bluuebunny/crossref_metadata_2025 huggingface dataset:
Beneficial effect of astaxanthin on 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced liver injury in rats
Authors: Turkez Hasan , Geyikoglu Fatime , Yousef Mokhtar I
Published: February 2012

Exposure to 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) represents a potential health risk and hepatotoxicity. Astaxanthin (ASTA) exhibits antioxidant properties and can influence hepatotoxicity. Therefore, the present study was carried out for using ASTA against hepatotoxicity induced by TCDD in the liver of rats. Animals were treated intraperitoneally daily with TCDD (8 µg/kg body weight (b.w.)), ASTA (12.5 mg/kg b.w. and 25 mg/kg b.w.) and TCDD plus ASTA (12.5 and 25 mg/kg b.w.) for 21 days. TCDD significantly decreased the activities of antioxidant enzymes and resulted in serious pathological findings. Moreover, the rate of micronucleus (MN) in hepatocytes increased after treating with TCDD. The activities of enzymes, frequencies of MNs and liver histology in lower dosage group of ASTA remained unchanged compared with the control group. In rats treated with ASTA, at higher dosage alone, the MNs remained unchanged and the activities of antioxidant enzymes significantly increased. The presence of ASTA (except for lower dose) with TCDD alleviated its pathological effects in hepatic tissue. ASTA also prevented the suppression of antioxidant enzymes in the livers of animals exposed to TCDD and displayed a strong protective effect against MNs. Thus, the present findings might provide new insight into the development of therapeutic and preventive approaches of TCDD toxicity.
Towards wake vortex safety and capacity increase: the integrated fusion approach and its demands on prediction models and detection sensors
Authors: Schönhals Shanna , Steen Meiko , Hecker Peter
Published: February 2012

Wake vortices and the prevention of wake vortex encounters are both an issue of safety and capacity in today’s air transportation system. Current wake vortex separations are safe but also very conservative and thus have an adverse effect on capacity of airports. This article deals with the concept of fused wake vortex prediction and detection with the objective to deliver wake vortex strength and position with a high level of accuracy and reliability. The collaboration approach aims at fusion of models and sensors available for forecast and detection of hazardous wake turbulence in order to improve the overall system performance using the complementary capabilities of the single components. Different methods of coupling models with measurements are introduced and resulting the aspect of requirements for the prediction model and measurement sensor is presented. The implementation of an error-state system is presented and compared to sole prediction and sole sensor results. The results indicate that the fusion approach delivers benefits like reduced uncertainty of prediction and increased availability of detection and thus has the ability to increase airport and air space capacity while maintaining or even improving current wake vortex safety.
Weight loss and improvements in fatigue in systemic lupus erythematosus: a controlled trial of a low glycaemic index diet versus a calorie restricted diet in patients treated with corticosteroids
Authors: Davies RJ , Lomer MCE , Yeo SI , Avloniti K , Sangle SR , D’Cruz DP
Published: February 2012

Background: Patients with systemic lupus erythematosus (SLE) may require prolonged periods of corticosteroid therapy which lead to excessive weight gain and increased cardiovascular risk. Objective: To assess the utility of a low glycaemic index diet in patients with corticosteroid dependent SLE in achieving weight loss and improving glycaemic control. Design: A total of 23 women were enrolled in a 6 week study. All had mild, stable SLE, were receiving corticosteroids and had a body mass index > 25 kg/m2. Subjects were randomly assigned to a low glycaemic index (Low GI) diet or a calorie restricted (Low Cal) diet. The primary end point was weight loss. Secondary end points included tolerability of diet, bio-markers of cardiovascular risk, disease activity, fatigue and sleep quality. Results: Weight loss in both treatment groups was significant (mean ± SD: Low GI diet 3.9 ± 0.9 kg; Low Cal diet 2.4 ± 2.2 kg, p < 0.01 from baseline in each group). There were also significant improvements in waist and hip measurements. However, the difference in weight loss and waist and hip measurements between the two diet groups was not statistically significant. There was a statistically significant reduction in Fatigue Severity Scale in both diet groups, ( p < 0.03). Both Low GI and Low Cal diets were well tolerated, resulting in no serious adverse effects or increase in disease activity. Conclusion: Significant weight loss is achievable over 6 weeks in a diet-specific trial in subjects with stable SLE, who are on low dose prednisolone. Both diets were equally tolerable, and did not cause flares in disease activity. Our results suggest that dietary manipulation may significantly improve fatigue in subjects with SLE.
Interactions of Oversulfated Chondroitin Sulfate (OSCS) From Different Sources With Unfractionated Heparin
Authors: Gray Angel , Litinas Evangelos , Jeske Walter , Fareed Jawed , Hoppensteadt Debra
Published: February 2012

In 2008, oversulfated chondroitin sulfate (OSCS) was identified as the main contaminant in recalled heparin. Oversulfated chondroitin sulfate can be prepared from bovine (B), porcine (P), shark (Sh), or skate (S) origin and may produce changes in the antithrombotic, bleeding, and hemodynamic profile of heparins. This study examines the interactions of various OSCSs on heparin in animal models of thrombosis and bleeding, as well as on the anticoagulant and antiprotease effects in in vitro assays. Mixtures of 70% unfractionated heparin (UFH) with 30% OSCS from different sources were tested. In the in vitro activated partial thromboplastin time (aPTT) assay, all contaminant mixtures showed a decrease in clotting times. In addition, a significant increase in bleeding time compared to the control (UFH/saline) was observed. In the thrombosis model, no significant differences were observed. The OSCSs significantly increased anti-Xa activity in ex vivo blood samples. These results indicate that various sources of OSCS affect the hemostatic properties of heparin.
Redistributional Effects of the National Flood Insurance Program
Authors: Bin Okmyung , Bishop John A. , Kousky Carolyn
Published: February 2012

