bluuebunny/crossref_metadata_2025 huggingface dataset:
RECENT DEVELOPMENTS IN NEMATOGENIC BENT-CORE MESOGENS: AN X-RAY DIFFRACTION PERSPECTIVE
Authors: VITA FRANCESCO , PLACENTINO IMMACOLATA F. , FRANCESCANGELI ORIANO
Published: February 2012

Bent-core mesogens are attracting great attention because of their potentially biaxial and polar nematic phase. In this paper, we review the results of our recent X-ray diffraction studies on the nematic phase of oxadiazole-based mesogens. The evolution of the small-angle diffraction signal with temperature points to the existence of nano-sized cybotactic clusters, characterized by short-range smectic-like fluctuations. However, in contrast to classical cybotaxis of calamitic nematics, these fluctuations do not have a pretransitional nature. They explain most of the extraordinary properties of bent-core mesogens and, in particular, are responsible for the unique ferroelectric response exhibited by one of our compounds.
FACET PREPARATION OF SILICON NANO-WAVEGUIDES BY CLEAVING THE SOI CHIP
Authors: MAHDI SHAIMAA , GREHN MORITZ , AL-SAADI AWS , HÖFNER MICHAEL , MEISTER STEFAN , EICHLER HANS J.
Published: February 2012

Optical facet preparation of silicon-on-insulator (SOI) waveguides was done by polishing after saw dicing or cleaving after two different techniques of scoring by a mechanical saw and fs-laser. Cleaving after fs-laser scoring leads to smooth facet surface of air covered SOI waveguides; polishing after dicing is more efficient with SiO2covered waveguides. The prepared end facets were investigated using an atomic force microscope (AFM) and scanning electron microscopy (SEM). The SOI waveguides were characterized by optical transmission of telecommunication wavelength (1.5 μm).
DIAGNOSING ASSETS IMPAIRMENT BY USING RANDOM FORESTS MODEL
Authors: CHEN CHING-LUNG , WU CHEI-WEI
Published: February 2012

This study develops a diagnosing model to examine the outcomes of assets write-off in enriching the literatures of assets impairment. Prior studies employed the Logit, linear and Tobit regression models to classify the determination of assets impairment and to diagnose the magnitude of the impairment, respectively. However, the drivers of assets write-off are somewhat complicated explicitly or implicitly, these models are unlikely to provide fairly satisfactory results. To improve the diagnosis, the Random Forests model is used for the classification determining and the magnitude diagnosing of assets impairment in this study. The result reveals that the Random Forests model outperforms the Logit and linear regression models in each case with variables selected by individual wrapping approach. This study also demonstrates diagnostic checks for both models with similar selected variables. The results are robust to these various specifications.
TWO GENERALIZATIONS OF AGGREGATED UNCERTAINTY MEASURE FOR EVALUATION OF DEZERT–SMARANDACHE THEORY
Authors: KHODABANDEH MAHDI , MOHAMMAD-SHAHRI ALIREZA
Published: February 2012

Generality of the model which is used in Dezert–Smarandache Theory (DSmT) rather than other fusion algorithms such as Dempster–Shafer theory and capability of DSmT for dealing with highly conflict problems are two main reasons to prefer DSmT for decision-making systems. Aggregated uncertainty measure, which is called AU measure, has been introduced for Dempster–Shafer theory as one of the best presented ways to quantify the total uncertainty or the ambiguity of a belief function. Since AU cannot be applied to DSmT, two generalized aggregated uncertainty measures for DSmT, which are called GAU1 measure and GAU2 measure, are proposed in this paper. The GAU1 measure is developed by extension of the frame of discernment with distinct sub-events. The GAU2 measure is developed by considering new conditions on probability assignments which are used in the uncertainty measure. The new conditions are the difference of this measure with AU measure. A rigorous discussion is presented to validate that the proposed uncertainty measures holds on the requirements for an uncertainty measure. Finally evaluation of uncertainty in a DSmT-based localization problem is presented to show how to apply the generalized uncertainty measures, GAU1 and GAU2.
EVALUATION OF CLASSIFICATION ALGORITHMS USING MCDM AND RANK CORRELATION
Authors: KOU GANG , LU YANQUN , PENG YI , SHI YONG
Published: February 2012

Classification algorithm selection is an important issue in many disciplines. Since it normally involves more than one criterion, the task of algorithm selection can be modeled as multiple criteria decision making (MCDM) problems. Different MCDM methods evaluate classifiers from different aspects and thus they may produce divergent rankings of classifiers. The goal of this paper is to propose an approach to resolve disagreements among MCDM methods based on Spearman's rank correlation coefficient. Five MCDM methods are examined using 17 classification algorithms and 10 performance criteria over 11 public-domain binary classification datasets in the experimental study. The rankings of classifiers are quite different at first. After applying the proposed approach, the differences among MCDM rankings are largely reduced. The experimental results prove that the proposed approach can resolve conflicting MCDM rankings and reach an agreement among different MCDM methods.
Herbal constituent sequoyitol improves hyperglycemia and glucose intolerance by targeting hepatocytes, adipocytes, and β-cells
Authors: Shen Hong , Shao Mengle , Cho Kae Won , Wang Suqing , Chen Zheng , Sheng Liang , Wang Ting , Liu Yong , Rui Liangyou
Published: February 2012

