bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of surface contamination in a hospital hematology—oncology pharmacy
Authors: Touzin Karine , Bussieres Jean-François , Langlois Éric , Lefebvre Michel
Published: September 2008

Objective. To describe environmental contamination with hazardous drugs in a hospital pharmacy setting before and after reorganizing a hematology— oncology satellite pharmacy.

Methods. This is a descriptive study of surface contamination with cyclophosphamide, ifosfamide, and methotrexate in two hematology—oncology satellite pharmacies. In order to measure surface contamination with hazardous drugs, samples from four distinct measurement sites within the pharmacy were taken in each of the two phases (pre-and postphases) using a sampling procedure and an analytical method modified from Larson et al.

Results. A total of 133 samples from four measurement sites were taken and analyzed over the course of the study (specifically 60 prephase samples and 73 postphase samples). The study showed a significant increase in the number of positive samples (from 66.7% to 90.4%, p<0.001) from the pre- to the postphase. The increase, however, is only significant in terms of the location where completed preparations were placed after they had come out from under the hood (from 0/15 to 21/28, p<0.001) and the work surface (from 8/15 to 15/15, p = 0.006) and only in terms of ifosfamide. Furthermore, for the other sites studied, the number of positive samples remained unchanged between the pre- and postphase. A statistically significant difference between the pre- and postphase was observed in terms of ifosfamide for three of the four measurement sites studied and methotrexate for one of the four sites. Average concentrations were higher in the post phase in three of the four cases.

Conclusion. This study describes environmental contamination with hazardous drugs in a hospital pharmacy setting before and after reorganizing a hematology—oncology satellite pharmacy. The study showed that a refitting of the hemato-oncology pharmacy is not a sufficient strategy to reduce the environmental contamination by ifosfamide because a significant increase in the number of positive samples from the pre- to the postphase have been observed. Many factors can contribute to influence the contamination of hazardous drugs such as the workflow and the training of the personal. Continuous environmental surveillance of hazardous drugs is required to document traces and help reduce risks. J Oncol Pharm Practice (2009) 15: 53—61.
Sex as Commodity
Authors: Mooney-Somers Julie , Ussher Jane M.
Published: September 2008

This article draws on a discursive analysis of individual and group interviews with forty-five heterosexual men to examine how men take up and resist discourses of sexuality and gender to (re)produce a recognizable heterosexual subjectivity. It explores the commodification of sex in men’s accounts and the various practices men described undertaking to obtain sex. The article argues that the contexts in which men (re)produce sexual subjectivity have significant implications for how they negotiate the discursive positions available to them. Three themes are presented to demonstrate the different discursive practices undertaken by single and partnered men. Finally, the article explores the difficulties, dilemmas, and ambivalences produced by the project of subjection and how individual men resolve them.
Identity and violent death
Authors: Davidson James M.
Published: September 2008

During the Freedman's Cemetery Project of the 1990s, evidence of lethal gun violence was recovered archaeologically from several early twentieth century burials. Although lying in unmarked graves, those who died violently still have the chance of being identified through the very bullets that robbed them of their lives. Forensic identification of the bullets and other archaeological criteria are compared to descriptions of gunshot victims in newspaper accounts and other archival records, and individual as well as group identity is examined in the process. These moments of violence also provide a unique window into exploring the extent and underlying causes of violence perpetrated within and against the African American community of Dallas, Texas, in the first decade of the twentieth century,
Metanarratives and the (re)invention of the Neolithic
Authors: Robinson David W. , Korisettar Ravi , Koshy Jinu
Published: September 2008

Rock-art reflects cultural narratives and is influential as a medium in the invention of narratives. Images found in South-Central Indian rock-art are particularly useful in considering archaeological transitions. Rock-art here shows a chronology spanning the Mesolithic, Neolithic, Megalithic, Historic, and Modern times. Imagery reflects changing human/animal relationships, from `agile' hunted animals to cattle and its domestication, with rock-art an active medium in the creation of new metanarratives focused obsessively upon bulls. While bulls in the singular appear early, later compositional elements imply a growing concern with ideas of herds as interconnecting communities. Through time, panels were focal points for the addition of subsequent anthropomorphic imagery, further reinventing the Neolithic. A Historic period efflorescence of densely applied rock-art perhaps reflects an appropriation of a locality redolent with the past as new mythologies were invented in the ancestral association with the now millennia-old Neolithic rock-art.
Negotiating the archaeology of destiny
Authors: Insoll Timothy
Published: September 2008

The concept of `destiny' is perhaps irrelevant to much of modern thinking in Western Europe and North America and hence fails to enter archaeological vocabulary. This is potentially an omission of consequence, for social psychology indicates that the belief that life is beyond the control of human agency can be a powerful one. Drawing upon ethnographic and archaeological data from the Tallensi of Northern Ghana, the potential resonance of `destiny' in archaeological interpretation is explored with reference to some examples of deposition from later British prehistory.
`Poor people in silk shirts'
Authors: Voss Barbara L.
Published: September 2008

