bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex steroids, growth factors and mammographic density: a cross-sectional study of UK postmenopausal Caucasian and Afro-Caribbean women
Authors: McCormack Valerie A , Dowsett Mitch , Folkerd Elizabeth , Johnson Nichola , Palles Claire , Coupland Ben , Holly Jeff M , Vinnicombe Sarah J , Perry Nicholas M , dos Santos Silva Isabel
Published: June 2009

Introduction

Sex steroids, insulin-like growth factors (IGFs) and prolactin are breast cancer risk factors but whether their effects are mediated through mammographic density, one of the strongest risk factors for breast cancer, is unknown. If such a hormonal basis of mammographic density exists, hormones may underlie ethnic differences in both mammographic density and breast cancer incidence rates.

Methods

In a cross-sectional study of 270 postmenopausal Caucasian and Afro-Caribbean women attending a population-based breast screening service in London, UK, we investigated whether plasma biomarkers (oestradiol, oestrone, sex hormone binding globulin (SHBG), testosterone, prolactin, leptin, IGF-I, IGF-II and IGF binding protein 3 (IGFBP3)) were related to and explained ethnic differences in mammographic percent density, dense area and nondense area, measured in Cumulus using the threshold method.

Results

Mean levels of oestrogens, leptin and IGF-I:IGFBP3 were higher whereas SHBG and IGF-II:IGFBP3 were lower in Afro-Caribbean women compared with Caucasian women after adjustment for higher mean body mass index (BMI) in the former group (by 3.2 kg/m2 (95% confidence interval (CI): 1.8, 4.5)). Age-adjusted percent density was lower in Afro-Caribbean compared with Caucasian women by 5.4% (absolute difference), but was attenuated to 2.5% (95% CI: -0.2, 5.1) upon BMI adjustment. Despite ethnic differences in biomarkers and in percent density, strong ethnic-age-adjusted inverse associations of oestradiol, leptin and testosterone with percent density were completely attenuated upon adjustment for BMI. There were no associations of IGF-I, IGF-II or IGFBP3 with percent density or dense area. We found weak evidence that a twofold increase in prolactin and oestrone levels were associated, respectively, with an increase (by 1.7% (95% CI: -0.3, 3.7)) and a decrease (by 2.0% (95% CI: 0, 4.1)) in density after adjustment for BMI.

Conclusions

These findings suggest that sex hormone and IGF levels are not associated with BMI-adjusted percent mammographic density in cross-sectional analyses of postmenopausal women and thus do not explain ethnic differences in density. Mammographic density may still, however, be influenced by much higher premenopausal hormone levels.
Full-length cytokeratin-19 is released by human tumor cells: a potential role in metastatic progression of breast cancer
Authors: Alix-Panabières Catherine , Vendrell Jean-Pierre , Slijper Monique , Pellé Olivier , Barbotte Eric , Mercier Grégoire , Jacot William , Fabbro Michel , Pantel Klaus
Published: June 2009

Introduction

We evaluated whether CK19, one of the main cytoskeleton proteins of epithelial cells, is released as full-length protein from viable tumor cells and whether this property is relevant for metastatic progression in breast cancer patients.

Methods

EPISPOT (EPithelial ImmunoSPOT) assays were performed to analyze the release of full-length CK19 by carcinoma cells of various origins, and the sequence of CK19 was analyzed with mass spectrometry. Additional functional experiments with cycloheximide, Brefeldin A, or vincristine were done to analyze the biology of the CK19-release. CK19-EPISPOT was used to detect disseminated tumor cells in bone marrow (BM) of 45 breast cancer patients who were then followed up over a median of 6 years.

Results

CK19 was expressed and released by colorectal (HT-29, HCT116, Caco-2) and breast (MCF-7, SKBR3, and MDA-MB-231) cancer cell lines. The CK19-EPISPOT was more sensitive than the CK19-ELISA. Dual fluorescent EPISPOT with antibodies against different CK19 epitopes showed the release of the full-length CK19, which was confirmed by mass spectrometry. Functional experiments indicated that CK19 release was an active process and not simply the consequence of cell death. CK19-releasing cells (RCs) were detectable in BM of 44% to 70% of breast cancer patients. This incidence and the number of CK19-RCs were correlated to the presence of overt metastases, and patients with CK19-RCs had a reduced survival as compared with patients without these cells (P = 0.025, log-rank test; P = 0.0019, hazard ratio, 4.7; multivariate analysis).

Conclusions

Full-length CK19 is released by viable epithelial tumor cells, and CK19-RCs might constitute a biologically active subset of breast cancer cells with high metastatic properties.
Expression of FOXA1 and GATA-3 in breast cancer: the prognostic significance in hormone receptor-negative tumours
Authors: Albergaria André , Paredes Joana , Sousa Bárbara , Milanezi Fernanda , Carneiro Vítor , Bastos Joana , Costa Sandra , Vieira Daniella , Lopes Nair , Lam Eric W , Lunet Nuno , Schmitt Fernando
Published: June 2009

Introduction

The expression of additional genes, other than oestrogen receptor (ER), may be important to the hormone-responsive phenotype of breast cancer. Microarray analyses have revealed that forkhead box A1 (FOXA1) and GATA binding protein 3 (GATA-3) are expressed in close association with ERα, both encoding for transcription factors with a potential involvement in the ERα-mediated action in breast cancer. The purpose of this study was to explore if the expression of FOXA1 and GATA-3 may provide an opportunity to stratify subsets of patients that could have better outcome, among the ERα-negative/poor prognosis breast cancer group.

