bluuebunny/crossref_metadata_2025 huggingface dataset:
Site-specific gene correction of a point mutation in human iPS cells derived from an adult patient with sickle cell disease
Authors: Zou Jizhong , Mali Prashant , Huang Xiaosong , Dowey Sarah N. , Cheng Linzhao
Published: September 2011

Human induced pluripotent stem cells (iPSCs) bearing monogenic mutations have great potential for modeling disease phenotypes, screening candidate drugs, and cell replacement therapy provided the underlying disease-causing mutation can be corrected. Here, we report a homologous recombination-based approach to precisely correct the sickle cell disease (SCD) mutation in patient-derived iPSCs with 2 mutated β-globin alleles (βs/βs). Using a gene-targeting plasmid containing a loxP-flanked drug-resistant gene cassette to assist selection of rare targeted clones and zinc finger nucleases engineered to specifically stimulate homologous recombination at the βs locus, we achieved precise conversion of 1 mutated βs to the wild-type βA in SCD iPSCs. However, the resulting co-integration of the selection gene cassette into the first intron suppressed the corrected allele transcription. After Cre recombinase-mediated excision of this loxP-flanked selection gene cassette, we obtained “secondary” gene-corrected βs/βA heterozygous iPSCs that express at 25% to 40% level of the wild-type transcript when differentiated into erythrocytes. These data demonstrate that single nucleotide substitution in the human genome is feasible using human iPSCs. This study also provides a new strategy for gene therapy of monogenic diseases using patient-specific iPSCs, even if the underlying disease-causing mutation is not expressed in iPSCs.
An integrative approach to ortholog prediction for disease-focused and other functional studies
Authors: Hu Yanhui , Flockhart Ian , Vinayagam Arunachalam , Bergwitz Clemens , Berger Bonnie , Perrimon Norbert , Mohr Stephanie E
Published: September 2011

Background

Mapping of orthologous genes among species serves an important role in functional genomics by allowing researchers to develop hypotheses about gene function in one species based on what is known about the functions of orthologs in other species. Several tools for predicting orthologous gene relationships are available. However, these tools can give different results and identification of predicted orthologs is not always straightforward.

Results

We report a simple but effective tool, the
D

rosophila RNAi Screening Center I ntegrative O rtholog P rediction T ool (DIOPT; http://www.flyrnai.org/diopt), for rapid identification of orthologs. DIOPT integrates existing approaches, facilitating rapid identification of orthologs among human, mouse, zebrafish, C. elegans, Drosophila, and S. cerevisiae. As compared to individual tools, DIOPT shows increased sensitivity with only a modest decrease in specificity. Moreover, the flexibility built into the DIOPT graphical user interface allows researchers with different goals to appropriately 'cast a wide net' or limit results to highest confidence predictions. DIOPT also displays protein and domain alignments, including percent amino acid identity, for predicted ortholog pairs. This helps users identify the most appropriate matches among multiple possible orthologs. To facilitate using model organisms for functional analysis of human disease-associated genes, we used DIOPT to predict high-confidence orthologs of disease genes in Online Mendelian Inheritance in Man (OMIM) and genes in genome-wide association study (GWAS) data sets. The results are accessible through the DIOPT diseases and traits query tool (DIOPT-DIST; http://www.flyrnai.org/diopt-dist).

Conclusions

DIOPT and DIOPT-DIST are useful resources for researchers working with model organisms, especially those who are interested in exploiting model organisms such as Drosophila to study the functions of human disease genes.
A fiber-modified adenoviral vector interacts with immunoevasion molecules of the B7 family at the surface of murine leukemia cells derived from dormant tumors
Authors: Grellier Elodie , Lécolle Katia , Rogée Sophie , Couturier Cyril , D'Halluin Jean-Claude , Hong Saw-See , Fender Pascal , Boulanger Pierre , Quesnel Bruno , Colin Morvane
Published: September 2011

Tumor cells can escape the immune system by overexpressing molecules of the B7 family, e.g. B7-H1 (PD-L1 or CD86), which suppresses the anti-tumor T-cell responses through binding to the PD-1 receptor, and similarly for B7.1 (CD80), through binding to CTLA-4. Moreover, direct interactions between B7-H1 and B7.1 molecules are also likely to participate in the immunoevasion mechanism. In this study, we used a mouse model of tumor dormancy, DA1-3b leukemia cells. We previously showed that a minor population of DA1-3b cells persists in equilibrium with the immune system for long periods of time, and that the levels of surface expression of B7-H1 and B7.1 molecules correlates with the dormancy time. We found that leukemia cells DA1-3b/d365 cells, which derived from long-term dormant tumors and overexpressed B7-H1 and B7.1 molecules, were highly permissive to Ad5FB4, a human adenovirus serotype 5 (Ad5) vector pseudotyped with chimeric human-bovine fibers. Both B7-H1 and B7.1 were required for Ad5FB4-cell binding and entry, since (i) siRNA silencing of one or the other B7 gene transcript resulted in a net decrease in the cell binding and Ad5FB4-mediated transduction of DA1-3b/d365; and (ii) plasmid-directed expression of B7.1 and B7-H1 proteins conferred to Ad5FB4-refractory human cells a full permissiveness to this vector. Binding data and flow cytometry analysis suggested that B7.1 and B7-H1 molecules played different roles in Ad5FB4-mediated transduction of DA1-3b/d365, with B7.1 involved in cell attachment of Ad5FB4, and B7-H1 in Ad5FB4 internalization. BRET analysis showed that B7.1 and B7-H1 formed heterodimeric complexes at the cell surface, and that Ad5FB4 penton, the viral capsomere carrying the fiber projection, could negatively interfere with the formation of B7.1/B7-H1 heterodimers, or modify their conformation. As interactors of B7-H1/B7.1 molecules, Ad5FB4 particles and/or their penton capsomeres represent potential therapeutic agents targeting cancer cells that had developed immunoevasion mechanisms.
Mesothelin confers pancreatic cancer cell resistance to TNF-α-induced apoptosis through Akt/PI3K/NF-κB activation and IL-6/Mcl-1 overexpression
Authors: Bharadwaj Uddalak , Marin-Muller Christian , Li Min , Chen Changyi , Yao Qizhi
Published: September 2011

