bluuebunny/crossref_metadata_2025 huggingface dataset:
The molecular basis of hepcidin-resistant hereditary hemochromatosis
Authors: Fernandes Augustine , Preza Gloria C. , Phung Yen , De Domenico Ivana , Kaplan Jerry , Ganz Tomas , Nemeth Elizabeta
Published: April 2009

The interaction between the hormone hepcidin and the iron exporter ferroportin (Fpn) regulates plasma iron concentrations. Hepcidin binds to Fpn and induces its internalization and degradation, resulting in decreased iron efflux from cells into plasma. Fpn mutations in N144, Y64N, and C326 residue cause autosomal dominant disease with parenchymal iron overload, apparently due to the resistance of mutant Fpn to hepcidin-mediated internalization. To define the mechanism of resistance, we generated human Fpn constructs bearing the pathogenic mutations. The mutants localized to the cell surface and exported iron normally, but were partially or completely resistant to hepcidin-mediated internalization and continued to export iron despite the presence of hepcidin. The primary defect with exofacial C326 substitutions was the loss of hepcidin binding, which resulted in the most severe phenotype. The thiol form of C326 was essential for interaction with hepcidin, suggesting that C326-SH homology is located in or near the binding site of hepcidin. In contrast, N144 and Y64 residues were not required for hepcidin binding, but their mutations impaired the subsequent internalization of the ligand-receptor complex. Our observations explain why the mutations in C326 Fpn residue produce a severe form of hemochromatosis with iron overload at an early age.
IL-15 produced and trans-presented by DCs underlies homeostatic competition between CD8 and γδ T cells in vivo
Authors: Do Jeong-su , Min Booki
Published: April 2009

Homeostatic mechanism by which peripheral T-cell subsets are maintained in vivo remains largely unknown. Using a T-cell proliferation model under lymphopenic settings, we now demonstrate that γδ T cells limit CD8 T-cell expansion but not the initial proliferation after transfer into lymphopenic recipients. Interleukin-15 (IL-15) produced by and trans-presented on the membrane of the CD11c+ dendritic cells (DCs) is the key factor that mediates homeostatic competition between CD8 and γδ T cells, revealing previously unrecognized IL-15–dependent homeostatic mechanisms between different T-cell subsets in vivo.
POINeT: protein interactome with sub-network analysis and hub prioritization
Authors: Lee Sheng-An , Chan Chen-Hsiung , Chen Tzu-Chi , Yang Chia-Ying , Huang Kuo-Chuan , Tsai Chi-Hung , Lai Jin-Mei , Wang Feng-Sheng , Kao Cheng-Yan , Huang Chi-Ying F
Published: April 2009

Background

Protein-protein interactions (PPIs) are critical to every aspect of biological processes. Expansion of all PPIs from a set of given queries often results in a complex PPI network lacking spatiotemporal consideration. Moreover, the reliability of available PPI resources, which consist of low- and high-throughput data, for network construction remains a significant challenge. Even though a number of software tools are available to facilitate PPI network analysis, an integrated tool is crucial to alleviate the burden on querying across multiple web servers and software tools.

Results

We have constructed an integrated web service, POINeT, to simplify the process of PPI searching, analysis, and visualization. POINeT merges PPI and tissue-specific expression data from multiple resources. The tissue-specific PPIs and the numbers of research papers supporting the PPIs can be filtered with user-adjustable threshold values and are dynamically updated in the viewer. The network constructed in POINeT can be readily analyzed with, for example, the built-in centrality calculation module and an integrated network viewer. Nodes in global networks can also be ranked and filtered using various network analysis formulas, i.e., centralities. To prioritize the sub-network, we developed a ranking filtered method (S3) to uncover potential novel mediators in the midbody network. Several examples are provided to illustrate the functionality of POINeT. The network constructed from four schizophrenia risk markers suggests that EXOC4 might be a novel marker for this disease. Finally, a liver-specific PPI network has been filtered with adult and fetal liver expression profiles.

Conclusion

The functionalities provided by POINeT are highly improved compared to previous version of POINT. POINeT enables the identification and ranking of potential novel genes involved in a sub-network. Combining with tissue-specific gene expression profiles, PPIs specific to selected tissues can be revealed. The straightforward interface of POINeT makes PPI search and analysis just a few clicks away. The modular design permits further functional enhancement without hampering the simplicity. POINeT is available at http://poinet.bioinformatics.tw/.
Most parsimonious haplotype allele sharing determination
Authors: Cai Zhipeng , Sabaa Hadi , Wang Yining , Goebel Randy , Wang Zhiquan , Xu Jiaofen , Stothard Paul , Lin Guohui
Published: April 2009

Background

The "common disease – common variant" hypothesis and genome-wide association studies have achieved numerous successes in the last three years, particularly in genetic mapping in human diseases. Nevertheless, the power of the association study methods are still low, in particular on quantitative traits, and the description of the full allelic spectrum is deemed still far from reach. Given increasing density of single nucleotide polymorphisms available and suggested by the block-like structure of the human genome, a popular and prosperous strategy is to use haplotypes to try to capture the correlation structure of SNPs in regions of little recombination. The key to the success of this strategy is thus the ability to unambiguously determine the haplotype allele sharing status among the members. The association studies based on haplotype sharing status would have significantly reduced degrees of freedom and be able to capture the combined effects of tightly linked causal variants.