The prevalence of insulin resistance and type 2 diabetes increases rapidly; however, treatments are limited. Various herbal extracts have been reported to reduce blood glucose in animals with either genetic or dietary type 2 diabetes; however, plant extracts are extremely complex, and leading compounds remain largely unknown. Here we show that 5- O-methyl- myo-inositol (also called sequoyitol), a herbal constituent, exerts antidiabetic effects in mice. Sequoyitol was chronically administrated into ob/ob mice either orally or subcutaneously. Both oral and subcutaneous administrations of sequoyitol decreased blood glucose, improved glucose intolerance, and enhanced insulin signaling in ob/ob mice. Sequoyitol directly enhanced insulin signaling, including phosphorylation of insulin receptor substrate-1 and Akt, in both HepG2 cells (derived from human hepatocytes) and 3T3-L1 adipocytes. In agreement, sequoyitol increased the ability of insulin to suppress glucose production in primary hepatocytes and to stimulate glucose uptake into primary adipocytes. Furthermore, sequoyitol improved insulin signaling in INS-1 cells (a rat β-cell line) and protected INS-1 cells from streptozotocin- or H2O2-induced injury. In mice with streptozotocin-induced β-cell deficiency, sequoyitol treatments increased plasma insulin levels and decreased hyperglycemia and glucose intolerance. These results indicate that sequoyitol, a natural, water-soluble small molecule, ameliorates hyperglycemia and glucose intolerance by increasing both insulin sensitivity and insulin secretion. Sequoyitol appears to directly target hepatocytes, adipocytes, and β-cells. Therefore, sequoyitol may serve as a new oral diabetes medication.
Molecular Mechanism of Pancreatic and Salivary Gland Fluid and HCO3−Secretion
Authors: Lee Min Goo , Ohana Ehud , Park Hyun Woo , Yang Dongki , Muallem Shmuel
Published: February 2012

Fluid and HCO3−secretion is a vital function of all epithelia and is required for the survival of the tissue. Aberrant fluid and HCO3−secretion is associated with many epithelial diseases, such as cystic fibrosis, pancreatitis, Sjögren's syndrome, and other epithelial inflammatory and autoimmune diseases. Significant progress has been made over the last 20 years in our understanding of epithelial fluid and HCO3−secretion, in particular by secretory glands. Fluid and HCO3−secretion by secretory glands is a two-step process. Acinar cells secrete isotonic fluid in which the major salt is NaCl. Subsequently, the duct modifies the volume and electrolyte composition of the fluid to absorb the Cl−and secrete HCO3−. The relative volume secreted by acinar and duct cells and modification of electrolyte composition of the secreted fluids varies among secretory glands to meet their physiological functions. In the pancreas, acinar cells secrete a small amount of NaCl-rich fluid, while the duct absorbs the Cl−and secretes HCO3−and the bulk of the fluid in the pancreatic juice. Fluid secretion appears to be driven by active HCO3−secretion. In the salivary glands, acinar cells secrete the bulk of the fluid in the saliva that is driven by active Cl−secretion and contains high concentrations of Na+and Cl−. The salivary glands duct absorbs both the Na+and Cl−and secretes K+and HCO3−. In this review, we focus on the molecular mechanism of fluid and HCO3−secretion by the pancreas and salivary glands, to highlight the similarities of the fundamental mechanisms of acinar and duct cell functions, and to point out the differences to meet gland-specific secretions.
Epoxides and Soluble Epoxide Hydrolase in Cardiovascular Physiology
Authors: Imig John D.
Published: February 2012

Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites that importantly contribute to vascular and cardiac physiology. The contribution of EETs to vascular and cardiac function is further influenced by soluble epoxide hydrolase (sEH) that degrades EETs to diols. Vascular actions of EETs include dilation and angiogenesis. EETs also decrease inflammation and platelet aggregation and in general act to maintain vascular homeostasis. Myocyte contraction and increased coronary blood flow are the two primary EET actions in the heart. EET cell signaling mechanisms are tissue and organ specific and provide significant evidence for the existence of EET receptors. Additionally, pharmacological and genetic manipulations of EETs and sEH have demonstrated a contribution for this metabolic pathway to cardiovascular diseases. Given the impact of EETs to cardiovascular physiology, there is emerging evidence that development of EET-based therapeutics will be beneficial for cardiovascular diseases.
Controlling the Stem Cell Compartment and Regeneration In Vivo: The Role of Pluripotency Pathways
Authors: Greenow Kirsty , Clarke Alan R.
Published: February 2012

Since the realization that embryonic stem cells are maintained in a pluripotent state through the interplay of a number of key signal transduction pathways, it is becoming increasingly clear that stemness and pluripotency are defined by the complex molecular convergence of these pathways. Perhaps this has most clearly been demonstrated by the capacity to induce pluripotency in differentiated cell types, so termed iPS cells. We are therefore building an understanding of how cells may be maintained in a pluripotent state, and how we may manipulate cells to drive them between committed and pluripotent compartments. However, it is less clear how cells normally pass in and out of the stem cell compartment under normal and diseased physiological states in vivo, and indeed, how important these pathways are in these settings. It is also clear that there is a potential “dark side” to manipulating the stem cell compartment, as deregulation of somatic stem cells is being increasingly implicated in carcinogenesis and the generation of “cancer stem cells.” This review explores these relationships, with a particular focus on the role played by key molecular regulators of stemness in tissue repair, and the possibility that a better understanding of this control may open the door to novel repair strategies in vivo. The successful development of such strategies has the potential to replace or augment intervention-based strategies (cell replacement therapies), although it is clear they must be developed with a full understanding of how such approaches might also influence tumorigenesis.
Hypoxic Pulmonary Vasoconstriction
Authors: Sylvester J. T. , Shimoda Larissa A. , Aaronson Philip I. , Ward Jeremy P. T.
Published: February 2012