Background

Previous studies showed that mesothelin (MSLN) plays important roles in survival of pancreatic cancer (PC) cells under anchorage dependent/independent conditions as well as resistance to chemotherapy. The recent success of intratumorally-injected adeno-encoded, chemo/radiation-inducible-promoter driven hTNF-α, (TNFerade) + gemcitabine in pre-clinical models of PC have renewed interest in use of TNF-α as a therapeutic component. To help find additional factors which might affect the therapy, we examined the resistance of MSLN-overexpressing pancreatic cancer cell lines to TNF-α-induced growth inhibition/apoptosis.

Methods

Stable MSLN overexpressing MIA PaCa-2 cells (MIA-MSLN), stable MSLN-silenced AsPC-1 cells (AsPC-shMSLN) and other pancreatic cells (MIA-PaCa2, Panc 28, Capan-1, BxPC3, PL 45, Hs 766T, AsPC-1, Capan-2, Panc 48) were used. NF-κB activation was examined by western blots and luciferase reporter assay. TNF-α induced growth inhibition/apoptosis was measured by MTT, TUNEL assay and caspase activation. IL-6 was measured using luminex based assay.

Results

Compared to low endogenous MSLN-expressing MIA PaCa-2 and Panc 28 cells, high endogenous MSLN-expressing Capan-1, BxPC3, PL 45, Hs 766T, AsPC-1, Capan-2, Panc 48 cells were resistant to TNF-α induced growth inhibition. Stable MSLN overexpressing MIA-PaCa2 cells (MIA-MSLN) were resistant to TNF-α-induced apoptosis while stable MSLN-silenced AsPC1 cells (AsPC-shMSLN) were sensitive. Interestingly, TNF-α-treated MIA-MSLN cells showed increased cell cycle progression and cyclin A induction, both of which were reversed by caspase inhibition. We further found that MIA-MSLN cells showed increased expression of anti-apoptotic Bcl-XL and Mcl-1; deactivated (p-Ser75) BAD, and activated (p-Ser70) Bcl-2. Constitutively activated NF-κB and Akt were evident in MIA-MSLN cells that could be suppressed by MSLN siRNA with a resultant increase in sensitivity of TNF-α induced apoptosis. Blocking NF-κB using IKK inhibitor wedelolactone also increased sensitivity to TNF-α-mediated cytotoxicity with concomitant decrease in Mcl-1. Blocking Akt using PI3K inhibitor also had a likewise effect presumably affecting cell cycle. MIA-MSLN cells produced increased IL-6 and were increased furthermore by TNF-α treatment. SiRNA-silencing of IL-6 increased TNF-α sensitivity of MIA-MSLN cells.

Conclusions

Our study delineates a MSLN-Akt-NF-κB-IL-6-Mcl-1 survival axis that may be operative in PC cells, and might help cancer cells' survival in the highly inflammatory milieu evident in PC. Further, for the success of TNFerade + gemcitabine to be successful, we feel the simultaneous inhibition of components of this axis is also essential.
Upregulation of microRNA-125b contributes to leukemogenesis and increases drug resistance in pediatric acute promyelocytic leukemia
Authors: Zhang Hua , Luo Xue-Qun , Feng Dan-Dan , Zhang Xing-Ju , Wu Jun , Zheng Yu-Sheng , Chen Xiao , Xu Ling , Chen Yue-Qin
Published: September 2011

Background

Although current chemotherapy regimens have remarkably improved the cure rate of pediatric acute promyelocytic leukemia (APL) over the past decade, more than 20% of patients still die of the disease, and the 5-year cumulative incidence of relapse is 17%. The precise gene pathways that exert critical control over the determination of cell lineage fate during the development of pediatric APL remain unclear.

Methods

In this study, we analyzed miR-125b expression in 169 pediatric acute myelogenous leukemia (AML) samples including 76 APL samples before therapy and 38 APL samples after therapy. The effects of enforced expression of miR-125b were evaluated in leukemic cell and drug-resistant cell lines.

