bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling cardiac β-adrenergic signaling with normalized-Hill differential equations: comparison with a biochemical model
Authors: Kraeutler Matthew J , Soltis Anthony R , Saucerman Jeffrey J 
Published: November 2010

AbstractBackgroundNew approaches are needed for large-scale predictive modeling of cellular signaling networks. While mass action and enzyme kinetic approaches require extensive biochemical data, current logic-based approaches are used primarily for qualitative predictions and have lacked direct quantitative comparison with biochemical models.ResultsWe developed a logic-based differential equation modeling approach for cell signaling networks based on normalized Hill activation/inhibition functions controlled by logical AND and OR operators to characterize signaling crosstalk. Using this approach, we modeled the cardiac β1-adrenergic signaling network, including 36 reactions and 25 species. Direct comparison of this model to an extensively characterized and validated biochemical model of the same network revealed that the new model gave reasonably accurate predictions of key network properties, even with default parameters. Normalized Hill functions improved quantitative predictions of global functional relationships compared with prior logic-based approaches. Comprehensive sensitivity analysis revealed the significant role of PKA negative feedback on upstream signaling and the importance of phosphodiesterases as key negative regulators of the network. The model was then extended to incorporate recently identified protein interaction data involving integrin-mediated mechanotransduction.ConclusionsThe normalized-Hill differential equation modeling approach allows quantitative prediction of network functional relationships and dynamics, even in systems with limited biochemical data.
MATH5 controls the acquisition of multiple retinal cell fates
Authors: Feng Liang , Xie Zheng-hua , Ding Qian , Xie Xiaoling , Libby Richard T , Gan Lin 
Published: November 2010

Abstract

Math5-null mutation results in the loss of retinal ganglion cells (RGCs) and in a concurrent increase of amacrine and cone cells. However, it remains unclear whether there is a cell fate switch of Math5-lineage cells in the absence of Math5 and whether MATH5 cell-autonomously regulates the differentiation of the above retinal neurons. Here, we performed a lineage analysis of Math5-expressing cells in developing mouse retinas using a conditional GFP reporter (Z/EG) activated by a Math5-Cre knock-in allele. We show that during normal retinogenesis, Math5-lineage cells mostly develop into RGCs, horizontal cells, cone photoreceptors, rod photoreceptors, and amacrine cells. Interestingly, amacrine cells of Math5-lineage cells are predominately of GABAergic, cholinergic, and A2 subtypes, indicating that Math5 plays a role in amacrine subtype specification. In the absence of Math5, more Math5-lineage cells undergo cell fate conversion from RGCs to the above retinal cell subtypes, and occasionally to cone-bipolar cells and Müller cells. This change in cell fate choices is accompanied by an up-regulation of NEUROD1, RXRγ and BHLHB5, the transcription factors essential for the differentiation of retinal cells other than RGCs. Additionally, loss of Math5 causes the failure of early progenitors to exit cell cycle and leads to a significant increase of Math5-lineage cells remaining in cell cycle. Collectively, these data suggest that Math5 regulates the generation of multiple retinal cell types via different mechanisms during retinogenesis.
Microbiological contamination of cubicle curtains in an out‐patient podiatry clinic
Authors: Woodland Ria , Whitham Deborah , O'Neil Bill , Otter Simon 
Published: November 2010

AbstractBackgroundExposure to potential pathogens on contaminated healthcare garments and curtains can occur through direct or indirect contact. This study aimed to identify the microorganisms present on podiatry clinic curtains and measure the contamination pre and post a standard hospital laundry process.MethodBaseline swabs were taken to determine colony counts present on cubical curtains before laundering. Curtains were swabbed again immediately after, one and three weeks post laundering. Total colony counts were calculated and compared to baseline, with identification of micro‐organisms.ResultsTotal colony counts increased very slightly by 3% immediately after laundry, which was not statistically significant, and declined significantly (p = 0.0002) by 56% one‐week post laundry. Three weeks post laundry colony counts had increased by 16%; although clinically relevant, this was not statistically significant. The two most frequent microorganisms present throughout were Coagulase Negative Staphylococcus and Micrococcus species. Laundering was not completely effective, as both species demonstrated no significant change following laundry.ConclusionThis work suggests current laundry procedures may not be 100% effective in killing all microorganisms found on curtains, although a delayed decrease in total colony counts was evident. Cubicle curtains may act as a reservoir for microorganisms creating potential for cross contamination. This highlights the need for additional cleaning methods to decrease the risk of cross infection and the importance of maintaining good hand hygiene.
Using mammographic density to predict breast cancer risk: dense area or percentage dense area
Authors: Stone Jennifer , Ding Jane , Warren Ruth ML , Duffy Stephen W , Hopper John L 
Published: November 2010

Abstract
Introduction
Mammographic density (MD) is one of the strongest risk factors for breast cancer. It is not clear whether this association is best expressed in terms of absolute dense area or percentage dense area (PDA).

