bluuebunny/crossref_metadata_2025 huggingface dataset:
Signalling pathways involved in the contractile response to 5-HT in the human pulmonary artery
Authors: Rodat-Despoix L. , Aires V. , Ducret T. , Marthan R. , Savineau J-P. , Rousseau E. , Guibert C.
Published: June 2009

Serotonin (5-hydroxytryptamine; 5-HT) is a potent pulmonary vasoconstrictor and mitogenic agent whose plasma level is increased in pulmonary hypertensive patients. Thus, we explored the signalling pathways involved in the contractile response to 5-HT in human pulmonary arteries (HPAs).

Intact and β-escin permeabilised rings from HPAs mounted in an organ bath system were used to assess both tension and myofilament Ca2+-sensitisation. Microspectrofluorimetry was used for intracellular Ca2+recordings in cultured HPA smooth muscle cells.

Voltage-operated Ca2+channel blockers (nitrendipine and nifedipine) partially reduced the contraction to 5-HT. Thapsigargin or cyclopiazonic acid (CPA), known to deplete sarcoplasmic reticulum Ca2+stores, also partially inhibited the contraction, whereas removal of extracellular Ca2+under these conditions further inhibited the contraction. Changing from Ca2+-free to Ca2+containing solution, in the presence of nitrendipine and CPA, a protocol known to stimulate store-operated Ca2+channels, induced HPA contractions that were blocked by nickel. Nickel or gadolinium also reduced the contraction to 5-HT. Finally, 5-HT increased intracellular Ca2+responses in cultured HPA smooth muscle cells and myofilament Ca2+-sensitisation in HPA rings.

Collectively, these results indicate that voltage-operated and voltage-independent Ca2+channels, as well as Ca2+release and myofilament Ca2+-sensitisation, participate in 5-HT-induced contraction in HPAs.
Corticosteroid responsiveness and clinical characteristics in childhood difficult asthma
Authors: Bossley C. J. , Saglani S. , Kavanagh C. , Payne D. N. R. , Wilson N. , Tsartsali L. , Rosenthal M. , Balfour-Lynn I. M. , Nicholson A. G. , Bush A.
Published: June 2009

This study describes the clinical characteristics and corticosteroid responsiveness of children with difficult asthma (DA). We hypothesised that complete corticosteroid responsiveness (defined as improved symptoms, normal spirometry, normal exhaled nitric oxide fraction (FeNO) and no bronchodilator responsiveness (BDR <12%)) is uncommon in paediatric DA.

We report on 102 children, mean±sdage 11.6±2.8 yrs, with DA in a cross-sectional study. 89 children underwent spirometry, BDR andFeNObefore and after 2 weeks of systemic corticosteroids (corticosteroid response study). Bronchoscopy was performed after the corticosteroid trial.

Of the 102 patients in the cross-sectional study, 88 (86%) were atopic, 60 (59%) were male and 52 (51%) had additional or alternative diagnoses. Out of the 81 patients in the corticosteroid response study, nine (11%) were complete responders. Of the 75 patients with symptom data available, 37 (49%) responded symptomatically, which was less likely if there were smokers in the home (OR 0.31, 95% CI 0.02–0.82). Of the 75 patients with available spirometry data, 35 (46%) had normal spirometry, with associations being BAL eosinophilia (OR 5.43, 95% CI 1.13–26.07) and high baseline forced expiratory volume in 1 s (FEV1) (OR 1.08, 95% CI 1.02–1.12). Of these 75 patients, BDR data were available in 64, of whom 36 (56%) had <12% BDR.FeNOdata was available in 70 patients, of whom 53 (75%) had normalFeNO. Airflow limitation data was available in 75 patients, of whom 17 (26%) had persistent airflow limitation, which was associated with low baseline FEV1(OR 0.93, 95% CI 0.90–0.97).

Only 11% of DA children exhibited complete corticosteroid responsiveness. The rarity of complete corticosteroid responsiveness suggests alternative therapies are needed for children with DA.
Admission hypoglycaemia is associated with adverse outcome in community-acquired pneumonia
Authors: Singanayagam A. , Chalmers J. D. , Hill A. T.
Published: June 2009

The aim of our study was to investigate if hypoglycaemia correlates with outcome in community-acquired pneumonia (CAP).

We performed a prospective, observational study of consecutive patients presenting with a primary diagnosis of CAP in Lothian (UK). Admission plasma glucose was measured and, on this basis, patients were divided into two groups, hypoglycaemic (<4.4 mmol·L−1or <79.0 mg·dL−1) and nonhypoglycaemic (≥4.4 mmol·L−1or ≥79.0 mg·dL−1). Outcomes of interest were 30-day mortality, need for mechanical ventilation and inotropic support. Multivariable logistic regression was used to compare these outcomes in hypoglycaemic patients to nonhypoglycaemic patients, adjusting for diabetes mellitus, prior statin use and Pneumonia Severity Index.

In total, 1,050 patients were included in the study with 5.4% classified as hypoglycaemic. Increased rates of 30-day mortality (28.1%versus7.5%, p<0.0001), need for mechanical ventilation (29.8%versus6.5%, p<0.0001) and need for inotropic support (21.1%versus4.8%, p<0.0001) were observed in hypoglycaemic patients compared with nonhypoglycaemic patients. On multivariable analysis, hypoglycaemia was independently associated with increased 30-day mortality (OR 2.25, 95% CI 1.1–4.7; p = 0.03), need for mechanical ventilation (OR 3.8, 95% CI 1.9–7.5; p = 0.0002) and need for inotropic support (OR, 2.9, 95% CI 1.4–6.3; p = 0.0006).

