bluuebunny/crossref_metadata_2025 huggingface dataset:
ON THE HERMITICITY OF q-DIFFERENTIAL OPERATORS AND FORMS ON THE QUANTUM EUCLIDEAN SPACES $\mathbb{R}_q^N$
Authors: FIORE GAETANO
Published: March 2006

We show that the complicated ⋆-structure characterizing for positive q the Uqso(N)-covariant differential calculus on the noncommutative manifold [Formula: see text] boils down to similarity transformations involving the ribbon element of a central extension of Uqso(N) and its formal square root ṽ. Subspaces of the spaces of functions and of p-forms on [Formula: see text] are made into Hilbert spaces by introducing non-conventional "weights" in the integrals defining the corresponding scalar products, namely suitable positive-definite q-pseudodifferential operators ṽ′±1 realizing the action of ṽ±1; this serves to make the partial q-derivatives anti-hermitean and the exterior coderivative equal to the hermitean conjugate of the exterior derivative, as usual. There is a residual freedom in the choice of the weight m(r) along the "radial coordinate" r. Unless we choose a constant m, then the square-integrables functions/forms must fulfill an additional condition, namely, their analytic continuations to the complex r plane can have poles only on the sites of some special lattice. Among the functions naturally selected by this condition there are q-special functions with "quantized" free parameters.
Equalizer Architectures for 40-Gb/s Optical Systems Limited by Polarization-Mode Dispersion
Authors: Sewter Jonathan , Carusone Anthony Chan
Published: March 2006

An analysis of first-order polarization-mode dispersion (PMD) effects in a 40-Gb/s optical system is used to compare different electronic equalizer architectures as potential PMD compensators. Both linear and nonlinear equalizers are considered employing symbol-spaced and fractionally-spaced taps. It is found that a decision feedback equalizer consisting of a 3-tap symbol-spaced feedforward equalizer and a 1-tap feedback equalizer effectively eliminates PMD as the dominant length-limiting factor in most 40-Gb/s optical systems. Such an equalizer would entail less complexity than several previously reported electronic PMD compensators.
Trade-offs in High-Speed Serial Link ICs
Authors: Li Shenggao
Published: March 2006

Serial IOs are widely used to expand the system bandwidth in communication systems. This paper provides an overview of serial IO design trade-offs with regard to power, cost, and performance. Circuit techniques are discussed to achieve low jitter and high bandwidth.
HIGH-SPEED ARCHITECTURES AND BUILDING BLOCKS FOR CLOCK AND DATA RECOVERY SYSTEMS
Authors: VAUCHER CICERO S. , FRAMBACH JAN-PETER , van der TANG JOHAN D.
Published: March 2006

This paper focuses on high performance architectures and building blocks for clock and data recovery (CDR) applications. After a review of basic concepts, a parallel CDR architecture for high operation speeds and low-power dissipation is introduced, followed by discussion of linear detectors for multiple octave operation CDR systems. A frequency acquisition architecture, based on standard PLL building blocks, is then presented. Finally, multi-phase and wide-tuning-range oscillators are discussed.
MOS CURRENT MODE LOGIC CIRCUITS: DESIGN CONSIDERATION IN HIGH-SPEED LOW-POWER APPLICATIONS AND ITS FUTURE TREND, A TUTORIAL
Authors: LIU YUYU , QUAN JINGUO , YANG HUAZHONG , WANG HUI
Published: March 2006

In this paper, a logic style that is becoming increasingly popular is presented, which is called MOS Current Mode Logic (MCML). MCML is a novel and useful logic style for high-speed, low-power and mixed-signal applications. Its high-speed switching, low supply voltage and reduced output voltage swing contribute to its high performance, low power dissipation, and low noise features. MCML circuits are compared to several other logic styles, such as conventional static CMOS, dynamic logic, and traditional emitter coupled logic (ECL) in terms of power, delay and common mode noise immunity. MCML circuits seem to be very promising in high-speed, low-power and mixed-signal digital circuit applications, such as portable electronic devices, gigahertz microprocessors, and optical transceivers.
ENHANCED NETWORK SIGNALING FOR 10 GIGABIT ETHERNET TO ACHIEVE A LAN-WAN SEAMLESS INTERFACE AND ITS IMPLEMENTATION IN THE PHY-LSI/TRANSCEIVER MODULE
Authors: Ichino Haruhiko , Terada Kazuhiko , Kawai Kenji , Ishida Osamu , Kishine Keishi , Iwasaki Noboru , Fukao Tetsuhiro , Shibao Shinji , Kubo Kazuo , Kondoh Harufusa
Published: March 2006

This paper describes Inter-frame Ling Signaling (ILS) protocol technology and its implementation in a 10-Gigabit Ethernet (10GbE) physical layer (PHY) LSI and optical transceiver module. The ILS can realize SDH/SONET-compatible operations, administration, maintenance, and provisioning (OAM&P) functions for PHY of 10GbE networks by inserting OAM&P information in the inter-frame gap periods. The coding features include 10GbE PHY upper compatibility, error detection capability, and disparity neutral characteristics. The 10GbE PHY LSI with the ILS function was fabricated using 0.18-um SOI CMOS technology to achieve high-speed and low-power performance. The main features of the high-speed circuit design are an inductive-load buffer, high-speed clock and data recovery (CDR), and pre-emphasis/equalizer circuits. The LSI function meets IEEE 802.3ae specifications with the very low-power consumption of about 1.2W. An XENPAK transceiver with ILS function using the LSI was also fabricated to make it easy to implement the ILS function in optical transport network systems such as WDM, OADM, OXC systems and L2/L3 switches. The key features of the module include a 1.3-um DFB laser module with highly reliable transmission performance and a small EML driver integrated module. ILS protocol operation is verified by experiment with XENPAK modules emulating the optical transport system.
ON STABILITY OF THE NEUTRON-RICH OXYGEN ISOTOPES
Authors: GRIDNEV K. A. , GRIDNEV D. K. , KARTAVENKO V. G. , MITROSHIN V. E. , TARASOV V. N. , TARASOV D. V. , GREINER W.
Published: March 2006

