bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of Mce4A protein of Mycobacterium tuberculosis: role in invasion and survival
Authors: Saini Neeraj Kumar , Sharma Monika , Chandolia Amita , Pasricha Rashmi , Brahmachari Vani , Bose Mridula
Published: November 2008

Background

The mce4 operon is one of the four homologues of mammalian cell entry (mce) operons of Mycobacterium tuberculosis. The mce4A (Rv3499c) gene within this operon is homologous to mce1A (Rv0169), that has a role in host cell invasion by M. tuberculosis. Our earlier reports show that mce4 operon is expressed during the stationary phase of growth of the bacillus in culture and during the course of infection in mammalian hosts. M. tuberculosis carrying mutation in mce4 operon shows growth defect and reduced survival in infected mice. However, the intracellular localization of Mce4A protein and its direct role in cell entry or survival of the bacillus has not been demonstrated so far.

Results

By transmission electron microscopy we have demonstrated that recombinant Mce4A protein facilitates the invasion of non-pathogenic strain of E. coli into non-phagocytic HeLa cells. We observe that mce4A gene has a role comparable to mce1A in the survival of recombinant E. coli in human macrophages. Using antibodies raised against Mce4A protein, we show that the protein is localized in the cell wall fraction of M. tuberculosis H37Rv stationary phase culture only.

Conclusion

Mce4A protein is expressed during the stationary phase of broth culture and localizes in the cell wall fraction of M. tuberculosis. Mce4A protein expressed in non-pathogenic E. coli enables it to enter and survive within HeLa cells and the macrophages. As Mce4A protein is expressed during later phase of mycobacterial growth, our results raise the possibility of it playing a role in maintenance of persistent tubercular infection.
Expression of the pstS gene of Streptomyces lividansis regulated by the carbon source and is partially independent of the PhoP regulator
Authors: Esteban Ana , Díaz Margarita , Yepes Ana , Santamaría Ramón I
Published: November 2008

Background

PstS is a phosphate-binding lipoprotein that is part of the high-affinity phosphate transport system. Streptomyces lividans accumulates high amounts of the PstS protein in the supernatant of liquid cultures grown in the presence of different carbon sources, such as fructose or mannose, but not in the presence of glucose or in basal complex medium.

Results

Functionality experiments revealed that this extracellular PstS protein does not have the capacity to capture phosphate and transfer it to the cell. Regulation of the pstS promoter was studied with Northern blot experiments, and protein levels were detected by Western blot analysis. We observed that the pstS gene was expressed in cultures containing glucose or fructose, but not in complex basal medium. Northern blot analyses revealed that the pst operon (pstSCAB) was transcribed as a whole, although higher transcript levels of pstS relative to those of the other genes of the operon (pstC, pstA and pstB) were observed. Deletion of the -329/-144 fragment of the pstS promoter, including eight degenerated repeats of a sequence of 12 nucleotides, resulted in a two-fold increase in the expression of this promoter, suggesting a regulatory role for this region. Additionally, deletion of the fragment corresponding to the Pho boxes recognized by the PhoP regulator (from nucleotide -141 to -113) resulted in constitutive pstS expression that was independent of this regulator. Thus, the PhoP-independent expression of the pstS gene makes this system different from all those studied previously.

Conclusion

1.- In S. lividans, only the PstS protein bound to the cell has the capacity to bind phosphate and transfer it there, whereas the PstS form accumulated in the supernatant lacks this capacity. 2.- The stretch of eight degenerated repeats present in the pstS promoter may act as a binding site for a repressor. 3.- There is a basal expression of the pstS gene that is not controlled by the main regulator: PhoP.
Preparation of alginate coated chitosan microparticles for vaccine delivery
Authors: Li XingYi , Kong XiangYe , Shi Shuai , Zheng XiuLing , Guo Gang , Wei YuQuan , Qian ZhiYong
Published: November 2008

Background

Absorption of antigens onto chitosan microparticles via electrostatic interaction is a common and relatively mild process suitable for mucosal vaccine. In order to increase the stability of antigens and prevent an immediate desorption of antigens from chitosan carriers in gastrointestinal tract, coating onto BSA loaded chitosan microparticles with sodium alginate was performed by layer-by-layer technology to meet the requirement of mucosal vaccine.

Results

The prepared alginate coated BSA loaded chitosan microparticles had loading efficiency (LE) of 60% and loading capacity (LC) of 6% with mean diameter of about 1 μm. When the weight ratio of alginate/chitosan microparticles was greater than 2, the stable system could be obtained. The rapid charge inversion of BSA loaded chitosan microparticles (from +27 mv to -27.8 mv) was observed during the coating procedure which indicated the presence of alginate layer on the chitosan microparticles surfaces. According to the results obtained by scanning electron microscopy (SEM), the core-shell structure of BSA loaded chitosan microparticles was observed. Meanwhile,in vitrorelease study indicated that the initial burst release of BSA from alginate coated chitosan microparticles was lower than that observed from uncoated chitosan microparticles (40% in 8 h vs. about 84% in 0.5 h). SDS-polyacrylamide gel electrophoresis (SDS-PAGE) assay showed that alginate coating onto chitosan microparticles could effectively protect the BSA from degradation or hydrolysis in acidic condition for at least 2 h. The structural integrity of alginate modified chitosan microparticles incubated in PBS for 24 h was investigated by FTIR.

