S.E. , Thomas E.L. , Nelson K.A.
Published: March 2007

We investigated the acoustic properties in the sub-GHz frequency regime of a multilayer system comprising alternating 100-nm scale TiO2/poly(methyl methacrylate) (PMMA) layers through a laser photoacoustic method, impulsive stimulated thermal scattering (ISTS). The acoustic dispersion curves were determined, and the mechanical properties were extracted from the experimental results.
Contact area and size effects in discrete dislocation modeling of wedge indentation
Authors: Widjaja Andreas , Van der Giessen Erik , Deshpande Vikram S. , Needleman Alan
Published: March 2007

Plane strain indentation of a single crystal by a rigid wedge is analyzed using discrete dislocation plasticity. We consider two wedge geometries having different sharpness, as specified by the half-angle of the indenter: α = 70° and 85°. The dislocations are all of edge character and modeled as line singularities in a linear elastic material. The crystal has initial sources and obstacles randomly distributed over three slip systems. The lattice resistance to dislocation motion, dislocation nucleation, dislocation interaction with obstacles, and dislocation annihilation are incorporated through a set of constitutive rules. Several definitions of the contact area (contact length in plane strain) are used to illustrate the sensitivity of the hardness value in the submicron indentation regime to the definition of contact area. The size dependence of the indentation hardness is found to be sensitive to the definition of contact area used and to depend on the wedge half-angle. For a relatively sharp indenter, with a half-angle of 70°, an indentation size effect is not obtained when the contact area is small and when the hardness is based on the actual contact length, while there does appear to be a size effect for some hardness values based on other measures of contact length.