bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence of EGFR Exon 19 Deletions and L858R in Tumor Specimens From Men and Cigarette Smokers With Lung Adenocarcinomas
Authors: D'Angelo Sandra P. , Pietanza M. Catherine , Johnson Melissa L. , Riely Gregory J. , Miller Vincent A. , Sima Camelia S. , Zakowski Maureen F. , Rusch Valerie W. , Ladanyi Marc , Kris Mark G.
Published: April 2011

Purpose

EGFR mutations underlie the sensitivity of lung cancers to erlotinib and gefitinib and can occur in any patient with this illness. Here we examine the frequency of EGFR mutations in smokers and men.

Methods

We determined the frequency of EGFR mutations and characterized their association with cigarette smoking status and male sex.

Results

We tested 2,142 lung adenocarcinoma specimens for the presence of EGFR exon 19 deletions and L858R. EGFR mutations were found in 15% of tumors from former smokers (181 of 1,218; 95% CI, 13% to 17%), 6% from current smokers (20 of 344; 95% CI, 4% to 9%), and 52% from never smokers (302 of 580; 95% CI, 48% to 56%; P < .001 for ever v never smokers). EGFR mutations in former or current smokers represented 40% of all those detected (201 of 503; 95% CI, 36% to 44%). EGFR mutations were found in 19% (157 of 827; 95% CI, 16% to 22%) of tumors from men and 26% (346 of 1,315; 95% CI, 24% to 29%) of tumors from women (P < .001). EGFR mutations in men represented 31% (157 of 503; 95% CI, 27% to 35%) of all those detected.

Conclusion

A large number of EGFR mutations are found in adenocarcinoma tumor specimens from men and people who smoked cigarettes. If only women who were never smokers were tested, 57% of all EGFR mutations would be missed. Testing for EGFR mutations should be considered for all patients with adenocarcinoma of the lung at diagnosis, regardless of clinical characteristics. This strategy can extend the use of EGFR tyrosine kinase inhibitors to the greatest number individuals with the potential for substantial benefit.
Molecular Pathogenesis of Hodgkin's Lymphoma: Increasing Evidence of the Importance of the Microenvironment
Authors: Steidl Christian , Connors Joseph M. , Gascoyne Randy D.
Published: April 2011

Hodgkin's lymphoma (HL) represents the most common subtype of malignant lymphoma in young people in the Western world. Most patients can be cured with modern treatment strategies, although approximately 20% will die after relapse or progressive disease. The histologic hallmark of the disease is the presence of the characteristic Hodgkin Reed-Sternberg (HRS) cells in classical HL and so-called lymphocyte-predominant (LP) cells in nodular lymphocyte-predominant HL. HL is unique among all cancers because malignant cells are greatly outnumbered by reactive cells in the tumor microenvironment and make up only approximately 1% of the tumor. Expression of a variety of cytokines and chemokines by the HRS and LP cells is believed to be the driving force for an abnormal immune response, perpetuated by additional factors secreted by reactive cells in the microenvironment that help maintain the inflammatory milieu. The malignant HRS and LP cells manipulate the microenvironment, permitting them to develop their malignant phenotype fully and evade host immune attack. Gene expression signatures derived from non-neoplastic cells correlate well with response to initial and subsequent therapies, reflecting their functional relevance. Recent biomarker studies have added texture to clinical outcome predictors, and their incorporation into prognostic models may improve our understanding of the biologic correlates of treatment failure. Moreover, recent preclinical and clinical studies have demonstrated that the tumor microenvironment represents a promising therapeutic target, raising hope that novel treatment strategies focused on the interface between malignant and reactive cells will soon emerge.
Long-Term Complications of Lymphoma and Its Treatment
Authors: Ng Andrea K. , LaCasce Ann , Travis Lois B.
Published: April 2011

As a result of therapeutic advances, there is a growing population of survivors of both Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). A thorough understanding of the late effects of cancer and its treatment, including the risk of developing a second malignancy and non-neoplastic complications, most notably cardiac disease, is essential for the proper long-term follow-up care of these patients. For HL survivors cured in the past 5 decades, a large body of literature describes a range of long-term effects, many of which are related to extent of treatment. These studies form the basis for many of the follow-up recommendations developed for HL survivors. As HL therapy continues to evolve, however, with an emphasis toward treatment reduction, in particular for early-stage disease, it will be important to rigorously observe this new generation of patients long term to document and quantify late effects associated with modern treatments. Although data on late effects after NHL therapy have recently emerged, the formulation of structured follow-up plans for this heterogeneous group of survivors is challenging, given the highly variable natural history, treatments, and overall prognosis. However, the chemotherapy and radiation therapy approaches for some types of NHL are similar to that for HL; thus, some of the follow-up guidelines for patients with HL may also be transferrable to selected survivors of NHL. Additional work focused on treatment-related complications after NHL will facilitate the development of follow-up programs, as well as treatment refinements to minimize late effects in patients with various types of NHL.
Active and Passive Immunotherapy for Lymphoma: Proving Principles and Improving Results
Authors: Brody Joshua , Kohrt Holbrook , Marabelle Aurelien , Levy Ronald
Published: April 2011