Conclusion

The prepared alginate coated chitosan microparticles, with mean diameter of about 1 μm, was suitable for oral mucosal vaccine. Moreover, alginate coating onto the surface of chitosan microparticles could modulate the release behavior of BSA from alginate coated chitosan microparticles and could effectively protect model protein (BSA) from degradation in acidic mediumin vitrofor at least 2 h. In all, the prepared alginate coated chitosan microparticles might be an effective vehicle for oral administration of antigens.
Ligand-induced conformational changes in a thermophilic ribose-binding protein
Authors: Cuneo Matthew J , Beese Lorena S , Hellinga Homme W
Published: November 2008

Background

Members of the periplasmic binding protein (PBP) superfamily are involved in transport and signaling processes in both prokaryotes and eukaryotes. Biological responses are typically mediated by ligand-induced conformational changes in which the binding event is coupled to a hinge-bending motion that brings together two domains in a closed form. In all PBP-mediated biological processes, downstream partners recognize the closed form of the protein. This motion has also been exploited in protein engineering experiments to construct biosensors that transduce ligand binding to a variety of physical signals. Understanding the mechanistic details of PBP conformational changes, both global (hinge bending, twisting, shear movements) and local (rotamer changes, backbone motion), therefore is not only important for understanding their biological function but also for protein engineering experiments.

Results

Here we present biochemical characterization and crystal structure determination of the periplasmic ribose-binding protein (RBP) from the hyperthermophile Thermotoga maritima in its ribose-bound and unliganded state. The T. maritima RBP (tmRBP) has 39% sequence identity and is considerably more resistant to thermal denaturation (
app

T

m
value is 108°C) than the mesophilic Escherichia coli homolog (ecRBP) (
app

T

m
value is 56°C). Polar ligand interactions and ligand-induced global conformational changes are conserved among ecRBP and tmRBP; however local structural rearrangements involving side-chain motions in the ligand-binding site are not conserved.

Conclusion

Although the large-scale ligand-induced changes are mediated through similar regions, and are produced by similar backbone movements in tmRBP and ecRBP, the small-scale ligand-induced structural rearrangements differentiate the mesophile and thermophile. This suggests there are mechanistic differences in the manner by which these two proteins bind their ligands and are an example of how two structurally similar proteins utilize different mechanisms to form a ligand-bound state.
Alterations on peripheral B cell subsets following an acute uncomplicated clinical malaria infection in children
Authors: Asito Amolo S , Moormann Ann M , Kiprotich Chelimo , Ng'ang'a Zipporah W , Ploutz-Snyder Robert , Rochford Rosemary
Published: November 2008

Background

The effects ofPlasmodium falciparumon B-cell homeostasis have not been well characterized. This study investigated whether an episode of acute malaria in young children results in changes in the peripheral B cell phenotype.

Methods

Using flow-cytofluorimetric analysis, the B cell phenotypes found in the peripheral blood of children aged 2–5 years were characterized during an episode of acute uncomplicated clinical malaria and four weeks post-recovery and in healthy age-matched controls.

Results

There was a significant decrease in CD19+B lymphocytes during acute malaria. Characterization of the CD19+B cell subsets in the peripheral blood based on expression of IgD and CD38 revealed a significant decrease in the numbers of naive 1 CD38-IgD+B cells while there was an increase in CD38+IgD-memory 3 B cells during acute malaria. Further analysis of the peripheral B cell phenotype also identified an expansion of transitional CD10+CD19+B cells in children following an episode of acute malaria with up to 25% of total CD19+B cell pool residing in this subset.

Conclusion

Children experiencing an episode of acute uncomplicated clinical malaria experienced profound disturbances in B cell homeostasis.
Vitamin E supplementation and pneumonia risk in males who initiated smoking at an early age: effect modification by body weight and dietary vitamin C
Authors: Hemilä Harri , Kaprio Jaakko
Published: November 2008

Background

We had found a 14% higher incidence of pneumonia with vitamin E supplementation in a subgroup of the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study cohort: participants who had initiated smoking by the age of 20 years. In this study, we explored the modification of vitamin E effect by body weight, because the same dose could lead to a greater effect in participants with low body weight.

Methods

The ATBC Study recruited males aged 50–69 years who smoked at least 5 cigarettes per day at the baseline; it was conducted in southwestern Finland in 1985–1993. The current study was restricted to 21,657 ATBC Study participants who initiated smoking by the age of 20 years; the median follow-up time was 6.0 years. The hospital-diagnosed pneumonia cases were retrieved from the national hospital discharge register (701 cases).

Results

Vitamin E supplementation had no effect on the risk of pneumonia in participants with body weight in a range from 70 to 89 kg (n = 12,495), risk ratio (RR) = 0.99 (95% CI: 0.81 to 1.22). Vitamin E increased the risk of pneumonia in participants with body weight less than 60 kg (n = 1054), RR = 1.61 (1.03 to 2.53), and in participants with body weight over 100 kg (n = 1328), RR = 2.34 (1.07 to 5.08). The harm of vitamin E supplementation was restricted to participants with dietary vitamin C intake above the median.

