bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia
Authors: Chen Lisa S. , Redkar Sanjeev , Taverna Pietro , Cortes Jorge E. , Gandhi Varsha
Published: June 2011

Pim kinases are Ser/Thr kinases with multiple substrates that affect survival pathways. These proteins are overexpressed in acute myeloid leukemia (AML) blasts and we hypothesized that Pim kinase inhibition would affect AML cell survival. Imidazo[1,2-b]pyridazine compound, SGI-1776 inhibits Pim-1, Pim-2 and Pim-3, and was evaluated in AML-cell line, -xenograft model, and -primary blasts. Treatment of AML cells with SGI-1776 results in a concentration-dependent induction of apoptosis and we investigated its effect on Pim kinase functions. Phosphorylation of traditional Pim kinase targets, c-Myc(Ser62) and 4E-BP1 (Thr36/Thr47), were both decreased in actively cycling AML cell lines MV-4-11, MOLM-13 and OCI-AML-3. Levels of antiapoptotic proteins Bcl-2, Bcl-xL, XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant reduction in Mcl-1 was observed. This was correlated with inhibition of global RNA and protein synthesis and MCL-1 transcript decline after SGI-1776 treatment. These data suggest that SGI-1776 mechanism in AML involves Mcl-1 protein reduction. Consistent with cell line data, xenograft model studies with mice bearing MV-4-11 tumors showed efficacy with SGI-1776. Importantly, SGI-1776 was also cytotoxic in AML primary cells, irrespective of FLT3 mutation status and resulted in Mcl-1 protein decline. Pim kinase inhibition may be a new strategy for AML treatment.
Low hepcidin accounts for the proinflammatory status associated with iron deficiency
Authors: Pagani Alessia , Nai Antonella , Corna Gianfranca , Bosurgi Lidia , Rovere-Querini Patrizia , Camaschella Clara , Silvestri Laura
Published: June 2011

Hepcidin is an antimicrobial peptide that controls systemic iron homeostasis. Hepcidin binding to its receptor ferroportin reduces iron availability, thus controlling microbial growth. In parallel it triggers an anti-inflammatory response in macrophages. Hepcidin is transcriptionally regulated by iron, through the bone morphogenetic protein–son of mothers against decapentaplegic (BMP-SMAD) pathway and by inflammation, through IL6-mediated STAT3 signaling. To investigate the mechanisms linking iron and inflammation, we treated C57BL/6 iron-deficient mice with a sublethal dose of lipopolysaccharide (LPS) and analyzed their inflammatory response in comparison with controls. We show that iron-deprived mice have a proinflammatory condition, exacerbated by LPS treatment leading to increased IL6 and TNFα mRNA in liver and spleen macrophages, and increased serum IL6 (482.29 ± 205.59 pg/mL) versus controls (69.01 ± 17.52 pg/mL; P < .05). Hepcidin was undetectable in iron-deficient mice but pretreatment with hepcidin normalized their response to LPS. Tmprss6−/− mice, characterized by iron deficiency and high hepcidin, show a blunted inflammatory response when challenged with LPS. Our data support a model in which the lack of hepcidin is responsible of the high inflammatory response to LPS in iron deficiency. The proinflammatory status associated with chronic iron deficiency could explain the resistance to infection seen in this condition.
The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma
Authors: Bhalla Savita , Evens Andrew M. , Dai Bojie , Prachand Sheila , Gordon Leo I. , Gartenhaus Ronald B.
Published: June 2011

The RAS/RAF/MEK/ERK signaling pathway has been largely unexplored as a potential therapeutic target in lymphoma. The novel 2nd generation anti-MEK small molecule, AZD6244, down-regulated its direct downstream target, phospho-ERK (pERK) in germinal center and nongerminal center diffuse large B-cell lymphoma (DLBCL) cell lines and primary cells. Similar decreased pERK levels were noted despite constitutive activation (CA) of MEK. Consequently, several lymphoma-related ERK substrates were down-regulated by AZD6244 including MCT-1, c-Myc, Bcl-2, Mcl-1, and CDK1/2. AZD6244 induced time- and dose-dependent antiproliferation and apoptosis in all DLBCL cell lines and fresh/primary cells (IC50 100nM-300nM). Furthermore, AZD6244 resulted in significantly less tumor compared with control in an in vivo DLBCL SCID xenograft model. Cell death was associated with cleaved PARP, caspases-8, -9, and -3, and apoptosis was caspase-dependent. In addition, there was stabilization of FoxO3a, activation of BIM and PUMA, and a significant decrease in c-Myc transcripts. Moreover, siRNA knockdown of BIM abrogated AZD6244-related apoptosis, while shRNA knockdown of ERK minimally sensitized cells. Finally, manipulation of AKT with transfection of OCI-LY3 cells with CA-AKT or through chemical inhibition (LY294002) had minimal effect on AZD6244-induced cell death. Altogether, these findings show that the novel anti-MEK agent, AZD6244, induced apoptosis in DLBCL and that cell death was BIM-dependent.
Long-term restoration of the human T-cell compartment after thymectomy during infancy: a role for thymic regeneration?
Authors: van Gent Rogier , Schadenberg Alvin W. L. , Otto Sigrid A. , Nievelstein Rutger A. J. , Sieswerda Gertjan T. , Haas Felix , Miedema Frank , Tesselaar Kiki , Jansen Nicolaas J. G. , Borghans José A. M.
Published: June 2011