Results

miR-125b is highly expressed in pediatric APL compared with other subtypes of AML and is correlated with treatment response, as well as relapse of pediatric APL. Our results further demonstrated that miR-125b could promote leukemic cell proliferation and inhibit cell apoptosis by regulating the expression of tumor suppressor BCL2-antagonist/killer 1 (Bak1). Remarkably, miR-125b was also found to be up-regulated in leukemic drug-resistant cells, and transfection of a miR-125b duplex into AML cells can increase their resistance to therapeutic drugs,

Conclusions

These findings strongly indicate that miR-125b plays an important role in the development of pediatric APL at least partially mediated by repressing BAK1 protein expression and could be a potential therapeutic target for treating pediatric APL failure.
Use of an amplatzer vascular plug in embolization of a pulmonary artery aneurysm in a case of hughes-stovin syndrome: a case report
Authors: Tzilalis Vasileios D , Vourliotakis Georgios , Tsironis Ioannis A , Tsiligiris Vasileios D , Brountzos Elias N
Published: September 2011

Introduction

Hughes-Stovin syndrome is a rare condition characterized by peripheral deep venous thrombosis accompanied by single or multiple pulmonary arterial aneurysms. The limited number of cases has precluded controlled studies of the management of pulmonary artery aneurysms, which usually cause massive hemoptysis leading to death. This is the first report of a new endovascular treatment of a single large pulmonary arterial aneurysm.

Case presentation

An 18-year-old Caucasian man was referred to our department with recurrent severe hemoptysis. His medical history included Hughes-Stovin syndrome diagnosed during a recent hospital admission. The patient was initially treated with corticosteroids. Because of his recurrent hemoptysis, we decided to embolize a 3.5 cm pulmonary arterial aneurysm using an Amplatzer Vascular Plug. The procedure was not complicated, and the patient's post-intervention course was uneventful. The patient has remained free from any complications of the embolization 36 months after the procedure.

Conclusion

Percutaneous embolization of a single large pulmonary artery aneurysm with an Amplatzer Vascular Plug in a patient with Hughes-Stovin syndrome is a less invasive procedure that represents the best multidisciplinary approach in treating these patients.
CD23+/CD21hi B-cell translocation and ipsilateral lymph node collapse is associated with asymmetric arthritic flare in TNF-Tg mice
Authors: Li Jie , Zhou Quan , Wood Ronald W , Kuzin Igor , Bottaro Andrea , Ritchlin Christopher T , Xing Lianping , Schwarz Edward M
Published: September 2011

Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune disease with episodic flares in affected joints. However, how arthritic flare occurs only in select joints during a systemic autoimmune disease remains an enigma. To better understand these observations, we developed longitudinal imaging outcomes of synovitis and lymphatic flow in mouse models of RA, and identified that asymmetric knee flare is associated with ipsilateral popliteal lymph node (PLN) collapse and the translocation of CD23+/CD21hi B-cells (B-in) into the paracortical sinus space of the node. In order to understand the relationship between this B-in translocation and lymph drainage from flaring joints, we tested the hypothesis that asymmetric tumor necrosis factor (TNF)-induced knee arthritis is associated with ipsilateral PLN and iliac lymph node (ILN) collapse, B-in translocation, and decreased afferent lymphatic flow.

Methods

TNF transgenic (Tg) mice with asymmetric knee arthritis were identified by contrast-enhanced (CE) magnetic resonance imaging (MRI), and PLN were phenotyped as "expanding" or "collapsed" using LNcap threshold = 30 (Arbitrary Unit (AU)). Inflammatory-erosive arthritis was confirmed by histology. Afferent lymphatic flow to PLN and ILN was quantified by near infrared imaging of injected indocyanine green (NIR-ICG). The B-in population in PLN and ILN was assessed by immunohistochemistry (IHC) and flow cytometry. Linear regression analyses of ipsilateral knee synovial volume and afferent lymphatic flow to PLN and ILN were performed.

Results

Afferent lymph flow to collapsed nodes was significantly lower (P < 0.05) than flow to expanding nodes by NIR-ICG imaging, and this occurred ipsilaterally. While both collapsed and expanding PLN and ILN had a significant increase (P < 0.05) of B-in compared to wild type (WT) and pre-arthritic TNF-Tg nodes, B-in of expanding lymph nodes (LN) resided in follicular areas while B-in of collapsed LN were present within LYVE-1+ lymphatic vessels. A significant correlation (P < 0.002) was noted in afferent lymphatic flow between ipsilateral PLN and ILN during knee synovitis.

Conclusions

Asymmetric knee arthritis in TNF-Tg mice occurs simultaneously with ipsilateral PLN and ILN collapse. This is likely due to translocation of the expanded B-in population to the lumen of the lymphatic vessels, resulting in a dramatic decrease in afferent lymphatic flow. PLN collapse phenotype can serve as a new biomarker of knee flare.
The association between systemic glucocorticoid therapy and the risk of infection in patients with rheumatoid arthritis: systematic review and meta-analyses
Authors: Dixon William G , Suissa Samy , Hudson Marie
Published: September 2011

Introduction

Infection is a major cause of morbidity and mortality in patients with rheumatoid arthritis (RA). The objective of this study was to perform a systematic review and meta-analysis of the effect of glucocorticoid (GC) therapy on the risk of infection in patients with RA.

Methods

A systematic review was conducted by using MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials database to January 2010 to identify studies among populations of patients with RA that reported a comparison of infection incidence between patients treated with GC therapy and patients not exposed to GC therapy.

Results

In total, 21 randomised controlled trials (RCTs) and 42 observational studies were included. In the RCTs, GC therapy was not associated with a risk of infection (relative risk (RR), 0.97 (95% CI, 0.69, 1.36)). Small numbers of events in the RCTs meant that a clinically important increased or decreased risk could not be ruled out. The observational studies generated a RR of 1.67 (1.49, 1.87), although significant heterogeneity was present. The increased risk (and heterogeneity) persisted when analyses were stratified by varying definitions of exposure, outcome, and adjustment for confounders. A positive dose-response effect was seen.