Results

For pedigree genotype datasets of medium density of SNPs, we present two methods for haplotype allele sharing status determination among the pedigree members. Extensive simulation study showed that both methods performed nearly perfectly on breakpoint discovery, mutation haplotype allele discovery, and shared chromosomal region discovery.

Conclusion

For pedigree genotype datasets, the haplotype allele sharing status among the members can be deterministically, efficiently, and accurately determined, even for very small pedigrees. Given their excellent performance, the presented haplotype allele sharing status determination programs can be useful in many downstream applications including haplotype based association studies.
Growth inhibition and ultrastructural alterations induced by Δ24(25)-sterol methyltransferase inhibitors in Candida spp. isolates, including non-albicans organisms
Authors: Ishida Kelly , Rodrigues Juliany Cola Fernandes , Ribeiro Marcos Dornelas , Vila Taíssa Vieira Machado , de Souza Wanderley , Urbina Julio A , Nakamura Celso Vataru , Rozental Sonia
Published: April 2009

Background

Although Candida species are commensal microorganisms, they can cause many invasive fungal infections. In addition, antifungal resistance can contribute to failure of treatment.

The purpose of this study was to evaluate the antifungal activity of inhibitors of Δ24(25)-sterol methyltransferase (24-SMTI), 20-piperidin-2-yl-5α-pregnan-3β-20(R)-diol (AZA), and 24(R,S),25-epiminolanosterol (EIL), against clinical isolates of Candida spp., analysing the ultrastructural changes.

Results

AZA and EIL were found to be potent growth inhibitors of Candida spp. isolates. The median MIC50 was 0.5 μg.ml-1 for AZA and 2 μg.ml-1 for EIL, and the MIC90 was 2 μg.ml-1 for both compounds. All strains used in this study were susceptible to amphotericin B; however, some isolates were fluconazole- and itraconazole-resistant. Most of the azole-resistant isolates were Candida non-albicans (CNA) species, but several of them, such as C. guilliermondii, C. zeylanoides, and C. lipolytica, were susceptible to 24-SMTI, indicating a lack of cross-resistance. Reference strain C. krusei (ATCC 6258, FLC-resistant) was consistently susceptible to AZA, although not to EIL. The fungicidal activity of 24-SMTI was particularly high against CNA isolates. Treatment with sub-inhibitory concentrations of AZA and EIL induced several ultrastructural alterations, including changes in the cell-wall shape and thickness, a pronounced disconnection between the cell wall and cytoplasm with an electron-lucent zone between them, mitochondrial swelling, and the presence of electron-dense vacuoles. Fluorescence microscopy analyses indicated an accumulation of lipid bodies and alterations in the cell cycle of the yeasts. The selectivity of 24-SMTI for fungal cells versus mammalian cells was assessed by the sulforhodamine B viability assay.

Conclusion

Taken together, these results suggest that inhibition of 24-SMT may be a novel approach to control Candida spp. infections, including those caused by azole-resistant strains.
Small molecule inhibitors of the Yersinia type III secretion system impair the development of Chlamydia after entry into host cells
Authors: Muschiol Sandra , Normark Staffan , Henriques-Normark Birgitta , Subtil Agathe
Published: April 2009

Background

Chlamydiae are obligate intracellular pathogens that possess a type III secretion system to deliver proteins into the host cell during infection. Small molecule inhibitors of type III secretion in Yersinia, termed INPs (In nate P harmaceuticals AB) were reported to strongly inhibit Chlamydia growth in epithelial cells. In this study we have analyzed the effect of these drugs on bacterial invasiveness.

Results

We demonstrate that INPs affect Chlamydia growth in a dose dependent manner after bacterial invasion. The efficiency of C. trachomatis L2 and C. caviae GPIC entry into host cells was not altered in the presence of INPs. In C. caviae, entry appears to proceed normally with recruitment of actin and the small GTPases Rac, Cdc42 and Arf6 to the site of bacterial entry.

Conclusion

INPs have a strong inhibitory effect on Chlamydia growth. However, bacterial invasion is not altered in the presence of these drugs. In the light of these results, we discuss several hypotheses regarding the mode of action of INPs on type III secretion during the Chlamydia infectious cycle.
N-acetylcysteine amide decreases oxidative stress but not cell death induced by doxorubicin in H9c2 cardiomyocytes
Authors: Shi Rong , Huang Chuan-Chin , Aronstam Robert S , Ercal Nuran , Martin Adam , Huang Yue-Wern
Published: April 2009

Background

While doxorubicin (DOX) is widely used in cancer chemotherapy, long-term severe cardiotoxicity limits its use. This is the first report of the chemoprotective efficacy of a relatively new thiol antioxidant, N-acetylcysteine amide (NACA), on DOX-induced cell death in cardiomyocytes. We hypothesized that NACA would protect H9c2 cardiomyocytes from DOX-induced toxicity by reducing oxidative stress. Accordingly, we determined the ability of NACA to mitigate the cytotoxicity of DOX in H9c2 cells and correlated these effects with the production of indicators of oxidative stress.

Results

DOX at 5 μM induced cardiotoxicity while 1) increasing the generation of reactive oxygen species (ROS), 2) decreasing levels and activities of antioxidants and antioxidant enzymes (catalase, glutathione peroxidase, glutathione reductase) and 3) increasing lipid peroxidation. NACA at 750 μM substantially reduced the levels of ROS and lipid peroxidation, as well as increased both GSH level and GSH/GSSG ratio. However, treating H9c2 cells with NACA did little to protect H9c2 cells from DOX-induced cell death.