Conventional chemotherapy for lymphoma has advanced greatly over the past 50 years, changing some lymphoma subtypes from uniformly lethal to curable; however, the majority of lymphomas in patients remain incurable, and there is a need for novel therapies with less toxicity and more specific targeting of tumor cells. The vertebrate immune system has evolved the capacity for such specific targeting through the B-cell and T-cell receptors; passive immunotherapies utilizing these receptors, such as monoclonal antibodies (mAbs) or T cells, have shown efficacy in treating lymphomas. The first generation of mAb-based therapies has transformed the standard of care for lymphoma, and newer antibodies may improve on this approach. Clinical activity has been shown by T cells bearing receptors that target viral antigens as well as T cells bearing re-engineered receptors that target antigens recognized by antibodies. Active immunotherapies, such as vaccines and immune checkpoint blockades, have prolonged survival in certain solid tumors and are being actively pursued to treat lymphoma. A variety of vaccines (eg, protein- and cell-based vaccines) are being tested in ongoing trials, and the most recent iterations show therapeutic activity. Newer trials are addressing the problem of tumor-induced immunosuppression by the use of antibodies against immunologic checkpoints or by the reinfusion of primed T cells after lymphodepletion, a process we refer to as immunotransplantation. Herein, we discuss results of the various immunotherapy strategies applied to lymphoma and the ongoing approaches for their improvement.
linesandbowlaffect the specification of cyst stem cells and niche cells in theDrosophilatestis
Authors: DiNardo Stephen , Okegbe Tishina , Wingert Lindsey , Freilich Sarah , Terry Natalie
Published: April 2011

To function properly, tissue-specific stem cells must reside in a niche. The Drosophila testis niche is one of few niches studied in vivo. Here, a single niche, comprising ten hub cells, maintains both germline stem cells (GSC) and somatic stem cells (CySC). Here, we show that lines is an essential CySC factor. Surprisingly, lines-depleted CySCs adopted several characteristics of hub cells, including the recruitment of new CySCs. This led us to examine the developmental relationship between CySCs and hub cells. In contrast to a previous report, we did not observe significant conversion of steady-state CySC progeny to hub fate. However, we found that these two cell types derive from a common precursor pool during gonadogenesis. Furthermore, lines mutant embryos exhibited gonads containing excess hub cells, indicating that lines represses hub cell fate during gonadogenesis. In many tissues, lines acts antagonistically to bowl, and we found that this is true for hub specification, establishing bowl as a positively acting factor in the development of the testis niche.
Protein kinase CK2 regulates the formation and clearance of aggresomes in response to stress
Authors: Watabe Masahiko , Nakaki Toshio
Published: April 2011

Misfolded protein aggregates elicit a stress response, and their clearance is crucial for cell survival. These aggregates are transported by cytoplasmic deacetylase HDAC6 and dynein motors to the aggresome via the microtubule network, and are removed by autophagic degradation. HDAC6 activity is necessary for both the transport and clearance of protein aggregates. However, the cellular factors that regulate HDAC6 activity remain unknown. Here we show that protein kinase CK2 is a crucial modulator of HDAC6 activity because CK2 directly phosphorylates HDAC6 and increases cytoplasmic deacetylase activity. Indeed, cells that expressed HDAC6 mutated at Ser458, a CK2-mediated phosphorylation site, failed to both form and clear aggresomes, and increased cytotoxicity. Interestingly, Ser458 is conserved only in higher primates, such as human and chimpanzee, but not in the rhesus macaque. These findings identify CK2 as a crucial protein involved in the formation and clearance of aggresomes, and hence in cell viability in response to misfolded protein stress.
Dynamin- and Rab5-dependent endocytosis is required to preventDrosophilaphotoreceptor degeneration
Authors: Pinal Noelia , Pichaud Franck
Published: April 2011

In Drosophila photoreceptors, Rhodopsin 1 (ninaE, Rh1) is required for proper morphogenesis and maintenance of the apical light-gathering organelle, the rhabdomere. It has been proposed that Rh1, coupled to the Rho GTPases Rac1 and Cdc42, promotes the morphogenesis of a sub-rhabdomeric F-actin meshwork or rhabdomere terminal web (RTW). The RTW provides mechanical support to the apical microvilli and is likely to guide Rab11-dependent delivery of Rh1-rich membrane to the rhabdomere from the trans Golgi network. However, the nature and function of the molecular pathway involved in RTW morphogenesis remains incomplete. Here, we show that Rh1 function in promoting RTW morphogenesis is light-independent and is conserved throughout evolution. This Rh1 function does not require Gqαe, which is required for phototransduction. Finally, we show that interfering with Dynamin- and Rab5-dependent endocytosis leads to a phenotype that is undistinguishable from that of the ninaE-null mutant. Importantly, the corresponding endocytic activity is essential to prevent early onset of rhabdomere degeneration. In conclusion, we propose that Rh1 function in promoting RTW morphogenesis is not only needed to sustain apical membrane delivery but is also required for proper rhabdomeric membrane endocytosis and turnover.
Temperature-dependent regulation of blood distribution in snakes
Authors: Amiel Joshua J. , Chua Beverly , Wassersug Richard J. , Jones David R.
Published: April 2011

