bluuebunny/crossref_metadata_2025 huggingface dataset:
Mapatumumab, an Antibody Targeting TRAIL-R1, in Combination With Paclitaxel and Carboplatin in Patients With Advanced Solid Malignancies: Results of a Phase I and Pharmacokinetic Study
Authors: Leong Stephen , Cohen Roger B. , Gustafson Daniel L. , Langer Corey J. , Camidge D. Ross , Padavic Kristin , Gore Lia , Smith Margaret , Chow Laura Q. , von Mehren Margaret , O'Bryant Cindy , Hariharan Sujatha , Diab Sami , Fox Norma Lynn , Miceli Renée , Eckhardt S. Gail
Published: August 2009

Purpose

A phase I study assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor effect of mapatumumab, a fully-human agonist monoclonal antibody to the tumor necrosis factor–related apoptosis-inducing ligand receptor 1 (TRAIL-R1, DR4), in combination with paclitaxel and carboplatin.

Patients and Methods

Patients with advanced solid malignancies received 3, 10, or 20 mg/kg of mapatumumab with standard doses of paclitaxel and carboplatin every 21 days for up to six cycles in the absence of disease progression. Additional cycles of paclitaxel and/or mapatumumab were permissible in selected cases.

Results

Twenty-seven patients (21 males), with a median age of 54 years, received mapatumumab in the following three cohorts: 3 mg/kg (n = 4), 10 mg/kg (n = 11), and 20 mg/kg (n = 12). The median number of cycles was four. Dose-limiting toxicities (DLTs) were grade 3 hypersensitivity reaction (n = 1) and neutropenic fever (n = 1), both at 10 mg/kg. Non-DLT treatment-related adverse events occurring in more than 10% of administered doses included alopecia, neutropenia, fatigue, nausea, anemia, thrombocytopenia, anorexia, and neuropathy. Paclitaxel and carboplatin exposures were similar in the presence or absence of mapatumumab. Plasma mapatumumab concentrations seemed similar to data from previous phase I monotherapy studies. Five patients (19%) achieved a confirmed radiologic partial response (including one pathologic complete response), and 12 patients (44%) had stable disease as their best response.

Conclusion

Mapatumumab is well-tolerated up to 20 mg/kg in combination with paclitaxel and carboplatin. There are no apparent pharmacokinetic interactions among the drugs. Preliminary anticancer activity demonstrated clinical benefit for the majority of these patients.
The Evolution of the Plagiarist: Natural History in Anna Seward's Order of Poetics
Authors: Bailes Melissa
Published: August 2009

This essay explains Anna Seward's famous, vitriolic attacks on the poetic plagiarisms of Charlotte Smith by examining them within the framework of natural history. In the eighteenth and early nineteenth centuries, the vocabularies and methodologies of natural history overlapped with those of literary criticism. Taxonomic concerns with fixity and dynamism, with order and hybridity, permeated Seward's critical endeavors, which were central to her literary reputation. It is my contention that Seward's thinking about literary imitation was shaped by a belief in fixed biological forms. Her response to the zoological texts of the naturalist Erasmus Darwin elucidates her disapproval of Smith's (and Darwin's) poetic borrowings as examples of degenerative, stylistic hybrids. This study thus explores the tendency of Seward and her contemporaries to think in terms of interrelations between biological and poetic forms.
Adaptive dynamic friction observer and recurrent fuzzy neural network estimator design with backstepping control
Authors: Han S I , Lee K S
Published: August 2009

In this study, robust non-linear dynamic friction control is considered using a dynamic friction observer and intelligent control. An adaptive dynamic friction observer based on the LuGre friction model is proposed to estimate the friction parameters and a directly immeasurable friction state variable. A recurrent fuzzy neural network (RFNN) approximator and reconstructed error compensator are also designed to give additional robustness to the control system under friction model uncertainty. A proposed composite control scheme with a basic backstepping controller is applied to the position tracking control of the servo system. The performances of the proposed friction observer and the friction controller are demonstrated by some simulations and experiments.
Enhancement of ignition characteristics of lean premixed hydrocarbon–air mixtures by repetitive pulse discharges
Authors: Tanoue K , Hotta E , Moriyoshi Y
Published: August 2009

A newly developed small-sized inductive energy storage (IES) circuit that uses a semiconductor switch for the turn-off action is successfully applied to an ignition system in spark ignition engines operating under lean fuel–air ratios. This IES circuit can generate repetitive nanosecond pulse discharges. Experiments are conducted by means of a spherically expanding flame configuration for C3H8–air mixtures under various conditions. Findings show the investigated ignition system improves the inflammability of lean combustible mixtures in terms of extended flammability limits, shorted ignition delay time, and extended dilution limits, compared with conventional spark ignition systems.
Ethanol Concentration Dependence of Photoinduced Charge Separation Reaction between Zinc Tetraphenylporphyrin and Duroquinone Studied by Laser Flash Photolysis
Authors: Yago Tomoaki , Gohdo Masao , Wakasa Masanobu
Published: August 2009

Ethanol concentration dependence of photoinduced charge separation between zinc tetraphenylporphyrin (ZnTPP) and duroquinone (DQ) in benzonitrile was studied by nanosecond laser flash photolysis. Acceleration of the photoinduced charge separation reaction rate by hydrogen bonding between DQ anion radical and ethanol was observed. A simple analysis in the framework of the Marcus theory indicated that the observed electron-transfer reaction rate was affected not only by the decrease of the reaction free energy but also an increase of the reorganization energy in the presence of hydrogen bonding.
Neomastoidin A, a Novel Monoacylglycerol with an Amino Acid Moiety from Macrolepiota neomastoidea
Authors: Kim Ki Hyun , Choi Sang Un , Lee Kang Ro
Published: August 2009

