bluuebunny/crossref_metadata_2025 huggingface dataset:
Zombie trouble: Zombie texts, bare life and displaced people
Authors: Stratton Jon
Published: June 2011

There has been a recent upsurge in texts featuring zombies. At the same time, members of western countries have become increasingly anxious about displaced peoples: asylum-seekers and other so-called illegal migrants who attempt to enter those countries. What displaced people, people without the protection of the state and zombies have in common is that both manifest the quality of what Giorgio Agamben calls ‘bare life’. Moreover, zombies have the qualities of workers or slaves driven to total exhaustion. The genre of the zombie apocalypse centres on laying siege to a place that is identified as a refuge for a group of humans. In these texts it is possible to read an equation of zombies with displaced people who are ‘threatening’ the state. Indeed, the rhetoric used to describe these people constructs them as similar to mythical zombies. This article includes analyses of a number of zombie films including Shaun of the Dead, Fido and Undead.
Managing public outrage: Power, scandal, and new media in contemporary Russia
Authors: Toepfl Florian
Published: June 2011

Over the past three decades, scholars studying the phenomenon of political scandal have mostly based their works on the premise that scandals can only occur in liberal democracies. Contradictory to this assumption, however, some of the most heavily discussed phenomena in contemporary semi-authoritarian Russia are scandals emanating from the new, vibrant sphere of social media thriving on a largely unfiltered internet. How are these ‘internet scandals’ impacting politics in the semi-authoritarian political environment? To address this and related questions, I juxtapose two case studies of police corruption scandals that erupted in the social media sphere in 2009/2010. Drawing on the findings, I argue that Russia’s ruling elites are presently very much capable of managing these outbursts of public outrage. Mainly with the help of the powerful state-controlled television, public anger is very swiftly redirected towards lower-level authorities and foreign, supposedly hostile powers.
The path to war: Exploring a second-level agenda-building analysis examining the relationship among the media, the public and the president
Authors: Fahmy Shahira S , Wanta Wayne , Johnson Thomas J , Juyan Zhang
Published: June 2011

This study combines both the agenda-building and the second-level agenda approaches. It proposes an expansion of agenda-building research by examining the interaction among the president, the media and the public for an event that was not considered an existing ‘real-world’ condition. Specifically, this study uses former President Bush’s five most prominent rationales for invading Iraq to explore the three-way reciprocal relationship among the media, the public and the president on attributes related to the pre-emptive strike on Iraq. The study found evidence of the information subsidies approach as Bush influenced media coverage of the Iraq War. The research also found more evidence of a linear model of agenda-building. The media and presidential agenda had only a limited influence on public concern about the war. Public concern influenced how much space the president devoted to the five issues on his Iraq War agenda and the press also had some limited influence on the issues stressed by the former president.
Believe it or not: Understanding the credibility and effectiveness of Radio Sawa in the UAE
Authors: Christie Thomas B , Clark Andrew M
Published: June 2011

As part of an overall strategy to influence public opinion in the Muslim world, the US government implemented two new international broadcasting tools — Radio Sawa and Alhurra (a satellite television network). In the face of declining support of US government policies in the Muslim world, this study examines the credibility and effectiveness of Radio Sawa in an attempt to understand its effectiveness as a communication tool. The study explores differences in credibility and other dimensions among the United Arab Emirates (UAE) population; surveying both those who use this new medium and those who do not. Results of the study reveal the effectiveness of the US government in reaching its objectives in the region.
Joint remembering: Cognition, communication and interaction in processes of memory-making
Authors: Bietti Lucas M.
Published: June 2011

This article provides a new cognitive- and discourse-based theory to memory research. Despite the fact that a large proportion of studies in memory research are based on investigations of (interactional) cognitive and discourse processes, neither linguistics nor cognitive and social psychologists have proposed an integrative, interdisciplinary and discursive-based theory to memory research. In this article I explore how groups of people who did not know each other jointly coordinate the interlocking of their individual experiences during a period of dictatorship and their self-positioning in the here and now. The interlocking of autobiographical memories is performed by discourse strategies such as agreements and corrections, which are dependent on the participants’ shifting representations of the communicative interaction. The conversations were about personal experiences related to the 1976–83 military dictatorship in Argentina.
The IDDEA project: a strategy for the detection of alpha-1 antitrypsin deficiency in COPD patients in the primary care setting
Authors: Molina Jesús , Flor Xavier , García Rosa , Timiraos Rosario , Tirado-Conde Gema , Miravitlles Marc
Published: June 2011

Objective: Primary care provides the main route for access to health care for patients with common chronic illnesses such as chronic obstructive pulmonary disease (COPD). Alpha-1 antitrypsin (AAT) deficiency is an underdiagnosed pathology associated with COPD risk which has a very low prevalence. The Information and Detection of the Deficiency of AAT (IDDEA) project was developed to identify AAT-deficient patients at primary care centres by providing adequate diagnostic tools to family doctors.

Methods: Patients with COPD were identified and registered on a specially designed website. Dried blood samples were collected on filter papers and sent to the laboratory for AAT levels and AAT deficiency-related genotype determinations. Results were uploaded to the website and analysed.

Results: Between January 2008 and April 2009, 596 patients were identified by 90 participating physicians. The number of patients who did not have AAT deficiency (serum concentrations ≥60 mg AAT/dl) was 549 (98.9%). Nineteen patients (3.2%) were carriers of the allelic variant Pi*Z among which two were homozygous PiZZ (one of them was an index case) and one was heterozygous PiSZ. These three newly detected cases were registered in the Spanish Registry of Patients with AAT Deficiency. An estimate of the gene frequency of the S allele was 7.65% and the severe deficiency Z allele was 1.76%.