At El Presidio de San Francisco, Spain's northernmost outpost in the Americas, military settlers refashioned their social identities by refusing the racializing sistema de castas and asserting a shared colonial identity as Californios. Dress was a central practice involved in this case of colonial ethnogenesis. Many studies of identity transformation in the Spanish Americas have treated dress as an individualistic medium for personal expression and social mobility. However, the artifacts and archives of El Presidio de San Francisco point instead towards the central role of colonial institutions in `fashioning' colonial subjects. While government-issue clothing functioned as a social leveler among the new Californios, dress also set firm constraints on the metamorphosis of social bodies. The findings of this study raise questions about the limits of ethnogenesis, both as a strategy used by historic subjects and as a theoretical model of identity transformation.
Grain boundary segregation of phosphorus and molybdenum in 2·25Cr–1Mo steel
Authors: Ding R. , Knott J.
Published: September 2008

Segregation of phosphorus and molybdenum to grain boundaries in a commercial grade of 2·25Cr–1Mo steel subjected to different heat treatments has been examined using a field emission gun scanning transmission electron microscope with energy dispersive X-ray microanalysis. The results indicate that P and Mo concentrations at prior austenite grain boundaries increase with aging time. This follows the prediction of McLean's equilibrium segregation model, when modified to take account of the interaction energy between phosphorus and molybdenum.
Electron backscattering diffraction study of coalesced bainite in high strength steel weld metals
Authors: Keehan E. , Karlsson L. , Bhadeshia H. K. D. H. , Thuvander M.
Published: September 2008

Coalesced bainite is a coarse constituent recently found to develop along with the classical martensite, lower and upper bainite in steel weld metals. Its crystallography has been characterised using electron backscattering diffraction in combination with field emission gun scanning electron microscopy. It is confirmed that coalesced bainite grains are crystallographically homogeneous but do contain orientation gradients. The misorientations across different grains of coalesced bainite and relative to conventional bainite have also been studied. The observations are discussed in the context of the mechanism by which coalesced bainite evolves.
Performance evaluation of LSM-metallic interconnect composite films prepared by plasma sputtering method
Authors: Chu C. L. , Lee S. , Lee J. , Lee T.-H.
Published: September 2008

The effect of the La0·67Sr0·33MnO3 (LSM) coating layer on the electric properties of the Fe–Cr alloys (Crofer22 and equivalent ZMG232) and the alloys themselves are examined in a hot air environment. A LSM thin film is coated on these materials using pulsed DC magnetron sputtering. The film is amorphous but is transformed into a perovskite structure after annealing at different temperatures and times. The coating structures and surface morphologies are analysed using X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and scanning electron microscopy (SEM). The result shows that the LSMO thin film on Crofer22 APU is good for compaction and adhesion. Thus, it could prevent the growth of oxides and the diffusion of Cr element to avoid cathode poisoning and decline of conductivity in solid oxide fuel cells (SOFCs) at high temperatures.
Carbon dioxide formation during initial stages of photodegradation of poly(ethyleneterephthalate) (PET) films
Authors: Fernando S. S. , Christensen P. A. , Egerton T. A. , Eveson R. , Martins-Franchetti S. M. , Voisin D. , White J. R.
Published: September 2008

Carbon dioxide (CO2) generation by ultraviolet irradiation of poly(ethyleneterephthalate) (PET) films in oxygen was monitored by in situ Fourier transform infrared spectroscopy. Typically, the CO2 absorbance increased by ∼100 × 10−4 in 180 min, with no evidence of hindrance by restricted diffusion of O2 into, or CO2 out of, the films. It was concluded that Fourier transform infrared spectrometry monitoring of CO2 conveniently, reliably and rapidly measures PET films photostability.

Quantitative analysis of the CO2 evolved from progressively thinner films from successive stages of the biaxial film drawing process indicated that CO2 was generated within a few microns of the film surface and that the same amounts were generated from the irradiated surface of 540 μm cast, 150 μm uniaxially drawn and 85 μm biaxially drawn films. Although drawing increased film crystallinity, photoreactivity appeared to be unchanged. However, total CO2 formation followed the pattern PET cast<PET uniaxial<PET biaxial because ultraviolet irradiation attenuation reduced photo generation at the rear of thick films.
Self-similar and self-affine characteristics of microstructural images of HSLA steel
Authors: Tarafder M. , Chattoraj I. , Tarafder S. , Nasipuri M.
Published: September 2008

This paper reports a procedure based on discrete Fourier transformation adopted for verifying statistical self-affinity and self-similarity in microstructural images of high strength low alloy steel. The procedure is first applied on synthetic images based on fractional Brownian motion to show the degree of self-similarity in them and finally, applied on microstructural images of three different magnifications. Effects of length scales on power spectral estimates of the microstructural images captured by scanning electron microscopy have been discussed. Importance of appropriate image resolutions and characteristic length for fractal based quantification of microstructural images is highlighted.
Evaluation of interfacial fracture toughness of SiC fibre reinforced titanium–matrix composite using pushout test
Authors: Yuan M. N. , Yang Y. Q.
Published: September 2008

The finite element method based on the equivalent domain integral technique was used to simulate the pushout test and determine the interfacial fracture toughness of SiC fibre reinforced titanium–matrix composites. A special subroutine was introduced while modelling the pushout test to control interfacial failure process. The failure criterion was based on the energy failure criterion. The results showed that the interfacial fracture toughness of SCS-6/Timetal 834 is ∼50 J m−2. The major contribution to the interfacial fracture toughness comes from thermal residual stresses for SiC reinforced titanium–matrix composites. Moreover, the variations of the energy release rates at both ends of the specimen were analysed.
Preparation and tribological investigation of resin–matrix contact strip with variable current
Authors: Chen Z. H. , Tu C. J. , Chen D. , Xia J. T. , Yan H. G.
Published: September 2008