This study examines the redistributional effects of the National Flood Insurance Program (NFIP) using a national database of premium, coverage, and claim payments at the county level between 1980 and 2006. Measuring progressivity as the departure from per capita county income proportionality, the authors find that NFIP premiums are typically proportional if the time horizon is extended beyond a single year, while claim payments are moderately progressive over all time horizons studied. The net effect of the NFIP program, defined as indemnity payments net of premiums, indicates that NFIP is proportional or at most mildly progressive, while the effect is modest. In sum, the authors find no evidence that the NFIP disproportionally advantages richer counties.
Cryptosporidium species screening using Kinyoun technique in domestic cats with diarrhea
Authors: de Oliveira Lemos Francesca , Almosny Nádia Pereira , Soares Ana Maria Barros , Alencar Nayro Xavier
Published: February 2012

Cryptosporidium is a coccidian that can lead to diarrhea, especially in immunosuppressed individuals. Retroviruses are considered a primary cause of immunosuppression in cats. Fecal specimens and blood collected from the 60 cats were evaluated for the presence of acid-fast cryptosporidia in three consecutive stool samples and for feline leukemia virus (FeLV) antigen and feline immunodeficiency virus (FIV) antibody by ELISA testing. Five animals (8.33%) shedding oocysts were found, one was both FIV- and FeLV-negative and four were FeLV-positive.
Amputation for histiocytic sarcoma in a cat
Authors: Teshima Takahiro , Hata Takashi , Nezu Yoko , Michishita Masaki , Matsumoto Hirotaka , Mizutani Hisashi , Takahashi Kimimasa , Koyama Hidekazu
Published: February 2012

A 9-year-old spayed female domestic shorthair cat presented with a skin lesion of the left tarsus. The lesion was biopsied and, based on the microscopic appearance and immunohistochemical characteristics, histiocytic sarcoma was diagnosed. Amputation was performed with improved demeanor seen postoperatively. However, between 44 and 60 days following the surgery, relapse of skin lesions appeared in multiple locations, including at the previous amputation site, and euthanasia was elected. This is the first report of a histiocytic sarcoma treated with amputation in a cat.
Quarantine protects Falkland Islands (Malvinas) cats from feline coronavirus infection
Authors: Addie Diane D , McDonald Mike , Audhuy Stéphane , Burr Paul , Hollins Jonathan , Kovacic Rémi , Lutz Hans , Luxton Zoe , Mazar Shlomit , Meli Marina L
Published: February 2012

Feline coronavirus (FCoV) causes feline infectious peritonitis (FIP). Since 2002, when 20 cats on the Falkland Islands were found to be FCoV seronegative, only seronegative cats could be imported. Between 2005–2007, 95 pet and 10 feral cats tested negative by indirect immunofluorescence antibody (IFA) analysis using two strains of type II FCoV, two transmissible gastroenteritis virus assays, an enzyme-linked immunosorbent assay and rapid immunomigration test. Twenty-four samples (23%) showed non-specific fluorescence, mostly attributable to anti-nuclear antibodies (ANA). The reason for ANA was unclear: reactive samples were negative for Erhlichia canis antibodies; seven were feline immunodeficiency virus positive, but 15 were negative. It was not possible to determine retrospectively whether the cats had autoimmune disease, hyperthyroidism treatment, or recent vaccination which may also cause ANA. The FCoV/ FIP-free status of the Falkland Islands cats should be maintained by FCoV testing incoming cats. However, ANA can complicate interpretation of IFA tests.
Analytical performance of commercially-available assays for feline insulin-like growth factor 1 (IGF-1), adiponectin and ghrelin measurements
Authors: Tvarijonaviciute Asta , German Alexander J , Martínez-Subiela Silvia , Tecles Fernando , Ceron Jose J
Published: February 2012

The objective of this study was to evaluate three commercially-available human assays for the determination of adiponectin, ghrelin and insulin-like growth factor 1 (IGF-1) concentrations in feline serum samples. Intra- and interassay coefficients of variation were lower than 20%, 15% and 6% for adiponectin, ghrelin and IGF-1 assays, respectively. Dilutions of feline serum pools resulted in linear regression equations in all kits. Mean recovery of adiponectin, ghrelin and IGF-1 assays were 107%, 102% and 105%, respectively. Significant differences were detected in adiponectin and ghrelin concentrations between lean and obese cats ( P <0.05 in both cases), but there was no difference in IGF-1 concentrations ( P = 0.12).
With power comes responsibility: Human rights protection in United Nations sanctions policy
Authors: Heupel Monika
Published: February 2012