Admission hypoglycaemia is associated with increased 30-day mortality, need for mechanical ventilation and inotropic support in patients presenting with CAP.
Biomarkers of infection for the differential diagnosis of pleural effusions
Authors: Porcel J. M. , Vives M. , Cao G. , Bielsa S. , Ruiz-González A. , Martínez-Iribarren A. , Esquerda A.
Published: June 2009

We aimed to investigate whether pleural fluid concentrations of biomarkers for bacterial infection, namely triggering receptor expressed on myeloid cells (sTREM-1), procalcitonin (PCT), lipopolysaccharide-binding protein (LBP) and C-reactive protein (CRP), might identify infectious effusions and discriminate between complicated (CPPEs) and uncomplicated parapneumonic effusions (UPPEs).

Stored pleural fluid samples from 308 patients with different causes of pleural effusion were used to measure the four biomarkers. Receiver-operating characteristic analysis determined the accuracy of the new tests.

Median pleural fluid levels of CRP, sTREM-1 and LBP were significantly higher in CPPE compared with those in other aetiologies. The area under the curve for distinguishing infectious (parapneumonics and tuberculosis) from noninfectious effusions was 0.87 for CRP, 0.86 for sTREM-1, 0.57 for PCT and 0.87 for LBP. Regarding the discrimination of nonpurulent CPPEversusUPPE, a multivariate analysis found that pleural fluid glucose ≤60 mg·dL−1, LBP ≥17 μg·mL−1and CRP ≥80 mg·L−1were the best parameters. Individually, none of the new biomarkers achieved better performance characteristics than pH, glucose or lactate dehydrogenase in labelling CPPE.

In conclusion, elevated pleural fluid levels of CRP, sTREM and LBP identify patients with infectious effusions, particularly those with CPPE. PCT has no value for the differential diagnosis of pleural effusions.
Maternal diabetes alters transcriptional programs in the developing embryo
Authors: Pavlinkova Gabriela , Salbaum J Michael , Kappen Claudia
Published: June 2009

Background

Maternal diabetes is a well-known risk factor for birth defects, such as heart defects and neural tube defects. The causative molecular mechanisms in the developing embryo are currently unknown, and the pathogenesis of developmental abnormalities during diabetic pregnancy is not well understood. We hypothesized that the developmental defects are due to alterations in critical developmental pathways, possibly as a result of altered gene expression. We here report results from gene expression profiling of exposed embryos from a mouse diabetes model.

Results

In comparison to normal embryos at mid-gestation, we find significantly altered gene expression levels in diabetes-exposed embryos. Independent validation of altered expression was obtained by quantitative Real Time Polymerase Chain Reaction. Sequence motifs in the promoters of diabetes-affected genes suggest potential binding of transcription factors that are involved in responses to oxidative stress and/or to hypoxia, two conditions known to be associated with diabetic pregnancies. Functional annotation shows that a sixth of the de-regulated genes have known developmental phenotypes in mouse mutants. Over 30% of the genes we have identified encode transcription factors and chromatin modifying proteins or components of signaling pathways that impinge on transcription.

Conclusion

Exposure to maternal diabetes during pregnancy alters transcriptional profiles in the developing embryo. The enrichment, within the set of de-regulated genes, of those encoding transcriptional regulatory molecules provides support for the hypothesis that maternal diabetes affects specific developmental programs.
Case report: Malignant teratoma of the uterine corpus
Authors: Newsom-Davis Thomas , Poulter Daniel , Gray Rebecca , Ameen Mohammed , Lindsay Iain , Papanikolaou Kyriakos , Butler-Manuel Simon , Christmas Timothy , Townsend Peter , Seckl Michael
Published: June 2009

Background

Teratomas are the commonest germ cell tumours and are most frequently found in the testes and ovary. Extragonadal teratomas are rare and mainly occur in midline structures. Uterine teratomas are extremely rare with only a few previous case reports, usually involving mature teratomas of the uterine cervix.

Case Presentation

We report an 82-year-old lady presenting with post-menopausal bleeding. Initial investigations revealed a benign teratoma of the uterus which was removed. Her symptoms persisted and a recurrent, now malignant, teratoma of the uterine corpus was resected at hysterectomy. Six months after surgery she relapsed with para-aortic lymphadenopathy and was treated with a taxane, etoposide and cisplatin-containing chemotherapy regimen followed by retroperitoneal lymph node dissection.

Conclusion

In this report we discuss the aetiology, diagnosis and management of uterine teratomas, and review previous case studies.
Technology assessment and resource allocation for predictive genetic testing: A study of the perspectives of Canadian genetic health care providers
Authors: Adair Alethea , Hyde-Lay Robyn , Einsiedel Edna , Caulfield Timothy
Published: June 2009

Background

With a growing number of genetic tests becoming available to the health and consumer markets, genetic health care providers in Canada are faced with the challenge of developing robust decision rules or guidelines to allocate a finite number of public resources. The objective of this study was to gain Canadian genetic health providers' perspectives on factors and criteria that influence and shape resource allocation decisions for publically funded predictive genetic testing in Canada.

