bluuebunny/crossref_metadata_2025 huggingface dataset:
Fast Identification of Multiple Indoor Constant Contaminant Sources by Ideal Sensors: A Theoretical Model and Numerical Validation
Authors: Cai Hao , Li Xianting , Chen Zhilong , Kong Lingjuan
Published: October 2012

If hazardous contaminants are suddenly released indoors, quickly identifying the pollutants characteristics, such as the locations and emission rates, of the contaminant sources is critical for developing fast and effective response measures. This study presents a theoretical model for quickly identifying the locations and emission rates of multiple constant sources indoors using a single or limited number of ideal sensors. The model combines a linear programming model with an analytical expression of indoor contaminant dispersion that was presented in our previous study. Before the release of contaminants, only a limited number of time-consuming computational fluid dynamics (CFD) simulations need to be conducted to cover a large number of possible scenarios because of the analytical expression integrated into the model. After the release of contaminants, the model can be solved in real-time. Through case studies of sixteen contaminant release scenarios in a three-dimensional office, the effectiveness of the model was numerically demonstrated and validated. The results revealed that the identification accuracy of the presented model was closely related to the sensor layouts and the total sampling time, rather than the sampling interval.
A ‘brave thing to do’ or a normative practice? Marriage after long-term cohabitation
Authors: Baker Maureen , Elizabeth Vivienne
Published: October 2012

For decades, sociologists have debated whether widespread cohabitation among opposite-sex and same-sex couples indicates the transformation of relationships or simply a new pathway to marriage. If it is the latter, what does this transition mean to couples who decide to marry? Using an interpretive framework, the article investigates why cohabiting couples legalise their relationships when there seem to be few legal or social advantages, and how they solemnise and celebrate this transition. Drawing on New Zealand interviews with celebrants and long-term cohabitants who have decided to legalise, we found widespread concern about traditional marriage and a desire to develop individualised pathways for couple relationships. Nevertheless, our participants eventually decided to make a public commitment and to celebrate their ‘successful’ relationships with family and friends. Furthermore, we found that wedding practices continue to be influenced by social pressures and cultural representations, and many couples incorporate traditional practices symbolising patriarchy and heterosexuality regardless of personal beliefs or sexual orientation. Although cohabitation rates are rising, our study concludes that weddings have retained much of their symbolic value as a cultural ideal, but have increasingly become subject to personalisation, as if to signify that couples are indeed the authors of their own biographies of love.
ACE2 gene polymorphisms and invasively measured central pulse pressure in cardiac patients indicated for coronarography
Authors: Vašků Anna , Bienertová-Vašků Julie , Pařenica Jiří , Goldbergová Monika Pávkova , Lipková Jolana , Zlámal Filip , Kala Petr. , Špinar Jindřich
Published: October 2012

Background and aim:

The objective of this research was to determine whether invasively measured central pulse pressure (PP) in patients indicated for coronarography is associated with two common polymorphisms in the ACE2 region (rs4646156 and rs4646174).

Methods:

A total of 307 patients were enrolled in the study. The genotyping of both SNPs from peripheral blood samples was carried out using 5′exonuclease (Taqman®) chemistry on the ABI Prism® 7000 system (Applied Biosystems, Foster City, CA, USA).

Results:

In both polymorphisms, the associations with central PP were found to be highly significant when all five possible genotypes in the population had been compared ( p = 0.0001). In men, there was a higher incidence of previous myocardial infarction in G0 genotype carriers of rs54646174 (OR ratio = 7; p = 0.005). The AA genotype of rs4646156 had a 7.81× higher risk of severe angina pectoris in women (OR = 7.81, p = 0.05). A significant difference in allelic frequency of ACE2rs4646174 was found between women with and without significant stenoses of the circumflex branch of the left coronary artery.

Conclusion:

More research into the role of ACE2 genetic variability in PP regulations is necessary for more detailed physiological and pathophysiological comprehension of PP regulation.
Looking healthy: visualizing mental health and illness online
Authors: Thompson Riki
Published: October 2012

Through a historical case study of the mental health community website HealthyPlace.com , the author applies social semiotics and critical discourse analysis to interrogate the visual discourse surrounding mental health online. Web design transformations over the course of a decade demonstrate how visual imagery conveys a shift from a biomedical discourse focused on illness to a social-therapeutic discourse centered on health and wellness. Ultimately, the author argues that the utilization of faces in stock photography, stylized images, and social media platforms on HealthyPlace reflects a growing trend in virtual visual synthetic personalization on the internet to market mental health disorders as a concern for the everyday person while selling the promise of wellness through online participation. This article explores the visual language of mental health and wellness online to expanding on research in the field of visual communication, health communication, and new media studies.
Graphic trinities: languages, literature, and words-in-pictures in Shaun Tan’s The Arrival
Authors: Johnston Rosemary Ross
Published: October 2012

This article brings together semiotics and literary theory, and notes the intrinsic and historical connectedness between words and images. It discusses the ‘language’ of Shaun Tan’s graphic novel The Arrival and describes the use of traditional language as illustration, and the use of image as language. In doing so, it notes the work of the Russian theorist Bakhtin on the chronotope, and the related idea, developed by the author of this article, of the visual chronotope as a tool of semiotic analysis.
Young students’ uses of visual composing resources in literacy classroom contexts: a cross-case analysis
Authors: Ranker Jason
Published: October 2012

