bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutations of key hydrophobic surface residues of 11β‐hydroxysteroid dehydrogenase type 1 increase solubility and monodispersity in a bacterial expression system
Authors: Lawson Alexander J. , Walker Elizabeth A. , White Scott A. , Dafforn Timothy R. , Stewart Paul M. , Ride Jonathan P. 
Published: April 2009

Abstract11β‐Hydroxysteroid dehydrogenase type 1 (11β‐HSD1) is a key enzyme in the conversion of cortisone to the functional glucocorticoid hormone cortisol. This activation has been implicated in several human disorders, notably the metabolic syndrome where 11β‐HSD1 has been identified as a novel target for potential therapeutic drugs. Recent crystal structures have revealed the presence of a pronounced hydrophobic surface patch lying on two helices at the C‐terminus. The physiological significance of this region has been attributed to facilitating substrate access by allowing interactions with the endoplasmic reticulum membrane. Here, we report that single mutations that alter the hydrophobicity of this patch (I275E, L266E, F278E, and L279E in the human enzyme and I275E, Y266E, F278E, and L279E in the guinea pig enzyme) result in greatly increased yields of soluble protein on expression in E. coli. Kinetic analyses of both reductase and dehydrogenase reactions indicate that the F278E mutant has unaltered Km values for steroids and an unaltered or increased kcat. Analytical ultracentrifugation shows that this mutation also decreases aggregation of both the human and guinea pig enzymes, resulting in greater monodispersity. One of the mutants (guinea pig F278E) has proven easy to crystallize and has been shown to have a virtually identical structure to that previously reported for the wild‐type enzyme. The human F278E enzyme is shown to be a suitable background for analyzing the effects of naturally occurring mutations (R137C, K187N) on enzyme activity and stability. Hence, the F278E mutants should be useful for many future biochemical and biophysical studies of the enzyme.
L2′ loop is critical for caspase‐7 active site formation
Authors: Witkowski Witold A. , Hardy Jeanne A. 
Published: April 2009

AbstractThe active sites of caspases are composed of four mobile loops. A loop (L2) from one half of the dimer interacts with a loop (L2′) from the other half of the dimer to bind substrate. In an inactive form, the two L2′ loops form a cross‐dimer hydrogen‐bond network over the dimer interface. Although the L2′ loop has been implicated as playing a central role in the formation of the active‐site loop bundle, its precise role in catalysis has not been shown. A detailed understanding of the active and inactive conformations is essential to control the caspase function. We have interrogated the contributions of the residues in the L2′ loop to catalytic function and enzyme stability. In wild‐type and all mutants, active‐site binding results in substantial stabilization of the complex. One mutation, P214A, is significantly destabilized in the ligand‐free conformation, but is as stable as wild type when bound to substrate, indicating that caspase‐7 rests in different conformations in the absence and presence of substrate. Residues K212 and I213 in the L2′ loop are shown to be essential for substrate‐binding and thus proper catalytic function of the caspase. In the crystal structure of I213A, the void created by side‐chain deletion is compensated for by rearrangement of tyrosine 211 to fill the void, suggesting that the requirements of substrate‐binding are sufficiently strong to induce the active conformation. Thus, although the L2′ loop makes no direct contacts with substrate, it is essential for buttressing the substrate‐binding groove and is central to native catalytic efficiency.
Daily consumption of Reliv Glucaffect™ for 8 weeks significantly lowered blood glucose and body weight in 50 subjects
Authors: Belcaro Gianni , Cesarone Maria , Silvia Errichi , Ledda Andrea , Stuard Stefano , G Vinciguerra , Dougall Mark , Cornelli Umberto , Hastings Carl , Schönlau Frank 
Published: April 2009