Conclusions: Results confirm that ATT deficiency is still underdiagnosed. The IDDEA system appears to be a useful tool for the detection of AAT deficiency in the primary care setting.
Management of Chronic Pain in the Rheumatic Diseases with Insights for the Clinician
Authors: Fitzcharles Mary-Ann , Shir Yoram
Published: June 2011

Pain that accompanies musculoskeletal conditions should be regarded as an illness entity in its own right and deserves treatment in parallel with the management of the underlying condition. Recent understanding of the pathophysiology of rheumatic pain invokes interplay of the nociceptive mechanisms driven by local tissue factors and the neurogenic responses that sustain chronic pain. In line with other pain conditions, ideal treatment of rheumatic pain should be through a multimodal approach, integrating nonpharmacologic as well as pharmacologic treatments. In the light of this new concept of pain mechanisms, future pharmacologic treatment options may encompass a wider scope than the use of traditional analgesics and nonsteroidal anti-inflammatory drugs. There is currently limited experience for use of pharmacologic treatments that act primarily on neurogenic mechanisms in rheumatic conditions. Drug combination studies are lacking, but this strategy seems clinically reasonable to allow for an approach to treating pain from different mechanistic perspectives. An added advantage would be the opportunity to use lower doses of individual drugs and thereby reduce the side effect profile. Ideal pain management must also include attention to the important co-associates of pain such as effects on sleep, mood and energy, which all have an impact on the global burden of suffering. Although complete relief of pain is still an unrealistic objective, reasonable outcome goals for symptom relief should be accompanied with an improvement in function.
The critical role of agrin in the hematopoietic stem cell niche
Authors: Mazzon Cristina , Anselmo Achille , Cibella Javier , Soldani Cristiana , Destro Annarita , Kim Natalie , Roncalli Massimo , Burden Steven J. , Dustin Michael L. , Sarukhan Adelaida , Viola Antonella
Published: June 2011

Hematopoiesis is the process leading to the sustained production of blood cells by hematopoietic stem cells (HSCs). Growth, survival, and differentiation of HSCs occur in specialized microenvironments called “hematopoietic niches,” through molecular cues that are only partially understood. Here we show that agrin, a proteoglycan involved in the neuromuscular junction, is a critical niche-derived signal that controls survival and proliferation of HSCs. Agrin is expressed by multipotent nonhematopoietic mesenchymal stem cells (MSCs) and by differentiated osteoblasts lining the endosteal bone surface, whereas Lin−Sca1+c-Kit+ (LSK) cells express the α-dystroglycan receptor for agrin. In vitro, agrin-deficient MSCs were less efficient in supporting proliferation of mouse Lin−c-Kit+ cells, suggesting that agrin plays a role in the hematopoietic cell development. These results were indeed confirmed in vivo through the analysis of agrin knockout mice (Musk-L;Agrn−/−). Agrin-deficient mice displayed in vivo apoptosis of CD34+CD135− LSK cells and impaired hematopoiesis, both of which were reverted by an agrin-sufficient stroma. These data unveil a crucial role of agrin in the hematopoietic niches and in the cross-talk between stromal and hematopoietic stem cells.
IL-7 mediates Ebf-1–dependent lineage restriction in early lymphoid progenitors
Authors: Tsapogas Panagiotis , Zandi Sasan , Åhsberg Josefine , Zetterblad Jenny , Welinder Eva , Jönsson Jan Ingvar , Månsson Robert , Qian Hong , Sigvardsson Mikael
Published: June 2011

Deficiencies in the IL-7 signaling pathway result in severe disruptions of lymphoid development in adult mice. To understand more about how IL-7 deficiency impacts early lymphoid development, we have investigated lineage restriction events within the common lymphoid progenitor (CLP) compartment in IL-7 knockout mice. This revealed that although IL-7 deficiency had a minor impact on the development of LY6D− multipotent CLPs, the formation of the lineage restricted LY6D+ CLP population was dramatically reduced. This was reflected in a low-level transcription of B-lineage genes as well as in a loss of functional B-cell commitment. The few Ly6D+ CLPs developed in the absence of IL-7 displayed increased lineage plasticity and low expression of Ebf-1. Absence of Ebf-1 could be linked to increased plasticity because even though Ly6D+ cells develop in Ebf-1–deficient mice, these cells retain both natural killer and dendritic cell potential. This reveals that IL-7 is essential for normal development of Ly6D+ CLPs and that Ebf-1 is crucial for lineage restriction in early lymphoid progenitors.
Increased basal intracellular signaling patterns do not correlate with JAK2 genotype in human myeloproliferative neoplasms
Authors: Anand Shubha , Stedham Frances , Gudgin Emma , Campbell Peter , Beer Philip , Green Anthony R. , Huntly Brian J. P.
Published: June 2011

