bluuebunny/crossref_metadata_2025 huggingface dataset:
Prolonged early G1 arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle–coupled loss of IRF4
Authors: Huang Xiangao , Di Liberto Maurizio , Jayabalan David , Liang Jun , Ely Scott , Bretz Jamieson , Shaffer Arthur L. , Louie Tracey , Chen Isan , Randolph Sophia , Hahn William C. , Staudt Louis M. , Niesvizky Ruben , Moore Malcolm A. S. , Chen-Kiang Selina
Published: June 2012

Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G1 arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G1 and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G1 block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy.
Manipulation of the carbon storage regulator system for metabolite remodeling and biofuel production in Escherichia coli
Authors: McKee Adrienne E , Rutherford Becky J , Chivian Dylan C , Baidoo Edward K , Juminaga Darmawi , Kuo Dwight , Benke Peter I , Dietrich Jeffrey A , Ma Suzanne M , Arkin Adam P , Petzold Christopher J , Adams Paul D , Keasling Jay D , Chhabra Swapnil R
Published: June 2012

Background

Microbial engineering strategies that elicit global metabolic perturbations have the capacity to increase organism robustness for targeted metabolite production. In particular, perturbations to regulators of cellular systems that impact glycolysis and amino acid production while simultaneously decreasing fermentation by-products such as acetate and CO2 make ideal targets. Intriguingly, perturbation of the Carbon Storage Regulator (Csr) system has been previously implicated in large changes in central carbon metabolism in E. coli. Therefore, we hypothesized that perturbation of the Csr system through the CsrA-CsrB ribonucleoprotein complex might increase production of biofuels and their intermediates from heterologous pathways.

Results

We engaged the CsrA-CsrB ribonucleoprotein complex of E. coli via overexpression of CsrB. CsrB is a 350-nucleotide non-coding RNA that antagonizes CsrA, an RNA-binding protein that regulates translation of specific mRNA targets. By using shotgun proteomics and targeted metabolomics we established that elevation of CsrB levels leads to alterations in metabolite and protein levels in glycolysis, the TCA cycle and amino acid levels. Consequently, we show that such changes can be suitably applied to improve the production of desired compounds through the native fatty acid and heterologous n-butanol and isoprenoid pathways by up to two-fold. We also observed concomitant decreases in undesirable fermentation by-products such as acetate and CO2.

Conclusions

We have demonstrated that simple engineering of the RNA-based Csr global regulatory system constitutes a novel approach to obtaining pathway-independent improvements within engineered hosts. Additionally, since Csr is conserved across most prokaryotic species, this approach may also be amenable to a wide variety of production hosts.
Geospatial examination of lithium in drinking water and suicide mortality
Authors: Helbich Marco , Leitner Michael , Kapusta Nestor D
Published: June 2012

Background

Lithium as a substance occurring naturally in food and drinking water may exert positive effects on mental health. In therapeutic doses, which are more than 100 times higher than natural daily intakes, lithium has been proven to be a mood-stabilizer and suicide preventive. This study examined whether natural lithium content in drinking water is regionally associated with lower suicide rates.

Methods

Previous statistical approaches were challenged by global and local spatial regression models taking spatial autocorrelation as well as non-stationarity into account. A Geographically Weighted Regression model was applied with significant independent variables as indicated by a spatial autoregressive model.

Results

The association between lithium levels in drinking water and suicide mortality can be confirmed by the global spatial regression model. In addition, the local spatial regression model showed that the association was mainly driven by the eastern parts of Austria.

Conclusions

According to old anecdotic reports the results of this study support the hypothesis of positive effects of natural lithium intake on mental health. Both, the new methodological approach and the results relevant for health may open new avenues in the collaboration between Geographic Information Science, medicine, and even criminology, such as exploring the spatial association between violent or impulsive crime and lithium content in drinking water.
CD109, a TGF-β co-receptor, attenuates extracellular matrix production in scleroderma skin fibroblasts
Authors: Man Xiao-Yong , Finnson Kenneth W , Baron Murray , Philip Anie
Published: June 2012

Introduction

Scleroderma or systemic sclerosis (SSc) is a complex connective tissue disease characterized by fibrosis of skin and internal organs. Transforming growth factor beta (TGF-β) plays a key role in the pathogenesis of SSc fibrosis. We have previously identified CD109 as a novel TGF-β co-receptor that inhibits TGF-β signaling. The aim of the present study was to determine the role of CD109 in regulating extracellular matrix (ECM) production in human SSc skin fibroblasts.

Methods

CD109 expression was determined in skin tissue and cultured skin fibroblasts of SSc patients and normal healthy subjects, using immunofluorescence, western blot and RT-PCR. The effect of CD109 on ECM synthesis was determined by blocking CD109 expression using CD109-specific siRNA or addition of recombinant CD109 protein, and analyzing the expression of ECM components by western blot.