Stability with respect to neutron emission is studied for highly neutron-excessive Oxygen isotopes in the framework of Hartree-Fock approach with Skyrme forces Sly4 and Ska. Our calculations show increase of stability around 40 O .
IMPROVEMENT OF RENORMALIZATION-SCALE UNCERTAINTIES WITHIN EMPIRICAL DETERMINATIONS OF THE b-QUARK MASS
Authors: AHMADY M. R. , ELIAS V. , SQUIRES A. , STEELE T. G. , ZHANG AILIN
Published: March 2006

Accurate determinations of the [Formula: see text]b-quark mass mb(mb) from σ(e+e-→ hadrons ) experimental data currently contain three comparable sources of uncertainty; the experimental uncertainty from moments of this cross-section, the uncertainty associated with αs(Mz), and the theoretical uncertainty associated with the renormalization scale. Through resummation of all logarithmic terms explicitly determined in the perturbative series by the renormalization-group (RG) equation, it is shown that the renormalization-scale dependence is virtually eliminated as a source of theoretical uncertainty in mb(mb). This resummation also reduces the estimated effect of higher-loop perturbative contributions, further reducing the theoretical uncertainties in mb(mb). Furthermore, such resummation techniques improve the agreement between the values of the [Formula: see text]b-quark mass extracted from the various moments of R(s) = σ(e+e-→ hadrons )/σpt [σpt = 4πα2/(3s)], obviating the need to choose an optimum moment for determining mb(mb). Based on this analysis, the resulting value of the b-mass is mb(mb) = 4.207 GeV ± 40 MeV , where the dominant uncertainty now arises from the experimental moments. Resummation techniques are also shown to reduce renormalization-scale dependence in the relation between b-quark [Formula: see text] and pole mass and in the relation between the pole and 1S mass.
COMPARISON OF QUARK MIXING IN THE STANDARD AND GENERATION MODELS
Authors: EVANS P. W. , ROBSON B. A.
Published: March 2006

The different interpretations of quark mixing involved in weak interaction processes in the Standard Model and the Generation Model are discussed with a view to obtaining a physical understanding of the Cabibbo angle and related quantities. It is proposed that hadrons are composed of mixed-quark states, with the quark mixing parameters being determined by the Cabibbo-Kobayashi-Maskawa matrix elements. In this model, protons and neutrons contain a contribution of about 5% and 10%, respectively, of strange valency quarks.
ENTRANCE-CHANNEL EFFECTS IN THE DYNAMICAL CLUSTER-DECAY MODEL FOR THE DECAY OF HOT AND ROTATING COMPOUND NUCLEUS 48Cr AT ${\rm E}_{CN}^{*}\approx 60\, {\rm MeV}$
Authors: SINGH BIRBIKRAM , SHARMA MANOJ K. , GUPTA RAJ K. , GREINER WALTER
Published: March 2006

The entrance-channel effects in the decay of hot and rotating compound nucleus 48 Cr *, formed in symmetric 24 Mg +24 Mg and asymmetric 36 Ar +12 C reactions, are studied as collective clusterization process, for emissions of both the light particles (LPs) as well as the intermediate mass fragments (IMFs), with in the dynamical cluster-decay model (DCM). We find that the little differences observed in the decay of equilibrated compound nucleus 48 Cr *, formed in the two entrance channels with about the same excitation energy, are not in variance with the Bohr's independence hypothesis. In other words, the present study confirms the entrance-channel independence of the decay of compound nucleus 48 Cr * formed due to different target-projectile combinations with similar excitation energies. The collective clusterization process is shown to contain the complete structure of the measured fragment cross sections as well as average total kinetic energies.
EXCITED STATES OF DEFORMABLE TRIAXIAL ODD 165Ho AND 167Er NUCLEI
Authors: SHARIPOV SH. , ERMAMATOV M. J. , BAYIMBETOVA J. K.
Published: March 2006

Rotationally single-particle and vibrational excitations of two deformable triaxial odd 165 Ho and 167 Er nuclei are investigated with allowance for the interaction of collective and single-particle states. The ratios of excitation energies, of reduced E2 transition probabilities, and of quadrupole moments of these nuclei are calculated up to high-spin states.
PROBABILISTIC ROLE MODELS AND THE GUARDED FRAGMENT
Authors: JAEGER MANFRED
Published: March 2006

We propose a uniform semantic framework for interpreting probabilistic concept subsumption and probabilistic role quantification through statistical sampling distributions. This general semantic principle serves as the foundation for the development of a probabilistic version of the guarded fragment of first-order logic. A characterization of equivalence in that logic in terms of bisimulations is given.
AUTOMORPHISMS OF POWERS OF LINEARLY ORDERED SETS
Authors: WALKER CAROL L. , WALKER ELBERT A.
Published: March 2006