In this study, the author draws upon a social semiotic framework, exploring the ways in which students can use visual semiotic resources while composing texts in literacy classroom contexts. His multi-case study involving three cases of students in primary-level classrooms focuses specifically on how several focal students created, accessed, and assembled sets of visual semiotic resources that they used while engaged in the literacy processes at hand. This study defines and develops the concept of a visual composing resource, and qualifies the range, scope, and type of visual resources that were available to the students while they engaged in literacy processes in various classroom settings. The author also illustrates how the students brought these sets of visual composing resources into a complex interaction with the semiotic assemblages that they were producing in each context, revealing important aspects of early literacy processes that incorporate visuality.
From Stalemate to Deadlock: Clement’s Letter to Theodore in Recent Scholarship
Authors: Paananen Timo S.
Published: October 2012

This article reviews the literature pertaining to the recent debate over the question of authenticity of Clement’s Letter to Theodore (including the so-called Secret Gospel of Mark) and argues that the academy has tied itself into a secure deadlock. The current ‘trench warfare’ situation is due to various scholarly malpractices, which include the practice of non-engagement with other scholars, abusive language towards them and mischaracterization of their position. In order to remedy the situation and move the discussion forwards a number of correcting acts are suggested.
Registered nurses’ collective safety organising behaviours: the association with perceptions of patient safety culture
Authors: Wilson Deleise S.
Published: October 2012

The cultivation of patient safety cultures is critical for the sustainability of positive patient outcomes. At the core of safety cultures are the safety organising behaviours of its workers. Yet, the assessment of patient safety culture in healthcare settings are usually associated with professional characteristics such as role, rank and their practice settings. Little attention has been given to exploring how collective safety organising behaviours of healthcare workers, in particular registered nurses, may be implicated in the perceptions of patient safety culture. The purpose of this paper was to examine the association between nurses’ collective safety organising behaviours and their perceptions of patient safety culture. This study utilised a cross-sectional design. A total of 381 nurses from 11 medical–surgical units completed questionnaires. Hierarchical regression analyses indicated that after controlling for key confounding variables, collective safety organising behaviours had significant associations with teamwork, communication openness, manager support, organisational learning, overall perceptions, feedback about errors, frequency of event reports, staffing, non-punitive response to error and safety grade for work area. Safety organising behaviours may provide additional insights into the black box of organisational contextual factors that may be implicated in perceptions of patient safety culture among nurses.
The potential for aclidinium bromide, a new anticholinergic, in the management of chronic obstructive pulmonary disease
Authors: Maltais François , Milot Julie
Published: October 2012

Long-acting muscarinic antagonists (LAMAs) play a central role in the management of chronic obstructive pulmonary disease (COPD). Previously, only one LAMA (tiotropium) was available for the treatment of COPD, necessitating the development of other therapeutic options due to the heterogeneity of COPD and patient responses to treatment. This article reviews the COPD management potential of aclidinium bromide, a LAMA administered twice daily (BID) by a multidose dry powder inhaler that is indicated for maintenance treatment of COPD. Aclidinium possesses kinetic selectivity for the M3 versus M2 receptor and is rapidly hydrolyzed in plasma to two major inactive metabolites, resulting in a low and transient systemic exposure and minimizing the potential for systemic side effects. A pharmacokinetic study with multiple doses of twice-daily aclidinium demonstrated the short half-life of aclidinium in plasma, suggesting that a steady state may be reached as early as the second day postdose. In a phase II study, twice-daily aclidinium 400 µg provided 24-hour bronchodilation, with significant improvements versus tiotropium during the second half of the day. In two phase III studies (ACCORD I and ATTAIN), both aclidinium 200 µg and 400 µg BID provided statistically significant improvements in trough forced expiratory volume in 1 second (FEV1) and other related lung function measurements. Improvements in peak FEV1 on day 1 were comparable to those at study end, demonstrating that aclidinium provides maximal bronchodilation after the first dose that is maintained over time. Health status was significantly improved and dyspnea, nighttime and morning symptoms of COPD were likewise significantly reduced with aclidinium. Numerically greater improvements in efficacy were observed with the 400 µg dose compared with the lower dose, with similar safety profiles between the two doses and a low incidence of anticholinergic side effects. The approved therapeutic dose of aclidinium 400 µg BID is thus an effective new treatment option for patients with COPD.
Investigation on interface of Al/Cu couples in compound casting
Authors: Zare G R , Divandari M , Arabi H
Published: October 2012

The joining of Al and Cu commercially pure metals using the compound casting process has been investigated where an aluminium melt is cast onto a solid cylindrical copper insert. The microstructure of the interface between copper core and surrounding aluminium was characterised by optical microscopy, scanning electron microscopy, energy dispersive X-ray spectroscopy and Vickers hardness tests. Results showed that five separate reaction layers are formed in the reaction interface of core and surrounding Al. These layers included Cu9Al4, AlCu and Al2Cu intermetallic compounds; a eutectic layer; and a eutectic α-Al dendritic structure layer. Owing to the presence of hard and brittle intermetallic compounds within reaction layers, microhardness profile showed a peak of 300 HV where both parent metals have hardness <50 HV. Microhardness profile also showed that hardness decreases from the copper to the aluminium side.
Notch is active in Langerhans cell histiocytosis and confers pathognomonic features on dendritic cells
Authors: Hutter Caroline , Kauer Max , Simonitsch-Klupp Ingrid , Jug Gunhild , Schwentner Raphaela , Leitner Judith , Bock Peter , Steinberger Peter , Bauer Wolfgang , Carlesso Nadia , Minkov Milen , Gadner Helmut , Stingl Georg , Kovar Heinrich , Kriehuber Ernst
Published: October 2012