Results

The expression of CD109 proteinis markedly increased in SSc skin tissue in vivo and in SSc skin fibroblasts in vitro as compared to their normal counterparts. Importantly, both SSc and normal skin fibroblasts transfected with CD109-specific siRNA display increased fibronectin, collagen type I and CCN2 protein levels and enhanced Smad2/3 phosphorylation compared with control siRNA transfectants. Furthermore, addition of recombinant CD109 protein decreases TGF-β1-induced fibronectin, collagen type I and CCN2 levels in SSc and normal fibroblasts.

Conclusion

The upregulation of CD109 protein in SSc may represent an adaptation or consequence of aberrant TGF-β signaling in SSc. Our finding that CD109 is able to decrease excessive ECM production in SSc fibroblasts suggest that this molecule has potential therapeutic value for the treatment of SSc.
Dual-energy contrast-enhanced digital mammography: initial clinical results of a multireader, multicase study
Authors: Dromain Clarisse , Thibault Fabienne , Diekmann Felix , Fallenberg Eva M , Jong Roberta A , Koomen Marcia , Hendrick R Edward , Tardivon Anne , Toledano Alicia
Published: June 2012

Introduction

The purpose of this study was to compare the diagnostic accuracy of dual-energy contrast-enhanced digital mammography (CEDM) as an adjunct to mammography (MX) ± ultrasonography (US) with the diagnostic accuracy of MX ± US alone.

Methods

One hundred ten consenting women with 148 breast lesions (84 malignant, 64 benign) underwent two-view dual-energy CEDM in addition to MX and US using a specially modified digital mammography system (Senographe DS, GE Healthcare). Reference standard was histology for 138 lesions and follow-up for 12 lesions. Six radiologists from 4 institutions interpreted the images using high-resolution softcopy workstations. Confidence of presence (5-point scale), probability of cancer (7-point scale), and BI-RADS scores were evaluated for each finding. Sensitivity, specificity and ROC curve areas were estimated for each reader and overall. Visibility of findings on MX ± CEDM and MX ± US was evaluated with a Likert scale.

Results

The average per-lesion sensitivity across all readers was significantly higher for MX ± US ± CEDM than for MX ± US (0.78 vs. 0.71 using BIRADS, p = 0.006). All readers improved their clinical performance and the average area under the ROC curve was significantly superior for MX ± US ± CEDM than for MX ± US ((0.87 vs 0.83, p = 0.045). Finding visibility was similar or better on MX ± CEDM than MX ± US in 80% of cases.

Conclusions

Dual-energy contrast-enhanced digital mammography as an adjunct to MX ± US improves diagnostic accuracy compared to MX ± US alone. Addition of iodinated contrast agent to MX facilitates the visualization of breast lesions.
Inversion-based method for interpretation of logging-while-drilling density measurements acquired in high-angle and horizontal wells
Authors: Mendoza Alberto , Ijasan Olabode , Torres-Verdín Carlos , Preeg William E. , Rasmus John , Radtke R. J. , Stockhausen Edward
Published: June 2012

We introduce a sector-based inversion method to improve the petrophysical interpretation of logging-while-drilling density measurements acquired in high-angle and horizontal wells. The central objective is to reduce shoulder-bed effects on the measurements. This approach is possible because of a recently developed technique to accurately and efficiently simulate borehole density measurements. The inversion-based interpretation method consists of first detecting bed boundaries from short-spacing detector or bottom-quadrant compensated density by calculating their variance, representative of the measurement inflection point, within a sliding window. Subsequently, a correlation algorithm calculates dip and azimuth from the density image. Depth shifts that vary azimuthally and depend on relative dip angle, together with the effective penetration length of each sensor, refine previously selected bed boundaries. Next, the inversion method combines sector-based density measurements acquired at all measurement points along the well trajectory to estimate layer-by-layer densities. In the presence of standoff, the method excludes upper sectors most affected by standoff to reduce inaccuracies due to borehole mud. To verify the reliability and applicability of the inversion method, we first use forward simulations to generate synthetic density images for a model constructed from field data. Results indicate that inversion improves the interpretation of azimuthal density data as it consistently reduces shoulder-bed effects. Inversion results obtained from field measurements are appraised by quantifying the corresponding integrated porosity-meter yielded by inversion methods in comparison to standard techniques that use simple cutoffs on field-processed compensated density. Integrated porosity-meter of inverted synthetic density measurements increases by 4.6% with respect to noninverted field measurements. Also, integrated porosity-meter obtained from inversion results that include only bottom sectors improved by 65.4% with respect to that calculated with field-compensated, bottom-quadrant density measurements.
Implications of the Fresnel-zone texture for seismic amplitude interpretation
Authors: Gao Dengliang
Published: June 2012