Methods

The authors conducted semi-structured interviews with 16 senior lab directors and clinicians at publically funded Canadian predictive genetic testing facilities. Participants were drawn from British Columbia, Alberta, Manitoba, Ontario, Quebec and Nova Scotia. Given the community sampled was identified as being relatively small and challenging to access, purposive sampling coupled with snowball sampling methodologies were utilized.

Results

Surveyed lab directors and clinicians indicated that predictive genetic tests were funded provincially by one of two predominant funding models, but they themselves played a significant role in how these funds were allocated for specific tests and services. They also rated and identified several factors that influenced allocation decisions and patients' decisions regarding testing. Lastly, participants provided recommendations regarding changes to existing allocation models and showed support for a national evaluation process for predictive testing.

Conclusion

Our findings suggest that largely local and relatively ad hoc decision making processes are being made in relation to resource allocations for predictive genetic tests and that a more coordinated and, potentially, national approach to allocation decisions in this context may be appropriate.
The complete genome of klassevirus – a novel picornavirus in pediatric stool
Authors: Greninger Alexander L , Runckel Charles , Chiu Charles Y , Haggerty Thomas , Parsonnet Julie , Ganem Donald , DeRisi Joseph L
Published: June 2009

Background

Diarrhea kills 2 million children worldwide each year, yet an etiological agent is not found in approximately 30–50% of cases. Picornaviral genera such as enterovirus, kobuvirus, cosavirus, parechovirus, hepatovirus, teschovirus, and cardiovirus have all been found in human and animal diarrhea. Modern technologies, especially deep sequencing, allow rapid, high-throughput screening of clinical samples such as stool for new infectious agents associated with human disease.

Results

A pool of 141 pediatric gastroenteritis samples that were previously found to be negative for known diarrheal viruses was subjected to pyrosequencing. From a total of 937,935 sequence reads, a collection of 849 reads distantly related to Aichi virus were assembled and found to comprise 75% of a novel picornavirus genome. The complete genome was subsequently cloned and found to share 52.3% nucleotide pairwise identity and 38.9% amino acid identity to Aichi virus. The low level of sequence identity suggests a novel picornavirus genus which we have designated klassevirus. Blinded screening of 751 stool specimens from both symptomatic and asymptomatic individuals revealed a second positive case of klassevirus infection, which was subsequently found to be from the index case's 11-month old twin.

Conclusion

We report the discovery of human klassevirus 1, a member of a novel picornavirus genus, in stool from two infants from Northern California. Further characterization and epidemiological studies will be required to establish whether klasseviruses are significant causes of human infection.
Linking reservoir geomechanics and time-lapse seismics: Predicting anisotropic velocity changes and seismic attributes
Authors: Herwanger Jorg V. , Horne Steve A.
Published: June 2009

Seismic technology has been used successfully to detect geomechanically induced signals in repeated seismic experiments from more than a dozen fields. To explain geomechanically induced time-lapse (4D) seismic signals, we use results from coupled reservoir and geomechanical modeling. The coupled simulation yields the 3D distribution, over time, of subsurface deformation and triaxial stress state in the reservoir and the surrounding rock. Predicted changes in triaxial stress state are then used to compute changes in anisotropic P- and S-wave velocities employing a stress sensitive rock-physics transform. We predict increasing vertical P-wave velocities inside the reservoir, accompanied by a negative change in P-wave anisotropy [Formula: see text]. Conversely, in the overburden and underburden, we have predicted a slowdown in vertical P-wave velocity and an increase in horizontal velocities. This corresponds to positive change in P-wave anisotropy [Formula: see text]. A stress sensitive rock-physics transform that predicts anisotropic velocity change from triaxial stress change offers an explanation for the apparent difference in stress sensitivity of P-wave velocity between the overburden and the reservoir. In a modeled example, the vertical velocity speedup per unit increase in vertical stress [Formula: see text] is more than twice as large in the overburden as in the reservoir. The difference is caused by the influence of the stress path [Formula: see text] (i.e., the ratio [Formula: see text] between change in minimum horizontal effective stress [Formula: see text] and change in vertical effective stress [Formula: see text]) on vertical velocity. The modeling suggests that time-lapse seismic technology has the potential to become a monitoring tool for stress path, a critical parameter in failure geomechanics.
Male-Biased Effects of Gonadotropin-Releasing Hormone Neuron-Specific Deletion of the Phosphoinositide 3-Kinase Regulatory Subunit p85α on the Reproductive Axis
Authors: Acosta-Martínez Maricedes , Luo Ji , Elias Carol , Wolfe Andrew , Levine Jon E.
Published: June 2009

GnRH neurosecretion is subject to regulation by insulin, IGF-I, leptin, and other neuroendocrine modulators whose effects may be conveyed by activation of phosphoinositide 3-kinase (PI3K)-mediated pathways. It is not known, however, whether any of these regulatory actions are exerted directly, via activation of PI3K in GnRH neurons, or whether they are primarily conveyed via effects on afferent circuitries governing GnRH neurosecretion. To investigate the role of PI3K signaling in GnRH neurons, we used conditional gene targeting to ablate expression of the major PI3K regulatory subunit, p85α, in GnRH neurons. Combined in situ hybridization and immunohistochemistry confirmed reduction of p85α mRNA expression in GnRH neurons of GnRH-p85α knockout (KO) animals. Females of both genotypes exhibited estrous cyclicity and had comparable serum LH, estradiol-17β, and FSH levels. In male GnRH-p85αKO mice, serum LH, testosterone, and sperm counts were significantly reduced compared with wild type. To investigate the role of the other major regulatory subunit, p85β, on the direct control of GnRH neuronal function, we generated mice with a GnRH-neuron-specific p85α deletion on a global βKO background. No additional reproductive effects in male or female mice were found, suggesting that p85β does not substitute p85 activity toward PI3K function in GnRH neurons. Our results suggest that p85α, and thus PI3K activity, participates in the control of GnRH neuronal activity in male mice. The sex-specific phenotype in these mice raises the possibility that PI3K activation during early development may establish sex differences in GnRH neuronal function.
Structural and Functional Characterization of the Interdomain Interaction in the Mineralocorticoid Receptor
Authors: Pippal Jyotsna B. , Yao Yizhou , Rogerson Fraser M. , Fuller Peter J.
Published: June 2009