Thymectomy during early childhood is generally thought to have serious consequences for the establishment of the T-cell compartment. In the present study, we investigated the composition of the T-cell pool in the first 3 decades after thymectomy during infancy due to cardiac surgery. In the first 5 years after thymectomy, naive and total CD4+ and CD8+ T-cell numbers in the blood and T-cell receptor excision circle (TREC) levels in CD4+ T cells were significantly lower than in healthy age-matched controls. In the first years after thymectomy, plasma IL-7 levels were significantly elevated and peripheral T-cell proliferation levels were increased by ∼ 2-fold. From 5 years after thymectomy onward, naive CD4+ and CD8+ T-cell counts and TRECs were within the normal range. Because TREC levels are expected to decline continuously in the absence of thymic output, we investigated whether normalization of the naive T-cell pool could be due to regeneration of thymic tissue. In the majority of individuals who had been thymectomized during infancy, thymic tissue could indeed be identified on magnetic resonance imaging scans. Whereas thymectomy has severe effects on the establishment of the naive T-cell compartment during early childhood, our data suggest that functional regrowth of thymic tissue can limit its effects in subsequent years.
Pulmonary alveolar proteinosis
Authors: Borie R. , Danel C. , Debray M-P. , Taille C. , Dombret M-C. , Aubier M. , Epaud R. , Crestani B.
Published: June 2011

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disease characterised by alveolar accumulation of surfactant. It may result from mutations in surfactant proteins or granulocyte macrophage-colony stimulating factor (GM-CSF) receptor genes, it may be secondary to toxic inhalation or haematological disorders, or it may be auto-immune, with anti-GM-CSF antibodies blocking activation of alveolar macrophages. Auto-immune alveolar proteinosis is the most frequent form of PAP, representing 90% of cases. Although not specific, high-resolution computed tomography shows a characteristic “crazy paving” pattern. In most cases, bronchoalveolar lavage findings establish the diagnosis. Whole lung lavage is the most effective therapy, especially for auto-immune disease. Novel therapies targeting alveolar macrophages (recombinant GM-CSF therapy) or anti-GM-CSF antibodies (rituximab and plasmapheresis) are being investigated. Our knowledge of the pathophysiology of PAP has improved in the past 20 yrs, but therapy for PAP still needs improvement.
Immunohistochemical localization of mu opioid receptor in the marginal division with comparison to patches in the neostriatum of the rat brain
Authors: Wang Chuanxing , Shu Si Yun , Guo Zhouyi , Cai Ye Feng , Bao Xinmin , Zeng Changchun , Wu Bingyi , Hu Ziyou , Liu Xuemei
Published: June 2011

Background

Mu opioid receptor (MOR), which plays key roles in analgesia and also has effects on learning and memory, was reported to distribute abundantly in the patches of the neostriatum. The marginal division (MrD) of the neostriatum, which located at the caudomedial border of the neostriatum, was found to stain for enkephalin and substance P immunoreactivities and this region was found to be involved in learning and memory in our previous study. However, whether MOR also exists in the MrD has not yet been determined.

Methods

In this study, we used western blot analysis and immunoperoxidase histochemical methods with glucose oxidase-DAB-nickel staining to investigate the expression of MOR in the MrD by comparison to the patches in the neostriatum.

Results

The results from western blot analyses revealed that the antibody to MOR detected a 53 kDa protein band, which corresponded directly to the molecular weight of MOR. Immunohistochemical results showed that punctate MOR-immunoreacted fibers were observed in the "patch" areas in the rostrodorsal part of the neostriatum but these previous studies showed neither labelled neuronal cell bodies, nor were they shown in the caudal part of the neostriatum. Dorsoventrally oriented dark MOR-immunoreactive nerve fibers with individual labelled fusiform cell bodies were firstly observed in the band at the caudomedial border, the MrD, of the neostriatum. The location of the MOR-immunoreactivity was in the caudomedial border of the neostriatum. The morphology of the labelled fusiform neuronal somatas and the dorsoventrally oriented MOR-immunoreacted fibers in the MrD was distinct from the punctate MOR-immunoreactive diffuse mosaic-patterned patches in the neostriatum.

Conclusions

The results indicated that MOR was expressed in the MrD as well as in patches in the neostriatum of the rat brain, but with different morphological characteristics. The punctate MOR-immunoreactive and diffuse mosaic-patterned patches were located in the rostrodorsal part of the neostriatum. By contrast, in the MrD, the dorsoventrally parallel oriented MOR-immunoreactive fibers with individual labelled fusiform neuronal somatas were densely packed in the caudomedial border of the neostriatum. The morphological difference in MOR immunoreactivity between the MrD and the patches indicated potential functional differences between them. The MOR most likely plays a role in learning and memory associated functions of the MrD.
The nuclear envelope localization of DYT1 dystonia torsinA-ΔE requires the SUN1 LINC complex component
Authors: Jungwirth Michael T , Kumar Dhivya , Jeong Danielle Y , Goodchild Rose E
Published: June 2011

Background

DYT1 dystonia is an autosomal dominant neurological condition caused by a mutation that removes a single glutamic acid residue (ΔE) from the torsinA (torA) AAA+ protein. TorA appears to possess a nuclear envelope (NE) localized activity that requires Lamina-Associated-Polypeptide 1 (LAP1), which is an inner nuclear membrane localized torA-binding partner. Although hypoactive, the DYT1 dystonia torA-ΔE isoform often concentrates in the NE, suggesting that torA-ΔE also interacts with an NE-localized binding partner.