Conclusion

Vitamin E supplementation may cause harmful effects on health in certain groups of male smokers. The dose of vitamin E used in the ATBC Study, 50 mg/day, is substantially smaller than conventional vitamin E doses that are considered safe. Our findings should increase caution towards taking vitamin E supplements.

Trial registration

ClinicalTrials.gov NCT00342992.
Circulating IGF-binding protein 7 (IGFBP7) levels are elevated in patients with endometriosis or undergoing diabetic hemodialysis
Authors: Kutsukake Masahiko , Ishihara Ryosuke , Momose Katsutoshi , Isaka Keiichi , Itokazu Osamu , Higuma Chinatsu , Matsutani Takeshi , Matsuda Akihisa , Sasajima Koji , Hara Takahiko , Tamura Kazuhiro
Published: November 2008

Background

Insulin-like growth factor-binding protein-7 (IGFBP7) is a secretory protein with a molecular mass of approximately 30 kDa. It is abundantly expressed in the uterine endometrium during the secretory phase of the menstrual cycle. Decreased IGFBP7 expression has been observed in some cancers and leiomyomata.

Methods

To determine whether serum IGFBP7 levels reflect changes in uterine IGFBP7 expression in humans during the menstrual cycle, and to examine whether serum IGFBP7 levels are altered in patients with various disorders, we developed a novel, dual-antibody sandwich enzyme-linked immunosorbent assay (ELISA). Firstly, concentrations of IGFBP7 released into the medium were determined in cultured endometrial stromal and glandular cells. Blood samples were collected from women who had normal menstrual cycles and who had been diagnosed with endometriosis. Serum from hemodialysis patients and gastrointestinal cancers was also used to determine the IGFBP7 levels.

Results

Using this new ELISA, we demonstrated that cultured uterine cells secrete IGFBP7 into the medium. Patients with endometriosis and those with type II diabetes mellitus undergoing hemodialysis had significantly higher serum concentrations of IGFBP7 than the relevant control subjects. There were no differences in serum IGFBP7 levels in women at different stages of the menstrual cycle. Furthermore, serum IGFBP7 levels in patients with colorectal, esophageal, or endometrial cancer were not different than normal healthy subjects.

Conclusion

Our observations suggest that IGFBP7 is associated with the pathophysiology of endometriosis and diabetes mellitus, and that serum IGFBP7 levels do not reflect enhanced uterine expression of IGFBP7 mRNA during the menstrual cycle.
Impaired urge-to-cough in elderly patients with aspiration pneumonia
Authors: Yamanda Shinsuke , Ebihara Satoru , Ebihara Takae , Yamasaki Miyako , Asamura Takaaki , Asada Masanori , Une Kaori , Arai Hiroyuki
Published: November 2008

Background

The down-regulation of the cough reflex in patients with aspiration pneumonia can involve both cortical facilitatory pathways for cough and medullary reflex pathways. In order to study the possible involvement of the supramedullary system in the down-regulation of cough reflex, we evaluated the urge-to-cough in patients with aspiration pneumonia.

Methods

Cough reflex sensitivity and the urge-to-cough to inhaled citric acid were evaluated in patients with at least a history of aspiration pneumonia and age-matched healthy elderly people. The cough reflex sensitivities were defined as the lowest concentration of citric acid that elicited two or more coughs (C2) and five or more coughs (C5). The urge-to-cough scores at the concentration of C2 and C5, and at the concentration of two times dilution of C2 (C2/2) and C5 (C5/2) were estimated for each subject.

Results

Both C2 and C5 in the control subjects were significantly greater than those for patients with aspiration pneumonia. There were no significant differences in the urge-to-cough at C2 and C5 between control subjects and patients with aspiration pneumonia. However, the urge-to-cough scores at both C2/2 and C5/2 in patients with aspiration pneumonia were significantly lower than those in control subjects. The number of coughs at C5/2 was significantly greater in the control subjects than those in the patients with aspiration pneumonia whereas the number of coughs at C2/2 did not show a significant difference between the control subjects and the patients with aspiration pneumonia.

Conclusion

The study suggests the involvement of supramedullary dysfunction in the etiology of aspiration pneumonia in the elderly. Therefore, restoration of the cough motivation system could be a new strategy to prevent aspiration pneumonia in the elderly.
Development of a fluorescence-based method for monitoring glucose catabolism and its potential use in a biomass hydrolysis assay
Authors: Haney Lisa J , Coors James G , Lorenz Aaron J , Raman DRaj , Anex Robert P , Scott MPaul
Published: November 2008

Background

The availability and low cost of lignocellulosic biomass has caused tremendous interest in the bioconversion of this feedstock into liquid fuels. One measure of the economic viability of the bioconversion process is the ease with which a particular feedstock is hydrolyzed and fermented. Because monitoring the analytes in hydrolysis and fermentation experiments is time consuming, the objective of this study was to develop a rapid fluorescence-based method to monitor sugar production during biomass hydrolysis, and to demonstrate its application in monitoring corn stover hydrolysis.

Results

Hydrolytic enzymes were used in conjunction with Escherichia coli strain CA8404 (a hexose and pentose-consuming strain), modified to produce green fluorescent protein (GFP). The combination of hydrolytic enzymes and a sugar-consuming organism minimizes feedback inhibition of the hydrolytic enzymes. We observed that culture growth rate as measured by change in culture turbidity is proportional to GFP fluorescence and total growth and growth rate depends upon how much sugar is present at inoculation. Furthermore, it was possible to monitor the course of enzymatic hydrolysis in near real-time, though there are instrumentation challenges in doing this.