Conclusions

Whereas observational studies suggested an increased risk of infection with GC therapy, RCTs suggested no increased risk. Inconsistent reporting of safety outcomes in the RCTs, as well as marked heterogeneity, probable residual confounding, and publication bias in the observational studies, limits the opportunity for a definitive conclusion. Clinicians should remain vigilant for infection in patients with RA treated with GC therapy.
Constitutive expression of cathepsin K in the human intervertebral disc: new insight into disc extracellular matrix remodeling via cathepsin K and receptor activator of nuclear factor-κB ligand
Authors: Gruber Helen E , Ingram Jane A , Hoelscher Gretchen L , Zinchenko Natalia , Norton H James , Hanley Edward N
Published: September 2011

Introduction

Cathepsin K is a recently discovered cysteine protease which cleaves the triple helical domains of type I to II collagen. It has been shown to be up-regulated in synovial tissue from osteoarthritic and rheumatoid patients, and is a component in normal and nonarthritic cartilage, where it increases with aging. Studies on heart valve development have recently shown that receptor activator of nuclear factor-κB ligand (RANKL) acts during valve remodeling to promote cathepsin K expression. Since extracellular matrix remodeling is a critical component of disc structure and biomechanical function, we hypothesized that cathepsin K and RANKL may be present in the human intervertebral disc.

Methods

Studies were performed following approval of the authors' Human Subjects Institutional Review Board. Six annulus specimens from healthier Thompson grade I to II discs, and 12 specimens from more degenerate grade III to IV discs were utilized in microarray analysis of RANKL and cathepsin K gene expression. Immunohistochemistry was also performed on 15 additional disc specimens to assess the presence of RANKL and cathepsin K.

Results

Cathepsin K gene expression was significantly greater in more degenerated grade III to IV discs compared to healthier grade I to II discs (P = 0.001). RANKL was also identified with immunohistochemistry and molecular analyses. RANKL gene expression was also significantly greater in more degenerated discs compared to healthier ones (P = 0.0001). A significant linear positive correlation was identified between expression of cathepsin K and RANKL (r2 = 92.2; P < 0.0001).

Conclusions

Extracellular matrix remodeling is a key element of disc biology. Our use of an appropriate antibody and gene expression studies showed that cathepsin K is indeed present in the human intervertebral disc. Immunolocalization and molecular analyses also confirmed that RANKL is present in the human disc. Expression of RANKL was found to be significantly greater in more degenerated compared to healthier discs (P = 0.0001). Cathepsin K gene expression levels showed a positive, significant correlation with RANKL expression. Based on these data, we propose that cathepsin K plays a significant role in disc matrix remodeling and in matrix degradation in the proinflammatory cytokine-rich microenvironment of the degenerating disc.
Culturally Relevant Inquiry-Based Laboratory Module Implementations in Upper-Division Genetics and Cell Biology Teaching Laboratories
Authors: Siritunga Dimuth , Montero-Rojas María , Carrero Katherine , Toro Gladys , Vélez Ana , Carrero-Martínez Franklin A.
Published: September 2011

Today, more minority students are entering undergraduate programs than ever before, but they earn only 6% of all science or engineering PhDs awarded in the United States. Many studies suggest that hands-on research activities enhance students’ interest in pursuing a research career. In this paper, we present a model for the implementation of laboratory research in the undergraduate teaching laboratory using a culturally relevant approach to engage students. Laboratory modules were implemented in upper-division genetics and cell biology courses using cassava as the central theme. Students were asked to bring cassava samples from their respective towns, which allowed them to compare their field-collected samples against known lineages from agricultural stations at the end of the implementation. Assessment of content and learning perceptions revealed that our novel approach allowed students to learn while engaged in characterizing Puerto Rican cassava. In two semesters, based on the percentage of students who answered correctly in the premodule assessment for content knowledge, there was an overall improvement of 66% and 55% at the end in the genetics course and 24% and 15% in the cell biology course. Our proposed pedagogical model enhances students’ professional competitiveness by providing students with valuable research skills as they work on a problem to which they can relate.
NEGATIVE INDUCED‐POLARIZATION EFFECTS FROM LAYERED MEDIA
Authors: Nabighian Misac N. , Elliot Charles L.
Published: September 2011

Negative induced‐polarization responses from lateral resistivity distributions such as near‐surface vertical contacts and dikes, three‐dimensional buried bodies, etc., have been well known for years. Recent comprehensive computations of resistivity and induced‐polarization response functions over a three horizontally layered earth have revealed that negative induced‐polarization effects can also occur whenever the geoelectric section is of K type (ρ1, < ρ2 > ρ3) or Q type (ρ1 > ρ2 > ρ3).

