bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effective fraction isolated from Radix Astragali alleviates glucose intolerance, insulin resistance and hypertriglyceridemia in db/db diabetic mice through its anti-inflammatory activity
Authors: Hoo Ruby LC , Wong Janice YL , Qiao CF , Xu A , Xu HX , Lam Karen SL 
Published: August 2010

Abstract

Background
Macrophage infiltration in adipose tissue together with the aberrant production of pro-inflammatory cytokines has been identified as the key link between obesity and its related metabolic disorders. This study aims to isolate bioactive ingredients from the traditional Chinese herb Radix Astragali (Huangqi) that alleviate obesity-induced metabolic damage through inhibiting inflammation.

Methods
Active fraction (Rx) that inhibits pro-inflammatory cytokine production was identified from Radix Astragali by repeated bioactivity-guided high-throughput screening. Major constituents in Rx were identified by column chromatography followed by high-performance liquid chromatography (HPLC) and mass-spectrometry. Anti-diabetic activity of Rx was evaluated in db/db mice.

Results
Treatment with Rx, which included calycosin-7-β-D-glucoside (0.9%), ononin (1.2%), calycosin (4.53%) and formononetin (1.1%), significantly reduced the secretion of pro-inflammatory cytokines (TNF-α, IL-6 and MCP-1) in human THP-1 macrophages and lipopolysaccharide (LPS)-induced activation of NF-κB in mouse RAW-Blue macrophages in a dose-dependent manner. Chronic administration of Rx in db/db obese mice markedly decreased the levels of both fed and fasting glucose, reduced serum triglyceride, and also alleviated insulin resistance and glucose intolerance when compared to vehicle-treated controls. The mRNA expression levels of inflammatory cell markers CD68 and F4/80, and cytokines MCP-1, TNF-α and IL-6 were significantly reduced in epididymal adipose tissue while the alternatively activated macrophage marker arginase I was markedly increased in the Rx-treated mice.

Conclusion
These findings suggest that suppression of the inflammation pathways in macrophages represents a valid strategy for high-throughput screening of lead compounds with anti-diabetic and insulin sensitizing properties, and further support the etiological role of inflammation in the pathogenesis of obesity-related metabolic disorders.
Familial Hemiplegic Migraine CaV2.1 Channel Mutation R192Q Enhances ATP-gated P2X3 Receptor Activity of Mouse Sensory Ganglion Neurons Mediating Trigeminal Pain
Authors: Nair Asha , Simonetti Manuela , Birsa Nicol , Ferrari Michel D , van den Maagdenberg Arn MJM , Giniatullin Rashid , Nistri Andrea , Fabbretti Elsa 
Published: August 2010

Background: The R192Q mutation of the CACNA1A gene, encoding for the α1 subunit of voltage-gated P/Q Ca2+ channels (Cav2.1), is associated with familial hemiplegic migraine-1. We investigated whether this gain-of-function mutation changed the structure and function of trigeminal neuron P2X3 receptors that are thought to be important contributors to migraine pain. Results: Using in vitro trigeminal sensory neurons of a mouse genetic model knockin for the CACNA1A R192Q mutation, we performed patch clamp recording and intracellular Ca2+ imaging that showed how these knockin ganglion neurons generated P2X3 receptor-mediated responses significantly larger than wt neurons. These enhanced effects were reversed by the Cav 2.1 blocker ω-agatoxin. We, thus, explored intracellular signalling dependent on kinases and phosphatases to understand the molecular regulation of P2X3 receptors of knockin neurons. In such cells we observed strong activation of CaMKII reversed by ω-agatoxin treatment. The CaMKII inhibitor KN-93 blocked CaMKII phosphorylation and the hyperesponsive P2X3 phenotype. Although no significant difference in membrane expression of knockin receptors was found, serine phosphorylation of knockin P2X3 receptors was constitutively decreased and restored by KN-93. No change in threonine or tyrosine phosphorylation was detected. Finally, pharmacological inhibitors of the phosphatase calcineurin normalized the enhanced P2X3 receptor responses of knockin neurons and increased their serine phosphorylation. Conclusions: The present results suggest that the CACNA1A mutation conferred a novel molecular phenotype to P2X3 receptors of trigeminal ganglion neurons via CaMKII-dependent activation of calcineurin that selectively impaired the serine phosphorylation state of such receptors, thus potentiating their effects in transducing trigeminal nociception.
Displaced proximal humeral fractures: an Indian experience with locking plates
Authors: Aggarwal Sameer , Bali Kamal , Dhillon Mandeep S , Kumar Vishal , Mootha Aditya K 
Published: August 2010