Conclusion

We found that instantaneous fluorescence is proportional to the bacterial growth rate. As growth rate is limited by the availability of sugar, the integral of fluorescence is proportional to the amount of sugar consumed by the microbe. We demonstrate that corn stover varieties can be differentiated based on sugar yields in enzymatic hydrolysis reactions using post-hydrolysis fluorescence measurements. Also, it may be possible to monitor fluorescence in real-time during hydrolysis to compare different hydrolysis protocols.
Salpingitis. A rare cause of acute abdomen in a sexually inactive girl: a case report
Authors: van der Putten Mayke E , Engel Monique , van Well Gijs THJ
Published: November 2008

Salpingitis is an acute inflammation of the fallopian tubes, most commonly caused by sexually transmitted micro-organisms in adolescent and adult women. It is rarely found in sexually inactive girls and generally the result of a blood-borne or genitourinary infection. In young girls without a history of consensual sexual contact, the possibility of sexual abuse should be considered.

Salpingitis usually presents as an acute abdomen. Appendicitis presents with almost the same symptoms as salpingitis. The diagnosis of salpingitis is often delayed until the presumed appendicitis is surgically explored.

We describe an 11-year-old girl with salpingitis caused by Streptococcus pneumoniae.
Malignant subdural effusion associated with disseminated adenocarcinoma: a case report
Authors: Mirsadeghi Seyed Mohammad Haji , Habibi Zohreh , Meybodi Keyvan Tayebi , Nejat Farideh , Tabatabai Seyed Ali Fakhr
Published: November 2008

Background

Subdural effusion in the setting of dural metastasis is very rare and may be difficult to be distinguished from chronic subdural hematoma.

Case presentation

A 44-year old woman with gastric adenocarcinoma was presented with headache and a hypodense subdural collection in right fronto-parietal in brain CT. Burr-hole irrigation was performed with the impression of chronic subdural hematoma, but nonhemorrhagic xantochromic fluid was evacuated without malignant cell. Brain CT on the 11th day depicted fluid re-accumulation and noticeable midline shift, necessitating craniotomy and removing the affected dura.

Conclusion

Because the affected dura can be supposed as the main source of subdural effusion, resection of the involved dura is obligatory for the appropriate palliative management of such patients.
1513A>C Polymorphism in the P2X7 Receptor Gene in Patients with Papillary Thyroid Cancer: Correlation with Histological Variants and Clinical Parameters
Authors: Dardano Angela , Falzoni Simonetta , Caraccio Nadia , Polini Antonio , Tognini Sara , Solini Anna , Berti Piero , Virgilio Francesco Di , Monzani Fabio
Published: November 2008

Introduction: The modulation of the purinergic receptor P2X7 may be implicated in human carcinogenesis. The 1513A>C and 489C>T polymorphisms of P2X7R gene induce loss of function and gain of function, respectively.

Aim: The aim of the study was to assess the frequency of both 1513A>C and 489C>T polymorphisms in patients with papillary thyroid carcinoma (PTC) and to evaluate the possible association with clinical and histological features.

Patients and Methods: P2X7R analysis was performed in lymphocytes from 121 PTC patients (100 women, 21 men; aged 43.4 ± 13.6 yr), 100 matched healthy subjects, and 80 patients with nodular goiter.

Results: The minor allele frequency for 1513A>C polymorphism in PTC patients with the classical variant was similar to controls (0.21 and 0.20, respectively), whereas it resulted in a significant increase in patients with the follicular variant (0.36; P = 0.01 vs. classical variant, and P = 0.005 vs. controls). In detail, 13.6% of patients with PTC follicular variant were homozygous for the 1513C allele, compared to 2.6% of patients with the classical variant and 2% of controls. Moreover, a positive relationship between 1513A>C polymorphism and either cancer diameter (Rho = 0.22; P = 0.02) or TNM stage (Rho = 0.38; P < 0.001) was found. No significant difference in the genotype frequency of 489C>T polymorphism between PTC patients and healthy controls was observed (0.42 and 0.47, respectively).

Conclusions: Our data show, for the first time, a strong association between 1513A>C polymorphism of P2X7R gene and the follicular variant of PTC. Further studies are needed to confirm the possible role of this polymorphism as a novel clinical marker of PTC follicular variant and its usefulness in selecting patients with different clinical outcome.
Accuracy of Combined Protein Gene Product 9.5 and Parafibromin Markers for Immunohistochemical Diagnosis of Parathyroid Carcinoma
Authors: Howell Viive M. , Gill Anthony , Clarkson Adele , Nelson Anne E. , Dunne Robert , Delbridge Leigh W. , Robinson Bruce G. , Teh Bin T. , Gimm Oliver , Marsh Deborah J.
Published: November 2008

Context: Parafibromin, encoded by HRPT2, is the first marker with significant benefit in the diagnosis of parathyroid carcinoma. However, because parafibromin is only involved in up to 70% of parathyroid carcinomas and loss of parafibromin immunoreactivity may not be observed in all cases of HRPT2 mutation, a complementary marker is needed.