Conclusion

Although NACA effectively reduced oxidative stress in DOX-treated H9c2 cells, it had minimal effects on DOX-induced cell death. NACA prevented oxidative stress by elevation of GSH and CYS, reduction of ROS and lipid peroxidation, and restoration of antioxidant enzyme activities. Further studies to identify oxidative stress-independent pathways that lead to DOX-induced cell death in H9c2 are warranted.
No evidence for protective erythropoietin alpha signalling in rat hepatocytes
Authors: Bramey Thorsten , Freitag Patricia , Fandrey Joachim , Rauen Ursula , Pamp Katja , Erhard Jochen , Frede Stilla , de Groot Herbert , Petrat Frank
Published: April 2009

Background

Recombinant human erythropoietin alpha (rHu-EPO) has been reported to protect the liver of rats and mice from ischemia-reperfusion injury. However, direct protective effects of rHu-EPO on hepatocytes and the responsible signalling pathways have not yet been described. The aim of the present work was to study the protective effect of rHu-EPO on warm hypoxia-reoxygenation and cold-induced injury to hepatocytes and the rHu-EPO-dependent signalling involved.

Methods

Loss of viability of isolated rat hepatocytes subjected to hypoxia/reoxygenation or incubated at 4°C followed by rewarming was determined from released lactate dehydrogenase activity in the absence and presence of rHu-EPO (0.2–100 U/ml). Apoptotic nuclear morphology was assessed by fluorescence microscopy using the nuclear fluorophores H33342 and propidium iodide. Erythropoietin receptor (EPOR), EPO and Bcl-2 mRNAs were quantified by real time PCR. Activation of JAK-2, STAT-3 and STAT-5 in hepatocytes and rat livers perfused in situ was assessed by Western blotting.

Results

In contrast to previous in vivo studies on ischemia-reperfusion injury to the liver, rHu-EPO was without any protective effect on hypoxic injury, hypoxia-reoxygenation injury and cold-induced apoptosis to isolated cultured rat hepatocytes. EPOR mRNA was identified in these cells but specific detection of the EPO receptor protein was not possible due to the lack of antibody specificity. Both, in the cultured rat hepatocytes (10 U/ml for 15 minutes) and in the rat liver perfused in situ with rHu-EPO (8.9 U/ml for 15 minutes) no evidence for EPO-dependent signalling was found as indicated by missing effects of rHu-EPO on phosphorylation of JAK-2, STAT-3 and STAT-5 and on the induction of Bcl-2 mRNA.

Conclusion

Together, these results indicate the absence of any protective EPO signalling in rat hepatocytes. This implies that the protection provided by rHu-EPO in vivo against ischemia-reperfusion and other causes of liver injury is most likely indirect and does not result from a direct effect on hepatocytes.
Living in rural New England amplifies the risk of depression in patients with HIV
Authors: Sheth Siddharth H , Jensen Paul T , Lahey Timothy
Published: April 2009

Background

The importance of depression as a complication of HIV infection is increasingly understood, and people living in rural areas are at increased risk for depression. However, it is not known whether living in rural areas amplifies the risk of depression in patients with HIV.

Methods

We compared the prevalence of depression between rural and metropolitan HIV patients seen at the Dartmouth-Hitchcock HIV Program in a retrospective cohort study. Using the validated Rural-Urban Commuting Area Score, we categorized patients as living in small town/rural areas, micropolitan or metropolitan towns. Then, using a multivariate logistic regression model to adjust for demographic factors that differed between rural and metropolitan patients, we estimated the impact of living in rural areas on the odds of depression.

Results

Among 646 patients with HIV (185 small town/rural, 145 micropolitan, 316 metropolitan), rural patients were older, white, male, and men who have sex with men (ANOVA, F-statistic < 0.05). The prevalence of depression was highest in rural patients (59.5 vs. 51.7 vs. 41.2%, F statistic < 0.001), particularly rural patients on antiretroviral therapy (72.4 vs. 53.5 vs. 38.2%, F-statistic < 0.001. A multivariate logistic regression model showed that the odds of depression in rural patients with HIV were 1.34 (P < 0.001).

Conclusion

HIV-infected patients living in rural areas, particularly those on antiretroviral therapy, are highly vulnerable to depression.
Clinical evaluation study of the German network of disorders of sex development (DSD)/intersexuality: study design, description of the study population, and data quality
Authors: Lux Anke , Kropf Siegfried , Kleinemeier Eva , Jürgensen Martina , Thyen Ute ,   The DSD Network Working Group
Published: April 2009

Background

The German Network of Disorders of Sex Development (DSD)/Intersexuality carried out a large scale clinical evaluation study on quality of life, gender identity, treatment satisfaction, coping, and problems associated with diagnoses and therapies in individuals with disorders of sex development (DSD). DSD are a heterogeneous group of various genetic disorders of sex determination or sex differentiation, all of which are rare conditions. In about half of all cases the molecular genetic diagnosis is unknown and diagnosis rests on clinical features.

Methods and design

The multi-centre clinical evaluation study includes short-term follow-up in some and cross-sectional assessments in all age and diagnostic groups fitting the criteria of DSD. Recruitment was from January 2005 until December 2007 in whole Germany and, additionally, in 2007 in Austria and German-speaking Switzerland. The study consists of a psychosocial inquiry for children, adolescents and their parents, and adults with standardized instruments and the collection of DSD-specific medical data by the attending physician. The main goal was the description of clinical outcomes and the health-care situation of individuals with DSD using a broad generic definition of DSD including all conditions with a mismatch of chromosomal, gonadal and phenotypical sex. 439 children and adolescents, their parents and adults with DSD participated.