Methods
We measured MD, including nondense area (here a surrogate for weight), in the mediolateral oblique (MLO) mammogram using a computer-assisted thresholding technique for 634 cases and 1,880 age-matched controls from the Cambridge and Norwich Breast Screening programs. Conditional logistic regression was used to estimate the risk of breast cancer, and fits of the models were compared using likelihood ratio tests and the Bayesian information criteria (BIC). All P values were two-sided.

Results
Square-root dense area was the best single predictor (for example, χ12 = 53.2 versus 44.4 for PDA). Addition of PDA and/or square-root nondense area did not improve the fit (both P > 0.3). Addition of nondense area improved the fit of the model with PDA (χ12 = 11.6; P < 0.001). According to the BIC, the PDA and nondense area model did not provide a better fit than the dense area alone model. The fitted values of the two models were highly correlated (r = 0.97). When a measure of body size is included with PDA, the predicted risk is almost identical to that from fitting dense area alone.

Conclusions
As a single parameter, dense area provides more information than PDA on breast cancer risk.
Macrophage motility requires distinct α5β1/FAK and α4β1/paxillin signaling events
Authors: Abshire Michelle Y , Thomas Keena S , Owen Katherine A , Bouton Amy H 
Published: November 2010

ABSTRACTMacrophages function as key inflammatory mediators at sites of infection and tissue damage. Integrin and growth factor receptors facilitate recruitment of monocytes/macrophages to sites of inflammation in response to numerous extracellular stimuli. We have shown recently that FAK plays a role in regulating macrophage chemotaxis and invasion. As FAK is an established downstream mediator of integrin signaling, we sought to define the molecular circuitry involving FAK and the predominant β1 integrin heterodimers expressed in these cells—α4β1 and α5β1. We show that α4β1 and α5β1 integrins are required for efficient haptotactic and chemotactic invasion and that stimulation of these integrin receptors leads to the adoption of distinct morphologies associated with motility. FAK is required downstream of α5β1 for haptotaxis toward FN and chemotaxis toward M-CSF-1 and downstream of α4β1 for the adoption of a polarized phenotype. The scaffolding molecule paxillin functions independently of FAK to promote chemotaxis downstream of α4β1. These studies expand our understanding of β1 integrin signaling networks that regulate motility and invasion in macrophages and thus, provide important new insights into mechanisms by which macrophages perform their diverse functions.
Dissociation of Osteogenic and Immunological Effects by the Selective Glucocorticoid Receptor Agonist, Compound A, in Human Bone Marrow Stromal Cells
Authors: Rauner Martina , Goettsch Claudia , Stein Nicola , Thiele Sylvia , Bornhaeuser Martin , De Bosscher Karolien , Haegeman Guy , Tuckermann Jan , Hofbauer Lorenz C. 
Published: November 2010