The 3D reflection seismic response is associated with a zone (the Fresnel zone), rather than with a single point used in the idealized 1D convolution model. Unlike a point of incidence, the Fresnel zone is complicated by its textural characters that are defined by the dip and azimuth of microreflectors in the zone. The Fresnel-zone texture makes seismic amplitude interpretation more complicated than previously documented. A conceptual model suggests that seismic amplitude variations with offset (AVO), azimuth (AVAz), and frequency (spectral decomposition) were physically related to textural roughness, textural anisotropy, and textural scale of the Fresnel zone, respectively. Textural roughness is defined by the dip deviation of microreflectors and contributes to the AVO intercept and gradient. Textural anisotropy is defined by the degree of the preferred orientation of the microreflectors and directly affects the AVAz signature. Textural scale is defined by the spacing of the microreflectors and controls the selective frequency tuning in spectral decomposition data. The Fresnel-zone texture gives rise to amplitude variations that can not be accurately modeled by using a 1D reflectivity-wavelet convolution algorithm, and thus poses challenges to the reliability of many previous predictions of rock properties and thickness from amplitude. The AVO, AVAz, and spectral decomposition data should be used to characterize Fresnel-zone texture for predicting depositional facies, deformational fabrics, and hydraulic properties in the subsurface.
Update on animal models of diabetic retinopathy: from molecular approaches to mice and higher mammals
Authors: Robinson Remya , Barathi Veluchamy A. , Chaurasia Shyam S. , Wong Tien Y. , Kern Timothy S.
Published: June 2012

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and one of the major causes of blindness worldwide. The pathogenesis of DR has been investigated using several animal models of diabetes. These models have been generated by pharmacological induction, feeding a galactose diet, and spontaneously by selective inbreeding or genetic modification. Among the available animal models, rodents have been studied most extensively owing to their short generation time and the inherited hyperglycemia and/or obesity that affect certain strains. In particular, mice have proven useful for studying DR and evaluating novel therapies because of their amenability to genetic manipulation. Mouse models suitable for replicating the early, non-proliferative stages of the retinopathy have been characterized, but no animal model has yet been found to demonstrate all of the vascular and neural complications that are associated with the advanced, proliferative stages of DR that occur in humans. In this review, we summarize commonly used animal models of DR, and briefly outline the in vivo imaging techniques used for characterization of DR in these models. Through highlighting the ocular pathological findings, clinical implications, advantages and disadvantages of these models, we provide essential information for planning experimental studies of DR that will lead to new strategies for its prevention and treatment.
Autocrine control of glioma cells adhesion/migration through Inositol Requiring enzyme 1α (IRE1α)-mediated cleavage of Secreted Protein Acidic Rich in Cysteine (SPARC) mRNA
Authors: Dejeans Nicolas , Pluquet Olivier , Lhomond Stéphanie , Grise Florence , Bouchecareilh Marion , Juin Amélie , Meynard-Cadars Maud , Bidaud-Meynard Aurélien , Gentil Catherine , Moreau Violaine , Saltel Frédéric , Chevet Eric
Published: June 2012

The endoplasmic reticulum (ER) is an organelle specialized for the folding and assembly of secretory and transmembrane proteins. ER homeostasis is often perturbed in tumor cells due to dramatic changes in solid tumor microenvironment, thereby leading to the activation of an adaptive mechanism named the Unfolded Protein Response (UPR). The activation of the UPR sensor IRE1α has been described to play an important role in tumor progression. However, the molecular events associated with this phenotype remain poorly characterized. In the present study, we examined the effects of IRE1α signaling on glioma cells adaptation to their microenvironment. We show that the characteristics of U87 cells migration are modified under conditions where IRE1α activity is impaired (DN_IRE1). This is linked to increased stress fiber formation and enhanced RhoA activity. Gene expression profiling also revealed that loss of functional IRE1α signaling mostly resulted in the up-regulation of genes encoding extracellular matrix proteins. Among these genes, SPARC, whose mRNA is a direct target of IRE1α endoribonuclease activity, was in part responsible for the phenotypic changes associated with IRE1α inactivation. Hence, our data demonstrate that IRE1α is a key regulator of SPARC expression in vitro in a glioma model. Our results also further support the critical role of IRE1α contribution to tumor growth and infiltration/invasion and extend the paradigm of secretome control in tumor microenvironment conditioning.
Differential expression of genes and proteins between electric organ and skeletal muscle in the mormyrid electric fishBrienomyrus brachyistius
Authors: Gallant Jason R. , Hopkins Carl D. , Deitcher David L.
Published: June 2012

Electric organs (EOs) have evolved independently in vertebrates six times from skeletal muscle (SM). The transcriptional changes accompanying this developmental transformation are not presently well understood. Mormyrids and gymnotiforms are two highly convergent groups of weakly electric fish that have independently evolved EOs: while much is known about development and gene expression in gymnotiforms, very little is known about development and gene expression in mormyrids. This lack of data limits prospects for comparative work. We report here on the characterization of 28 differentially expressed genes between SM and EO tissues in the mormyrid Brienomyrus brachyistius, which were identified using suppressive subtractive hybridization (SSH). Forward and reverse SSH was performed on tissue samples of EO and SM resulting in one cDNA library enriched with mRNAs expressed in EO, and a second library representing mRNAs unique to SM. Nineteen expressed sequence tags (ESTs) were identified in EO and nine were identified in SM using BLAST searching of Danio rerio sequences available in NCBI databases. We confirmed differential expression of all 28 ESTs using RT-PCR. In EO, these ESTs represent four classes of proteins: (1) ion pumps, including the α- and β-subunits of Na+/K+-ATPase, and a plasma membrane Ca2+-ATPase; (2) Ca2+-binding protein S100, several parvalbumin paralogs, calcyclin-binding protein and neurogranin; (3) sarcomeric proteins troponin I, myosin heavy chain and actin-related protein complex subunit 3 (Arcp3); and (4) the transcription factors enhancer of rudimentary homolog (ERH) and myocyte enhancer factor 2A (MEF2A). Immunohistochemistry and western blotting were used to demonstrate the translation of seven proteins (myosin heavy chain, Na+/K+-ATPase, plasma membrane Ca2+-ATPase, MEF2, troponin and parvalbumin) and their cellular localization in EO and SM. Our findings suggest that mormyrids express several paralogs of muscle-specific genes and the proteins they encode in EOs, unlike gymnotiforms, which may post-transcriptionally repress several sarcomeric proteins. In spite of the similarity in the physiology and function of EOs in mormyrids and gymnotiforms, this study indicates that the mechanisms of development in the two groups may be considerably different.
Lateralized behavior in the attacks of largemouth bass on Rhinogobius gobies corresponding to their morphological antisymmetry
Authors: Yasugi Masaki , Hori Michio
Published: June 2012