AbstractBackgroundThe treatment of displaced proximal humerus fractures, especially in elderly, remains controversial. The objective of this study was to evaluate functional outcome of locking plate used for fixation of these fractures after open reduction. We also attempted to evaluate the complications and predictors of loss of fixation for such an implant.MethodsOver two and a half years, 56 patients with an acute proximal humerus fracture were managed with locking plate osteosynthesis. 47 of these patients who completed a minimum follow up of 1 year were evaluated using Constant score calculation. Statistical analysis was done using SPSS 16 and a p value of less than 0.05 was taken as statistically significant.ResultsThe average follow up period was around 21.5 months. Outcomes were excellent in 17%, good in 38.5%, moderate in 34% while poor in 10.5%. The Constant score was poorer for AO-OTA type 3 fractures as compared to other types. The scores were also inferior for older patients (> 65 years old). Complications included screw perforation of head, AVN, subacromial impingement, loss of fixation, axillary nerve palsy and infection. A varus malalignment was found to be a strong predictor of loss of fixation.ConclusionLocking plate osteosynthesis leads to satisfactory functional outcomes in all the patients. Results are better than non locking plates in osteoporotic fractures of the elderly. However the surgery has steep learning curve and various complications could be associated with its use. Nevertheless we believe that a strict adherence to the principles of locking plate use can ensure good result in such challenging fractures.
BACE1-/- mice exhibit seizure activity that does not correlate with sodium channel level or axonal localization
Authors: Hitt Brian D , Jaramillo Thomas C , Chetkovich Dane M , Vassar Robert 
Published: August 2010

Abstract

Background
BACE1 is a key enzyme in the generation of the Aβ peptide that plays a central role in the pathogenesis of Alzheimer's disease. While BACE1 is an attractive therapeutic target, its normal physiological function remains largely unknown. Examination of BACE1-/- mice can provide insight into this function and also help anticipate consequences of BACE1 inhibition. Here we report a seizure-susceptibility phenotype that we have identified and characterized in BACE1-/- mice.

Results
We find that electroencephalographic recordings reveal epileptiform abnormalities in some BACE1-/- mice, occasionally including generalized tonic-clonic and absence seizures. In addition, we find that kainic acid injection induces seizures of greater severity in BACE1-/- mice relative to BACE1+/+ littermates, and causes excitotoxic cell death in a subset of BACE1-/- mice. This hyperexcitability phenotype is variable and appears to be manifest in approximately 30% of BACE1-/- mice. Finally, examination of the expression and localization of the voltage-gated sodium channel α-subunit Nav1.2 reveals no correlation with BACE1 genotype or any measure of seizure susceptibility.

Conclusions
Our data indicate that BACE1 deficiency predisposes mice to spontaneous and pharmacologically-induced seizure activity. This finding has implications for the development of safe therapeutic strategies for reducing Aβ levels in Alzheimer's disease. Further, we demonstrate that altered sodium channel expression and axonal localization are insufficient to account for the observed effect, warranting investigation of alternative mechanisms.
Systems approach to investigating host-pathogen interactions in infections with the biothreat agent Francisella. Constraints-based model of Francisella tularensis
Authors: Raghunathan Anu , Shin Sookil , Daefler Simon 
Published: August 2010

Abstract

Background

Francisella tularensis is a prototypic example of a pathogen for which few experimental datasets exist, but for which copious high-throughout data are becoming available because of its re-emerging significance as biothreat agent. The virulence of Francisella tularensis depends on its growth capabilities within a defined environmental niche of the host cell.