Methods

We evaluate FOXA1 and GATA-3 expression in 249 breast carcinomas by immunohistochemistry, associating it with breast cancer molecular markers, clinicopathological features and patient's survival. The clinicopathological features and immunohistochemical markers of the tumours were compared using the chi-square test and ANOVA. Disease-free survival was analysed through Kaplan–Meier survival curves and Cox regression.

Results

FOXA1 expression was demonstrated in 42% of invasive carcinomas, while GATA-3 was detected in 48% of the cases. FOXA1 expression was inversely associated with tumour size, Nottingham Prognostic Index, histological grade, lymph vascular invasion, lymph node stage and human epidermal growth factor receptor-2 (HER-2) overexpression, while GATA-3 expression showed inverse association with histological grade and HER-2. Both FOXA1 and GATA-3 were directly associated with ERα and progesterone receptor. Among FOXA1-positive tumours, 83.1% are comprised in the luminal A subtype, similar to GATA-3 where 87.7% of positive tumours were classified within this molecular subtype. In the subset of ERα-negative patients, those who were FOXA1-negative had a 3.61-fold increased risk of breast cancer recurrence when compared with the FOXA1-positive.

Conclusions

FOXA1 was a significant predictor of good outcome in breast cancer, whereas GATA-3 was an important luminal marker. The expression of FOXA1 may be used for risk stratification among ERα-negative patients.
Cost-effectiveness of micafungin as an alternative to fluconazole empiric treatment of suspected ICU-acquired candidemia among patients with sepsis: a model simulation
Authors: Zilberberg Marya D , Kothari Smita , Shorr Andrew F
Published: June 2009

Introduction

Recent epidemiologic literature indicates that candidal species resistant to azoles are becoming more prevalent in the face of increasing incidence of hospitalizations with candidemia. Echinocandins, a new class of antifungal agents, are effective against resistant candidal species. As delaying appropriate antifungal coverage leads to increased mortality, we evaluated the cost-effectiveness of 100 mg daily empiric micafungin (MIC) vs. 400 mg daily fluconazole (FLU) for suspected intensive care unit-acquired candidemia (ICU-AC) among septic patients.

Methods

We designed a decision model with inputs from the literature in a hypothetical 1000-patient cohort with suspected ICU-AC treated empirically with either MIC or FLU or no treatment accompanied by a watchful waiting strategy. We examined the differences in the number of survivors, acquisition costs of antifungals, and lifetime costs among survivors in the cohort under each scenario, and calculated cost per quality adjusted life year (QALY). We conducted Monte Carlo simulations and sensitivity analyses to determine the stability of our estimates.

Results

In the base case analysis, assuming ICU-AC attributable mortality of 0.40 and a 52% relative risk reduction in mortality with appropriate timely therapy, compared with FLU (total deaths 31), treatment with MIC (total deaths 27) would result in four fewer deaths at an incremental cost/death averted of $61,446. Similarly, in reference case, incremental cost-effectiveness of MIC over FLU was $34,734 (95% confidence interval $26,312 to $49,209) per QALY. The estimates were most sensitive to the QALY adjustment factor and the risk of candidemia among septic patients.

Conclusions

Given the increasing likelihood of azole resistance among candidal isolates, empiric treatment of ICU-AC with 100 mg daily MIC is a cost-effective alternative to FLU.
Serum resistin levels in critically ill patients are associated with inflammation, organ dysfunction and metabolism and may predict survival of non-septic patients
Authors: Koch Alexander , Gressner Olav A , Sanson Edouard , Tacke Frank , Trautwein Christian
Published: June 2009

Introduction

Blood glucose levels and insulin resistance in critically ill patients on admission to intensive care units (ICUs) have been identified as factors influencing mortality. The pathogenesis of insulin resistance (IR) in critically ill patients is complex and not fully understood. Resistin is a hormone mainly derived from macrophages in humans and from adipose tissue in rodents, which regulates glucose metabolism and insulin sensitivity. In non-critically ill patients, resistin was found to be related to impaired glucose tolerance, insulin resistance, metabolic syndrome, obesity and type 2 diabetes. Therefore, resistin might represent a link between inflammation, acute phase response and insulin resistance in critically ill patients. We aimed to examine the correlation of serum resistin concentrations to parameters of inflammation, organ function, metabolism, disease severity and survival in critically ill patients.

Methods

On admission to the Medical ICU, 170 patients (122 with sepsis, 48 without sepsis) were studied prospectively and compared with 60 healthy non-diabetic controls. Clinical data, various laboratory parameters, metabolic and endocrine functions as well as investigational inflammatory cytokine profiles were assessed. Patients were followed for approximately three years.

Results

Resistin serum concentrations were significantly elevated in all critical care patients compared with healthy controls, and significantly higher in sepsis than in non-sepsis patients. Serum resistin concentrations were not associated with pre-existing type 2 diabetes or obesity. For all critically ill patients, a correlation to the homeostasis model assessment index of insulin resistance (HOMA-IR) was shown. Serum resistin concentrations were closely correlated to inflammatory parameters such as C-reactive protein, leukocytes, procalcitonin, and cytokines such as IL6 and TNF-α, as well as associated with renal failure and liver synthesis capacity. High resistin levels (> 10 ng/ml) were associated with an unfavourable outcome in non-sepsis patients on ICU and the overall survival.