Langerhans cell histiocytosis (LCH) is an enigmatic disease defined by the accumulation of Langerhans cell-like dendritic cells (DCs). In the present study, we demonstrate that LCH cells exhibit a unique transcription profile that separates them not only from plasmacytoid and myeloid DCs, but also from epidermal Langerhans cells, indicating a distinct DC entity. Molecular analysis revealed that isolated and tissue-bound LCH cells selectively express the Notch ligand Jagged 2 (JAG2) and are the only DCs that express both Notch ligand and its receptor. We further show that JAG2 signaling induces key LCH-cell markers in monocyte-derived DCs, suggesting a functional role of Notch signaling in LCH ontogenesis. JAG2 also induced matrix-metalloproteinases 1 and 12, which are highly expressed in LCH and may account for tissue destruction in LCH lesions. This induction was selective for DCs and was not recapitulated in monocytes. The results of the present study suggest that JAG2-mediated Notch activation confers phenotypic and functional aspects of LCH to DCs; therefore, interference with Notch signaling may be an attractive strategy to combat this disease.
Prediagnosis biomarkers of insulin-like growth factor-1, insulin, and interleukin-6 dysregulation and multiple myeloma risk in the Multiple Myeloma Cohort Consortium
Authors: Birmann Brenda M. , Neuhouser Marian L. , Rosner Bernard , Albanes Demetrius , Buring Julie E. , Giles Graham G. , Lan Qing , Lee I-Min , Purdue Mark P. , Rothman Nathaniel , Severi Gianluca , Yuan Jian-Min , Anderson Kenneth C. , Pollak Michael , Rifai Nader , Hartge Patricia , Landgren Ola , Lessin Lawrence , Virtamo Jarmo , Wallace Robert B. , Manson JoAnn E. , Colditz Graham A.
Published: October 2012

Insulin-like growth factor-1 (IGF-1), insulin, and IL-6 are dysregulated in multiple myeloma pathogenesis and may also contribute to multiple myeloma etiology. To examine their etiologic role, we prospectively analyzed concentrations of serologic markers in 493 multiple myeloma cases and 978 controls from 8 cohorts in the Multiple Myeloma Cohort Consortium. We computed odds ratios (ORs) and 95% confidence intervals (CIs) for multiple myeloma per 1-SD increase in biomarker concentration using conditional logistic regression. We examined heterogeneity by time since blood collection (≤ 3, 4- ≤ 6, and > 6 years) in stratified models. Fasting IGF binding protein-1 concentration was associated with multiple myeloma risk within 3 years (OR, 95% CI per 1-SD increase: 2.3, 1.4-3.8, P = .001) and soluble IL-6 receptor level was associated within 6 years after blood draw (OR ≤ 3 years, 95% CI, 1.4, 1.1-1.9, P = .01; OR4- ≤ 6 years, 95% CI, 1.4, 1.1-1.7, P = .002). No biomarker was associated with longer-term multiple myeloma risk (ie, > 6 years). Interactions with time were statistically significant (IGF binding protein-1, P-heterogeneity = .0016; sIL6R, P-heterogeneity = .016). The time-restricted associations probably reflect the bioactivity of tumor and microenvironment cells in transformation from monoclonal gammopathy of undetermined significance or smoldering multiple myeloma to clinically manifest multiple myeloma.
Antagonism of VEGF-A–induced increase in vascular permeability by an integrin α3β1-Shp-1-cAMP/PKA pathway
Authors: Kim Soo Hyeon , Cho Young-Rak , Kim Hyeon-Ju , Oh Joa Sub , Ahn Eun-Kyung , Ko Hye-Jin , Hwang Byung Joon , Lee Seo-Jin , Cho Yongwan , Kim Yong Kee , Stetler-Stevenson William G. , Seo Dong-Wan
Published: October 2012

In cancer, VEGF-induced increase in vascular permeability results in increased interstitial pressure, reducing perfusion and increasing hypoxia, which reduce delivery of chemotherapeutic agents and increase resistance to ionizing radiation. Here, we show that both TIMP-2 and Ala + TIMP-2, a TIMP-2 mutant without matrix metalloproteinase inhibitory activity, antagonize the VEGF-A–induced increase in vascular permeability, both in vitro and in vivo. Like other agents known to preserve endothelial barrier function, TIMP-2 elevates cytosolic levels of cAMP and increases cytoskeletal-associated vascular endothelial cadherin in human microvascular endothelial cells. All of these effects are completely ablated by selective knockdown of integrin α3β1 expression, expression of a dominant negative protein tyrosine phosphatase Shp-1 mutant, administration of the protein tyrosine phosphatase inhibitor orthovanadate, or the adenylate cyclase inhibitor SQ22536. This TIMP-2–mediated inhibition of vascular permeability involves an integrin α3β1-Shp-1-cAMP/protein kinase A-dependent vascular endothelial cadherin cytoskeletal association, as evidenced by using siRNAs to integrin α3β1 and Shp-1, or treatment with Shp-1 inhibitor NSC87877 and protein kinase A inhibitor H89. Our results demonstrate the potential utility for TIMP-2 in cancer therapy through “normalization” of vascular permeability in addition to previously described antiangiogenic effects.
Endothelial endoglin is involved in inflammation: role in leukocyte adhesion and transmigration
Authors: Rossi Elisa , Sanz-Rodriguez Francisco , Eleno Nelida , Düwell Annette , Blanco Francisco J. , Langa Carmen , Botella Luisa M. , Cabañas Carlos , Lopez-Novoa José M. , Bernabeu Carmelo
Published: October 2012