Regional control of blood flow is often suggested as a mechanism for fine thermoregulatory adjustments in snakes. However, the flow of blood to different body regions at various temperatures has never been visualized to confirm this mechanism. We used 99mtechnetium-labelled macroaggregated albumin (99mTc-MAA), a radioactive tracer, to follow the flow of blood through the bodies of garter snakes (Thamnophis sirtalis) near their thermal maxima and minima. We injected snakes with 99mTc-MAA at cold (6–8°C) and hot (27–32°C) temperatures and imaged them using a gamma scanner. At cold ambient temperatures, snakes significantly reduced the blood flow to their tails and significantly increased the blood flow to their heads. Conversely, at hot ambient temperatures, snakes significantly increased the blood flow to their tails and significantly reduced the blood flow to their heads. This confirms that snakes are able to use differential blood distribution to regulate temperature. Our images confirm that snakes use regional control of blood flow as a means of thermoregulation and that vasomotor control of vascular beds is likely to be the mechanism of control.
Organic Charge-transfer Salts and the Component Molecules in Organic Transistors
Authors: Mori Takehiko
Published: April 2011

Electron donors and acceptors such as tetrathiafulvalene (TTF) and tetracyanoquinodimethane (TCNQ), which have been long known as components of organic metals, act as p- and n-channel organic semiconductors in organic field-effect transistors. High performance, good thin-film properties, and long-term stability have been achieved on the basis of appropriate molecular design. In addition, their charge-transfer complexes work as the active layers as well as conducting electrode materials showing low contact resistance.
Selective Transformation of N-(Propargylic)hydroxylamines into 4-Isoxazolines and Acylaziridines Promoted by Metal Salts
Authors: Wada Norihiro , Kaneko Kentaro , Ukaji Yutaka , Inomata Katsuhiko
Published: April 2011

Cyclization of N-(propargylic)hydroxylamines catalyzed by AgBF4 afforded the corresponding 4-isoxazolines in good yields. Copper salts were found to promote the further transformation to acylaziridines. The combined use of AgBF4 and CuCl realized direct transformation of N-(propargylic)hydroxylamines into cis-acylaziridines.
Preparation of Crystalline Tungsten Oxide Nanorods with Enhanced Photocatalytic Activity under Visible Light Irradiation
Authors: Sadakane Masahiro , Tamura Naoya , Kanome Naoko , Sumiya Sadanobu , Abe Ryu , Sano Tsuneji
Published: April 2011

Crystalline tungsten oxide (WO3) nanorods with diameters of approximately 8 nm were prepared using SBA-15 mesoporous silica as a hard template and ammonium metatungstate as a tungsten source, which have larger surface area (ca. 90 m2 g−1) than other WO3 materials and, therefore, exhibit superior photocatalytic activity for the decomposition of acetic acid under visible light irradiation after Pt loading.
Novel Molecular Conductors Based on Cyclopenteno-TTP Showing Strong Self-aggregation
Authors: Nishiwaki Masataka , Nakamura Ken-ichi , Shirahata Takashi , Misaki Yohji
Published: April 2011

Several molecular conductors based on CP-TTP, where CP-TTP is 2-(4,5-cyclopenteno-1,3-dithiol-2-ylidene)-5-(1,3-dithiol-2-ylidene)-1,3,4,6-tetrathiapentalene, have been prepared. X-ray structure analyses revealed that all the CP-TTP conductors obtained so far have β-type array of the donors regardless of the counter anions. Among them, the ReO4− and Au(CN)2− salts exhibited metallic conducting behavior down to 10 K.
Stationary Concepts for Experimental 2 × 2 Games: Comment
Authors: Brunner Christoph , Camerer Colin F , Goeree Jacob K
Published: April 2011

Reinhard Selten and Thorsten Chmura (2008) recently reported laboratory results for completely mixed 2 X 2 games used to compare Nash equilibrium with four other stationary concepts: quantal response equilibrium, action-sampling equilibrium, payoff-sampling equilibrium, and impulse balance equilibrium. We reanalyze their data, correct some errors, and find that Nash clearly fits worst while the four other concepts perform about equally well. We also report new analysis of other previous experiments that illustrate the importance of the loss aversion hardwired into impulse balance equilibrium: when the other non-Nash concepts are augmented with loss aversion, they outperform impulse balance equilibrium.
Stationary Concepts for Experimental 2 × 2 Games: Reply
Authors: Selten Reinhard , Chmura Thorsten , Goerg Sebastian J
Published: April 2011

This is a reply to “Stationary Concepts for Experimental 2 X 2 Games: Comment” by Brunner, Camerer, and Goeree which corrects some computational errors in Selten and Chmura (2008) and extends the comparison of five stationary concepts to data from previous experimental studies. We critically discuss their new findings and relate them to the data of Selten and Chmura (2008). We conclude that the parametric concepts of action-sampling equilibrium and payoff-sampling equilibrium perform better than quantal response equilibrium, and that the non-parametric concept of impulse-balance equilibrium performs at least as well as quantal response equilibrium. (JEL C70)
The Long Slump
Authors: Hall Robert E
Published: April 2011

In a market-clearing economy, declines in demand from one sector do not cause large declines in aggregate output because other sectors expand. The key price mediating the response is the interest rate. A decline in the rate stimulates all categories of spending. But in a low-inflation economy, the room for a decline in the rate is small, because of the notorious lower limit of zero on the nominal interest rate. In the Great Depression, substantial deflation caused the real interest rate to reach high levels. In the Great Slump that began at the end of 2007, low inflation resulted in an only slightly negative real rate when full employment called for a much lower real rate because of declines in demand. Fortunately, the inflation rate hardly responded to conditions in product and labor markets, else deflation might have occurred, with an even higher real interest rate. I concentrate on three closely related sources of declines in demand: the buildup of excess stocks of housing and consumer durables, the corresponding expansion of consumer debt that financed the buildup, and financial frictions that resulted from the decline in real-estate prices. (JEL E23, E24, E31, E32, E65)
Are Risk Preferences Stable across Contexts? Evidence from Insurance Data
Authors: Barseghyan Levon , Prince Jeffrey , Teitelbaum Joshua C
Published: April 2011