For such sections, the induced‐polarization function of the first layer (as defined by Seigel) can be negative. As a result, if the first layer is polarizable the response from deeper layers can be severely masked solely as a function of the resistivity distribution, thus limiting the depth of detection of buried sources. It is shown that for an m‐layered earth, negative induced‐polarization functions can be expected for those layers lying above a K or Q type sequence in the resistivity section. Any application of induced‐polarization surveys must thus be preceded by a thorough evaluation of the resistivity data. The same applies for the quantitative interpretation of IP data.
Hepatitis C: a patient's journey from a psychiatrist's perspective
Authors: Badrakalimuthu Vellingiri Raja , Rumball Daphne , Chawla Amit
Published: September 2011

There is an increasing prevalence of hepatitis C, particularly among intravenous drug users. Estimates of infection with the hepatitis C virus (HCV) in patients with severe mental illness in the USA have ranged from 8.5% to 19.6%. Alcohol use and misuse is the single biggest contributory factor to the development of fatal liver disease in people with hepatitis C. Neuropsychiatric symptoms are present in HCV infection, independent of any treatment. Despite such alarming observations, the success rate of antiviral treatment in chronic hepatitis C has improved considerably in recent years. This article explores psychiatrists' involvement in advocating for treatment inclusion, assessing patients' capacity to make treatment-related decisions and supporting the medical team in managing the complex journey a patient undertakes from being at high risk to receiving treatment for neuropsychiatric symptoms.
The practice of evidence-based psychiatry today
Authors: Wallace John
Published: September 2011

Research that should change clinical practice is often ignored for years. Fifty-five new trials are reported in medicine every day. Psychiatrists need to have some way to sift, digest and act on new research to benefit their patients. This article outlines the key elements of evidence-based psychiatry in an attempt to address these needs. Initially, an evidence-based approach is about asking an answerable question, searching for the evidence and then critically appraising the available information for its validity and relevance. The fourth step involves integrating the evidence with clinical expertise and the patient's values. The whole idea is to improve real-life patient care. This article outlines a number of the tools needed to overcome some of the common problems that psychiatrists face when trying to find and use published research results to help solve patients' problems.
Combining routine outcomes measurement and ‘Payment by Results’:
will it work and is it worth it?
Authors: Macdonald Alastair J. D. , Elphick Martin
Published: September 2011

The Department of Health in England has long encouraged the routine
measurement of clinical outcomes in mental health services but has now
decided to use outcome measures as part of a new payments system – Payment
by Results. We examine how these two policies should or might interact.
New York City, 9/11, and Comics
Authors: Worcester Kent
Published: September 2011

The shock of 9/11 generated a long wave of graphic commentary, memoir, and thinly disguised fiction from cartoonists and graphic artists who in many cases watched the towers burn with their own eyes. While individual filmmakers, poets, playwrights, and novelists have addressed 9/11–related themes, 9/11 and its aftermath resonated in a singular way within an industry and subculture that remains anchored in the five boroughs. The destruction and horror of the attack on downtown Manhattan affected many cartoonists personally, and in a few cases inspired their best work. The events produced some cartoon kitsch as well. The outpouring of 9/11 comics speaks to the reassuring intimacy of the handcrafted text-image, the undiminished role of cultural geography, and the long-standing connection between the city and visual narrative.
Enjoying 9/11
Authors: Stone James
Published: September 2011

Cloverfield (dir. Matt Reeves, 2008), a Hollywood movie about a giant, reptilian monster attacking New York City, includes many moments reminiscent of the iconic video footage captured on 9/11. The film presents these scenes of destruction as thrilling spectacle and, in so doing, reveals the idea that the terrorist attacks of 2001 always made for, on some level, an exciting event. This essay ponders our attraction to the aesthetics of violence. It details the ways that Cloverfield drains 9/11 of any significance other than its potential to yield pleasurable images of carnage.
The Depiction of 9/11 in Literature
Authors: Baelo-Allué Sonia
Published: September 2011

The 9/11 terrorist attack on the United States has become one of the most represented disasters in history since it produced an unprecedented visual impact on those around the world who watched the second plane crash into the South Tower live on television. In an atmosphere in which reality resembled fiction, fiction was initially rejected as a suitable means for understanding and relating to the enormity of the events because it apparently had nothing to offer that journalism and the news could not provide. Ten years later, these initial misgivings have been overcome and 9/11 fiction has become a genre in itself. This essay explores the use of newspaper articles, radio transcripts, phone messages, e-mails, and interviews with eyewitnesses in Frédéric Beigbeder's Windows on the World (2004); the use of moving images—a flip book—and other visuals inserted in Jonathan Safran Foer's Extremely Loud and Incredibly Close (2005); and the references to well-known photographs of 9/11 in Don DeLillo's Falling Man (2007). These authors do not ignore the mediated nature of 9/11 but display it through the incorporation of other media in their fiction, which renders their representation of the trauma more effective.
Integrin-dependent and -independent functions of astrocytic fibronectin in retinal angiogenesis
Authors: Stenzel Denise , Lundkvist Andrea , Sauvaget Dominique , Busse Marta , Graupera Mariona , van der Flier Arjan , Wijelath Errol S. , Murray Jacqueline , Sobel Michael , Costell Mercedes , Takahashi Seiichiro , Fässler Reinhard , Yamaguchi Yu , Gutmann David H. , Hynes Richard O. , Gerhardt Holger
Published: September 2011