A novel monoacylglycerol with an amino acid moiety, neomastoidin A (1), was isolated from the fruiting bodies of the poisonous mushroom Macrolepiota neomastoidea. The structure of 1 was established by extensive spectroscopic analysis and further confirmed by application of a dibenzoate chirality method. Neomastoidin A (1) exhibited cytotoxicity against SK-OV-3 and SK-MEL-2 cell lines.
The use of MRI to detect occult fractures of the proximal femur
Authors: Sankey R. A. , Turner J. , Lee J. , Healy J. , Gibbons C. E. R.
Published: August 2009

An MR scan was performed on all patients who presented to our hospital with a clinical diagnosis of a fracture of the proximal femur, but who had no abnormality on plain radiographs. This was a prospective study of 102 consecutive patients over a ten-year period. There were 98 patients who fulfilled our inclusion criteria, of whom 75 were scanned within 48 hours of admission, with an overall mean time between admission and scanning of 2.4 days (0 to 10). A total of 81 patients (83%) had abnormalities detected on MRI; 23 (23%) required operative management.

The use of MRI led to the early diagnosis and treatment of occult hip pathology. We recommend that incomplete intertrochanteric fractures are managed non-operatively with protected weight-bearing. The study illustrates the high incidence of fractures which are not apparent on plain radiographs, and shows that MRI is useful when diagnosing other pathology such as malignancy, which may not be apparent on plain films.
Spectroscopy of a single Sb2Se3 nanorod
Authors: Sun Kien Wen , Yang Cheng-Hang , Ko Ting-Yu , Chang Hao-Wei , Liu Chen-Wei
Published: August 2009

In this paper, we present solvothermal methods to chemically synthesize Sb2Se3 nanorods using dialkyl diselenophosphate (dsep) complexes of antimony. Energy-dispersive X-ray analysis shows the products are phase pure. We have also studied the Raman and photoluminescence spectroscopy of a single Sb2Se3 nanorod with an average size of 60 nm in diameter and a length less than 1 μm. Techniques have been devised to immobilize and allocate a single nano-object on an electron beam (E-beam) patterned smart substrate with metallic coordination markers. This also overcomes the limitation of spatial resolution of conventional optical techniques (~1 μm) to perform optical spectroscopy on an individual nano-object less than 100 nm in size. Raman spectroscopy reveals that Sb2Se3 nanorods synthesized at a lower temperature contain a small amount of Sb2Se3. The broad linewidth observed in luminescence spectra from a single rod is attributed to the increasing number of surface defects, impurities, and dangle bonds attached on the surface as the nanoparticle size reduced to nanometer scale.
Charge-transfer processes at the interface between hydrophobic ionic liquid and water
Authors: Samec Zdenĕk , Langmaier Jan , Kakiuchi Takashi
Published: August 2009

This article provides a brief review of theoretical and methodological concepts in the area of the charge-transfer processes at the interface between a hydrophobic ionic liquid (IL) and an electrolyte solution in water (W). Electrochemical methods of study of the W|IL interfaces are described, current experimental problems are indicated, and the most important experimental results are summarized. The relevance of electrochemistry at the W|IL interfaces to the extraction behavior of ILs is outlined.
Thermodynamics of trivalent actinides and neodymium in NaCl, MgCl2, and CaCl2 solutions: Solubility, hydrolysis, and ternary Ca-M(III)-OH complexes
Authors: Neck Volker , Altmaier Marcus , Rabung Thomas , Lützenkirchen Johannes , Fanghänel Thomas
Published: August 2009

Known data on the solubility of Am(OH)3(s) and the hydrolysis of Am(III) and Cm(III), additional information from an extensive solubility study with Nd(OH)3(s) in NaCl, MgCl2, and CaCl2 media of various ionic strengths and spectroscopic (time-resolved laser fluorescence spectroscopy, TRLFS) data for Cm(III) in alkaline CaCl2 solutions are used to evaluate a comprehensive set of standard-state equilibrium constants and ion interaction parameters for the specific ion interaction theory (SIT) and Pitzer equations at 25 °C. The thermodynamic model takes into account the analogous solubility and hydrolysis behavior of trivalent actinides and Nd(III) and covers the entire pH range in dilute to concentrated NaCl, MgCl2, and CaCl2 solutions. In alkali chloride/hydroxide solutions, the formation of the tetrahydroxide complex M(OH)4
– requires OH– concentration above 3 mol l–1, whereas in alkaline CaCl2 solutions (at pHc < 12) M(III) complexes with four and six hydroxide ligands are formed. Similar as the recently detected ternary Ca–M(IV)–OH complexes Ca3[Zr(OH)6]4+ and Ca4[Th(OH)8]4+, these complexes are stabilized by the association of Ca2+ ions. The solubility and hydrolysis of Am(III), Cm(III), and Nd(III) in both Ca-free and -containing solutions is consistently described with a model including the ternary Ca–M(III)–OH complexes Ca[M(OH)3]2+, Ca2[M(OH)4]3+, and Ca3[M(OH)6]3+.
Bone marrow changes in adolescent girls with anorexia nervosa
Authors: Ecklund Kirsten , Vajapeyam Sridhar , Feldman Henry A , Buzney Catherine D , Mulkern Robert V , Kleinman Paul K , Rosen Clifford J , Gordon Catherine M
Published: August 2009