Conclusions

Serum resistin concentrations are elevated in acute inflammation due to sepsis or systemic inflammatory response syndrome (SIRS). The close correlation with other acute phase proteins suggests a predominant, clinically relevant resistin release from macrophages in ICU patients. Moreover, resistin could potentially serve as a prognostic biomarker in non-sepsis critically ill patients.
Low-dose vasopressin infusion results in increased mortality and cardiac dysfunction following ischemia-reperfusion injury in mice
Authors: Indrambarya Toonchai , Boyd John H , Wang Yingjin , McConechy Melissa , Walley Keith R
Published: June 2009

Introduction

Arginine vasopressin is a vasoactive drug commonly used in distributive shock states including mixed shock with a cardiac component. However, the direct effect of arginine vasopressin on the function of the ischemia/reperfusion injured heart has not been clearly elucidated.

Methods

We measured left ventricular ejection fraction using trans-thoracic echocardiography in C57B6 mice, both in normal controls and following ischemia/reperfusion injury induced by a one hour ligation of the left anterior descending coronary artery. Mice were treated with one of normal saline, dobutamine (8.33 μg/kg/min), or arginine vasopressin (0.00057 Units/kg/min, equivalent to 0.04 Units/min in a 70 kg human) delivered by an intraperitoneal micro-osmotic pump. Arterial blood pressure was measured using a micromanometer catheter. In addition, mortality was recorded and cardiac tissues processed for RNA and protein.

Results

Baseline left ventricular ejection fraction was 65.6% (60 to 72). In normal control mice, there was no difference in left ventricular ejection fraction according to infusion group. Following ischemia/reperfusion injury, AVP treatment significantly reduced day 1 left ventricular ejection fraction 46.2% (34.4 to 52.0), both in comparison with baseline and day 1 saline treated controls 56.9% (42.4 to 60.2). There were no significant differences in preload (left ventricular end diastolic volume), afterload (blood pressure) or heart rate to account for the effect of AVP on left ventricular ejection fraction. The seven-day mortality rate was highest in the arginine vasopressin group. Following ischemia/reperfusion injury, we found no change in cardiac V1 Receptor expression but a 40% decrease in Oxytocin Receptor expression.

Conclusions

Arginine vasopressin infusion significantly depressed the myocardial function in an ischemia/reperfusion model and increased mortality in comparison with both saline and dobutamine treated animals. The use of vasopressin may be contraindicated in non-vasodilatory shock states associated with significant cardiac injury.
Comparative genomic analysis of C4 photosynthetic pathway evolution in grasses
Authors: Wang Xiyin , Gowik Udo , Tang Haibao , Bowers John E , Westhoff Peter , Paterson Andrew H
Published: June 2009

Background

Sorghum is the first C4 plant and the second grass with a full genome sequence available. This makes it possible to perform a whole-genome-level exploration of C4 pathway evolution by comparing key photosynthetic enzyme genes in sorghum, maize (C4) and rice (C3), and to investigate a long-standing hypothesis that a reservoir of duplicated genes is a prerequisite for the evolution of C4 photosynthesis from a C3 progenitor.

Results

We show that both whole-genome and individual gene duplication have contributed to the evolution of C4 photosynthesis. The C4 gene isoforms show differential duplicability, with some C4 genes being recruited from whole genome duplication duplicates by multiple modes of functional innovation. The sorghum and maize carbonic anhydrase genes display a novel mode of new gene formation, with recursive tandem duplication and gene fusion accompanied by adaptive evolution to produce C4 genes with one to three functional units. Other C4 enzymes in sorghum and maize also show evidence of adaptive evolution, though differing in level and mode. Intriguingly, a phosphoenolpyruvate carboxylase gene in the C3 plant rice has also been evolving rapidly and shows evidence of adaptive evolution, although lacking key mutations that are characteristic of C4 metabolism. We also found evidence that both gene redundancy and alternative splicing may have sheltered the evolution of new function.

Conclusions

Gene duplication followed by functional innovation is common to evolution of most but not all C4 genes. The apparently long time-lag between the availability of duplicates for recruitment into C4 and the appearance of C4 grasses, together with the heterogeneity of origins of C4 genes, suggests that there may have been a long transition process before the establishment of C4 photosynthesis.
Phase II Study of Thalidomide Plus Dexamethasone Induction Followed by Tandem Melphalan-Based Autotransplantation and Thalidomide-Plus-Prednisone Maintenance for Untreated Multiple Myeloma: A Southwest Oncology Group Trial (S0204)
Authors: Hussein Mohamad A. , Bolejack Vanessa , Zonder Jeffrey A. , Durie Brian G.M. , Jakubowiak Andrzej J. , Crowley John J. , Barlogie Bart
Published: June 2009

Purpose

Thalidomide-dexamethasone (THAL-DEX) is standard induction therapy for multiple myeloma (MM). Tandem melphalan-based transplantations have yielded superior results to single transplantations. Phase II trial S0204 was designed to improve survival results reported for the predecessor, phase III trial S9321 by 50%.

Patients and Methods

Newly diagnosed patients with MM were eligible for S0204 with THAL-DEX induction, tandem melphalan-based tandem transplantation, and THAL-prednisone maintenance.