Vertebrates show left–right biases in turning direction, limb usage, predator-escape response and use of sensory organs. In particular, some fishes are known to have lateral biases in predatory behaviors corresponding to their morphological antisymmetry. To reveal the effects of these laterally biased behaviors on predator–prey interaction, we conducted behavioral tests of predatory events between largemouth bass, Micropterus salmoides, and freshwater gobies, Rhinogobius sp., both of which have individuals with a well-developed left side and individuals with a well-developed right side. The left-developed bass tended to approach the goby clockwise from behind, whereas right-developed individuals tended to approach counterclockwise. Congruently, left-developed gobies began their escape maneuvers at a longer distance from bass when they were approached clockwise than when they were approached counterclockwise, whereas right-developed gobies showed the reverse tendency. The longer the distance between bass and gobies at the start of goby escape, the more the subsequent bass strike or dash was delayed. Under these conditions, predation should be more successful when a left (right)-developed bass meets a right (left)-developed goby, and less successful when a left (right)-developed bass meets a left (right)-developed goby. This prediction was consistent with the difference in predation success in our test and in field data from Lake Biwa, Japan. We conclude that lateral biases in the behavioral direction of each morphological type will generate bias in predation success between different combinations of predator and prey types, leading to the maintenance of antisymmetric dimorphism through negative frequency-dependent natural selection.
Deciphering the signature of cuticular lipids with contact sex pheromone function in a parasitic wasp
Authors: Kühbandner Stephan , Sperling Sergej , Mori Kenji , Ruther Joachim
Published: June 2012

The surface of insects is covered by a complex mixture of cuticular hydrocarbons (CHCs) to prevent desiccation. In many species these lipids also have communicative functions, but often it is unknown which components are crucial for the behavioural response. Furthermore, it is often ignored that polar lipids also occur on the insects' cuticle and might interact with CHCs. In the parasitic wasp Lariophagus distinguendus, CHCs function as a contact sex pheromone eliciting wing-fanning in males. Interestingly, not only females but also newly emerged males have the pheromone, resulting regularly in homosexual courtship. However, males deactivate the pheromone within the first two days after emergence. This deactivation is accompanied by the disappearance of 3-methylheptacosane (3-MeC27) and some minor components from the CHC profile of males. Here we show that 3-MeC27 is a key component of the contact sex pheromone which, however, triggers courtship behaviour only if an olfactory background of other cuticular lipids is present. Males responded to (S)-3-MeC27 enantioselectively when applied to filter paper but on three-dimensional dummies both enantiomers were behaviourally active, suggesting that physical stimuli also play a role in sexual communication of the wasps. Finally, we report that triacylglycerides (TAGs) are also essential components of the pheromone, and present evidence that TAGs actually occur on the cuticle of L. distinguendus. Our data provide novel insights into the semiochemical function of cuticular lipids by showing that the bioactivity of CHCs may be influenced by the stereochemistry and a synergetic interaction with long time ignored TAGs.
Ultrafast Vibrational Dynamics of a Charged Aqueous Interface by Femtosecond Time-Resolved Heterodyne-Detected Vibrational Sum Frequency Generation
Authors: Nihonyanagi Satoshi , Singh Prashant C , Yamaguchi Shoichi , Tahara Tahei
Published: June 2012

Newly developed time-, frequency-, and phase-resolved heterodyne-detected vibrational sum frequency generation (TR-HD-VSFG) spectroscopy opens a new door to explore ultrafast vibrational dynamics of interfacial water. Here, we present the first observation of TR-HD-VSFG spectra of water at a charged monolayer/aqueous solution interface.
Peptide-Induced Formation of Crystalline Sn6O4(OH)4 Nanoparticles under Ambient Conditions
Authors: Matsuno Hisao , Kawashima Yuki , Serizawa Takeshi
Published: June 2012