Human endoglin is an RGD-containing transmembrane glycoprotein identified in vascular endothelial cells. Although endoglin is essential for angiogenesis and its expression is up-regulated in inflammation and at sites of leukocyte extravasation, its role in leukocyte trafficking is unknown. This function was tested in endoglin heterozygous mice (Eng+/−) and their wild-type siblings Eng+/+ treated with carrageenan or LPS as inflammatory agents. Both stimuli showed that inflammation-induced leukocyte transendothelial migration to peritoneum or lungs was significantly lower in Eng+/− than in Eng+/+ mice. Leukocyte transmigration through cell monolayers of endoglin transfectants was clearly enhanced in the presence of endoglin. Coating transwells with the RGD-containing extracellular domain of endoglin, enhanced leukocyte transmigration, and this increased motility was inhibited by soluble endoglin. Leukocytes stimulated with CXCL12, a chemokine involved in inflammation, strongly adhered to endoglin-coated plates and to endoglin-expressing endothelial cells. This endoglin-dependent adhesion was abolished by soluble endoglin, RGD peptides, the anti-integrin α5β1 inhibitory antibody LIA1/2 and the chemokine receptor inhibitor AMD3100. These results demonstrate for the first time that endothelial endoglin interacts with leukocyte integrin α5β1 via its RGD motif, and this adhesion process is stimulated by the inflammatory chemokine CXCL12, suggesting a regulatory role for endoglin in transendothelial leukocyte trafficking.
Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia
Authors: Faham Malek , Zheng Jianbiao , Moorhead Martin , Carlton Victoria E. H. , Stow Patricia , Coustan-Smith Elaine , Pui Ching-Hon , Campana Dario
Published: October 2012

The persistence of minimal residual disease (MRD) during therapy is the strongest adverse prognostic factor in acute lymphoblastic leukemia (ALL). We developed a high-throughput sequencing method that universally amplifies antigen-receptor gene segments and identifies all clonal gene rearrangements (ie, leukemia-specific sequences) at diagnosis, allowing monitoring of disease progression and clonal evolution during therapy. In the present study, the assay specifically detected 1 leukemic cell among greater than 1 million leukocytes in spike-in experiments. We compared this method with the gold-standard MRD assays multiparameter flow cytometry and allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) using diagnostic and follow-up samples from 106 patients with ALL. Sequencing detected MRD in all 28 samples shown to be positive by flow cytometry and in 35 of the 36 shown to be positive by ASO-PCR and revealed MRD in 10 and 3 additional samples that were negative by flow cytometry and ASO-PCR, respectively. We conclude that this new method allows monitoring of treatment response in ALL and other lymphoid malignancies with great sensitivity and precision. The www.clinicaltrials.gov identifier number for the Total XV study is NCT00137111.
Dysregulation of MicroRNAs in cancer
Authors: Chen Pai-Sheng , Su Jen-Liang , Hung Mien-Chie
Published: October 2012

MicroRNAs (miRNAs) are involved in multiple biological activities as well as disease progression including cancer. Interestingly, miRNAs could act as either tumor suppressors or oncogenes depending on the functions of their targets. Using high-throughput profiling, dysregulation of miRNAs has been widely observed in different stages of cancer, and there is mounting evidence demonstrating several misguided mechanisms that cause miRNA dysregulation. In this review, we summarize the key functions of miRNAs in cancer, especially those affecting tumor metastasis and drug resistance. Moreover, the mechanisms leading to dysregulation of miRNAs, including genomic abnormalities, DNA/histone modifications, transcriptional regulation, abnormal biogenesis, and interaction between miRNAs, are also discussed.
Effects of coffee, smoking, and alcohol on liver function tests: a comprehensive cross-sectional study
Authors: Jang Eun Sun , Jeong Sook-Hyang , Hwang Sung Ho , Kim Hyun Young , Ahn So Yeon , Lee Jaebong , Lee Sang Hyub , Park Young Soo , Hwang Jin Hyeok , Kim Jin-Wook , Kim Nayoung , Lee Dong Ho
Published: October 2012

Background

Liver function tests (LFTs) can be affected by many factors and the proposed effects of coffee on LFT require a comprehensive evaluation. The aim of this study was to elucidate whether drinking coffee, smoking, or drinking alcohol have independent effects on LFTs in Korean health-check examinees.

Methods

We used the responses of 500 health-check examinees, who had participated in a self-administered questionnaire survey about coffee, alcohol drinking, and smoking habits.

Results

Coffee consumption was closely related to male gender, high body mass index (BMI), alcohol drinking, and smoking. On univariable and multivariable analyses, drinking coffee lowered serum levels of total protein, albumin, and aspartate aminotransferases (AST). On multivariable analyses, smoking raised serum γ-glutamyl transferase (GGT) level and decreased serum protein and albumin levels, while alcohol drinking raised GGT level after adjustment for age, gender, regular medication, BMI, coffee and alcohol drinking amounts, and smoking.