It has been known for more than 60 years, and suspected for over 100, that alveolar hypoxia causes pulmonary vasoconstriction by means of mechanisms local to the lung. For the last 20 years, it has been clear that the essential sensor, transduction, and effector mechanisms responsible for hypoxic pulmonary vasoconstriction (HPV) reside in the pulmonary arterial smooth muscle cell. The main focus of this review is the cellular and molecular work performed to clarify these intrinsic mechanisms and to determine how they are facilitated and inhibited by the extrinsic influences of other cells. Because the interaction of intrinsic and extrinsic mechanisms is likely to shape expression of HPV in vivo, we relate results obtained in cells to HPV in more intact preparations, such as intact and isolated lungs and isolated pulmonary vessels. Finally, we evaluate evidence regarding the contribution of HPV to the physiological and pathophysiological processes involved in the transition from fetal to neonatal life, pulmonary gas exchange, high-altitude pulmonary edema, and pulmonary hypertension. Although understanding of HPV has advanced significantly, major areas of ignorance and uncertainty await resolution.
Simvastatin Blocks Blood-Brain Barrier Disruptions Induced by Elevated Cholesterol Both In Vivo and In Vitro
Authors: Jiang Xijuan , Guo Maojuan , Su Jinling , Lu Bin , Ma Dongming , Zhang Ruifeng , Yang Lin , Wang Qiang , Ma Yiwen , Fan Yingchang
Published: February 2012

Background. Hypercholesterolemia and disruptions of the blood brain barrier (BBB) have been implicated as underlying mechanisms in the pathogenesis of Alzheimer's disease (AD). Simvastatin therapy may be of benefit in treating AD; however, its mechanism has not been yet fully understood.Objective. To explore whether simvastatin could block disruption of BBB induced by cholesterol both in vivo and in vitro.Methods. New Zealand rabbits were fed cholesterol-enriched diet with or without simvastatin. Total cholesterol of serum and brain was measured. BBB dysfunction was evaluated. To further test the results in vivo, rat brain microvascular endothelial cells (RBMECs) were stimulated with cholesterol in the presence/absence of simvastatin in vitro. BBB disruption was evaluated.Results. Simvastatin blocked cholesterol-rich diet induced leakage of Evan's blue dye. Cholesterol content in the serum was affected by simvastatin, but not brain cholesterol. Simvastatin blocked high-cholesterol medium-induced decrease in TEER and increase in transendothelial FITC-labeled BSA Passage in RBMECs.Conclusions. The present study firstly shows that simvastatin improves disturbed BBB function both in vivo and in vitro. Our data provide that simvastatin may be useful for attenuating disturbed BBB mediated by hypercholesterolemia.
Reconstructing Organophosphorus Pesticide Doses Using the Reversed Dosimetry Approach in a Simple Physiologically-Based Pharmacokinetic Model
Authors: Lu Chensheng , Andres Leo
Published: February 2012

We illustrated the development of a simple pharmacokinetic (SPK) model aiming to estimate the absorbed chlorpyrifos doses using urinary biomarker data, 3,5,6-trichlorpyridinol as the model input. The effectiveness of the SPK model in the pesticide risk assessment was evaluated by comparing dose estimates using different urinary composite data. The dose estimates resulting from the first morning voids appeared to be lower than but not significantly different to those using before bedtime, lunch or dinner voids. We found similar trend for dose estimates using three different urinary composite data. However, the dose estimates using the SPK model for individual children were significantly higher than those from the conventional physiologically based pharmacokinetic (PBPK) modeling using aggregate environmental measurements of chlorpyrifos as the model inputs. The use of urinary data in the SPK model intuitively provided a plausible alternative to the conventional PBPK model in reconstructing the absorbed chlorpyrifos dose.
Retroperitoneal Bronchogenic Cyst Mimicking Hydatid Liver: A Case Report
Authors: Parray Fazl Q. , Sherwani Afak Yusuf , Dangroo Sajad Ahmad , Bisati Rafia Aziz , Malik Nighat Shaffi
Published: February 2012

Bronchogenic cysts frequently occur in the mediastinum. They may be rarely encountered in the abdomen and retroperitoneum. Bronchogenic cysts can in fact mimic hydatid cysts. We report a case of retroperitoneal bronchogenic cyst below the right hemidiaphragm mimicking a hydatid cyst of the liver in a 30-year-old female.
Ichthyofauna Used in Traditional Medicine in Brazil
Authors: El-Deir Ana Carla Asfora , Collier Carolina Alves , Almeida Neto Miguel Santana de , Silva Karina Maria de Souza , Policarpo Iamara da Silva , Araújo Thiago Antonio S. , Alves Rômulo Romeu Nóbrega , de Albuquerque Ulysses Paulino , Moura Geraldo Jorge Barbosa de
Published: February 2012

Fish represent the group of vertebrates with the largest number of species and the largest geographic distribution; they are also used in different ways by modern civilizations. The goal of this study was to compile the current knowledge on the use of ichthyofauna in zootherapeutic practices in Brazil, including ecological and conservational commentary on the species recorded. We recorded a total of 85 species (44 fresh-water species and 41 salt-water species) used for medicinal purposes in Brazil. The three most commonly cited species wereHoplias malabaricus, Hippocampus reidi,andElectrophorus electricus. In terms of conservation status, 65% of species are in the “not evaluated” category, and 14% are in the “insufficient data” category. Three species are in the “vulnerable” category:Atlantoraja cyclophora,Balistes vetula,andHippocampus erectus. Currently, we cannot avoid considering human pressure on the population dynamics of these species, which is an essential variable for the conservation of the species and the ecosystems in which they live and for the perpetuation of traditional medical practices.
Clinical Manifestations and Diagnosis of Acromegaly
Authors: Lugo Gloria , Pena Lara , Cordido Fernando
Published: February 2012

