bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of Sulfotransferase and UDP‐Glucuronosyltransferase Gene Expression by the PPARs
Authors: Runge-Morris Melissa , Kocarek Thomas A.
Published: August 2009

During phase II metabolism, a substrate is rendered more hydrophilic through the covalent attachment of an endogenous molecule. The cytosolic sulfotransferase (SULT) and UDP‐glucuronosyltransferase (UGT) families of enzymes account for the majority of phase II metabolism in humans and animals. In general, phase II metabolism is considered to be a detoxication process, as sulfate and glucuronide conjugates are more amenable to excretion and elimination than are the parent substrates. However, certain products of phase II metabolism (e.g., unstable sulfate conjugates) are genotoxic. Members of the nuclear receptor superfamily are particularly important regulators of SULT and UGT gene transcription. In metabolically active tissues, increasing evidence supports a major role for lipid‐sensing transcription factors, such as peroxisome proliferator‐activated receptors (PPARs), in the regulation of rodent and human SULT and UGT gene expression. This review summarizes current information regarding the regulation of these two major classes of phase II metabolizing enzyme by PPARs.
Delayed Diagnoses: Nonspecific Findings and Diagnostic Challenges in Eating Disorders
Authors: Schwarz Dan , Ponder Kathryn L. , Feller Edward R.
Published: August 2009

Objective. Eating disorders commonly present with nonspecific findings, masquerading as other, more common etiologies of malnutrition and wasting. In low-prevalence populations, these ambiguities can complicate clinicians’ diagnostic reasoning, resulting in delayed or missed diagnoses.Method. We report the atypical case of a 51-year-old male with a five-year history of unexplained weight loss despite extensive past medical evaluation. Previous documentation of profound lymphopenia and bone marrow atrophy had not been linked to a known association with eating disorders.Results. Evaluation for medical etiologies of wasting was negative. Following psychiatric evaluation, the patient was diagnosed with an eating disorder, not otherwise specified, and admitted to a specialized nutritional rehabilitation program.Conclusion. The nonspecific clinical history, physical exam, and laboratory abnormalities of eating disorders can make these diagnoses challenging and delay appropriate treatment. Clinicians should consider eating disorders in patients with malnutrition, severe lymphopenias, and gelatinous marrow transformation early in their workup, so as to avoid potentially negative outcomes.
Generalizing Benford′s Law Using Power Laws: Application to Integer Sequences
Authors: Hürlimann Werner
Published: August 2009

Many distributions for first digits of integer sequences are not Benford. A simple method to derive parametric analytical extensions of Benford′s law for first digits of numerical data is proposed. Two generalized Benford distributions are considered, namely, the two‐sided power Benford (TSPB) distribution, which has been introduced in Hürlimann (2003), and the new Pareto Benford (PB) distribution. Based on the minimum chi‐square estimators, the fitting capabilities of these generalized Benford distributions are illustrated and compared at some interesting and important integer sequences. In particular, it is significant that much of the analyzed integer sequences follow with a highP‐value the generalized Benford distributions. While the sequences of prime numbers less than 1000, respectively, 10 000 are not at all Benford or TSPB distributed, they are approximately PB distributed with highP‐values of 93.3% and 99.9% and reveal after a further deeper analysis of longer sequences a new interesting property. On the other side, Benford′s law of a mixing of data sets is rejected at the 5% significance level while the PB law is accepted with a 93.6%P‐value, which improves theP‐value of 25.2%, which has been obtained previously for the TSPB law.
Experimental Studies of Natural Convection Heat Transfer of Al2O3/DI Water Nanoparticle Suspensions (Nanofluids)
Authors: Li Calvin H. , Peterson G. P.
Published: August 2009

The natural convection heat transfer characteristics of [Formula: see text] nanofluids comprised of 47 nm, [Formula: see text] and water, with volume fractions ranging from 0.5% through 6%, has been investigated through a set of experimental measurements. The temperature of the heated surface and the Nusselt number of different volume fractions of [Formula: see text] nanofluids natural convection tests clearly demonstrated a deviation from that of pure base fluids (distilled water). In the investigation, a deterioration of the natural convection heat transfer coefficient was observed with increases of the volume fraction of the nanoparticles in the nanofluids. The deterioration phenomenon was further investigated through a visualization study on a 850 nm diameter polystyrene particle/water suspension in a bottom heating rectangular enclosure. The influence of particle movements on the heat transfer and natural flow of the polystyrene particle/DI water suspension were filmed, and the temperature changes on the heating and cooling surfaces were recorded. The results were analyzed in an effort to explain the causes of the natural convection heat transfer deterioration of the 47 nm [Formula: see text] nanofluids observed in the experiments. The visualization results confirmed the natural convective heat transfer deterioration, and further explained the causes of the deterioration of the nanofluids natural convective heat transfer.
Laser-Induced Optical Breakdown in Methane: Diagnostic Using H-Gamma Line Broadening
Authors: Parigger Christian G. , Oks Eugene
Published: August 2009