The short peptides that specifically bind to SnO2 nanoparticles (NPs) were selected by using a phage display method. After the fourth round selection, ten kinds of amino acid sequences were identified, and it was revealed that affinities of the obtained phages for SnO2 NPs were relatively higher than that of the unselected library phages. The identified peptide sequences showed that amino acids having a hydroxy group and hydrophobic amino acids were enriched in the selection process. Binding constants (Ka) of the chemically synthesized heptapeptides having the identified sequences were quantitatively estimated. The pTO-7 peptide (Ser–Ser–Ile–Leu–Arg–Phe–Pro) showed the greatest Ka value (5.80 × 105 M−1 at 25 °C) among the investigated peptides, and also showed binding specificity to SnO2. The SnO2-recognizing peptides functioned as nanostructure stabilizer during pH-dependent preparation of water-insoluble tin-based compound (Sn6O4(OH)4) at room temperature. These effects as stabilizers to disperse nanostructures in water phase were greater than that of a general purpose stabilizer poly(vinylpyrrolidone). Dynamic light scattering and transmission electron microscope analyses revealed that the formed structures in the presence of the pTO-7 peptide were squarish NPs with an approximately 60 nm diameter, and wide-angle powder X-ray diffraction analyses suggested that its crystallinity was increased by existence of the peptide.
Ethyl pyruvate reduces ventilation-induced neutrophil infiltration and oxidative stress
Authors: Li Li-Fu , Kao Kuo-Chin , Yang Cheng-Ta , Huang Chung-Chi , Liu Yung-Yang
Published: June 2012

Mechanical ventilation with high tidal volume causes intense inflammatory responses and oxidative stress, including the release of high-mobility group box-1 (HMGB1), plasminogen activator inhibitor-1 (PAI-1) and heme oxygenase-1 (HO-1). The mechanisms regulating ventilator-induced lung injury (VILI) are unclear. We hypothesized that ethyl pyruvate attenuated acute lung injury as adjunctive pharmacological strategy by down-regulating neutrophil infiltration, oxidative stress and HMGB1 mRNA expression. C57BL/6 mice, weighing 20–25 g, were exposed to either low-tidal-volume (6 mL/kg) or high-tidal-volume (30 mL/kg) mechanical ventilation with room air for 2–5 h and subjected to 100 mg/kg ethyl pyruvate administration intraperitoneally. Non-ventilated mice served as the control group. Evans blue dye, lung wet-to-dry weight ratio, lung neutrophil infiltration and myeloperoxidase, free radicals, gene expression of HMGB1, active PAI-1 and HMGB1 production and HO-1 expression were measured. The expression of HO-1 was studied by immunohistochemistry. High-tidal-volume ventilation induced microvascular leak, neutrophil recruitment, oxidative injury, HMGB1 and active PAI-1 protein production, and upregulation of HMGB1 mRNA and stress-inducible protein HO-1. In contrast, administration of ethyl pyruvate before high stretch mechanical ventilation prevented lung edema formation, inflammatory cytokine production, neutrophil accumulation, oxidative stress and HMGB1 and HO-1 expression. High-tidal-volume mechanical ventilation increased microvascular permeability, neutrophil influx and inflammatory cytokines. Ethyl pyruvate is capable of suppressing the VILI related to the reduction of HMGB1 and our findings support the potential use of ethyl pyruvate as a therapeutic agent for the prevention of VILI.
Lac color inhibits development of rat thyroid carcinomas through targeting activation of plasma hyaluronan-binding protein
Authors: Kemmochi Sayaka , Yamamichi Shingo , Shimamoto Keisuke , Onda Nobuhiko , Hasumi Keiji , Suzuki Kazuhiko , Mitsumori Kunitoshi , Shibutani Makoto
Published: June 2012

Coccid-derived natural food colorants contain active ingredients that potentiate inhibition of tissue proteolysis mediated by activation of plasma hyaluronan-binding protein (PHBP). In the present study, we examined the effect of lac color (LC) and cochineal extract (CE), representative coccid-derived colorants containing laccaic acid and carminic acid as active ingredients, in an intracapsular invasion model of experimental thyroid cancers using rats. One week after initiation with N-bis(hydroxypropyl)nitrosamine, male F344/NSIc rats were fed a powdered diet containing 5.0% LC or 3.0% CE during promotion with 0.15% sulfadimethoxine (SDM) in the drinking water for 13 weeks. Capsular invasive carcinomas (CICs) and lung metastases were decreased by LC treatment and accompanied by transcript downregulation on angiogenesis and PHBP-related tissue proteolysis in CICs. In contrast, CE upregulated angiogenesis-related genes in CICs. PHBP was expressed in capsular macrophages and thyroid proliferative lesions with increased intensity in CICs, and LC decreased PHBP-expressing CICs. The size of CICs and their proliferation activity, however, were unchanged compared with those treated with SDM alone. Suppression of cancer by invasion by LC was more evident after an eight-week treatment, exhibiting a profound decrease in tenascin-C-positive early invasive foci and marked reductions in capsular inflammation and fibrosis. These results suggest that LC and CE exerted dissimilar effects on CIC development, the former suppressing the initial step of neoplastic cell invasion into the capsule by targeting PHBP activity of macrophages and neoplastic cells on tissue proteolysis involving inflammatory responses and angiogenesis, and the latter promoting angiogenesis of developed CICs at later stages.
Bi-ventricular pacing improves pump function only with adequate myocardial perfusion in canine hearts with pseudo-left bundle branch block
Authors: Svendsen Mark , Prinzen Frits W , Das Mithilesh K , Berwick Zachary , Rybka Matthew , Tune Johnathan D , Combs William , Berbari Edward J , Kassab Ghassan S
Published: June 2012