Fibronectin (FN) is a major component of the extracellular matrix and functions in cell adhesion, cell spreading and cell migration. In the retina, FN is transiently expressed and assembled on astrocytes (ACs), which guide sprouting tip cells and deposit a provisional matrix for sprouting angiogenesis. The precise function of FN in retinal angiogenesis is largely unknown. Using genetic tools, we show that astrocytes are the major source of cellular FN during angiogenesis in the mouse retina. Deletion of astrocytic FN reduces radial endothelial migration during vascular plexus formation in a gene dose-dependent manner. This effect correlates with reduced VEGF receptor 2 and PI3K/AKT signalling, and can be mimicked by selectively inhibiting VEGF-A binding to FN through intraocular injection of blocking peptides. By contrast, AC-specific replacement of the integrin-binding RGD sequence with FN-RGE or endothelial deletion of itga5 shows little effect on migration and PI3K/AKT signalling, but impairs filopodial alignment along AC processes, suggesting that FN-integrin α5β1 interaction is involved in filopodial adhesion to the astrocytic matrix. AC FN shares its VEGF-binding function and cell-surface distribution with heparan-sulfate (HS), and genetic deletion of both FN and HS together greatly enhances the migration defect, indicating a synergistic function of FN and HS in VEGF binding. We propose that in vivo the VEGF-binding properties of FN and HS promote directional tip cell migration, whereas FN integrin-binding functions to support filopodia adhesion to the astrocytic migration template.
Age-Related Changes in Orienting Attention in Time
Authors: Zanto Theodore P. , Pan Peter , Liu Helen , Bollinger Jacob , Nobre Anna C. , Gazzaley Adam
Published: September 2011

Temporal cues guide attentional resources toward relevant points in time, resulting in optimized behavioral performance. Although deficits in aspects of attention have been documented in older adults, it remains unknown whether the critical ability to orient attention in time is affected by normal aging. To address this, younger and older adults participated in a temporally cued target–response experiment while electroencephalographic data were recorded. Three conditions (one detection and two discrimination tasks) were used to manipulate task complexity. Response times show that younger adults, but not older adults, used temporal cues to enhance performance regardless of task complexity. Similarly, alpha band activity (8–12 Hz) and the contingent negative variation preceding targets indicated that only younger adults engaged prestimulus, anticipatory neural mechanisms associated with temporal cues. Overall, these results provide novel evidence that older adults do not use temporal cues to orient attention in time and support an expectation deficit in normal aging.
Corticotropin-Releasing Factor Receptor 1 Antagonist Alters Regional Activation and Effective Connectivity in an Emotional–Arousal Circuit during Expectation of Abdominal Pain
Authors: Hubbard Catherine S. , Labus Jennifer S. , Bueller Joshua , Stains Jean , Suyenobu Brandall , Dukes George E. , Kelleher Dennis L. , Tillisch Kirsten , Naliboff Bruce D. , Mayer Emeran A.
Published: September 2011

Alterations in corticotropin-releasing factor (CRF) signaling pathways have been implicated in irritable bowel syndrome (IBS) pathophysiology. We aimed to (1) determine the effect of the selective CRF receptor 1 antagonist (CRF1) GW876008 relative to placebo, on regional activation and effective connectivity of a stress-related emotional–arousal circuit during expectation of abdominal pain using functional magnetic resonance imaging in human subjects with a diagnosis of IBS and healthy controls (HCs), and (2) examine GW876008 effects on state–trait anxiety and hypothalamic–pituitary–adrenal (HPA) axis response. Although there were no drug-related effects on peripheral HPA activity, significant central effects were observed in brain regions associated with the stress response. Effective connectivity analysis showed drug-induced normalizations between key regions of the emotional–arousal circuit in patients. During pain expectation, orally administered GW876008 relative to placebo produced significant blood oxygen level-dependent (BOLD) signal reductions in the amygdala, hippocampus, insula, anterior cingulate, and orbitomedial prefrontal cortices across groups. Patients showed significantly greater BOLD responses in the left locus coeruleus and hypothalamus after placebo compared with HCs, and BOLD signal decreases in the left hypothalamus after drug. The inhibitory effects of GW876008 in the hypothalamus in patients were moderated by anxiety; patients having average and high levels of state anxiety showed drug-related BOLD decreases. GW876008 represents a novel tool for elucidating the neuronal mechanisms and circuitry underlying hyperactivation of CRF/CRF1signaling and its role in IBS pathophysiology. The unique state anxiety effects observed suggest a potential pathway for therapeutic benefit of CRF1receptor antagonism for patients with stress-sensitive disorders.
Oberflächenrekonstruktion mittels Stereodeflektometrie
Authors: Werling Stefan , Beyerer Jürgen
Published: September 2011

Stereoverfahren zur Inspektion und Rekonstruktion spiegelnder Oberflächen können global versagen. Hierzu wird ein konstruktives Verfahren zur Erzeugung von nicht unterscheidbaren Flächenpaaren vorgestellt. Es ergeben sich daraus Bedingungen für die Anwendung von Stereoverfahren zur Rekonstruktion spiegelnder Objekte. Die Rekonstruktion komplex geformter Objekte basiert in der Regel auf vielen einzelnen Teilmessungen. Überlappen sich diese Messbereiche, so kann dort das deflektometrische Stereo zur Regularisierung des Rekonstruktionsproblems gewinnbringend eingesetzt werden.
Innate Immunity in the Small Intestine of the Preterm Infant
Authors: McElroy Steven J. , Weitkamp Jörn-Hendrik
Published: September 2011