Using a unique dataset, we test whether households' deductible choices in auto and home insurance reflect stable risk preferences. Our test relies on a structural model that assumes households are objective expected utility maximizers and claims are generated by household-coverage specific Poisson processes. We find that the hypothesis of stable risk preferences is rejected by the data. Our analysis suggests that many households exhibit greater risk aversion in their home deductible choices than their auto deductible choices. Our results are robust to several alternative modeling assumptions. (JEL D11, D83)
Procedural Analysis of Choice Rules with Applications to Bounded Rationality
Authors: Salant Yuval
Published: April 2011

I study how limited abilities to process information affect choice behavior. I model the decision-making process by an automaton, and measure the complexity of a specific choice rule by the minimal number of states an automaton implementing the rule uses to process information. I establish that any choice rule that is less complicated than utility maximization displays framing effects. I then prove that choice rules that result from an optimal trade-off between maximizing utility and minimizing complexity are history-dependent satisficing procedures that display primacy and recency effects. (JEL D01, D03, D11, D83)
The Bidder's Curse
Authors: Malmendier Ulrike , Lee Young Han
Published: April 2011

We employ a novel approach to identify overbidding in auctions. We compare online auction prices to fixed prices for the same item on the same webpage. In detailed data on auctions of a board game, 42 percent of auctions exceed the simultaneous fixed price. The result replicates in a broad cross-section of auctions (48 percent overbidding). A small fraction of overbidders, 17 percent of bidders, suf fices to generate the large fraction of auctions with overbidding. We show that the observed behavior is inconsistent with rational behavior, even allowing for uncertainty about prices and switching costs, since the expected auction price also exceeds the fixed price. Limited attention best explains our results. (JEL D12, D44)
Mammographic morphology and distribution of calcifications in ductal carcinoma in situ diagnosed in organized screening
Authors: Hofvind Solveig , Iversen Barbro F , Eriksen Liv , Styr Bodil M , Kjellevold Kjell , Kurz Kathinka D
Published: April 2011

Background

Ductal carcinoma in situ of the breast (DCIS) represents a challenge in mammographic screening due to its unknown progression into invasive cancer. The majority of the DCIS is detected due to signs of calcifications on the mammograms.

Purpose

To analyze the combinations of mammographic morphology and distribution of calcifications by Van Nuys nuclear grade (grade).

Material and Methods

A total of 217 DCIS diagnosed in women aged 50–69 years old who participated in the Norwegian Breast Cancer Screening Program in the period November 1995 to December 2007 were reviewed by four breast imaging specialists. The mammograms were classified according to the morphology and distribution of the calcifications, using BI-RADS nomenclature. Chi square test was used to compare the groups of morphology and distribution by grade.

Results

Calcifications were identified in 93% (202/217) of the cases, 15% (30/202) as grade 1 and 74% (149/202) as grade 3. Fine pleomorphic calcifications were seen in 38% (77/202) of the lesions and fine linear and fine linear branching in 31% (62/202). Sixty-nine percent (53/77) of the fine pleomorphic and 84% (52/62) of the fine linear and fine linear branching calcifications were high grade lesions. Grouped distribution was seen in about half of all the cases (104/202). Among the high grade lesions with fine pleomorphic or fine linear and fine linear branching calcifications, 75% (40/53) and 69% (36/52), respectively, had grouped or segmental distribution.

Conclusion

DCIS presented overlapping groups of morphology and distribution of calcification by grade, but fine pleomorphic and fine linear and fine linear branching calcifications with grouped and segmental distributions were associated with high grade DCIS. Seeking for further knowledge that allows separation of non-high grade from high grade DCIS has to continue to improve the quality of mammographic screening.
Evolution of quality and surgical risk assessment in the USA
Authors: DePalma Ralph G
Published: April 2011

As health-care reforms progress, quality and risk assessment in the health-care system of the USA surface as critical issues. This review considers past, present and possible future changes in quality assessment along with formal programs of complication reduction and pay for performance (PFP) as related to surgery and vascular interventions. Strategies for quality improvement include aggregate and risk-adjusted outcome measurement, process compliance with the Surgical Complication Improvement Program, oversight and PFP, now policies of the Centers for Medicare and Medicaid Services (CMS). Advantages, disadvantages and unintended consequences of these policies are discussed. While ongoing system changes will influence vascular surgical practice, unique opportunities and obligations exist for vascular surgeons to contribute to quality assessment of their interventions, to evaluate long-term outcomes and to devise strategies for comprehensive cost-effective care for the conditions affecting patients with vascular disease.
Innovative Ideas and Theoretical System of Coal Geological Comprehensive Exploration in China
Authors: Wang Tong
Published: April 2011