Abstract
Glucocorticoids (GCs) regulate various physiological processes, including bone remodeling. Whereas physiological amounts of GCs are required for proper human osteoblast differentiation, prolonged exposure to GCs leads to substantial bone loss in vivo predominantly by inhibiting osteoblast functions. Compound A (CpdA) is a novel GC receptor modulator with the potential of an improved benefit/risk profile. Here we tested the osteoimmunological effects of CpdA on primary human osteoblasts and their paracrine interactions with osteoclasts. To assess the antiinflammatory potential of CpdA in human bone marrow stromal cell (BMSC)-derived osteoblasts, cells were stimulated with lipopolysaccharide and cytokine expression was determined. Similar to dexamethasone (DEX), CpdA profoundly suppressed lipopolysaccharide-induced TNF-α (−63%), IL-1β (−38%), and IL-6 (−36%) (P &lt; 0.05) mRNA levels. Of note, CpdA failed to induce osteogenic differentiation of BMSCs, whereas DEX and budesonide enhanced matrix mineralization an d increased runt-related transcription factor 2 and alkaline phosphatase mRNA levels up to 5-fold in a dose-dependent manner. Interestingly, each substance promoted cell proliferation by 7–10% and suppressed apoptosis by 25–30% at low concentrations and early differentiation stages, whereas high concentrations (1 μm) suppressed proliferation and stimulated apoptosis in mature osteoblasts. Finally, CpdA did not increase the receptor activator of nuclear factor-κB ligand to osteoprotegerin mRNA ratio as compared with DEX and did not stimulate the formation of osteoclasts in coculture with BMSCs. In summary, CpdA displays dissociated osteogenic and immunological effects in human BMSCs that are distinct from those of conventional GCs. Whether the specific osteoimmunological profile of CpdA translates into a relevant in vivo effect needs to be further explored.
The Somatotrope as a Metabolic Sensor: Deletion of Leptin Receptors Causes Obesity
Authors: Childs Gwen V. , Akhter Noor , Haney Anessa , Syed Mohsin , Odle Angela , Cozart Michael , Brodrick Zachary , Gaddy Dana , Suva Larry J. , Akel Nisreen , Crane Christopher , Beneš Helen , Charlesworth Amanda , Luque Raul , Chua Streamson , Kineman Rhonda D. 
Published: November 2010

Abstract
Leptin, the product of the Lep gene, reports levels of adiposity to the hypothalamus and other regulatory cells, including pituitary somatotropes, which secrete GH. Leptin deficiency is associated with a decline in somatotrope numbers and function, suggesting that leptin may be important in their maintenance. This hypothesis was tested in a new animal model in which exon 17 of the leptin receptor (Lepr) protein was selectively deleted in somatotropes by Cre-loxP technology. Organ genotyping confirmed the recombination of the floxed LepR allele only in the pituitary. Deletion mutant mice showed a 72% reduction in pituitary cells bearing leptin receptor (LEPR)-b, a 43% reduction in LEPR proteins and a 60% reduction in percentages of immunopositive GH cells, which correlated with reduced serum GH. In mutants, LEPR expression by other pituitary cells was like that of normal animals. Leptin stimulated phosphorylated Signal transducer and activator of transcription 3 expression in somatotropes from normal animals but not from mutants. Pituitary weights, cell numbers, IGF-I, and the timing of puberty were not different from control values. Growth curves were normal during the first 3 months. Deletion mutant mice became approximately 30–46% heavier than controls with age, which was attributed to an increase in fat mass. Serum leptin levels were either normal in younger animals or reflected the level of obesity in older animals. The specific ablation of the Lepr exon 17 gene in somatotropes resulted in GH deficiency with a consequential reduction in lipolytic activity normally maintained by GH and increased adiposity.
Minireview: Fibroblast Growth Factor 23 in Phosphate Homeostasis and Bone Metabolism
Authors: Hori Michiko , Shimizu Yuichiro , Fukumoto Seiji 
Published: November 2010

Abstract
Fibroblast growth factor 23 (FGF23) was identified in 2000. Since then, FGF23 has been found to physiologically regulate phosphate metabolism and aberrant actions of FGF23 results in several disorders of phosphate and bone metabolism. In addition, FGF23 plays an important role in the development of chronic kidney disease–mineral and bone disorder. However, further investigations are necessary, especially with regard to the regulation of FGF23 expression. In this minireview, we focus on the physiological and pathophysiological significance of FGF23 in phosphate and bone metabolism.
Plasticity of the Reproductive Axis Caused by Social Status Change in an African Cichlid Fish: II. Testicular Gene Expression and Spermatogenesis
Authors: Maruska Karen P. , Fernald Russell D. 
Published: November 2010