Measurements and analysis are reported of Stark-broadened profiles of the H-gamma line emitted from plasma formed by Laser-Induced Optical Breakdown (LIOB) in a pulsed methane flow. Electron densities Ne are deduced for 18 instants of time in the range between 0.4 and 2.1 microseconds after LIOB and for 2 different gas pressures. The obtained values of Ne are in a good agreement with the corresponding values found previously from Stark-broadened profiles of the H-alpha and H-beta lines.
Synoptic and Meso-α Scale Aspects of Flash Flood Events1
Authors: Maddox R. A. , Chappell C. F. , Hoxit L. R.
Published: August 2009

Meteorological conditions associated with more than 150 intense convective precipitation events have been examined. These heavy rainfalls caused flash floods and affected most geographic regions of the conterminous United States. Heavy rains associated with weather systems of tropical origin were not considered. Analyses of surface and standard level upper-air data were undertaken to identify and define important synoptic and mesoscale mechanisms that act to intensify and focus precipitation events over specific regions. These analyses indicated that three basic meteorological patterns were associated with flash flooding in the central and eastern United States. Heavy convective precipitation episodes that occurred in the West were considered as a separate category event. Climatological characteristics, composite analyses, and upper-air data are presented for these four classifications of events.

The large variability of associated meteorological patterns and parameters (especially winds aloft) makes identification of necessary conditions for flash flood-producing rainfall quite difficult; however, a number of features were common to many of the events. An advancing middle-level, short-wave trough often helped to trigger and focus thunderstorm activity. The storm areas were often located very near the mid-tropospheric, large-scale ridge position and occurred within normally benign surface pressure patterns. Many of the intense rainfalls occurred during nighttime hours. These elusive characteristics further complicate a difficult forecast problem.
The Impact of Outflow Environment on Tropical Cyclone Intensification and Structure
Authors: Rappin Eric D. , Morgan Michael C. , Tripoli Gregory J.
Published: August 2009

In this study, the impacts of regions of weak inertial stability on tropical cyclone intensification and peak strength are examined. It is demonstrated that weak inertial stability in the outflow layer minimizes an energy sink of the tropical cyclone secondary circulation and leads to more rapid intensification to the maximum potential intensity. Using a full-physics, three-dimensional numerical weather prediction model, a symmetric distribution of environmental inertial stability is generated using a variable Coriolis parameter. It is found that the lower the value of the Coriolis parameter, the more rapid the strengthening. The lower-latitude simulation is shown to have a significantly stronger secondary circulation with intense divergent outflow against a comparatively weak environmental resistance. However, the impacts of differences in the gradient wind balance between the different latitudes on the core structure cannot be neglected. A second study is then conducted using an asymmetric inertial stability distribution generated by the presence of a jet stream to the north of the tropical cyclone. The initial intensification is similar, or even perhaps slower, in the presence of the jet as a result of increased vertical wind shear. As the system evolves, convective outflow from the tropical cyclone modifies the jet resulting in weaker shear and more rapid intensification of the tropical cyclone–jet couplet. It is argued that the generation of an outflow channel as the tropical cyclone outflow expands into the region of weak inertial stability on the anticyclonic shear side of the jet stream minimizes the energy expenditure of forced subsidence by ventilating all outflow in one long narrow path, allowing radiational cooling to lessen the work of subsidence. Furthermore, it is hypothesized that evolving conditions in the outflow layer modulate the tropical cyclone core structure in such a way that tropical cyclone outflow can access weak inertial stability in the environment.
Convective-Scale Structure and Evolution during a High-Resolution Simulation of Tropical Cyclone Rapid Intensification
Authors: Rogers Robert
Published: August 2009

The role of convective-scale processes in a 1.67-km mesoscale model simulation of the rapid intensification (RI) of Hurricane Dennis (2005) is presented. The structure and evolution of inner-core precipitating areas during RI, the statistical properties of precipitation during times experiencing vigorous convection (termed convective bursts here) and how they differ from nonburst times, possible differences in convective bursts associated with RI and those not associated with RI, and the impacts of precipitation morphology on the vortex-scale structure and evolution during RI are all examined. The onset of RI is linked to an increase in the areal extent of convective precipitation in the inner core, while the inner-core stratiform precipitating area remains unchanged and the intensity increases only after RI has begun. RI is not tied to a dramatic increase in the number of convective bursts nor in the characteristics of the bursts, such as burst intensity. Rather, the immediate cause of RI is a significant increase in updraft mass flux, particularly in the lowest 1.5 km. This increase in updraft mass flux is accomplished primarily by updrafts on the order of 1–2 m s−1, representing the bulk of the vertical motion distribution. However, a period of enhanced updraft mass flux in the midlevels by moderate to strong (>5 m s−1) updrafts located inside the radius of maximum winds occurs ∼6 h prior to RI, indicating a synergistic relationship between convective bursts and the background secondary circulation prior to RI. This result supports the assertion that both buoyantly driven updrafts and slantwise near-neutral ascent are important features in eyewall structure, evolution, and intensification, including RI.
Airborne Observations of Fetch-Limited Waves in the Gulf of Tehuantepec
Authors: Romero Leonel , Melville W. Kendall
Published: August 2009