The resin–matrix contact strip (RMCS) with high friction reducing function and good wear resistance under current has been studied to improve the performance of the traditional contact strips, such as high maintenance cost, high wear rate under current and severe damage to contact wire. The tribological behaviours of RMCS against copper were investigated under laboratory conditions with a wear tester which simulated the train motion. The results showed that the current played a major role in determining the wear behaviour and wear rate of RMCS increased with current density and sliding velocity. The wear rate of RMCS was 21·75 × 10−4 mm3 m−1 under the conditions of a sliding velocity of 41·7 m s−1 for 30 min with the current density of 285 A cm−2. The dominant wear mechanisms and arc erosion processes of the worn surface were discussed based on the microscopic observation of the worn surface and wear debris, which indicated that arc erosion wear, oxidative wear and adhesive wear were the dominant mechanisms of RMCS against copper during the electrical sliding processes, while mild adhesive wear and low stress abrasive grains wear are the main mechanisms during the sliding process without current.
Effect of solid content on formation of sol–gel derived mullite fibres
Authors: Chen X. T. , Gu L. X.
Published: September 2008

Continuous mullite fibres were prepared from dry spinning a sol prepared from aluminium nitrate, aluminium isopropoxide and tetraethylorthosilicate. By adjusting temperature, gelling degree could stabilise at a certain value and the sol–gel transition could be transferred to the spinning line. Continuous fibres could be formed from such spinnable sols immediately before complete gelling by controlling the spinning temperature and the various processing parameters. The samples were characterised by thermal gravity analysis/differential scanning calorimetry, scanning electron microscopy and X-ray diffraction. The results show that sintering of the precursor fibres from sols with solid content above 50% at 1100°C yields crack free mullite ceramic fibres. The calcined fibres were flexible with good handing characteristics and had smooth surfaces. Sintering of the precursor fibres at 1100°C yields complete crystal, which is a tetragonal metric like mullite.
Lenalidomide down-regulates the CD20 antigen and antagonizes direct and antibody-dependent cellular cytotoxicity of rituximab on primary chronic lymphocytic leukemia cells
Authors: Lapalombella Rosa , Yu Bo , Triantafillou Georgia , Liu Qing , Butchar Jonathan P. , Lozanski Gerard , Ramanunni Asha , Smith Lisa L. , Blum William , Andritsos Leslie , Wang Da-Sheng , Lehman Amy , Chen Ching-Shih , Johnson Amy J. , Marcucci Guido , Lee Robert J. , Lee L. James , Tridandapani Susheela , Muthusamy Natarajan , Byrd John C.
Published: September 2008

Lenalidomide, an immunomodulatory agent that enhances antibody-dependent cellular cytotoxicity (ADCC), is currently being investigated as a therapy for chronic lymphocytic leukemia (CLL). The anti-CD20 antibody rituximab is active in CLL and represents a rational agent to combine with lenalidomide. We therefore examined whether lenalidomide combined with rituximab enhances direct apoptosis and ADCC in CLL cells. In contrast to previous reports using CD20-positive lymphoma cell lines, lenalidomide down-regulated CD20 surface antigen expression in CLL patient cells via enhanced internalization, without influencing transcription. The CD20 surface antigen internalization enhanced delivery of an oligonucleotide incorporated into anti-CD20 immunoliposomes. In addition, CD20 surface antigen down-modulation by lenalidomide in CLL was accompanied by diminished rituximab-mediated apoptosis and ADCC. These observations suggest a need for alternative sequencing strategies to avoid antagonism between lenalidomide and rituximab therapy in CLL. In addition, they suggest that lenalidomide therapy might be useful to enhance targeted delivery of RNAi-based therapies using CD20 immunoliposomes in B-cell malignancies.
WASP confers selective advantage for specific hematopoietic cell populations and serves a unique role in marginal zone B-cell homeostasis and function
Authors: Westerberg Lisa S. , de la Fuente Miguel A. , Wermeling Fredrik , Ochs Hans D. , Karlsson Mikael C. I. , Snapper Scott B. , Notarangelo Luigi D.
Published: September 2008

Development of hematopoietic cells depends on a dynamic actin cytoskeleton. Here we demonstrate that expression of the cytoskeletal regulator WASP, mutated in the Wiskott-Aldrich syndrome, provides selective advantage for the development of naturally occurring regulatory T cells, natural killer T cells, CD4+ and CD8+ T lymphocytes, marginal zone (MZ) B cells, MZ macrophages, and platelets. To define the relative contribution of MZ B cells and MZ macrophages for MZ development, we generated wild-type and WASP-deficient bone marrow chimeric mice, with full restoration of the MZ. However, even in the presence of MZ macrophages, only 10% of MZ B cells were of WASP-deficient origin. We show that WASP-deficient MZ B cells hyperproliferate in vivo and fail to respond to sphingosine-1-phosphate, a crucial chemoattractant for MZ B-cell positioning. Abnormalities of the MZ compartment in WASP−/− mice lead to aberrant uptake of Staphylococcus aureus and to a reduced immune response to TNP-Ficoll. Moreover, WASP-deficient mice have increased levels of “natural” IgM antibodies. Our findings reveal that WASP regulates both development and function of hematopoietic cells. We demonstrate that WASP deficiency leads to an aberrant MZ that may affect responses to blood-borne pathogens and peripheral B-cell tolerance.
A dual role for integrin-linked kinase in platelets: regulating integrin function and α-granule secretion
Authors: Tucker Katherine L. , Sage Tanya , Stevens Joanne M. , Jordan Peter A. , Jones Sarah , Barrett Natasha E. , St-Arnaud Rene , Frampton Jonathan , Dedhar Shoukat , Gibbins Jonathan M.
Published: September 2008