The ability to violate and the duty to protect human rights have traditionally been ascribed to states. Yet, since international organizations increasingly take decisions that directly affect individuals, it has been alleged that they, too, have human rights obligations. Against this background, we can witness a trend among international organizations establishing provisions to prevent human rights violations and to enable individuals to hold them accountable for such violations. This can be seen as a specific manifestation of a more general trend that has been described as the spread of good governance standards to, or the constitutionalization of, international organizations. The purpose of this article is to reveal the mechanisms that can account for the introduction of human rights protection provisions in international organizations. The empirical basis of the article forms a case study on the evolution of such provisions in United Nations sanctions policy. I first develop a conceptual framework that draws on diffusion mechanisms that have been used to explain the spread of norms and institutional design among states and to trace reform processes in international organizations. The empirical analysis suggests that shaming, defiance, litigation and instances of learning can account for the advancement of human rights protection provisions in United Nations sanctions policy: the Security Council was exposed to and responded to various forms of pressure from a variety of different actors. At the same time, it was approached with arguments concerning why it should institute reforms and advice in terms of how such reforms should look and engaged in a learning process.
Liberty versus libertarianism
Authors: Callahan Gene
Published: February 2012

This article aims to persuade its reader that libertarianism, at least in several of its varieties, is a species of the genus that Michael Oakeshott referred to as ‘rationalism in politics’. I hope to demonstrate, employing the work of Oakeshott as well as Aristotle and Onora O’Neill, how many libertarian theorists, who generally have a sincere and admirable commitment to personal liberty, have been led astray by the rationalist promise that we might be able to approach deductive certainty concerning the ‘correctness’ of some political programme. The article will argue that a concept such as Pettit’s freedom as non-domination is more robust and inclusive of all that we value about freedom than is the libertarian concept of freedom as non-interference.
Concurrent and Longitudinal Patterns and Trends in Performance on Early Numeracy Curriculum-Based Measures in Kindergarten Through Third Grade
Authors: Missall Kristen N. , Mercer Sterett H. , Martínez Rebecca S. , Casebeer Dian
Published: February 2012

The purpose of this study was to extend the research on the Tests of Early Numeracy Curriculum-Based Measurement (TEN-CBM) tools by examining concurrent and predictive relations from kindergarten through third grade. Using a longitudinal sample of 535 students, this study included logistic regression, latent cluster, and latent transition analyses to examine the patterns and trends of student performance on all four TEN-CBM measures in kindergarten and first grade, math CBM (M-CBM) in first grade, and mathematics performance on a statewide high-stakes assessment in third grade. Results suggest that two of the TEN-CBM tools, Quantity Discrimination and Missing Number, are most robust at predicting later math performance. Longitudinal analysis indicated that students who are low performing in early numeracy at the beginning of kindergarten tend to be low performing in math at third grade. Low-achieving students also demonstrated a greater decrease in math skills over summer months when compared to higher-achieving peers.
Tendon transfer for radial nerve palsy: a single tendon to restore finger extension as well as thumb extension/radial abduction
Authors: Al-Qattan M. M.
Published: February 2012

Since 1994, the author has been treating irreparable radial nerve palsy with pronator teres to the extensor carpi radialis brevis (for wrist extension) and a single tendon (flexor carpi radialis or ulnaris) transfer to restore finger extension as well as thumb extension/radial abduction. We sought to investigate whether these patients are able to flex the fingers with the thumb in abduction/extension posture. This was a prospective study over a 5-year period, and the results of this transfer in 15 consecutive patients (mean age 28 years) were analyzed. At final follow-up (mean 30 months), all patients had reasonable wrist movement, finger extension, and thumb extension/radial abduction. The overall results were rated excellent in 12 patients and good in the remaining three patients according to the Bincaz scale. More interesting was the ability of all patients to flex their fingers with only mild relaxation of the extended/abducted thumb.
Modes of Professional Campaigning
Authors: Tenscher Jens , Mykkänen Juri , Moring Tom
Published: February 2012

In recent years, political parties have reacted to far-reaching transformations in their media and sociocultural environments. These changes and adaptations, often assembled under the catchword “professionalization,” become most apparent during electoral campaigns. However, the campaign professionalism of political parties has not yet been systematically “measured,” having been examined mostly in single case studies. Against this background, we present an empirical test of the party-centered theory of professionalization. Ours is a four-country comparison of the campaign structures and strategies of political parties during the most recent European parliamentary elections. Our analyses demonstrate a wide variety in professional electoral campaigning. There are differences in campaign structures that not only point to country specifics but also to the impact of the size of the parties. We also ask whether there are differences between parties owing to their position on a right–left scale. Our findings point to some general trends in electoral campaigning that seem to be typical of societies with democratic corporatist media systems. Those similarities and country-specifics should be taken into account in future empirical analyses, which might benefit from our methodological approach.
Viral infection triggers rapid differentiation of human blood monocytes into dendritic cells
Authors: Hou Wanqiu , Gibbs James S. , Lu Xiuju , Brooke Christopher B. , Roy Devika , Modlin Robert L. , Bennink Jack R. , Yewdell Jonathan W.
Published: February 2012