Due to the complicated geological conditions and the differences of physical geography conditions in China, it is difficult to solve the exploration problems with single exploration technique. According to coal geological characteristics and coal industrial requirements in China, innovative ideas and theoretical system of coal geological comprehensive exploration are proposed in this paper. The system can be summarized as “one innovative idea and two supporting theories”. One innovative idea is the comprehensive exploration. Two supporting theories are the coal accumulating theory and the tectonic controlling theory of coalfield. The innovative ideas and theoretical system of coal geological comprehensive exploration provide theory and technique support for coal mine construction, improve support ability of coal resources of our country and are of great significance in coal industry sustainable development.
QBO of the Equatorial-Stratospheric Winds Revisited: New Methods to Verify the Dominance of 28-Month Cycle
Authors: Mazzarella A. , Giuliacci A. , Liritzis I.
Published: April 2011

The equatorial-stratospheric wind that shows a Quasi Biennial Oscillation (22–32 months) has been revisited using a dual statistical detail regarding the search of the dominance harmonics. Data were used from the Freie Universitat of Berlin since 1953 for different heights combining the observations of the three radiosonde stations. The dominant period of 28 months has been reaffirmed but with a discernible amplitude and a phase, respectively, inversely varying with height. Such a cycle suggests an estimate for the coming easterly equatorial wind occurrence at 15 hPa level at the end of 2009. The 28-month harmonic is found to take about a year to descend from 15 to 70 hPa with a progressive lag of about 1 month/km. At the top of the stratosphere, easterlies dominate, while at the bottom, westerlies are more likely to be found. Correlation with sunspot numbers and seasonal rainfall is discussed.
Prediction of Mean Winds at an Indian Coastal Station Using a Data–Driven Technique Applied on Weibull Parameters
Authors: Mathew Thomas , George Smitha , Sarkar Abhijit , Basu Sujit
Published: April 2011

Statistical analysis of the wind speed has been carried out in the surface boundary layer at an Indian coastal station for the years 2006 and 2007 using a best fit two-parameter Weibull distribution. The seasonal variation of Weibull scale and shape parameters has been studied. Further, the predictability of the mean wind speed has been investigated using genetic algorithm in conjunction with Weibull parameters. The prediction of winds has been carried out for half an hour, one hour and one and a half hour in advance. The performance of the algorithm as reflected in the correlation coefficient and root mean square error has been found to be quite satisfactory.
Ship Generated Exhaust Emissions and Their Externalities for Greece
Authors: Tzannatos Ernestos
Published: April 2011

Amidst growing international awareness on the impact ship exhaust emissions on climate and air quality, the case of Greece is of particular interest because the dense ship traffic within the Greek seas directly imposes the impact of its exhaust emission pollutants (NOX, SO2 and PM) upon the highly populated, physically sensitive and culturally precious Greek coastline, as well as upon the land and seas of Greece in general, whereas the contribution of Greece in the global CO2 inventory at a time of climatic change awareness cannot be ignored. With regard to the shipping activity within the Greek seas, the utilization of the fuel-based methodology for domestic shipping and the activity-based methodology for international shipping shows that in 2008 the ship generated emissions of CO2, SO2, NOX and PM reached 7.4 million tons (7 million tons of CO2) and their externalities totaled 2.95 billion euro (155 million euro for CO2). Finally, the internalization of the emission externalities of domestic shipping was found to produce an increase of 12.96 and 2.71 euro per passenger and transported ton of cargo, respectively.
Creating Safety in Primary Care Practice with Electronic Medical Records Requires the Consideration of System Dynamics
Authors: McEwen Timothy R. , Elder Nancy C. , Flach John M.
Published: April 2011

Improvement in quality and safety in health care often depends on eliminating errors. Using examples from our research on the medical testing processes in primary care medical practices, we argue that designing safer systems requires moving beyond frameworks that focus exclusively on error elimination to consider the broader system dynamics including information loops that can be critical to the overall stability of the system. We focus on describing the nature of information coupling in relation to the constructs of essential friction, autonomation, and ecological interface design and how these can lead to more resilient systems. With the recent push in the United States to move towards electronic medical records (EMR), we conclude with suggestions for improving EMR systems based on these concepts.
Evaluation of Predictive Methods for Airblast Propagation through an Enclosed Structure
Authors: Price C. , Sherburn J.A. , Nelson D. , Slawson T. , Boone R.N.
Published: April 2011

Accurate predictions of peak pressure and impulse values of explosively-generated shock waves within a structure are both of interest to structural engineers and are difficult to generate analytically. On one hand, rudimentary scoping programs, such as BlastX, are simple to use and obtain general pressure-impulse predictions for a given scenario. The primary drawback to such programs is their lack of detail and their inability to account for any complexity within a structure. On the other hand, existing advanced hydrocodes, such as CTH, are capable of accurately modeling blast-wave characteristics in a very detailed environment. The tradeoff in this instance is that CTH requires advanced training, tools, and resources that are often not readily available. As a result, the structural engineer is often required to determine whether a simple “scoping” of the blast environment is sufficient, or whether the additional resources and expenditures are justified in providing a more accurate model. The focus of this paper is to evaluate the analytical and computational predictive methods described above—including the required simplifying assumptions, strengths, and limitations of each—by comparing the results of their respective analyses of the same target structure and comparing their results to data gathered from a 1/8-scale experiment of the structure in question.
Secretion of Glycosylated Pro–B-Type Natriuretic Peptide from Normal Cardiomyocytes
Authors: Tonne Jason M , Campbell Jarryd M , Cataliotti Alessandro , Ohmine Seiga , Thatava Tayaramma , Sakuma Toshie , Macheret Fima , Huntley Brenda K , Burnett John C , Ikeda Yasuhiro
Published: April 2011