Results
We reconstructed the metabolism of Francisella as a stoichiometric matrix. This systems biology approach demonstrated that changes in carbohydrate utilization and amino acid metabolism play a pivotal role in growth, acid resistance, and energy homeostasis during infection with Francisella. We also show how varying the expression of certain metabolic genes in different environments efficiently controls the metabolic capacity of F. tularensis. Selective gene-expression analysis showed modulation of sugar catabolism by switching from oxidative metabolism (TCA cycle) in the initial stages of infection to fatty acid oxidation and gluconeogenesis later on. Computational analysis with constraints derived from experimental data revealed a limited set of metabolic genes that are operational during infection.

Conclusions
This integrated systems approach provides an important tool to understand the pathogenesis of an ill-characterized biothreat agent and to identify potential novel drug targets when rapid target identification is required should such microbes be intentionally released or become epidemic.
Subchondral bone microstructural damage by increased remodelling aggravates experimental osteoarthritis preceded by osteoporosis
Authors: Bellido Miriam , Lugo Laura , Roman-Blas Jorge A , Castañeda Santos , Caeiro Jose R , Dapia Sonia , Calvo Emilio , Largo Raquel , Herrero-Beaumont Gabriel 
Published: August 2010

Abstract
Introduction
Osteoporosis (OP) increases cartilage damage in a combined rabbit model of OP and osteoarthritis (OA). Accordingly, we assessed whether microstructure impairment at subchondral bone aggravates cartilage damage in this experimental model.

Methods
OP was induced in 20 female rabbits, by ovariectomy and intramuscular injections of methylprednisolone hemisuccinate for four weeks. Ten healthy animals were used as controls. At week 7, OA was surgically induced in left knees of all rabbits. At 22 weeks, after sacrifice, microstructure parameters were assessed by micro-computed tomography, and osteoprotegerin (OPG), receptor activator of nuclear factor-κB ligand (RANKL), alkaline phosphatase (ALP) and metalloproteinase 9 (MMP9) protein expressions were evaluated by Western Blot at subchondral bone. In addition, cartilage damage was estimated using the histopathological Mankin score. Mann-Whitney and Spearman statistical tests were performed as appropriate, using SPSS software v 11.0. Significant difference was established at P < 0.05.

Results
Subchondral bone area/tissue area, trabecular thickness and polar moment of inertia were diminished in OPOA knees compared with control or OA knees (P < 0.05). A decrease of plate thickness, ALP expression and OPG/RANKL ratio as well as an increased fractal dimension and MMP9 expression occurred at subchondral bone of OA, OP and OPOA knees vs. controls (P < 0.05). In addition, the severity of cartilage damage was increased in OPOA knees vs. controls (P < 0.05). Remarkably, good correlations were observed between structural and remodelling parameters at subchondral bone, and furthermore, between subchondral structural parameters and cartilage Mankin score.

Conclusions
Microstructure impairment at subchondral bone associated with an increased remodelling aggravated cartilage damage in OA rabbits with previous OP. Our results suggest that an increased subchondral bone resorption may account for the exacerbation of cartilage damage when early OA and OP coexist simultaneously in same individuals.
Association of invasion-promoting tenascin-C additional domains with breast cancers in young women
Authors: Guttery David S , Hancox Rachael A , Mulligan Kellie T , Hughes Simon , Lambe Sinead M , Pringle J Howard , Walker Rosemary A , Jones J Louise , Shaw Jacqueline A 
Published: August 2010

Abstract
Introduction
Tenascin-C (TNC) is a large extracellular matrix glycoprotein that shows prominent stromal expression in many solid tumours. The profile of isoforms expressed differs between cancers and normal breast, with the two additional domains AD1 and AD2 considered to be tumour associated. The aim of the present study was to investigate expression of AD1 and AD2 in normal, benign and malignant breast tissue to determine their relationship with tumour characteristics and to perform in vitro functional assays to investigate the role of AD1 in tumour cell invasion and growth.