Let S be a bounded, partially ordered set, and n a positive integer. We investigate automorphism groups of Sn and of S[n], the non-decreasing n-tuples of Sn. Our main interest is in the case where S is the unit interval of real numbers with the usual order.
FUZZY PRINCIPAL COMPONENT REGRESSION (FPCR) FOR FUZZY INPUT AND OUTPUT DATA
Authors: HUANG JIH-JENG , TZENG GWO-HSHIUNG , ONG CHORNG-SHYONG
Published: March 2006

Although fuzzy regression is widely employed to solve many problems in practice, what seems to be lacking is the problem of multicollinearity. In this paper, the fuzzy centers principal component analysis is proposed to first derive the fuzzy principal component scores. Then the fuzzy principal component regression (FPCR) is formed to overcome the problem of multicollinearity in the fuzzy regression model. In addition, a numerical example is used to demonstrate the proposed method and compare with other methods. On the basis of the results, we can conclude that the proposed method can provide a correct fuzzy regression model and avoid the problem of multicollinearity.
INTERVAL METHODS IN KNOWLEDGE REPRESENTATION
Authors: Kreinovich V.
Published: March 2006

This section is maintained by Vladik Kreinovich. Please send your abstracts (or copies of papers that you want to see reviewed here) to vladik@utep.edu, or by regular mail to: V. Kreinovich, Department of Computer Science, University of Texas, El Paso, TX 79968, USA.
A REGIONAL ENTREPRENEURIAL ORIENTATION (REO) MODEL FOR A NORTHERN ENGLISH TOWN?
Authors: POWNALL IAN , LAWSON VALERIE
Published: March 2006

The entrepreneurial orientation (EO) concept of an individual is understood to be a complex mix of personal and situational factors. In this paper, we review the emerging body of literature focusing upon entrepreneurial discourse and identity, through a concept of an organisation having a Regional Entrepreneurial Orientation which explicitly includes regional and organisational values into the EO concept. This case is explored through textual and metaphorical evidence for a North Yorkshire town in the UK.
SCALE BARRIERS AND GROWTH OPPORTUNITIES: A RESOURCE-BASED MODEL OF NEW VENTURE EXPANSION
Authors: SHELTON LOIS M.
Published: March 2006

The concept of scale barriers is introduced to shed light on new venture growth. Growth is a process of overcoming resource deficiencies, or scale barriers, resulting from the liabilities of newness and smallness. New ventures employ a variety of resource accumulation strategies to surmount three types of barriers - competitive deficiencies, management and organizational deficiencies, and financial deficiencies. A theoretical model shows how environmental munificence and industry conditions influence barrier size while resource accumulation strategies and initial venture endowments determine a venture's ability to overcome these barriers. The difficulties of growth are illustrated as an extension of the difficulties of survival.
HOW DO FIRMS IN STRATEGIC SME NETWORKS BUILD COMPETITIVENESS?
Authors: WINCENT JOAKIM
Published: March 2006

This study attempts to improve the present understanding of how firms build competitiveness in strategic SME networks. In particular, it empirically tests and identifies patterns among potentially important factors as mentioned in prior literature and suggests propositions as potential providers for middle-range theorizing. Using data from a population of 54 firms, influences of firm-related factors, partner-related factors, and inter-firm relation factors on competitive outcomes (i.e., organizational entrepreneurship, resource contributions to the network entity, and direct firm performance effects) were identified by using path analysis techniques. Findings suggest all factors are influential, but effects are seldom direct. Based on the results from path analysis and interviews with CEOs in the firms studied, a number of propositions are offered for future middle-range theorizing in this domain. Implications for policy and practice are suggested.
RELIABILITY ANALYSIS OF LARGE SYSTEMS WITH DEPENDENT COMPONENTS
Authors: BLOKUS AGNIESZKA
Published: March 2006

Dependent failures of components in parallel and parallel-series systems are defined. Reliability functions of parallel and parallel-series systems composed of dependent components and their limit forms are determined. The results are applied to the reliability evaluation of an exemplary parallel system and to the shipyard rope transportation parallel-series system.
COHERENT CONCURRENT TASKS SCHEDULING AND RESOURCES ASSIGNMENT IN DEPENDABLE COMPUTER SYSTEMS DESIGN
Authors: DRABOWSKI MIECZYSLAW , WANTUCH EDWARD
Published: March 2006

The paper includes a proposal of a new model of coherent concurrent tasks scheduling and a of resources assignment, that are characteristic for the problem of dependable system synthesis. Optimal tasks scheduling, partition at resources, allocation tasks and resources are basic problems in high-level synthesis of computer systems. Coherent synthesis may have a practical application in developing tools for computer aided rapid prototyping of such systems.
MODEL OF SYSTEM AVAILABILITY CAUSED BY SPARE PARTS INVENTORY LEVEL
Authors: JODEJKO ANNA
Published: March 2006

There are many models and methods that enable estimation system availability when set size of spares inventory is accessible. Correct determining of standby of a system should consider also the lack of inventory delivery precision effect. The paper presents model of inventory critical level of spare element impact on technical system availability when delivery moment is assumed to be a random. Presented approach allows to calculate the probability of the system down time and probability of its availability-based consequences.
REAL TIME UPDATING OF RISK ASSESSMENTS DURING A DRILLING OPERATION — ALTERNATIVE BAYESIAN APPROACHES
Authors: SANDØY MALENE , AVEN TERJE
Published: March 2006