Early osteoporosis is common among adolescent girls with anorexia nervosa (AN) and may result from premature conversion of red (RM) to yellow bone marrow. We performed right knee magnetic resonance imaging (MRI) on a 1.0 T extremity scanner in 20 patients and 20 healthy controls, aged 16.2 ± 1.6 years (mean ± SD). Coronal T1-weighted (T1W) images and T1 maps were generated from T1 relaxometry images. Blinded radiologists visually assessed RM in the distal femoral and proximal tibial metaphyses in T1W images using a scale of signal intensity from 0 (homogeneous hyperintensity, no RM) to 4 (all dark, complete RM). Subjects with AN exhibited nearly twofold lower metaphyseal RM scores in both the femur (0.64 versus 1.22, p = .03) and tibia (0.54 versus 0.96, p = .08). In relaxometric measurements of four selected regions (femur and tibia amd epiphysis and metaphysis), subjects with AN showed higher mean epiphyseal but lower metaphyseal T1. The net AN-control difference between epiphysis and metaphysis was 70 ms in the femur (+31 versus −35 ms, p = .02) and of smaller magnitude in the tibia. In relaxometry data from the full width of the femur adjacent to the growth plate, AN subjects showed mean T1 consistently lower than in controls by 30 to 50 ms in virtually every part of the sampling region. These findings suggest that adolescents with AN exhibit premature conversion of hematopoietic to fat cells in the marrow of the peripheral skeleton potentially owing to adipocyte over osteoblast differentiation in the mesenchymal stem cell pool. © 2010 American Society for Bone and Mineral Research
Endosseous implant anchorage is critically dependent on mechanostructural determinants of peri-implant bone trabeculae
Authors: Gabet Yankel , Kohavi David , Voide Romain , Mueller Thomas L , Müller Ralph , Bab Itai
Published: August 2009

Low bone mass is highly prevalent among patients receiving endosseous implants. In turn, the implantation prognosis in low-density skeletal sites is poor. However, little is known about the mechanostructural determinants of implant anchorage. Using metabolic manipulations that lead to low bone density and to its rescue, we show here that anchorage is critically dependent on the peri-implant bone (PIB). Titanium implants were inserted horizontally into the proximal tibial metaphysis of adult rats 6 weeks after orchiectomy (ORX) or sham ORX. Systemic intermittent administration of human parathyroid hormone (1–34) [iahPTH(1–34)] or vehicle commenced immediately thereafter for 6 weeks. The bone-implant apparatus was then subjected to image-guided failure assessment, which assesses biomechanical properties and microstructural deformation concomitantly. Anchorage failure occurred mainly in PIB trabeculae, 0.5 to 1.0 mm away from the implant. Mechanically, the anchorage performed poorly in ORX-induced low-density bone, attributable mainly to decreased trabecular number. iahPTH(1–34) rescued the PIB density and implant mechanical function by augmenting trabecular thickness (Tb.Th). However, implant biomechanical properties in low-density bone were relatively insensitive to implant surface treatment that affected only the osseointegration (%bone-implant contact). These results support a model wherein anchorage failure involves buckling of the weakest trabecular struts followed by sequential failure of the stronger trabeculae. Treatment with iahPTH(1–34) induced thicker struts, which were able to delay and even prevent failure of individual elements, thus implicating trabecular thickness as a prime target for enhancing implant anchorage by systemic bone anabolic therapy. © 2010 American Society for Bone and Mineral Research.
Early smoking is associated with peak bone mass and prevalent fractures in young, healthy men
Authors: Taes Youri , Lapauw Bruno , Vanbillemont Griet , Bogaert Veerle , De Bacquer Dirk , Goemaere Stefan , Zmierczak Hans , Kaufman Jean-Marc
Published: August 2009

Smoking is associated with lower areal bone mineral density (aBMD) and higher fracture risk, although most evidence has been derived from studies in elderly subjects. This study investigates smoking habits in relation to areal and volumetric bone parameters and fracture prevalence in young, healthy males at peak bone mass. Healthy male siblings (n = 677) at the age of peak bone mass (25 to 45 years) were recruited in a cross-sectional population-based study. Trabecular and cortical bone parameters of the radius and cortical bone parameters of the tibia were assessed using peripheral quantitative computed tomography (pQCT). Areal bone mass was determined using dual energy X-ray absorptiometry (DXA). Sex steroids and bone markers were determined using immunoassays. Prevalent fractures and smoking habits were assessed using questionnaires. Self-reported fractures were more prevalent in the current and early smokers than in the never smokers (p < .05), with a fracture prevalence odds ratio for early smokers of 1.96 (95% confidence interval 1.18–3.24) after adjustment for age, weight, educational level, and alcohol use and exclusion of childhood fractures. Current smoking was associated with a larger endosteal circumference (β = 0.027 ± 0.009, p = .016) and a decreased cortical thickness (β = −0.034 ± 0.01, p = .020) at the tibia. In particular, early smokers (≤16 years) had a high fracture risk and lower areal BMD, together with a lower cortical bone area at the tibia and lower trabecular and cortical bone density at the radius. An interaction between free estradiol and current smoking was observed in statistical models predicting cortical area and thickness (β = 0.29 ± 0.11, p = .01). In conclusion, smoking at a young age is associated with unfavorable bone geometry and density and is associated with increased fracture prevalence, providing arguments for a disturbed acquisition of peak bone mass during puberty by smoking, possibly owing to an interaction with sex steroid action. © 2010 American Society for Bone and Mineral Research
Heritability of Risk-Taking in Adolescence: A Longitudinal Twin Study
Authors: Anokhin Andrey P. , Golosheykin Simon , Grant Julia , Heath Andrew C.
Published: August 2009