Myeloproliferative neoplasms (MPNs) are associated with recurrent activating mutations of signaling proteins such as Janus kinase 2 (JAK2). However, the actual downstream signaling events and how these alter myeloid homeostasis are poorly understood. We developed an assay to measure basal levels of phosphorylated signaling intermediates by flow cytometry during myeloid differentiation in MPN patients. Our study provides the first systematic demonstration of specific signaling events and their comparison with disease phenotype and JAK2 mutation status. We demonstrate increased basal signaling in MPN patients, which occurs in both early and later stages of myeloid differentiation. In addition, the pattern of signaling is not correlated with JAK2 mutation status and signaling intensity is poorly correlated with mutant JAK2 allele burden. In contrast, signaling differences are detected between different MPN disease phenotypes. Finally, we demonstrate that signaling can be inhibited by a JAK2-selective small molecule, but that this inhibition is not JAK2 V617F specific, because MPN patients with mutant JAK2, wild-type JAK2, and control patients were inhibited to a similar degree. Our data suggest that, in addition to JAK2 mutations, other factors contribute significantly to the MPN phenotype, results that are relevant to both the pathogenesis and therapy of MPN.
Self-antigen presentation by mouse B cells results in regulatory T-cell induction rather than anergy or clonal deletion
Authors: Morlacchi Sara , Soldani Cristiana , Viola Antonella , Sarukhan Adelaida
Published: June 2011

Multiple mechanisms operate to ensure T-cell tolerance toward self-antigens. Three main processes have been described: clonal deletion, anergy, and deviation to CD4+ regulatory T cells (Tregs) that suppress autoreactive T cells that have escaped the first 2 mechanisms. Although it is accepted that dendritic cells (DCs) and B cells contribute in maintaining T-cell tolerance to self-antigens, their relative contribution and the processes involved under physiologic conditions remain only partially characterized. In this study, we used different transgenic mouse models to obtain chimeras where a neo self-antigen is expressed by thymic epithelium and/or by DCs or B cells. We found that expression of cognate ligand in the thymus enhances antigen-specific FoxP3+ cells independently of whether the self-antigen is expressed on thymic epithelium or only on DCs, but not on B cells. On the contrary, self-antigen expression by B cells was very efficient in inducing FoxP3+ cells in the periphery, whereas self-antigen expression by DC led mainly to deletion and anergy of antigen-specific FoxP3− cells. The results presented in this study underline the role of B cells in Treg induction and may have important implications in clinical protocols aimed at the peripheral expansion of Tregs in patients.
CalDAG-GEFI deficiency protects mice in a novel model of FcγRIIA-mediated thrombosis and thrombocytopenia
Authors: Stolla Moritz , Stefanini Lucia , André Pierrette , Ouellette Timothy D. , Reilly Michael P. , McKenzie Steven E. , Bergmeier Wolfgang
Published: June 2011

Platelet activation via Fcγ receptor IIA (FcγRIIA) is a critical event in immune-mediated thrombocytopenia and thrombosis syndromes (ITT). We recently identified signaling by the guanine nucleotide exchange factor CalDAG-GEFI and the adenosine diphosphate receptor P2Y12 as independent pathways leading to Rap1 small GTPase activation and platelet aggregation. Here, we evaluated the contribution of CalDAG-GEFI and P2Y12 signaling to platelet activation in ITT. Mice transgenic for the human FcγRIIA (hFcR) and deficient in CalDAG-GEFI−/− (hFcR/CDGI−/−) were generated. Compared with controls, aggregation of hFcR/CDGI−/− platelets or P2Y12 inhibitor-treated hFcR platelets required more than 5-fold and approximately 2-fold higher concentrations of a FcγRIIA stimulating antibody against CD9, respectively. Aggregation and Rap1 activation were abolished in P2Y12 inhibitor-treated hFcR/CDGI−/− platelets. For in vivo studies, a novel model for antibody-induced thrombocytopenia and thrombosis was established. FcγRIIA-dependent platelet thrombosis was induced by infusion of Alexa750-labeled antibodies to glycoprotein IX (CD42a), and pulmonary thrombi were detected by near-infrared imaging technology. Anti-GPIX antibodies dose-dependently caused thrombocytopenia and pulmonary thrombosis in hFcR-transgenic but not wild-type mice. CalDAG-GEFI-deficient but not clopidogrel-treated hFcR-transgenic mice were completely protected from ITT. In summary, we established a novel mouse model for ITT, which was used to identify CalDAG-GEFI as a potential new target in the treatment of ITT.
Deletion of Adam10 in endothelial cells leads to defects in organ-specific vascular structures
Authors: Glomski Krzysztof , Monette Sébastien , Manova Katia , De Strooper Bart , Saftig Paul , Blobel Carl P.
Published: June 2011

During vertebrate angiogenesis, Notch regulates the cell-fate decision between vascular tip cells versus stalk cells. Canonical Notch signaling depends on sequential proteolytic events, whereby interaction of Notch with membrane-anchored ligands triggers proteolytic processing, first by Adam10 and then presenilins. This liberates the Notch intracellular domain, allowing it to enter the nucleus and activate Notch-dependent genes. Here we report that conditional inactivation of Adam10 in endothelial cells (A10ΔEC) recapitulates the increased branching and density of the retinal vasculature that is also caused by interfering with Notch signaling. Moreover, A10ΔEC mice have additional vascular abnormalities, including aberrant subcapsular hepatic veins, enlarged glomeruli, intestinal polyps containing endothelial cell masses, abnormal endochondral ossification, leading to stunted long bone growth and increased pathologic neovascularization following oxygen-induced retinopathy. Our findings support a model in which Adam10 is a crucial regulator of endothelial cell-fate decisions, most likely because of its essential role in canonical Notch signaling.
Overwhelming postsplenectomy infection due to Mycoplasma pneumoniaein an asplenic cirrhotic patient: Case report
Authors: Xu Feng , Dai Chao-Liu , Wu Xing-Mao , Chu Peng
Published: June 2011

Background

Mycoplasma
pneumoniae infection is usually self-limited, but some fulminant cases are fatal, even when occurring in previously healthy individuals. It can also be the cause of overwhelming postsplenectomy infection (OPSI).