Results

Of 143 eligible patients, 142 started induction, 73% completed first transplantation, 58% completed second transplantation, and 56% started maintenance. The quantity of stem cells required for two transplantations was reached in 88% of 111 patients undergoing collection, 74% of whom completed both transplantations. Partial response, very good partial remission, and complete response were documented after 12 months of maintenance therapy in 87%, 72%, and 22% of patients, respectively. During a median follow-up time of 37 months, 4-year estimates of event-free and overall survival were 50% and 64%, respectively. Survival outcomes were superior for International Staging System (ISS) stage 1 disease, when lactate dehydrogenase (LDH) levels were normal and a second transplantation was applied in a timely fashion.

Conclusion

Both overall survival (P = .0002) and event-free survival (P < .0001) were significantly improved with S0204 compared with S9321 when 121 and 363 patients, respectively, were matched on ISS stage and LDH.
Quality of Life After Pelvic Radiotherapy or Vaginal Brachytherapy for Endometrial Cancer: First Results of the Randomized PORTEC-2 Trial
Authors: Nout Remi A. , Putter Hein , Jürgenliemk-Schulz Ina M. , Jobsen Jan J. , Lutgens Ludy C.H.W. , van der Steen-Banasik Elzbieta M. , Mens Jan Willem M. , Slot Annerie , Stenfert Kroese Marika C. , van Bunningen Bart N.F.M. , Smit Vincent T.H.B.M. , Nijman Hans W. , van den Tol Philine P. , Creutzberg Carien L.
Published: June 2009

Purpose

Studies on quality of life (QOL) among women with endometrial cancer have shown that patients who undergo pelvic radiotherapy report lower role functioning and more diarrhea and fatigue. In the Post Operative Radiation Therapy in Endometrial Cancer (PORTEC) trial, patients with endometrial carcinoma were randomly assigned to receive external-beam radiotherapy (EBRT) or vaginal brachytherapy (VBT). QOL was evaluated by using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and subscales from the prostate cancer module, PR-25, and the ovarian cancer module, OV-28.

Patients and Methods

PORTEC-2 accrued 427 patients between 2002 and 2006, of whom 214 were randomly assigned to EBRT, and 213 were randomly assigned to VBT. Three-hundred forty-eight patients (81%) were evaluable for QOL. QOL outcomes were analyzed at a median follow-up of 2 years.

Results

At baseline after surgery, patient functioning was at the lowest level, and it increased during and after radiotherapy to reach a plateau after 12 months. Patients in the VBT group reported better social functioning (P < .002) and lower symptom scores for diarrhea, fecal leakage, the need to stay close to the toilet, and limitation in daily activities because of bowel symptoms (P < .001). At baseline, 15% of patients were sexually active; this increased significantly to 39% during the first year (P < .001). Sexual functioning and symptoms did not differ between the treatment groups.

Conclusion

Patients who received EBRT reported significantly higher levels of diarrhea and bowel symptoms. This resulted in a higher need to remain close to a toilet and, as a consequence, more limitation of daily activities because of bowel symptoms and decreased social functioning. Vaginal brachytherapy provides a better QOL, and should be the preferred treatment from a QOL perspective.
Secondary Causes of Low Bone Mass in Patients With Breast Cancer: A Need for Greater Vigilance
Authors: Mann G. Bruce , Kang Y. Chiu , Brand Caroline , Ebeling Peter R. , Miller Julie A.
Published: June 2009

Purpose

An observational study to assess the prevalence of secondary causes of low bone density in patients with breast cancer.

Patients and Methods

Female patients within 5 years of breast cancer diagnosis and age older than 50 years at diagnosis were recruited. Consenting patients completed a questionnaire and had blood taken for serum calcium, vitamin D, parathyroid hormone (PTH), and thyroid function testing. Bone mineral density (BMD) was assessed. Abnormalities were additionally investigated and treated.

Results

Two hundred patients were recruited. The median age at diagnosis was 62 years. One hundred sixty-nine patients had hormone receptor (HR) –positive cancer. Vitamin D and thyroid function were assessed in 200 patients; PTH was assessed in 197 patients; and BMD was assessed in 187 patients. Eighty-seven patients (46.5%) had osteopenia, and 24 patients (12.8%) had osteoporosis. Vitamin D levels were insufficient (ie, 50 to 75 nmol/L) in 74 patients (37%) and were deficient (ie, < 50 nmol/L) in 54 patients (27%). Only 24 of 65 patients taking vitamin D supplements were replete (ie, > 75 nmol/L). Thirty-nine (21%) of 197 patients had PTH concentrations greater than the normal range. Six had primary hyperparathyroidism (PHPT), and two more had recent surgery for PHPT. Twenty-seven had secondary hyperparathyroidism (HPT) from vitamin D deficiency and six had normocalcemic HPT. Of 90 patients with low BMD and HR-positive cancer, 8% (seven of 90 patients) had new or recent PHPT, and 63% (57 of 90 patients) had insufficient or deficient vitamin D. More patients with HR-positive cancer than with HR-negative cancer had elevated PTH (38 of 167 v three of 30 patients, respectively; P = .10).

Conclusion

Secondary causes of low BMD are common in postmenopausal women. Identification and management of secondary causes should be included in bone health management algorithms.
Minimal Disseminated Disease in Childhood T-Cell Lymphoblastic Lymphoma: A Report From the Children's Oncology Group
Authors: Coustan-Smith Elaine , Sandlund John T. , Perkins Sherrie L. , Chen Helen , Chang Myron , Abromowitch Minnie , Campana Dario
Published: June 2009

Purpose

Disease dissemination to the bone marrow is detected at diagnosis in approximately 15% of children with T-cell lymphoblastic lymphoma (T-LL). It is unclear whether the remaining patients have submicroscopic systemic disease and, if so, what is the clinical significance of this finding.