Conclusions

Coffee consumption, smoking, and alcohol drinking affect the individual components of LFT in different ways, and the above 3 habits each have an impact on LFTs. Therefore, their effects on LFTs should be carefully interpreted, and further study on the mechanism of the effects is warranted.
P276-00, a cyclin-dependent kinase inhibitor, modulates cell cycle and induces apoptosis in vitro and in vivo in mantle cell lymphoma cell lines
Authors: Shirsath Nitesh P , Manohar Sonal M , Joshi Kalpana S
Published: October 2012

Background

Mantle cell lymphoma (MCL) is a well-defined aggressive lymphoid neoplasm characterized by proliferation of mature B-lymphocytes that have a remarkable tendency to disseminate. This tumor is considered as one of the most aggressive lymphoid neoplasms with poor responses to conventional chemotherapy and relatively short survival. Since cyclin D1 and cell cycle control appears as a natural target, small-molecule inhibitors of cyclin-dependent kinases (Cdks) and cyclins may play important role in the therapy of this disorder. We explored P276-00, a novel selective potent Cdk4-D1, Cdk1-B and Cdk9-T1 inhibitor discovered by us against MCL and elucidated its potential mechanism of action.

Methods

The cytotoxic effect of P276-00 in three human MCL cell lines was evaluated in vitro. The effect of P276-00 on the regulation of cell cycle, apoptosis and transcription was assessed, which are implied in the pathogenesis of MCL. Flow cytometry, western blot, immunoflourescence and siRNA studies were performed. The in vivo efficacy and effect on survival of P276-00 was evaluated in a Jeko-1 xenograft model developed in SCID mice. PK/PD analysis of tumors were performed using LC-MS and western blot analysis.

Results

P276-00 showed a potent cytotoxic effect against MCL cell lines. Mechanistic studies confirmed down regulation of cell cycle regulatory proteins with apoptosis. P276-00 causes time and dose dependent increase in the sub G1 population as early as from 24 h. Reverse transcription PCR studies provide evidence that P276-00 treatment down regulated transcription of antiapoptotic protein Mcl-1 which is a potential pathogenic protein for MCL. Most importantly, in vivo studies have revealed significant efficacy as a single agent with increased survival period compared to vehicle treated. Further, preliminary combination studies of P276-00 with doxorubicin and bortezomib showed in vitro synergism.

Conclusion

Our studies thus provide evidence and rational that P276-00 alone or in combination is a potential therapeutic molecule to improve patients’ outcome in mantle cell lymphoma.
The multi-step process of building TB/HIV collaboration in Cambodia
Authors: Eang Mao Tan , Vun Mean Chhi , Eam Khun Kim , Sovannarith Samreth , Sopheap Seng , Bora Ngauv , Yadav Rajendra , Fujita Masami , Tomas Bernard , Ghidinelli Massimo , van Maaren Pieter , Wells William A
Published: October 2012

Tuberculosis and HIV/AIDS have synergistic health impacts in terms of disease development and progression. Therefore, collaborative TB and HIV/AIDS activities are a logical health systems response. However, the establishment of these activities presents a challenge for countries that have strong vertical disease programs that differ in their implementation philosophies. Here, we review the process by which TB/HIV collaboration was established in Cambodia. A cycle of overlapping and mutually reinforcing initiatives – local research; piloted implementation with multiple options; and several rounds of policy formulation guided by a cross-functional Technical Working Group – was used to drive nationwide introduction of a full set of TB/HIV collaborative activities. Senior Ministry of Health officials and partner organizations brought early attention to TB/HIV. Both national programs implemented initial screening and testing interventions, even in the absence of a detailed, overarching framework. The use of multiple options for HIV testing identified which programmatic options worked best, and early implementation and pilots determined what unanswered questions required further research. Local conduct of this research – on co-treatment timing and TB symptom screening – speeded adoption of the results into policy guidance, and clarified the relative roles of the two programs. Roll-out is continuing, and results for a variety of key indicators, including screening PLHIV for TB, and testing TB patients for HIV, are at 70-80% and climbing. This experience in Cambodia illustrates the influence of health research on policy, and demonstrates that clear policy guidance, the pursuit of incremental advances, and the use of different approaches to generate evidence can overcome structural barriers to change and bring direct benefits to patients.
Successful resolution of refractory chronic cough induced by gastroesophageal reflux with treatment of baclofen
Authors: Xu Xianghuai , Chen Qiang , Liang Siwei , LÜ Hanjing , Qiu Zhongmin
Published: October 2012

Gastroesophageal reflux induced cough is a common cause of chronic cough, and proton pump inhibitors are a standard therapy. However, the patients unresponsive to the standard therapy are difficult to treat and remain a challenge to doctors. Here, we summarized the experience of successful resolution of refractory chronic cough due to gastroesophageal reflux with baclofen in three patients. It is concluded that baclofen may be a viable option for gastroesophageal reflux induced cough unresponsive to proton pump inhibitor therapy.
CellNOptR: a flexible toolkit to train protein signaling networks to data using multiple logic formalisms
Authors: Terfve Camille , Cokelaer Thomas , Henriques David , MacNamara Aidan , Goncalves Emanuel , Morris Melody K , Iersel Martijn van , Lauffenburger Douglas A , Saez-Rodriguez Julio
Published: October 2012

Background

Cells process signals using complex and dynamic networks. Studying how this is performed in a context and cell type specific way is essential to understand signaling both in physiological and diseased situations. Context-specific medium/high throughput proteomic data measured upon perturbation is now relatively easy to obtain but formalisms that can take advantage of these features to build models of signaling are still comparatively scarce.