Integrin-linked kinase (ILK) has been implicated in the regulation of a range of fundamental biological processes such as cell survival, growth, differentiation, and adhesion. In platelets ILK associates with β1- and β3-containing integrins, which are of paramount importance for the function of platelets. Upon stimulation of platelets this association with the integrins is increased and ILK kinase activity is up-regulated, suggesting that ILK may be important for the coordination of platelet responses. In this study a conditional knockout mouse model was developed to examine the role of ILK in platelets. The ILK-deficient mice showed an increased bleeding time and volume, and despite normal ultrastructure the function of ILK-deficient platelets was decreased significantly. This included reduced aggregation, fibrinogen binding, and thrombus formation under arterial flow conditions. Furthermore, although early collagen stimulated signaling such as PLCγ2 phosphorylation and calcium mobilization were unaffected in ILK-deficient platelets, a selective defect in α-granule, but not dense-granule, secretion was observed. These results indicate that as well as involvement in the control of integrin affinity, ILK is required for α-granule secretion and therefore may play a central role in the regulation of platelet function.
Mutation in the DC-SIGN cytoplasmic triacidic cluster motif markedly attenuates receptor activity for phagocytosis and endocytosis of mannose-containing ligands by human myeloid cells
Authors: Azad Abul K , Torrelles Jordi B , Schlesinger Larry S
Published: September 2008

The transmembrane C-type lectin, dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN), has three conserved cytoplasmic tail motifs: the tyrosine (Y)-based, dileucine (LL), and triacidic cluster (EEE), which are believed to regulate ligand binding, uptake, and trafficking. We mutated each of these motifs by alanine substitution and tested their roles in phagocytosis and receptor-mediated endocytosis of the highly mannosylated ligands, Mycobacterium tuberculosis mannose-capped lipoarabinomannan (ManLAM) and HIV-1 surface glycoprotein gp120, respectively, in transfected human myeloid K-562 cells. Compared with wild-type and other mutants, the EEE mutant of DC-SIGN showed a reduced cell-surface expression, near abolishment in the phagocytosis of ManLAM-coated beads (90.5±0.4%), and a marked reduction in the endocytosis of soluble gp120 (79.3±0.7%). Although, the Y mutant of DC-SIGN did not exhibit any effect on phagocytosis and intracellular trafficking to the phagolysosome, the LL mutant caused the majority of the receptor and/or ligands to remain bound to the cell surface, indicating a role for the LL motif as an internalization signal. The majority of the EEE mutant protein was found to be retained by the intracellular trans-Golgi network and not by the late endosomal/lysosomal compartment of transfected K-562 cells. Collectively, our data indicate a dual role for the EEE motif as a sorting signal in the secretory pathway and a lysosomal targeting signal in the endocytic pathway.
Protective Role of Autophagy in Palmitate-Induced INS-1 β-Cell Death
Authors: Choi Sung-E , Lee Sung-Mi , Lee Youn-Jung , Li Ling-Ji , Lee Soo-Jin , Lee Ji-Hyun , Kim Youngsoo , Jun Hee-Sook , Lee Kwan-Woo , Kang Yup
Published: September 2008

Autophagy, a vacuolar degradative pathway, constitutes a stress adaptation that avoids cell death or elicits the alternative cell-death pathway. This study was undertaken to determine whether autophagy is activated in palmitate (PA)-treated β-cells and, if activated, what the role of autophagy is in the PA-induced β-cell death. The enhanced formation of autophagosomes and autolysosomes was observed by exposure of INS-1 β-cells to 400 μm PA in the presence of 25 mm glucose for 12 h. The formation of green fluorescent protein-LC3-labeled structures (green fluorescent protein-LC3 dots), with the conversion from LC3-I to LC3-II, was also distinct in the PA-treated cells. The phospho-mammalian target of rapamycin level, a typical signal pathway that inhibits activation of autophagy, was gradually decreased by PA treatment. Blockage of the mammalian target of rapamycin signaling pathway by treatment with rapamycin augmented the formation of autophagosomes but reduced PA-induced INS-1 cell death. In contrast, reduction of autophagosome formation by knocking down the ATG5, inhibition of fusion between autophagosome and lysosome by treatment with bafilomycin A1, or inhibition of proteolytic degradation by treatment with E64d/pepstatin A, significantly augmented PA-induced INS-1 cell death. These findings showed that the autophagy system could be activated in PA-treated INS-1 β-cells, and suggested that the induction of autophagy might play an adaptive and protective role in PA-induced cell death.