Results

We confirm that NE-localized torA-ΔE does not co-immunoprecipitate with LAP1, and find that torA-ΔE continues to concentrate in the NE of cells that lack LAP1. Instead, we find that variability in torA-ΔE localization correlates with the presence of the SUN-domain and Nesprin proteins that assemble into the LINC complex. We also find that siRNA depletion of SUN1, but not other LINC complex components, removes torA-ΔE from the NE. In contrast, the LAP1-dependent NE-accumulation of an ATP-locked torA mutant is unaffected by loss of LINC complex proteins. This SUN1 dependent torA-ΔE localization requires the torA membrane association domain, as well as a putative substrate-interaction residue, Y147, neither of which are required for torA interaction with LAP1. We also find that mutation of these motifs, or depletion of SUN1, decreases the amount of torA-WT that colocalizes with NE markers, indicating that each also underlies a normal NE-localized torA binding interaction.

Conclusions

These data suggest that the disease causing ΔE mutation promotes an association between torA and SUN1 that is distinct to the interaction between LAP1 and ATP-bound torA. This evidence for two NE-localized binding partners suggests that torA may act on multiple substrates and/or possesses regulatory co-factor partners. In addition, finding that the DYT1 mutation causes abnormal association with SUN1 implicates LINC complex dysfunction in DYT1 dystonia pathogenesis, and suggests a gain-of-function activity contributes to this dominantly inherited disease.
A study on the immunological basis of the dissociation between type I-hypersensitivity skin reactions to Blomia tropicalis antigens and serum anti-B. tropicalis IgE antibodies
Authors: Ponte João CM , Junqueira Samuel B , Veiga Rafael V , Barreto Mauricio L , Pontes-de-Carvalho Lain C , Alcântara-Neves Neuza M
Published: June 2011

Background

Two conditions are used as markers of atopy: the presence of circulating anti-allergen IgE antibodies and the presence of positive skin prick test (SPT) reactions to allergenic extracts. The correlation between these conditions is not absolute. This study aimed at investigating immunological parameters that may mediate this lack of correlation. Individuals whose sera contained anti-B. tropicalis extract IgE antibodies (α-Bt E IgE) were divided into two groups, according to the presence or absence of skin reactivity to B. tropicalis extract (Bt E). The following parameters were investigated: total IgE levels; α-Bt E IgE levels; an arbitrary α-Bt E IgE/total IgE ratio; the proportion of carbohydrate-reactive α-Bt E IgE; the proportion of α-Bt E IgE that reacted with Ascaris lumbricoides extract (Al E); the production of IL-10 by Bt E- and Al E-stimulated peripheral blood cells (PBMC).

Results

Total IgE levels were similar in the two groups, but α-Bt E IgE was significantly higher in the SPT-positive group (SPT+). A large overlap of α-Bt E IgE levels was found in individuals of both groups, indicating that these levels alone cannot account for the differences in SPT outcome. Individuals of the two groups did not differ, statistically, in the proportion of α-Bt E IgE that reacted with carbohydrate and in the production of IL-10 by Bt E- and Al E-stimulated PBMC. Both groups had part of α-Bt E IgE activity absorbed out by Al E, indicating the existence of cross-reactive IgE antibodies. However, the α-Bt E IgE from the SPT-negative individuals (SPT-) was more absorbed with AlE than the α-Bt E IgE from the SPT+ individuals. This finding may be ascribed to avidity differences of the α-Bt E IgE that is present in the two groups of individuals, and could occur if at least part of the α-Bt E IgE from the SPT- individuals were elicited by A. lumbricoides infection.

Conclusion

The present results suggest that a low ratio of specific IgE to total IgE levels (in a minority of individuals), and differences in α-Bt E IgE avidities (which would have high affinities for A. lumbricoides antigens in SPT- than in SPT+ individuals) may play a role in the down-modulation of type-I hypersensitivity reaction against aeroallergens described in helminth-infected individuals.
Evaluation of medical student self-rated preparedness to care for limited english proficiency patients
Authors: Rodriguez Fatima , Cohen Amy , Betancourt Joseph R , Green Alexander R
Published: June 2011

Background

Patients with limited English proficiency (LEP) represent a growing proportion of the US population and are at risk of receiving suboptimal care due to difficulty communicating with healthcare providers who do not speak their language. Medical school curricula are required to prepare students to care for all patients, including those with LEP, but little is known about how well they achieve this goal. We used data from a survey of medical students' cross-cultural preparedness, skills, and training to specifically explore their self-rated preparedness to care for LEP patients.

Methods

We electronically surveyed students at one northeastern US medical school. We used bivariate analyses to identify factors associated with student self-rated preparedness to care for LEP patients including gender, training year, first language, race/ethnicity, percent LEP and minority patients seen, and skill with interpreters. We used multivariate logistic regression to examine the independent effect of each factor on LEP preparedness. In a secondary analysis, we explored the association between year in medical school and self-perceived skill level in working with an interpreter.

Results

Of 651 students, 416 completed questionnaires (63.9% response rate). Twenty percent of medical students reported being very well or well-prepared to care for LEP patients. Of these, 40% were in their fourth year of training. Skill level working with interpreters, prevalence of LEP patients seen, and training year were correlated (p < 0.001) with LEP preparedness. Using multivariate logistic regression, only student race/ethnicity and self-rated skill with interpreters remained statistically significant. Students in third and fourth years were more likely to feel skilled with interpreters (p < 0.001).