Surprisingly little is known about the interaction of human blood mononuclear cells with viruses. Here, we show that monocytes are the predominant cell type infected when peripheral blood mononuclear cells are exposed to viruses ex vivo. Remarkably, infection with vesicular stomatitis virus, vaccinia virus, and a variety of influenza A viruses (including circulating swine-origin virus) induces monocytes to differentiate within 18 hours into CD16−CD83+ mature dendritic cells with enhanced capacity to activate T cells. Differentiation into dendritic cells does not require cell division and occurs despite the synthesis of viral proteins, which demonstrates that monocytes counteract the capacity of these highly lytic viruses to hijack host cell biosynthetic capacity. Indeed, differentiation requires infectious virus and viral protein synthesis. These findings demonstrate that monocytes are uniquely susceptible to viral infection among blood mononuclear cells, with the likely purpose of generating cells with enhanced capacity to activate innate and acquired antiviral immunity.
IL-5 promotes induction of antigen-specific CD4+CD25+ T regulatory cells that suppress autoimmunity
Authors: Tran Giang T. , Hodgkinson Suzanne J. , Carter Nicole M. , Verma Nirupama D. , Plain Karren M. , Boyd Rochelle , Robinson Catherine M. , Nomura Masaru , Killingsworth Murray , Hall Bruce M.
Published: February 2012

Immune responses to foreign and self-Ags can be controlled by regulatory T cells (Tregs) expressing CD4 and IL-2Rα chain (CD25). Defects in Tregs lead to autoimmunity, whereas induction of Ag-specific CD4+CD25+ Tregs restores tolerance. Ag-specific CD4+CD25+ FOXP3+Tregs activated by the T helper type 2 (Th2) cytokine, IL-4, and specific alloantigen promote allograft tolerance. These Tregs expressed the specific IL-5Rα and in the presence of IL-5 proliferate to specific but not third-party Ag. These findings suggest that recombinant IL-5 (rIL-5) therapy may promote Ag-specific Tregs to mediate tolerance. This study showed normal CD4+CD25+ Tregs cultured with IL-4 and an autoantigen expressed Il-5rα. Treatment of experimental autoimmune neuritis with rIL-5 markedly reduced clinical paralysis, weight loss, demyelination, and infiltration of CD4+ (Th1 and Th17) CD8+ T cells and macrophages in nerves. Clinical improvement was associated with expansion of CD4+CD25+FOXP3+ Tregs that expressed Il-5rα and proliferated only to specific autoantigen that was enhanced by rIL-5. Depletion of CD25+ Tregs or blocking of IL-4 abolished the benefits of rIL-5. Thus, rIL-5 promoted Ag-specific Tregs, activated by autoantigen and IL-4, to control autoimmunity. These findings may explain how Th2 responses, especially to parasitic infestation, induce immune tolerance. rIL-5 therapy may be able to induce Ag-specific tolerance in autoimmunity.
Determinants of insecticide-treated net ownership and utilization among pregnant women in Nigeria
Authors: Ankomah Augustine , Adebayo Samson B , Arogundade Ekundayo D , Anyanti Jennifer , Nwokolo Ernest , Ladipo Olaronke , Meremikwu Martin M
Published: February 2012

Background

Malaria during pregnancy is a major public health problem in Nigeria leading to increase in the risk of maternal mortality, low birth weight and infant mortality. This paper is aimed at highlighting key predictors of the ownership of insecticide treated nets (ITNs) and its use among pregnant women in Nigeria.

Methods

A total of 2348 pregnant women were selected by a multi-stage probability sampling technique. Structured interview schedule was used to elicit information on socio-demographic characteristics, ITN ownership, use, knowledge, behaviour and practices. Logistic regression was used to detect predictors of two indicators: ITN ownership, and ITN use in pregnancy among those who owned ITNs.

Results

ITN ownership was low; only 28.8% owned ITNs. Key predictors of ITN ownership included women who knew that ITNs prevent malaria (OR = 3.85; p < 0001); and registration at antenatal clinics (OR = 1.34; p = 0.003). The use of ITNs was equally low with only 7.5% of all pregnant women, and 25.7% of all pregnant women who owned ITNs sleeping under a net. The predictors of ITN use in pregnancy among women who owned ITNs (N = 677) identified by logistic regression were: urban residence (OR = 1.87; p = 0.001); knowledge that ITNs prevent malaria (OR = 2.93; p < 0001) and not holding misconceptions about malaria prevention (OR = 1.56; p = 0.036). Educational level was not significantly related to any of the two outcome variables. Although registration at ANC is significantly associated with ownership of a bednet (perhaps through free ITN distribution) this does not translate to significant use of ITNs.

Conclusions

ITN use lagged well behind ITN ownership. This seems to suggest that the current mass distribution of ITNs at antenatal facilities and community levels may not necessarily lead to use unless it is accompanied by behaviour change interventions that address the community level perceptions, misconceptions and positively position ITN as an effective prevention device to prevent malaria
Effects of sterol regulatory element-binding protein (SREBP) in chickens
Authors: Alipour Fahimeh , Hassanabadi Ahmad
Published: February 2012

Sterol regulatory element binding protein- 1 and -2 (SREBP-1 and -2) are key transcription factors involved in the biosynthesis of cholesterol and fatty acids. The SREBP have mostly been studied in rodents in which lipogenesis is regulated in both liver and adipose tissue. There is, though, a paucity of information on birds, in which lipogenesis occurs essentially in the liver as in humans. Since a prelude to the investigation of the role of SREBP in lipid metabolism regulation in chicken, we review Size and Tissue expression Pattern of SREBP and role of this protein in chickens.
Clara cell protein in nasal lavage fluid and nasal nitric oxide - biomarkers with anti-inflammatory properties in allergic rhinitis
Authors: Irander Kristina , Palm Jörgen P , Borres Magnus P , Ghafouri Bijar
Published: February 2012

Background

Clara cell protein (CC16) is ascribed a protective and anti-inflammatory role in airway inflammation. Lower levels have been observed in asthmatic subjects as well as in subjects with intermittent allergic rhinitis than in healthy controls. Nasal nitric oxide (nNO) is present in high concentrations in the upper airways, and considered a biomarker with beneficial effects, due to inhibition of bacteria and viruses along with stimulation of ciliary motility. The aim of this study was to evaluate the presumed anti-inflammatory effects of nasal CC16 and nNO in subjects with allergic rhinitis.