Autophagy is activated in palmitate-treated insulinoma-1 beta cells, and the induction of autophagy plays a protective role in palmitate-induced beta cell death.
Hypoxia and Leucine Deprivation Induce Human Insulin-Like Growth Factor Binding Protein-1 Hyperphosphorylation and Increase Its Biological Activity
Authors: Seferovic Maxim D. , Ali Rashad , Kamei Hiroyasu , Liu Suya , Khosravi Javad M. , Nazarian Steven , Han Victor K. M. , Duan Cunming , Gupta Madhulika B.
Published: September 2008

Fetal growth restriction is often caused by uteroplacental insufficiency that leads to fetal hypoxia and nutrient deprivation. Elevated IGF binding protein (IGFBP)-1 expression associated with fetal growth restriction has been documented. In this study we tested the hypothesis that hypoxia and nutrient deprivation induce IGFBP-1 phosphorylation and increase its biological potency in inhibiting IGF actions. HepG2 cells were subjected to hypoxia and leucine deprivation to mimic the deprivation of metabolic substrates. The total IGFBP-1 levels measured by ELISA were approximately 2- to 2.5-fold higher in hypoxia and leucine deprivation-treated cells compared with the controls. Two-dimensional immunoblotting showed that whereas the nonphosphorylated isoform is the predominant IGFBP-1 in the controls, the highly phosphorylated isoforms were dominant in hypoxia and leucine deprivation-treated cells. Liquid chromatography-tandem mass spectrometry analysis revealed four serine phosphorylation sites: three known sites (pSer 101, pSer 119, and pSer 169); and a novel site (pSer 98). Liquid chromatography-mass spectrometry was used to estimate the changes of phosphorylation upon treatment. Biacore analysis indicated that the highly phosphorylated IGFBP-1 isoforms found in hypoxia and leucine deprivation-treated cells had greater affinity for IGF-I [dissociation constant 5.83E (times 10 to the power)−10 m and 6.40E−09 m] relative to the IGFBP-1 from the controls (dissociation constant ∼1.54E−07 m). Furthermore, the highly phosphorylated IGFBP-1 had a stronger effect in inhibiting IGF-I-stimulated cell proliferation. These findings suggest that IGFBP-1 phosphorylation may be a novel mechanism of fetal adaptive response to hypoxia and nutrient restriction.

The use of HepG2 cells demonstrates that IGF binding protein-1 hyper-phosphorylation may be a novel mechanism of fetal adaptive response to hypoxia and under-nutrition.
Preclinical Characterization of a (S)-N-(4-Cyano-3-Trifluoromethyl-Phenyl)-3-(3-Fluoro, 4-Chlorophenoxy)-2-Hydroxy-2-Methyl-Propanamide: A Selective Androgen Receptor Modulator for Hormonal Male Contraception
Authors: Jones Amanda , Chen Jiyun , Hwang Dong Jin , Miller Duane D. , Dalton James T.
Published: September 2008

The pharmacologic effects of (S)-N-(4-cyano-3-trifluoromethyl-phenyl)-3-(3-fluoro, 4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide (S-23) were characterized in male rats as an animal model of hormonal male contraception. S-23 showed high binding affinity (inhibitory constant = 1.7 ± 0.2 nm) and was identified as a full agonist in vitro. In castrated male rats, the ED50 of S-23 in the prostate and levator ani muscle was 0.43 and 0.079 mg/d, respectively. In intact male rats treated for 14 d, S-23 alone suppressed LH levels by greater than 50% at doses greater than 0.1 mg/d, with corresponding decreases in the size of the prostate but increases in the size of levator ani muscle. In intact male rats treated for up to 10 wk with S-23 and estradiol benzoate (EB; necessary to maintain sexual behavior in rats), S-23 showed biphasic effects on androgenic tissues and spermatogenesis by suppressing serum concentrations of LH and FSH. EB alone showed no effect on spermatogenesis. In the EB + S-23 (0.1 mg/d) group, four of six animals showed no sperm in the testis and zero pregnancies (none of six) in mating trials. After termination of treatment, infertility was fully reversible, with a 100% pregnancy rate observed after 100 d of recovery. S-23 increased bone mineral density and lean mass but reduced fat mass in a dose-dependent manner. This is the first study to show that a selective androgen receptor modulator combined with EB is an effective and reversible regimen for hormonal male contraception in rats. The beneficial effects of S-23 on the muscle, tissue selectivity, and favorable pharmacokinetic properties make it a strong candidate for use in oral male contraception.

An aryl-propionamide selective androgen receptor modulator (S-23) is an effective and reversible agent for hormonal male contraception in rats.
Increased Energy Expenditure and Insulin Sensitivity in the High Bone Mass ΔFosB Transgenic Mice
Authors: Rowe Glenn C. , Choi Cheol Soo , Neff Lynn , Horne William C. , Shulman Gerald I. , Baron Roland
Published: September 2008

Obesity and osteoporosis are major health issues affecting millions of individuals. Transgenic mice overexpressing ΔFosB, an activator protein-1 transcription factor, under the control of the enolase 2 (ENO2) promoter exhibit both an increase in bone density and a decrease in adipose mass. Here we demonstrate that ΔFosB overexpression increases fatty-acid oxidation and energy expenditure, leading to a decrease in adipocyte size and adipose mass. In addition, the ENO2-ΔFosB mice exhibit increased insulin sensitivity and glucose tolerance. Targeted overexpression of ΔFosB in adipocytes using the adipocyte protein 2 promoter failed to induce changes in fat or in bone, showing that the effect on metabolic activity is not due to cell-autonomous effects of ΔFosB within adipocytes. Detailed analysis of the ENO2-ΔFosB mice demonstrated that energy expenditure was increased in muscle, independent of locomotor activity. These findings provide evidence that signaling downstream of ΔFosB is a potential target for not only osteoporosis but also obesity and diabetes.