Conclusions

Increasingly, medical students will need to be prepared to care for LEP patients. Our study supports two strategies to improve student preparedness: training students to work effectively with interpreters and increasing student diversity to better reflect the changing US demographics.
Are Australian immigrants at a risk of being physically inactive?
Authors: Dassanayake Jayantha , Dharmage Shyamali C , Gurrin Lyle , Sundararajan Vijaya , Payne Warren R
Published: June 2011

Background

We examined whether physical activity risk differed between migrant sub-groups and the Australian-born population.

Methods

Data were drawn from the Australian National Health Survey (2001) and each resident's country of birth was classified into one of 13 regions. Data were gathered on each resident's physical activity level in the fortnight preceding the survey. Multivariable logistic regression, adjusted for potential confounders examined the risk of physical inactivity of participants from each of the 13 regions compared to the Australian-born population.

Results

There was a greater prevalence of physical inactivity for female immigrants from most regions compared to male immigrants from a like region. Immigrants from South East Asia (OR 2.04% 95% CI 1.63, 2.56), Other Asia (OR 1.53 95% CI 1.10, 2.13), Other Oceania (1.81 95% CI 1.11, 2.95), the Middle East (OR 1.42 95% CI 0.97, 2.06 [note: border line significance]) and Southern & Eastern Europe are at a significantly higher risk of being physically inactive compared to those born in Australian. In contrast, immigrants from New Zealand (OR 0.77 95% CI 0.62, 0.94), the UK & Ireland (OR 0.82 95% CI 0.73, 0.92), and other Africa (OR 0.69 95% CI 0.51, 0.94) are at a significantly lower risk of being physically inactive compared to the Australian born population.

Conclusion

Future research identifying potential barriers and facilitators to participation in physical activity will inform culturally sensitive physical activity programs that aim to encourage members of specific regional ethnic sub-groups to undertake physical activity.
Tuning photoluminescence of organic rubrene nanoparticles through a hydrothermal process
Authors: Kim Mi Suk , Cho Eun Hei , Park Dong Hyuk , Jung Hyunjung , Bang Joona , Joo Jinsoo
Published: June 2011

Light-emitting 5,6,11,12-tetraphenylnaphthacene (rubrene) nanoparticles (NPs) prepared by a reprecipitation method were treated hydrothermally. The diameters of hydrothermally treated rubrene NPs were changed from 100 nm to 2 μm, depending on hydrothermal temperature. Photoluminescence (PL) characteristics of rubrene NPs varied with hydrothermal temperatures. Luminescence of pristine rubrene NPs was yellow-orange, and it changed to blue as the hydrothermal temperature increased to 180°C. The light-emitting color distribution of the NPs was confirmed using confocal laser spectrum microscope. As the hydrothermal temperature increased from 110°C to 160°C, the blue light emission at 464 to approximately 516 nm from filtered-down NPs was enhanced by H-type aggregation. Filtered-up rubrene NPs treated at 170°C and 180°C exhibited blue luminescence due to the decrease of intermolecular excimer densities with the rapid increase in size. Variations in PL of hydrothermally treated rubrene NPs resulted from different size distributions of the NPs.
Polymer-stabilized palladium nanoparticles for catalytic membranes: ad hoc polymer fabrication
Authors: Domènech Berta , Muñoz Maria , Muraviev Dmitri N , Macanás Jorge
Published: June 2011

Metal nanoparticles are known as highly effective catalysts although their immobilization on solid supports is frequently required to prevent aggregation and to facilitate the catalyst application, recovery, and reuse. This paper reports the intermatrix synthesis of Pd0 nanoparticles in sulfonated polyethersulfone with Cardo group membranes and their use as nanocomposite catalytic membrane reactors. The synthesized polymer and the corresponding nanocomposite were characterized by spectroscopic and microscopic techniques. The catalytic efficiency of catalytic membranes was evaluated by following the reduction of p-nitrophenol in the presence of NaBH4.
Establishment of real-time quantitative reverse transcription polymerase chain reaction assay for transcriptional analysis of duck enteritis virus UL55 gene
Authors: Wu Ying , Cheng Anchun , Wang Mingshu , Zhang Shunchuan , Zhu Dekang , Jia Renyong , Luo Qihui , Chen Zhengli , Chen Xiaoyue
Published: June 2011

Background

Real-time quantitative reverse transcription polymerase chain reaction assay (qRT-PCR) has become the benchmark for detection and quantification of target gene expression level and been utilized increasingly in detection of viral load and therapy monitoring. The dynamic transcription variation of duck enteritis virus UL55 gene during the life cycle of duck enteritis virus in infected cells has not been reported yet.

Results

The newly identified duck enteritis virus UL55 gene was amplified and cloned into pMD18-T vector after digestion to generate a recombinant plasmid pMD18-T/UL55 for the establishment of qRT-PCR as standard DNA. The results of agarose gel electrophoresis and melting curve analysis demonstrated the primers we designed for qRT-PCR were specific and available. We used β-actin as a reference gene for normalization and established two standard curves based on pMD18-T/UL55 and pMD18-T/β-actin successfully. Based on that, the transcriptional analysis of DEV UL55 gene was performed, and the result suggested the expression of UL55 mRNA was at a low level from 0 to 8 h post-infection(p.i.), then accumulated quickly since 12 h p.i. and peaked at 36 h p.i., it can be detected till 60 h p.i.. Nucleic acid inhibition test was carried out for analyzing a temporal regulation condition of DEV UL55 gene, result revealed that it was sensitive to ganciclovir. Synthesis procedures of DEV UL55 gene can be inhibited by ganciclovir.