The mineralocorticoid receptor (MR) plays a central role in electrolyte homeostasis and in cardiovascular disease. We have previously reported a ligand-dependent N/C-interaction in the MR. In the present study we sought to fully characterize the MR N/C-interaction. By using a range of natural and synthetic MR ligands in a mammalian two-hybrid assay we demonstrate that in contrast to aldosterone, which strongly induces the interaction, the physiological ligands deoxycorticosterone and cortisol weakly promote the interaction but predominantly inhibit the aldosterone-mediated N/C-interaction. Similarly, progesterone and dexamethasone antagonize the interaction. In contrast, the synthetic agonist 9α-fludrocortisol robustly induces the interaction. The ability of the N/C interaction to discriminate between MR agonists suggests a subtle conformational difference in the ligand-binding domain induced by these agonists. We also demonstrate that the N/C interaction is not cell specific, consistent with the evidence from a glutathione-S-transferase pull-down assay, of a direct protein-protein interaction between the N- and C-terminal domains of the MR. Examination of a panel of deletions in the N terminus suggests that several regions may be critical to the N/C-interaction. These studies have identified functional differences between physiological MR ligands, which suggest that the ligand-specific dependence of the N/C-interaction may contribute to the differential activation of the MR that has been reported in vivo.
Subcellular Trafficking of the TRH Receptor: Effect of Phosphorylation
Authors: Jones Brian W. , Hinkle Patricia M.
Published: June 2009

Activation of the G protein-coupled TRH receptor leads to its phosphorylation and internalization. These studies addressed the fundamental question of whether phosphorylation regulates receptor trafficking or endosomal localization regulates the phosphorylation state of the receptor. Trafficking of phosphorylated and dephosphorylated TRH receptors was characterized using phosphosite-specific antibody after labeling surface receptors with antibody to an extracellular epitope tag. Rab5 and phosphoreceptor did not colocalize at the plasma membrane immediately after TRH addition but overlapped extensively by 15 min. Dominant-negative Rab5-S34N inhibited receptor internalization. Later, phosphoreceptor was in endosomes containing Rab5 and Rab4. Dephosphorylated receptor colocalized with Rab4 but not with Rab5. Dominant-negative Rab4, -5, or -11 did not affect receptor phosphorylation or dephosphorylation, showing that phosphorylation determines localization in Rab4+/Rab5− vesicles and not vice versa. No receptor colocalized with Rab7; a small amount of phosphoreceptor colocalized with Rab11. To characterize recycling, surface receptors were tagged with antibody, or surface receptors containing an N-terminal biotin ligase acceptor sequence were labeled with biotin. Most recycling receptors did not return to the plasma membrane for more than 2 h after TRH was removed, whereas the total cell surface receptor density was largely restored in less than 1 h, indicating that recruited receptors contribute heavily to early repopulation of the plasma membrane.
The Aesthetics of Self-Management: Intelligence, Capital, andThe House of Mirth
Authors: Mullen Patrick
Published: June 2009

This essay uses the figure of Lily Bart in terms of the trope of self-management in order to consider relations among forms of gendered and embodied consciousness, formations of knowledge, and the contradictory flows of capital at the turn of the twentieth century. The author argues that the seeming weaknesses of Lily's character—her gendered embodiment and embedded position within the forces of the capitalist market—are actually, from the point of view of the novel as a whole, key strengths that allow Wharton to imagine possibilities for critical thinking from within the forces of capitalism. The essay places the novel into a broader philosophical conversation with the works of William James, Henry Adams, and Karl Marx and suggests new understandings of the body-subject (James), American imperial management (Adams), and commodity fetishism (Marx). So contextualized, we see Lily's self-managerial aesthetic as a form of social labor whose capitalized temporality is brought into focus and arrested by the form of the novel itself. By offering the self-managerial aesthetic as an object of thought, the novel opens it to the dynamics of intellectual reproduction and continued critical thinking.
The transcriptional foundation of pluripotency
Authors: Chambers Ian , Tomlinson Simon R.
Published: June 2009

A fundamental goal in biology is to understand the molecular basis of cell identity. Pluripotent embryonic stem (ES) cell identity is governed by a set of transcription factors centred on the triumvirate of Oct4, Sox2 and Nanog. These proteins often bind to closely localised genomic sites. Recent studies have identified additional transcriptional modulators that bind to chromatin near sites occupied by Oct4, Sox2 and Nanog. This suggests that the combinatorial control of gene transcription might be fundamental to the ES cell state. Here we discuss how these observations advance our understanding of the transcription factor network that controls pluripotent identity and highlight unresolved issues that arise from these studies.
The RNA-binding protein Mex3b has a fine-tuning system for mRNA regulation in earlyXenopusdevelopment
Authors: Takada Hitomi , Kawana Takahiro , Ito Yuzuru , Kikuno Reiko F. , Mamada Hiroshi , Araki Toshiyuki , Koga Hisashi , Asashima Makoto , Taira Masanori
Published: June 2009