Discussion

The clinical evaluation study represents the most comprehensive study in this clinical field. The paper discusses the study protocol, the data management and data quality as well as the classification used, and it describes the study population. Given the lack of large datasets in rare conditions such as DSD and often biased results from small scale clinical case series, the study aims to generate concrete hypotheses for evidence-based guidelines, which should be tested in further studies.
The variability and predictors of quality of AIDS care services in Brazil
Authors: Nemes Maria Ines Battistella , Melchior Regina , Basso Cáritas Relva , Castanheira Elen Rose Lodeiro , de Britto e Alves Maria Teresa Seabra Soares , Conway Shaun
Published: April 2009

Background

Since establishing universal free access to antiretroviral therapy in 1996, the Brazilian Health System has increased the number of centers providing HIV/AIDS outpatient care from 33 to 540. There had been no formal monitoring of the quality of these services until a survey of 336 AIDS health centers across 7 Brazilian states was undertaken in 2002. Managers of the services were asked to assess their clinics according to parameters of service inputs and service delivery processes. This report analyzes the survey results and identifies predictors of the overall quality of service delivery.

Methods

The survey involved completion of a multiple-choice questionnaire comprising 107 parameters of service inputs and processes of delivering care, with responses assessed according to their likely impact on service quality using a 3-point scale. K-means clustering was used to group these services according to their scored responses. Logistic regression analysis was performed to identify predictors of high service quality.

Results

The questionnaire was completed by 95.8% (322) of the managers of the sites surveyed. Most sites scored about 50% of the benchmark expectation. K-means clustering analysis identified four quality levels within which services could be grouped: 76 services (24%) were classed as level 1 (best), 53 (16%) as level 2 (medium), 113 (35%) as level 3 (poor), and 80 (25%) as level 4 (very poor). Parameters of service delivery processes were more important than those relating to service inputs for determining the quality classification. Predictors of quality services included larger care sites, specialization for HIV/AIDS, and location within large municipalities.

Conclusion

The survey demonstrated highly variable levels of HIV/AIDS service quality across the sites. Many sites were found to have deficiencies in the processes of service delivery processes that could benefit from quality improvement initiatives. These findings could have implications for how HIV/AIDS services are planned in Brazil to achieve quality standards, such as for where service sites should be located, their size and staffing requirements. A set of service delivery indicators has been identified that could be used for routine monitoring of HIV/AIDS service delivery for HIV/AIDS in Brazil (and potentially in other similar settings).
Predictive models of insulin resistance derived from simple morphometric and biochemical indices related to obesity and the metabolic syndrome in baboons
Authors: Chavez Alberto O , Gastaldelli Amalia , Guardado-Mendoza Rodolfo , Lopez-Alvarenga Juan C , Leland M Michelle , Tejero M Elizabeth , Sorice GianPio , Casiraghi Francesca , Davalli Alberto , Bastarrachea Raúl A , Comuzzie Anthony G , DeFronzo Ralph A , Folli Franco
Published: April 2009

Background

Non-human primates are valuable models for the study of insulin resistance and human obesity. In baboons, insulin sensitivity levels can be evaluated directly with the euglycemic clamp and is highly predicted by adiposity, metabolic markers of obesity and impaired glucose metabolism (i.e. percent body fat by DXA and HbA1c). However, a simple method to screen and identify obese insulin resistant baboons for inclusion in interventional studies is not available.

Methods

We studied a population of twenty baboons with the euglycemic clamp technique to characterize a population of obese nondiabetic, insulin resistant baboons, and used a multivariate linear regression analysis (adjusted for gender) to test different predictive models of insulin sensitivity (insulin-stimulated glucose uptake = Rd) using abdominal circumference and fasting plasma insulin. Alternatively, we tested in a separate baboon population (n = 159), a simpler model based on body weight and fasting plasma glucose to predict the whole-body insulin sensitivity (Rd/SSPI) derived from the clamp.

Results

In the first model, abdominal circumference explained 59% of total insulin mediated glucose uptake (Rd). A second model, which included fasting plasma insulin (log transformed) and abdominal circumference, explained 64% of Rd. Finally, the model using body weight and fasting plasma glucose explained 51% of Rd/SSPI. Interestingly, we found that percent body fat was directly correlated with the adipocyte insulin resistance index (r = 0.755, p < 0.0001).

Conclusion

In baboons, simple morphometric measurements of adiposity/obesity, (i.e. abdominal circumference), plus baseline markers of glucose/lipid metabolism, (i.e. fasting plasma glucose and insulin) provide a feasible method to screen and identify overweight/obese insulin resistant baboons for inclusion in interventional studies aimed to study human obesity, insulin resistance and type 2 diabetes mellitus.
Metallic nickel nano- and fine particles induce JB6 cell apoptosis through a caspase-8/AIF mediated cytochrome c-independent pathway
Authors: Zhao Jinshun , Bowman Linda , Zhang Xingdong , Shi Xianglin , Jiang Binghua , Castranova Vincent , Ding Min
Published: April 2009

Background

Carcinogenicity of nickel compounds has been well documented. However, the carcinogenic effect of metallic nickel is still unclear. The present study investigates metallic nickel nano- and fine particle-induced apoptosis and the signal pathways involved in this process in JB6 cells. The data obtained from this study will be of benefit for elucidating the pathological and carcinogenic potential of metallic nickel particles.