Results

Here we present CellNOptR, an open-source R software package for building predictive logic models of signaling networks by training networks derived from prior knowledge to signaling (typically phosphoproteomic) data. CellNOptR features different logic formalisms, from Boolean models to differential equations, in a common framework. These different logic model representations accommodate state and time values with increasing levels of detail. We provide in addition an interface via Cytoscape (CytoCopteR) to facilitate use and integration with Cytoscape network-based capabilities.

Conclusions

Models generated with this pipeline have two key features. First, they are constrained by prior knowledge about the network but trained to data. They are therefore context and cell line specific, which results in enhanced predictive and mechanistic insights. Second, they can be built using different logic formalisms depending on the richness of the available data. Models built with CellNOptR are useful tools to understand how signals are processed by cells and how this is altered in disease. They can be used to predict the effect of perturbations (individual or in combinations), and potentially to engineer therapies that have differential effects/side effects depending on the cell type or context.
Seroprevalence of Toxoplasma gondii infection in slaughtered chickens, ducks, and geese in Shenyang, northeastern China
Authors: Yang Na , Mu Ming-Yang , Li Hong-Kui , Long Miao , He Jian-Bin
Published: October 2012

Background

In recent years, investigations of Toxoplasma gondii infection in poultry (chickens, ducks, and geese) have been reported worldwide, including China. However, little is known about the prevalence of T. gondii infection in poultry in northeastern China. Therefore, the present study was performed to determine the prevalence of T. gondii infection in slaughtered chickens, ducks, and geese in Shenyang, northeastern China.

Methods

In the present study, the seroprevalence of T. gondii in 502 adult chickens, 268 adult ducks, and 128 adult geese was surveyed using the modified agglutination test (MAT).

Results

The seroprevalences of T. gondii were 5.8%, 7.8%, and 4.7% in chickens, ducks, and geese, respectively. Prevalence was higher in free-range groups (11.2%, 12.3%, and 8.9%) than caged groups (4.7%, 7.5%, and 6.0%), and there was a statistically significant difference only between free-range chickens and caged chickens, but no significant difference was found between free-range ducks, geese and caged ducks, geese.

Conclusions

The present study shows the prescence of T. gondii infection in slaughtered chickens, ducks, and geese in Shenyang, northeastern China, which suggests that consumption of poultry meat in Shenyang may pose a potential threat to human health and should be given attention.
Nitric oxide and histone deacetylases modulate cocaine-induced mu-opioid receptor levels in PC12 cells
Authors: Winick-Ng Warren , Leri Francesco , Kalisch Bettina E
Published: October 2012

Background

Cocaine exposure has been reported to alter central μ-opioid receptor (MOR) expressionin vivo. The present study employed anin vitrocellular model to explore possible mechanisms that may be involved in this action of cocaine.

Methods

To assess the effects of cocaine on MOR levels, two treatment regimens were tested in PC12 cells: single continuous or multiple intermittent. MOR protein levels were assessed by western blot analysis and quantitative PCR was used to determine relative MOR mRNA expression levels. To evaluate the role of nitric oxide (NO) and histone acetylation in cocaine-induced MOR expression, cells were pre-treated with the NO synthase inhibitor Nω-nitro-L-arginine methylester (L-NAME) or the non-selective histone acetyltransferase inhibitor curcumin.

Results

Both cocaine treatment regimens significantly increased MOR protein levels and protein stability, but only multiple intermittent treatments increased MOR mRNA levels as well asc-fosmRNA levels and activator protein 1 binding activity. Both regimens increased NO production, and pre-treatment with L-NAME prevented cocaine-induced increases in MOR protein and mRNA levels. Single and multiple cocaine treatment regimens inhibited histone deacetylase activity, and pre-treatment with curcumin prevented cocaine-induced up-regulation of MOR protein expression.

Conclusions

In the PC12 cell model, both NO and histone deacetylase activity regulate cocaine-induced MOR expression at both the transcriptional and post-transcriptional levels. Based on these novel findings, it is hypothesized that epigenetic mechanisms are implicated in cocaine’s action on MOR expression in neurons.
Endothelin-receptor antagonists for aneurysmal subarachnoid hemorrhage: an updated meta-analysis of randomized controlled trials
Authors: Ma Junpeng , Huang Siqing , Ma Lu , Liu Yi , Li Hao , You Chao
Published: October 2012

Introduction

The previous meta-analysis on the use of endothelin-receptor antagonists (ETRAs) to treat aneurysmal subarachnoid hemorrhage (SAH) has become outdated due to recently published phase 3 clinical trials. An up-to-date meta-analysis is needed to provide the best available evidence for the efficacy of ETRAs for aneurysmal SAH.

Methods

We performed a systematic review and meta-analysis of published randomized controlled trials that investigate efficacy of ETRAs in patients with aneurysmal SAH. Mortality, unfavorable outcome, delayed ischemic neurological deficit (DIND), delayed cerebral infarction (DCI), angiographic vasospasm and adverse events were analyzed. Meta-analysis was performed in terms of the risk ratio (RR) and 95% confidence interval (CI).