Post-transcriptional control by RNA-binding proteins is a precise way to assure appropriate levels of gene expression. Here, we identify a novel mRNA regulatory system involving Mex3b (RKHD3) and demonstrate its role in FGF signaling. mex3b mRNA has a 3′ long conserved UTR, named 3′LCU, which contains multiple elements for both mRNA destabilization and translational enhancement. Notably, Mex3b promotes destabilization of its own mRNA by binding to the 3′LCU, thereby forming a negative autoregulatory loop. The combination of positive regulation and negative autoregulation constitutes a fine-tuning system for post-transcriptional control. In early embryogenesis, Mex3b is involved in anteroposterior patterning of the neural plate. Consistent with this, Mex3b can attenuate FGF signaling and destabilize mRNAs for the FGF signaling components Syndecan 2 and Ets1b through their 3′ UTRs. These data suggest that the 3′LCU-mediated fine-tuning system determines the appropriate level of mex3b expression, which in turn contributes to neural patterning through regulating FGF signaling.
Cux2functions downstream of Notch signaling to regulate dorsal interneuron formation in the spinal cord
Authors: Iulianella Angelo , Sharma Madhulika , Vanden Heuvel Greg B. , Trainor Paul A.
Published: June 2009

Obtaining the diversity of interneuron subtypes in their appropriate numbers requires the orchestrated integration of progenitor proliferation with the regulation of differentiation. Here we demonstrate through loss-of-function studies in mice that the Cut homeodomain transcription factor Cux2 (Cutl2) plays an important role in regulating the formation of dorsal spinal cord interneurons. Furthermore, we show that Notch regulates Cux2 expression. Although Notch signaling can be inhibitory to the expression of proneural genes, it is also required for interneuron formation during spinal cord development. Our findings suggest that Cux2 might mediate some of the effects of Notch signaling on interneuron formation. Together with the requirement for Cux2 in cell cycle progression, our work highlights the mechanistic complexity in balancing neural progenitor maintenance and differentiation during spinal cord neurogenesis.
Promotion of proliferation in the developing cerebral cortex by EphA4 forward signaling
Authors: North Hilary A. , Zhao Xiumei , Kolk Sharon M. , Clifford Meredith A. , Ziskind Daniela M. , Donoghue Maria J.
Published: June 2009

Eph receptors are widely expressed during cerebral cortical development,yet a role for Eph signaling in the generation of cells during corticogenesis has not been shown. Cortical progenitor cells selectively express one receptor, EphA4, and reducing EphA4 signaling in cultured progenitors suppressed proliferation, decreasing cell number. In vivo, EphA4-/- cortex had a reduced area, fewer cells and less cell division compared with control cortex. To understand the effects of EphA4 signaling in corticogenesis, EphA4-mediated signaling was selectively depressed or elevated in cortical progenitors in vivo. Compared with control cells, cells with reduced EphA4 signaling were rare and mitotically inactive. Conversely, overexpression of EphA4 maintained cells in their progenitor states at the expense of subsequent maturation, enlarging the progenitor pool. These results support a role for EphA4 in the autonomous promotion of cell proliferation during corticogenesis. Although most ephrins were undetectable in cortical progenitors, ephrin B1 was highly expressed. Our analyses demonstrate that EphA4 and ephrin B1 bind to each other, thereby initiating signaling. Furthermore, overexpression of ephrin B1 stimulated cell division of neighboring cells, supporting the hypothesis that ephrin B1-initiated forward signaling of EphA4 promotes cortical cell division.
Regulation of stem cell maintenance by the Polycomb protein FIE has been conserved during land plant evolution
Authors: Mosquna Assaf , Katz Aviva , Decker Eva L. , Rensing Stefan A. , Reski Ralf , Ohad Nir
Published: June 2009

The Polycomb group (PcG) complex is involved in the epigenetic control of gene expression profiles. In flowering plants, PcG proteins regulate vegetative and reproductive programs. Epigenetically inherited states established in the gametophyte generation are maintained after fertilization in the sporophyte generation, having a profound influence on seed development. The gametophyte size and phase dominance were dramatically reduced during angiosperm evolution, and have specialized in flowering plants to support the reproductive process. The moss Physcomitrella patens is an ideal organism in which to study epigenetic processes during the gametophyte stage,as it possesses a dominant photosynthetic gametophytic haploid phase and efficient homologous recombination, allowing targeted gene replacement. We show that P. patens PcG protein FIE (PpFIE) accumulates in haploid meristematic cells and in cells that undergo fate transition during dedifferentiation programs in the gametophyte. In the absence of PpFIE, meristems overproliferate and are unable to develop leafy gametophytes or reach the reproductive phase. This aberrant phenotype might result from failure of the PcG complex to repress proliferation and differentiation of three-faced apical stem cells, which are designated to become lateral shoots. The PpFIE phenotype can be partially rescued by FIE of Arabidopsis thaliana, a flowering plant that diverged >450 million years ago from bryophytes. PpFIE can partially complement the A. thaliana fie mutant, illustrating functional conservation of the protein during evolution in regulating the differentiation of meristematic cells in gametophyte development, both in bryophytes and angiosperms. This mechanism was harnessed at the onset of the evolution of alternating generations, facilitating the establishment of sporophytic developmental programs.
Cell rearrangements, cell divisions and cell death in a migrating epithelial sheet in the abdomen ofDrosophila
Authors: Bischoff Marcus , Cseresnyés Zoltán
Published: June 2009