Results

Using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, we found that metallic nickel nanoparticles exhibited higher cytotoxicity than fine particles. Both metallic nickel nano- and fine particles induced JB6 cell apoptosis. Metallic nickel nanoparticles produced higher apoptotic induction than fine particles. Western-blot analysis showed an activation of proapoptotic factors including Fas (CD95), Fas-associated protein with death domain (FADD), caspase-8, death receptor 3 (DR3) and BID in apoptotic cells induced by metallic nickel particles. Immunoprecipitation (IP) western blot analysis demonstrated the formation of the Fas-related death-inducing signaling complex (DISC) in the apoptotic process. Furthermore, lamin A and beta-actin were cleaved. Moreover, we found that apoptosis-inducing factor (AIF) was up-regulated and released from mitochondria to cytoplasm. Interestingly, although an up-regulation of cytochrome c was detected in the mitochondria of metallic nickel particle-treated cells, no cytochrome c release from mitochondria to cytoplasm was found. In addition, activation of antiapoptotic factors including phospho-Akt (protein kinase B) and Bcl-2 was detected. Further studies demonstrated that metallic nickel particles caused no significant changes in the mitochondrial membrane permeability after 24 h treatment.

Conclusion

In this study, metallic nickel nanoparticles caused higher cytotoxicity and apoptotic induction than fine particles in JB6 cells. Apoptotic cell death induced by metallic nickel particles in JB6 cells is through a caspase-8/AIF mediated cytochrome c-independent pathway. Lamin A and beta-actin are involved in the process of apoptosis. Activation of Akt and Bcl-2 may play an important role in preventing cytochrome c release from mitochondria to the cytoplasm and may also be important in the carcinogenicity of metallic nickel particles. In addition, the results may be useful as an important reference when comparing the toxicities of different nickel compounds.
Modulation of immunity in young-adult and aged squirrel, Funambulus pennanti by melatonin and p-chlorophenylalanine
Authors: Rai Seema , Haldar Chandana , Singh Rajesh
Published: April 2009

Background

Our interest was to find out whether pineal gland and their by melatonin act as modulator of immunosenescence. Parachlorophenylalanine (PCPA) – a β adrenergic blocker, is known to perform chemical pinealectomy (Px) by suppressing indirectly the substrate 5-hydroxytryptamine (5-HT) for melatonin synthesis and thereby melatonin itself. The role of PCPA, alone and in combination with melatonin was recorded in immunomodulation and free radical load in spleen of young adult and aged seasonal breeder Indian palm squirrelFunambulus pennanti.

Results

Aged squirrel presented reduced immune parameters (i.e. total leukocyte count (TLC), Lymphocytes Count (LC), % stimulation ratio of splenocytes (% SR) against T cell mitogen concanavalin A (Con A), delayed type hypersensitivity (DTH) to oxazolone) when compared to young adult group. Melatonin administration (25 μg/100 g body mass/day) significantly increased the immune parameters in aged more than the young adult squirrel while PCPA administration (4.5 mg/100 g body mass/day) reduced all the immune parameters more significantly in young than aged. Combination of PCPA and melatonin significantly increased the immune parameters to the normal control level of both the age groups. TBARS level was significantly high in aged than the young group. PCPA treatment increased TBARS level of young and aged squirrels both while melatonin treatment decreased it even than the controls. Nighttime peripheral melatonin level was low in control aged group than the young group. Melatonin injection at evening hours significantly increased the peripheral level of nighttime melatonin, while combined injection of PCPA and melatonin brought it to control level in both aged and young adult squirrels.

Conclusion

PCPA suppressed immune status more in aged than in adult by reducing melatonin level as it did chemical Px. Melatonin level decreased in control aged squirrels and so there was a decrease in immune parameters with a concomitant increase in free radical load of spleen. Decreased immune status can be restored following melatonin injection which decreased free radical load of spleen and suggest that immune organs of aged squirrels were sensitive to melatonin. Increased free radical load and decreased peripheral melatonin could be one of the reasons of immunosenescence.
A novel Respiratory Health Score (RHS) supports a role of acute lung damage and pig breed in the course of an Actinobacillus pleuropneumoniaeinfection
Authors: Hoeltig Doris , Hennig-Pauka Isabel , Thies Kerstin , Rehm Thomas , Beyerbach Martin , Strutzberg-Minder Katrin , Gerlach Gerald F , Waldmann Karl-Heinz ,   FUGATO-consortium IRAS
Published: April 2009

Background

Bacterial lung infections are a major cause of economic losses in the pig industry; they are responsible for approximately 50% of the antibiotics used in pigs and, therefore, also present an increasing concern to consumer protection agencies. In response to this changing market we investigated the feasibility of an old approach aimed at the breeding selection of more resistant pigs. As a first step in this direction we applied a new respiratory health score system to study the susceptibility of four different pig breeding lines (German Landrace, Piétrain, Hampshire, Large White) towards the respiratory tract pathogenActinobacillus(A.)pleuropneumoniae.