Patients and Methods

Using a flow cytometric method that can detect one T-LL cell among 10,000 normal cells, we examined bone marrow and peripheral-blood samples collected from 99 children with T-LL at diagnosis, as well as blood samples collected from 42 patients during treatment.

Results

In 71 (71.7%) of the 99 marrow samples obtained at diagnosis, T-LL cells represented 0.01% to 31.6% (median, 0.22%) of mononuclear cells; 57 of the 71 T-LL–positive samples were from patients with stage II/III disease. Results of studies in bilateral marrow aspirates were highly concordant. Two-year event-free survival (EFS) was 68.1% ± 11.1% (SE) for patients with ≥ 1% T-LL cells in bone marrow versus 90.7% ± 4.4% for those with lower levels of marrow involvement (P = .031); EFS for patients with ≥ 5% lymphoblasts was 51.9% ± 18.0% (P = .009). T-LL cells were as prevalent in blood as in marrow; monitoring residual T-LL cells in blood during remission induction therapy identified patients with slower disease clearance.

Conclusion

More than two thirds of children with T-LL have disseminated disease at diagnosis, a proportion much higher than previously demonstrated. Measurements of disease dissemination at diagnosis might provide useful prognostic information, which can be further refined by monitoring response to therapy through blood testing.
Robust design of finned-tube evaporators: A scalable product platform approach
Authors: Wang M H , Lee H-T
Published: June 2009

In this paper, a systematic approach to the design of industrial evaporator platforms is presented. Two popular design methodologies, the robust design and the compromise decision support problem (Compromise-DSP) procedures, are integrated into one unique design system. Design variables are first identified and then categorized into two groups: common platform parameters and non-platform variables. Multiple objectives are formed to evaluate the evaporator platform, including minimization of cost, maximization of fin efficiency, and minimization of the deviation. The methodology is demonstrated with a real industrial case in which a family of evaporators are to be designed.
Modelling the response of a standing person to the slipstream generated by a passenger train
Authors: Jordan S C , Sterling M , Baker C J
Published: June 2009

This article develops two relatively simple models that are combined in order to model the response of a standing person to a passing train. The first model combines potential flow theory, boundary layer theory, and autoregressive modelling in order to simulate the slipstream of a passenger train. The second moment simulates the response of a person to the wind velocities generated in the slipstream model. For the first 0.375 s the person is assumed to respond as a solid object, whereas after this time a spring—mass—damper system is used to represent the response of a person. A Monte Carlo analysis is used in order to establish the probability of a person becoming destabilized as a result of increasing train speed. Finally, a parametric analysis is undertaken and illustrates that the output of the models that represent the response of a person is sensitive to the parameter values chosen.
Vibration control of base-isolated structures using mixed H2/H∞ output-feedback control
Authors: Karimi H R , Zapateiro M , Luo N
Published: June 2009

A mixed H2/ H∞ output-feedback control design methodology for vibration reduction of base-isolated building structures modelled in the form of second-order linear systems is presented. Sufficient conditions for the design of a desired control are given in terms of linear matrix inequalities. A controller that guarantees asymptotic stability and a mixed H2/ H∞ performance for the closed-loop system of the structure is developed, based on a Lyapunov function. The performance of the controller is evaluated by means of simulations in MATLAB/Simulink.
Pseudo-random binary sequence closed-loop system identification error with integration control
Authors: Ren Z , Zhu G G
Published: June 2009

This paper studies the closed-loop system identification (ID) error when a dynamic integral controller is used. Pseudo-random binary sequence (PRBS) q-Markov covariance equivalent realization (Cover) is used to identify the closed-loop model, and the open-loop model is obtained based upon the identified closed-loop model. Accurate open-loop models were obtained using PRBS q-Markov Cover system ID directly. For closed-loop system ID, accurate open-loop identified models were obtained with a proportional controller, but when a dynamic controller was used, low-frequency system ID error was found. This study suggests that extra caution is required when a dynamic integral controller is used for closed-loop system identification. The closed-loop identification framework also has significant effects on closed-loop identification error. Both first- and second-order examples are provided in this paper.
Effect of fuel cetane number on a premixed diesel combustion mode
Authors: Ickes A M , Bohac S V , Assanis D N
Published: June 2009

The ability of premixed low-temperature diesel combustion to deliver low particulate matter (PM) and NO x emissions is dependent on achieving optimal combustion phasing. Small deviations in combustion phasing can shift the combustion to less optimal modes, yielding increased emissions, increased noise, and poor stability. This paper demonstrates how variations in fuel cetane number affect the detailed combustion behaviour of a direct-injection, diesel-fuelled, premixed combustion mode. Testing was conducted under light load conditions on a modern single-cylinder engine, fuelled with a range of ultra-low sulphur fuels with cetane numbers ranging from 42 to 53. Fuel cetane number is found to affect ignition delay and, accordingly, combustion phasing. Gaseous emissions are a function of combustion phasing and exhaust gas recirculation (EGR) quantity, but are not directly tied to fuel cetane number. Fuel cetane number is merely one of many different engine parameters that shift combustion phasing. Furthermore, the operating range is constrained by the changes in cetane number: no injection timings yield acceptable combustion across the whole spread of tested cetane numbers. However, in terms of combustion phasing, the operating range is consistent, independent of fuel cetane number.
The cap binding complex influences H2B ubiquitination by facilitating splicing of the SUS1 pre-mRNA
Authors: Hossain Munshi Azad , Claggett Julia M. , Nguyen Tiffany , Johnson Tracy L.
Published: June 2009