Conclusions

The method we established in this paper can provide quantitative values reflecting the amounts of measured mRNA in samples. It's available for detection and quantification, also can be used in DEV diagnosis. The DEV UL55 gene was produced most abundantly during the late phase of replication in DEV-infected cells and the transcription of it depended on the synthesized DNA. DEV UL55 gene is a γ2 gene which occurs last and have a strict requirement for viral DNA synthesis.
Can Genetics and Genomics Nursing Competencies Be Successfully Taught in a Prenursing Microbiology Course?
Authors: Shuster Michèle
Published: June 2011

In recognition of the entry into the era of personalized medicine, a new set of genetics and genomics competencies for nurses was introduced in 2006. Since then, there have been a number of reports about the critical importance of these competencies for nursing practices and about the challenges of addressing these competencies in the preservice (basic science) nursing curriculum. At least one suggestion has been made to infuse genetics and genomics throughout the basic science curriculum for prenursing students. Based on this call and a review of the competencies, this study sought to assess the impact of incorporation of genetics and genomics content into a prenursing microbiology course. Broadly, two areas that address the competencies were incorporated into the course: 1) the biological basis and implications of genetic diversity and 2) the technological aspects of assessing genetic diversity in bacteria and viruses. These areas address how genetics and genomics contribute to healthcare, including diagnostics and selection of treatment. Analysis of learning gains suggests that genetics and genomics content can be learned as effectively as microbiology content in this setting. Future studies are needed to explore the most effective ways to introduce genetics and genomics technology into the prenursing curriculum.
Increased Course Structure Improves Performance in Introductory Biology
Authors: Freeman Scott , Haak David , Wenderoth Mary Pat
Published: June 2011

We tested the hypothesis that highly structured course designs, which implement reading quizzes and/or extensive in-class active-learning activities and weekly practice exams, can lower failure rates in an introductory biology course for majors, compared with low-structure course designs that are based on lecturing and a few high-risk assessments. We controlled for 1) instructor effects by analyzing data from quarters when the same instructor taught the course, 2) exam equivalence with new assessments called the Weighted Bloom's Index and Predicted Exam Score, and 3) student equivalence using a regression-based Predicted Grade. We also tested the hypothesis that points from reading quizzes, clicker questions, and other “practice” assessments in highly structured courses inflate grades and confound comparisons with low-structure course designs. We found no evidence that points from active-learning exercises inflate grades or reduce the impact of exams on final grades. When we controlled for variation in student ability, failure rates were lower in a moderately structured course design and were dramatically lower in a highly structured course design. This result supports the hypothesis that active-learning exercises can make students more skilled learners and help bridge the gap between poorly prepared students and their better-prepared peers.
How Well Do Undergraduate Research Programs Promote Engagement and Success of Students?
Authors: Fechheimer Marcus , Webber Karen , Kleiber Pamela B.
Published: June 2011

Assessment of undergraduate research (UR) programs using participant surveys has produced a wealth of information about design, implementation, and perceived benefits of UR programs. However, measurement of student participation university wide, and the potential contribution of research experience to student success, also require the study of extrinsic measures. In this essay, institutional data on student credit-hour generation and grade point average (GPA) from the University of Georgia are used to approach these questions. Institutional data provide a measure of annual enrollment in UR classes in diverse disciplines. This operational definition allows accurate and retrospective analysis, but does not measure all modes of engagement in UR. Cumulative GPA is proposed as a quantitative extrinsic measure of student success. Initial results show that extended participation in research for more than a single semester is correlated with an increase in GPA, even after using SAT to control for the initial ability level of the students. While the authors acknowledge that correlation does not prove causality, continued efforts to measure the impact of UR programs on student outcomes using GPA or an alternate extrinsic measure is needed for development of evidence-based programmatic recommendations.
Teaching Students How to Study: A Workshop on Information Processing and Self-Testing Helps Students Learn
Authors: Stanger-Hall Kathrin F. , Shockley Floyd W. , Wilson Rachel E.
Published: June 2011

We implemented a “how to study” workshop for small groups of students (6–12) for N = 93 consenting students, randomly assigned from a large introductory biology class. The goal of this workshop was to teach students self-regulating techniques with visualization-based exercises as a foundation for learning and critical thinking in two areas: information processing and self-testing. During the workshop, students worked individually or in groups and received immediate feedback on their progress. Here, we describe two individual workshop exercises, report their immediate results, describe students’ reactions (based on the workshop instructors’ experience and student feedback), and report student performance on workshop-related questions on the final exam. Students rated the workshop activities highly and performed significantly better on workshop-related final exam questions than the control groups. This was the case for both lower- and higher-order thinking questions. Student achievement (i.e., grade point average) was significantly correlated with overall final exam performance but not with workshop outcomes. This long-term (10 wk) retention of a self-testing effect across question levels and student achievement is a promising endorsement for future large-scale implementation and further evaluation of this “how to study” workshop as a study support for introductory biology (and other science) students.
The historical milestones in the understanding of leukocyte biology initiated by Elie Metchnikoff
Authors: Cavaillon Jean-Marc
Published: June 2011