Adolescents are prone to risk-taking behaviors leading to adverse consequences such as substance abuse, accidents, violence, and victimization. However, little is known about the contribution of genetic and environmental factors to individual differences in the propensity for risk-taking. This study investigated developmental changes, longitudinal stability, and heritability of risk-taking using data from 752 adolescent twins including 169 MZ and 203 DZ pairs. The Balloon Analogue Risk Task (BART), an experimental behavioral measure of risk taking, was administered to the twins at age 12 and then re-administered to a part of this sample at age 14. Risk-taking increased with age, but individual differences showed a significant longitudinal stability. Genetic model fitting showed that at age 12, heritability of risk-taking was modest but significant in both sexes, whereas at age 14, heritability increased to 55% in males and became nonsignificant in females. The findings suggest that propensity for risk-taking as measured by BART can be a useful endophenotype for genetic studies of adolescent externalizing psychopathology, however, the utility of this measure may be limited by sex differences in heritability.
Laminar Box System for 1-g Physical Modeling of Liquefaction and Lateral Spreading
Authors: Thevanayagam S. , Kanagalingam T. , Reinhorn A. , Tharmendhira R. , Dobry R. , Pitman M. , Abdoun T. , Elgamal A. , Zeghal M. , Ecemis N. , El Shamy U.
Published: August 2009

Details of a large scale modular 1-g laminar box system capable of simulating seismic induced liquefaction and lateral spreading response of level or gently sloping loose deposits of up to 6 m depth are presented. The internal dimensions of the largest module are 5 m in length and 2.75 m in width. The system includes a two dimensional laminar box made of 24 laminates stacked on top of each other supported by ball bearings, a base shaker resting on a strong floor, two computer controlled high speed actuators mounted on a strong wall, a dense array advanced instrumentation, and a novel system for laboratory hydraulic placement of loose sand deposit, which mimics underwater deposition in a narrow density range. The stacks of laminates slide on each other using a low-friction high-load capacity ball bearing system placed between each laminate. It could also be reconfigured into two smaller modules that are 2.5 m wide, 2.75 m long, and up to 3 m high. The maximum shear strain achievable in this system is 15 %. A limited set of instrumentation data is presented to highlight the capabilities of this equipment system. The reliability of the dense array sensor data is illustrated using cross comparison of accelerations and displacements measured by different types of sensors.
Selection of Sequestering Agents Having Affinity for Calcium Ion for Stabilization of the Emulsifiable Concentrate Formulations
Authors: Kozuki Y. , Ohtsubo T. , Sasaki M.
Published: August 2009

Emulsifiable concentrates (ECs) are often used for pesticides, which are highly soluble in a non-polar solvent. When a pesticide is hardly soluble in a normal non-polar solvent, it is difficult to prepare an EC formulation with high pesticide content. In order to overcome this difficulty, polar solvents are used to enhance the solubility of the pesticide. N-methyl-2-pyrrolidone (NMP) is well-known as one of the most preferred polar solvents. However, many agrochemical manufacturers have started research to remove this solvent from EC formulations because of recent regulations by the authorities. However, it is not easy to find alternative solvents that have both good solvency and a good safety profile. The authors selected diethyl oxalate as an alternative candidate for NMP by using the organic conceptual diagram discussed in the previous report. A pesticide in an EC formulation containing diethyl oxalate as a co-solvent was chemically stable and showed good emulsion stability even after accelerated storage. These results suggested that this solvent could be used as an alternative to NMP. However, a decrease in pH and water content were also observed, and the sample became turbid after storage. As this turbidity was confirmed to be derived from the generation of calcium oxalate, the calcium oxalate generation process was studied. As a result, it is speculated that diethyl oxalate was hydrolyzed to oxalic acid under the acidic conditions and calcium ion, derived from an anionic surfactant contained in the EC formulation, reacted with the oxalic acid to form calcium oxalate. In order to inhibit this reaction, several kinds of sequestering agents were tested. Among them, mono-alcohols were the best though they did not completely inhibit the reaction. Though the mechanism is still unclear, mono-alcohols were effective in blocking the binding of calcium ion and oxalic acid. A mono-alcohol is a structured molecule having a hydrophilic head region and a lipophilic tail region like a surfactant. If calcium ions are dissolved in the water in the EC formulations, even though the water content is low, a mono-alcohol may form something like an inverse micelle, which captures the calcium ions inside.
Assessing the Durability of Engineered Cementitious Composites Under Freezing and Thawing Cycles
Authors: Şahmaran Mustafa , Lachemi Mohamed , Li Victor C.
Published: August 2009