Results

A controlled experimental aerosol infection with anA. pleuropneumoniaeserotype 7 isolate was performed using 106 weaning pigs of defined breeding lines from the breeds German Landrace, Piétrain, Hamphire, and Large White. Pigs were clinically assessed on days 4 and 20 post infection following a novel scoring system, the Respiratory Health Score (RHS), which combines clinical, sonographic and radiographic examination results. The ranking on day 4 was significantly correlated with the ranking based on the pathomorphological Lung Lesion Score (LLS; Spearman Rank Correlation Coefficient of 0.86 [p < 0.0001]). Based on their RHS pigs were assigned to the different quartiles independent of the breeding line. The RHS-based rankings of pigs on day 4 and on day 20 were highly correlated (Spearman Rank Correlation Coefficient of 0.82 [p < 0.0001]) independent of the breeding line. Pigs of the Hampshire line were predominantly found in the lowest scoring quartile (47.6%) and absent in the highest scoring quartile. In contrast, pigs of the German Landrace and Piétrain breeding lines were predominantly found in the highest scoring quartile (32.3% and 35.7%, respectively).

Conclusion

These results demonstrate that the RHS obtained from live pigs shows a highly significant correlation to the lung lesion score considered as a "gold standard". The correlation of the ranking at days 4 and 20 post infection implies that the course of disease is highly dependent on the acute lung damage. The different severity of signs among the tested pig breeding lines clearly suggests a genetic difference in the susceptibility of pigs toA. pleuropneumoniaeinfection.
Surgical technique and clinical results for scapular allograft reconstruction following resection of scapular tumors
Authors: Zhang Kaiwei , Duan Hong , Xiang Zhou , Tu Chongqi
Published: April 2009

Background

Progress in developing effective surgical techniques, such as scapular allograft reconstruction, enhance shoulder stability and extremity function, in patients following scapular tumor resection.

Methods

Case details from seven patients who underwent scapular allograft reconstruction following scapular tumor resection were reviewed. A wide marginal resection (partial scapulectomy) was performed in all patients and all affected soft tissues were resected to achieve a clean surgical margin. The glenoid-resected and glenoid-saved reconstructions were performed in three and four patients, respectively. The residual host scapula were fixed to the size-matched scapular allografts with plates and screws. The rotator cuff was affected frequently and was mostly resected. The deltoid and articular capsule were infrequently involved, but reconstructed preferentially. The remaining muscles were reattached to the allografts.

Results

The median follow-up was 26 months (range, 14–50 months). The average function scores were 24 points (80%) according to the International Society of Limb Salvage criteria. The range of active shoulder abduction and forward flexion motion were 40°–110° and 30°–90°, respectively. There was no difference between the glenoid-saved and glenoid-resected reconstructions in the total scores (mean, 24.5 points/81% versus 24 points/79%), but the glenoid-saved procedure was superior to the later in terms of abduction/flexion motion (mean, 72°/61° versus 55°/43°). During the study follow-up period, one patient died following a relapse, one patient lived despite of local recurrence, and five patients survived with no evidence of recurrence of the original cancer. Post-surgical complications such as shoulder dislocations, non-unions, and articular degeneration were not noted during this study period.

Conclusion

Scapular allograft reconstruction had a satisfactory functional, cosmetic, and oncological outcome in this case series. Preservation and reconstruction of the articular capsule and deltoid are proposed to be a prerequisite for using scapular allografts and rotator cuff reconstruction is recommended, although technically challenging to perform.
Chromatin conformation signatures of cellular differentiation
Authors: Fraser James , Rousseau Mathieu , Shenker Solomon , Ferraiuolo Maria A , Hayashizaki Yoshihide , Blanchette Mathieu , Dostie Josée
Published: April 2009

One of the major genomics challenges is to better understand how correct gene expression is orchestrated. Recent studies have shown how spatial chromatin organization is critical in the regulation of gene expression. Here, we developed a suite of computer programs to identify chromatin conformation signatures with 5C technology http://Dostielab.biochem.mcgill.ca. We identified dynamic HoxA cluster chromatin conformation signatures associated with cellular differentiation. Genome-wide chromatin conformation signature identification might uniquely identify disease-associated states and represent an entirely novel class of human disease biomarkers.
Transcriptional features of genomic regulatory blocks
Authors: Akalin Altuna , Fredman David , Arner Erik , Dong Xianjun , Bryne Jan Christian , Suzuki Harukazu , Daub Carsten O , Hayashizaki Yoshihide , Lenhard Boris
Published: April 2009

Background

Genomic regulatory blocks (GRBs) are chromosomal regions spanned by highly conserved non-coding elements (HCNEs), most of which serve as regulatory inputs of one target gene in the region. The target genes are most often transcription factors involved in embryonic development and differentiation. GRBs often contain extensive gene deserts, as well as additional 'bystander' genes intertwined with HCNEs but whose expression and function are unrelated to those of the target gene. The tight regulation of target genes, complex arrangement of regulatory inputs, and the differential responsiveness of genes in the region call for the examination of fundamental rules governing transcriptional activity in GRBs. Here we use extensive CAGE tag mapping of transcription start sites across different human tissues and differentiation stages combined with expression data and a number of sequence and epigenetic features to discover these rules and patterns.

Results

We show evidence that GRB target genes have properties that set them apart from their bystanders as well as other genes in the genome: longer CpG islands, a higher number and wider spacing of alternative transcription start sites, and a distinct composition of transcription factor binding sites in their core/proximal promoters. Target gene expression correlates with the acetylation state of HCNEs in the region. Additionally, target gene promoters have a distinct combination of activating and repressing histone modifications in mouse embryonic stem cell lines.