Case presentation

We report a case of OPSI in a 41-year-old woman with hypersplenism associated with hepatitis B cirrhosis. We detected a significant Mycoplasma pneumoniae agglutination titer, but no evidence of infection with Chlamydia pneumoniae, Legionnella spp., or any other bacterial or fungal pathogens. She eventually died despite aggressive therapy.

Conclusions

M. pneumoniae could be an underestimated cause of OPSI, and should be suspected in fulminant infectious cases in asplenic patients.
Levels of soluble fms-like tyrosine kinase one in first trimester and outcomes of pregnancy: a systematic review
Authors: Jacobs Marni , Nassar Natasha , Roberts Christine L , Hadfield Ruth , Morris Jonathan M , Ashton Anthony W
Published: June 2011

Angiogenic factors are involved in formation of new blood vessels required for placental development and function; and critical for fetal growth and development. Soluble fms-like tyrosine kinase 1(sFlt-1) is an anti-angiogenic protein that inhibits formation of new blood vessels resulting in potential pregnancy complications. The objective of this study was to undertake a systematic review to assess levels of sFlt-1 in early pregnancy and association with adverse pregnancy outcomes. PubMed and Medline databases and reference lists were searched up to July 2010. Inclusion criteria were pregnant women, blood sample taken during first trimester and assessment/reporting of sFlt-1 concentrations and subsequent pregnancy complications. Twelve relevant studies were identified of 71 to 668 women. No pooling of results was undertaken due to variation in sFlt-1 concentrations (range, 166-6,349 pg/ml amongst controls), samples used (serum, plasma), different summary statistics (mean, median, odds ratio) and outcome definitions applied. Levels of sFlt-1 were generally higher among women who developed preeclampsia (11 studies) or gestational hypertension (two studies), but not significantly different to normotensive women in most studies. There was no consistent pattern in association between sFlt-1 concentrations and fetal growth restriction (4 studies); and levels were non-significantly higher for women with postpartum bleeding (1 study) and significantly lower for stillbirths (1 study).This review found no clear evidence of an association between sFlt-1 levels in first trimester and adverse pregnancy outcomes. However, findings were affected by methodological, biological and testing variations between studies; highlighting the need for consistent testing of new biomarkers and reporting of outcome measures.
Evidence that polymorphonuclear neutrophils infiltrate into the developing corpus luteum and promote angiogenesis with interleukin-8 in the cow
Authors: Jiemtaweeboon Sineenard , Shirasuna Koumei , Nitta Akane , Kobayashi Ayumi , Schuberth Hans-Joachim , Shimizu Takashi , Miyamoto Akio
Published: June 2011

Background

After ovulation in the cow, the corpus luteum (CL) rapidly develops within a few days with angiogenesis and progesterone production. CL formation resembles an inflammatory response due to the influx of immune cells. Neutrophils play a role in host defense and inflammation, and secrete chemoattractants to stimulate angiogenesis. We therefore hypothesized that neutrophils infiltrate in the developing CL from just after ovulation and may play a role in angiogenesis of the CL.

Methods and Results

Polymorphonuclear neutrophils (PMN) were detected in CL tissue by Pas-staining, and interleukin-8 (IL-8, a neutrophil-specific chemoattractant) was measured in supernatant of the CL tissue culture: considerable amounts of PMNs and the high level of IL-8 were observed during the early luteal phase (days 1-4 of the estrous cycle). PMNs and IL-8 were low levels in the mid and late luteal phases, but IL-8 was increased during luteal regression. The PMN migration in vitro was stimulated by the supernatant from the early CL but not from the mid CL, and this activity was inhibited by neutralizing with an anti-IL-8 antibody, indicating the major role of IL-8 in inducing active PMN migration in the early CL. Moreover, IL-8 stimulated proliferation of CL-derived endothelial cells (LECs), and both the supernatant of activated PMNs and IL-8 stimulated formation of capillary-like structures of LECs.

Conclusion

PMNs migrate into the early CL partially due to its major chemoattractant IL-8 produced at high levels in the CL, and PMNs is a potential regulator of angiogenesis together with IL-8 in developing CL in the cow.
Body fluid derived exosomes as a novel template for clinical diagnostics
Authors: Keller Sascha , Ridinger Johannes , Rupp Anne-Kathleen , Janssen Johannes WG , Altevogt Peter
Published: June 2011

Background

Exosomes are small membrane vesicles with a size of 40-100 nm that are released by different cell types from a late endosomal cellular compartment. They can be found in various body fluids including plasma, malignant ascites, urine, amniotic fluid and saliva. Exosomes contain proteins, miRNAs and mRNAs (exosome shuttle RNA, esRNA) that could serve as novel platform for diagnosis.

Method

We isolated exosomes from amniotic fluid, saliva and urine by differential centrifugation on sucrose gradients. Marker proteins were identified by Western blot and FACS analysis after adsorption of exosomes to latex beads. We extracted esRNA from exosomes, carried out RT-PCR, and analyzed amplified products by restriction length polymorphism.

Results

Exosomes were positive for the marker proteins CD24, CD9, Annexin-1 and Hsp70 and displayed the correct buoyant density and orientation of antigens. In sucrose gradients the exosomal fractions contained esRNA that could be isolated with sufficient quantity for further analysis. EsRNAs were protected in exosomes from enzymatic degradation. Amniotic fluid esRNA served as template for the typing of the CD24 single nucleotide polymorphism (rs52812045). It also allowed sex determination of the fetus based on the detection of the male specific ZFY gene product.