This paper reports the durability performance of non-air-entrained engineered cementitious composites (ECC) when subjected to freezing and thawing cycles. ECC is a newly developed, high-performance, fiber-reinforced, cementitious composite with substantial benefits both in terms of high ductility under uniaxial tensile loading and improved durability due to intrinsically tight crack width of less than 100 μm. To evaluate the frost durability of ECC, freezing and thawing testing in accordance with ASTM C666 Procedure A was conducted. The mass loss, pulse velocity change, and flexural parameters (ultimate deflection and flexural strength) of specimens subjected to freezing and thawing cycles were determined in the test. In addition, air-void parameters, in accordance with ASTM C457, modified point count method, and pore size distribution obtained by mercury intrusion porosimetry technique were studied. To analyze the influence of micro-fibers and high tensile strain capacity on the freezing and thawing durability of ECC, all of the above-mentioned properties were also investigated for a control ECC matrix (ECC without fibers). After 210 cycles of freezing and thawing, the control ECC matrix specimens were severely deteriorated, requiring removal from the test, but still exhibited better performance than the conventional non-air-entrained concrete, which would fail at much earlier cycles. On the other hand, ECC with fibers without air-entrainment had excellent resistance to cycles of freezing and thawing with minimal reduction in ultimate tensile strength and ductility. The observed superior frost durability of ECC over control ECC matrix in terms of lower weight loss, pulse velocity change, and higher flexural load and ductility can be attributed to the following reasons: Increase of pore volume larger than approximately 0.30 μm in diameter, intrinsically high tensile ductility and strength due to the presence of micro-poly-vinyl-alcohol fibers.
Silencing CENPF in bovine preimplantation embryo induces arrest at 8-cell stage
Authors: Toralová Tereza , Šušor Andrej , Němcová Lucie , Kepková Kateřina , Kaňka Jiří
Published: August 2009

Identification of genes that are important for normal preimplantation development is essential for understanding the basics of early mammalian embryogenesis. In our previous study, we have shown thatCENPF(mitosin) is differentially expressed during preimplantation development of bovine embryos. CENPF is a centromere–kinetochore complex protein that plays a crucial role in the cell division of somatic cells. To our best knowledge, no study has yet been done on either bovine model, or oocytes and preimplantation embryos. In this study, we focused on the fate of bovine embryos after injection ofCENPFdouble-stranded RNA (dsRNA) into the zygotes. An average decrease ofCENPFmRNA abundance by 94.9% or more and an extensive decline in immunofluorescence staining intensity was detected relative to controls. There was no disparity between individual groups in the developmental competence before the 8-cell stage. However, the developmental competence rapidly decreased then and only 28.1% ofCENPFdsRNA injected 8-cell embryos were able to develop further (uninjected control: 71.8%; green fluorescent protein dsRNA injected control: 72.0%). In conclusion, these results show that depletion ofCENPFmRNA in preimplantation bovine embryos leads to dramatic decrease of developmental competence after embryonic genome activation.
Effects of Recombination on Complex Regulatory Circuits
Authors: Martin Olivier C , Wagner Andreas
Published: August 2009

Mutation and recombination are the two main forces generating genetic variation. Most of this variation may be deleterious. Because recombination can reorganize entire genes and genetic circuits, it may have much greater consequences than point mutations. We here explore the effects of recombination on models of transcriptional regulation circuits that play important roles in embryonic development. We show that recombination has weaker deleterious effects on the expression phenotypes of these circuits than mutations. In addition, if a population of such circuits evolves under the influence of mutation and recombination, we find that three key properties emerge: (1) deleterious effects of mutations are reduced dramatically; (2) the diversity of genotypes in the population is greatly increased, a feature that may be important for phenotypic innovation; and (3) cis-regulatory complexes appear. These are combinations of regulatory interactions that influence the expression of one gene and that mitigate deleterious recombination effects.
The Fitness Cost of Streptomycin Resistance Depends on rpsL Mutation, Carbon Source and RpoS (σS)
Authors: Paulander Wilhelm , Maisnier-Patin Sophie , Andersson Dan I
Published: August 2009

Mutations that cause antibiotic resistance often produce associated fitness costs. These costs have a detrimental effect on the fate of resistant organisms in natural populations and could be exploited in designing drugs, therapeutic regimes, and intervention strategies. The streptomycin resistance (StrR) mutations K42N and P90S in ribosomal protein S12 impair growth on rich medium. Surprisingly, in media with poorer carbon sources, the same StrR mutants grow faster than wild type. This improvement reflects a failure of these StrR mutants to induce the stress-inducible sigma factor RpoS (σS), a key regulator of many stationary-phase and stress-inducible genes. On poorer carbon sources, wild-type cells induce σS, which retards growth. By not inducing σS, StrR mutants escape this self-imposed inhibition. Consistent with this interpretation, the StrR mutant loses its advantage over wild type when both strains lack an RpoS (σS) gene. Failure to induce σS produced the following side effects: (1) impaired induction of several stress-inducible genes, (2) reduced tolerance to thermal stress, and (3) reduced translational fidelity. These results suggest that RpoS may contribute to long-term cell survival, while actually limiting short-term growth rate under restrictive growth conditions. Accordingly, the StrR mutant avoids short-term growth limitation but is sensitized to other stresses. These results highlight the importance of measuring fitness costs under multiple experimental conditions not only to acquire a more relevant estimate of fitness, but also to reveal novel physiological weaknesses exploitable for drug development.
The Mother Enrichment Program: A Genetic System for Facile Replicative Life Span Analysis in Saccharomyces cerevisiae
Authors: Lindstrom Derek L , Gottschling Daniel E
Published: August 2009