Conclusions

GRB targets are genes with a number of unique features that are the likely cause of their ability to respond to regulatory inputs from very long distances.
FANTOM4 EdgeExpressDB: an integrated database of promoters, genes, microRNAs, expression dynamics and regulatory interactions
Authors: Severin Jessica , Waterhouse Andrew M , Kawaji Hideya , Lassmann Timo , van Nimwegen Erik , Balwierz Piotr J , de Hoon Michiel JL , Hume David A , Carninci Piero , Hayashizaki Yoshihide , Suzuki Harukazu , Daub Carsten O , Forrest Alistair RR
Published: April 2009

EdgeExpressDB is a novel database and set of interfaces for interpreting biological networks and comparing large high-throughput expression datasets that requires minimal development for new data types and search patterns. The FANTOM4 EdgeExpress database http://fantom.gsc.riken.jp/4/edgeexpress summarizes gene expression patterns in the context of alternative promoter structures and regulatory transcription factors and microRNAs using intuitive gene-centric and sub-network views. This is an important resource for gene regulation in acute myeloid leukemia, monocyte/macrophage differentiation and human transcriptional networks.
Phase II Study of the Anti–Insulin-Like Growth Factor Type 1 Receptor Antibody CP-751,871 in Combination With Paclitaxel and Carboplatin in Previously Untreated, Locally Advanced, or Metastatic Non–Small-Cell Lung Cancer
Authors: Karp Daniel D. , Paz-Ares Luis G. , Novello Silvia , Haluska Paul , Garland Linda , Cardenal Felipe , Blakely L. Johnetta , Eisenberg Peter D. , Langer Corey J. , Blumenschein George , Johnson Faye M. , Green Stephanie , Gualberto Antonio
Published: April 2009

Purpose

We conducted a phase II study of combination of the anti–insulin-like growth factor 1 receptor antibody CP-751,871 with paclitaxel and carboplatin (PCI) in advanced treatment-naïve non–small-cell lung cancer (NSCLC).

Patients and Methods

Patients were randomly assigned (2:1) to paclitaxel 200 mg/m2, carboplatin (area under the plasma concentration-time curve of 6), and CP-751,871 10 to 20 mg/kg (PCI10, PCI20) or paclitaxel and carboplatin alone (PC) every 3 weeks for up to six cycles. PCI10-20 patients could continue CP-751,871 (figitumumab) treatment after chemotherapy discontinuation. Patients treated with PC experiencing disease progression were eligible to receive CP-751,871 at investigator's discretion. An additional nonrandomized single-arm cohort of 30 patients with nonadenocarcinoma tumor histology receiving PCI20 was enrolled on completion of the randomized study.

Results

A total of 156 patients were enrolled onto the randomized portion of the study. Safety and efficacy information are available for 151 patients (98 patients treated with PCI and 53 patients treated with PC). Forty-eight patients treated with PCI received PCI10 and 50 patients received PCI20 in two sequential stages. Twenty of 53 patients treated with PC received CP-751,871 after disease progression. PCI was well tolerated. Fifty-four percent of patients treated with PCI and 42% of patients treated with PC had objective responses. Sixteen of 23 patients assessable for efficacy in the nonrandomized single-arm extension cohort also responded to treatment. Of note, 14 of 18 randomly assigned and 11 of 14 nonrandomly assigned patients treated with PCI with squamous cell carcinoma histology had response to treatment, including nine objective responses in bulky disease. Responses were also observed in two patients with squamous histology receiving CP-751,871 on PC discontinuation. PCI20/PC hazard ratio for progression-free survival was 0.8 to 0.56, according to censorship.

Conclusion

These data suggest that PCI20 is safe and effective in patients with NSCLC.
Single Nucleotide Polymorphism at rs1982073:T869C of the TGFβ1 Gene Is Associated With the Risk of Radiation Pneumonitis in Patients With Non–Small-Cell Lung Cancer Treated With Definitive Radiotherapy
Authors: Yuan Xianglin , Liao Zhongxing , Liu Zhensheng , Wang Li-E , Tucker Susan L. , Mao Li , Wang Xin Shelley , Martel Mary , Komaki Ritsuko , Cox James D. , Milas Luka , Wei Qingyi
Published: April 2009

Purpose

In search of reliable biologic markers to predict the risk of normal tissue damage by radio(chemo)therapy before treatment, we investigated the association between single nucleotide polymorphisms (SNPs) in the transforming growth factor 1 (TGFβ1) gene and risk of radiation pneumonitis (RP) in patients with non–small-cell lung cancer (NSCLC).

Patients and Methods

Using 164 available genomic DNA samples from patients with NSCLC treated with definitive radio(chemo)therapy, we genotyped three SNPs of the TGFβ1 gene (rs1800469:C-509T, rs1800471:G915C, and rs1982073:T869C) by polymerase chain reaction restriction fragment length polymorphism method. We used Kaplan-Meier cumulative probability to assess the risk of grade ≥ 3 RP and Cox proportional hazards analyses to evaluate the effect of TGFβ1 genotypes on such risk.