Methods
Expression of AD1 and AD2 was related to hypoxanthine phosphoribosyltransferase 1 as a housekeeping gene in breast tissue using quantitative RT-PCR, and the results were related to clinicopathological features of the tumours. Constructs overexpressing an AD1-containing isoform (TNC-14/AD1/16) were transiently transfected into breast carcinoma cell lines (MCF-7, T-47 D, ZR-75-1, MDA-MB-231 and GI-101) to assess the effect in vitro on invasion and growth. Statistical analysis was performed using a nonparametric Mann-Whitney test for comparison of clinicopathological features with levels of TNC expression and using Jonckheere-Terpstra trend analysis for association of expression with tumour grade.

Results
Quantitative RT-PCR detected AD1 and AD2 mRNA expression in 34.9% and 23.1% of 134 invasive breast carcinomas, respectively. AD1 mRNA was localised by in situ hybridisation to tumour epithelial cells, and more predominantly to myoepithelium around associated normal breast ducts. Although not tumour specific, AD1 and AD2 expression was significantly more frequent in carcinomas in younger women (age ≤40 years; P < 0.001) and AD1 expression was also associated with oestrogen receptor-negative and grade 3 tumours (P < 0.05). AD1 was found to be incorporated into a tumour-specific isoform, not detected in normal tissues. Overexpression of the TNC-14/AD1/16 isoform significantly enhanced tumour cell invasion (P < 0.01) and growth (P < 0.01) over base levels.

Conclusions
Together these data suggest a highly significant association between AD-containing TNC isoforms and breast cancers in younger women (age ≤40 years), which may have important functional significance in vivo.
Evolutionary divergence in the fungal response to fluconazole revealed by soft clustering
Authors: Kuo Dwight , Tan Kai , Zinman Guy , Ravasi Timothy , Bar-Joseph Ziv , Ideker Trey 
Published: August 2010

Abstract
Background
Fungal infections are an emerging health risk, especially those involving yeast that are resistant to antifungal agents. To understand the range of mechanisms by which yeasts can respond to anti-fungals, we compared gene expression patterns across three evolutionarily distant species - Saccharomyces cerevisiae, Candida glabrata and Kluyveromyces lactis - over time following fluconazole exposure.

Results
Conserved and diverged expression patterns were identified using a novel soft clustering algorithm that concurrently clusters data from all species while incorporating sequence orthology. The analysis suggests complementary strategies for coping with ergosterol depletion by azoles - Saccharomyces imports exogenous ergosterol, Candida exports fluconazole, while Kluyveromyces does neither, leading to extreme sensitivity. In support of this hypothesis we find that only Saccharomyces becomes more azole resistant in ergosterol-supplemented media; that this depends on sterol importers Aus1 and Pdr11; and that transgenic expression of sterol importers in Kluyveromyces alleviates its drug sensitivity.

Conclusions
We have compared the dynamic transcriptional responses of three diverse yeast species to fluconazole treatment using a novel clustering algorithm. This approach revealed significant divergence among regulatory programs associated with fluconazole sensitivity. In future, such approaches might be used to survey a wider range of species, drug concentrations and stimuli to reveal conserved and divergent molecular response pathways.
Offensive jokes: How do they impact long-term relationships?
Authors: Hall Jeffrey A. , Sereno Ken 
Published: August 2010