Conclusions

Our data demonstrate that exosomes from body fluids carry esRNAs which can be analyzed and offers access to the transcriptome of the host organism. The exosomal lipid bilayer protects the genetic information from degradation. As the isolation of exosomes is a minimally invasive procedure, this technique opens new possibilities for diagnostics.
FTO gene polymorphisms and obesity risk: a meta-analysis
Authors: Peng Sihua , Zhu Yimin , Xu Fangying , Ren Xiaobin , Li Xiaobo , Lai Maode
Published: June 2011

Background

The pathogenesis of obesity is reportedly related to variations in the fat mass and an obesity-associated gene (FTO); however, as the number of reports increases, particularly with respect to varying ethnicities, there is a need to determine more precisely the effect sizes in each ethnic group. In addition, some reports have claimed ethnic-specific associations with alternative SNPs, and to that end there has been a degree of confusion.

Methods

We searched PubMed, MEDLINE, Web of Science, EMBASE, and BIOSIS Preview to identify studies investigating the associations between the five polymorphisms and obesity risk. Individual study odds ratios (OR) and their 95% confidence intervals (CI) were estimated using per-allele comparison. Summary ORs were estimated using a random effects model.

Results

We identified 59 eligible case-control studies in 27 articles, investigating 41,734 obesity cases and 69,837 healthy controls. Significant associations were detected between obesity risk and the five polymorphisms: rs9939609 (OR: 1.31, 95% CI: 1.26 to 1.36), rs1421085 (OR: 1.43, 95% CI: 1.33 to 1.53), rs8050136 (OR: 1.25, 95% CI: 1.13 to 1.38), rs17817449 (OR: 1.54, 95% CI: 1.41 to 1.68), and rs1121980 (OR: 1.34, 95% CI: 1.10 to 1.62). Begg's and Egger's tests provided no evidence of publication bias for the polymorphisms except rs1121980. There is evidence of higher heterogeneity, with I
2 test values ranging from 38.1% to 84.5%.

Conclusions

This meta-analysis suggests that FTO may represent a low-penetrance susceptible gene for obesity risk. Individual studies with large sample size are needed to further evaluate the associations between the polymorphisms and obesity risk in various ethnic populations.
Curcumin ameliorates macrophage infiltration by inhibiting NF-κB activation and proinflammatory cytokines in streptozotocin induced-diabetic nephropathy
Authors: Soetikno Vivian , Sari Flori R , Veeraveedu Punniyakoti T , Thandavarayan Rajarajan A , Harima Meilei , Sukumaran Vijayakumar , Lakshmanan Arun Prasath , Suzuki Kenji , Kawachi Hiroshi , Watanabe Kenichi
Published: June 2011

Background

Chronic inflammation plays an important role in the progression of diabetic nephropathy (DN) and that the infiltration of macrophages in glomerulus has been implicated in the development of glomerular injury. We hypothesized that the plant polyphenolic compound curcumin, which is known to exert potent anti-inflammatory effect, would ameliorate macrophage infiltration in streptozotocin (STZ)-induced diabetic rats.

Methods

Diabetes was induced with STZ (55 mg/kg) by intraperitoneal injection in rats. Three weeks after STZ injection, rats were divided into three groups, namely, control, diabetic, and diabetic treated with curcumin at 100 mg/kg/day, p.o., for 8 weeks. The rats were sacrificed 11 weeks after induction of diabetes. The excised kidney was used to assess macrophage infiltration and expression of various inflammatory markers.

Results

At 11 weeks after STZ injection, diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, increased blood glucose, blood urea nitrogen and proteinuria, along with marked reduction in the body weight. All of these abnormalities were significantly reversed by curcumin. Hyperglycemia induced the degradation of IκBα and NF-κB activation and as a result increased infiltration of macrophages (52%) as well as increased proinflammatory cytokines: TNF-α and IL-1β. Curcumin treatment significantly reduced macrophage infiltration in the kidneys of diabetic rats, suppressed the expression of above proinflammatory cytokines and degradation of IκBα. In addition, curcumin treatment also markedly decreased ICAM-1, MCP-1 and TGF-β1 protein expression. Moreover, at nuclear level curcumin inhibited the NF-κB activity.

Conclusion

Our results suggested that curcumin treatment protect against the development of DN in rats by reducing macrophage infiltration through the inhibition of NF-κB activation in STZ-induced diabetic rats.
Antagonistic Gcn5-Hda1 interactions revealed by mutations to the Anaphase Promoting Complex in yeast
Authors: Islam Azharul , Turner Emma L , Menzel Johannes , Malo Mackenzie E , Harkness Troy AA
Published: June 2011

Background

Histone post-translational modifications are critical for gene expression and cell viability. A broad spectrum of histone lysine residues have been identified in yeast that are targeted by a variety of modifying enzymes. However, the regulation and interaction of these enzymes remains relatively uncharacterized. Previously we demonstrated that deletion of either the histone acetyltransferase (HAT)GCN5or the histone deacetylase (HDAC)HDA1exacerbated the temperature sensitive (ts) mutant phenotype of the Anaphase Promoting Complex (APC)apc5CAallele. Here, theapc5CAmutant background is used to study a previously uncharacterized functional antagonistic genetic interaction between Gcn5 and Hda1 that is not detected inAPC5cells.