The authors present airborne observations of fetch-limited waves during strong offshore winds in the Gulf of Tehuantepec. The measurements, collected over a wide range of fetches, include one- and two-dimensional surface wavenumber spectra and turbulent fluxes in winds up to 25 m s−1. The evolution of the wave spectra is in good agreement with the fetch relationships from previous observations. The tails of the observed one-dimensional k1 spectra, in the dominant wave direction, exhibit a power law over a wide range of wavenumbers. The authors present the first quantification of the transition between the equilibrium and saturation ranges for the omnidirectional spectrum in the wavenumber domain. The energy density within the equilibrium range shows a dependence on the wave age. At wavenumbers higher than the spectral peak, the width of the spectrum in the direction orthogonal to the dominant waves is nearly independent of the wave age. However, in the azimuthal direction, the spreading of the spectrum decreases with increasing effective wave age. The bimodal directional distribution, characterized by the lobe amplitude and separation, shows a consistent scaling with both parameters collapsing when scaled by the square root of the wave age. The one-dimensional fetch-limited k1 spectrum is well parameterized with dependence on the effective fetch and friction velocity. At higher wavenumbers within the saturation range, although the one-dimensional saturation in the dominant wave direction is independent of the wind forcing, the saturation in the crosswind direction is weakly dependent on the effective wave age and on average 30% larger than that in the downwind direction. The results are discussed in the context of previous observations and current numerical wind-wave prediction models.
Numerical Modeling of Fetch-Limited Waves in the Gulf of Tehuantepec
Authors: Romero Leonel , Melville W. Kendall
Published: August 2009

During the Gulf of Tehuantepec Experiment (GOTEX), conducted in February 2004, surface-wave measurements were collected using a scanning lidar [Airborne Topographic Mapper (ATM)] on the National Science Foundation (NSF)/NCAR C-130 aircraft during fetch-limited conditions with winds speeds ranging from 10 to 25 m s−1. The authors present direct comparisons between the observed evolution of the wave field and numerical simulations using a parameterization of the wave energy dissipation. For low and intermediate wavenumbers, the dissipation corresponds to the saturation-based parameterization by Alves and Banner. However, at higher wavenumbers, their formulation cannot maintain saturation of the spectrum. Here, the authors use a dissipation term that forces the spectrum to match the empirical degree of saturation and explicitly balances the wind input and the nonlinear energy fluxes. All model simulations were carried out with “exact” computations of the nonlinear energy transfer because of four-wave resonant interactions and two empirical wind input functions. There is a good agreement for the integral parameters between the observations and the simulations, with root-mean-square (rms) errors between 5% and 12%. The tail of the computed omnidirectional wavenumber spectrum ϕ(k) can be approximated by two ranges: an equilibrium range, where ϕ ∝ k−5/2, and a saturation range, where ϕ = Bk−3, where B is the empirically determined degree of saturation. However, within the equilibrium range, the modeled ϕ overestimates the energy with rms errors between 20% and 50%, and the computed spectra are found to be narrower than the observations by about 10°. Similarly, the modeled bimodal directional distributions, at wavenumbers higher than the spectral peak, exhibit lobe separations and amplitudes that are consistently smaller than the observations. The lobe separation of the bimodal directional distribution for all simulations approximately scales with the square root of the wave age, which is consistent with the observations. The reasons for differences between the measurements and the simulations are discussed.
The Airborne Demonstrator for the Direct-Detection Doppler Wind Lidar ALADIN on ADM-Aeolus. Part II: Simulations and Rayleigh Receiver Radiometric Performance
Authors: Paffrath Ulrike , Lemmerz Christian , Reitebuch Oliver , Witschas Benjamin , Nikolaus Ines , Freudenthaler Volker
Published: August 2009

In the frame of the Atmospheric Dynamics Mission Aeolus (ADM-Aeolus) satellite mission by the European Space Agency (ESA), a prototype of a direct-detection Doppler wind lidar was developed to measure wind from ground and aircraft at 355 nm. Wind is measured from aerosol backscatter signal with a Fizeau interferometer and from molecular backscatter signal with a Fabry–Perot interferometer. The aim of this study is to validate the satellite instrument before launch, improve the retrieval algorithms, and consolidate the expected performance. The detected backscatter signal intensities determine the instrument wind measurement performance among other factors, such as accuracy of the calibration and stability of the optical alignment. Results of measurements and simulations for a ground-based instrument are compared, analyzed, and discussed. The simulated atmospheric aerosol models were validated by use of an additional backscatter lidar. The measured Rayleigh backscatter signals of the wind lidar prototype up to an altitude of 17 km are compared to simulations and show a good agreement by a factor better than 2, including the analyses of different error sources. First analyses of the signal at the Mie receiver from high cirrus clouds are presented. In addition, the simulations of the Rayleigh signal intensities of the Atmospheric Laser Doppler Instrument (ALADIN) Airborne Demonstrator (A2D) instrument on ground and aircraft were compared to simulations of the satellite system. The satellite signal intensities above 11.5 km are larger than those from the A2D ground-based instrument and always smaller than those from the aircraft for all altitudes.
Calibration of a Multichannel Water Vapor Raman Lidar through Noncollocated Operational Soundings: Optimization and Characterization of Accuracy and Variability
Authors: Dionisi Davide , Congeduti Fernando , Liberti Gian Luigi , Cardillo Francesco
Published: August 2009