Risk analyses of drilling operations performed in the planning phase of wells often fail to meet their objectives as decision support tools as they become outdated when more information is made available during the drilling operation. To ensure that drilling operation risk analyses at all times reflect the available knowledge and that decisions are made on a sufficiently strong basis, the risk analyses should be updated as valuable information reducing the uncertainty about important quantities is acquired during the drilling operation. Such updating requires procedures that automatically update uncertainty assessments as new information arrives. In this paper we present an updating procedure for assessments of the formation pore pressure in a reservoir, within a Bayesian context. We show that the problem can be solved by different Bayesian approaches, generated by introducing or not introducing an underlying probability model. Our recommended approach is based on assessment of uncertainties about quantities that can be given a physical interpretation. The drilling operation is the starting point for the paper, but the discussion is to large extent general and applies to other areas as well.
Role of bradykinin B1and B2receptors in normal blood pressure regulation
Authors: Duka Arvi , Duka Irena , Gao Guohong , Shenouda Sherene , Gavras Irene , Gavras Haralambos
Published: March 2006

With inhibition or absence of the bradykinin B2receptor (B2R), B1R is upregulated and assumes some of the hemodynamic properties of B2R, indicating that both participate in the maintenance of normal vasoregulation or to development of hypertension. Herein we further evaluate the role of bradykinin in normal blood pressure (BP) regulation and its relationship with other vasoactive factors by selectively blocking its receptors. Six groups of Wistar rats were treated for 3 wk: one control group with vehicle alone, one with concurrent administration of B1R antagonist R-954 (70 μg·kg−1·day−1) and B2R antagonist HOE-140 (500 μg·kg−1·day−1), one with R-954 alone, one with HOE 140 alone, one with concurrent administration of both R-954 and HOE-140 plus the angiotensin antagonist losartan (5 mg·kg−1·day−1), and one with only losartan. BP was measured continuously by radiotelemetry. Only combined administration of B1R and B2R antagonists produced a significant BP increase from a baseline of 107–119 mmHg at end point, which could be partly prevented by losartan and was not associated with change in catecholamines, suggesting no involvement of the sympathoadrenal system. The impact of blockade of bradykinin on other vasoregulating systems was assessed by evaluating gene expression of different vasoactive factors. There was upregulation of the eNOS, AT1receptor, PGE2receptor, and tissue kallikrein genes in cardiac and renal tissues, more pronounced when both bradykinin receptors were blocked; significant downregulation of AT2receptor gene in renal tissues only; and no consistent changes in B1R and B2R genes in either tissue. The results indicate that both B1R and B2R contribute to the maintenance of normal BP, but one can compensate for inhibition of the other, and the chronic inhibition of both leads to significant upregulation in the genes of related vasoactive systems.
Binaural-Level Functions in Ferret Auditory Cortex: Evidence for a Continuous Distribution of Response Properties
Authors: Campbell Robert A. A. , Schnupp Jan W. H. , Shial Akhil , King Andrew J.
Published: March 2006

Many previous studies have subdivided auditory neurons into a number of physiological classes according to various criteria applied to their binaural response properties. However, it is often unclear whether such classifications represent discrete classes of neurons or whether they merely reflect a potentially convenient but ultimately arbitrary partitioning of a continuous underlying distribution of response properties. In this study we recorded the binaural response properties of 310 units in the auditory cortex of anesthetized ferrets, using an extensive range of interaural level differences (ILDs) and average binaural levels (ABLs). Most recordings were from primary auditory fields on the middle ectosylvian gyrus and from neurons with characteristic frequencies >5 kHz. We used simple multivariate statistics to quantify a fundamental coding feature: the shapes of the binaural response functions. The shapes of all 310 binaural response surfaces were represented as points in a five-dimensional principal component space. This space captured the underlying shape of all the binaural response surfaces. The distribution of binaural level functions was not homogeneous because some shapes were more common than others. Despite this, clustering validation techniques revealed no evidence for the existence of discrete, or partially overlapping, clusters that could serve as a basis for an objective classification of binaural-level functions. We also examined the gradients of the response functions for the population of units; these gradients were greatest near the midline, which is consistent with free-field data showing that cortical neurons are most sensitive to changes in stimulus location in this region of space.
Altered metabolic responses to intermittent hypoxia in mice with partial deficiency of hypoxia-inducible factor-1α
Authors: Li Jianguo , Bosch-Marce Marta , Nanayakkara Ashika , Savransky Vladimir , Fried Susan K. , Semenza Gregg L. , Polotsky Vsevolod Y.
Published: March 2006

We have previously shown that exposure of C57BL/6J mice to intermittent hypoxia (IH) leads to 1) hypertriglyceridemia due to upregulation of pathways of lipid biosynthesis, including sterol regulatory element binding protein (SREBP)-1 and stearoyl CoA desaturase (SCD)-1; and 2) hypercholesterolemia due to impaired cholesterol uptake. The goal of the present study was to examine whether hypoxia-inducible factor (HIF)-1 is implicated in changes in lipid metabolism induced by IH. Lean HIF-1α ( Hif1a)+/−mice, which are heterozygous for a null allele at the locus encoding the HIF-1α subunit, and their wild-type (WT) Hif1a+/+littermates were exposed to IH or control conditions for 5 days. IH increased fasting blood glucose, serum total cholesterol, and high-density lipoprotein-cholesterol, phospholipids, triglycerides (TG), and leptin in mice of both genotypes, whereas serum insulin and interleukin-6 were elevated only in WT mice. The impact of IH on serum TG levels in WT mice was significantly greater than that in Hif1a+/−mice (95 ± 9 vs. 66 ± 6 mg/dl, P < 0.05), whereas cholesterol and glucose levels were affected independently of genotype. Under hypoxic conditions, mRNA and protein levels of SREBP cleavage-activating protein (SCAP) and SCD-1 and protein levels of nuclear isoform of SREBP-1 in the liver were induced to significantly higher levels in WT mice than in Hif1a+/−mice. We conclude that 1) the effect of IH on serum TG levels is mediated through HIF-1, 2) HIF-1 may impact on posttranscriptional regulation of SREBP-1, and 3) the effect of IH on serum cholesterol levels was not altered by partial HIF-1α deficiency.
Inhibition of VEGFR-3 Activation with the Antagonistic Antibody More Potently Suppresses Lymph Node and Distant Metastases than Inactivation of VEGFR-2
Authors: Roberts Nicole , Kloos Bryan , Cassella Melanie , Podgrabinska Simona , Persaud Kris , Wu Yan , Pytowski Bronislaw , Skobe Mihaela
Published: March 2006