Acromegaly and gigantism are due to excess GH production, usually as a result of a pituitary adenoma. The incidence of acromegaly is 5 cases per million per year and the prevalence is 60 cases per million. Clinical manifestations in each patient depend on the levels of GH and IGF-I, age, tumor size, and the delay in diagnosis. Manifestations of acromegaly are varied and include acral and soft tissue overgrowth, joint pain, diabetes mellitus, hypertension, and heart and respiratory failure. Acromegaly is a disabling disease that is associated with increased morbidity and reduced life expectancy. The diagnosis is based primarily on clinical features and confirmed by measuring GH levels after oral glucose loading and the estimation of IGF-I. It has been suggested that the rate of mortality in patients with acromegaly is correlated with the degree of control of GH. Adequately treated, the relative mortality risk can be markedly reduced towards normal.
An Empirical Investigation on System and Statement Level Parallelism Strategies for Accelerating Scatter Search Using Handel‐C and Impulse‐C
Authors: Walton M. , Ahmed O. , Grewal G. , Areibi S.
Published: February 2012

Scatter Search is an effective and established population‐based metaheuristic that has been used to solve a variety of hard optimization problems. However, the time required to find high‐quality solutions can become prohibitive as problem sizes grow. In this paper, we present a hardware implementation of Scatter Search on a field-programmable gate array (FPGA). Our objective is to improve the run time of Scatter Search by exploiting the potentially massive performance benefits that are available through the native parallelism in hardware. When implementing Scatter Search we employ two different high-level languages (HLLs): Handel‐C and Impulse‐C. Our empirical results show that by effectively exploiting source‐code optimizations, data parallelism, and pipelining, a 28x speed up over software can be achieved.
Statistical Analysis of Ratio of Random Variables and Its Application in Performance Analysis of Multihop Wireless Transmissions
Authors: Mekić Edis , Stefanović Mihajlo , Spalević Petar , Sekulović Nikola , Stanković Ana
Published: February 2012

The distributions of random variables are of interest in many areas of science. In this paper, the probability density function (PDF) and cumulative distribution function (CDF) of ratio of products of two random variables and random variable are derived. Random variables are described with Rayleigh, Nakagami‐m, Weibull, and α‐μ distributions. An application of obtained results in performance analysis of multihop wireless communication systems in different transmission environments described in detail. The proposed mathematical analysis is also complemented by various graphically presented numerical results.
Semiautomated Multimodal Breast Image Registration
Authors: Curtis Charlotte , Frayne Richard , Fear Elise
Published: February 2012

Consideration of information from multiple modalities has been shown to have increased diagnostic power in breast imaging. As a result, new techniques such as microwave imaging continue to be developed. Interpreting these novel image modalities is a challenge, requiring comparison to established techniques such as the gold standard X-ray mammography. However, due to the highly deformable nature of breast tissues, comparison of 3D and 2D modalities is a challenge. To enable this comparison, a registration technique was developed to map features from 2D mammograms to locations in the 3D image space. This technique was developed and tested using magnetic resonance (MR) images as a reference 3D modality, as MR breast imaging is an established technique in clinical practice. The algorithm was validated using a numerical phantom then successfully tested on twenty-four image pairs. Dice's coefficient was used to measure the external goodness of fit, resulting in an excellent overall average of 0.94. Internal agreement was evaluated by examining internal features in consultation with a radiologist, and subjective assessment concludes that reasonable alignment was achieved.
The Dark Side of E2F1: In Transit beyond Apoptosis
Authors: Engelmann David , Pützer Brigitte M.
Published: February 2012

E2F1 plays a critical role in cell-cycle progression and the induction of apoptosis in response to DNA damage. The latest evidence has uncovered that this tumor suppressor is most relevant for cancer progression and chemoresistance. Increased abundance of E2F1 triggers invasion and metastasis by activating growth receptor signaling pathways, which in turn promote an antiapoptotic tumor environment. The data shed light on the molecular mechanisms underlying E2F1-induced prometastatic activity and predict its radical switch from a mediator of cell death toward an accelerator of tumor progression. This raises the perspective of new drug targets at late-stage cancer. Cancer Res; 72(3); 571–5. ©2012 AACR.
Cancer Stem Cells: Distinct Entities or Dynamically Regulated Phenotypes?
Authors: Li Yunqing , Laterra John
Published: February 2012

The origins of tumor-propagating neoplastic stem-like cells [cancer stem cells (CSC)] and their relationship to the bulk population of tumor cells that lack stem-like tumor-propagating features (i.e., transit-amplifying cancer progenitor cells) remain unclear. Recent findings from multiple laboratories show that cancer progenitor cells have the capacity to dedifferentiate and acquire a stem-like phenotype in response to either genetic manipulation or environmental cues. These findings suggest that CSCs and relatively differentiated progenitors coexist in dynamic equilibrium and are subject to bidirectional conversion. In this review, we discuss emerging concepts regarding the stem-like phenotype, its acquisition by cancer progenitor cells, and the molecular mechanisms involved. Understanding the dynamic equilibrium between CSCs and cancer progenitor cells is critical for the development of therapeutic strategies to deplete tumors of their tumor-propagating and treatment-resistant cell subpopulations. Cancer Res; 72(3); 576–80. ©2012 AACR.
Correlation between Gene Expression of IGF-1R Pathway Markers and Cetuximab Benefit in Metastatic Colorectal Cancer
Authors: Huang Fei , Xu Li-an , Khambata-Ford Shirin
Published: February 2012

Purpose: This study examined potential correlations between markers related to the insulin-like growth factor-1 receptor (IGF-1R) pathway and clinical benefit from the anti–epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in metastatic colorectal cancer (mCRC).