Results

Five eligible studies were reviewed and analyzed, involving 2,595 patients. The pooled RRs of mortality and unfavorable outcome after SAH were 1.03 (95% CI = 0.77 to 1.36) and 1.07 (95% CI = 0.93 to 1.22), respectively. The pooled RRs were 0.87 (95% CI = 0.74 to 1.03) for DCI, 0.77 (95% CI = 0.66 to 0.90) for DIND, and 0.66 (95% CI = 0.57 to 0.77) for angiographic vasospasm. There were significant increases in lung complications (RR = 1.80, 95% CI = 1.55 to 2.09), hypotension (RR = 2.42, 95% CI = 1.78 to 3.29) and anemia (RR = 1.47, 95% CI = 1.19 to 1.83) in patients administered ETRAs.

Conclusion

There is no evidence that ETRAs could benefit clinical outcome in patients with SAH. Owing to the increased adverse events, further clinical trials of ETRAs in SAH patients should be more carefully formulated and designed. The present results also suggest that DCI may be a better outcome measure than vasospasm and DIND in SAH clinical trials and observational studies.
Anti-Gr-1 antibody depletion fails to eliminate hepatic myeloid-derived suppressor cells in tumor-bearing mice
Authors: Ma Chi , Kapanadze Tamar , Gamrekelashvili Jaba , Manns Michael P , Korangy Firouzeh , Greten Tim F
Published: October 2012

Systemic anti-Gr-1 antibody treatment fails to deplete hepatic MDSC.

Recent studies show that the liver is a preferred organ for the accumulation of MDSC. In this study, we examined the effect of systemic RB6-8C5 treatment on hepatic MDSC in tumor-bearing mice. EL4 tumor-bearing mice were injected i.p. with RB6-8C5, and hepatic, splenic, and blood MDSCs were analyzed by flow cytometry. Unexpectedly, hepatic MDSC remained in the liver, although RB6-8C5 completely eliminated them from the spleen and peripheral blood 24 h after treatment. Secondary antibody staining confirmed the presence of RB6-8C5-bound MDSC in the liver of mice with s.c. tumors. Similar observations were made in two other (colon and melanoma) tumor models. Whereas RB6-8C5 injection induced cell death of hepatic MDSC, as shown by Annexin V/7-AAD staining, these cells were replaced immediately, leading to a constant, increased frequency of hepatic MDSC. Adoptively transferred MDSC migrated preferentially to the liver after RB6-8C5 treatment, suggesting that hepatic MDSCs are reconstituted rapidly after depletion. Finally, hepatic MDSC remained immunosuppressive despite RB6-8C5 injection. Our study demonstrates that RB6-8C5 is not suitable for depletion of hepatic MDSCs and analysis of their function.
Role of TLR2-dependent IL-10 production in the inhibition of the initial IFN-γ T cell response to Porphyromonas gingivalis
Authors: Gaddis Dalia E , Maynard Craig L , Weaver Casey T , Michalek Suzanne M , Katz Jannet
Published: October 2012

IL-10 produced by T cells and CD11b+ cells utilizes TLR2 signaling and FimA antigen to inhibit early IFN-γ T cell responses to Porphyromonas gingivalis.

P.g., a Gram-negative bacterium, is one of the main etiological agents of the chronic inflammatory disease, periodontitis. Disease progression is thought to occur as a result of an inadequate immune response, which although happens locally, can also occur distally as a result of the dissemination of P.g. into the circulation. As IL-10 and TLR2 are pivotal molecules in the immune response that P.g. elicits, we hypothesized that TLR2-mediated IL-10 production, following the initial systemic exposure to P.g., inhibits the IFN-γ T cell response. To address this hypothesis, mice were primed with P.g., and the types of cells producing IL-10 and the capacity of T cells to produce IFN-γ following blocking or neutralization of IL-10 were assessed. Our results showed that upon initial encounter with P.g., splenic T cells and CD11b+ cells produce IL-10, which when neutralized, resulted in a substantial increase in IFN-γ production by T cells. Furthermore, IL-10 production was dependent on TLR2/1 signaling, partly in response to the major surface protein, FimA of P.g. In addition, P.g. stimulation resulted in the up-regulation of PD-1 and its ligand PD-L1 on CD4 T cells and CD11b+ cells, respectively. Up-regulation of PD-1 was partially dependent on IL-10 but independent of TLR2 or FimA. These results highlight the role of IL-10 in inhibiting T cell responses to the initial systemic P.g. exposure and suggest multiple inhibitory mechanisms potentially used by P.g. to evade the hostˈs immune response, thus allowing its persistence in the host.
Macrophage-tropic HIV-1 variants from brain demonstrate alterations in the way gp120 engages both CD4 and CCR5
Authors: Salimi Hamid , Roche Michael , Webb Nicholas , Gray Lachlan R , Chikere Kelechi , Sterjovski Jasminka , Ellett Anne , Wesselingh Steve L , Ramsland Paul A , Lee Benhur , Churchill Melissa J , Gorry Paul R
Published: October 2012

Along with an enhanced interaction with CD4, highly M-tropic HIV-1 Envs have an altered mechanism of engagement with CCR5.