The replicative life span (RLS) of Saccharomyces cerevisiae has been established as a model for the genetic regulation of longevity despite the inherent difficulty of the RLS assay, which requires separation of mother and daughter cells by micromanipulation after every division. Here we present the mother enrichment program (MEP), an inducible genetic system in which mother cells maintain a normal RLS—a median of 36 generations in the diploid MEP strain—while the proliferative potential of daughter cells is eliminated. Thus, the viability of a population over time becomes a function of RLS, and it displays features of a survival curve such as changes in hazard rate with age. We show that viability of mother cells in liquid culture is regulated by SIR2 and FOB1, two opposing regulators of RLS in yeast. We demonstrate that viability curves of these short- and long-lived strains can be easily distinguished from wild type, using a colony formation assay. This provides a simplified screening method for identifying genetic or environmental factors that regulate RLS. Additionally, the MEP can provide a cohort of cells at any stage of their life span for the analysis of age-associated phenotypes. These capabilities effectively remove the hurdles presented by RLS analysis that have hindered S. cerevisiae aging studies since their inception 50 years ago.
InSaccharomyces cerevisiae, yKu and Subtelomeric Core X Sequences Repress Homologous Recombination Near Telomeres as Part of the Same Pathway
Authors: Marvin Marcus E , Griffin Craig D , Eyre David E , Barton David B H , Louis Edward J
Published: August 2009

Unlike in meiosis where recombination near telomeres is repressed, subtelomeric regions appear to recombine with each other frequently in vegetative cells with no detrimental consequences. To test whether or not such recombination is prevented in the core of chromosomes for maintenance of genome stability, we measured allelic homologous recombination (HR) along chromosome arms and between different ectopic locations. We found that there is an increase of recombination at telomeres in wild-type cells compared with sequences at proximal subtelomeric and interstitial regions of the genome. We also screened for mutations that result in an increase in HR between a telomeric sequence and a more internal sequence, which normally exhibit very low rates of HR. YKU80 was hit most frequently in our screen, and we show that the yKu heterodimer specifically represses HR in the vicinity of telomeres. This repression of HR is not explained solely by the role of yKu in maintaining telomere length, silencing, or tethering to the nuclear periphery. Analysis of mutant strains harboring deleted core X sequences revealed a role for this subtelomeric element in preventing telomeric recombination. Furthermore, core X bestowed this protection as part of the same pathway as yKu. Our findings implicate a role for both yKu and core X in stabilizing the genome against recombination events involving telomeric sequences.
The Association of yKu With Subtelomeric Core X Sequences Prevents Recombination Involving Telomeric Sequences
Authors: Marvin Marcus E , Becker Marion M , Noel Pawan , Hardy Sue , Bertuch Alison A , Louis Edward J
Published: August 2009

The yKu protein of Saccharomyces cerevisiae is important for genome stability by repressing recombination involving telomeric sequences. The mechanism of this repression is not known, but silent heterochromatin such as HML, HMR, and telomeres are compartmentalized at the nuclear periphery and yKu is proposed to interact with these regions and to play a role in telomeric silencing and tethering. We have utilized ChIP on chip, quantitative PCR, and quantitative recombination assays to analyze yKu binding and its effect on genome stability in wild-type and mutant backgrounds. Our data suggest that, although yKu binds to the TG1-3 repeats and other parts of the genome when needed, such as during nonhomologous end-joining, it specifically binds to core X sequences in addition to the mating-type loci, HML and HMR. Association with core X occurred in the absence of Sir proteins, and enhanced binding was observed at silenced ends compared to nonsilenced ends. In contrast, binding to HML and HMR was totally dependent on Sir2–4p and partially dependent on Sir1p with a stronger association at HML in both MATa and MATα strains. Using yku80 separation-of-function mutants, we show a direct correlation between core X binding and recombination rate. We believe our findings support our hypothesis that yKu and core X play a pivotal role in maintaining genome stability through nuclear architecture by mediating a defensive fold-back structure at yeast chromosome ends.
Efficient Ensemble-Based Closed-Loop Production Optimization
Authors: Chen Yan , Oliver Dean S. , Zhang Dongxiao
Published: August 2009

With the advances in smart well technology, substantially higher oil recovery can be achieved by intelligently managing the operations in a closed-loop optimization framework. The closed-loop optimization consists of two parts: geological model updating and production optimization. Both of these parts require gradient information to minimize or maximize an objective function: squared data mismatch or the net present value (or other quantities depending on financial goals), respectively. Alternatively, an ensemble-based method can acquire the gradient information through the correlations provided by the ensemble. Computation of the optimal controls in this way is nearly independent of the number of control variables, reservoir simulator, and simulation solver. In this paper, we propose an ensemble-based closed-loop optimization method that combines a novel ensemble-based optimization scheme (EnOpt) with the ensemble Kalman filter (EnKF). EnKF has recently been found suitable for sequential data assimilation in large-scale nonlinear dynamics. It adjusts reservoir model variables to honor observations and propagates uncertainty in time. EnOpt optimizes the expectation of the net present value based on the updated reservoir models. The proposed method is fairly robust, completely adjoint-free and can be readily used with any reservoir simulator. The ensemble-based closed-loop optimization method is illustrated with a waterflood example subject to uncertain reservoir description. Results are compared with other possible reservoir operation scenarios, such as wells with no controls, reactive control, and optimization with known geology. The comparison shows that the ensemble-based closed-loop optimization is able to history match the main geological features and increase the net present value to a level comparable with the hypothetical case of optimizing based on known geology.
Forcing minimal degree of constructibility
Authors: Judah Haim , Shelah Saharon
Published: August 2009

In this paper we will study four forcing notions, two of them giving a minimal degree of constructibility. These constructions give answers to questions in [Ih].
SEM morphological analysis of fertilized cysts in the genus Branchipus (Branchiopoda, Anostraca): Can cyst morphology be used as a reliable taxonomic criterion?
Authors: Milicic Dragana , Petrov Brigita
Published: August 2009