Experimental Design: Gene expression profiles for 70 pretreatment specimens from metastatic lesions of patients with chemorefractory mCRC receiving cetuximab monotherapy were analyzed using 74 predefined Gene-Chip probesets representing 33 unique IGF-1R pathway markers to determine correlations with progression-free survival (PFS) and disease control rate.

Results: Higher IGF-1R, higher GRB7, and lower INSIG2 expression were associated with longer PFS with cetuximab in univariate analyses, particularly in patients with wild-type K-Ras tumors: median, 122 versus 60 days (P = 0.01), 122 versus 57 days (P = 0.011), and 57 versus 156 days (P < 0.0001), favoring higher IGF-1R, higher GRB7, and lower INSIG2 expression, respectively. Lower IGF-1 expression was associated with a PFS benefit with cetuximab, whereas lower IGFBP3 and INSR expression levels showed trends for a PFS benefit. Lower INSIG2 expression (vs. higher expression) was associated with greater PFS in the high epiregulin-expressing group (P = 0.001), but not in the low-expressing cohort suggesting an effect independent from the previously reported effect of epiregulin expression. Lower INSIG2 expression was also associated with higher disease control rate in the overall population (51.4% vs. 11.4%; P = 0.001) and wild-type K-Ras subset (76.2% vs. 18.2%; P < 0.0001).

Conclusions: These results suggest that markers of the IGF-1R pathway may play a role in predicting benefit from cetuximab therapy in mCRC. Additional clinical studies are warranted to validate these findings. Clin Cancer Res; 18(4); 1156–66. ©2012 AACR.
Activation of β-Catenin Signaling in Androgen Receptor–Negative Prostate Cancer Cells
Authors: Wan Xinhai , Liu Jie , Lu Jing-Fang , Tzelepi Vassiliki , Yang Jun , Starbuck Michael W. , Diao Lixia , Wang Jing , Efstathiou Eleni , Vazquez Elba S. , Troncoso Patricia , Maity Sankar N. , Navone Nora M.
Published: February 2012

Purpose: To study Wnt/β-catenin in castrate-resistant prostate cancer (CRPC) and understand its function independently of the β-catenin–androgen receptor (AR) interaction.

Experimental Design: We carried out β-catenin immunocytochemical analysis, evaluated TOP-flash reporter activity (a reporter of β-catenin–mediated transcription), and sequenced the β-catenin gene in MDA prostate cancer 118a, MDA prostate cancer 118b, MDA prostate cancer 2b, and PC-3 prostate cancer cells. We knocked down β-catenin in AR-negative MDA prostate cancer 118b cells and carried out comparative gene-array analysis. We also immunohistochemically analyzed β-catenin and AR in 27 bone metastases of human CRPCs.

Results: β-Catenin nuclear accumulation and TOP-flash reporter activity were high in MDA prostate cancer 118b but not in MDA prostate cancer 2b or PC-3 cells. MDA prostate cancer 118a and MDA prostate cancer 118b cells carry a mutated β-catenin at codon 32 (D32G). Ten genes were expressed differently (false discovery rate, 0.05) in MDA prostate cancer 118b cells with downregulated β-catenin. One such gene, hyaluronan synthase 2 (HAS2), synthesizes hyaluronan, a core component of the extracellular matrix. We confirmed HAS2 upregulation in PC-3 cells transfected with D32G-mutant β-catenin. Finally, we found nuclear localization of β-catenin in 10 of 27 human tissue specimens; this localization was inversely associated with AR expression (P = 0.056, Fisher's exact test), suggesting that reduced AR expression enables Wnt/β-catenin signaling.

Conclusion: We identified a previously unknown downstream target of β-catenin, HAS2, in prostate cancer, and found that high β-catenin nuclear localization and low or no AR expression may define a subpopulation of men with bone metastatic prostate cancer. These findings may guide physicians in managing these patients. Clin Cancer Res; 18(3); 726–36. ©2011 AACR.
A Hexane Fraction of American Ginseng Suppresses Mouse Colitis and Associated Colon Cancer: Anti-inflammatory and Proapoptotic Mechanisms
Authors: Poudyal Deepak , Mai Le Phuong , Davis Tia , Hofseth Anne B. , Chumanevich Alena , Chumanevich Alexander A. , Wargovich Michael J. , Nagarkatti Mitzi , Nagarkatti Prakash S. , Windust Anthony , Hofseth Lorne J.
Published: February 2012

Ulcerative colitis is a chronic inflammatory condition associated with a high colon cancer risk. We have previously reported that American ginseng extract significantly reduced the inflammatory parameters of chemically induced colitis. The aim of this study was to further delineate the components of American ginseng that suppress colitis and prevent colon cancer. Among five different fractions of American ginseng (butanol, hexane, ethylacetate, dichloromethane, and water), a hexane fraction has particularly potent antioxidant and proapoptotic properties. The effects of this fraction were shown in a mouse macrophage cell line (ANA-1 cells), in a human lymphoblastoid cell line (TK6), and in an ex vivo model (CD4+/CD25− primary effector T cells). A key in vivo finding was that compared with the whole American ginseng extract, the hexane fraction of American ginseng was more potent in treating colitis in a dextran sodium sulfate (DSS) mouse model, as well as suppressing azoxymethane/DSS-induced colon cancer. Furthermore, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL) labeling of inflammatory cells within the colonic mesenteric lymph nodes was elevated in mice consuming DSS + the hexane fraction of American ginseng. Results are consistent with our in vitro data and with the hypothesis that the hexane fraction of American ginseng has anti-inflammatory properties and drives inflammatory cell apoptosis in vivo, providing a mechanism by which this fraction protects from colitis in this DSS mouse model. This study moves us closer to understanding the molecular components of American ginseng that suppress colitis and prevent colon cancer associated with colitis. Cancer Prev Res; 5(4); 685–96. ©2012 AACR.
Pannexin Protein Expression in the Rat Middle Cerebral Artery
Authors: Burns Alan R. , Phillips Sharon C. , Sokoya Elke M.
Published: February 2012