Objective: We sought to determine the efficacy of increased expression of protein gene product 9.5 (PGP9.5), encoded by ubiquitin carboxyl-terminal esterase L1 (UCHL1) as an additional marker to loss of parafibromin immunoreactivity for the diagnosis of parathyroid carcinoma.

Design: In total, 146 parathyroid tumors and nine normal tissues were analyzed for the expression of parafibromin and PGP9.5 by immunohistochemistry and for UCHL1 by quantitative RT-PCR. These samples included six hyperparathyroidism-jaw tumor syndrome-related tumors and 24 sporadic carcinomas.

Results: In tumors with evidence of malignancy, strong staining for PGP9.5 had a sensitivity of 78% for the detection of parathyroid carcinoma and/or HRPT2 mutation and a specificity of 100%. Complete lack of nuclear parafibromin staining had a sensitivity of 67% and a specificity of 100%. PGP9.5 was positive in a tumor with the HRPT2 mutation L64P that expressed parafibromin. Furthermore, UCHL1 was highly expressed in the carcinoma/hyperparathyroidism-jaw tumor syndrome group compared to normal (P < 0.05) and benign specimens (P < 0.001).

Conclusion: These results suggest that positive staining for PGP9.5 has utility as a marker for parathyroid malignancy, with a slightly superior sensitivity (P = 0.03) and similar high specificity to that of parafibromin.
Variabilism
Authors: Cumming Samuel
Published: November 2008

Variabilism is the view that proper names (like pronouns) are semantically represented as variables. Referential names, like referential pronouns, are assigned their referents by a contextual variable assignment (Kaplan 1989). The reference parameter (like the world of evaluation) may also be shifted by operators in the representation language. Indeed verbs that create hyperintensional contexts, like `think', are treated as operators that simultaneously shift the world and assignment parameters. By contrast, metaphysical modal operators shift the world of assessment only. Names, being variables, refer rigidly in the latter merely intensional contexts, but may vary their reference in hyperintensional contexts. This conforms to the intuition that the content of attitude ascriptions encapsulates referential uncertainty. Furthermore, names in hyperintensional contexts are ambiguous between de re* and de dicto* interpretations. This fact is used to account for asymmetric mistaken identity attributions (for example, Biron thinks Katherine is Rosaline, but he doesn't think Rosaline is Katherine).

The variable theory compares favorably with its alternatives, including Millianism and descriptivism. Millians cannot account for the behavior of names in hyperintensional contexts, while descriptivists cannot generate a necessary contrast between intensional and hyperintensional contexts. No other theory can capture the facts pertaining to the existentially bound use of names.
The Relevance of Self-Locating Beliefs
Authors: Titelbaum Michael G.
Published: November 2008

Can self-locating beliefs be relevant to non-self-locating claims? Traditional Bayesian modeling techniques have trouble answering this question because their updating rule fails when applied to situations involving contextsensitivity. This essay develops a fully general framework for modeling stories involving context-sensitive claims. The key innovations are a revised conditionalization rule and a principle relating models of the same story with different modeling languages. The essay then applies the modeling framework to the Sleeping Beauty Problem, showing that when Beauty awakens her degree of belief in heads should be one-third. This demonstrates that it can be rational for an agent who gains only self-locating beliefs between two times to alter her degree of belief in a non-self-locating claim.
ATR and Rad17 collaborate in modulating Rad9 localisation at sites of DNA damage
Authors: Medhurst Annette L. , Warmerdam Daniël O. , Akerman Ildem , Verwayen Edward H. , Kanaar Roland , Smits Veronique A. J. , Lakin Nicholas D.
Published: November 2008

The cell cycle checkpoint kinase Chk1 is phosphorylated and activated by ATR in response to DNA damage and is crucial for initiating the DNA damage response. A number of factors act in concert with ATR to facilitate Chk1 phosphorylation, including Rad17-RFC, the Rad9-Rad1-Hus1 complex, TopBP1 and Claspin. Rad17 is required for loading of Rad9-Rad1-Hus1 (9-1-1) onto sites of DNA damage. Although phosphorylation of Rad17 by ATR is required for checkpoint function, how this affects 9-1-1 regulation remains unclear. We report that exposure of cells to DNA damage or replication stress results in Rad17-dependent immobilisation of Rad9 into nuclear foci. Furthermore, expression of mutant Rad17 that cannot be phosphorylated by ATR (Rad17AA), or downregulation of ATR, results in a decreased number of cells that display Rad9 foci. Photobleaching experiments reveal an increase in the dynamic behaviour of Rad9 within remaining foci in the absence of ATR or following expression of Rad17AA. Together, these data suggest a model in which Rad17 and ATR collaborate in regulating Rad9 localisation and association at sites of DNA damage.
Volume and Price Patterns Around a Stock's 52-Week Highs and Lows: Theory and Evidence
Authors: Huddart Steven , Lang Mark , Yetman Michelle H.
Published: November 2008