Results

Using Northerns, Westerns, reverse transcriptase PCR (rtPCR), chromatin immunoprecipitation (ChIP), and mutant phenotype suppression analysis, we observed that Hda1 and Gcn5 appear to compete for recruitment to promoters. We observed that the presence of Hda1 can partially occlude the binding of Gcn5 to the same promoter. Occlusion of Gcn5 recruitment to these promoters involved Hda1 and Tup1. Using sequential ChIP we show that Hda1 and Tup1 likely form complexes at these promoters, and that complex formation can be increased by deletingGCN5.

Conclusions

Our data suggests large Gcn5 and Hda1 containing complexes may compete for space on promoters that utilize the Ssn6/Tup1 repressor complex. We predict that inapc5CAcells the accumulation of an APC target may compensate for the loss of bothGCN5andHDA1.
Intensity modulated radiation therapy (IMRT): differences in target volumes and improvement in clinically relevant doses to small bowel in rectal carcinoma
Authors: Mok Henry , Crane Christopher H , Palmer Matthew B , Briere Tina M , Beddar Sam , Delclos Marc E , Krishnan Sunil , Das Prajnan
Published: June 2011

Background

A strong dose-volume relationship exists between the amount of small bowel receiving low- to intermediate-doses of radiation and the rates of acute, severe gastrointestinal toxicity, principally diarrhea. There is considerable interest in the application of highly conformal treatment approaches, such as intensity-modulated radiation therapy (IMRT), to reduce dose to adjacent organs-at-risk in the treatment of carcinoma of the rectum. Therefore, we performed a comprehensive dosimetric evaluation of IMRT compared to 3-dimensional conformal radiation therapy (3DCRT) in standard, preoperative treatment for rectal cancer.

Methods

Using RTOG consensus anorectal contouring guidelines, treatment volumes were generated for ten patients treated preoperatively at our institution for rectal carcinoma, with IMRT plans compared to plans derived from classic anatomic landmarks, as well as 3DCRT plans treating the RTOG consensus volume. The patients were all T3, were node-negative (N = 1) or node-positive (N = 9), and were planned to a total dose of 45-Gy. Pairwise comparisons were made between IMRT and 3DCRT plans with respect to dose-volume histogram parameters.

Results

IMRT plans had superior PTV coverage, dose homogeneity, and conformality in treatment of the gross disease and at-risk nodal volume, in comparison to 3DCRT. Additionally, in comparison to the 3DCRT plans, IMRT achieved a concomitant reduction in doses to the bowel (small bowel mean dose: 18.6-Gy IMRT versus 25.2-Gy 3DCRT; p = 0.005), bladder (V40Gy: 56.8% IMRT versus 75.4% 3DCRT; p = 0.005), pelvic bones (V40Gy: 47.0% IMRT versus 56.9% 3DCRT; p = 0.005), and femoral heads (V40Gy: 3.4% IMRT versus 9.1% 3DCRT; p = 0.005), with an improvement in absolute volumes of small bowel receiving dose levels known to induce clinically-relevant acute toxicity (small bowel V15Gy: 138-cc IMRT versus 157-cc 3DCRT; p = 0.005). We found that the IMRT treatment volumes were typically larger than that covered by classic bony landmark-derived fields, without incurring penalty with respect to adjacent organs-at-risk.

Conclusions

For rectal carcinoma, IMRT, compared to 3DCRT, yielded plans superior with respect to target coverage, homogeneity, and conformality, while lowering dose to adjacent organs-at-risk. This is achieved despite treating larger volumes, raising the possibility of a clinically-relevant improvement in the therapeutic ratio through the use of IMRT with a belly-board apparatus.
Gastrin-Deficient Mice Have Disturbed Hematopoiesis in Response to Iron Deficiency
Authors: Kovac Suzana , Anderson Gregory J. , Alexander Warren S. , Shulkes Arthur , Baldwin Graham S.
Published: June 2011

Gastrins are peptide hormones important for gastric acid secretion and growth of the gastrointestinal mucosa. We have previously demonstrated that ferric ions bind to gastrins, that the gastrin-ferric ion complex interacts with the iron transport protein transferrin in vitro, and that circulating gastrin concentrations positively correlate with transferrin saturation in vivo. Here we report the effect of long-term dietary iron modification on gastrin-deficient (Gas−/−) and hypergastrinemic cholecystokinin receptor 2-deficient (Cck2r−/−) mice, both of which have reduced basal gastric acid secretion. Iron homeostasis in both strains appeared normal unless the animals were challenged by iron deficiency. When fed an iron-deficient diet, Gas−/− mice, but not Cck2r−/−mice, developed severe anemia. In iron-deficient Gas−/−mice, massive splenomegaly was also apparent with an increased number of splenic megakaryocytes accompanied by thrombocytosis. The expression of the mRNA encoding the iron-regulatory peptide hepcidin, Hamp, was down-regulated in both Cck2r−/− and Gas−/−mice on a low-iron diet, but, interestingly, the reduction was greater in Cck2r−/− mice and smaller in Gas−/− mice than in the corresponding wild-type strains. These data suggest that gastrins play an important direct role, unrelated to their ability to stimulate acid secretion, in hematopoiesis under conditions of iron deficiency.
Type-2 Iodothyronine 5′Deiodinase (D2) in Skeletal Muscle of C57Bl/6 Mice. II. Evidence for a Role of D2 in the Hypermetabolism of Thyroid Hormone Receptor α-Deficient Mice
Authors: Ramadan W. , Marsili A. , Larsen P. R. , Zavacki A. M. , Silva J. E.
Published: June 2011