AbstractA public change to healthier lifestyles with more physical activity and better nutrition, including caloric restriction, is required to address the obesity epidemic. Weight loss can be achieved by caloric restrictions; current research suggests that this may be achieved by consumption of slowly absorbed carbohydrates owing to the resulting prolonged satiety.Our rationale was to prolong the satiety of overweight volunteers by supplementation with a proprietary formulation Glucaffect™ which delays absorption of carbohydrates. Glucaffect™ provides potent α‐glucosidase inhibitors of herbal source such Pycnogenol®, Madeglucyl™ and various others which obstruct absorption of carbohydrates, such as starch.Fifty overweight subjects received either Glucaffect™ or an inactive control product for eight weeks. Consumption of Glucaffect™ was found to statistically significantly lower blood‐fasting glucose from baseline 145.3 mg/dL to 101.1 mg/dL (−30.4%) and Hba1c from 7.59% to 6.33% as compared to the control group where values decreased only marginally.The weight and the body mass index (BMI) decreased significantly from an average of 88.5 kg (BMI 26.8 kg/m2) to 81.3 kg (BMI 24.5 kg/m2) as compared to the control group.In conclusion, Glucaffect™ enabled subjects with metabolic syndrome to achieve healthy BMI and blood glucose levels. Glucaffect™ was well tolerated and no subject dropped out. Copyright © 2009 John Wiley & Sons, Ltd.
Development, Validation and Inspection of the Applicability Domain of QSPR Models for Physicochemical Properties of Polybrominated Diphenyl Ethers
Authors: Papa Ester , Kovarich Simona , Gramatica Paola 
Published: April 2009

AbstractPolybrominated diphenyl ethers (PBDEs) are a group of brominated flame retardants (BFRs), which were widely used in a variety of consumer products. Because of evidences of toxicity effects on different organisms and humans, as well as the ubiquitary profile of these compounds, PBDEs are considered an emerging group of toxic and persistent organic pollutants. However, due to the small amount of experimental data available, still little is known about the properties of most of these chemicals. In this study several physicochemical properties, experimentally available for few PBDE congeners and hexabromobenzene (HBB), were investigated through a modelling approach based on quantitative structure–property relationships (QSPR). The OLS regression models, based on theoretical molecular descriptors, are calculated for Henry's law constant, melting point, subcooled liquid vapor pressure, water solubility, octanol‐air partition coefficient, and octanol‐water partition coefficient. These models can be useful to predict the big amount of missing data and to plan safer alternatives to dangerous BFRs. The innovative aspect of the proposed models, compared to those already published in the literature, is their development according to the OECD principles for regulatory acceptability of QSARs. This includes the validation for predictivity (both by internal and external statistical validation) and the inspection of the applicability domain.
Global or Local QSAR: Is There a Way Out?
Authors: Feher Miklos , Ewing Todd 
Published: April 2009

AbstractWe recently developed a global‐local fusion model for CYP450 predictions. This model has the advantages of both global and local models. The expected error of the model is also estimated that helps to qualify the reliability of the predictions. It is described how different potential errors in QSAR model generation and prediction were averted and how the method was applied in an industrial environment.
Standardization of the first‐trimester fetal cardiac examination using spatiotemporal image correlation with tomographic ultrasound and color Doppler imaging
Authors: Turan S. , Turan O. M. , Ty‐Torredes K. , Harman C. R. , Baschat A. A. 
Published: April 2009

AbstractObjectiveThe challenges of the first‐trimester examination of the fetal heart may in part be overcome by technical advances in three‐dimensional (3D) ultrasound techniques. Our aim was to standardize the first‐trimester 3D imaging approach to the cardiac examination to provide the most consistent and accurate display of anatomy.MethodsLow‐risk women with normal findings on first‐trimester screening at 11 to 13 + 6 weeks had cardiac ultrasound using the following sequence: (1) identification of the four‐chamber view; (2) four‐dimensional (4D) volume acquisition with spatiotemporal image correlation (STIC) and color Doppler imaging (angle = 20°, sweep 10 s); (3) offline, tomographic ultrasound imaging (TUI) analysis with standardized starting plane (four‐chamber view), slice number and thickness; (4) assessment of fetal cardiac anatomy (four‐chamber view, cardiac axis, size and symmetry, atrioventricular valves, great arteries and descending aorta) with and without color Doppler.Results107 consecutive women (age, 16–42 years, body mass index 17.2–50.2 kg/m2) were studied. A minimum of three 3D volumes were obtained for each patient, transabdominally in 91.6%. Fetal motion artifact required acquisition of more than three volumes in 20%. The median time for TUI offline analysis was 100 (range, 60–240) s. Individual anatomic landmarks were identified in 89.7–99.1%. Visualization of all structures in one panel was observed in 91 patients (85%).ConclusionStarting from a simple two‐dimensional cardiac landmark—the four‐chamber view—the standardized STIC‐TUI technique enables detailed segmental cardiac evaluation of the normal fetal heart in the first trimester. Copyright © 2009 ISUOG. Published by John Wiley & Sons, Ltd.
Shape optimization of wind turbine blades
Authors: Xudong Wang , Shen Wen Zhong , Zhu Wei Jun , Sørensen Jens Nørkær , Jin Chen 
Published: April 2009