We provide large sample evidence that past price extremes influence investors' trading decisions. Volume is strikingly higher, in both economic and statistical terms, when the stock price crosses either the upper or lower limit of its past trading range. This increase in volume is more pronounced the longer the time since the stock price last achieved the price extreme, the smaller the firm, the higher the individual investor interest in the stock, and the greater the ambiguity regarding valuation. These results are robust across model specifications and controls for past returns and news arrival. Volume spikes when price crosses either the upper or lower limit of the past trading range, then gradually subsides. After either event, returns are reliably positive and, among small investors, trades classified as buyer-initiated are elevated. Overall, results are more consistent with bounded rationality than with other candidate explanations.
Causal Ambiguity, Complexity, and Capability-Based Advantage
Authors: Ryall Michael D.
Published: November 2008

This paper presents the first formal examination of role of causal ambiguity as a barrier to imitation. Here, the aspiring imitator faces a knowledge (i.e., “capabilities-based”) barrier to imitation that is both causal and ambiguous in a precise sense of both words. Imitation conforms to a well-explicated process of learning by observing. I provide a precise distinction between the intrinsic causal ambiguity associated with a particular strategy and the subjective ambiguity perceived by a challenger. I find that intrinsic ambiguity is a necessary but insufficient condition for a sustained capability-based advantage. I also demonstrate that combinatorial complexity, a phenomenon that has attracted the recent attention of strategy theorists, and causal ambiguity are distinct barriers to imitation. The former acts as a barrier to explorative/active learning and the latter as one to absorptive/passive learning. One implication of this is that learning by doing and learning by observing are complementary strategic activities, not substitutes—in most cases, we should expect firm strategies to seek performance enhancement using efforts of both types.
Supply Disruptions, Asymmetric Information, and a Backup Production Option
Authors: Yang Zhibin (Ben) , Aydın Göker , Babich Volodymyr , Beil Damian R.
Published: November 2008

We study a manufacturer that faces a supplier privileged with private information about supply disruptions. We investigate how risk-management strategies of the manufacturer change and examine whether risk-management tools are more or less valuable in the presence of such asymmetric information. We model a supply chain with one manufacturer and one supplier, in which the supplier's reliability is either high or low and is the supplier's private information. On disruption, the supplier chooses to either pay a penalty to the manufacturer for the shortfall or use backup production to fill the manufacturer's order. Using mechanism design theory, we derive the optimal contract menu offered by the manufacturer. We find that information asymmetry may cause the less reliable supplier type to stop using backup production while the more reliable supplier type continues to use it. Additionally, the manufacturer may stop ordering from the less reliable supplier type altogether. The value of supplier backup production for the manufacturer is not necessarily larger under symmetric information; for the more reliable supplier type, it could be negative. The manufacturer is willing to pay the most for information when supplier backup production is moderately expensive. The value of information may increase as supplier types become uniformly more reliable. Thus, higher reliability need not be a substitute for better information.
OR PRACTICE—Optimization of Vacation Timeshare Scheduling
Authors: Sampson Scott E.
Published: November 2008

This paper reports on an application of network-flow integer programming to a vacation timeshare exchange problem. A typical timeshare owner has purchased yearly access to a specific week at a specific resort. The resulting lack of vacation variety is mitigated by systems that allow owners to exchange owned weeks for different weeks at different resorts according to their preferences, the assessed value of what they are exchanging, their contractual priority, and resort availability. The timeshare exchange problem is similar to other preference-based assignment problems such as labor scheduling, preferential bidding, and traditional timetabling, but different in the formulation of the objective function. This paper demonstrates how the effectiveness of timeshare exchange processes can be improved through mathematical optimization, as measured by increased satisfaction of participant preferences. Optimization also presents exchange managers with the opportunity to more precisely manage preference and priority trade-offs among various classes of participants. The trade-off decisions are aided by sensitivity analysis utilizing a minmax criterion.
Technical Note—A Make-to-Stock System with Multiple Customer Classes and Batch Ordering
Authors: Huang Boray , Iravani Seyed M. R.
Published: November 2008

This paper examines the impact of customer order sizes on a make-to-stock system with multiple demand classes. We first characterize the manufacturer's optimal production and rationing policies when the demand is nonunitary and lost if unsatisfied. We also investigate the optimal policies of a backorder system with two demand classes and fixed order sizes. Through a numerical study, we show the effects of batch orders on the manufacturer's inventory cost as well as on the benefit of optimal stock rationing. It is shown that batch ordering may reduce the manufacturer's overall cost if carefully introduced in a first-come-first-served (FCFS) system. With the same effective demand rates, the customers' order sizes also have a strong impact on the benefit of optimal stock rationing.
Fast Simulation of Multifactor Portfolio Credit Risk
Authors: Glasserman Paul , Kang Wanmo , Shahabuddin Perwez
Published: November 2008

This paper develops rare-event simulation methods for the estimation of portfolio credit risk—the risk of losses to a portfolio resulting from defaults of assets in the portfolio. Portfolio credit risk is measured through probabilities of large losses, which are typically due to defaults of many obligors (sources of credit risk) to which a portfolio is exposed. An essential element of a portfolio view of credit risk is a model of dependence between these sources of credit risk: large losses occur rarely and are most likely to result from systematic risk factors that affect multiple obligors. As a consequence, estimating portfolio credit risk poses a challenge both because of the rare-event property of large losses and the dependence between defaults. To address this problem, we develop an importance sampling technique within the widely used Gaussian copula model of dependence. We focus on difficulties arising in multifactor models—that is, models in which multiple factors may be common to multiple obligors, resulting in complex dependence between defaults. Our importance sampling procedure shifts the mean of the common factor to increase the frequency of large losses. In multifactor models, different combinations of factor outcomes and defaults can produce large losses, so our method combines multiple importance sampling distributions, each associated with a shift in the mean of common factors. We characterize “optimal” mean shifts. Finding these points is both a combinatorial problem and a convex optimization problem, so we address computational aspects of this step as well. We establish asymptotic optimality results for our method, showing that—unlike standard simulation—it remains efficient as the event of interest becomes rarer.
Modeling the Impact of Market Interventions on the Strategic Evolution of Electricity Markets
Authors: Bunn Derek W. , Oliveira Fernando S.
Published: November 2008