During morphogenesis, cell movements, cell divisions and cell death work together to form complex patterns and to shape organs. These events are the outcome of decisions made by many individual cells, but how these decisions are controlled and coordinated is elusive. The adult abdominal epidermis of Drosophila is formed during metamorphosis by divisions and extensive cell migrations of the diploid histoblasts, which replace the polyploid larval cells. Using in vivo 4D microscopy, we have studied the behaviour of the histoblasts and analysed in detail how they reach their final position and to what extent they rearrange during their spreading. Tracking individual cells,we show that the cells migrate in two phases that differ in speed, direction and amount of cellular rearrangement. Cells of the anterior (A) and posterior(P) compartments differ in their behaviour. Cells near the A/P border are more likely to change their neighbours during migration. The mitoses do not show any preferential orientation. After mitosis, the sisters become preferentially aligned with the direction of movement. Thus, in the abdomen, it is the extensive cell migrations that appear to contribute most to morphogenesis. This contrasts with other developing epithelia, such as the wing imaginal disc and the embryonic germband in Drosophila, where oriented mitoses and local cell rearrangements appear to direct morphogenesis. Furthermore, our results suggest that an active force created by the histoblasts contributes to the formation of the adult epidermis. Finally, we show that histoblasts occasionally undergo apoptosis.
C. elegansRab GTPase activating protein TBC-2 promotes cell corpse degradation by regulating the small GTPase RAB-5
Authors: Li Weida , Zou Wei , Zhao Dongfeng , Yan Jiacong , Zhu Zuoyan , Lu Jing , Wang Xiaochen
Published: June 2009

During apoptosis, dying cells are quickly internalized by neighboring cells or phagocytes, and are enclosed in phagosomes that undergo a maturation process to generate the phagoslysosome, in which cell corpses are eventually degraded. It is not well understood how apoptotic cell degradation is regulated. Here we report the identification and characterization of the C. elegans tbc-2 gene, which is required for the efficient degradation of cell corpses. tbc-2 encodes a Rab GTPase activating protein (GAP) and its loss of function affects several events of phagosome maturation, including RAB-5 release, phosphatidylinositol 3-phosphate dynamics, phagosomal acidification, RAB-7 recruitment and lysosome incorporation, which leads to many persistent cell corpses at various developmental stages. Intriguingly, the persistent cell corpse phenotype of tbc-2 mutants can be suppressed by reducing gene expression of rab-5, and overexpression of a GTP-locked RAB-5 caused similar defects in phagosome maturation and cell corpse degradation. We propose that TBC-2 functions as a GAP to cycle RAB-5 from an active GTP-bound to an inactive GDP-bound state, which is required for maintaining RAB-5 dynamics on phagosomes and serves as a switch for the progression of phagosome maturation.
Evaluation of machinability in the micro end milling of printed circuit boards
Authors: Park J-B , Wie K-H , Park J-S , Ahn S-H
Published: June 2009

Printed circuit boards (PCBs) have slots and holes that aid in the assembly of electronic devices. To produce these shapes, advances in manufacturing methods have been made in processes including machining, laser, plasma, and punching. In this study, to evaluate the capability of a micro end mill in the machining of PCBs, cutting forces were measured using a dynamometer under various cutting speed and feed per tooth conditions. Copper-clad laminate (CCL), which is a PCB raw material, was selected as the workpiece to evaluate the machining capabilities of the PCB end mill. The cross-section of a machined slot in a workpiece was observed under a microscope, and the burr height of the cross-section was measured. Finally, the relationship between cutting force and burr height was determined. The cutting force increased with increasing feed per tooth, and the burr height decreased with increasing feed per tooth; thus, it was inversely proportional to the cutting force.
Design optimization of cutting conditions and analysis of their effect on tool wear and surface roughness during hard turning of AISI-H11 steel with a coated—mixed ceramic tool
Authors: Dureja J S , Gupta V K , Sharma V S , Dogra M
Published: June 2009

The present study is an attempt to model the tool wear and surface roughness, through response surface methodology (RSM) during hard turning of AISI-H11 steel with TiN-coated—mixed ceramic inserts. The effect of machining parameters — i.e. cutting speed, feed rate, depth of cut, and workpiece hardness — on the response factors, viz. flank wear and surface roughness, have been investigated by applying analysis of variance (ANOVA) and through factor interaction graphs in the RSM. The non-linear quadratic models best fit the experimental data points. The desirability function approach has been used for multiple response factors optimization. The confirmation experiments carried out to check the validity of developed models predicted response factors within 5 per cent error. The feed rate, depth of cut, and workpiece hardness are observed to have a statistically significant impact on the flank wear, whereas feed rate and workpiece hardness are the significant factors affecting the surface roughness. The tool wear was monitored with a toolmaker's microscope, and wear characterization of some of the representative inserts was carried out using scanning electron microscope/energy dispersive X-ray (SEM-EDX) analysis. The tool appears to be worn out by abrasion, notch wear, and chipping of the tool surface owing to rubbing and impingement of hard particles in the work material and also by adhesion wear.
Delay-dependent guaranteed cost control for a non-linear stochastic system with distributed delays
Authors: Qiu J , He H , Shi P
Published: June 2009