Background: Connexin proteins are well known to participate in cell-to-cell communication within the cerebral vasculature. Pannexins are a recently discovered family of proteins that could potentially be involved in cell-to-cell communication. Herein, we sought to determine whether pannexins are expressed in rat middle cerebral artery (MCA). Methods: A combination of RT-PCR, immunoblotting and immunohistochemistry techniques was used to characterize the expression pattern of pannexins in rat MCA. A fluorescent dye uptake approach in cultured smooth muscle cells was used to determine whether these cells have functional hemichannels. Results: We report for the first time that pannexins are expressed in the cerebral vasculature. We reveal that pannexin 1 is expressed in smooth muscle but not in endothelium and pannexin 2 is expressed in both endothelium and smooth muscle. Fluorescent dye entered cultured smooth muscle cells in the absence of extracellular calcium or when the cells were depolarized, which was prevented by the putative hemichannel blocker carbenoxolone. Conclusions: The identification of pannexins in rat MCA indicates that pannexin expression is not restricted to neuronal cells. Dye uptake in cultured smooth muscle cells exhibited properties similar to those of connexin and pannexin hemichannels, which may represent another form of cell-to-cell communication within the vasculature.
Dysregulation of Ca2+ Homeostasis in Alzheimer’s Disease: Role in Acetylcholinesterase Production and AMPA Receptor Internalization
Authors: Small David H.
Published: February 2012

Amyloid-β (Aβ)-induced Ca2+ influx into neurons has been well described since it was first reported almost 20 years ago. Ca2+ influx can disrupt mechanisms of long-term potentiation and long-term depression and increase neuronal susceptibility to excitotoxicity. Our studies show that Aβ also causes an increase in acetylcholinesterase (AChE) levels and induces AMPA receptor internalization through Ca2+-dependent mechanisms. As Aβ-induced Ca2+ entry may increase neuronal excitability, the increase in AChE and the downregulation of cell surface AMPA receptors may be part of a homeostatic mechanism which maintains normal levels of cholinergic and glutamatergic signaling.
The Role of S100a9 in the Pathogenesis of Alzheimer’s Disease: The Therapeutic Effects of S100a9 Knockdown or Knockout
Authors: Chang Keun-A , Kim Hee Jin , Suh Yoo-Hun
Published: February 2012

Neuroinflammation is one of the important pathogenic features of Alzheimer’s disease (AD). Recently, S100a9 was found to be increased within neuritic plaques and reactive glia and was proposed to participate in the inflammation associated with the pathogenesis of AD. Our study showed that S100a9 expression was increased in the brains of AD mice and AD patients. In Tg2576 mice, knockdown by short hairpin RNA or knockout of the S100a9 gene significantly reduced the neuropathology, greatly improved the learning and memory impairment and reduced the amount of Aβ and APP-CTs by increasing neprilysin and decreasing BACE activity. These results clearly show that the upregulation of the S100a9 gene plays an important role in the neuropathology and memory impairment in AD, suggesting that the knockdown and knockout of this gene have a great therapeutic potential for AD.
Acitretin, an Enhancer of Alpha-Secretase Expression, Crosses the Blood-Brain Barrier and Is Not Eliminated by P-Glycoprotein
Authors: Holthoewer David , Endres Kristina , Schuck Florian , Hiemke Christoph , Schmitt Ulrich , Fahrenholz Falk
Published: February 2012

Background: ADAM10 (a disintegrin and metalloproteinase 10) has been demonstrated to act as the main physiological α-secretase. Enzymatic activity of the α-secretase on the one hand prevents the formation of toxic Aβ peptides and on the other hand promotes the secretion of a neurotrophic and neuroprotective amyloid precursor protein fragment (APPs-α) by cleaving the amyloid precursor protein within its Aβ sequence. Enhancement of ADAM10’s gene expression may therefore present a valuable therapeutic approach for the treatment of Alzheimer’s disease (AD), where Aβ peptides are severely involved in the pathogenesis. Objective: In cell culture and in a transgenic mouse model of AD, retinoids led to increased ADAM10 expression and activity. We therefore endeavor to develop a clinical application of synthetic retinoids such as acitretin in AD. Methods: The effect of synthetic retinoids on ADAM10 gene expression was analyzed by reporter gene assays in human neuroblastoma cell line SH-SY5Y. Penetrance of acitretin into the murine brain was analyzed by high-performance liquid chromatography. P-glycoprotein (P-gp) double-knockout mice with a deficiency in both isoforms, mdr1a and 1b, were used to analyze a possible role of P-gp-dependent efflux on acitretin distribution. Results: Acitretin and tamibarotene are both potent activators of ADAM10 promoter activity. Acitretin crosses the murine blood-brain barrier and its level in the mouse brain is not reduced by P-gp. Conclusion: Synthetic retinoids and especially acitretin seem to be ideal candidates to establish an ADAM10-based AD treatment, and therefore have already entered first clinical trials.
Simultaneous Occurrence of Biphenotypic T Cell/Myeloid Lesions Involving t(12;13)(p13;q14) in a Pediatric Patient
Authors: Carneiro Borba Claudio , de Lourdes Chauffaille Maria , Saeed Sanabnai Sabri , Folloni Fernandes Juliana , Aiko Kumeda Cristina , Rodrigues Pereira Velloso Elvira Deolinda , Jarandilha dos Santos Katia , Puato Vieira Pupim Marcia , Hamerschlak Nelson , Odone Filho Vicente , Bendit Israel
Published: February 2012