Methods

The levels of CC16 in nasal lavage fluids, achieved from subjects with persistent allergic rhinitis (n = 13), intermittent allergic rhinitis in an allergen free interval (n = 5) and healthy controls (n = 7), were analyzed by Western blot. The levels of nNO were measured by the subtraction method using NIOX®. The occurrences of effector cells in allergic inflammation, i.e. metachromatic cells (MC, mast cells and basophiles) and eosinophils (Eos) were analyzed by light microscopy in samples achieved by nasal brushing.

Results

The levels of CC16 correlated with nNO levels (r2 = 0.37; p = 0.02) in allergic subjects.

The levels of both biomarkers showed inverse relationships with MC occurrence, as higher levels of CC16 (p = 0.03) and nNO (p = 0.05) were found in allergic subjects with no demonstrable MC compared to the levels in subjects with demonstrable MC. Similar relationships, but not reaching significance, were observed between the CC16 and nNO levels and Eos occurrence. The levels of CC16 and nNO did not differ between the allergic and the control groups.

Conclusions

The correlation between nasal CC16 and nNO levels in patients with allergic rhinitis, along with an inverse relationship between their levels and the occurrences of MC in allergic inflammation, may indicate that both biomarkers have anti-inflammatory effects by suppression of cell recruitment. The mechanisms behind these observations warrant further analyses.
Polo-like kinase 1 (Plk1): an Unexpected Player in DNA Replication
Authors: Song Bing , Liu X Shawn , Liu Xiaoqi
Published: February 2012

Regulation of cell cycle progression is important for the maintenance of genome integrity, and Polo-like kinases (Plks) have been identified as key regulators of this process. It is well established that Polo-like kinase 1 (Plk1) plays critical roles in mitosis but little is known about its functions at other stages of the cell cycle. Here we summarize the functions of Plk1 during DNA replication, focusing on the molecular events related to Origin Recognition Complex (ORC), the complex that is essential for the initiation of DNA replication. Within the context of Plk1 phosphorylation of Orc2, we also emphasize regulation of Orc2 in different organisms. This review is intended to provide some insight into how Plk1 coordinates DNA replication in S phase with chromosome segregation in mitosis, and orchestrates the cell cycle as a whole.
Caenorhabditis elegans Muscleblind homolog mbl-1 functions in neurons to regulate synapse formation
Authors: Spilker Kerri A , Wang George J , Tugizova Madina S , Shen Kang
Published: February 2012

Background

The sequestration of Muscleblind splicing regulators results in myotonic dystrophy. Previous work on Muscleblind has largely focused on its roles in muscle development and maintenance due to the skeletal and cardiac muscle degeneration phenotype observed in individuals with the disorder. However, a number of reported nervous system defects suggest that Muscleblind proteins function in other tissues as well.

Results

We have identified a mutation in the Caenorhabditis elegans homolog of Muscleblind, mbl-1, that is required for proper formation of neuromuscular junction (NMJ) synapses. mbl-1 mutants exhibit selective loss of the most distal NMJ synapses in a C. elegans motorneuron, DA9, visualized using the vesicle-associated protein RAB-3, as well as the active zone proteins SYD-2/liprin-α and UNC-10/Rim. The proximal NMJs appear to have normal pre- and postsynaptic specializations. Surprisingly, expressing a mbl-1 transgene in the presynaptic neuron is sufficient to rescue the synaptic defect, while muscle expression has no effect. Consistent with this result, mbl-1 is also expressed in neurons.

Conclusions

Based on these results, we conclude that in addition to its functions in muscle, the Muscleblind splice regulators also function in neurons to regulate synapse formation.
targetTB: A target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis
Authors: Raman Karthik , Yeturu Kalidas , Chandra Nagasuma
Published: February 2012

Background

Tuberculosis still remains one of the largest killer infectious diseases, warranting the identification of newer targets and drugs. Identification and validation of appropriate targets for designing drugs are critical steps in drug discovery, which are at present major bottle-necks. A majority of drugs in current clinical use for many diseases have been designed without the knowledge of the targets, perhaps because standard methodologies to identify such targets in a high-throughput fashion do not really exist. With different kinds of 'omics' data that are now available, computational approaches can be powerful means of obtaining short-lists of possible targets for further experimental validation.