This paper presents a large-scale computationally intensive model for understanding the dynamic strategic evolution of electricity-generating asset portfolios in response to various market interventions, and the consequent longer-term effects of such changes on market structure and prices. We formulate a multistage model involving a Cournot representation of the wholesale electricity market, the performance of which then determines plant trading between players and the coevolution of market structure. An algorithm to model this game is presented. We apply this model to the full England and Wales system, as it was in 2000, and simulate the strategic responses to divestiture, capacity targets, and the two market mechanism variants of pool and bilateral market clearing.
Approximation Algorithms for Capacitated Stochastic Inventory Control Models
Authors: Levi Retsef , Roundy Robin O. , Shmoys David B. , Truong Van Anh
Published: November 2008

We develop the first algorithmic approach to compute provably good ordering policies for a multiperiod, capacitated, stochastic inventory system facing stochastic nonstationary and correlated demands that evolve over time. Our approach is computationally efficient and guaranteed to produce a policy with total expected cost no more than twice that of an optimal policy. As part of our computational approach, we propose a novel scheme to account for backlogging costs in a capacitated, multiperiod environment. Our cost-accounting scheme, called the forced marginal backlogging cost-accounting scheme, is significantly different from the period-by-period accounting approach to backlogging costs used in dynamic programming; it captures the long-term impact of a decision on system performance in the presence of capacity constraints. In the likely event that the per-unit order costs are large compared to the holding and backlogging costs, a transformation of cost parameters yields a significantly improved guarantee. We also introduce new semimyopic policies based on our new cost-accounting scheme to derive bounds on the optimal base-stock levels. We show that these bounds can be used to effectively improve any policy. Finally, empirical evidence is presented that indicates that the typical performance of this approach is significantly stronger than these worst-case guarantees.
OR FORUM—Catching the “Network Science” Bug: Insight and Opportunity for the Operations Researcher
Authors: Alderson David L.
Published: November 2008

Recent efforts to develop a universal view of complex networks have created both excitement and confusion about the way in which knowledge of network structure can be used to understand, control, or design system behavior. This paper offers perspective on the emerging field of “network science” in three ways. First, it briefly summarizes the origins, methodological approaches, and most celebrated contributions within this increasingly popular field. Second, it contrasts the predominant perspective in the network science literature (that abstracts away domain-specific function and instead focuses on graph-theoretic measures of system structure and dynamics) with that of engineers and practitioners of decision science (who emphasize the importance of network performance, constraints, and trade-offs). Third, it proposes optimization-based reverse engineering to address some important open questions within network science from an operations research perspective. We advocate for increased, yet cautious, participation in this field by operations researchers.
Joint Design and Pricing on a Network
Authors: Brotcorne Luce , Labbé Martine , Marcotte Patrice , Savard Gilles
Published: November 2008

To optimize revenue, service firms must integrate within their pricing policies the rational reaction of customers to their price schedules. In the airline or telecommunication industry, this process is all the more complex due to interactions resulting from the structure of the supply network. In this paper, we consider a streamlined version of this situation where a firm's decision variables involve both prices and investments. We model this situation as a joint design and pricing problem that we formulate as a mixed-integer bilevel program, and whose properties are investigated. In particular, we take advantage of a feature of the model that allows the development of an algorithmic framework based on Lagrangean relaxation. This approach is entirely novel, and numerical results show that it is capable of solving problems of significant sizes.
A Single-Unit Decomposition Approach to Multiechelon Inventory Systems
Authors: Muharremoglu Alp , Tsitsiklis John N.
Published: November 2008

We show the optimality of state-dependent echelon base-stock policies in uncapacitated serial inventory systems with Markov-modulated demand and Markov-modulated stochastic lead times in the absence of order crossing. Our results cover finite-time horizon problems as well as infinite-time horizon formulations, with either a discounted or an average cost criterion. We employ a novel approach, based on a decomposition of the problem into a series of single-unit single-customer problems that are essentially decoupled. Besides providing a simple proof technique, this approach also gives rise to efficient algorithms for the calculation of the base-stock levels.
Sex Differences in Blood Pressure Response to Antihypertensive Therapy in Chinese Patients with Hypertension
Authors: Fan XiaoHan , Han Yunfeng , Sun Kai , Wang Yibo , Xin Ying , Bai Yongyi , Li Weiju , Yang Tao , Song Xiaodong , Wang Hu , Fu Chunyan , Chen Jingzhou , Shi Yi , Zhou XianLiang , Wu Haiying , Hui Rutai
Published: November 2008

Background:

Sex-specific responsos to antihypertensive drugs are not very well understood.