This paper presents a parametric automatic procedure to calibrate the multichannel Rayleigh–Mie–Raman lidar at the Institute for Atmospheric Science and Climate of the Italian National Research Council (ISAC-CNR) in Tor Vergata, Rome, Italy, using as a reference the operational 0000 UTC soundings at the WMO station 16245 (Pratica di Mare) located about 25 km southwest of the lidar site. The procedure, which is applied to both channels of the system, first identifies portions of the lidar and radiosonde profiles that are assumed to sample the same features of the water vapor profile, taking into account the different time and space sampling. Then, it computes the calibration coefficient with a best-fit procedure, weighted by the instrumental errors of both radiosounding and lidar. The parameters to be set in the procedure are described, and values adopted are discussed. The procedure was applied to a set of 57 sessions of nighttime 1-min-sampling lidar profiles (roughly about 300 h of measurements) covering the whole annual cycle (February 2007–September 2008). A calibration coefficient is computed for each measurement session. The variability of the calibration coefficients (∼10%) over periods with the same instrumental setting is reduced compared to the values obtained with the previously adopted, operator-assisted, and time-consuming calibration procedure. Reduction of variability, as well as the absence of evident trends, gives confidence both on system stability as well as on the developed procedure. Because of the definition of the calibration coefficient and of the different sampling between lidar and radiosonde, a contribution to the variability resulting from aerosol extinction and to the spatial and temporal variability of the water vapor mixing ratio is expected. A preliminary analysis aimed at identifying the contribution to the variability from these factors is presented. The parametric nature of the procedure makes it suitable for application to similar Raman lidar systems.
Economics Imperialism
Authors: Mäki Uskali
Published: August 2009

The paper seeks to offer [1] an explication of a concept of economics imperialism, focusing on its epistemic aspects; and [2] criteria for its normative assessment. In regard to [1], the defining notion is that of explanatory unification across disciplinary boundaries. As to [2], three kinds of constraints are proposed. An ontological constraint requires an increased degree of ontological unification in contrast to mere derivational unification. An axiological constraint derives from variation in the perceived relative significance of the facts explained. An epistemological constraint requires strong fallibilism acknowledging a particularly severe epistemic uncertainty and proscribing against over-confident arrogance.
In Defense of Organizational Evolution
Authors: Lemos John
Published: August 2009

Organizational ecology applies Darwinian principles of natural selection to understand the evolution of new forms of organizations over time. The idea here is that there are different forms of human organizations, such as different business organizations, religious organizations, political organizations, etc. The growth of new forms of organizations within each of these fields is to be understood in terms of a struggle for existence among organizations with different traits. In a recent article, Reydon and Scholz (2009) argue that this Darwinian view of the evolution of new organizational forms is highly problematic because organizational populations do not exhibit the levels of internal cohesion, isolation, and closure that are necessary for something like Darwinian evolution to occur. In this article, I defend organizational ecology by rebutting the arguments of Reydon and Scholz.
The Impact of Multidimensionality on the Detection of Differential Bundle Functioning Using Simultaneous Item Bias Test
Authors: Furlow Carolyn F. , Raiford Ross Terris , Gagné Phill
Published: August 2009

Douglas, Roussos, and Stout introduced the concept of differential bundle functioning (DBF) for identifying the underlying causes of differential item functioning (DIF). In this study, reference group was simulated to have higher mean ability than the focal group on a nuisance dimension, resulting in DIF for each of the multidimensional items that, when examined together, produced DBF. The empirical power and the Type I error of the Simultaneous Item Bias Test for DBF analysis were examined under various sample sizes, ratios of reference to focal group sizes, correlations between target and nuisance dimensions, magnitudes of DIF/ DBF, test lengths, percentages of test items in the bundle, and item discriminations. Power was generally high in cells with larger DIF magnitudes, higher percentages of items in the bundle, larger sample sizes, and with the nuisance dimension having a higher discrimination than the target dimension. Type I error rates approximated the nominal alpha rate for all conditions.
Explaining multiple sclerosis prevalence by ultraviolet exposure: a geospatial analysis
Authors: Beretich BD , Beretich TM
Published: August 2009

Background

Epidemiologic studies have shown a positive correlation of multiple sclerosis (MS) prevalence with latitude. However, there has not been a causal association found. Increased dietary intake and increased serum levels of vitamin D showed to be protective for the development of MS. Ultraviolet (UV) radiation plays an important role in vitamin D synthesis and could potentially explain both latitude differences in MS prevalence and the low levels of vitamin D in individuals with MS.

Objective

To evaluate the relationship between UV radiation and MS prevalence using geospatial analysis.

Methods

Geospatial analysis was performed on North American regions and separately for the continental United States. The correlation of UV radiation (measured as UV index [UVI]) versus MS prevalence and UV radiation versus case-control ratios was calculated. In addition, the relative risk (RR) of MS was determined for regions/states with low UV radiation exposure.

Results

Case-control ratios by US state and MS prevalence by North American region showed a strong negative (inverse) correlation with UVI ( R = −0.72 and −0.86, respectively). The RR for the five highest risk states/lowest UVI versus the five lowest risk states/highest UVI was increased (RR = 1.8–5.4). The RR for MS, when comparing North American regions with lowest and highest UVI, was 3.78 and within US regions was 1.52.