AbstractThis paper presents a design tool for optimizing wind turbine blades. The design model is based on an aerodynamic/aero‐elastic code that includes the structural dynamics of the blades and the Blade Element Momentum (BEM) theory. To model the main aero‐elastic behaviour of a real wind turbine, the code employs 11 basic degrees of freedom corresponding to 11 elastic structural equations. In the BEM theory, a refined tip loss correction model is used. The objective of the optimization model is to minimize the cost of energy which is calculated from the annual energy production and the cost of the rotor. The design variables used in the current study are the blade shape parameters, including chord, twist and relative thickness. To validate the implementation of the aerodynamic/aero‐elastic model, the computed aerodynamic results are compared to experimental data for the experimental rotor used in the European Commision‐sponsored project Model Experiments in Controlled Conditions, (MEXICO) and the computed aero‐elastic results are examined against the FLEX code for flow past the Tjæreborg 2 MW rotor. To illustrate the optimization technique, three wind turbine rotors of different sizes (the MEXICO 25 kW experimental rotor, the Tjæreborg 2 MW rotor and the NREL 5 MW virtual rotor) are applied. The results show that the optimization model can reduce the cost of energy of the original rotors, especially for the investigated 2 MW and 5 MW rotors. Copyright © 2009 John Wiley & Sons, Ltd.
Optimal positioning of wind turbines on Gökçeada using multi‐objective genetic algorithm
Authors: Şişbot Sedat , Turgut Özgü , Tunç Murat , Çamdalı Ünal 
Published: April 2009

AbstractThis paper addresses the problem of optimal placement of wind turbines in a farm on Gokçeada Island located at the north‐east of Aegean Sea bearing full potential of wind energy generation. A multi‐objective genetic algorithm approach is employed to obtain optimal placement of wind turbines by maximizing the power production capacity while constraining the budget of installed turbines. Considering the speed and direction history, wind with constant intensity from a single direction is used during optimization. This study is based on wake deficit model mainly because of its simplicity, accuracy and fast calculation time. The individuals of the Pareto optimal solution set are evaluated with respect to various criteria, and the best configurations are presented. In addition to best placement layouts, results include objective function values, total power output, cost and number of turbines for each configuration. Copyright © 2009 John Wiley & Sons, Ltd.
Sox2 and Oct‐3/4: a versatile pair of master regulators that orchestrate the self‐renewal and pluripotency of embryonic stem cells
Authors: Rizzino Angie 
Published: April 2009

AbstractDuring the past 10 years, remarkable progress has been made in understanding the transcriptional mechanisms that control the biology of stem cells. Given the importance of stem cells in development, regenerative medicine, and cancer, it is no surprise that the pace of discovery continues to accelerate—paradigm‐shifting models proposed only a few years ago are quickly giving way to even more sophisticated models of regulation. This review summarizes some of the major advances made in delineating the roles of two transcription factors, Sox2 and Oct‐3/4, in stem cell biology. Additionally, unanswered questions related to their mechanisms of action are discussed. When viewed together, it is evident that Sox2 and Oct‐3/4 exhibit the major properties expected of master regulators. They are each essential for mammalian development, they help regulate the transcription of other genes that are essential for development, and they influence their own transcription by both positive and negative feedback loops. Moreover, small changes in the levels of either Sox2 or Oct‐3/4 trigger the differentiation of embryonic stem (ES) cells. Thus, each functions as a molecular rheostat to control the self‐renewal and pluripotency of ES cells. Overall, understanding how Sox2 and Oct‐3/4 function mechanistically will not only provide important insights into stem cells in general, but should also have a significant impact on our understanding of induced pluripotent stem (iPS) cells and, hence, the emerging field of regenerative medicine. Copyright © 2009 John Wiley & Sons, Inc.This article is categorized under:

Developmental Biology > Stem Cell Biology and Regeneration
Kidney modeling and systems physiology
Authors: Randall Thomas S. 
Published: April 2009

AbstractWe present an overview of currently available resources in renal systems physiology and indicate directions for development toward the renal physiome. After a brief resumé of objectives, we summarize legacy‐modeling studies that can serve as the foundation for a more complete toolset. These include detailed models of practically all renal cell types and nephron segments and a variety of models of nephro‐vascular exchanges in the medulla, of renal hemodynamics, and studies of tubuloglomerular feedback and autoregulation. Recent detailed anatomical reconstructions have brought surprising new results to bear on classic unsolved problems. In parallel with the modeling environment, progress has been made toward the quantitative database and model repository resources that must accompany the modeling environment in order to attain the goal of an open‐ended, flexible, and collaborative infrastructure for renal systems biology, with an indication of prospects for integration with initiatives in the larger IUPS Physiome Project. Copyright © 2009 John Wiley & Sons, Inc.This article is categorized under:

Models of Systems Properties and Processes > Cellular Models
Physiology > Mammalian Physiology in Health and Disease
Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models
Translational, Genomic, and Systems Medicine > Translational Medicine
Computational modeling of epithelial tissues
Authors: Smallwood Rod 
Published: April 2009

AbstractThere is an extensive literature on the computational modeling of epithelial tissues at all levels from subcellular to whole tissue. This review concentrates on behavior at the individual cell to whole tissue level, and particularly on organizational aspects, and provides an indication of where information from other areas, such as the modeling of angiogenesis, is relevant. The skin, and the lining of all of the body cavities (lung, gut, cervix, bladder etc) are epithelial tissues, which in a topological sense are the boundary between inside and outside the body. They are thin sheets of cells (usually of the order of 0.5 mm thick) without extracellular matrix, have a relatively simple structure, and contain few types of cells. They have important barrier, secretory and transport functions, which are essential for the maintenance of life, so homeostasis and wound healing are important aspects of the behavior of epithelial tissues. Carcinomas originate in epithelial tissues.There are essentially two approaches to modeling tissues—to start at the level of the tissue (i.e., a length scale of the order of 1 mm) and develop generalized equations for behavior (a continuum approach); or to start at the level of the cell (i.e., a length scale of the order of 10 µm) and develop tissue behavior as an emergent property of cellular behavior (an individual‐based approach). As will be seen, these are not mutually exclusive approaches, and they come in a variety of flavors. Copyright © 2009 John Wiley & Sons, Inc.This article is categorized under:Analytical and Computational Methods > Computational MethodsModels of Systems Properties and Processes > Organ, Tissue, and Physiological ModelsAnalytical and Computational Methods > Topological MethodsTranslational, Genomic, and Systems Medicine > Translational Medicine
Networks and pathways in pigmentation, health, and disease
Authors: Baxter Laura L. , Loftus Stacie K. , Pavan William J. 
Published: April 2009

AbstractExtensive studies of the biology of the pigment‐producing cell (melanocyte) have resulted in a wealth of knowledge regarding the genetics and developmental mechanisms governing skin and hair pigmentation. The ease of identification of altered pigment phenotypes, particularly in mouse coat color mutants, facilitated early use of the pigmentary system in mammalian genetics and development. In addition to the large collection of developmental genetics data, melanocytes are of interest because their malignancy results in melanoma, a highly aggressive and frequently fatal cancer that is increasing in Caucasian populations worldwide. The genetic programs regulating melanocyte development, function, and malignancy are highly complex and only partially understood. Current research in melanocyte development and pigmentation is revealing new genes important in these processes and additional functions for previously known individual components. A detailed understanding of all the components involved in melanocyte development and function, including interactions with neighboring cells and response to environmental stimuli, will be necessary to fully comprehend this complex system. The inherent characteristics of pigmentation biology as well as the resources available to researchers in the pigment cell community make melanocytes an ideal cell type for analysis using systems biology approaches. In this review, the study of melanocyte development and pigmentation is considered as a candidate for systems biology‐based analyses. Copyright © 2009 John Wiley & Sons, Inc.This article is categorized under:

Developmental Biology > Lineages
Vertebrate retina and hypothalamus development
Authors: Byerly Mardi S. , Blackshaw Seth 
Published: April 2009

AbstractThe vertebrate retina and hypothalamus, which emerge from adjacent regions of the ventral diencephalon, provide accessible experimental systems for analysis of the molecular mechanisms by which neuronal subtype diversity is specified, and how this neuronal subtype diversity regulates perception and behavior. Although the retina emerges as a lateral extension of the hypothalamus prior to the onset of neurogenesis, the retina and hypothalamus go on to eventually be comprised of almost entirely different cell types, and differ extensively in the spatial organization, function, and connectivity of these cells. Despite these differences in cell composition, there are a number of mechanistic and molecular similarities in the process of cell fate specification in both organs, including a stereotyped temporal sequence in which major cell types are generated. Although a handful of genes have been identified in both systems that direct cell fate specification, many more remain to be characterized, and large numbers of candidate genes have been identified in recent high‐throughput screens, particularly in retina. Experimental challenges for the near future include functional analysis of the genes identified so far, and the use of the molecular pathways gained from analysis of the development of specific neuronal lineages to study the contribution of these cells to perception and behavior. Copyright © 2009 John Wiley & Sons, Inc.This article is categorized under:Developmental Biology > Developmental Processes in Health and Disease
Left–right axis determination
Authors: Ibañes Marta , Izpisúa Belmonte Juan Carlos 
Published: April 2009

AbstractVertebrates display left‐right (L‐R) asymmetric organ positioning and morphologies, which are established during embryonic development. These asymmetries are conserved among individuals and species. How, when and where do embryos first break the symmetry? Why is it broken in a consistent direction? How is the asymmetry transmitted to and coordinated within the whole embryo? Which of these elements are conserved between different organisms? These questions have been the focus of intense research during the last decade, and much has been learned. Nonetheless, our understanding of how tissue and organ L‐R differences are established during embryogenesis is scarce. A systems biology approach may enable us to better understand the dynamics of gene networks, epigenetics, cilia, fluids, and charged molecules as well as other processes involved in the generation of the vertebrate L‐R axis. Copyright © 2009 John Wiley & Sons, Inc.This article is categorized under:

Developmental Biology > Stem Cell Biology and Regeneration
Signals controlling neural crest contributions to the heart
Authors: Scholl Ann Marie , Kirby Margaret L. 
Published: April 2009

AbstractCardiac neural crest cells represent a unique subpopulation of cranial neural crest cells that are specified, delaminate and migrate from the developing neural tube to the caudal pharynx where they support aortic arch artery development. From the caudal pharynx, a subset of these cells migrates into the cardiac outflow tract where they are needed for outflow septation. Many signaling factors are known to be involved in specifying and triggering the migration of neural crest cells. These factors have not been specifically studied in cardiac crest but are assumed to be the same as for the other regions of crest. Signaling factors like Ephs and semaphorins guide the cells into the caudal pharynx. Support of the cells in the pharynx is from endothelin, platelet‐derived growth factor (PDGF), and the transforming growth factor beta (TGFβ)/bone morphogenetic protein (BMP) signaling pathways. Mutants in the TGFβ/BMP pathway show abnormal migration or survival in the pharynx, whereas the migration of the neural crest cells into the outflow tract is orchestrated by semaphorin/plexin signaling. Although TGFβ family members have been well studied and show defective neural crest function in outflow septation, their mechanism of action remains unclear. Copyright © 2009 John Wiley & Sons, Inc.This article is categorized under:Developmental Biology > Lineages