This paper chronicles a 2-year-old girl who presented with acute leukemia/lymphoma syndrome of the T cell immunophenotype. At this time, the cytogenetic analysis of her bone marrow cells showed a reciprocal translocation between the short arm of chromosome 12 and the long arm of chromosome 13, t(12;13)(p13;q14). The immunophenotyping of bone marrow blast cells by flow cytometry revealed a population of cells positive for CD56, CD117, CD45, partial CD33, partial HLA-DR, CD13, CD7, CD2 and CD5. Therefore, a diagnosis of acute leukemia with a mixed T cell/myeloid phenotype was made. The patient had a poor response to classic T cell acute lymphocytic leukemia/lymphoma therapy; thus, her treatment was changed to a myeloid leukemia protocol, which produced a good response. She underwent a successful cord blood transplantation from an unrelated HLA partially matched donor. The coexistence of these two phenotypes prompts questions about the existence of clonal instability, which might influence the choice of therapy. The rarity of the t(12;13)(p13;q14) and the coexistence of T cell/myeloid markers suggest a nonrandom association. To the best of our knowledge, this is the first reported case in which a cell clone bearing a t(12;13)(p13;q14) translocation in a mixed T cell/myeloid lesion was detected.
Antihypertensive and Cardiorenal Protective Effects of SM-368229, a Novel Mineralocorticoid Receptor Antagonist, in Aldosterone/Salt-Treated Rats
Authors: Nariai Tetsuro , Fujita Katsuya , Mori Masaya , Katayama Seiji , Hori Seiji , Matsui Kazuki
Published: February 2012

The purpose of this study was to evaluate the effects of SM-368229, a novel mineralocorticoid receptor (MR) antagonist, on the blood pressure and cardiorenal injury markers in aldosterone/salt-treated hypertensive rats, in comparison to those of spironolactone (SPI). Uninephrectomized rats, given 1% NaCl to drink, were infused with aldosterone (0.75 µg/h, s.c.). In experiment 1, SM-368229 (10, 30 mg/kg) or SPI (100 mg/kg) were administered for 14 days immediately after aldosterone/salt loading. In experiment 2, SM-368229 (10 mg/kg) or SPI (100 mg/kg) were administered for 10 days after 10 days of aldosterone/salt loading. In both experiments, SM-368229 prevented the increase in systolic blood pressure, heart/kidney weights, and urinary protein/N-acetyl-β-D- glucosaminidase excretion caused by aldosterone infusion. In real-time polymerase chain reaction analysis, SM-368229 abolished aldosterone-induced gene expression levels for inflammatory, fibrosis and oxidative stress markers in hearts and kidneys. The antihypertensive effect of SM-368229 (30 mg/kg) was superior to that of SPI, and the antihypertensive and cardiorenal protective effects of SM-368229 (10 mg/kg) were similar to those of SPI (100 mg/kg) in both experiments. These results clearly demonstrated that SM-368229 strongly attenuated the progression of hypertension and exerted cardiorenal protection in aldosterone/salt-treated hypertensive rats.
Matrix Metalloproteinase (MMP)-2 Genetic Variants Modify the Circulating MMP-2 Levels in End-Stage Kidney Disease
Authors: Marson Bernardo P. , Lacchini Riccardo , Belo Vanessa , Dickel Samantha , da Costa Bartira P. , Poli de Figueiredo Carlos E. , Tanus-Santos Jose E.
Published: February 2012

Background: Matrix metalloproteinases (MMPs) play important roles in the pathophysiology of renal diseases, and imbalanced MMP-2 and its endogenous inhibitor (the tissue inhibitor of metalloproteinases-2; TIMP-2) are implicated in the vascular alterations of end-stage kidney disease (ESKD) patients. We have examined whether MMP-2 gene polymorphisms and haplotypes modify MMP-2 and TIMP-2 levels in ESKD patients as well as the effects of hemodialysis on the concentrations of these biomarkers. Methods: We determined MMP-2 and TIMP-2 plasma levels by gelatin zymography and ELISA, respectively, in 98 ESKD patients and in 38 healthy controls. Genotypes for two relevant MMP-2 polymorphisms (C–1306T and C–735T in the promoter region) were determined by TaqMan® allele discrimination assay and real-time polymerase chain reaction. The software program PHASE 2.1 was used to estimate the haplotype frequencies. Results: We found increased plasma MMP-2 and TIMP-2 levels in ESKD patients compared to controls (p < 0.05), and hemodialysis decreased MMP-2 (but not TIMP-2) levels (p < 0.05). The T allele for the C–735T polymorphism and the C-T haplotype were associated with higher MMP-2 (but not TIMP-2) levels (p < 0.05), whereas the C–1306T had no effects. Hemodialysis decreased MMP-2 (but not TIMP-2) levels independently of MMP-2 genotypes or haplotypes (p < 0.05). Conclusions: MMP-2 genotypes or haplotypes modify MMP-2 levels in ESKD patients, and may help to identify patients with increased MMP-2 activity in plasma. Hemodialysis reduces MMP-2 levels independently of MMP-2 genetic variants.
Rheb is a Critical Regulator of Autophagy During Myocardial Ischemia
Authors: Sciarretta Sebastiano , Zhai Peiyong , Shao Dan , Maejima Yasuhiro , Robbins Jeffrey , Volpe Massimo , Condorelli Gianluigi , Sadoshima Junichi
Published: February 2012

Background—

Rheb is a GTP-binding protein that promotes cell survival and mediates the cellular response to energy deprivation (ED). The role of Rheb in the regulation of cell survival during ED has not been investigated in the heart.