Lymph nodes are the first site of metastases for most types of cancer, and lymph node status is a key indicator of patient prognosis. Induction of tumor lymphangiogenesis by vascular endothelial growth factor-C (VEGF-C) has been shown to play an important role in promoting tumor metastases to lymph nodes. Here, we employed receptor-specific antagonist antibodies in an orthotopic spontaneous breast cancer metastasis model to provide direct evidence for the key role of VEGFR-3 activation in metastasis. Inhibition of VEGFR-3 activation more potently suppressed regional and distant metastases than inactivation of VEGFR-2, although VEGFR-2 blockade was more effective in inhibiting angiogenesis and tumor growth. Despite prominent proliferation, metastases were not vascularized in any of the control and treatment groups, indicating that the growth of metastases was not dependent on angiogenesis at the secondary site for the duration of the experiment. Systemic treatment with either VEGFR-2 or VEGFR-3 antagonistic antibodies suppressed tumor lymphangiogenesis, indicating that VEGFR-3 signaling affects the rate of tumor cell entry into lymphatic vessels through both lymphangiogenesis-dependent and independent mechanisms. Combination treatment with the anti-VEGFR-2 and anti-VEGFR-3 antibodies more potently decreased lymph node and lung metastases than each antibody alone. These results validate the concept of targeting the lymphatic dissemination and thereby very early steps of the metastatic process for metastasis control and suggest that a combination therapy with antiangiogenic agents may be a particularly promising approach for controlling metastases. (Cancer Res 2006; 66(5): 2650-7)
The Small Organic Compound HA14-1 Prevents Bcl-2 Interaction with Bax to Sensitize Malignant Glioma Cells to Induction of Cell Death
Authors: Manero Florence , Gautier Fabien , Gallenne Tristan , Cauquil Nicolas , Grée Danielle , Cartron Pierre-François , Geneste Olivier , Grée René , Vallette François M. , Juin Philippe
Published: March 2006

A functional imbalance between proapoptotic Bax and antiapoptotic Bcl-2 is likely to participate in the resistance of cancer cells to therapy. We show here that ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA14-1), a small organic compound recently proposed to function as an inhibitor of Bcl-2, increases the sensitivity of human glioblastoma cells to radiotherapy and chemotherapy. This sensitizing effect is lost if Bcl-2 expression, but not Bcl-xL expression, is knocked down or if cells only express a mutant of Bax that does not interact with Bcl-2. This points to a specific Bcl-2 inhibitory function of HA14-1 and implies that it selectively involves hindrance of Bcl-2 binding to Bax, which HA14-1 inhibits in cell-free assays and in cells in receipt of an apoptotic stimulation. Moreover, HA14-1, in combination with a cytotoxic treatment, slows down the growth of glioblastoma in vivo. Thus, the inhibition of Bcl-2 achieved by HA14-1 might improve treatment outcome. (Cancer Res 2006; 66(5): 2757-64)
Expression of RASSF1A, an Epigenetically Silenced Tumor Suppressor, Overcomes Resistance to Apoptosis Induction by Interferons
Authors: Reu Frederic J. , Leaman Douglas W. , Maitra Ratan R. , Bae Soo In , Cherkassky Leonid , Fox Mark W. , Rempinski Donald R. , Beaulieu Normand , MacLeod A. Robert , Borden Ernest C.
Published: March 2006

Resistance of human renal cell carcinoma (RCC) and melanoma to the apoptosis-inducing effects of IFNs was postulated to result from epigenetic silencing of genes by DNA methylation, a common feature of human cancers. To reverse silencing, 5-AZA-deoxycytidine (5-AZA-dC) or selective depletion of DNA methyltransferase 1 (DNMT1) by phosphorothioate oligonucleotide antisense (DNMT1 AS) were employed in cells resistant (<5% terminal deoxynucleotidyl transferase–mediated nick-end labeling positive) to apoptosis induction by IFN-α2 and IFN-β (ACHN, SK-RC-45, and A375). 5-AZA-dC and DNMT1 AS similarly depleted available DNMT1 protein and, at doses that did not cause apoptosis alone, resulted in apoptotic response to IFNs. The proapoptotic tumor suppressor RASSF1A was reactivated by DNMT1 inhibitors in all three cell lines. This was associated with demethylation of its promoter region. IFNs augmented RASSF1A protein expression after reactivation by DNMT1 inhibition. In IFN-sensitive WM9 melanoma cells, expression of RASSF1A was constitutive but also augmented by IFNs. RASSF1A small interfering RNA reduced IFN-induced apoptosis in WM9 cells and in DNMT1-depleted ACHN cells. Conversely, lentiviral expression of RASSF1A but not transduction with empty virus enabled IFN-induced apoptosis. IFN induced tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and TRAIL-neutralizing antibody inhibited apoptotic response to IFN in RASSF1A-expressing ACHN cells. Accordingly, RASSF1A markedly sensitized to recombinant TRAIL. Normal kidney epithelial cells, although expressing RASSF1A, did not undergo apoptosis in response to IFN or TRAIL but had >400-fold higher TRAIL decoy receptor 1 expression than transduced ACHN cells (real-time reverse transcription-PCR). Results identified RASSF1A as regulated by IFNs and participating in IFN-induced apoptosis at least in part by sensitization to TRAIL. (Cancer Res 2006; 66(5): 2785-93)
Proteolytic Release of Soluble UL16-Binding Protein 2 from Tumor Cells
Authors: Waldhauer Inja , Steinle Alexander
Published: March 2006