AbstractThis article explores the impact of the use of negative humor on relational satisfaction and the importance of humor in long-term relationships from a coorientation perspective. Dyadic data from 123 couples were gathered using a survey measuring positive and negative humor use. These data were analyzed using structural equations modeling and the Actor-Partner Independence Model (Kenny et al., Dyadic data analysis, The Guilford Press, 2006: 144). Negative humor weakly predicted relational outcomes, but was valuable when partners saw themselves as possessing a shared sense of humor. Men acknowledge that their own public negative humor use negatively impacts the importance of humor in their relationship. Perceived similarity in negative humor use positively predicts relational satisfaction for both partners, and positively predicts the importance of humor for men, regardless of how much positive humor the couple uses. Accurately knowing a partner's negative humor use, or having greater understanding, negatively predicted relational outcomes.
Globalization of Pediatric Research: Analysis of Clinical Trials Completed for Pediatric Exclusivity
Authors: Pasquali Sara K. , Burstein Danielle S. , Benjamin Daniel K. , Smith P. Brian , Li Jennifer S. 
Published: August 2010

OBJECTIVE:
We evaluated the setting of published studies conducted under the US Pediatric Exclusivity Provision, which provides economic incentives to pharmaceutical companies to conduct drug studies with children.

METHODS:
Published studies containing the main results of trials conducted in 1998–2007 under the Pediatric Exclusivity Provision were included. Data were extracted from each study and described, including the therapeutic area of drug studied, number of patients enrolled, number of sites, and location where the study was conducted, if reported.

RESULTS:
Overall, 174 trials were included (sample size: 8–27 065 patients); 9% did not report any information regarding the location or number of sites where the study was conducted. Of trials that did report such information, 65% were conducted in ≥1 country outside the United States, and 11% did not include any sites in the United States. Fifty-four countries were represented, and 38% of trials enrolled patients in ≥1 site located in a developing/transition country, including more than one-third of infectious disease, cardiovascular, and allergy/immunology trials.

CONCLUSIONS:
The majority of published pediatric trials conducted under the Pediatric Exclusivity Provision included sites outside the United States, and more than one-third of trials enrolled patients in developing/transition countries.
A Noninterventional Study Documenting Use and Success of Implants With a New Chemically Modified Titanium Surface in Daily Dental Practice
Authors: Luongo Giuseppe , Oteri Giacomo 
Published: August 2010

Abstract
A new chemically modified titanium surface, SLActive, has recently been developed. The results obtained in controlled clinical trials indicate that this implant can be safely used and that it offers predictable results. The goal of this noninterventional study was to verify that the success rates of implants used in daily dental practice are comparable to those reported in controlled clinical trials. This study was a prospective, noninterventional study using implants with a chemically modified surface according to the daily dental practice procedures applied by private practitioners. The choice of the implantation procedure and the loading protocol were the responsibility of the investigator and were chosen according to the patient's needs. Thirty clinical centers actively participated in this study, and 226 patients were treated, of which, 8 patients were lost to follow-up. Because of the noninterventional design of the study, the patients were not selected according to strictly defined inclusion/exclusion criteria. Thus, the study included individuals with risk factors such as smoking (24%), untreated gingivitis or periodontitis (9%), and bruxism (6%). The implants were equally distributed between mandible (46%) and maxilla (54%). A bone augmentation procedure was done in 31% of the cases. Early loading (functional loading between 48 hours and 3 months after implant insertion) was applied most frequently (48%), followed by the conventional loading protocol (3 to 6 months after implant placement, 34%). Immediate restoration and immediate loading were rare (7% and 2%, respectively). Of 276 implants inserted and documented, 5 implants failures were reported, all of which were associated with a sinus floor augmentation procedure. The survival rate was 98.2% at the 1-year follow-up visit. The results showed that implants with a chemically modified surface can be successfully restored with success rates similar to those reported in formal clinical trials under more controlled conditions.
Equalities for orthogonal projectors and their operations
Authors: Tian Yongge 
Published: August 2010

Abstract
A complex square matrix A is called an orthogonal projector if A
2 = A = A*, where A* denotes the conjugate transpose of A. In this paper, we give a comprehensive investigation to matrix expressions consisting of orthogonal projectors and their properties through ranks of matrices. We first collect some well-known rank formulas for orthogonal projectors and their operations, and then establish various new rank formulas for matrix expressions composed by orthogonal projectors. As applications, we derive necessary and sufficient conditions for various equalities for orthogonal projectors and their operations to hold.