Results

We report a comprehensive in silico target identification pipeline, targetTB, for Mycobacterium tuberculosis. The pipeline incorporates a network analysis of the protein-protein interactome, a flux balance analysis of the reactome, experimentally derived phenotype essentiality data, sequence analyses and a structural assessment of targetability, using novel algorithms recently developed by us. Using flux balance analysis and network analysis, proteins critical for survival of M. tuberculosis are first identified, followed by comparative genomics with the host, finally incorporating a novel structural analysis of the binding sites to assess the feasibility of a protein as a target. Further analyses include correlation with expression data and non-similarity to gut flora proteins as well as 'anti-targets' in the host, leading to the identification of 451 high-confidence targets. Through phylogenetic profiling against 228 pathogen genomes, shortlisted targets have been further explored to identify broad-spectrum antibiotic targets, while also identifying those specific to tuberculosis. Targets that address mycobacterial persistence and drug resistance mechanisms are also analysed.

Conclusion

The pipeline developed provides rational schema for drug target identification that are likely to have high rates of success, which is expected to save enormous amounts of money, resources and time in the drug discovery process. A thorough comparison with previously suggested targets in the literature demonstrates the usefulness of the integrated approach used in our study, highlighting the importance of systems-level analyses in particular. The method has the potential to be used as a general strategy for target identification and validation and hence significantly impact most drug discovery programmes.
Hemoglobin Q-Iran detected in family members from Northern Iran: a case report
Authors: Khorshidi Mohammad , Roshan Payam , Bayat Nooshin , Mahdavi Mohammad Reza , Najmabadi Hossein
Published: February 2012

Introduction

Hemoglobin Q-Iran (α75Asp→His) is an important member of the hemoglobin Q family, molecularly characterized by the replacement of aspartic acid by histidine. The first report of hemoglobin Q-Iran and the nomenclature of this hemoglobinopathy dates back to 1970. Iran is known as a country with a high prevalence of α- and β-thalassemia and different types of hemoglobinopathy. Many of these variants are yet to be identified as the practice of molecular laboratory techniques is limited in this part of the world. Applying such molecular methods, we report the first hemoglobin Q-Iran cases in Northern Iran.

Case presentation

An unusual band was detected in an isoelectric focusing test and cellulose acetate electrophoresis of a sample from a 22-year-old Iranian man from Mazandaran Province. Capillary zone electrophoresis analysis identified this band as hemoglobin Q. A similar band was also detected in his mother's electrophoresis (38 years, Iranian ethnicity). The cases underwent molecular investigation and the presence of a hemoglobin Q-Iran mutation was confirmed by the amplification refractory mutation system polymerase chain reaction method. Direct conventional sequencing revealed a single guanine to cytosine missense mutation (c.226G > C; G AC > C AC) at codon 75 in the α-globin gene in both cases.

Conclusion

The wide spectrum and high frequency of nondeletional α-globin mutations in Mazandaran Province is remarkable and seem to differ considerably from what has been found in Mediterranean populations. This short communication reports the first cases of patients with hemoglobin Q found in that region.
Transcriptional profiling of the murine cutaneous response during initial and subsequent infestations with Ixodes scapularis nymphs
Authors: Heinze Dar M , Wikel Stephen K , Thangamani Saravanan , Alarcon-Chaidez Francisco J
Published: February 2012

Background

Ixodes scapularisticks are hematophagous arthropods capable of transmitting many infectious agents to humans. The process of blood feeding is an extended and continuous interplay between tick and host responses. While this process has been studied extensivelyin vitro, no global understanding of the host response to ticks has emerged.

Methods

To address this issue, we used PCR-arrays to measure skin-specific expression of 233 discrete genes at 8 time points during primary and secondary infestations of mice with pathogen-freeI. scapularisnymphs. Selected results were then validated at the mRNA and protein levels by additional real-time PCR and bioplex assay.

Results

Primary infestation was characterized by the late induction of an innate immune response. Lectin pattern recognition receptors, cytokines, and chemokines were upregulated consistent with increased neutrophil and macrophage migration. Gene ontology and pathway analyses of downregulated genes suggested inhibition of gene transcription and Th17 immunity. During the secondary infestation, additional genes were modulated suggesting a broader involvement of immune cells including CD8 and CD4 positive T lymphocytes. The cytokine response showed a mixed Th1/Th2 profile with a potential for T regulatory cell activity. Key gene ontology clusters observed during the secondary infestation were cell migration and activation. Matrix metalloproteinases were upregulated, apoptosis-related genes were differentially modulated, and immunoreceptor signaling molecules were upregulated. In contrast, transcripts related to mitogenic, WNT, Hedgehog, and stress pathways were downregulated.

Conclusions

Our results support a model of tick feeding where lectin pattern recognition receptors orchestrate an innate inflammatory response during primary infestation that primes a mixed Th1/Th2 response upon secondary exposure. Tick feeding inhibits gene transcription and Th17 immunity. Salivary molecules may also inhibit upregulation of mitogenic, WNT, Hedgehog, and stress pathways and enhance the activity of T regulatory cells, production of IL-10, and suppressors of cytokine signaling molecules (SOCS). This study provides the first comprehensive transcriptional analysis of the murine host response at theI. scapularisbite site and suggests both a potential model of the host cutaneous response and candidate genes for further description and investigation.
The neuropeptide neuromedin U promotes autoantibody-mediated arthritis
Authors: Rao Sindhuja M , Auger Jennifer L , Gaillard Philippe , Weissleder Ralph , Wada Etsuko , Torres Richard , Kojima Masayasu , Benoist Christophe , Mathis Diane , Binstadt Bryce A
Published: February 2012

Introduction

Neuromedin U (NMU) is a neuropeptide with pro-inflammatory activity. The primary goal of this study was to determine if NMU promotes autoantibody-induced arthritis. Additional studies addressed the cellular source of NMU and sought to define the NMU receptor responsible for its pro-inflammatory effects.