Methods and Results—

Rheb is inactivated during cardiomyocyte (CM) glucose deprivation (GD) in vitro, and during acute myocardial ischemia in vivo. Rheb inhibition causes mTORC1 inhibition, because forced activation of Rheb, through Rheb overexpression in vitro and through inducible cardiac-specific Rheb overexpression in vivo, restored mTORC1 activity. Restoration of mTORC1 activity reduced CM survival during GD and increased infarct size after ischemia, both of which were accompanied by inhibition of autophagy, whereas Rheb knockdown increased autophagy and CM survival. Rheb inhibits autophagy mostly through Atg7 depletion. Restoration of autophagy, through Atg7 reexpression and inhibition of mTORC1, increased cellular ATP content and reduced endoplasmic reticulum stress, thereby reducing CM death induced by Rheb activation. Mice with high-fat diet–induced obesity and metabolic syndrome (HFD mice) exhibited deregulated cardiac activation of Rheb and mTORC1, particularly during ischemia. HFD mice presented inhibition of cardiac autophagy and displayed increased ischemic injury. Pharmacological and genetic inhibition of mTORC1 restored autophagy and abrogated the increase in infarct size observed in HFD mice, but they failed to protect HFD mice in the presence of genetic disruption of autophagy.

Conclusions—

Inactivation of Rheb protects CMs during ED through activation of autophagy. Rheb and mTORC1 may represent therapeutic targets to reduce myocardial damage during ischemia, particularly in obese patients.
The Computational Power of Interactive Recurrent Neural Networks
Authors: Cabessa Jérémie , Siegelmann Hava T.
Published: February 2012

In classical computation, rational- and real-weighted recurrent neural networks were shown to be respectively equivalent to and strictly more powerful than the standard Turing machine model. Here, we study the computational power of recurrent neural networks in a more biologically oriented computational framework, capturing the aspects of sequential interactivity and persistence of memory. In this context, we prove that so-called interactive rational- and real-weighted neural networks show the same computational powers as interactive Turing machines and interactive Turing machines with advice, respectively. A mathematical characterization of each of these computational powers is also provided. It follows from these results that interactive real-weighted neural networks can perform uncountably many more translations of information than interactive Turing machines, making them capable of super-Turing capabilities.
Statistical Mechanics of Reward-Modulated Learning in Decision-Making Networks
Authors: Katahira Kentaro , Okanoya Kazuo , Okada Masato
Published: February 2012

The neural substrates of decision making have been intensively studied using experimental and computational approaches. Alternative-choice tasks accompanying reinforcement have often been employed in investigations into decision making. Choice behavior has been empirically found in many experiments to follow Herrnstein's matching law. A number of theoretical studies have been done on explaining the mechanisms responsible for matching behavior. Various learning rules have been proved in these studies to achieve matching behavior as a steady state of learning processes. The models in the studies have consisted of a few parameters. However, a large number of neurons and synapses are expected to participate in decision making in the brain. We investigated learning behavior in simple but large-scale decision-making networks. We considered the covariance learning rule, which has been demonstrated to achieve matching behavior as a steady state (Loewenstein & Seung, 2006 ). We analyzed model behavior in a thermodynamic limit where the number of plastic synapses went to infinity. By means of techniques of the statistical mechanics, we can derive deterministic differential equations in this limit for the order parameters, which allow an exact calculation of the evolution of choice behavior. As a result, we found that matching behavior cannot be a steady state of learning when the fluctuations in input from individual sensory neurons are so large that they affect the net input to value-encoding neurons. This situation naturally arises when the synaptic strength is sufficiently strong and the excitatory input and the inhibitory input to the value-encoding neurons are balanced. The deviation from matching behavior is caused by increasing variance in the input potential due to the diffusion of synaptic efficacies. This effect causes an undermatching phenomenon, which has been often observed in behavioral experiments.
Dynamical Synapses Enhance Neural Information Processing: Gracefulness, Accuracy, and Mobility
Authors: Fung C. C. Alan , Wong K. Y. Michael , Wang He , Wu Si
Published: February 2012

Experimental data have revealed that neuronal connection efficacy exhibits two forms of short-term plasticity: short-term depression (STD) and short-term facilitation (STF). They have time constants residing between fast neural signaling and rapid learning and may serve as substrates for neural systems manipulating temporal information on relevant timescales. This study investigates the impact of STD and STF on the dynamics of continuous attractor neural networks and their potential roles in neural information processing. We find that STD endows the network with slow-decaying plateau behaviors: the network that is initially being stimulated to an active state decays to a silent state very slowly on the timescale of STD rather than on that of neuralsignaling. This provides a mechanism for neural systems to hold sensory memory easily and shut off persistent activities gracefully. With STF, we find that the network can hold a memory trace of external inputs in the facilitated neuronal interactions, which provides a way to stabilize the network response to noisy inputs, leading to improved accuracy in population decoding. Furthermore, we find that STD increases the mobility of the network states. The increased mobility enhances the tracking performance of the network in response to time-varying stimuli, leading to anticipative neural responses. In general, we find that STD and STP tend to have opposite effects on network dynamics and complementary computational advantages, suggesting that the brain may employ a strategy of weighting them differentially depending on the computational purpose.