Results

There were 90 men and 74 women in the study, with median age of 63 years. Radiation doses ranging from 60 to 70 Gy (median = 63 Gy) in 30 to 58 fractions were given to 158 patients (96.3%) and platinum-based chemotherapy to 147 (89.6%). Grade ≥ 2 and grade ≥ 3 RP were observed in 74 (45.1%) and 36 patients (22.0%), respectively. Multivariate analysis found CT/CC genotypes of TGFβ1 rs1982073:T869C to be associated with a statistically significantly lower risk of RP grades ≥ 2 (hazard ratio [HR] = 0.489; 95% CI, 0.227 to 0.861; P = .013) and grades ≥ 3 (HR = 0.390; 95% CI, 0.197 to .774; P = 0.007), respectively, compared with the TT genotype, after adjustment for Karnofsky performance status, smoking status, pulmonary function, and dosimetric parameters.

Conclusion

Our results showed that CT/CC genotypes of TGFβ1 rs1982073:T869C gene were associated with lower risk of RP in patients with NSCLC treated with definitive radio(chemo)therapy and thus may serve as a reliable predictor of RP.
A critical constant for the k nearest-neighbour model
Authors: Balister Paul , Bollobás Béla , Sarkar Amites , Walters Mark
Published: April 2009

Let 𝒫 be a Poisson process of intensity 1 in a square Sn of area n. For a fixed integer k, join every point of 𝒫 to its k nearest neighbours, creating an undirected random geometric graph Gn,k. We prove that there exists a critical constant ccrit such that, for c < ccrit, Gn,⌊c log n⌋ is disconnected with probability tending to 1 as n → ∞ and, for c > ccrit, Gn,⌊c log n⌋ is connected with probability tending to 1 as n → ∞. This answers a question posed in Balister et al. (2005).
A discrete-time approximation for doubly reflected BSDEs
Authors: Chassagneux Jean-François
Published: April 2009

We study the discrete-time approximation of doubly reflected backward stochastic differential equations (BSDEs) in a multidimensional setting. As in Ma and Zhang (2005) or Bouchard and Chassagneux (2008), we introduce the discretely reflected counterpart of these equations. We then provide representation formulae which allow us to obtain new regularity results. We also propose an Euler scheme type approximation and give new convergence results for both discretely and continuously reflected BSDEs.
The odds algorithm based on sequential updating and its performance
Authors: Bruss F. Thomas , Louchard Guy
Published: April 2009

Let I1,I2,…,In be independent indicator functions on some probability space We suppose that these indicators can be observed sequentially. Furthermore, let T be the set of stopping times on (Ik), k=1,…,n, adapted to the increasing filtration where The odds algorithm solves the problem of finding a stopping time τ ∈ T which maximises the probability of stopping on the last Ik=1, if any. To apply the algorithm, we only need the odds for the events {Ik=1}, that is, rk=pk/(1-pk), where The goal of this paper is to offer tractable solutions for the case where the pk are unknown and must be sequentially estimated. The motivation is that this case is important for many real-world applications of optimal stopping. We study several approaches to incorporate sequential information. Our main result is a new version of the odds algorithm based on online observation and sequential updating. Questions of speed and performance of the different approaches are studied in detail, and the conclusiveness of the comparisons allows us to propose always using this algorithm to tackle selection problems of this kind.
Lévy processes with adaptable exponent
Authors: Bekker R. , Boxma O. J. , Resing J. A. C.
Published: April 2009

In this paper we consider Lévy processes without negative jumps, reflected at the origin. Feedback information about the level of the Lévy process (‘workload level’) may lead to adaptation of the Lévy exponent. Examples of such models are queueing models in which the service speed or customer arrival rate changes depending on the workload level, and dam models in which the release rate depends on the buffer content. We first consider a class of models where information about the workload level is continuously available. In particular, we consider dam processes with a two-step release rule and M/G/1 queues in which the arrival rate, service speed, and/or jump size distribution may be adapted depending on whether the workload is above or below some level K. Secondly, we consider a class of models in which the workload can only be observed at Poisson instants. At these Poisson instants, the Lévy exponent may be adapted based on the amount of work present. For both classes of models, we determine the steady-state workload distribution.
Finite-time ruin probability with an exponential Lévy process investment return and heavy-tailed claims
Authors: Heyde C. C. , Wang Dingcheng
Published: April 2009

By expressing the discounted net loss process as a randomly weighted sum, we investigate the finite-time ruin probabilities for the Poisson risk model with an exponential Lévy process investment return and heavy-tailed claims. It is found that in finite time, however, the extreme of insurance risk dominates the extreme of financial risk, but, for the case of dangerous investment (see Klüppelberg and Kostadinova (2008) for an accurate definition of dangerous investment), the extreme of financial risk has more and more of an effect on the total risk, and as time passes, the extreme of financial risk finally dominates the extreme of insurance risk.
Multitype Bienaymé–Galton–Watson processes escaping extinction
Authors: Sagitov Serik , Serra Maria Conceição
Published: April 2009

In the framework of a multitype Bienaymé–Galton–Watson (BGW) process, the event that the daughter's type differs from the mother's type can be viewed as a mutation event. Assuming that mutations are rare, we study a situation where all types except one produce on average less than one offspring. We establish a neat asymptotic structure for the BGW process escaping extinction due to a sequence of mutations toward the supercritical type. Our asymptotic analysis is performed by letting mutation probabilities tend to 0. The limit process, conditional on escaping extinction, is another BGW process with an enriched set of types, allowing us to delineate a stem lineage of particles that leads toward the escape event. The stem lineage can be described by a simple Markov chain on the set of particle types. The total time to escape becomes a sum of a random number of independent, geometrically distributed times spent at intermediate types.