In this paper, the problem of guaranteed cost control for stochastic systems is considered. The system is non-linear, and the delays are distributed. Based on Lyapunov stability theory combined with the linear matrix inequality (LMI) technique, delay-dependent stability and stabilization conditions are proposed. Furthermore, sufficient conditions for the existence of guaranteed cost controllers are derived. Finally, a numerical example is used to illustrate the effectiveness and feasibility of the approaches proposed in this paper.
Infrared absorption technique for measuring local fuel concentration near the spark plug of a port injection gasoline engine
Authors: Kakuho A , Hashizume Y , Urushihara T , Itoh T , Mansion T
Published: June 2009

The mixture concentration in the vicinity of the spark plug at the time of spark ignition is a critical parameter for the performance of SI engines. Infrared absorption is often used to measure this parameter in firing cycles. Although it is well known that the mixture concentration near the spark plug is a primary factor explaining combustion stability in direct injection engines, the effect of the local mixture concentration has not been confirmed for nearly homogeneous mixtures. In this research, the mixture concentration in the vicinity of the spark plug was measured quantitatively using infrared absorption with an optical fibre sensor built into the spark plug of a port injection engine. Measurements were made across a range of air—fuel ratios for both steady state conditions at three different overall air—fuel ratios and for a rich-to-lean transient condition. It was experimentally confirmed that the mixture concentration near the spark plug has little impact on combustion stability for steady state operation with a homogeneous mixture distribution. It has also been confirmed that fibre-sensor-based infrared absorption can be used for cycle-by-cycle analysis of the local mixture concentration even for a homogeneous mixture distribution.
Maintenance optimization for a system with a gamma deterioration process and intervention delay: Application to track maintenance
Authors: Meier-Hirmer C , Riboulet G , Sourget F , Roussignol M
Published: June 2009

This paper presents a maintenance strategy model of a system with a gamma deterioration process, regular inspection times, and intervention delay. Interventions are deemed necessary when the deterioration process is greater than an intervention level at inspection time. The objective is to determine the long-term mean costs of different maintenance strategies and to optimize these costs with respect to specific parameters, such as the intervention level or the inspection interval. Semi-regeneration properties at the inspection times and associated Markov renewal techniques are used in order to compute the long-term mean costs. This model is applied to the maintenance of railway tracks.
Reliability analysis of primary battery packs based on the universal generating function method
Authors: Li C-Y , Chen X , Yi X-S
Published: June 2009

The different performances of batteries can affect the reliability of primary battery packs, but the traditional reliability method does not consider this effect properly. In this paper, the universal generating function method is proposed and extended to analyse the reliability of primary battery packs, and a numerical example is illustrated. The results show that the reliability of primary battery packs estimated by the traditional reliability method is conservative, and the universal generating function method is very effective for analysing the reliability of primary battery packs.
Identification of the HIT-45 protein from Trypanosoma brucei as an FHIT protein/dinucleoside triphosphatase: Substrate specificity studies on the recombinant and endogenous proteins
Authors: Banerjee Hiren , Palenchar Jennifer B. , Lukaszewicz Maciej , Bojarska Elzbieta , Stepinski Janusz , Jemielity Jacek , Guranowski Andrzej , Ng Stephanie , Wah David A. , Darzynkiewicz Edward , Bellofatto Vivian
Published: June 2009

A new member of the FHIT protein family, designated HIT-45, has been identified in the African trypanosome Trypanosoma brucei. Recombinant HIT-45 proteins were purified from trypanosomal and bacterial protein expression systems and analyzed for substrate specificity using various dinucleoside polyphosphates, including those that contain the 5′-mRNA cap, i.e., m7GMP. This enzyme exhibited typical dinucleoside triphosphatase activity (EC 3.6.1.29), having its highest specificity for diadenosine triphosphate (ApppA). However, the trypanosome enzyme contains a unique amino-terminal extension, and hydrolysis of cap dinucleotides with monomethylated guanosine or dimethylated guanosine always yielded m7GMP (or m2,7GMP) as one of the reaction products. Interestingly, m7Gpppm3N6, N6, 2′OA was preferred among the methylated substrates. This hypermethylated dinucleotide is unique to trypanosomes and may be an intermediate in the decay of cap 4, i.e., m7Gpppm3N6, N6, 2′OApm2′OApm2′OCpm2N3, 2′OU, that occurs in these organisms.
IGF2BP1 enhances HCV IRES-mediated translation initiation via the 3′UTR
Authors: Weinlich Susan , Hüttelmaier Stefan , Schierhorn Angelika , Behrens Sven-Erik , Ostareck-Lederer Antje , Ostareck Dirk H.
Published: June 2009