Progress in science is made with key discoveries, correct analyses, wrong statements, and disputes within the scientific community. Despite scientific controversies, Elie Metchnikoff has allowed the theory of phagocytes to triumph. Starting his career as a zoologist, Metchnikoff became a pathologist, beautifully defining the role of monocytes, macrophages, and neutrophils during inflammation and innate immunity. The discoveries of immune cells were made by other outstandings scientists, such as Paul Ehrlich, whose key contributions to humoral immunity led him to share the Nobel Prize with Metchnikoff. Ludwig Aschoff grouped certain cells under the term RES, according to their propensity for absorbing and storing vital stains. This classification was not always a source of accurate discoveries, and research on the exact function of RES cells led to some wanderings. This is illustrated by studies about the nature of the antibody-producing cells, which were first thought to belong to the RES, before being identified as plasmocytes and lymphocytes.
Gene expression analysis of dendritic cells that prevent diabetes in NOD mice: analysis of chemokines and costimulatory molecules
Authors: Morel Penelope A , Srinivas Mangala , Turner Michael S , Fuschiotti Patrizia , Munshi Rajan , Bahar Ivet , Feili-Hariri Maryam , Ahrens Eric T
Published: June 2011

We have demonstrated previously that BM-derived DCs can prevent diabetes development and halt progression of insulitis in NOD mice, the mouse model of type 1 diabetes. The DC population that was most effective in this therapy had a mature phenotype, expressed high levels of costimulatory molecules, and secreted low levels of IL-12p70. The protective DC therapy induced Treg and Th2 cells in vitro and in vivo. Microarray analysis of therapeutic and nontherapeutic DC populations revealed differences in the expression of OX40L, CD200, Ym-1, CCL2, and CCL5, which could play important roles in the observed DC-mediated therapy. The unique pattern of costimulatory molecules and chemokines expressed by the therapeutic DCs was confirmed by flow cytometry and ELISA. Using a novel cell-labeling and 19F NMR, we observed that the chemokines secreted by the therapeutic DCs altered the migration of diabetogenic Th1 cells in vivo and attracted Th2 cells. These results suggest that the therapeutic function of DCs is mediated by a combination of costimulatory and chemokine properties that results in the attraction of diabetogenic Th1 and the induction of Th2 and/or Treg differentiation.
Beta-Blocker Use Is Associated With Improved Relapse-Free Survival in Patients With Triple-Negative Breast Cancer
Authors: Melhem-Bertrandt Amal , Chavez-MacGregor Mariana , Lei Xiudong , Brown Erika N. , Lee Richard T. , Meric-Bernstam Funda , Sood Anil K. , Conzen Suzanne D. , Hortobagyi Gabriel N. , Gonzalez-Angulo Ana-Maria
Published: June 2011

Purpose

To examine the association between beta-blocker (BB) intake, pathologic complete response (pCR) rates, and survival outcomes in patients with breast cancer treated with neoadjuvant chemotherapy.

Patients and Methods

We retrospectively reviewed 1,413 patients with breast cancer who received neoadjuvant chemotherapy between 1995 and 2007. Patients taking BBs at the start of neoadjuvant therapy were compared with patients with no BB intake. Rates of pCR between the groups were compared using a χ2 test. Cox proportional hazards models were fitted to determine the association between BB intake, relapse-free survival (RFS), and overall survival (OS).

Results

Patients who used BBs (n = 102) were compared with patients (n = 1,311) who did not. Patients receiving BBs tended to be older and obese (P < .001). The proportion of pCR was not significantly different between the groups (P = .48). After adjustment for age, race, stage, grade, receptor status, lymphovascular invasion, body mass index, diabetes, hypertension, and angiotensin-converting enzyme inhibitor use, BB intake was associated with a significantly better RFS (hazard ratio [HR], 0.52; 95% CI, 0.31 to 0.88) but not OS (P = .09). Among patients with triple-negative breast cancer (TNBC; n = 377), BB intake was associated with improved RFS (HR, 0.30; 95% CI, 0.10 to 0.87;P = .027) but not OS (HR, 0.35; 95% CI, 0.12 to 1.00;P = .05).

Conclusion

In this study, BB intake was associated with improved RFS in all patients with breast cancer and in patients with TNBC. Additional studies evaluating the potential benefits of beta-adrenergic blockade on breast cancer recurrence with a focus on TNBC are warranted.
Decreased IGF Type 1 Receptor Signaling in Mammary Epithelium during Pregnancy Leads to Reduced Proliferation, Alveolar Differentiation, and Expression of Insulin Receptor Substrate (IRS)-1 and IRS-2
Authors: Sun Zhaoyu , Shushanov Sain , LeRoith Derek , Wood Teresa L.
Published: June 2011

The IGFs and the IGF type 1 receptor (IGF-1R) are essential mediators of normal mammary gland development in mice. IGF-I and the IGF-1R have demonstrated functions in formation and proliferation of terminal end buds and in ductal outgrowth and branching during puberty. To study the functions of IGF-1R during pregnancy and lactation, we established transgenic mouse lines expressing a human dominant-negative kinase dead IGF-1R (dnhIGF-1R) under the control of the whey acidic protein promoter. We provide evidence that the IGF-1R pathway is necessary for normal epithelial proliferation and alveolar formation during pregnancy. Furthermore, we demonstrate that the whey acidic protein-dnhIGF-1R transgene causes a delay in alveolar differentiation including lipid droplet formation, lumen expansion, and β-casein protein expression. Analysis of IGF-1R signaling pathways showed a decrease in P-IGF-1R and P-Akt resulting from expression of the dnhIGF-1R. We further demonstrate that disruption of the IGF-1R decreases mammary epithelial cell expression of the signaling intermediates insulin receptor substrate (IRS)-1 and IRS-2. No alterations were observed in downstream signaling targets of prolactin and progesterone, suggesting that activation of the IGF-1R may directly regulate expression of IRS-1/2 during alveolar development and differentiation. These data show that IGF-1R signaling is necessary for normal alveolar proliferation and differentiation, in part, through induction of signaling intermediates that mediate alveolar development.
STX, a Novel Nonsteroidal Estrogenic Compound, Induces Rapid Action in Primate GnRH Neuronal Calcium Dynamics and Peptide Release
Authors: Kenealy B. P. , Keen K. L. , Rønnekleiv O. K. , Terasawa E.
Published: June 2011