In order to illuminate taxonomic significance of cyst variability (as a part of total morphological variability) in the genus Branchipus, cysts (fertilized eggs) originating from southern parts of the Pannonian Plain are described on the basis of scanning electron microscopy (SEM) observations. The present study sets out to: 1) improve knowledge on use of egg morphology as a reliable taxonomic criterion in the genus Branchipus; 2) discuss egg variability in Pannonian populations; and 3) briefly discuss possible adaptive implications of egg morphology from the evolutionary point of view.
Business communication and mobbing
Authors: Baltezarevic Vesna
Published: August 2009

This paper emphasizes the necessity of quality communication skills in management. Business communication needs to be adaptable and to have the ability to flexibly react to dynamic changes in the environment and to give positive response to the demands imposed by the environment. Business communication promoters, i.e. managers, must be capable of utilizing all available data with speed and efficiency and to distribute the information to both the internal and external environments. The author intends to point out the need for business organizations to establish harmonic communication, thus creating conditions underpinning a better working atmosphere that contributes to motivation of employees.
Psychological abuse in the work place: The analysis of the VDS info and victim support service's work in 2008
Authors: Tripkovic Mirjana
Published: August 2009

The aim of this paper is to present the data and the experience of the victim support service VDS info and victim support service in regard to the issue of psychological abuse at the work place. Data relates to the period from January 1st until December 31st 2008. The data presented in this paper refer to victims' characteristics as well as the ways of providing them assistance and support.
FoxO1 Links Insulin Resistance to Proinflammatory Cytokine IL-1β Production in Macrophages
Authors: Su Dongming , Coudriet Gina M. , Hyun Kim Dae , Lu Yi , Perdomo German , Qu Shen , Slusher Sandra , Tse Hubert M. , Piganelli Jon , Giannoukakis Nick , Zhang Jian , Henry Dong H.
Published: August 2009

OBJECTIVE

Macrophages play an important role in the pathogenesis of insulin resistance via the production of proinflammatory cytokines. Our goal is to decipher the molecular linkage between proinflammatory cytokine production and insulin resistance in macrophages.

RESEARCH DESIGN AND METHODS

We determined cytokine profiles in cultured macrophages and identified interleukin (IL)-1β gene as a potential target of FoxO1, a key transcription factor that mediates insulin action on gene expression. We studied the mechanism by which FoxO1 mediates insulin-dependent regulation of IL-1β expression in cultured macrophages and correlated FoxO1 activity in peritoneal macrophages with IL-1β production profiles in mice with low-grade inflammation or insulin resistance.

RESULTS

FoxO1 selectively promoted IL-1β production in cultured macrophages. This effect correlated with the ability of FoxO1 to bind and enhance IL-1β promoter activity. Mutations of the FoxO1 binding site within the IL-1β promoter abolished FoxO1 induction of IL-1β expression. Macrophages from insulin-resistant obese db/db mice or lipopolysaccharide-inflicted mice were associated with increased FoxO1 production, correlating with elevated levels of IL-1β mRNA in macrophages and IL-1β protein in plasma. In nonstimulated macrophages, FoxO1 remained inert with benign effects on IL-1β expression. In response to inflammatory stimuli, FoxO1 activity was augmented because of an impaired ability of insulin to phosphorylate FoxO1 and promote its nuclear exclusion. This effect along with nuclear factor-κB acted to stimulate IL-1β production in activated macrophages.

CONCLUSIONS

FoxO1 signaling through nuclear factor-κB plays an important role in coupling proinflammatory cytokine production to insulin resistance in obesity and diabetes.
Reductive Metabolism of AGE Precursors: A Metabolic Route for Preventing AGE Accumulation in Cardiovascular Tissue
Authors: Baba Shahid P. , Barski Oleg A. , Ahmed Yonis , O'Toole Timothy E. , Conklin Daniel J. , Bhatnagar Aruni , Srivastava Sanjay
Published: August 2009

OBJECTIVE

To examine the role of aldo-keto reductases (AKRs) in the cardiovascular metabolism of the precursors of advanced glycation end products (AGEs).

RESEARCH DESIGN AND METHODS

Steady-state kinetic parameters of AKRs with AGE precursors were determined using recombinant proteins expressed in bacteria. Metabolism of methylglyoxal and AGE accumulation were studied in human umbilical vein endothelial cells (HUVECs) and C57 wild-type, akr1b3 (aldose reductase)-null, cardiospecific-akr1b4 (rat aldose reductase), and akr1b8 (FR-1)-transgenic mice. AGE accumulation and atherosclerotic lesions were studied 12 weeks after streptozotocin treatment of C57, akr1b3-null, and apoE- and akr1b3-apoE–null mice.

RESULTS

Higher levels of AGEs were generated in the cytosol than at the external surface of HUVECs cultured in high glucose, indicating that intracellular metabolism may be an important regulator of AGE accumulation and toxicity. In vitro, AKR 1A and 1B catalyzed the reduction of AGE precursors, whereas AKR1C, AKR6, and AKR7 were relatively ineffective. Highest catalytic efficiency was observed with AKR1B1. Acetol formation in methylglyoxal-treated HUVECs was prevented by the aldose reductase inhibitor sorbinil. Acetol was generated in hearts perfused with methylglyoxal, and its formation was increased in akr1b4- or akr1b8-transgenic mice. Reduction of AGE precursors was diminished in hearts from akr1b3-null mice. Diabetic akr1b3-null mice accumulated more AGEs in the plasma and the heart than wild-type mice, and deletion of akr1b3 increased AGE accumulation and atherosclerotic lesion formation in apoE-null mice.