Conclusion

This analysis suggests a strong association between UV radiation and MS distribution, and an increase in risk for MS in those areas with a low UVI.
Allergy and multiple sclerosis: a population-based case-control study
Authors: Pedotti R , Farinotti M , Falcone C , Borgonovo L , Confalonieri P , Campanella A , Mantegazza R , Pastorello E , Filippini G
Published: August 2009

Background

Epidemiological studies on the association between allergic disorders, T-helper type 2 (Th2) mediated, and multiple sclerosis (MS), a T-helper type 1 (Th1)/Th17-mediated disease, provided conflicting results.

Objective

The aim of this study was to further examine the association between allergic disorders and MS.

Methods

The association between MS and previous medical history of any type of allergy has been investigated in a population-based case-control study conducted in Northern Italy, based on telephone interviews to 423 cases and 643 population controls (refusal rates 3.7% and 9.4%, respectively). Controls were a random sample of the general population.

Results

A history of atopic allergies seems to confer protection against MS (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.38–0.89; P = 0.012). In particular, the prevalence of allergic asthma was 4.9% in people with MS and 12% in control subjects (OR = 0.38; 95% CI 0.22–0.66, P < 0.01). No association was found between MS and nonatopic allergies.

Conclusions

Our findings are confirmatory of the putative protective effect of Th2-mediated disorders on Th1 immune responses associated with MS. A unifying theory on the mechanisms by which previous history of atopic allergies may modify the risk of MS is still lacking.
Serum leptin levels during pregnancy in multiple sclerosis
Authors: Neuteboom RF , Verbraak E , Voerman JSA , van Meurs M , Steegers EAP , de Groot CJM , Laman JD , Hintzen RQ
Published: August 2009

Background

Disease activity in patients with multiple sclerosis (MS) is suppressed during pregnancy, whereas attack frequency increases after delivery. It is yet unclear, which immuno – endocrinological processes mediate these disease fluctuations. Leptin has been identified as a hormone that can influence inflammatory activity.

Objective

The aim of this study was to investigate whether pregnancy-induced fluctuations of serum leptin levels differed between patients with MS and controls and whether serum leptin levels correlate with periods of enhanced and diminished disease activity.

Methods

Women with MS and healthy women were prospectively followed during and after pregnancy. The MS group could be studied already at a timepoint before pregnancy. Serum leptin and soluble leptin receptor (SLR) levels were measured using enzyme-linked immunosorbent assay.

Results

Pre-pregnancy serum leptin levels were (mean ± SD) 22.9 ± 12.8 ng/ml in the MS group. These levels increased in the third trimester to 28.5 ± 15.0 ng/ml ( P = 0.007). The third trimester serum leptin levels in healthy women were comparable, 29.4 ± 19.0 ng/ml. Serum leptin levels after delivery dropped to 18.5 ± 12.8 ng/ml in women with MS ( P < 0.001) and to a lesser extend (22.0 ± 17.5 ng/ml) in healthy women ( P = 0.04). SLR levels showed the same pattern. Remarkably, women with the highest relative decrease in serum leptin levels after delivery had more often a postpartum relapse ( P = 0.008).

Conclusion

In women with MS, leptin increased during late pregnancy. A postdelivery drop in leptin levels was observed in both the MS and control group. The postdelivery drop was associated with the occurrence of postpartum relapse.
Bayesian design using adult data to augment pediatric trials
Authors: Schoenfeld David A , Hui Zheng  , Finkelstein Dianne M
Published: August 2009

Background It can be difficult to conduct pediatric clinical trials because there is often a low incidence of the disease in children, making accrual slow or infeasible. In addition, low mortality and morbidity in this population make it impractical to achieve adequate power. In this case, the only evidence for treatment efficacy comes from adult trials. Since pediatric care providers are accustomed to relying on evidence from adult studies, it is natural to consider borrowing information from adult trials.

Purpose The goal of this article is to propose a Bayesian approach to the design and analysis of pediatric trials to allow borrowing strength from previous or simultaneous adult trials.

Methods We apply a hierarchical model for which the efficacy parameter from the adult trial and that of the pediatric trail are considered to be draws from a normal distribution. The choice of (the variance of) this distribution is guided by discussion with medical experts. We show that with this information, one can calculate the sample size required for the pediatric trial. We discuss how inference of these studies in pediatric populations depends on the parameter that captures the similarity of the treatment efficacy in adults compared to children.

Results The Bayesian approach can substantially increase the power of a pediatric clinical trial (or equivalently decrease the number of subjects required) by formally leveraging the data from the adult trial.

Limitations Our method relies on obtaining a value for the inter-study variability, ν, which may be difficult to describe to a clinical investigator.