Previously, we reported that 1 nm 17ß-estradiol (E2) induces a rapid action, which is, in part, mediated through the G protein-coupled receptor GPR30 in primate GnRH neurons. Because it has been reported that the diphenylacrylamide compound, STX, causes estrogenic action in the mouse and guinea pig hypothalamus, the present study examined effects of STX in primate GnRH neurons and whether there is an action independent of GPR30. Results are summarized as follows. STX (10 nm) exposure increased 1) the oscillation frequency of intracellular calcium concentration ([Ca2+]i), 2) the percentage of cells stimulated, and 3) the synchronization frequency of [Ca2+]i oscillations. STX (10–100 nm) also stimulated GnRH release. The effects of STX on both [Ca2+]i oscillations and GnRH release were similar to those caused by E2 (1 nm), although with less magnitude. STX (10 nm)-induced changes in [Ca2+]i oscillations were not altered by GPR30 small interfering RNA transfection, indicating that STX-sensitive receptors differ from GPR30. Finally, a higher dose of E2 (10 nm) induced a larger change in [Ca2+]i oscillations than that with a smaller dose of E2 (1 nm), and the effects of 10 nm E2 were reduced but not completely blocked by GPR30 small interfering RNA transfection, indicating that the effects of 10 nm E2 in primate GnRH neurons are mediated by multiple membrane receptors, including GPR30 and STX-sensitive receptors. Collectively, the rapid action of E2 mediated through GPR30 differs from that mediated through STX-sensitive receptors. The molecular structure of the STX-sensitive receptor remains to be identified.
Type-2 Iodothyronine 5′Deiodinase in Skeletal Muscle of C57Bl/6 Mice. I. Identity, Subcellular Localization, and Characterization
Authors: Ramadan W. , Marsili A. , Huang S. , Larsen P. R. , Silva J. E.
Published: June 2011

RT-PCR shows that mouse skeletal muscle contains type-2 iodothyronine deiodinase (D2) mRNA. However, the D2 activity has been hard to measure. Except for newborn mice, muscle homogenates have no detectable activity. However, we have reported D2 activity in mouse muscle microsomes. As the mRNA, activity is higher in slow- than in fast-twitch muscle. We addressed here the major problems in measuring D2 activity in muscle by: homogenizing muscle in high salt to improve yield of membranous structures; separating postmitochondrial supernatant between 38 and 50% sucrose, to eliminate lighter membranes lacking D2; washing these with 0.1 m Na2CO3 to eliminate additional contaminating proteins; pretreating all buffers with Chelex, to eliminate catalytic metals; and eliminating the EDTA from the assay, as this can bind iron that enhances dithiothreitol oxidation and promotes peroxidation reactions. Maximum velocity of T3 generation by postgradient microsomes from red muscles was approximately 1100 fmol/(h · mg) protein with a Michaelis-Menten constant for T4 of 1.5 nm. D2-specific activity of Na2CO3-washed microsomes was 6–10 times higher. The enrichment in D2 activity increased in parallel with the capacity of microsomes to load (sarco/endoplasmic reticulum Ca2+-ATPase) and bind Ca2+ (calsequestrin), indicating that D2 resides in the inner sarcoplasmic reticulum, close to the nuclei. The presence of D3 in the sarcolemma suggests that the most of D2-generated T3 acts locally. Estimates from maximum velocity, Michaelis-Menten constant, and muscle T4 content suggest that mouse red, type-1, aerobic mouse muscle fibers can generate physiologically relevant amounts of T3 and, further, that muscle D2 plays an important role in thyroid hormone-dependent muscle thermogenesis.
Nutrition and Modernity
Authors: Aguilar-Rodríguez Sandra
Published: June 2011

This article explores the rhetoric of milk in Mexico considering medical discourses, publicity campaigns, state programs, and women's experiences. I look at the difference in milk consumption across class and the lack of regulation in milk production and sale in 1940s and 1950s Mexico. I analyze the discourse of doctors and policy makers who worked at the Institute of National Nutrition (INN) and the Secretaría de Salubridad y Asistencia (Ministry of Public Health and Assistance; SSA). I explore the main programs through which powdered milk was distributed among Mexico's working classes. Finally, I present women's perceptions regarding fresh and powdered milk. At home, women had a key role in introducing milk to their family diet, as they were in charge of buying groceries and cooking daily meals. In the public sphere, women working as teachers, nurses, and social workers implemented state food programs promoting milk drinking. In order to provide a clearer picture, this work draws from a variety of sources such as archives, cookbooks, women's magazines, censuses, and life history interviews.