Mice with ablation of the Thra gene have cold intolerance due to an as yet undefined defect in the activation of brown adipose tissue (BAT) uncoupling protein (UCP). They develop an alternate form of facultative thermogenesis, activated at temperatures below thermoneutrality and associated with hypermetabolism and reduced sensitivity to diet-induced obesity. A consistent finding in Thra-0/0 mice is increased type-2 iodothyronine deiodinase (D2) mRNA in skeletal muscle and other tissues. With an improved assay to measure D2 activity, we show here that this enzyme activity is increased in proportion to the mRNA and as a function of the ambient cold. The activation is mediated by the sympathetic nervous system in Thra-0/0, as it is in wild-type genotype mice, but the sympathetic nervous system effect is greater in Thra-0/0 mice. Using D2-ablated mice (Dio2−/−), we reported elsewhere and show here that, in spite of sharing a severe deficiency in BAT thermogenesis with Thra-0/0 and UCP1-knockout mice, they do not have an increase in oxygen consumption, and they gain more weight than wild-type controls when fed a high-fat diet. UCP3 mRNA is highly responsive to thyroid hormone, and it is increased in Thra-0/0 mice, particularly when fed high-fat diets. We show here that muscle UCP3 mRNA in hypothyroid Thra-0/0 mice is responsive to small dose-short regimens of T4, indicating a role for locally, D2-generated T3. Lastly, we show that bile acids stimulate not only BAT but also muscle D2 activity, and this is associated with stimulation of muscle UCP3 mRNA expression provided T4 is present. These observations strongly support the concept that enhanced D2 activity in Thra-0/0 plays a critical role in their alternate form of facultative thermogenesis, stimulating increased fat oxidation by increasing local T3 generation in skeletal muscle.
Involvement of afadin in barrier function and homeostasis of mouse intestinal epithelia
Authors: Tanaka-Okamoto Miki , Hori Keiko , Ishizaki Hiroyoshi , Itoh Yu , Onishi Sachiko , Yonemura Shigenobu , Takai Yoshimi , Miyoshi Jun
Published: June 2011

Afadin interacts with the cytoplasmic region of nectins, which are immunoglobulin-like cell adhesion molecules at adherens junctions, and links them to the actin cytoskeleton. Afadin regulates activities of cells in culture such as directional motility, proliferation and survival. We used Cre-loxP technology to generate mice conditionally lacking afadin specifically in the intestinal epithelia after birth. The loss of afadin caused increased paracellular permeability in the intestinal mucosa and enhanced susceptibility to the tissue destruction induced by dextran sulfate sodium. The junctional architecture of the intestinal epithelia appeared to be preserved, whereas the deficiency of afadin caused the mislocalization of nectin-2 and nectin-3 from adherens junctions to basolateral membrane domains but not that of other components of apical junctions. By contrast, such phenotypic changes were undetected in mice lacking nectin-2, nectin-3 or both. These findings suggest that afadin plays crucial roles, independently of the role as the nectin–afadin module, in barrier function and homeostasis of the intestinal epithelia once the epithelial structure has been established.
Transgenic overexpression of the α7 integrin reduces muscle pathology and improves viability in the dyW mouse model of merosin-deficient congenital muscular dystrophy type 1A
Authors: Doe Jinger A. , Wuebbles Ryan D. , Allred Erika T. , Rooney Jachinta E. , Elorza Margaret , Burkin Dean J.
Published: June 2011

Merosin-deficient congenital muscular dystrophy 1A (MDC1A) is a devastating neuromuscular disease that results in children being confined to a wheelchair, requiring ventilator assistance to breathe and premature death. MDC1A is caused by mutations in the LAMA2 gene, which results in the partial or complete loss of laminin-211 and laminin-221, the major laminin isoforms found in the basal lamina of skeletal muscle. MDC1A patients exhibit reduced α7β1 integrin; however, it is unclear how the secondary loss of α7β1 integrin contributes to MDC1A disease progression. To investigate whether restoring α7 integrin expression can alleviate the myopathic phenotype observed in MDC1A, we produced transgenic mice that overexpressed the α7 integrin in the skeletal muscle of the dyW−/− mouse model of MDC1A. Enhanced expression of the α7 integrin restored sarcolemmal localization of the α7β1 integrin to laminin-α2-deficient myofibers, changed the composition of the muscle extracellular matrix, reduced muscle pathology, maintained muscle strength and function and improved the life expectancy of dyW−/− mice. Taken together, these results indicate that enhanced expression of α7 integrin prevents muscle disease progression through augmentation and/or stabilization of the existing extracellular matrix in laminin-α2-deficient mice, and strategies that increase α7 integrin in muscle might provide an innovative approach for the treatment of MDC1A.
Characterization of Mug33 reveals complementary roles for actin cable-dependent transport and exocyst regulators in fission yeast exocytosis
Authors: Snaith Hilary A. , Thompson James , Yates John R. , Sawin Kenneth E.
Published: June 2011