BACKGROUND

B-type natriuretic peptide (BNP), a key cardiac hormone in cardiorenal homeostasis, is produced as a 108 amino acid prohormone, proBNP1-108, which is converted to a biologically active peptide BNP1-32 and an inactive N-terminal (NT)-proBNP1-76. The widely accepted model is that the normal heart releases a proteolytically processed BNP1-32 and NT-proBNP, whereas the diseased heart secretes high amounts of unprocessed/glycosylated proBNP1-108 or inappropriately processed BNPs. In contrast, circulating proBNP1-108 has recently been identified in healthy individuals, indicating that the normal heart also secretes unprocessed proBNP1-108. However, the mechanism of proBNP1-108 secretion from the normal heart remains elusive. Our goal was to determine the molecular mechanisms underlying proBNP1-108 intracellular trafficking and secretion from the normal heart.

METHODS

We expressed preproBNP in cardiomyocytes, and determined the subcellular localization and dominant intracellular and extracellular forms of BNP.

RESULTS

Intracellular immunoreactive BNPs were first accumulated in the Golgi apparatus, and then distributed throughout the cytoplasm as secretory vesicles. The predominant intracellular form of BNP was nonglycosylated proBNP1-108, rather than BNP1-32. Glycosylated proBNP1-108, but not nonglycosylated proBNP1-108, was detected as the major extracellular form in the culture supernatants of preproBNP-expressing cell lines and primary human cardiomyocytes. Ablation of O-glycosylation of proBNP1-108 at T71 residue, near the convertase recognition site, reduced the extracellular proBNP1-108 and increased extracellular BNP1-32.

CONCLUSIONS

Intracellular proBNP trafficking occurs through a conventional Golgi–endoplasmic reticulum pathway. Glycosylation of proBNP1-108 controls the stability and processing of extracellular proBNP1-108. Our data establish a new BNP secretion model in which the normal cardiac cells secrete glycosylated proBNP1-108.
Die Schönste dem Nachbarn. Die Verabschiedung des Brautwerbungsschemas in der ›Kudrun‹
Authors: Dörrich Corinna
Published: April 2011

In Kudrun, the narrative of the dangerous bridal quest is presented in an elaborate yet typical way in the so-called Hilde-section. The ›bridal-quest‹ in the Kudrun-section is, however, just as essential for the plot. This essay will show that in the Kudrun-section the treatment of the bridal quest is not limited to variations and repetitions of this narrative sequence, but rather the central premises, basic rules and elements, such as the emphasis on long-distance romance and the premise that the best man wins the most beautiful wife, are challenged by complicating the narrative with three different suitors for a single bride. In this way the text replaces the principle tenets of the literary scheme with pragmatic arguments, which reflect contemporary politics. Although one would expect Siegfried, the most powerful of the three, or Hartmut, who most closely fulfils the expectations of the scheme, to win Kudrun's hand, it is Herwig, the aggressive and socially inferior neighbour, who is pacified by winning the bride.
Die Leser des ›Secretum‹ im 15. Jahrhundert Außerhalb Italiens. Beobachtungen anhand der Handschriften
Authors: de Hartmann Carmen Cardelle
Published: April 2011

In this article the catalogue entries of Petrarch's ›Secretum‹ manuscripts in England, France, the German area – including Bohemia – and Spain are examined in order to find clues about the work's audience. It becomes apparent that it is not possible to distinguish (as has occasionally been done) between a monastic and a humanistic audience of Petrarch's Latin oeuvre. The ›Secretum‹ was often read in the cloister and the author explores the causes of this interest. She argues that Petrarch begins this work by evoking conventions of monastic literature, only to subvert them in the following dialogue, and thus present a new model of spiritual life.
Anatomical reference frame versus planar analysis: implications for the kinematics of the rat hindlimb during locomotion
Authors: João Filipa , Amado Sandra , Veloso António , Armada-da-Silva Paulo , Maurício Ana C.
Published: April 2011

No abstract available
Globally Altered Structural Brain Network Topology in Grapheme-Color Synesthesia
Authors: Hänggi Jürgen , Wotruba Diana , Jäncke Lutz
Published: April 2011

Synesthesia is a perceptual phenomenon in which stimuli in one particular modality elicit a sensation within the same or another sensory modality (e.g., specific graphemes evoke the perception of particular colors). Grapheme-color synesthesia (GCS) has been proposed to arise from abnormal local cross-activation between grapheme and color areas because of their hyperconnectivity. Recently published studies did not confirm such a hyperconnectivity, although morphometric alterations were found in occipitotemporal, parietal, and frontal regions of synesthetes. We used magnetic resonance imaging surface-based morphometry and graph-theoretical network analyses to investigate the topology of structural brain networks in 24 synesthetes and 24 nonsynesthetes. Connectivity matrices were derived from region-wise cortical thickness correlations of 2366 different cortical parcellations across the whole cortex and from 154 more common brain divisions as well. Compared with nonsynesthetes, synesthetes revealed a globally altered structural network topology as reflected by reduced small-worldness, increased clustering, increased degree, and decreased betweenness centrality. Connectivity of the fusiform gyrus (FuG) and intraparietal sulcus (IPS) was changed as well. Hierarchical modularity analysis revealed increased intramodular and intermodular connectivity of the IPS in GCS. However, connectivity differences in the FuG and IPS showed a low specificity because of global changes. We provide first evidence that GCS is rooted in a reduced small-world network organization that is driven by increased clustering suggesting global hyperconnectivity within the synesthetes' brain. Connectivity alterations were widespread and not restricted to the FuG and IPS. Therefore, synesthetic experience might be only one phenotypic manifestation of the globally altered network architecture in GCS.
A Unique Role of RGS9-2 in the Striatum as a Positive or Negative Regulator of Opiate Analgesia
Authors: Psigfogeorgou Kassi , Terzi Dimitra , Papachatzaki Maria Martha , Varidaki Artemis , Ferguson Deveroux , Gold Stephen J. , Zachariou Venetia
Published: April 2011