AbstractReproduction in all vertebrates is controlled by the brain-pituitary-gonad (BPG) axis, which is regulated socially in males of the African cichlid fish Astatotilapia burtoni. Although social information influences GnRH1 neurons at the apex of the BPG axis, little is known about how the social environment and dominance affects the cellular and molecular composition of the testes to regulate reproductive capacity. We created an opportunity for reproductively suppressed males to ascend in status and then measured changes in gene expression and tissue morphology to discover how quickly the perception of this opportunity can influence the testes. Our results show rapid up-regulation of mRNA levels of FSH receptor and several steroid receptor subtypes in the testes during social ascent. In contrast, LH receptor was not elevated until 72 h after ascent, but this increase was coincident with elevated circulating androgens and early stages of spermatogenesis, suggesting a role in steroidogenesis. The spermatogenic potential of the testes, as measured by cellular composition, was also elevated before the overall increase in testes size. The presence of cysts at all stages of spermatogenesis, coupled with lower levels of gonadotropin and steroid receptors in subordinate males, suggests that the BPG axis and spermatogenesis are maintained at a subthreshold level in anticipation of the chance to gain a territory and become reproductively active. Our results show that the testis is stimulated extremely quickly after perception of social opportunity, presumably to allow suppressed males to rapidly achieve high reproductive success in a dynamic social environment.
Effect of Insulin and Dexamethasone on Fetal Assimilation of Maternal Glucose
Authors: Norris Andrew W. , Wang Chunlin , Yao Jianrong , Walsh Susan A. , Sawatzke Alexander B. , Hu Shanming , Sunderland John J. , Segar Jeffrey L. , Ponto Laura L. B. 
Published: November 2010

Abstract
The growing fetus depends upon transfer of glucose from maternal blood to fetal tissues. Insulin and glucocorticoid impact maternal glucose metabolism, but the effects of these hormones on fetal glucose assimilation in vivo are understudied. We thus used positron emission tomography imaging to determine the disposition of [18F]fluorodeoxyglucose (FDG) in rats on gestational d 20, quantifying the kinetic competition of maternal tissues and fetus for glucose. Three fasting maternal states were studied: after 2-d dexamethasone (DEX), during euglycemic hyperinsulinemic clamp insulin receiving (INS), and control (CON). In CON and DEX mothers, FDG accumulation in fetuses and placentae was substantial, rivaling that of maternal brain. By contrast, FDG accumulation was reduced in INS fetuses, placentae, and maternal brain by approximately 2-fold, despite no diminution in FDG extraction kinetics from maternal blood into these structures. The reduced FDG accumulation was due to more rapid clearance of FDG from the circulation in INS mothers, related to increased FDG avidity in INS select maternal tissues, including skeletal muscle, brown adipose tissue, and heart. DEX treatment of mothers reduced fetal weight by nearly 10%. Nonetheless, the accumulation of FDG into placentae and fetuses was similar in DEX and CON mothers. In our rat model, fetal growth restriction induced by DEX does not involve diminished glucose transport to the fetus. Maternal insulin action has little effect on the inherent avidity of the fetal-placental unit for glucose but increases glucose utilization by maternal tissues, thus indirectly reducing the glucose available to the fetus.
Do the Effects of Testosterone on Muscle Strength, Physical Function, Body Composition, And Quality of Life Persist Six Months after Treatment in Intermediate-Frail and Frail Elderly Men?
Authors: O'Connell Matthew D. L. , Roberts Stephen A. , Srinivas-Shankar Upendram , Tajar Abdelouahid , Connolly Martin J. , Adams Judith E. , Oldham Jackie A. , Wu Frederick C. W. 
Published: November 2010

abstract

Context:
Short-term testosterone (T) treatment in frail elderly men improves muscle mass and strength. It is unclear whether these effects can be maintained post treatment.

Objective:
To assess the durability of androgen effects in frail men.

Design and Setting:
Single center, randomized, double-blind, placebo-controlled trial to investigate the effects of 6 months T (25–75 mg daily) on muscle strength, body composition, physical function, and quality of life (QoL). Participants were assessed at the end of treatment (6 months) and 6 months after treatment cessation (12 months).

Participants:
274 intermediate-frail and frail elderly men aged 65–90 years with low T levels.

Results:
Mean T increased from 11.1 (3.1) nmol/liter at baseline to 18.4 (3.5) nmol/liter at 6 months, then declined to 10.5 (3.7) nmol/L at 12 months, in the T-treated group. Isometric knee extension peak torque increased in the T-treated group compared with placebo to give an adjusted mean difference (95% CI) between groups of 8.1 (−0.2 to 16.5) Nm at 6 months. Lean mass increased in the T-treated group giving a difference between groups of 1.2 (0.8 to 1.7) kg at 6 months. Somatic and sexual symptoms improved during treatment. None of these differences between groups remained at 12 months. Prostate specific antigen (PSA) levels and haematocrit increased slightly during treatment but returned to baseline by 12 months.