Pre-messenger RNA splicing is carried out by a large ribonucleoprotein complex called the spliceosome. Despite the striking evolutionary conservation of the spliceosomal components and their functions, controversy persists about the relative importance of splicing in Saccharomyces cerevisiae—particularly given the paucity of intron-containing genes in yeast. Here we show that splicing of one pre-messenger RNA, SUS1, a component of the histone H2B ubiquitin protease machinery, is essential for establishing the proper modification state of chromatin. One protein complex that is intimately involved in pre-mRNA splicing, the yeast cap-binding complex, appears to be particularly important, as evidenced by its extensive and unique genetic interactions with enzymes that catalyze histone H2B ubiquitination. Microarray studies show that cap binding complex (CBC) deletion has a global effect on gene expression, and for ∼20% of these genes, this effect is suppressed when ubiquitination of histone H2B is eliminated. Consistent with this finding of histone H2B dependent effects on gene expression, deletion of the yeast cap binding complex leads to overubiquitination of histone H2B. A key component of the ubiquitin-protease module of the SAGA complex, Sus1, is encoded by a gene that contains two introns and is misspliced when the CBC is deleted, leading to destabilization of the ubiquitin protease complex and defective modulation of cellular H2B levels. These data demonstrate that pre-mRNA splicing plays a critical role in histone H2B ubiquitination and that the CBC in particular helps to establish the proper state of chromatin and proper expression of genes that are regulated at the level of histone H2B ubiquitination.
Quality Disclosure Formats in a Distribution Channel
Authors: Guo Liang
Published: June 2009

Firms normally disclose quality information to consumers using two alternative formats: either directly to consumers or indirectly through downstream retailers. This study investigates optimal disclosure strategies/formats in a channel setting with bilateral monopolies. It shows that retail disclosure leads to more equilibrium information revelation. This is because the manufacturer can, through wholesale price cuts, partially absorb the retailer's effective disclosure cost and thus increase the retailer's incentive for disclosure. The conditions under which a particular disclosure format arises as the manufacturer's optimal choice are also examined. Even though direct disclosure is the ex post dominated option, the manufacturer may benefit from committing ex ante to the direct disclosure format when the cost of disclosure is sufficiently high.
Cause Marketing: Spillover Effects of Cause-Related Products in a Product Portfolio
Authors: Krishna Aradhna , Rajan Uday
Published: June 2009

The number of firms carrying a cause-related product has significantly increased in recent years. We consider a duopoly model of competition between firms in two products to determine which products a firm will link to a cause. We first test the behavioral underpinnings of our model in two laboratory experiments to demonstrate the existence of both a direct utility benefit to consumers from cause marketing (CM) and a spillover benefit onto other products in the portfolio. Linking one product in a product portfolio to a cause can therefore increase sales both of that product and, via a spillover effect, of other products in the firm's portfolio. We construct a CM game in which each firm chooses which products, if any, to place on CM. In the absence of a spillover benefit, a firm places a product on CM if and only if it can increase its price by enough to compensate for the cost of CM. Thus, in equilibrium, firms either have both products or neither product on CM. However, with the introduction of a spillover benefit to the second product, this result changes. We show that if a single firm in the market links only one product to a cause, it can raise prices on both products and earn a higher profit. We assume each firm has an advantage in one product and show that there is an equilibrium in which each firm links only its disadvantaged product to a cause. If the spillover effect is strong, there is a second equilibrium in which each firm links only its advantaged product to a cause. In each case, firms raise their prices on both products and earn higher profits than when neither firm engages in CM. We also show that a firm will never place its entire portfolio on CM. Overall, our work implies that, by carrying cause-related products, companies can not only improve their image in the public eye but also increase profits.
Why Defeating Insurgencies Is Hard: The Effect of Intelligence in Counterinsurgency Operations—A Best-Case Scenario
Authors: Kress Moshe , Szechtman Roberto
Published: June 2009

In insurgency situations, the government-organized force is confronted by a small guerrilla group that is dispersed in the general population with no or a very small signature. Effective counterinsurgency operations require good intelligence. Absent intelligence, not only might the insurgents escape unharmed and continue their violent actions, but collateral damage caused to the general population from poor targeting may generate adverse response against the government and create popular support for the insurgents, which may result in higher recruitment to the insurgency. We model the dynamic relations among intelligence, collateral casualties in the population, attrition, recruitment to the insurgency, and reinforcement to the government force. Even under best-case assumptions, we show that the government cannot totally eradicate the insurgency by force. The best it can do is contain it at a certain fixed level.
Toll-like Receptors 3, 4, and 7 Are Expressed in the Enteric Nervous System and Dorsal Root Ganglia
Authors: Barajon Isabella , Serrao Graziano , Arnaboldi Francesca , Opizzi Emanuela , Ripamonti Gerlomina , Balsari Andrea , Rumio Cristiano
Published: June 2009