Overexpression of ΔFosB under the control of the enolase 2 promoter increases bone mass and energy expenditure by increasing fatty-acid oxidation within muscle, reducing adiposity.
Development and Characterization of a Simian Virus 40 Immortalized Bovine Endometrial Stromal Cell Line
Authors: Krishnaswamy Narayanan , Chapdelaine Pierre , Tremblay Jacques P. , Fortier Michel A.
Published: September 2008

In ruminants, interferon-τ (IFNτ) is the maternal recognition signal inhibiting prostaglandin (PG) F2α production by endometrial epithelial cells and stimulating interferon-stimulated genes in the stroma. Stromal cells mediate the action of progesterone on epithelial cells during pregnancy. Our working hypothesis is that IFNτ acts as a molecular switch that turns on PGE2 production in endometrial stromal cells while suppressing PGF2α production from epithelial cells. In this report we document immortalization and functional characterization of a bovine stromal cell line from the caruncular region of the endometrium [caruncular stromal cell (CSC)]. Primary stromal cells were immortalized by nucleofection with simian virus 40 large T antigen and integrase. The resulting cell line, CSC, expresses stromal cell-specific vimentin, estrogen, and progesterone receptors, and is amenable for transient transfection. Basal and stimulated production of PGE2 is higher than PGF2α and associated with cyclooxygenase (COX) 2 expression. Phorbol myristate acetate (PMA) and IFNτ up-regulate COX2 and PG production in a dose-dependent manner. When added together, low concentrations of IFNτ inhibit PMA-induced COX2 expression; whereas this inhibition is lost at high concentrations. Expression of signal transducer and activator of transcription 1 is induced by IFNτ at all concentrations studied but is not modulated by PMA. Because expression of signal transducer and activator of transcription 1 does not exhibit the biphasic response to IFNτ, we investigated the p38 MAPK pathway using the selective inhibitor SB203580. Inhibition of the p38 MAPK pathway abolishes IFNτ action on PG production. In summary, CSC appears as a good stromal cell model for investigating the molecular mechanisms related to IFNτ action and PG production in the bovine.

Interferon-t stimulates prostaglandin E2 production, and expression of cyclooxygenase 2 and signal transducer and activator of transcription 1 through two distinct signaling pathways in immortalized bovine endometrial stromal cells.
Progesterone Influence on Neurite Outgrowth Involves Microglia
Authors: Wong Angela M. , Rozovsky Irina , Arimoto Jason M. , Du Yizhou , Wei Min , Morgan Todd E. , Finch Caleb E.
Published: September 2008

Progesterone (P4) antagonizes estradiol (E2) in synaptic remodeling in the hippocampus during the rat estrous cycle. To further understand how P4 modulates synaptic plasticity, we used entorhinal cortex lesions, which induce E2-dependent neurite sprouting in the hippocampus. In young ovariectomized rats, the E2-dependent entorhinal cortex lesion-induced sprouting was attenuated by concurrent treatment with P4 and E2. Microglial activation also showed the E2-P4 antagonism. These findings extend reports on the estrous cycle synaptic remodeling without lesions by showing the P4-E2 antagonism during simultaneous treatment with both E2 and P4. Glial mechanisms were analyzed with the wounding-in-a-dish model of cocultured glia and embryonic d-18 cortical neurons from rat. In cocultures of mixed glia (astrocytes plus 30% microglia), P4 antagonized the E2-dependent neurite outgrowth (number and length) and neuron viability in the presence of E2, as observed in vivo. However, removal of microglia (astrocyte-neuron coculture) abolished the antagonism of E2 by P4 on neuron sprouting. The P4 receptor antagonists ORG-31710 and RU-486 blocked the antagonism of P4 on E2-dependent sprouting. These findings suggest a new role for microglia in P4 antagonism of E2 in neuronal plasticity and show its dependence on progesterone receptors. These findings are also relevant to the inclusion of progestins in hormone therapy, which is controversial in relation to cognitive declines during aging and in Alzheimer’s disease.

Brain glia mediate progesterone–estradiol cross-talk in neuronal sprouting after axotomy in rat models.
Structural Determinants Critical for Localization and Signaling within the Seventh Transmembrane Domain of the Type 1 Corticotropin Releasing Hormone Receptor: Lessons from the Receptor Variant R1d
Authors: Markovic Danijela , Lehnert Hendrik , Levine Michael A. , Grammatopoulos Dimitris K.
Published: September 2008