Objective:

To investigate sex-related differences in blood pressure response to antihypertensive drugs in a community-based prospective clinical trial.

Methods:

We recruited 3535 untreated hypertensive patients (2326 women), aged 40–75 years, from 7 rural communities in China. Subjects were randomized to 1 of 4 drug groups: atenolol, hydrochlorothiazide (HCTZ), captopril, or sustained-released nifedipine; duration of the study was 8 weeks. Mean blood pressure reduction, blood pressure control rates, and frequency of adverse events were compared between men and women.

Results:

Women had a better response to HCTZ in relation to diastolic blood pressure (1.8 mm Hg lower) than did men (p <0.05) and were 57% more likely to reach the control goal of diastolic blood pressure than were men (p <0.05). In the atenolol group, mean systolic blood pressure decreased 3.9 mm Hg more in women than in men (p <0.05), and women were 65% more likely to reach the control goal of systolic blood pressure and 57% more likely to reach the control goal of diastolic blood pressure than were men (p <0.05). Significant sex-related differences were also found in drug-related adverse events in the nifedipine group (15.8% in women vs 9.8% in men; p = 0.017) and in the captopril group (14.3% in women vs 8.4% in men; p = 0.005), but no differences were seen with HCTZ or atenolol.

Conclusions:

Women have better blood pressure responses to HCTZ and atenolol and experience more adverse effects with sustained-release nifedipine and captopril than do men, indicating that sex should be taken into account when selecting antihypertensive drugs.
Cushing's Syndrome Induced by Misuse of Moderate- to High-Potency Topical Corticosteroids
Authors: Coureau Bénédicte , Bussières Jean-François , Tremblay Stéphanie
Published: November 2008

Objective:

To report a case of Cushing's syndrome caused by continuous use of moderate- to high-potency topical corticosteroids over several months.

Case Summary:

An 11-month-old patient with atopic dermatitis received uninterrupted treatment with moderate- to high-potency topical corticosteroids. He presented with several food allergies and was admitted to the hospital after atopic dermatitis worsened. Signs of growth retardation, which had begun at 6 months of age, were also noted during the child's hospital stay. An endocrinologist concluded that a lower-than-normal bone density scan and growth retardation on both weight and growth curves were due to suppression of the hypothalamic–pituitary–adrenal (HPA) axis and a multifactorial failure to thrive.

Discussion:

This is a case of an infant overexposed to topical corticosteroid treatment who developed Cushing's syndrome within a few months. Local treatment of atopic dermatitis is classically based on the use of topical corticosteroids in combination with an emollient or other drugs. To limit local and general damaging effects, the choice of topical corticosteroid must be made in terms of patient age, severity and site of the rash, and the extent of skin involvement. Several factors influence the systemic absorption of topical corticosteroids. While our literature review indicated the possibility of a multifactorial origin of the child's growth retardation, the use of topical corticosteroids was shown to have contributed to suppression of the HPA axis. Application of the Naranjo probability scale indicated a probable relationship between the continuous and sustained administration of topical corticosteroids over several months and suppression of the HPA axis. Although topical corticosteroids are widely used and can be perceived by parents and patients to be safe, daily documentation of agents used and body surfaces exposed should be done during long-term treatment.

Conclusions:

Continuous use of moderate- to high-potency topical corticosteroids over several months can contribute to Cushing's syndrome. Growth and development as well as cortisol levels should be monitored in children on long-term topical corticosteroid treatment.
Tumor Progression Associated with Erythropoiesis-Stimulating Agents
Authors: Newland Ashley M , Black Curtis D
Published: November 2008

Objective:

To evaluate, characterize, compare, and critique trials reporting increased tumor progression in patients with cancer who are receiving erythropoiesis-stimulating agents (ESAs) that led to Food and Drug Administration (FDA) actions for black box warnings and labeling changes.

Data Sources:

Literature was accessed through MEDLINE (1950–August 2008) and PubMed (1975–August 2008) using the search terms recombinant erythropoietin, darbepoetin, epoetin, anemia, neoplasms, and disease progression. Articles cited in MedWatch alerts, Oncologic Drugs Advisory Committee meeting briefs, and bibliographies from identified articles were also reviewed.

Study Selection and Data Extraction:

All studies published in English with data suggesting increased tumor progression or death due to disease progression in patients receiving ESAs were included.

Data Synthesis:

ESAs are approved for treatment of anemia in several different disease states, including chemotherapy-induced anemia. Ten trials investigating off-label use of ESAs in patients with cancer have reported an increased risk of tumor progression and/or treatment-associated death. Two of these trials reported worse overall survival with ESA treatment compared with placebo (28% vs 23% and 21.9% vs 16.4%), while another trial reported shorter time to death with treatment (68 vs 131 days; p = 0.04). Many of these studies had important limitations, including imbalanced groups at baseline and poor design. Moreover, none of these trials was designed to detect a statistically worse outcome with ESAs; thus, absolute conclusions regarding tumor progression cannot be drawn. As a result, better designed trials with safety as the primary outcome are ongoing.

Conclusions:

Additional studies are needed and being undertaken to qualify and quantify the possible risk of tumor progression with use of ESAs. Prudent practice dictates that until results of these trials are available, ESAs should be used in accordance with FDA labeling.