The MHC class I–related ligands of the immunoreceptor NKG2D are frequently expressed by tumor cells and stimulate tumor immunity mediated by CD8 T cells and natural killer (NK) cells. In humans, NKG2D ligands (NKG2DL) are encoded by the MHC-encoded MIC and non–MHC-encoded UL16-binding protein (ULBP) families of proteins. Recently, we and others showed that tumor cells release soluble MICA (sMICA), thereby counteracting NKG2D-mediated tumor immunosurveillance. Here, we now report that ULBP2 molecules are likewise released from tumor cells in a processed soluble form, and that soluble ULBP2 (sULBP2) can be detected in sera of some patients with hematopoietic malignancies. Tumor cell–derived sULBP2 as opposed to cell-bound ULBP2 does not down-regulate NKG2D on NK cells. Unexpectedly, the glycosylphosphatidylinositol-anchored ULBP2 molecules are not released by phospholipases but by the action of metalloproteases. Proteolytic shedding of both NKG2D ligands MICA and ULBP2 by tumor cells was strongly enhanced after phorbol 12-myristate 13-acetate treatment and paralleled by a markedly reduced susceptibility to NKG2D-mediated cytotoxicity. Shedding of MICA and ULBP2 can be blocked by the same inhibitors, suggesting the involvement of related metalloproteases. Thus, our data suggest that reducing NKG2DL surface densities is due to a common cleavage process executed by metalloproteases that promotes escape of tumors from NKG2D-mediated immunosurveillance. (Cancer Res 2006; 66(5): 2520-6)
Pharmacogenomic Identification of Novel Determinants of Response to Chemotherapy in Colon Cancer
Authors: Boyer John , Allen Wendy L. , McLean Estelle G. , Wilson Peter M. , McCulla Andrea , Moore Stephen , Longley Daniel B. , Caldas Carlos , Johnston Patrick G.
Published: March 2006

DNA microarray analysis was used to analyze the transcriptional profile of HCT116 colorectal cancer cells that were treated with 5-fluorouracil (5-FU) or oxaliplatin and selected for resistance to these agents. Bioinformatic analyses identified sets of genes that were constitutively dysregulated in drug-resistant cells and transiently altered following acute exposure of parental cells to drug. We propose that these genes may represent molecular signatures of sensitivity to 5-FU and oxaliplatin. Using real-time reverse transcription-PCR (RT-PCR), the robustness of our microarray data was shown with a strong overall concordance of expression trends for ≥82% (oxaliplatin) and ≥85% (5-FU) of a representative subset of genes. Furthermore, strong correlations between the microarray and real-time RT-PCR measurements of average fold changes in gene expression were observed for both the 5-FU (R2 ≥ 0.73) and oxaliplatin gene sets (R2 ≥ 0.63). Functional analysis of three genes identified in the microarray study [prostate-derived factor (PDF), calretinin, and spermidine/spermine N1-acetyl transferase (SSAT)] revealed their importance as novel regulators of cytotoxic drug response. These data show the power of this novel microarray-based approach to identify genes which may be important markers of response to treatment and/or targets for therapeutic intervention. (Cancer Res 2006; 66(5): 2765-77)
Matrix Metalloproteinase 26 Proteolysis of the NH2-Terminal Domain of the Estrogen Receptor β Correlates with the Survival of Breast Cancer Patients
Authors: Savinov Alexei Y. , Remacle Albert G. , Golubkov Vladislav S. , Krajewska Maryla , Kennedy Susan , Duffy Michael J. , Rozanov Dmitri V. , Krajewski Stan , Strongin Alex Y.
Published: March 2006

Estrogens have many cellular functions, including their interactions with estrogen receptors α and β (ERα and ERβ). Earlier, we determined that the estrogen-ER complex stimulates the transcriptional activity of the matrix metalloproteinase 26 (MMP-26) gene promoter. We then determined that ERβ is susceptible to MMP-26 proteolysis whereas ERα is resistant to the protease. MMP-26 targets the NH2-terminal region of ERβ coding for the divergent NH2-terminal A/B domain that is responsible for the ligand-independent transactivation function. As a result, MMP-26 proteolysis generates the COOH-terminal fragments of ERβ. Immunohistochemical analysis of tissue microarrays derived from 121 cancer patients corroborated these data and revealed an inverse correlation between the ERα-dependent expression of MMP-26 and the levels of the intact ERβ in breast carcinomas. MMP-26 is not expressed in normal mammary epithelium. The levels of MMP-26 are strongly up-regulated in ductal carcinoma in situ (DCIS). In the course of further disease progression through stages I to III, the expression of MMP-26 decreases. In contrast to many tumor-promoting MMPs, the expression of MMP-26 in DCIS correlated with a longer patient survival. Our data suggest the existence of an MMP-26–mediated intracellular pathway that targets ERβ and that MMP-26, a novel and valuable cancer marker, contributes favorably to the survival of the ERα/β–positive cohort of breast cancer patients. (Cancer Res 2006; 66(5): 2716-24)
Hypoxia-Inducible Factor-1-Dependent Repression of E-cadherin in von Hippel-Lindau Tumor Suppressor–Null Renal Cell Carcinoma Mediated by TCF3, ZFHX1A, and ZFHX1B
Authors: Krishnamachary Balaji , Zagzag David , Nagasawa Hideko , Rainey Karin , Okuyama Hiroaki , Baek Jin H. , Semenza Gregg L.
Published: March 2006