CONCLUSIONS

Aldose reductase–catalyzed reduction is an important pathway in the endothelial and cardiac metabolism of AGE precursors, and it prevents AGE accumulation and atherosclerotic lesion formation.
Genetic Variant in HK1 Is Associated With a Proanemic State and A1C but Not Other Glycemic Control–Related Traits
Authors: Bonnefond Amélie , Vaxillaire Martine , Labrune Yann , Lecoeur Cécile , Chèvre Jean-Claude , Bouatia-Naji Nabila , Cauchi Stéphane , Balkau Beverley , Marre Michel , Tichet Jean , Riveline Jean-Pierre , Hadjadj Samy , Gallois Yves , Czernichow Sébastien , Hercberg Serge , Kaakinen Marika , Wiesner Susanne , Charpentier Guillaume , Lévy-Marchal Claire , Elliott Paul , Jarvelin Marjo-Riitta , Horber Fritz , Dina Christian , Pedersen Oluf , Sladek Robert , Meyre David , Froguel Philippe
Published: August 2009

OBJECTIVE

A1C is widely considered the gold standard for monitoring effective blood glucose levels. Recently, a genome-wide association study reported an association between A1C and rs7072268 within HK1 (encoding hexokinase 1), which catalyzes the first step of glycolysis. HK1 deficiency in erythrocytes (red blood cells [RBCs]) causes severe nonspherocytic hemolytic anemia in both humans and mice.

RESEARCH DESIGN AND METHODS

The contribution of rs7072268 to A1C and the RBC-related traits was assessed in 6,953 nondiabetic European participants. We additionally analyzed the association with hematologic traits in 5,229 nondiabetic European individuals (in whom A1C was not measured) and 1,924 diabetic patients. Glucose control–related markers other than A1C were analyzed in 18,694 nondiabetic European individuals. A type 2 diabetes case-control study included 7,447 French diabetic patients.

RESULTS

Our study confirms a strong association between the rs7072268–T allele and increased A1C (β = 0.029%; P = 2.22 × 10−7). Surprisingly, despite adequate study power, rs7072268 showed no association with any other markers of glucose control (fasting- and 2-h post-OGTT–related parameters, n = 18,694). In contrast, rs7072268–T allele decreases hemoglobin levels (n = 13,416; β = −0.054 g/dl; P = 3.74 × 10−6) and hematocrit (n = 11,492; β = −0.13%; P = 2.26 × 10−4), suggesting a proanemic effect. The T allele also increases risk for anemia (836 cases; odds ratio 1.13; P = 0.018).

CONCLUSIONS

HK1 variation, although strongly associated with A1C, does not seem to be involved in blood glucose control. Since HK1 rs7072268 is associated with reduced hemoglobin levels and favors anemia, we propose that HK1 may influence A1C levels through its anemic effect or its effect on glucose metabolism in RBCs. These findings may have implications for type 2 diabetes diagnosis and clinical management because anemia is a frequent complication of the diabetes state.
Sleep Duration, Lifestyle Intervention, and Incidence of Type 2 Diabetes in Impaired Glucose Tolerance
Authors: Tuomilehto Henri , Peltonen Markku , Partinen Markku , Lavigne Gilles , Eriksson Johan G. , Herder Christian , Aunola Sirkka , Keinänen-Kiukaanniemi Sirkka , Ilanne-Parikka Pirjo , Uusitupa Matti , Tuomilehto Jaakko , Lindström Jaana ,   on behalf of the Finnish Diabetes Prevention Study Group
Published: August 2009

OBJECTIVE

Both short and long sleep duration have frequently been found to be associated with an increased risk for diabetes. The aim of the present exploratory analysis was to examine the association between sleep duration and type 2 diabetes after lifestyle intervention in overweight individuals with impaired glucose tolerance in a 7-year prospective follow-up.

RESEARCH DESIGN AND METHODS

A total of 522 individuals (aged 40–64 years) were randomly allocated either to an intensive diet-exercise counseling group or to a control group. Diabetes incidence during follow-up was calculated according to sleep duration at baseline. Sleep duration was obtained for a 24-h period. Physical activity, dietary intakes, body weight, and immune mediators (C-reactive protein and interleukin-6) were measured.

RESULTS

Interaction between sleep duration and treatment group was statistically significant (P = 0.003). In the control group, the adjusted hazard ratios (HRs) (95% CI) for diabetes were 2.29 (1.38–3.80) and 2.74 (1.67–4.50) in the sleep duration groups 9–9.5 h and ≥10 h, respectively, compared with for that of the 7–8.5 h group. In contrast, sleep duration did not influence the incidence of diabetes in the intervention group; for sleep duration groups 9–9.5 h and ≥10 h, the adjusted HRs (95% CI) were 1.10 (0.60–2.01) and 0.73 (0.34–1.56), respectively, compared with that in the reference group (7–8.5 h sleep). Lifestyle intervention resulted in similar improvement in body weight, insulin sensitivity, and immune mediator levels regardless of sleep duration.

CONCLUSIONS

Long sleep duration is associated with increased type 2 diabetes risk. Lifestyle intervention with the aim of weight reduction, healthy diet, and increased physical activity may ameliorate some of this excess risk.