The gastrointestinal tract comprises the largest surface area of the human body. This area is constantly exposed to myriad antigens as well as the large number of bacteria that coexist in the intestinal lumen. To protect against this exposure and help distinguish “self” from “foreign,” the intestinal tract has evolved a sophisticated barrier defense system that includes both innate and adaptive immune systems. However, infants who are born preterm do not have the benefit of an adequate immune response and, therefore, are more susceptible to bacterial injury, inflammation, and intestinal diseases such as necrotizing enterocolitis. In this review, we discuss the components of innate immunity that help to protect the small intestine as well as current knowledge about the role of these components in the pathophysiology of necrotizing enterocolitis.
Payment for Obesity Services: Examples and Recommendations for Stage 3 Comprehensive Multidisciplinary Intervention Programs for Children and Adolescents
Authors: Slusser Wendy , Staten Karan , Stephens Karen , Liu Lenna , Yeh Christine , Armstrong Sarah , DeUgarte Daniel A. , Haemer Matthew
Published: September 2011

OBJECTIVE:

The Reimbursement and Payment Subcommittee of the National Association of Children's Hospitals and Related Institutions FOCUS on a Fitter Future group sought to guide medical providers, patients, and payers to better serve obese children and adolescents to enable optimum health. Recommendations are provided for the essential components of a stage 3 comprehensive multidisciplinary intervention program as defined by the 2007 Expert Committee recommendations. In addition, suggestions are offered for a stepwise approach to implement these recommendations.

METHODS:

In 2009, key informant interviews were conducted with 15 children's hospitals participating in FOCUS on a Fitter Future and 1 nonparticipating hospital. Interview transcripts identified 5 financially sustainable stage 3 programs, each funded differently.

RESULTS:

The stage 3 programs interviewed ranged from being nascent to 21 years old (27%, <2 years; 47%, 2–6 years; 27%, >6 years). All of them had multidisciplinary teams that delivered services through 1 of 3 institutional structures: 60% freestanding; 7% specialty; and 33% hospital within a hospital. One-third of them had 1 to 2 funding sources, and 67% had ≥3 sources.

CONCLUSIONS:

The stage 3 programs in this review shared some common strategies for achieving financial stability. All of them followed key strategies of the chronic care model, the details of which led to the following recommendation: stage 3 programs should include a health care team with a medical provider, registered dietitian, physical activity specialist, mental health specialist, and coordinator who, as a team, provide service to overweight and obese children at no less than moderate intensity (26–75 hours).
Differing Success of Defense Strategies in Two Parasitoid Wasps in Protecting their Pupae Against a Secondary Hyperparasitoid
Authors: Harvey Jeffrey A , Gols Rieta , Tanaka Toshiharu
Published: September 2011

During their larval development, endoparasitoids are known to dispose of host resources in several different ways. Some parasitoid wasps consume most or all tissues of the host, whereas others consume a small fraction of host resources and either ensure that the host moves away from the pupation site or allow the host to remain close to the parasitoid cocoon(s). Using a single host species, Mythimna separata Walker (Lepidoptera: Noctuidae), this study compares the success of the two pupation strategies in the solitary parasitoids Microplitis sp. and Meteorus pulchricornis Wesmael (Hymenoptera: Braconidae) against attack from a secondary hyperparasitoid, Gelis agilis F. (Hymenoptera: Ichneumonidae). The caudal appendages of M. separata caterpillars parasitized by Microplitis sp. remain physically attached to parasitoid cocoons and the caterpillars behave aggressively when disturbed. However, after Me. pulchricornis larvae emerge from caterpillars of their host, M. separata, the parasitoid larvae pupate in cocoons that are suspended by a single thick thread that hangs 1–2 cm from under a leaf. In choice tests conducted in petri dishes, significantly fewer cocoons of Microplitis sp. attended by caterpillars than unattended cocoons were hyperparasitized by G. agilis. By contrast, Me. pulchricornis cocoons that were hanging from corn, Zea mays L., plants were hyperparasitized as frequently as those which were attached to leaves. We discuss the potentially different selection pressures generated among natural enemies such as predators and hyperparasitoids in determining optimal pupal defense strategies in primary parasitoids.
Context-Dependent Stridulatory Responses ofLeptogenys kitteli(Hymenoptera: Formicidae) to Social, Prey, and Disturbance Stimuli
Authors: Chiu Y-K , Mankin R W , Lin C-C
Published: September 2011

Individual Leptogenys kitteli (Hymenoptera: Formicidae) workers produce stridulatory pulses at faster rates after exposure to prey larvae placed nearby the nest and after air-puff disturbances at the nest entrance than during unstimulated social interactions within the nest. Workers produce chirps (trains of stridulatory pulses) at faster rates after exposure to prey larvae than during unstimulated social interactions, including groups of chirps (bursts) where the intervals between chirps decrease below 60 ms. Such bursts do not occur in unstimulated social interactions. Chirp bursts with intervals <10 ms (disturbance bursts) occur immediately after air puffs at the nest entrance. Disturbance bursts are not observed after exposure to prey larvae or during unstimulated social interactions. The rates of disturbance bursts decline rapidly within 10 s after an air puff, whereas episodes of chirp bursts extend over periods of 30 s or longer when groups of ants are moving prey larvae into the nest. The differences in the rates of stridulatory pulses and chirps and in the durations of stridulatory activity observed in the context of different types, intensities, and durations of stimulation contribute to evidence that stridulation has a significant communicatory role in colony activities of many ant species, even in genera, such as Leptogenys, in which a stridulatory organ has not been retained in every species. A better understanding of how ants produce and interpret vibrations may lead to new methods that to improve attractiveness of baits, or repel ants from electrical equipment housings where opportunistic colonies frequently nest.
Meta‐ecosystem engineering: Nutrient fluxes reveal intraspecific and interspecific feedbacks in fragmented mussel beds
Authors: Largaespada César , Guichard Frédéric , Archambault Philippe
Published: September 2011