Conclusions The Bayesian approach has the potential of making pediatric clinical trials feasible because it has the effect of borrowing strength from adult trials, thus requiring a smaller pediatric trial to show efficacy of a drug in children. Clinical Trials 2009; 6: 297—304. http://ctj.sagepub.com
A human monoclonal antibody drug and target discovery platform for B-cell chronic lymphocytic leukemia based on allogeneic hematopoietic stem cell transplantation and phage display
Authors: Baskar Sivasubramanian , Suschak Jessica M. , Samija Ivan , Srinivasan Ramaprasad , Childs Richard W. , Pavletic Steven Z. , Bishop Michael R. , Rader Christoph
Published: August 2009

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only potentially curative treatment available for patients with B-cell chronic lymphocytic leukemia (B-CLL). Here, we show that post-alloHSCT antibody repertoires can be mined for the discovery of fully human monoclonal antibodies to B-CLL cell-surface antigens. Sera collected from B-CLL patients at defined times after alloHSCT showed selective binding to primary B-CLL cells. Pre-alloHSCT sera, donor sera, and control sera were negative. To identify post-alloHSCT serum antibodies and subsequently B-CLL cell-surface antigens they recognize, we generated a human antibody-binding fragment (Fab) library from post-alloHSCT peripheral blood mononuclear cells and selected it on primary B-CLL cells by phage display. A panel of Fab with B-CLL cell-surface reactivity was strongly enriched. Selection was dominated by highly homologous Fab predicted to bind the same antigen. One Fab was converted to immunoglobulin G1 and analyzed for reactivity with peripheral blood mononuclear cells from B-CLL patients and healthy volunteers. Cell-surface antigen expression was restricted to primary B cells and up-regulated in primary B-CLL cells. Mining post-alloHSCT antibody repertoires offers a novel route to discover fully human monoclonal antibodies and identify antigens of potential therapeutic relevance to B-CLL and possibly other cancers. Trials described herein were registered at www.clinicaltrials.gov as nos. NCT00055744 and NCT00003838.
Modeling the functional heterogeneity of leukemia stem cells: role of STAT5 in leukemia stem cell self-renewal
Authors: Heuser Michael , Sly Laura M. , Argiropoulos Bob , Kuchenbauer Florian , Lai Courteney , Weng Andrew , Leung Malina , Lin Grace , Brookes Christy , Fung Stephen , Valk Peter J. , Delwel Ruud , Löwenberg Bob , Krystal Gerald , Humphries R. Keith
Published: August 2009

Although the cancer stem cell (CSC) concept implies that CSCs are rare, recent reports suggest that CSCs may be frequent in some cancers. We hypothesized that the proportion of leukemia stem cells would vary as a function of the number of dysregulated pathways. Constitutive expression of MN1 served as a 1-oncogene model, and coexpression of MN1 and a HOX gene served as a 2-oncogene model. Leukemia-initiating cell (LIC) number and in vitro expansion potential of LICs were functionally assessed by limiting dilution analyses. LIC expansion potential was 132-fold increased in the 2- compared with the 1-oncogene model, although phenotypically, both leukemias were similar. The 2-oncogene model was characterized by granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity and activated STAT/ERK signaling. GM-CSF hypersensitivity of the 2-oncogene model (MN1/HOXA9) was lost in Stat5b−/− cells, and the LIC expansion potential was reduced by 86- and 28-fold in Stat5b−/− and Stat1−/− cells, respectively. Interestingly, in 201 acute myeloid leukemia (AML) patients, coexpression of MN1 and HOXA9 was restricted to patients with the poorest prognosis and was associated with highly active STAT signaling. Our data demonstrate the functional heterogeneity of LICs and show that STAT signaling is critical for leukemia stem cell self-renewal in MN1- and HOXA9-expressing leukemias.
Formation of 1,2-Bis(1-methyl-1,4-dihydro-4-pyridinylidene)cyclobutane by Dehydrogenated Intermolecular Cyclization of 4-Vinyl-1-methylpyridinyl Radical
Authors: Muramatsu Takashi , Toyota Azumao , Satou Yusuke
Published: August 2009

The one-electron reduction of 4-vinyl-1-methylpyridinium bromide with sodium amalgam in degassed acetonitrile at 0 °C leads to the formation of 1,2-bis(1-methyl-1,4-dihydro-4-pyridinylidene)cyclobutane, which is characterized by means of 1H NMR, 13C NMR, and UV–vis absorption spectroscopy.
Aquacatalytic Aerobic Oxidation of Benzylic Alcohols with a Self-supported Bipyridyl–Palladium Complex
Authors: Osako Takao , Uozumi Yasuhiro
Published: August 2009

The aerobic oxidation of alcohols was promoted in water under atmospheric molecular oxygen by a readily recyclable self-supported bipyridyl–palladium polymeric complex, which was prepared via construction of a metal–organic framework (MOF) of a bipyridyl–palladium complex bearing carboxylic groups and a copper(II) linker.
Placental expression of proteases and their inhibitors in patients with HELLP syndrome
Authors: von Steinburg Stephanie Pildner , Krüger Achim , Fischer Thorsten , Mario Schneider Karl-Theodor , Schmitt Manfred
Published: August 2009