Although endocytosis and exocytosis have been extensively studied in budding yeast, there have been relatively few investigations of these complex processes in the fission yeast Schizosaccharomyces pombe. Here we identify and characterize fission yeast Mug33, a novel Tea1-interacting protein, and show that Mug33 is involved in exocytosis. Mug33 is a Sur7/PalI-family transmembrane protein that localizes to the plasma membrane at the cell tips and to cytoplasmic tubulovesicular elements (TVEs). A subset of Mug33 TVEs make long-range movements along actin cables, co-translocating with subunits of the exocyst complex. TVE movement depends on the type V myosin Myo52. Although mug33Δ mutants are viable, with only a mild cell-polarity phenotype, mug33Δ myo52Δ double mutants are synthetically lethal. Combining mug33 Δ with deletion of the formin For3 (for3Δ) leads to synthetic temperature-sensitive growth and strongly reduced levels of exocytosis. Interestingly, mutants in non-essential genes involved in exocyst function behave in a manner similar to mug33Δ when combined with myo52Δ and for3Δ. By contrast, combining mug33Δ with mutants in non-essential exocyst genes has only minor effects on growth. We propose that Mug33 contributes to exocyst function and that actin cable-dependent vesicle transport and exocyst function have complementary roles in promoting efficient exocytosis in fission yeast.
Insulin-like growth factor (IGF) signalling and genome-wide transcriptional regulation in fast muscle of zebrafish following a single-satiating meal
Authors: Amaral Ian P. G. , Johnston Ian A.
Published: June 2011

Male zebrafish (Danio rerio) were fasted for 7 days and fed to satiation over 3 h to investigate the transcriptional responses to a single meal. The intestinal content at satiety (6.3% body mass) decreased by 50% at 3 h and 95% at 9 h following food withdrawal. Phosphorylation of the insulin-like growth factor (IGF) signalling protein Akt peaked within 3 h of feeding and was highly correlated with gut fullness. Retained paralogues of IGF hormones genes were regulated with feeding, with igf1a showing a pronounced peak in expression after 3 h and igf2b after 6 h. Igf-I receptor transcripts were markedly elevated with fasting, and decreased to their lowest levels 45 min after feeding. igf1rb transcripts increased more quickly than igf1ra transcripts as the gut emptied. Paralogues of the insulin-like growth factor binding proteins (IGFBPs) were constitutively expressed, except for igfbp1a and igfbp1b transcripts, which were significantly elevated with fasting. Genome-wide transcriptional responses were analysed using the Agilent 44K oligonucleotide microarray and selected genes validated by qPCR. Fasting was associated with the upregulation of genes for the ubiquitin-proteasome degradation pathway, anti-proliferative and pro-apoptotic genes. Protein chaperones (unc45b, hspd1, hspa5, hsp90a.1, hsp90a.2) and chaperone interacting proteins (ahsa1 and stip1) were upregulated 3 h after feeding along with genes for the initiation of protein synthesis and mRNA processing. Transcripts for the enzyme ornithine decarboxylase 1 showed the largest increase with feeding (11.5-fold) and were positively correlated with gut fullness. This study demonstrates the fast nature of the transcriptional responses to a meal and provides evidence for differential regulation of retained paralogues of IGF signalling pathway genes.
Energetics of burrowing by the cirratulid polychaeteCirriformia moorei
Authors: Dorgan Kelly M. , Lefebvre Stephane , Stillman Jonathon H. , Koehl M. A. R.
Published: June 2011

Burrowing through marine sediments has been considered to be much more energetically expensive than other forms of locomotion, but previous studies were based solely on external work calculations and lacked an understanding of the mechanical responses of sediments to forces applied by burrowers. Muddy sediments are elastic solids through which worms extend crack-shaped burrows by fracture. Here we present data on energetics of burrowing by Cirriformia moorei. We calculated the external energy per distance traveled from the sum of the work to extend the burrow by fracture and the elastic work done to displace sediment as a worm moves into the newly formed burrow to be 9.7 J kg–1 m–1 in gelatin and 64 J kg–1 m–1 in sediment, much higher than for running or walking. However, because burrowing worms travel at slow speeds, the increase in metabolic rate due to burrowing is predicted to be small. We tested this prediction by measuring aerobic metabolism (oxygen consumption rates) and anaerobic metabolism (concentrations of the anaerobic metabolite tauropine and the energy-storage molecule phosphocreatine) of C. moorei. None of these components was significantly different between burrowing and resting worms, and the low increases in oxygen consumption rates or tauropine concentrations predicted from external work calculations were within the variability observed across individuals. This result suggests that the energy to burrow, which could come from aerobic or anaerobic sources, is not a substantial component of the total metabolic energy of a worm. Burrowing incurs a low cost per unit of time.
Perch size and structure have species-dependent effects on the arboreal locomotion of rat snakes and boa constrictors
Authors: Jayne Bruce C. , Herrmann Michael P.
Published: June 2011

Arboreal habitats create diverse challenges for animal locomotion, but the numerical and phylogenetic diversity of snakes that climb trees suggest that their overall body plan is well suited for this task. Snakes have considerable diversity of axial anatomy, but the functional consequences of this diversity for arboreal locomotion are poorly understood because of the lack of comparative data. We simulated diverse arboreal surfaces to test whether environmental structure had different effects on the locomotion of snakes belonging to two distantly related species with differences in axial musculature and stoutness. On most cylindrical surfaces lacking pegs, both species used concertina locomotion, which always involved periodic stopping and gripping but was kinematically distinct in the two species. On horizontal cylinders that were a small fraction of body diameter, the boa constrictors used a balancing form of lateral undulation that was not observed for rat snakes. For all snakes the presence of pegs elicited lateral undulation and enhanced speed. For both species maximal speeds decreased with increased incline and were greatest on cylinders with intermediate diameters that approximated the diameter of the snakes. The frictional resistances that we studied had small effects compared with those of cylinder diameter, incline and the presence of pegs. The stouter and more muscular boa constrictors were usually faster than the rat snakes when using the gripping gait, whereas rat snakes were faster when using lateral undulation on the surfaces with pegs. Thus, variation in environmental structure had several highly significant effects on locomotor mode, performance and kinematics that were species dependent.