Ecologists still have to elucidate the complex feedback interactions operating among biodiversity and ecosystem processes in engineered systems. To address this, a field experiment was conducted to mimic natural mussel bed meta‐ecosystems (Mytilus spp.) of the lower St. Lawrence Estuary (Quebec, Canada) and partition the effects of their biotic and abiotic properties and spatial structure on ecosystem processes and community dynamics of associated macro‐invertebrates. We found positive intraspecific feedbacks between mussels and their recruits, and negative interspecific feedbacks between mussels and their associated ecosystem. These feedbacks were associated with mussel bed ecosystem processes (fluxes of ammonium and oxygen). In addition, we showed that proximity between mussel patches increased within‐patch nutrient fluxes. Our study revealed the potential for meta‐ecosystem engineering to drive feedback interactions between community and ecosystem functioning in marine fragmented systems. It also shows the relevance of meta‐ecosystem theories as a conceptual framework to elucidate biotic and abiotic processes controlling ecosystem and community structure. Such framework could contribute to ecosystem‐based management of spatially structured systems such as reserve networks and fragmented ecosystems.
A FEEDBACK INTERVENTION TO INCREASE DIGITAL AND PAPER CHECKLIST PERFORMANCE IN TECHNICALLY ADVANCED AIRCRAFT SIMULATION
Authors: Rantz William G. , Van Houten Ron
Published: September 2011

This study examined whether pilots operating a flight simulator completed digital or paper flight checklists more accurately after receiving postflight graphic and verbal feedback. The dependent variable was the number of checklist items completed correctly per flight. Following treatment, checklist completion with paper and digital checklists increased from 38% and 39%, respectively, to nearly 100% and remained close to 100% after feedback and praise for improvement were withdrawn. Performance was maintained at or near 100% during follow‐up probes.
Accuracy of the use of triaxial accelerometry for measuring daily activity as a predictor of daily maintenance energy requirement in healthy adult Labrador Retrievers
Authors: Wrigglesworth David J. , Mort Emily S. , Upton Sarah L. , Miller Andrew T.
Published: September 2011

Objective—To determine accuracy of the use of triaxial accelerometry for measuring daily activity as a predictor of maintenance energy requirement (MER) in healthy adult Labrador Retrievers.

Animals—10 healthy adult Labrador Retrievers.

Procedures—Dogs wore an accelerometer for two 2-week periods, with data on daily activity successfully collected for 24 to 26 days. These data, along with body weight, were used as independent variables in a multiple linear regression model to predict the dependent variable of daily MER. The predictive accuracy of the model was compared with that of a model that excluded activity. Dietary energy intake at a stated amount of body weight stability was used as an equivalent measure of MER in these analyses.

Results—The multiple linear regression model that included body weight and daily activity as independent variables could be used to predict observed MER with a mean absolute error of 63.5 kcal and an SE of estimation of 94.3 kcal. Removing activity from the model reduced the predictive accuracy to a mean absolute error of 129.8 kcal and an SE of estimation of 165.4 kcal.

Conclusions and Clinical Relevance—Use of triaxial accelerometers to provide an independent variable of daily activity yielded a marked improvement in predictive accuracy of the regression model, compared with that for a model that used only body weight. Improved accuracy in estimations of MER could be made for each dog if an accelerometer was used to record its daily activity.
Evaluation of the effect of computed tomography scan protocols and freeform fabrication methods on bone biomodel accuracy
Authors: Fitzwater Kathryn L. , Marcellin-Little Denis J. , Harrysson Ola L. A. , Osborne Jason A. , Poindexter E. Christine
Published: September 2011

Objective—To assess the effect of computed tomography (CT) scan protocols (radiation amounts) and fabrication methods on biomodel accuracy and variability.

Sample—Cadaveric femur of a Basset Hound.

Procedures—Retroreconstructions (n = 158) were performed of 16 original scans and were visually inspected to select 17 scans to be used for biomodel fabrication. Biomodels of the 17 scans were made in triplicate by use of 3 freeform fabrication processes (stereolithography, fused deposition modeling, and 3-D printing) for 153 models. The biomodels and original bone were measured by use of a coordinate measurement machine.

Results—Differences among fabrication methods accounted for 2% to 29% of the total observed variation in inaccuracy and differences among method-specific radiation configurations accounted for 4% to 44%. Biomodels underestimated bone length and width and femoral head diameter and overestimated cortical thickness. There was no evidence of a linear association between thresholding adjustments and biomodel accuracy. Higher measured radiation dose led to a decrease in absolute relative error for biomodel diameter and for 4 of 8 cortical thickness measurements.

Conclusions and Clinical Relevance—The outside dimensions of biomodels have a clinically acceptable accuracy. The cortical thickness of biomodels may overestimate cortical thickness. Variability among biomodels was caused by model fabrication reproducibility and, to a lesser extent, by the radiation settings of the CT scan and differences among fabrication methods.