The type 1 CRH receptor (CRH-R1) plays a fundamental role in homeostatic adaptation to stressful stimuli. CRH-R1 gene activity is regulated through alternative splicing and generation of various CRH-R1 mRNA variants. One such variant is the CRH-R1d, which has 14 amino acids missing from the putative seventh transmembrane domain due to exon 13 deletion, a splicing event common to other members of the B1 family of G protein-coupled receptors. In this study, using overexpression of recombinant receptors in human embryonic kidney 293 and myometrial cells, we showed by confocal microscopy that in contrast to CRH-R1α, the R1d variant is primarily retained in the cytoplasm, although some cell membrane expression is also evident. Use of antibodies against the CRH-R1 C terminus in nonpermeabilized cells showed that membrane-expressed CRH-R1d contains an extracellular C terminus. Interestingly, treatment of CRH-R1d-expressing cells with CRH (100 nM) for 45–60 min elicited functional responses associated with a significant reduction of plasma membrane receptor expression, redistribution of intracellular receptors, and increased receptor degradation. Site-directed mutagenesis studies identified the cassette G356-F358 within transmembrane domain 7 as crucial for CRH-R1α stability to the plasma membrane because deletion of this cassette caused substantial intracellular localization of CRH-R1 α. Most importantly, coexpression studies between CRH-R1d and CRH-R2β demonstrated that the CRH-R2β could partially rescue CRH-R1d membrane expression, and this was associated with a significant attenuation of urocotrin II-induced cAMP production and ERK1/2 and p38MAPK activation, suggesting that CRH-R1d might specifically induce heterologous impairment of CRH-R2 signaling responses. This mechanism appears to involve accelerated CRH-R2β endocytosis.
Regulative feedback in pattern formation: towards a general relativistic theory of positional information
Authors: Jaeger Johannes , Irons David , Monk Nick
Published: September 2008

Positional specification by morphogen gradients is traditionally viewed as a two-step process. A gradient is formed and then interpreted, providing a spatial metric independent of the target tissue, similar to the concept of space in classical mechanics. However, the formation and interpretation of gradients are coupled, dynamic processes. We introduce a conceptual framework for positional specification in which cellular activity feeds back on positional information encoded by gradients, analogous to the feedback between mass-energy distribution and the geometry of space-time in Einstein's general theory of relativity. We discuss how such general relativistic positional information (GRPI) can guide systems-level approaches to pattern formation.
Teashirt 3 is necessary for ureteral smooth muscle differentiation downstream of SHH and BMP4
Authors: Caubit Xavier , Lye Claire M. , Martin Elise , Coré Nathalie , Long David A. , Vola Christine , Jenkins Dagan , Garratt Alistair N. , Skaer Helen , Woolf Adrian S. , Fasano Laurent
Published: September 2008

Ureteric contractions propel foetal urine from the kidney to the urinary bladder. Here, we show that mouse ureteric smooth muscle cell (SMC) precursors express the transcription factor teashirt 3 (TSHZ3), and that Tshz3-null mutant mice have congenital hydronephrosis without anatomical obstruction. Ex vivo, the spontaneous contractions that occurred in proximal segments of wild-type embryonic ureter explants were absent in Tshz3 mutant ureters. In vivo, prior to the onset of hydronephrosis,mutant proximal ureters failed to express contractile SMC markers, whereas these molecules were detected in controls. Mutant embryonic ureters expressed Shh and Bmp4 transcripts as normal, with appropriate expression of Ptch1 and pSMAD1/5/8 in target SM precursors, whereas myocardin, a key regulator for SMC differentiation, was not expressed in Tshz3-null ureters. In wild-type embryonic renal tract explants,exogenous BMP4 upregulated Tshz3 and myocardin expression. More interestingly, in Tshz3 mutant renal tract explants, exogenous BMP4 did not improve the Tshz3 phenotype. Thus, Tshz3 is required for proximal ureteric SMC differentiation downstream of SHH and BMP4. Furthermore, the Tshz3 mutant mouse model of `functional' urinary obstruction resembles congenital pelvi-ureteric junction obstruction, a common human malformation, suggesting that TSHZ, or related, gene variants may contribute to this disorder.
Mypt1-mediated spatial positioning of Bmp2-producing cells is essential for liver organogenesis
Authors: Huang Honghui , Ruan Hua , Aw Meng Yuan , Hussain Alamgir , Guo Lin , Gao Chuan , Qian Feng , Leung Thomas , Song Haiwei , Kimelman David , Wen Zilong , Peng Jinrong
Published: September 2008

Mesodermal tissues produce various inductive signals essential for morphogenesis of endodermal organs. However, little is known about how the spatial relationship between the mesodermal signal-producing cells and their target endodermal organs is established during morphogenesis. Here, we report that a mutation in the zebrafish myosin phosphatase targeting subunit 1 (mypt1) gene causes abnormal bundling of actin filaments and disorganization of lateral plate mesoderm (LPM) and endoderm cells. As a result, the coordination between mesoderm and endoderm cell movements is disrupted. Consequently, the two stripes of Bmp2a-expressing cells in the LPM fail to align in a V-shaped pocket sandwiching the liver primordium. Mispositioning Bmp2a-producing cells with respect to the liver primordium leads to a reduction in hepatoblast proliferation and final abortion of hepatoblasts by apoptosis, causing the liverless phenotype. Our results demonstrate that Mypt1 mediates coordination between mesoderm and endoderm cell movements in order to carefully position the liver primordium such that it receives a Bmp signal that is essential for liver formation in zebrafish.
Cathepsin proteases have distinct roles in trophoblast function and vascular remodelling
Authors: Screen Mark , Dean Wendy , Cross James C. , Hemberger Myriam
Published: September 2008