The aim of the present study was to evaluate the expression of innate immunity receptors belonging to the Toll-like family in the neural plexuses of the different tracts of murine intestine, of the human ileum, and in lower dorsal root ganglia (DRGs) from where extrinsic afferents to these plexuses originate. Results obtained by immunohistochemistry and immunofluorescence on paraffin-embedded tissue and whole-mount preparations show that Toll-like receptors (TLRs) −3 and −7, recognizing viral RNA, and TLR4, recognizing lipopolysaccharide (membrane component of Gram-negative bacteria), are expressed in the myenteric and submucous plexuses of murine intestine and human ileum, and in DRGs primary sensory neurons. They also show that TLR4 immunostaining is stronger in murine distal large bowel. In murine tissue, expression of TLRs was present in both neurons and glial cells. These observations indicate that the enteric neural network might be directly activated by bacterial and viral components and is therefore more in the forefront than previously envisaged in defense responses of the intestinal wall and in the cross-talk with intestinal microbiota. They also highlight the presence of a peripheral neural network that by way of hardwired neurotransmission could potentially convey to the central nervous system specific information on our microbial counterpart and invading or potentially invading pathogens.
Advanced Osteoarthritis in Humans Is Associated With Altered Collagen VI Expression and Upregulation of ER-stress Markers Grp78 and Bag-1
Authors: Nugent Ashleigh E. , Speicher Danielle M. , Gradisar Ian , McBurney Denise L. , Baraga Anthony , Doane Kathleen J. , Horton Walter E.
Published: June 2009

To test the hypothesis that a perturbation of endoplasmic reticulum (ER) function is involved in the pathogenesis of osteoarthritis (OA), articular cartilage was isolated from non-OA patients secondary to resection of osteo- or chondrosarcomas. Intra-joint samples of minimal and advanced osteoarthritic cartilage were isolated from patients undergoing total knee arthroplasty and scored for disease severity. Glucose-regulated protein-78 (grp78) and bcl-2-associated athanogene-1 (bag-1) were detected via immunofluorescence as markers of non-homeostatic ER function. Additionally, the expression of type VI collagen and its integrin receptor, NG2, was determined to examine cartilage matrix health and turnover. There was an upregulation of grp78 in advanced OA, and variable expression in minimal OA. Non-OA cartilage was consistently grp78 negative. The downstream regulator bag-1 was also upregulated in OA compared with normal cartilage. Collagen VI was mainly cell-associated in non-OA cartilage, with a more widespread distribution observed in OA cartilage along with increased intracellular staining intensity. The collagen VI integral membrane proteoglycan receptor NG2 was downregulated in advanced OA compared with its patient-matched minimally involved cartilage sample. These results suggest that chondrocytes exhibit ER stress during OA, in association with upregulation of a large secreted molecule, type VI collagen.
First structural insights into the TpsB/Omp85 superfamily
Authors: Jacob-Dubuisson Françoise , Villeret Vincent , Clantin Bernard , Delattre Anne-Sophie , Saint Nathalie
Published: June 2009

Proteins of the TpsB/Omp85 superfamily are involved in protein transport across, or assembly into, the outer membrane of Gram-negative bacteria, and their distant eukaryotic relatives exert similar functions in chloroplasts and mitochondria. The X-ray structure of one TpsB transporter, FhaC, provides the bases to decipher the mechanisms of action of these proteins. With two POTRA domains in the periplasm, a transmembrane β barrel and a large loop harboring a functionally important motif, FhaC epitomizes the conserved features of the super-family.
Protein targeting by the signal recognition particle
Authors: Grudnik Przemyslaw , Bange Gert , Sinning Irmgard
Published: June 2009

Protein targeting by the signal recognition particle (SRP) is universally conserved and starts with the recognition of a signal sequence in the context of a translating ribosome. SRP54 and FtsY, two multidomain proteins with guanosine triphosphatase (GTPase) activity, are the central elements of the SRP system. They have to coordinate the presence of a signal sequence with the presence of a vacant translocation channel in the membrane. For coordination the two GTPases form a unique, nearly symmetric heterodimeric complex in which the activation of GTP hydrolysis plays a key role for membrane insertion of substrate proteins. Recent results are integrated in an updated perception of the order of events in SRP-mediated protein targeting.
Protein transport across the peroxisomal membrane
Authors: Girzalsky Wolfgang , Platta Harald W. , Erdmann Ralf
Published: June 2009

The maintenance of peroxisome function depends on the formation of the peroxisomal membrane and the subsequent import of both membrane and matrix proteins. Without exception, peroxisomal matrix proteins are nuclear encoded, synthesized on free ribosomes and subsequently imported post-translationally. In contrast to other translocation systems that transport unfolded polypeptide chains, the peroxisomal import apparatus can facilitate the transport of folded and oligomeric proteins across the peroxisomal membrane. The peroxisomal protein import is mediated by cycling receptors that shuttle between the cytosol and peroxisomal lumen and depends on ATP and ubiquitin. In this brief review, we will summarize our current knowledge on the import of soluble proteins into the peroxisomal matrix.
Catalytic properties of recombinant dipeptidyl carboxypeptidase from Escherichia coli: a comparative study with angiotensin I-converting enzyme
Authors: Cunha Carlos Eduardo L. , de Fátima Magliarelli Helena , Paschoalin Thaysa , Nchinda Aloysius T. , Lima Jackson C. , Juliano Maria A. , Paiva Paulo B. , Sturrock Edward D. , Travassos Luiz R. , Carmona Adriana K.
Published: June 2009