This research reveals that there was little criticism of the spread of powdered milk, as the international consensus established that milk was essential for children's development and for the health and progress of a nation. Even if INN reports show that some doctors realized that traditional foodstuffs such as insects were rich in animal protein, the hegemonic discourse was moving in the opposite direction. Insects and other foodstuffs were identified with indigenous peoples and were seen as the source of their “backwardness.” Milk had not only a nutritional value but also a symbolic meaning that in the long run proved to be more appealing. If Mexico wanted to be modern, its citizens had to change their eating habits and follow European and U.S. standards.
Memories of Mothers in the Kitchen
Authors: Deutsch Tracey
Published: June 2011

This article surveys the popular discourse around local foods and sustainable eating programs, exploring the widely circulated premise that women's demands for convenience have allowed for the triumph of supermarkets and processed foods over traditional, more labor intensive ways of provisioning. This article counters that demand did not drive mass retail, that work was not always saved by shopping at supermarkets or buying premade foods and that provisioning remained an ongoing, and sometimes frustrating, negotiation through the twentieth century. This new work on local foods comes from the Cold War notion that female consumers' desires drive change, and that consumer society in general is fundamentally apolitical, operating best when it operates outside the realm of the state. Ultimately, I argue that neoliberal markets, conventional gender systems, and a misunderstanding of women's history are central to many proposed solutions to food problems. This alternative history of consumption points to the ways politics has always been part of shopping, and that a truly new food system will need to unseat the structures of family life, gender systems, and labor in which food provisioning is embedded.
The non-receptor tyrosine kinase Lyn controls neutrophil adhesion by recruiting the CrkL–C3G complex and activating Rap1 at the leading edge
Authors: He Yuan , Kapoor Ashish , Cook Sara , Liu Shubai , Xiang Yang , Rao Christopher V. , Kenis Paul J. A. , Wang Fei
Published: June 2011

Establishing new adhesions at the extended leading edges of motile cells is essential for stable polarity and persistent motility. Despite recent identification of signaling pathways that mediate polarity and chemotaxis in neutrophils, little is known about molecular mechanisms governing cell–extracellular-matrix (ECM) adhesion in these highly polarized and rapidly migrating cells. Here, we describe a signaling pathway in neutrophils that is essential for localized integrin activation, leading edge attachment and persistent migration during chemotaxis. This pathway depends upon Gi-protein-mediated activation and leading edge recruitment of Lyn, a non-receptor tyrosine kinase belonging to the Src kinase family. We identified the small GTPase Rap1 as a major downstream effector of Lyn to regulate neutrophil adhesion during chemotaxis. Depletion of Lyn in neutrophil-like HL-60 cells prevented chemoattractant-induced Rap1 activation at the leading edge of the cell, whereas ectopic expression of Rap1 largely rescued the defects induced by Lyn depletion. Furthermore, Lyn controls spatial activation of Rap1 by recruiting the CrkL–C3G protein complex to the leading edge. Together, these results provide novel mechanistic insights into the poorly understood signaling network that controls leading edge adhesion during chemotaxis of neutrophils, and possibly other amoeboid cells.
Nuclear Chk1 prevents premature mitotic entry
Authors: Matsuyama Makoto , Goto Hidemasa , Kasahara Kousuke , Kawakami Yoshitaka , Nakanishi Makoto , Kiyono Tohru , Goshima Naoki , Inagaki Masaki
Published: June 2011

Chk1 inhibits the premature activation of the cyclin-B1–Cdk1. However, it remains controversial whether Chk1 inhibits Cdk1 in the centrosome or in the nucleus before the G2–M transition. In this study, we examined the specificity of the mouse monoclonal anti-Chk1 antibody DCS-310, with which the centrosome was stained. Conditional Chk1 knockout in mouse embryonic fibroblasts reduced nuclear but not centrosomal staining with DCS-310. In Chk1+/myc human colon adenocarcinoma (DLD-1) cells, Chk1 was detected in the nucleus but not in the centrosome using an anti-Myc antibody. Through the combination of protein array and RNAi technologies, we identified Ccdc-151 as a protein that crossreacted with DCS-310 on the centrosome. Mitotic entry was delayed by expression of the Chk1 mutant that localized in the nucleus, although forced immobilization of Chk1 to the centrosome had little impact on the timing of mitotic entry. These results suggest that nuclear but not centrosomal Chk1 contributes to correct timing of mitotic entry.
Forecasting Gasoline Prices Using Consumer Surveys
Authors: Anderson Soren T , Kellogg Ryan , Sallee James M , Curtin Richard T
Published: June 2011

This paper analyzes the predictive power of a new data set of consumer gasoline price forecasts taken from the Michigan Survey of Consumers (MSC). MSC data generally perform as well as a no-change forecast in predicting future gasoline prices, and they substantially out-perform the no-change forecast during the recent economic crisis, during which time they track futures market prices. Finally, the cross-respondent dispersion of the MSC forecasts increases substantially during the economic crisis, paralleling the large increase in price volatility at this time.
Credit Ratings Accuracy and Analyst Incentives
Authors: Bar-Isaac Heski , Shapiro Joel
Published: June 2011

The financial crisis has brought a new focus on the accuracy of credit rating agencies (CRAs). In this paper, we highlight the incentives of analysts at the CRAs to provide accurate ratings. We construct a model in which analysts initially work at a CRA and can then either remain or move to a bank. The CRA uses incentive contracts to motivate analysts, but does not capture the benefits if the analyst moves. We find that rating agency accuracy increases with CRA monitoring, bank profitability (a positive “revolving door” effect), and can be non-monotonic in the probability of an analyst leaving.