Trophoblast giant cells are instrumental in promoting blood flow towards the mouse embryo by invading the uterine endometrium and remodelling the maternal vasculature. This process involves the degradation of the perivascular smooth muscle layer and the displacement of vascular endothelial cells to form trophoblast-lined blood sinuses. How this vascular remodelling is achieved at the molecular level remains largely elusive. Here, we show that two placenta-specific cathepsins, Cts7 and Cts8, are expressed in distinct but largely overlapping subsets of giant cells that are in direct contact with maternal arteries. We find that Cts8, but not Cts7, has the capacity to mediate loss of smooth muscle α-actin and to disintegrate blood vessels. Consequently, conditional ubiquitous overexpression of Cts8 leads to midgestational embryonic lethality caused by severe vascularization defects. In addition, both cathepsins determine trophoblast cell fate by inhibiting the self-renewing capacity of trophoblast stem cells when overexpressed in vitro. Similarly, transgenic overexpression of Cts7 and Cts8 affects trophoblast proliferation and differentiation by prolonging mitotic cell cycle progression and promoting giant cell differentiation, respectively. We also show that the cell cycle effect is directly caused by some proportion of CTS7 localizing to the nucleus, highlighting the emerging functional diversity of these typically lysosomal proteases in distinct intracellular compartments. Our findings provide evidence for the highly specialized functions of closely related cysteine cathepsin proteases in extra-embryonic development, and reinforce their importance for a successful outcome of pregnancy.
Running on uneven ground: leg adjustment to vertical steps and self-stability
Authors: Grimmer Sten , Ernst Michael , Günther Michael , Blickhan Reinhard
Published: September 2008

Human running is characterized by comparably simple whole-body dynamics. These dynamics can be modelled with a point mass bouncing on a spring leg. Theoretical studies using such spring–mass models predict that running can be self-stable. In simulations, this self-stability allows for running on uneven ground without paying attention to the ground irregularities. Whether humans actually use this property of the mechanical system in such an irregular environment is, however, unclear. One way to approach this question is to study how the leg stiffness in stance and the leg orientation in flight are changed in response to ground perturbations. Here, for 11 human subjects we studied two consecutive contacts during running on uneven ground with a force plate of adjustable height (step of +5, +10 and +15 cm). We found that runners adjust their leg stiffness to the height of a vertical step. The adjustment is characterized by a 9% increase in leg stiffness in preparation for the perturbation and by a systematic decrease in proportion to the step height. At the highest vertical step (+15 cm), leg stiffness was reduced by about 26%. We also observed that the angle of attack decreased from 68 deg. to 62 deg. with increasing ground height. These leg adjustments are in accordance with the predictions of a stable spring–mass system. Furthermore, we could describe the identified leg forces and leg compressions with a simple spring–mass simulation for a given body mass, leg stiffness, angle of attack and initial conditions. We compared the experimental findings with the self-stabilizing properties of the spring–mass model, and discuss how humans use a combination of strategies that include purely mechanical self-stabilization and active neuromuscular control. Finally, beyond self-stability, we suggest that control may apply to smooth centre of mass kinematics.
Multisensory enhancement of electromotor responses to a single moving object
Authors: Pluta Scott R. , Kawasaki Masashi
Published: September 2008

Weakly electric fish possess three cutaneous sensory organs structured in arrays with overlapping receptive fields. Theoretically, these tuberous electrosensory, ampullary electrosensory and mechanosensory lateral line receptors receive spatiotemporally congruent stimulation in the presence of a moving object. The current study is the first to quantify the magnitude of multisensory enhancement across these mechanosensory and electrosensory systems during moving-object recognition. We used the novelty response of a pulse-type weakly electric fish to quantitatively compare multisensory responses to their component unisensory responses. Principally, we discovered that multisensory novelty responses are significantly larger than their arithmetically summed component unisensory responses. Additionally, multimodal stimulation yielded a significant increase in novelty response amplitude,probability and the rate of a high-frequency burst, known as a `scallop'. Supralinear multisensory enhancement of the novelty response may signify an augmentation of perception driven by the ecological significance of multimodal stimuli. Scalloping may function as a sensory scan aimed at rapidly facilitating the electrolocation of novel stimuli.
Caste-dependent sleep of worker honey bees
Authors: Klein Barrett A. , Olzsowy Kathryn M. , Klein Arno , Saunders Katharine M. , Seeley Thomas D.
Published: September 2008

Sleep is a dynamic phenomenon that changes throughout an organism's lifetime, relating to possible age- or task-associated changes in health,learning ability, vigilance and fitness. Sleep has been identified experimentally in many animals, including honey bees (Apis mellifera). As worker bees age they change castes, typically performing a sequence of different task sets (as `cell cleaners', `nurse bees', `food storers' and `foragers'). Belonging to a caste could differentially impact the duration, constitution and periodicity of a bee's sleep. We observed individually marked bees within observation hives to determine caste dependent patterns of sleep behavior. We conducted three studies to investigate the duration and periodicity of sleep when bees were outside comb cells, as well as duration of potential sleep when bees were immobile inside cells. All four worker castes we examined exhibited a sleep state. As bees aged and changed tasks, however, they spent more time and longer uninterrupted periods in a sleep state outside cells, but spent less time and shorter uninterrupted periods immobile inside cells. Although c cleaners and nurse bees exhibited no sleep:wake rhythmicity, food storers and foragers experienced a 24 h sleep:wake cycle, with more sleep and longer unbroken bouts of sleep during the night than during the day. If immobility within cells is an indicator of sleep, our study reveals that the youngest adult bees sleep the most, with all older castes sleeping the same amount. This in-cell potential sleep may compensate for what would otherwise indicate an exceptional increase of sleep in an aging animal.