The signaling molecule RGS9-2 is a potent modulator of G-protein-coupled receptor function in striatum. Our earlier work revealed a critical role for RGS9-2 in the actions of the μ-opioid receptor (MOR) agonist morphine. In this study, we demonstrate that RGS9-2 may act as a positive or negative modulator of MOR-mediated behavioral responses in mice depending on the agonist administered. Paralleling these findings we use coimmunoprecipitation assays to show that the signaling complexes formed between RGS9-2 and Gα subunits in striatum are determined by the MOR agonist, and we identify RGS9-2 containing complexes associated with analgesic tolerance. In striatum, MOR activation promotes the formation of complexes between RGS9-2 and several Gα subunits, but morphine uniquely promotes an association between RGS9-2 and Gαi3. In contrast, RGS9-2/Gαq complexes assemble after acute application of several MOR agonists but not after morphine application. Repeated morphine administration leads to the formation of distinct complexes, which contain RGS9-2, Gβ5, and Gαq. Finally, we use simple pharmacological manipulations to disrupt RGS9-2 complexes formed during repeated MOR activation to delay the development of analgesic tolerance to morphine. Our data provide a better understanding of the brain-region-specific signaling events associated with opiate analgesia and tolerance and point to pharmacological approaches that can be readily tested for improving chronic analgesic responsiveness.
Grasping Neurons of Monkey Parietal and Premotor Cortices Encode Action Goals at Distinct Levels of Abstraction during Complex Action Sequences
Authors: Bonini Luca , Ugolotti Serventi Francesca , Simone Luciano , Rozzi Stefano , Ferrari Pier Francesco , Fogassi Leonardo
Published: April 2011

Natural actions are formed by distinct motor acts, each of which is endowed with its own motor purpose (i.e., grasping), chained together to attain the final action goal. Previous studies have shown that grasping neurons of parietal area PFG and premotor area F5 can code the goal of simple actions in which grasping is embedded. While during simple actions the target is usually visible, directly cueing the final goal, during complex action sequences is often concealed and has to be kept in mind to shape action unfolding. The aim of this study was to assess the relative contribution of sensory-cued or memory-driven information about the final goal to PFG and F5 grasping neurons activity. To this purpose, we trained two monkeys to perform complex action sequences, each including two successive grasping acts, aimed at specific final goals (eating or placing). We recorded 122 PFG and 89 F5 neurons. Forty-seven PFG and 26 F5 neurons displayed action goal selectivity only during the late phase of the action, when sensory information cueing the action goal became available. Reward contingency did not affect neuronal selectivity. Notably, 17 PFG neurons reflected the final goal from the early phase of action unfolding, when only memory-driven information was available. Crucially, when monkeys were prevented from obtaining such information before action onset, neurons lost their early selectivity. Our findings suggest that external sensory cues and individual's motor intention integrate at different level of abstraction within a large anatomo-functional network, encompassing parietal and premotor cortices.
Amyloid β-Induced Impairments in Hippocampal Synaptic Plasticity Are Rescued by Decreasing Mitochondrial Superoxide
Authors: Ma Tao , Hoeffer Charles A. , Wong Helen , Massaad Cynthia A. , Zhou Ping , Iadecola Costantino , Murphy Michael P. , Pautler Robia G. , Klann Eric
Published: April 2011

Generation of reactive oxygen species (ROS) causes cellular oxidative damage and has been implicated in the etiology of Alzheimer's disease (AD). In contrast, multiple lines of evidence indicate that ROS can normally modulate long-term potentiation (LTP), a cellular model for memory formation. We recently showed that decreasing the level of superoxide through the overexpression of mitochondrial superoxide dismutase (SOD-2) prevents memory deficits in the Tg2576 mouse model of AD. In the current study, we explored whether AD-related LTP impairments could be prevented when ROS generation from mitochondria was diminished either pharmacologically or via genetic manipulation. In wild-type hippocampal slices treated with exogenous amyloid β peptide (Aβ1-42) and in slices from APP/PS1 mutant mice that model AD, LTP was impaired. The LTP impairments were prevented by MitoQ, a mitochondria-targeted antioxidant, and EUK134, an SOD and catalase mimetic. In contrast, inhibition of NADPH oxidase either by diphenyliodonium (DPI) or by genetically deleting gp91phox, the key enzymatic component of NADPH oxidase, had no effect on Aβ-induced LTP blockade. Moreover, live staining with MitoSOX Red, a mitochondrial superoxide indicator, combined with confocal microscopy, revealed that Aβ-induced superoxide production could be blunted by MitoQ, but not DPI, in agreement with our electrophysiological findings. Finally, in transgenic mice overexpressing SOD-2, Aβ-induced LTP impairments and superoxide generation were prevented. Our data suggest a causal relationship between mitochondrial ROS imbalance and Aβ-induced impairments in hippocampal synaptic plasticity.
Circuit-Specific Intracortical Hyperconnectivity in Mice with Deletion of the Autism-AssociatedMetReceptor Tyrosine Kinase
Authors: Qiu Shenfeng , Anderson Charles T. , Levitt Pat , Shepherd Gordon M. G.
Published: April 2011