Dipeptidyl carboxypeptidase from Escherichia coli (EcDcp) is a zinc metallopeptidase with catalytic properties closely resembling those of angiotensin I-converting enzyme (ACE). However, EcDcp and ACE are classified in different enzyme families (M3 and M2, respectively) due to differences in their primary sequences. We cloned and expressed EcDcp and studied in detail the enzyme's S3 to S1′ substrate specificity using positional-scanning synthetic combinatorial (PS-SC) libraries of fluorescence resonance energy transfer (FRET) peptides. These peptides contain ortho-aminobenzoic acid (Abz) and 2,4-dinitrophenyl (Dnp) as donor/acceptor pair. In addition, using FRET substrates developed for ACE [Abz-FRK(Dnp)P-OH, Abz-SDK(Dnp)P-OH and Abz-LFK(Dnp)-OH] as well as natural ACE substrates (angiotensin I, bradykinin, and Ac-SDKP-OH), we show that EcDcp has catalytic properties very similar to human testis ACE. EcDcp inhibition studies were performed with the ACE inhibitors captopril (K
i=3 nm) and lisinopril (K
i=4.4 μm) and with two C-domain-selective ACE inhibitors, 5-S-5-benzamido-4-oxo-6-phenylhexanoyl-L-tryptophan (kAW; K
i=22.0 μm) and lisinopril-Trp (K
i=0.8 nm). Molecular modeling was used to provide the basis for the differences found in the inhibitors potency. The phylogenetic relationship of EcDcp and related enzymes belonging to the M3 and M2 families was also investigated and the results corroborate the distinct origins of EcDcp and ACE.
Mechanism of activation of Saccharomyces cerevisiae calcineurin by Mn2+
Authors: Ren Yan , Wang Zhi-Xin , Wei Qun
Published: June 2009

Saccharomyces cerevisiae calcineurin (CN) consists of a catalytic subunit CNA1 or CNA2 and a regulatory subunit CNB1. The kinetics of activation of yeast CN holoenzymes and their catalytic domains by Mn2+ were investigated. We report that the in vitro phosphatase reaction activated by Mn2+ typically has a pronounced initial lag phase caused by slow conformational rearrangement of the holoenzyme-Mn2+. A similar lag phase was detected using just the catalytic domain of yeast CN, indicating that the slowness of Mn2+-induced conformational change of CN results from a rearrangement within the catalytic domain. The Mn2+-activation of CN was reversible. The dissociation constant of the CN heterodimer containing the CNA2 subunit in the presence of Mn2+ was 3-fold higher than that of CN containing the CNA1 subunit and that of the catalytic domains of CNA1 and CNA2, pointing to differences between the residues surrounding the Mn2+-binding sites of CNA1 and CNA2.
The Rate-Limiting Mechanism for the Heterogeneous Burning of Cylindrical Iron Rods
Authors: Ward Nicholas R. , Steinberg Theodore A.
Published: June 2009

This paper presents the findings of an investigation into the rate-limiting mechanism for the heterogeneous burning in oxygen under normal gravity and microgravity of cylindrical iron rods. The original objective of the work was to determine why the observed melting rate for the burning of 3.2-mm-diameter iron rods is significantly higher in microgravity than in normal gravity. This work, however, also provided fundamental insight into the rate-limiting mechanism for heterogeneous burning. The paper includes a summary of normal-gravity and microgravity experimental results, heat transfer analysis, and post-test microanalysis of quenched samples. These results are then used to show that heat transfer across the solid/liquid interface is the rate-limiting mechanism for melting and burning, limited by the interfacial surface area between the molten drop and solid rod. In normal gravity, the work improves the understanding of trends reported during standard flammability testing for metallic materials, such as variations in melting rates between test specimens with the same cross-sectional area but different cross-sectional shape. The work also provides insight into the effects of configuration and orientation, leading to an improved application of standard test results in the design of oxygen system components. For microgravity applications, the work enables the development of improved methods for lower cost metallic material flammability testing programs. In these ways, the work provides fundamental insight into the heterogeneous burning process and contributes to improved fire safety for oxygen systems in applications involving both normal-gravity and microgravity environments.
Mitochondrial Superoxide Radicals Differentially Affect Muscle Activity and Neural Function
Authors: Godenschwege Tanja , Forde Renée , Davis Claudette P , Paul Anirban , Beckwith Kristopher , Duttaroy Atanu
Published: June 2009

Cellular superoxide radicals (O2−) are mostly generated during mitochondrial oxygen metabolism. O2− serves as the raw material for many reactive oxygen species (ROS) members like H2O2 and OH.− radicals following its catalysis by superoxide dismutase (SOD) enzymes and also by autocatalysis (autodismutation) reactions. Mitochondrial ROS generation could have serious implications on degenerative diseases. In model systems overproduction of mitochondrial O2− resulting from the loss of SOD2 function leads to movement disorders and drastic reduction in life span in vertebrates and invertebrates alike. With the help of a mitochondrial SOD2 loss-of-function mutant, Sod2n283, we measured the sensitivity of muscles and neurons to ROS attack. Neural outputs from flight motor neurons and sensory neurons were unchanged in Sod2n283 and the entire neural circuitry between the giant fiber (GF) and the dorsal longitudinal muscles (DLM) showed no overt defect due to elevated ROS. Such insensitivity of neurons to mitochondrial superoxides was further established through neuronal expression of SOD2, which failed to improve survival or locomotive ability of Sod2n283. On the other hand, ultrastructural analysis of Sod2n283 muscles revealed fewer mitochondria and reduced muscle ATP production. By targeting the SOD2 expression to the muscle we demonstrate that the early mortality phenotype of Sod2n283 can be ameliorated along with signs of improved mobility. In summary, muscles appear to be more sensitive to superoxide attack relative to the neurons and such overt phenotypes observed in SOD2-deficient animals can be directly attributed to the muscle.