In preeclampsia and hemolysis, elevated liver enzymes and low platelet (HELLP) syndrome, impaired trophoblast invasion and excessive fibrin deposition in the placental intervillous space is associated with fetal compromise. However, little information is available whether modulation of placental protease expression – potentially causing impaired trophoblast invasion – is associated with the HELLP syndrome. Total RNA and protein were extracted from placental tissue from 11 females with HELLP syndrome and 8 controls matched for gestational age. mRNA expression of matrix metalloprotease (MMP) -2 and -9, tissue inhibitors of metalloprotease (TIMP) -1, -2, and -3, and urokinase-type plasminogen activator receptor (uPAR) was determined by Northern blotting. Protein expression of MMP-2 and -9, and TIMP-1 and -2 was detected by Western blotting and that of uPA, uPAR, and plasminogen activator inhibitor (PAI) -1 by ELISA. In patients with HELLP syndrome, mRNA expression of MMP-2 and TIMP-2 was decreased, whereas TIMP-1 and -3 levels were unchanged. MMP-9 and uPAR mRNA was undetectable in both groups. Protein expression of all investigated proteolytic factors remained unchanged. Our findings at the mRNA level suggest a decrease in matrix remodeling in placentae from patients with HELLP syndrome compared with control pregnancies, although this is not supported at the protein level.
CA/C1 peptidases of the malaria parasites Plasmodium falciparum and P. berghei and their mammalian hosts – a bioinformatical analysis
Authors: Xiao Ke , Jehle Franz , Peters Christoph , Reinheckel Thomas , Schirmer R. Heiner , Dandekar Thomas
Published: August 2009

In genome-wide screens we studied CA/C1 peptidases of malaria-causing plasmodia and their hosts (man and mouse). For Plasmodium falciparum and P. berghei, several new CA/C1 peptidase genes encoding proteases of the L- and B-family with specific promoter modules were identified. In addition, two new human CA/C1 peptidase loci and one new mouse gene locus were found; otherwise, the sets of CA/C1 peptidase genes in man and mouse seem to be complete now. In each species studied there is a multitude of CA/C1 peptidases with lysosomal localization signals and partial functional overlap according to similar but subfamily-specific structures. Individual target structures in plasmodia include residues specifically different in CA/C1 peptidase subsite 2. This is of medical interest considering CA/C1 peptidase inhibition for chemotherapy in malaria, malignancies and other diseases. Promoter structures and mRNA regulation differ widely among CA/C1 peptidase subfamilies and between mammals and plasmodia. We characterized promoter modules conserved in mouse and man for the CA/C1 peptidase families B and L (with the L-like subfamily, F-like subfamily and mouse-specific J-like subfamily). RNA motif searches revealed conserved regulatory elements such as GAIT elements; plasmodial CA/C1 peptidase mRNA elements include ARE elements and mammalian mRNAs contain 15-lox DICE elements.
Ultrafast memory loss and relaxation processes in hydrogen-bonded systems
Authors: Elsaesser Thomas
Published: August 2009

Structural memory of aqueous systems, such as neat water and biomolecules, in an aqueous environment is strongly influenced by hydrogen bond dynamics. Vibrational spectroscopy in the femtosecond (fs) time domain is applied to map structural dynamics in real-time and identify underlying molecular interactions. Neat liquid water displays an ultrafast loss of structural memory with the fastest decay of structural correlations occurring in the sub-100 fs regime. Both OH stretching and bending excitations of water molecules decay on a subpicosecond time scale, followed by dissipation of excess energy in the hydrogen bond network within a few picoseconds. Water shells around fully hydrated DNA show similar although slightly slower dynamics. A detailed study of hydration shells around ionic phosphate groups in the DNA backbone demonstrates a strong phosphate-water coupling and a subpicosecond rearrangement of hydrogen bonds upon energy disposal. Hydration shells serve as primary heat sinks for excess energy.
Plasmodium falciparum glyoxalase II: Theorell-Chance product inhibition patterns, rate-limiting substrate binding via Arg257/Lys260, and unmasking of acid-base catalysis
Authors: Urscher Miriam , Deponte Marcel
Published: August 2009

Glyoxalase II (GloII) is a ubiquitous thioester hydrolase catalyzing the last step of the glutathione-dependent conversion of 2-oxoaldehydes to 2-hydroxycarboxylic acids. Here, we present a detailed structure-function analysis of cGloII from the malaria parasite Plasmodium falciparum. The activity of the enzyme was salt-sensitive and pH-log k
cat and pH-log k
cat/K
m profiles revealed acid-base catalysis. An acidic pK
a
app value of approximately 6 probably reflects hydroxide formation at the metal center. The glutathione-binding site was analyzed by site-directed mutagenesis. Substitution of residue Arg154 caused a 2.5-fold increase of K
m
app, whereas replacements of Arg257 or Lys260 were far more detrimental. Although the glutathione-binding site and the catalytic center are separated, six of six single mutations at the substrate-binding site decreased the k
cat
app value. Furthermore, product inhibition studies support a Theorell-Chance Bi Bi mechanism with glutathione as the second product. We conclude that the substrate is predominantly bound via ionic interactions with the conserved residues Arg257 and Lys260, and that correct substrate binding is a pH- and salt-dependent rate-limiting step for catalysis. The presented mechanistic model is presumably also valid for GloII from many other organisms. Our study could be valuable for drug development strategies and enhances the understanding of the chemistry of binuclear metallohydrolases.
Grenzüberschreitende Mobilität von Gesellschaften nach der Rechtsprechung des EuGH – von Daily Mail bis Cartesio
Authors: Grohmann Uwe
Published: August 2009