A critical event in the pathogenesis of invasive and metastatic cancer is E-cadherin loss of function. Renal clear cell carcinoma (RCC) is characterized by loss of function of the von Hippel-Lindau tumor suppressor (VHL), which negatively regulates hypoxia-inducible factor-1 (HIF-1). Loss of E-cadherin expression and decreased cell-cell adhesion in VHL-null RCC4 cells were corrected by enforced expression of VHL, a dominant-negative HIF-1α mutant, or a short hairpin RNA directed against HIF-1α. In human RCC biopsies, expression of E-cadherin and HIF-1α was mutually exclusive. The expression of mRNAs encoding TCF3, ZFHX1A, and ZFHX1B, which repress E-cadherin gene transcription, was increased in VHL-null RCC4 cells in a HIF-1–dependent manner. Thus, HIF-1 contributes to the epithelial-mesenchymal transition in VHL-null RCC by indirect repression of E-cadherin. (Cancer Res 2006; 66(5): 2725-31)
Caspase Recruitment Domain-Containing Protein 15 Mutations in Patients with Colorectal Cancer
Authors: Roberts Rebecca L. , Gearry Richard B. , Allington Melanie D.E. , Morrin Helen R. , Robinson Bridget A. , Frizelle Frank A.
Published: March 2006

The caspase recruitment domain-containing protein 15 (CARD15) plays a crucial role in mediating the innate immune response. Mutations within this protein have been shown to be independent risk factors for the development of Crohn's disease in Caucasians. As Crohn's disease patients are at increased risk of developing sporadic colorectal cancer, it is conceivable that genetic variability within CARD15 may also play a role in determining susceptibility to this gastrointestinal malignancy in individuals without Crohn's disease. This hypothesis is supported by the findings of two case-control studies that found the frequencies of CARD15 mutations were significantly elevated in Polish and Greek colorectal cancer patients. Given the results of these previous studies, we examined whether the high incidence of sporadic colorectal cancer observed in New Zealand Caucasians was due to mutations within CARD15. To answer this question, we genotyped 133 colorectal cancer patients and 201 Caucasian controls for R702W, G908R, 1007fs, and P268S. χ2 Testing found that the combined frequency of R702W, G908R, and 1007fs was significantly elevated in colorectal cancer patients compared with controls (P = 0.001; odds ratio, 2.8; 95% confidence interval, 1.5-5.4), but no association was detected between tumor behavior or age of disease onset and CARD15 mutations in our colorectal cancer cohort. This study is the first to explore the link between CARD15 mutations and colorectal cancer in New Zealand Caucasians. Our results strongly suggest that CARD15 influences susceptibility to colorectal cancer, but we have found no evidence to indicate that CARD15 mutations predict the clinicopathologic characteristics of this disease. (Cancer Res 2006; 66(5): 2532-5)
Cross-Talk between F3/Contactin and Notch at Axoglial Interface: A Role in Oligodendrocyte Development
Authors: Hu Qi-Dong , Ma Quan-Hong , Gennarini Gianfranco , Xiao Zhi-Cheng
Published: March 2006

Increasing evidence has shown that the Notch signalling pathway regulates oligodendrogliogenesis. Upon binding to classical Delta/Serrate/Lag-2 ligands, Notch signalling promotes generation of oligodendrocyte precursor cells while inhibiting their further differentiation into myelinating oligodendrocytes. In our recent studies, we have found that two neural cell adhesion molecules, F3/contactin and NB-3 interact with Notch receptors and promote oligodendrocyte development. Remarkably, all these F3 and NB-3/Notch cascade-related events required Deltex1 as the intermediate element. Experiments using several animal models further imply the function of F3/Notch signalling in vivo, which designates Notch signalling as a ligand-dependent, multipotential cascade involved in oligodendrocyte development.
Jagged1 Ablation Results in Cerebellar Granule Cell Migration Defects and Depletion of Bergmann Glia
Authors: Weller Mathias , Krautler Nike , Mantei Ned , Suter Ueli , Taylor Verdon
Published: March 2006

Jagged1 is a ligand for members of the Notch family of receptors. Mutations in the human JAG1 gene are the major cause of Alagille syndrome, an autosomal dominant disorder affecting the liver, heart, eye, skeleton, kidneys, and craniofacial structures. Although expressed throughout mammalian embryonic development and in the adult, the function of Jagged1 in the central nervous system is not clear. Jagged1 is broadly expressed in the cerebellum suggesting an important role in Notch signaling. In order to address the function of Jagged1 in the mouse central nervous system, we have inactivated the Jag1 gene in the cerebellar primordium at mid-embryogenesis. Loss of Jagged1 results in aberrant granule cell migration and ectopic differentiation in the external germinal layer and molecular layer of the early postnatal cerebellum. We show that Bergmann glia in the cerebellum lose contact to the pial surface and have stunted processes. In vitro analysis revealed a depletion of Bergmann glia in the Jagged1 mutant mice. Our findings suggest that Jagged1 plays a role in cell fate specification and survival in the cerebellum.
Notch Signaling in Astrocytes and Neuroblasts of the Adult Subventricular Zone in Health and after Cortical Injury
Authors: Givogri Maria I. , de Planell Maria , Galbiati Francesca , Superchi Daniela , Gritti Angela , Vescovi Angelo , de Vellis Jean , Bongarzone Ernesto R.
Published: March 2006