Local hyperconnectivity in the neocortex is a hypothesized pathophysiological state in autism spectrum disorder (ASD).MET, a receptor tyrosine kinase that regulates dendrite and spine morphogenesis, has been established as a risk gene for ASD. Here, we analyzed the synaptic circuit organization of identified pyramidal neurons in the anterior frontal cortex of mice with a dorsal pallium-derived, conditional knock-out (cKO) ofMet. Synaptic mapping by glutamate uncaging identified layer 2/3 as the main source of local excitatory input to layer 5 projection neurons in controls. In both cKO and heterozygotes, this pathway was stronger by a factor of ∼2. This increase was both sublayer and projection-class specific, restricted to corticostriatal neurons in upper layer 5B and not neighboring corticopontine neurons. Paired recordings in cKO slices demonstrated increased unitary connectivity. We propose that excitatory hyperconnectivity in specific neocortical microcircuits constitutes a physiological basis for Met-mediated ASD risk.
Genetic and Environmental Factors Shape Infant Sleep Patterns: A Study of 18-Month-Old Twins
Authors: Brescianini Sonia , Volzone Anna , Fagnani Corrado , Patriarca Valeria , Grimaldi Valentina , Lanni Roberta , Serino Laura , Mastroiacovo Pierpaolo , Antonietta Stazi Maria
Published: April 2011

OBJECTIVE:

Between 25% and 30% of children and adolescents experience sleep disorders. These disorders are complex phenotypes that are regulated by many genes, the environment, and gene-environment interactions. The objective of this study was to evaluate the contribution of genetic and environmental factors to sleep behaviors in early childhood and to contribute to the knowledge on appropriate therapeutic approaches, using a twin design.

PATIENTS AND METHODS:

Data on sleeping behavior were collected from 314 18-month-old twin pairs (127 monozygotic and 187 dizygotic)using a parent-rated questionnaire. We used structural equation modeling to estimate genetic and environmental variance components for different sleep behaviors (cosleeping, sleep duration, and night awakenings).

RESULTS:

Shared environment explained almost all (98.3%) of the total variance in cosleeping. Sleep duration was substantially influenced by shared environmental factors (64.1% nocturnal sleep and 61.2% diurnal sleep), with a moderate contribution of additive genetic effects (30.8% and 36.3% for nocturnal and diurnal sleep, respectively). For nocturnal waking episodes, we found a shared environmental contribution of 63.2% and a heritability estimate of 35.3%.

CONCLUSIONS:

Most sleep disturbances during early childhood are explained by common shared environmental factors, and behavioral interventions adopted by parents and focused on modifying sleep behavior could contribute to solving sleep disturbances in this age group. However, the influence of genetic factors should not be underestimated, and research in this area could clarify the physiologic architecture of sleeping and contribute to selecting appropriate personalized therapeutic approaches.
Everolimus Induces Rapid Plasma Glucose Normalization in Insulinoma Patients by Effects on Tumor As Well As Normal Tissues
Authors: Fiebrich Helle-Brit , Siemerink Ester J.M. , Brouwers Adrienne H. , Links Thera P. , Remkes Wouter S. , Hospers Geke A.P. , Vries Elisabeth G. E.
Published: April 2011

Background.

Mammalian target of rapamycin inhibitor everolimus administered to four insulinoma patients rapidly controlled hypoglycemia (Kulke et al., N Engl J Med 2009;360:195–197). We wanted to identify the kinetics of everolimus effects on controlling hypoglycemia and understand underlying mechanisms.

Methods.

Three consecutive patients with a metastasized symptomatic insulinoma were started on 100 μg of octreotide subcutaneously three times daily. Because of persisting hypoglycemias, treatment with daily 10 mg of oral everolimus was initiated. Serial plasma glucose levels and serum insulin levels were measured. Computer tomography (CT) scans were performed before and after 2 and 5 months of treatment. [18F]fluoro-2-deoxy-d-glucose positron emission tomography (18F-FDG-PET) scans, to visualize glucose metabolism, were made before and after 2 weeks, 5 weeks, and 5 months of treatment. The 18F-FDG uptake was quantified as the maximum standardized uptake value.

Results.

All patients achieved control of hypoglycemia on everolimus within 14 days. Insulin levels were 2.5- to 6.3-fold elevated before start of treatment and declined 14%–64% after 4 weeks of treatment. CT scans showed stable disease at 2 months in all patients, with progressive disease after 5 months in one. Before treatment, both the tumor lesions and the muscles and myocardium showed high 18F-FDG uptake. Everolimus reduced tumor and muscle 18F-FDG uptake after 2 weeks by 26% ± 14% and 19% ± 41%, and after 5 months by 31% ± 13% and 27% ± 41%.

Conclusions.

Everolimus normalizes plasma glucose levels in metastatic insulinoma within 14 days, coinciding with a lower glucose uptake in tumor and muscles and declining (pro)insulin levels. This effect on tumor as well as normal tissues explains the rapid controlling of hypoglycemia.