Methods

Serum containing arthritogenic autoantibodies from K/BxN mice was used to induce arthritis in mice genetically lacking NMU. Parallel experiments examined whether NMU deficiency impacted the early mast-cell-dependent vascular leak response induced by these autoantibodies. Bone-marrow chimeric mice were generated to determine whether pro-inflammatory NMU is derived from hematopoietic cells or stromal cells. Mice lacking the known NMU receptors singly and in combination were used to determine susceptibility to serum-transferred arthritis and in vitro cellular responses to NMU.

Results

NMU-deficient mice developed less severe arthritis than control mice. Vascular leak was not affected by NMU deficiency. NMU expression by bone-marrow-derived cells mediated the pro-arthritogenic effect. Deficiency of all of the known NMU receptors, however, had no impact on arthritis severity and did not affect the ability of NMU to stimulate intracellular calcium flux.

Conclusions

NMU-deficient mice are protected from developing autoantibody-induced inflammatory arthritis. NMU derived from hematopoietic cells, not neurons, promotes the development of autoantibody-induced inflammatory arthritis. This effect is mediated by a receptor other than the currently known NMU receptors.
Small interfering RNA library screen identified polo-like kinase-1 (PLK1) as a potential therapeutic target for breast cancer that uniquely eliminates tumor-initiating cells
Authors: Hu Kaiji , Law Jennifer H , Fotovati Abbas , Dunn Sandra E
Published: February 2012

Introduction

Triple-negative breast cancer (TNBC) high rate of relapse is thought to be due to the presence of tumor-initiating cells (TICs), molecularly defined as being CD44high/CD24-/low. TICs are resilient to chemotherapy and radiation. However, no currently accepted molecular target exists against TNBC and, moreover, TICs. Therefore, we sought the identification of kinase targets that inhibit TNBC growth and eliminate TICs.

Methods

A genome-wide human kinase small interfering RNA (siRNA) library (691 kinases) was screened against the TNBC cell line SUM149 for growth inhibition. Selected siRNAs were then tested on four different breast cancer cell lines to confirm the spectrum of activity. Their effect on the CD44high subpopulation and sorted CD44high/CD24-/low cells of SUM149 also was studied. Further studies were focused on polo-like kinase 1 (PLK1), including its expression in breast cancer cell lines, effect on the CD44high/CD24-/low TIC subpopulation, growth inhibition, mammosphere formation, and apoptosis, as well as the activity of the PLK1 inhibitor, BI 2536.

Results

Of the 85 kinases identified in the screen, 28 of them were further silenced by siRNAs on MDA-MB-231 (TNBC), BT474-M1 (ER+/HER2+, a metastatic variant), and HR5 (ER+/HER2+, a trastuzumab-resistant model) cells and showed a broad spectrum of growth inhibition. Importantly, 12 of 28 kinases also reduced the CD44high subpopulation compared with control in SUM149. Further tests of these 12 kinases directly on a sorted CD44high/CD24-/low TIC subpopulation of SUM149 cells confirmed their effect. Blocking PLK1 had the greatest growth inhibition on breast cancer cells and TICs by about 80% to 90% after 72 hours. PLK1 was universally expressed in breast cancer cell lines, representing all of the breast cancer subtypes, and was positively correlated to CD44. The PLK1 inhibitor BI 2536 showed similar effects on growth, mammosphere formation, and apoptosis as did PLK1 siRNAs. Finally, whereas paclitaxel, doxorubicin, and 5-fluorouracil enriched the CD44high/CD24-/low population compared with control in SUM149, subsequent treatment with BI 2536 killed the emergent population, suggesting that it could potentially be used to prevent relapse.

Conclusion

Inhibiting PLK1 with siRNA or BI 2536 blocked growth of TNBCs including the CD44high/CD24-/low TIC subpopulation and mammosphere formation. Thus, PLK1 could be a potential therapeutic target for the treatment of TNBC as well as other subtypes of breast cancer.
Uptake and Economic Impact of First-Cycle Colony-Stimulating Factor Use During Adjuvant Treatment of Breast Cancer
Authors: Hershman Dawn L. , Wilde Elizabeth T. , Wright Jason D. , Buono Donna L. , Kalinsky Kevin , Malin Jennifer L. , Neugut Alfred I.
Published: February 2012

Purpose

In 2002, pegfilgrastim was approved by the US Food and Drug Administration and the benefits of dose-dense breast cancer chemotherapy, especially for hormone receptor (HR) –negative tumors, were reported. We examined first-cycle colony-stimulating factor use (FC-CSF) before and after 2002 and estimated US expenditures for dose-dense chemotherapy.

Methods

We identified patients in Surveillance, Epidemiology, and End Results–Medicare greater than 65 years old with stages I to III breast cancer who had greater than one chemotherapy claim within 6 months of diagnosis(1998 to 2005) and classified patients with an average cycle length less than 21 days as having received dose-dense chemotherapy. The associations of patient, tumor, and physician-related factors with the receipt of any colony-stimulating factor (CSF) and FC-CSF use were analyzed by using generalized estimating equations. CSF costs were estimated for patients who were undergoing dose-dense chemotherapy.