The postnatal subventricular zone (SVZ) is a niche for continuous neurogenesis in the adult brain and likely plays a fundamental role in self-repair responses in neurodegenerative conditions. Maintenance of the pool of neural stem cells within this area depends on cell-cell communication such as that provided by the Notch signaling pathway. Notch1 receptor mRNA has been found distributed in different areas of the postnatal brain including the SVZ. Although the identity of Notch1-expressing cells has been established in the majority of these areas, it is still unclear what cell types within the SVZ are expressing components of this pathway. Here we demonstrate that most of expression of Notch1 in the adult SVZ occurs in polysialylated neural cell adhesion molecule (PSA-NCAM)-positive neural precursors and in glial fibrillary acidic protein-positive SVZ astrocytes. Notch1 was also found in PSA-NCAM-positive neuroblasts located within the rostral migratory stream (RMS) but much less in those that have reached the olfactory bulb. We show that two of the naturally occurring Notch1 activators, Jagged1 and Delta1, are also expressed in the SVZ and within the RMS in the adult mouse brain. Finally, using a model of cortical stab wound, we show that the astrogliogenic response of the SVZ to injury is accompanied by activation of the Notch pathway.
Notch Activity Is Downregulated Just prior to Retinal Ganglion Cell Differentiation
Authors: Nelson Branden R. , Gumuscu Burak , Hartman Byron H. , Reh Thomas A.
Published: March 2006

The Notch signaling pathway is important at several stages of retinal development including the differentiation of retinal ganglion cells and Müller glia. The downstream effectors of Notch signaling, Hes1 and Hes5, have been shown to be critical in the retina as well. While Notch activity directly regulates Hes1 and Hes5 elsewhere in the nervous system, it has been unclear whether Hes1 and/or Hes5 are directly regulated by Notch activity in the developing retina. Here, we report that both Hes1 and Hes5 are directly regulated by Notch activity during retinal development. Using fluorescence-based Hes1 and Hes5 reporter constructs, we can monitor Notch activity in progenitor cells in the intact retina, and we find that Notch activity is downregulated just prior to retinal ganglion cell differentiation.
The Enigma of the Numb-Notch Relationship during Mammalian Embryogenesis
Authors: Petersen Petur H. , Tang Haiyan , Zou Kaiyong , Zhong Weimin
Published: March 2006

Asymmetric cell division is an attractive means to diversify cell fates during development and for stem cells to balance self-renewal and differentiation. In Drosophila, two signaling pathways, one mediated by Numb and the other by Notch, play essential but antagonistic roles in enabling the two daughters to adopt different fates after a wide variety of asymmetric cell divisions. However, recent studies show that mutating mammalian Numb homologues, m-Numb and Numblike (Numbl or Nbl), and eliminating Notch signaling in the developing nervous system both lead to premature depletion of neural stem/progenitor cells in mice. These findings raise an interesting question as to whether and how the antagonistic roles of Numb and Notch signaling are conserved in vertebrates. Here we provide evidence that loss of m-Numb and Numbl outside the embryonic nervous system also causes phenotypes similar to those exhibited by mice with defective Notch signaling. We further show that very little Numb protein is necessary for embryogenesis and that the presence of different m-Numb isoforms is unlikely to provide a molecular basis for differential regulation of Notch signaling in mammals, as these isoforms are functionally indistinguishable in cell fate specification. We discuss possible mechanisms by which the antagonistic roles of Numb and Notch are evolutionarily conserved to meet the needs of stem cell maintenance during mammalian neurogenesis.
Depressive Symptoms, Social Isolation, and Progression of Coronary Artery Atherosclerosis: The Stockholm Female Coronary Angiography Study
Authors: Wang Hui-Xin , Mittleman Murray A. , Leineweber Constanze , Orth-Gomer Kristina
Published: March 2006

Background: Although both depressive symptoms and social isolation in relation to coronary heart disease have been studied previously, few have examined their joint effects on coronary atherosclerosis progression in women. Method: Among the women enrolled in the Stockholm Female Coronary Angiography Study, Sweden, between 1991 and 1994, 102 were evaluated for coronary atherosclerosis progression using a computer-assisted standardized assessment, repeated quantitative coronary angiographic documentation, of the mean luminal diameter change over 3 years in 10 predefined coronary segments. Depressive symptoms and social isolation were assessed by standard questionnaires. Results: Multivariable controlled mixed model ANOVAs revealed that women who were both depressed and socially isolated had the greatest disease progression: their absolute mean luminal diameter decreased by 0.18 mm [95% confidence interval (CI) = 0.11–0.24] and their percent narrowing was 5.5% (95% CI = 3.6–7.4), whereas in women who lacked both psychological risk factors, the mean luminal diameter decrease was 0.04 mm and their percent narrowing was 0.9%. These associations were independent of the baseline luminal diameter and standard risk factors, including age, smoking history, hypertension, and high-density lipoproteins. Conclusions:In women with coronary disease, depressive symptoms and social isolation in combination accelerated disease progression, suggesting a direct psychosocial effect on the atherosclerotic process. These findings provide an additional opportunity for therapeutic and preventive efforts against progression of coronary disease in women.