Bi-ventricular (BiV) pacing is an effective therapy for the treatment of cardiac electromechanical (EM) dysfunction. The reason(s), however, for therapy non-response in approximately one-third of the subjects remains unclear, especially as it relates to myocardial perfusion and pacing location. In this study, we examined how acute BiV pacing response may be related to underlying myocardial perfusion coupled with pacing near or distant to the area of perfusion. In 10 open-chest anesthetized canines, coronary blood flow to the left ventricular (LV) anterior wall (AW: n = 5) and lateral wall (LW: n = 5) was controlled during four pacing conditions: right atrial, right ventricular (pseudo-left bundle branch block; [pseudo-LBBB]), BiV-LW and BiV-AW. Local EM function (piezo-electrical crystals and electrodes), along with global hemodynamic parameters, were measured during all pacing conditions at three coronary perfusion rates (≥0.40 mL/min/g, 0.20–0.40 mL/min/g and <0.20 mL/min/g). A positive BiV therapy response was assessed by a significant increase in the maximum cardiac output compared with the pseudo-LBBB condition. Despite no improvement in QRS duration, BiV-LW pacing improved LV function compared with the pseudo-LBBB pacing condition ( P value <0.01). This improvement with BiV-LW pacing was seen above a certain myocardial perfusion threshold and was independent of any increases in regional coronary blood flow with BiV pacing. At lower myocardial perfusion rates, LV function was not improved with BiV pacing at any location. This study underscores the significance of even mild ischemia on BiV pacing response.
Book Reviews
Authors: Rand Graham K.
Published: June 2012

In Book Reviews, we review an extensive and diverse range of books. They cover theory and applications in operations research, statistics, management science, econometrics, mathematics, computers, and information systems. In addition, we include books in other fields that emphasize technical applications. The editor will be pleased to receive an e-mail from those willing to review a book, with an indication of specific areas of interest. If you are aware of a specific book that you would like to review, or that you think should be reviewed, please contact the editor.

The following books are reviewed in this issue of Interfaces, 42(3), May–June 2012: Introduction to Discrete Event Simulation and Agent-based Modeling: Voting Systems, Health Care, Military, and Manufacturing, Theodore T. Allen; Benchmarking with DEA, SFA, and R, Peter Bogetoft and Lars Otto; Linear Programming and Generalizations: A Problem-based Introduction with Spreadsheets, Eric V. Denardo; The Linear Ordering Problem: Exact and Heuristic Methods in Combinatorial Optimization, Rafael Martí and Gerhard Reinelt.
RNA regulons and the RNA-protein interaction network
Authors: Imig Jochen , Kanitz Alexander , Gerber André P.
Published: June 2012

The development of genome-wide analysis tools has prompted global investigation of the gene expression program, revealing highly coordinated control mechanisms that ensure proper spatiotemporal activity of a cell’s macromolecular components. With respect to the regulation of RNA transcripts, the concept of RNA regulons, which – by analogy with DNA regulons in bacteria – refers to the coordinated control of functionally related RNA molecules, has emerged as a unifying theory that describes the logic of regulatory RNA-protein interactions in eukaryotes. Hundreds of RNA-binding proteins and small non-coding RNAs, such as microRNAs, bind to distinct elements in target RNAs, thereby exerting specific and concerted control over posttranscriptional events. In this review, we discuss recent reports committed to systematically explore the RNA-protein interaction network and outline some of the principles and recurring features of RNA regulons: the coordination of functionally related mRNAs through RNA-binding proteins or non-coding RNAs, the modular structure of its components, and the dynamic rewiring of RNA-protein interactions upon exposure to internal or external stimuli. We also summarize evidence for robust combinatorial control of mRNAs, which could determine the ultimate fate of each mRNA molecule in a cell. Finally, the compilation and integration of global protein-RNA interaction data has yielded first insights into network structures and provided the hypothesis that RNA regulons may, in part, constitute noise ‘buffers’ to handle stochasticity in cellular transcription.
Viscoelasticity in thermoforming
Authors: Johnson Leann M. , Giacomin A. Jeffrey , Mix Adam W.
Published: June 2012

This analysis for thermoforming cones from a viscoelastic melt gives the speed of the stresses in the deforming melt. We follow the mechanics of Kershner and Giacomin developed for thermoforming cones from a Newtonian melt, deriving an analytical solution for the corotational Maxwell (CM) model. We have distinguished what happens before and after the melt touches the conical mold (free vs. constrained forming). The CM reduces to the Newtonian solution of Kershner and Giacomin. The upper convected Maxwell (UCM) model is also investigated, but does not yield an analytical solution for conical thermoforming. Our results are confined to forming with a conical mold, the simplest relevant problem in thermoforming, using the simplest relevant constitutive equation, the CM model.
Metabolomics in diabetes research
Authors: Friedrich Nele
Published: June 2012