In den letzten Jahrzehnten hatte der EuGH die Reichweite der Niederlassungsfreiheit und damit einhergehend die grenzüberschreitende Mobilität von Gesellschaften in Europa erheblich erweitert und gestärkt. Der nachfolgende Beitrag beleuchtet die wichtigsten Entscheidungen des EuGH und bewertet die europäischen Unternehmen danach offen stehenden Möglichkeiten, grenzüberschreitend tätig zu werden.
A Predictive Solubility Tool for Pesticide Emulsifiable Concentrate Formulations
Authors: Kozuki Y. , Ohtsubo T.
Published: August 2009

Emulsifiable concentrates (ECs) are one of the most widely used pesticide formulations because they have a lot of advantages, such as good storage stability, relatively high biological activity, easy weighing, easy production, and so on. An EC is normally prepared by dissolving a pesticide in a nonpolar solvent with surfactants. When a pesticide is hardly soluble in a common nonpolar solvent, a polar solvent is used as a co-solvent. One of the preferred polar solvents, which have been used for this purpose is N-methyl-2-pyrrolidone (NMP). However, because of its toxic profile, which has recently become apparent, the commercial use of NMP is recently restricted in many fields. Under the circumstances, it is desirable to look for an alternative solvent in the pesticide formulation area. The organic conceptual diagram was tried to search for the alternative solvents because it is a useful tool for predicting the physico-chemical properties of an organic compound. In the organic conceptual diagram, the physico-chemical properties are expressed by the combination of the organic value (OV) and the inorganic value (IV). According to the theory, organic compounds that have similar IV/OV ratios (the inorganic organic balance=IOB) are mutually miscible in each other. In order to investigate the applicability of this concept to search for a suitable solvent for a pesticide that is hardly soluble in nonpolar solvents, the relationship of the IOB between two hardly soluble pesticides (i.e., a neonicotinoid insecticide and an herbicide) and several types of solvents was evaluated. As expected, solvents having an IOB close to the targeted pesticide showed high solvency against it, while the pesticide did not dissolve in solvents, which have an IOB farther off. It was demonstrated that the organic conceptual diagram can be a good tool for the selection of a solvent for a pesticide that is hardly soluble in the usual nonpolar solvents.
Effect of polymers on swelling potential of expansive soils
Authors: Mirzababaei M. , Yasrobi S. , Al-Rawas A.
Published: August 2009

This paper introduces new soil stabilisers for reducing the swelling potential of expansive soils. In this study three different polymers (furan, poly(methyl methacrylate) (PMMA) and poly(vinyl acetate) (PVA)) were utilised as soil stabilisers. For evaluating the effect of these polymers on swelling potential and microfabric of expansive soils, three soil samples of high plasticity index were selected. First the engineering, chemical and mineralogical characteristics of the untreated soils were determined, and three different pairs of dry density and water content (dry of optimum, optimum and wet of optimum) were chosen, from standard Proctor compaction curve. Treated soil specimens were prepared at 3%, 5% and 10% of furan content and 1%, 3% and 5% of polymethyl methacrylate and polyvinyl acetate content. The addition of polymethyl methacrylate and polyvinyl acetate can also diminish the swelling potential of soil specimens, but to a lesser degree. The addition of additives produced aggregations and clay-granular matrices within the fabric, which reduced the swelling potential of the soil samples.
Densification of granular soil by dynamic compaction
Authors: Bo M. W. , Na Y. M. , Arulrajah A. , Chang M. F.
Published: August 2009

Land reclamation often involves the placement of loose granular soil by means of hydraulic filling. Sand fill formed by hydraulic filling generally does not allow densification by surface compaction methods because of their limited depth of influence. Loose granular soil is susceptible to liquefaction upon the impact of dynamic forces. Even under static conditions, loose granular soil may be subjected to bearing capacity failure and large settlements, because of its low shearing resistance and high compressibility. Various densification methods are used for improving such soils to increase the friction angle and elastic modulus. Several methods of deep compaction are available for such applications; among these, dynamic compaction is one of the most effective ways of densifying granular soils to a significant depth. However, the success of dynamic compaction is affected by many factors, several of which are not yet fully understood. This paper deals with the dynamic compaction densification method utilised at the Changi East reclamation site in Singapore for the improvement of reclaimed sand fill. Field data collected are used as a basis to investigate the effectiveness of the densification method and the effect of various influencing factors critical to the success of dynamic compaction treatment.
Stabilisation of desert sands using cement and cement dust
Authors: Al-Aghbari M. Y. , Mohamedzein Y. E.-A. , Taha R.
Published: August 2009

Desert sands cover vast areas in Oman, and create major problems for the construction of infrastructure. The low bearing capacity of the desert sands, and their susceptibility to collapse on wetting, preclude the support of structures on them. This paper presents experimental results on the use of different additives to stabilise desert sands for possible use as a foundation-bearing soil. Stabilising agents included Portland cement and cement by-pass dust (or cement kiln dust), and were added in amounts of 2%, 4%, 8%, 10% and 12% by dry weight of soil. Laboratory tests such as compaction, unconfined compression and shear box tests were performed to measure the engineering characteristics of the stabilised material. The results showed substantial improvements in maximum dry density, unconfined compressive strength, and shear strength parameters (c and φ). Thus cement and cement by-pass dust can be used to improve the compressibility and shear strength characteristics of desert sands.