The positive-strand RNA genome of the Hepatitis C virus (HCV) contains an internal ribosome entry site (IRES) in the 5′untranslated region (5′UTR) and structured sequence elements within the 3′UTR, but no poly(A) tail. Employing a limited set of initiation factors, the HCV IRES coordinates the 5′cap-independent assembly of the 43S pre-initiation complex at an internal initiation codon located in the IRES sequence. We have established a Huh7 cell-derived in vitro translation system that shows a 3′UTR-dependent enhancement of 43S pre-initiation complex formation at the HCV IRES. Through the use of tobramycin (Tob)-aptamer affinity chromatography, we identified the Insulin-like growth factor-II mRNA-binding protein 1 (IGF2BP1) as a factor that interacts with both, the HCV 5′UTR and 3′UTR. We report that IGF2BP1 specifically enhances translation at the HCV IRES, but it does not affect 5′cap-dependent translation. RNA interference against IGF2BP1 in HCV replicon RNA-containing Huh7 cells reduces HCV IRES-mediated translation, whereas replication remains unaffected. Interestingly, we found that endogenous IGF2BP1 specifically co-immunoprecipitates with HCV replicon RNA, the ribosomal 40S subunit, and eIF3. Furthermore eIF3 comigrates with IGF2BP1 in 80S ribosomal complexes when a reporter mRNA bearing both the HCV 5′UTR and HCV 3′UTR is translated. Our data suggest that IGF2BP1, by binding to the HCV 5′UTR and/or HCV 3′UTR, recruits eIF3 and enhances HCV IRES-mediated translation.
Responding to Unexpected Overloads in Large-Scale Service Systems
Authors: Perry Ohad , Whitt Ward
Published: June 2009

We consider how two networked large-scale service systems that normally operate separately, such as call centers, can help each other when one encounters an unexpected overload and is unable to immediately increase its own staffing. Our proposed control activates serving some customers from the other system when a ratio of the two queue lengths (numbers of waiting customers) exceeds a threshold. Two thresholds, one for each direction of sharing, automatically detect the overload condition and prevent undesired sharing under normal loads. After a threshold has been exceeded, the control aims to keep the ratio of the two queue lengths at a specified value. To gain insight, we introduce an idealized stochastic model with two customer classes and two associated service pools containing large numbers of agents. To set the important queue-ratio parameters, we consider an approximating deterministic fluid model. We determine queue-ratio parameters that minimize convex costs for this fluid model. We perform simulation experiments to show that the control is effective for the original stochastic model. Indeed, the simulations show that the proposed queue-ratio control with thresholds outperforms the optimal fixed partition of the servers given known fixed arrival rates during the overload, even though the proposed control does not use information about the arrival rates.
Optimal Markdown Pricing: Implications of Inventory Display Formats in the Presence of Strategic Customers
Authors: Yin Rui , Aviv Yossi , Pazgal Amit , Tang Christopher S.
Published: June 2009

We propose a game-theoretical model of a retailer who sells a limited inventory of a product over a finite selling season by using one of two inventory display formats: display all (DA) and display one (DO). Under DA, the retailer displays all available units so that each arriving customer has perfect information about the actual inventory level. Under DO, the retailer displays only one unit at a time so that each customer knows about product availability but not the actual inventory level. Recent research suggests that when faced with strategic consumers, the retailer could increase expected profits by making an upfront commitment to a price path. We focus on such pricing strategies in this paper, and study the potential benefit of DO compared to DA, and its effectiveness in mitigating the adverse impact of strategic consumer behavior. We find support for our hypothesis that the DO format could potentially create an increased sense of shortage risk, and hence it is better than the DA format. However, although potentially beneficial, a move from DA to DO is typically very far from eliminating the adverse impact of strategic consumer behavior. We observe that, generally, it is not important for a retailer to modify the level of inventory when moving from a DA to a DO format; a change in the display format, along with an appropriate price modification, is typically sufficient. Interestingly, across all scenarios in which a change in inventory is significantly beneficial, we observed that only one of the following two actions takes place: either the premium price is increased along with a reduction in inventory, or inventory is increased along with premium price reduction. We find that the marginal benefit of DO can vary dramatically as a function of the per-unit cost to the retailer. In particular, when the retailer's per-unit cost is relatively high, but not too high to make sales unprofitable or to justify exclusive sales to high-valuation customers only, the benefits of DO appear to be at their highest level, and could reach up to 20% increase in profit. Finally, we demonstrate that by moving from DA to DO, while keeping the price path unchanged, the volatility of the retailer's profit decreases.
Experimentation in Financial Markets
Authors: Massa Massimo , Simonov Andrei
Published: June 2009

In this paper, we use a unique data set on the Italian interdealer bond market to empirically estimate the process of strategic experimentation. The results show how the information generated in the process of interdealer trading affects the incentive to experiment. Upon receipt of an order, dealers deliberately engage in trade with other dealers either to exploit the information contained in the order they receive or, if they are uncertain about its quality, to assess it by actively experimenting with other dealers. We therefore identify “hiding” and “experimenting” as main types of dealer strategies.
Product Differentiation, Store Differentiation, and Assortment Depth
Authors: Hamilton Stephen F. , Richards Timothy J.
Published: June 2009

This paper considers the relationship between product differentiation, store differentiation, and the equilibrium depth of the product assortment. We find an inverted U-shaped relationship between product differentiation and assortment depth, with the depth of the assortment rising at first and then falling with the degree of product differentiation. For product categories that consist of relatively nondifferentiatied variants, a positive relationship arises between assortment depth and category sales, whereas a negative relationship emerges between assortment depth and sales in categories with more differentiated variants. Both the extent and manner in which store differentiation changes has important implications for assortment depth. If retailer market power is augmented following the closure of rival retailers, product assortments become deeper; however, if retailers gain market power by investing in store attributes that facilitate customer loyalty, product assortments become shallower.