Diabetes represents one of the most important global health problems because it is associated with a large economic burden on the health systems of many countries. Whereas the diagnosis and treatment of manifest diabetes have been well investigated, the identification of novel pathways or early biomarkers indicative of metabolic alterations or insulin resistance related to the development of diabetes is still in progress. Over half of the type 2 diabetes patients show manifestations of diabetes-related diseases, which highlight the need for early screening markers of diabetes. During the last decade, the rapidly growing research field of metabolomics has introduced new insights into the pathology of diabetes as well as methods to predict disease onset and has revealed new biomarkers. Recent epidemiological studies first used metabolism to predict incident diabetes and revealed branched-chain and aromatic amino acids including isoleucine, leucine, valine, tyrosine and phenylalanine as highly significant predictors of future diabetes. This review summarises the current findings of metabolic research regarding diabetes in animal models and human investigations.
Introduction
Authors: Milani Tommaso M.
Published: June 2012

Tommaso M. Milani introduces this special edition of Gender and Language: Re-casting Language and Masculinities.
Identity Matters
Authors: Cummins Jim
Published: June 2012

Policies designed to improve educational outcomes in the United States (and many other countries) over the past decade have failed to raise overall achievement or close the gap between middle-class and low-income students in any significant way. Little tangible impact is evident despite the expenditure of billions of dollars ($6 billion for the Reading First program alone). Alienated adolescents, primarily from culturally and linguistically diverse backgrounds, continue to drop out of high school in large numbers. I argue that the persistent failure of educational policies designed to close the achievement gap is largely a result of implementing evidence-free policies and instructional practices. Policy-makers have chosen to ignore extensive empirical evidence suggesting the following: (a) factors associated with socioeconomic status (SES) and broader patterns of societal power relations exert a major influence on educational outcomes; (b) literacy engagement is a stronger predictor of reading performance than socioeconomic status (SES), and low-income students have significantly less access to books and print than do higher-income students; (c) students will engage academically only to the extent that classroom interactions and academic effort are identity-affirming. The framework proposed for stimulating school-based policy discussions argues that school polices need to maximize print access and literacy engagement among marginalized group students and in addition that they need to enable students to use language and literacy in ways that will affirm their identities and challenge the deficit orientation that is frequently built into programs and curriculum for low-income and bilingual learners.
Making Room for Identity in Second Language Writing
Authors: Cohen Sarah L
Published: June 2012

The case studies in this article represent the work of two elementary teachers who integrated their students’ identities into the literacy curriculum. Drawing on Cummins’ (2001) concept of identity investment, academic engagement, and multiliteracies theory, I discuss and analyze samples of students’ dual language writing and document the teaching practices that made these identity texts possible. Interview data from student participants and examples of their work illustrate the ways in which students re-imagine their identities by engaging with writing in both languages. The work of these students demonstrates the power that writing can have as a medium for students to express their identities. This study further shows that teaching writing through the use of personal narratives and cultural stories affords students opportunities to build their own cultural capital in relation to the expectations of academic writing.
Co-Creating Identities through Bilingual Identity Texts and Dialogical Ethnography
Authors: López-Gopar Mario E , Clemente Ángeles , Sughrua William
Published: June 2012

This article focuses on student teachers of English in the Bachelor of Arts in Teaching English as a Second Language (BA TESL) program of the public state university of Oaxaca, Mexico. In Oaxaca, and Mexico at large, proficient English users are mainly from the upper socioeconomic classes. In general, the schools value Spanish and English to the exclusion of the prevailing Indigenous languages. Moreover, to be a legitimate English teacher, one is expected to look or act “American” or “gringo” and/or to have a “native-like” English accent. The Oaxacan student teachers are mainly from the lower or middle socioeconomic classes. They do not have “American” characteristics and lack a “native-like” English accent. Within this context is the present discussion situated. It demonstrates that the student teachers in two BA TESL classes utilize bilingual identity texts and dialogical ethnography as autobiographies and collages in order to co-create identities with which to assert their legitimacy as English teachers and multilingual speakers. The student teachers also validate their students’ multilingual identities, resist the “native speaker” versus “non-native speaker” dichotomy, confront the hegemony of Spanish over Indigenous languages, and attribute an international importance to their formation as English teachers. The bilingual identity texts and dialogic ethnography allow multilingual identity and intelligence to enter the TESL classroom and curriculum.
Internet-based Sister Classes and Writing
Authors: Kourtis-Kazoullis Vasilia
Published: June 2012

In this article, two case studies of Internet-based sister classes designed to foster second language learning are described with a focus on student writing. Writing is examined within the context of social constructivist and transformative orientations to pedagogy. In the context of these pedagogical orientations, writing is initially analyzed as communication within an environment that merges writing with speaking and also promotes changes in pedagogy. These pedagogical changes enable students’ writing to become a vehicle for generating new knowledge, creation of literature, and critical examination of social realities relevant to students’ lives.
Effective Second Language Writing Susan Kasten (ed.) (2010)
Authors: Fyn Dawn
Published: June 2012