BR-derived HIV-1 strains have an exceptional ability to enter macrophages via mechanisms involving their gp120 Env that remain incompletely understood. Here, we used cell-based affinity-profiling methods and mathematical modeling to generate quantitative VERSA metrics that simultaneously measure Env-CD4 and Env-CCR5 interactions. These metrics were analyzed to distinguish the phenotypes of M-tropic and non-M-tropic CCR5-using HIV-1 variants derived from autopsy BRs and LNs, respectively. We show that highly M-tropic Env variants derived from brain can be defined by two distinct and simultaneously occurring phenotypes. First, BR-derived Envs demonstrated an enhanced ability to interact with CD4 compared with LN-derived Envs, permitting entry into cells expressing scant levels of CD4. Second, BR-derived Envs displayed an altered mechanism of engagement between CD4-bound gp120 and CCR5 occurring in tandem. With the use of epitope mapping, mutagenesis, and structural studies, we show that this altered mechanism is characterized by increased exposure of CD4-induced epitopes in gp120 and by a more critical interaction between BR-derived Envs and the CCR5 N-terminus, which was associated with the predicted presence of additional atomic contacts formed at the gp120-CCR5 N-terminus interface. Our results suggest that BR-derived HIV-1 variants with highly efficient macrophage entry adopt conformations in gp120 that simultaneously alter the way in which the Env interacts with CD4 and CCR5.
How microRNAs facilitate reprogramming to pluripotency
Authors: Anokye-Danso Frederick , Snitow Melinda , Morrisey Edward E.
Published: October 2012

The ability to generate pluripotent stem cells from a variety of cell and tissue sources through the ectopic expression of a specific set of transcription factors has revolutionized regenerative biology. The development of this reprogramming technology not only makes it possible to perform basic research on human stem cells that do not have to be derived from embryos, but also allows patient-specific cells and tissues to be generated for therapeutic use. Optimizing this process will probably lead to a better and more efficient means of generating pluripotent stem cells. Here, we discuss recent findings that show that, in addition to transcription factors, microRNAs can promote pluripotent reprogramming and can even substitute for these pluripotency transcription factors in some cases. Taking into consideration that microRNAs have the potential to be used as small-molecule therapeutics, such findings open new possibilities for both pluripotent stem cell reprogramming and the reprogramming of cells into other cell lineages.
Contribution of the long form of syntaxin 5 to the organization of the endoplasmic reticulum
Authors: Miyazaki Kaori , Wakana Yuichi , Noda Chikano , Arasaki Kohei , Furuno Akiko , Tagaya Mitsuo
Published: October 2012

The SNARE protein syntaxin 5 exists as long (42 kDa) and short (35 kDa) isoforms. The short form is principally localized in the Golgi complex, whereas the long form resides not only in the Golgi but also in the endoplasmic reticulum (ER). Although the Golgi-localized short form has been extensively investigated, little is known about the long form. In the present study, we demonstrate that the long form of syntaxin 5 functions to shape the ER. We found that overexpression of the long form of syntaxin 5 induces rearrangement and co-alignment of the ER membrane with microtubules, the pattern of which is quite similar to that observed in cells overexpressing CLIMP-63, a linker between the ER membrane and microtubules. The ability of syntaxin 5 to induce ER-microtubule rearrangement is not related to its SNARE function, but correlates with its binding affinities for CLIMP-63, and CLIMP-63 is essential for the induction of this rearrangement. Microtubule co-sedimentation assays demonstrated that the long form of syntaxin 5 has a substantial microtubule-binding activity. These results suggest that the long form of syntaxin 5 contributes to the regulation of ER structure by interacting with both CLIMP-63 and microtubules. Indeed, depletion of syntaxin 5 caused the spreading of the ER to the cell periphery, similar to the phenotype observed in cells treated with the microtubule-depolymerizing reagent nocodazole. Our results disclose a previously undescribed function of the long form of syntaxin 5 that is not related to its function as a SNARE.
Atomic force microscopy – looking at mechanosensors on the cell surface
Authors: Heinisch Jürgen J. , Lipke Peter N. , Beaussart Audrey , Chatel Sofiane El Kirat , Dupres Vincent , Alsteens David , Dufrêne Yves F.
Published: October 2012

Living cells use cell surface proteins, such as mechanosensors, to constantly sense and respond to their environment. However, the way in which these proteins respond to mechanical stimuli and assemble into large complexes remains poorly understood at the molecular level. In the past years, atomic force microscopy (AFM) has revolutionized the way in which biologists analyze cell surface proteins to molecular resolution. In this Commentary, we discuss how the powerful set of advanced AFM techniques (e.g. live-cell imaging and single-molecule manipulation) can be integrated with the modern tools of molecular genetics (i.e. protein design) to study the localization and molecular elasticity of individual mechanosensors on the surface of living cells. Although we emphasize recent studies on cell surface proteins from yeasts, the techniques described are applicable to surface proteins from virtually all organisms, from bacteria to human cells.
Crosslinks in the cell wall of budding yeast control morphogenesis at the mother–bud neck
Authors: Blanco Noelia , Reidy Michael , Arroyo Javier , Cabib Enrico
Published: October 2012

Previous work has shown that, in cla4Δ cells of budding yeast, where septin ring organization is compromised, the chitin ring at the mother–daughter neck becomes essential for prevention of neck widening and for cytokinesis. Here, we show that it is not the chitin ring per se, but its linkage to β(1-3)glucan that is required for control of neck growth. When in a cla4Δ background, crh1Δ crh2Δ mutants, in which the chitin ring is not connected to β(1-3)glucan, grew very slowly and showed wide and growing necks, elongated buds and swollen cells with large vacuoles. A similar behavior was elicited by inhibition of the Crh proteins. This aberrant morphology matched that of cla4Δ chs3Δ cells, which have no chitin at the neck. Thus, this is a clear case in which a specific chemical bond between two substances, chitin and glucan, is essential for the control of morphogenesis. This defines a new paradigm, in which chemistry regulates growth.