Results

Among the 10,773 patients identified, 5,266 patients (48.9%) had a CSF claim. CSF use was stable between 1998 and 2002 and increased from 36.8% to 73.7% between 2002 and 2005, FC-CSF use increased from 13.2% to 67.9%, and pegfilgrastim use increased from 4.1% to 83.6%. In a multivariable analysis, CSF use was associated with age and chemotherapy type and negatively associated with black/Hispanic race, rural residence, and shorter chemotherapy duration. FC-CSF use was associated with high socioeconomic status but not with age or race/ethnicity. The US annual CSF expenditure for women with HR-positive tumors treated with dose-dense chemotherapy is estimated to be $38.8 million.

Conclusion

A rapid increase in FC-CSF use occurred over a short period of time, which was likely a result of the reported benefits of dose-dense chemotherapy and the ease of pegfilgrastim administration. Because of the increasing evidence that elderly HR-positive patients do not benefit from dose-dense chemotherapy, limiting pegfilgrastim use would combat the increasing costs of cancer care.
Retinoic acid signalling during development
Authors: Rhinn Muriel , Dollé Pascal
Published: February 2012

Retinoic acid (RA) is a vitamin A-derived, non-peptidic, small lipophilic molecule that acts as ligand for nuclear RA receptors (RARs), converting them from transcriptional repressors to activators. The distribution and levels of RA in embryonic tissues are tightly controlled by regulated synthesis through the action of specific retinol and retinaldehyde dehydrogenases and by degradation via specific cytochrome P450s (CYP26s). Recent studies indicate that RA action involves an interplay between diffusion (morphogen-like) gradients and the establishment of signalling boundaries due to RA metabolism, thereby allowing RA to finely control the differentiation and patterning of various stem/progenitor cell populations. Here, we provide an overview of the RA biosynthesis, degradation and signalling pathways and review the main functions of this molecule during embryogenesis.
Org-1, the Drosophila ortholog of Tbx1, is a direct activator of known identity genes during muscle specification
Authors: Schaub Christoph , Nagaso Hideyuki , Jin Hong , Frasch Manfred
Published: February 2012

Members of the T-Box gene family of transcription factors are important players in regulatory circuits that generate myogenic and cardiogenic lineage diversities in vertebrates. We show that during somatic myogenesis in Drosophila, the single ortholog of vertebrate Tbx1, optomotor-blind-related-gene-1 (org-1), is expressed in a small subset of muscle progenitors, founder cells and adult muscle precursors, where it overlaps with the products of the muscle identity genes ladybird (lb) and slouch (slou). In addition, org-1 is expressed in the lineage of the heart-associated alary muscles. org-1 null mutant embryos lack Lb and Slou expression within the muscle lineages that normally co-express org-1. As a consequence, the respective muscle fibers and adult muscle precursors are either severely malformed or missing, as are the alary muscles. To address the mechanisms that mediate these regulatory interactions between Org-1, Lb and Slou, we characterized distinct enhancers associated with somatic muscle expression of lb and slou. We demonstrate that these lineage- and stage-specific cis-regulatory modules (CRMs) bind Org-1 in vivo, respond to org-1 genetically and require T-box domain binding sites for their activation. In summary, we propose that org-1 is a common and direct upstream regulator of slou and lb in the developmental pathway of these two neighboring muscle lineages. Cross-repression between slou and lb and combinatorial activation of lineage-specific targets by Org-1–Slou and Org-1–Lb, respectively, then leads to the distinction between the two lineages. These findings provide new insights into the regulatory circuits that control the proper pattering of the larval somatic musculature in Drosophila.
Effects of the Blair/Brown NHS Reforms on Socioeconomic Equity in Health Care
Authors: Cookson Richard , Laudicella Mauro , Donni Paolo Li , Dusheiko Mark
Published: February 2012

The central objectives of the ‘Blair/Brown’ reforms of the English NHS in the 2000s were to reduce hospital waiting times and improve the quality of care. However, critics raised concerns that the choice and competition elements of reform might undermine socioeconomic equity in health care. By contrast, the architects of reform predicted that accelerated growth in NHS spending combined with increased patient choice of hospital would enhance equity for poorer patients. This paper draws together and discusses the findings of three large-scale national studies designed to shed empirical light on this issue. Study one developed methods for monitoring change in neighbourhood level socioeconomic equity in the utilization of health care, and found no substantial change in equity between 2001-02 and 2008-09 for non-emergency hospital admissions, outpatient admissions (from 2004-05) and a basket of specific hospital procedures (hip replacement, senile cataract, gastroscopy and coronary revascularization). Study two found that increased competition between 2003-04 and 2008-09 had no substantial effect on socioeconomic equity in health care. Study three found that potential incentives for public hospitals to select against socioeconomically-disadvantaged hip replacement patients were small, compared with incentives to select against elderly and co-morbid patients. Taken together, these findings suggest that the Blair/Brown reforms had little effect on socioeconomic equity in health care. This may be because the ‘dose’ of competition was small and most hospital services continued to be provided by public hospitals which did not face strong incentives to select against socioeconomically-disadvantaged patients.