Effective Second Language Writing Susan Kasten (ed.) (2010) Alexandria, Virginia: TESOL. pp. 219 ISBN: 978-193118563-9
Osteomalacia: The Missing Link in the Pathogenesis of Bisphosphonate-Related Osteonecrosis of the Jaws?
Authors: Bedogni Alberto , Saia Giorgia , Bettini Giordana , Tronchet Anita , Totola Andrea , Bedogni Giorgio , Tregnago Paolo , Valenti Maria Teresa , Bertoldo Francesco , Ferronato Giuseppe , Nocini Pier Francesco , Blandamura Stella , Dalle Carbonare Luca
Published: June 2012

Background.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-documented adverse event from treatment with nitrogen-containing bisphosphonates (NBPs). During a preliminary histomorphometric study aimed at assessing the rate of bone remodeling in the jaws of patients with surgically resected BRONJ, we found a defect of bone mineralization (unpublished data). We hypothesized that osteomalacia could be a risk factor for BRONJ in patients taking NBPs. Therefore, we looked for static and dynamic histomorphometric evidence of osteomalacia in biopsies from subjects with and without BRONJ.

Methods.

This case-control study used histomorphometric analysis of bone specimens of patients using NBPs (22 patients with BRONJ and 21 patients without BRONJ) who required oral surgical interventions for the treatment/prevention of osteonecrosis. Patients were given tetracycline hydrochloride according to a standardized protocol before taking bone biopsies from their jaws. Biopsies with evidence of osteomyelitis or necrosis at histology were excluded from the study. Osteomalacia was defined as a mineralization lag time >100 days, a corrected mean osteoid thickness >12.5 mm, and an osteoid volume >10%.

Results.

In all, 77% of patients with BRONJ were osteomalacic compared with 5% of patients without BRONJ, according to histomorphometry. Because osteomalacia was found almost exclusively in NBP users with BRONJ, this is likely to be a generalized process in which the use of NBPs further deteriorates mechanisms of bone repair.

Conclusions.

Osteomalacia represents a new and previously unreported risk factor for disease development. This finding may contribute to a better understanding of the pathogenesis of this disease and help with the development of strategies to increase the safety of NBP administration.
Finasteride and Prostate Cancer: A Commentary
Authors: Paller Channing J. , Smith Thomas J.
Published: June 2012

This commentary discusses the risks and benefits of using finasteride to prevent prostate cancer.
Becoming-Nomadic through Experimental Art Making with Children
Authors: Clark Vanessa
Published: June 2012

The author draws on her own experiences through art, along with her experiences with children, to inform her understanding of art making as nomadic thinking, a means to disrupt the power structures and boundaries that developmental psychology imposes on early childhood practice. The author altered the classrooms of two early childhood centres with an art provocation; through images and text she attempts to draw attention to the encounters between and among herself, materials, children, and environment. This article explores nomadic thought as emerging through these entanglements, interruptions, and connections with the potential to open up developmental psychology and allow for a reimagining of art practice in early childhood.
Places for Pedagogies, Pedagogies for Places
Authors: Duhn Iris
Published: June 2012

Working with an understanding of assemblage as the ad hoc groupings of vibrant materials and elements, this article argues that conceptualizing place as an assemblage opens possibilities for bridging the gap between subjects and objects that continue to structure pedagogy. Considering ‘place’ as an assemblage of humans and their multiple ‘others' puts emphasis on the productive nature of forces and forms as vibrant matter. While much of the literature on ‘place-based pedagogy’ argues for a commitment to place-based local environments as a counterpoint to globalization, ‘place-as-assemblage’ circumvents such politics of resistance. Instead of critique and opposition, the emphasis lies on finding ways for critical engagement and new perspectives through an understanding of the forces and forms that make places, and shape pedagogies. The article draws on New Zealand-based research to reconsider the often taken-for-granted relationship between place and pedagogy.
Determinants of the Persistence of Internal Control Weaknesses
Authors: Klamm Bonnie K. , Kobelsky Kevin W. , Watson Marcia Weidenmier
Published: June 2012

SYNOPSIS

This paper analyzes the degree to which material weaknesses (MWs) in internal control reported under the Sarbanes-Oxley Act of 2002 (SOX) affect the future reporting of MWs. Particularly, we examine information technology (IT) and non-IT MWs and their breakdown into specific IT-related entity-level, non-IT-related entity-level, and account-level deficiencies. Analysis reveals that most account-level and entity-level deficiencies occur at a significantly higher rate in SOX 404 reports with at least one IT MW than in MW reports with only non-IT MWs. Further, the presence and count of both types of MWs and all three types of deficiencies are associated with increased future MWs, as are lower profitability, non-Big 6 auditor, and firm complexity. Specific control deficiencies related to senior management, training, and IT control environment have the strongest impact on future MWs. These results indicate that effective corporate governance of both the IT and non-IT domains is pivotal in establishing and maintaining strong internal controls over financial reporting.

Data Availability:  Data are available from the public sources identified in the paper.