Conclusion:
The effects of 6-month T treatment on muscle strength, lean mass, and QoL in frail men are not maintained at 6 months post treatment.
Clinical, Biochemical, and Molecular Characterization of Macronodular Adrenocortical Hyperplasia of the Zona Reticularis: A New Syndrome
Authors: Ghayee Hans K. , Rege Juilee , Watumull Lori M. , Nwariaku Fiemu E. , Carrick Kelley S. , Rainey William E. , Miller Walter L. , Auchus Richard J. 
Published: November 2010

abstractContext:Macronodular adrenocortical hyperplasia classically presents with progressive hypercortisolemia and Cushing syndrome. We describe a 29-yr-old man with massive macronodular adrenocortical hyperplasia without hypercortisolemia but rather markedly elevated and nonsuppressible production of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS).Objective:To characterize the clinical and molecular features of this case and to determine whether the tissue biochemically resembles the zona reticularis or fetal adrenal.Setting:University clinic, hospital, and laboratories.Design:Static and dynamic blood and urine testing were performed preoperatively. Tissue was studied by light microscopy, immunoblot, RNA microarray, and enzyme assay.Participant:A 29-yr-old man with incidentally discovered bilateral adrenal enlargement.Intervention:Bilateral adrenalectomy.Main Outcome Measures:Molecular studies compared with control samples.Results:Hypercortisolism and 21-hydroxylase deficiency were excluded. DHEA, DHEAS, and 17-hydroxypregnenolone were markedly elevated and did not suppress with dexamethasone 2 mg/d for 4 d. Homogenates of the adrenals demonstrated high 17-hydroxylase, good 17,20-lyase, and low or absent 21-hydroxylase and 3β-hydroxysteroid dehydrogenase activities. Immunoblots confirmed robust expression of cytochrome P450c17 and AKR1C3 but not P450c21. Microarray analysis demonstrated high CYP11A1 and CYP17A1 expression but low or absent HSD3B1, HSD3B2, and CYP21A2 expression. Expression of mRNA for cytochrome b5 (CYB5A) and AKR1C3, markers of the zona reticularis, were markedly elevated.Conclusion:This is the first case of macronodular hyperplasia of the adrenal zona reticularis confirmed with studies of enzyme activity, mRNA expression, and protein identification. We speculate that this condition can be clinically silent in men but might cause severe hyperandrogenemia in women.
Ectopic Fat Storage in the Pancreas, Liver, and Abdominal Fat Depots: Impact on β-Cell Function in Individuals with Impaired Glucose Metabolism
Authors: van der Zijl N. J. , Goossens G. H. , Moors C. C. M. , van Raalte D. H. , Muskiet M. H. A. , Pouwels P. J. W. , Blaak E. E. , Diamant M. 
Published: November 2010

abstract

Context:
Pancreatic fat content (PFC) may have deleterious effects on β-cell function.

Objective:
We hypothesized that ectopic fat deposition, in particular pancreatic fat accumulation, is related to β-cell dysfunction in individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT).

Design, Setting and Participants:
This was a cross-sectional study in 64 age- and body mass index-matched individuals, with normal glucose tolerance (NGT; n = 16, 60% males), IFG (n = 29, 52% males), or IFG/IGT (n = 19, 63% males) was conducted.

Intervention and Main Outcome Measures:
Participants underwent the following: 1) a combined hyperinsulinemic-euglycemic and hyperglycemic clamp, with subsequent arginine stimulation to quantify insulin sensitivity and β-cell function; 2) proton-magnetic resonance spectroscopy to assess PFC and liver fat content (LFC); and 3) magnetic resonance imaging to quantify visceral (VAT) and sc (SAT) adipose tissue. The disposition index (DI; insulin sensitivity adjusted β-cell function) was assessed.

Results:
IFG and IFG/IGT were more insulin resistant (P &lt; 0.001) compared with NGT. Individuals with IFG/IGT had the lowest values of glucose- and arginine-stimulated C-peptide secretion (both P &lt; 0.03) and DI (P &lt; 0.001), relative to IFG and NGT. PFC and LFC gradually increased between NGT, IFG, and IFG/IGT (P = 0.02 and P = 0.01, respectively), whereas VAT and SAT were similar between groups. No direct associations were found between PFC, LFC, VAT, and SAT and C-peptide secretion. The DI was inversely correlated with PFC, LFC, and VAT (all P &lt; 0.05).

Conclusions:
PFC was increased in individuals with IFG and/or IGT, without a direct relation with β-cell function.