bluuebunny/crossref_metadata_2025 huggingface dataset:
Domains of Axin Involved in Protein–Protein Interactions, Wnt Pathway Inhibition, and Intracellular Localization
Authors: Fagotto François , Jho Eek-hoon , Zeng Li , Kurth Thomas , Joos Thomas , Kaufmann Christine , Costantini Frank
Published: July 2002

Axin was identified as a regulator of embryonic axis induction in vertebrates that inhibits the Wnt signal transduction pathway. Epistasis experiments in frog embryos indicated that Axin functioned downstream of glycogen synthase kinase 3β (GSK3β) and upstream of β-catenin, and subsequent studies showed that Axin is part of a complex including these two proteins and adenomatous polyposis coli (APC). Here, we examine the role of different Axin domains in the effects on axis formation and β-catenin levels. We find that the regulators of G-protein signaling domain (major APC-binding site) and GSK3β-binding site are required, whereas the COOH-terminal sequences, including a protein phosphatase 2A binding site and the DIX domain, are not essential. Some forms of Axin lacking the β-catenin binding site can still interact indirectly with β-catenin and regulate β-catenin levels and axis formation. Thus in normal embryonic cells, interaction with APC and GSK3β is critical for the ability of Axin to regulate signaling via β-catenin. Myc-tagged Axin is localized in a characteristic pattern of intracellular spots as well as at the plasma membrane. NH2-terminal sequences were required for targeting to either of these sites, whereas COOH-terminal sequences increased localization at the spots. Coexpression of hemagglutinin-tagged Dishevelled (Dsh) revealed strong colocalization with Axin, suggesting that Dsh can interact with the Axin/APC/GSK3/β-catenin complex, and may thus modulate its activity.
Polyploidy Induces Centromere Association
Authors: Martinez-Perez Enrique , Shaw Peter J. , Moore Graham
Published: July 2002

Many species exhibit polyploidy. The presence of more than one diploid set of similar chromosomes in polyploids can affect the assortment of homologous chromosomes, resulting in unbalanced gametes. Therefore, a mechanism is required to ensure the correct assortment and segregation of chromosomes for gamete formation. Ploidy has been shown to affect gene expression. We present in this study an example of a major effect on a phenotype induced by ploidy within the Triticeae. We demonstrate that centromeres associate early during anther development in polyploid species. In contrast, centromeres in diploid species only associate at the onset of meiotic prophase. We propose that this mechanism provides a potential route by which chromosomes can start to be sorted before meiosis in polyploids. This explains previous reports indicating that meiotic prophase is shorter in polyploids than in their diploid progenitors. Even artificial polyploids exhibit this phenotype, suggesting that the mechanism must be present in diploids, but only expressed in the presence of more than one diploid set of chromosomes.
MAD3 Encodes a Novel Component of the Spindle Checkpoint Which Interacts with Bub3p, Cdc20p, and Mad2p
Authors: Hardwick Kevin G. , Johnston Raymond C. , Smith Dana L. , Murray Andrew W.
Published: July 2002

We show that MAD3 encodes a novel 58-kD nuclear protein which is not essential for viability, but is an integral component of the spindle checkpoint in budding yeast. Sequence analysis reveals two regions of Mad3p that are 46 and 47% identical to sequences in the NH2-terminal region of the budding yeast Bub1 protein kinase. Bub1p is known to bind Bub3p (Roberts et al. 1994) and we use two-hybrid assays and coimmunoprecipitation experiments to show that Mad3p can also bind to Bub3p. In addition, we find that Mad3p interacts with Mad2p and the cell cycle regulator Cdc20p. We show that the two regions of homology between Mad3p and Bub1p are crucial for these interactions and identify loss of function mutations within each domain of Mad3p. We discuss roles for Mad3p and its interactions with other spindle checkpoint proteins and with Cdc20p, the target of the checkpoint.
Regulation of Programmed Cell Death by Basement Membranes in Embryonic Development
Authors: Murray Patricia , Edgar David
Published: July 2002

The formation of the proamniotic cavity in the mammalian embryo is the earliest of many instances throughout development in which programmed cell death and the formation of epithelia play fundamental roles (Coucouvanis, E., and G.R. Martin. 1995. Cell. 83:279–287). To determine the role of the basement membrane (BM) in cavitation, we use embryoid bodies derived from mouse embryonic stem cells in which the LAMC1 genes have been inactivated to prevent BM deposition (Smyth, N., H.S. Vatansever, P. Murray, M. Meyer, C. Frie, M. Paulsson, and D. Edgar. 1999. J. Cell Biol. 144:151–610). We demonstrate here that LAMC1−/− embryoid bodies are unable to cavitate, and do not form an epiblast epithelium in the absence of a BM, although both embryonic ectodermal cells and extraembryonic endodermal cells do differentiate, as evidenced by the expression of cell-specific markers. Acceleration or rescue of BM deposition by exogenous laminin in wild-type or LAMC1−/− embryoid bodies, respectively, results in cavitation that is temporally and spatially associated with restoration of epiblast epithelial development. We conclude that the BM not only directly regulates development of epiblast epithelial cells, but also indirectly regulates the programmed cell death necessary for cavity formation.
Cell Cycle Programs of Gene Expression Control Morphogenetic Protein Localization
Authors: Lord Matthew , Yang Melody C. , Mischke Michelle , Chant John
Published: July 2002

Genomic studies in yeast have revealed that one eighth of genes are cell cycle regulated in their expression. Almost without exception, the significance of cell cycle periodic gene expression has not been tested. Given that many such genes are critical to cellular morphogenesis, we wanted to examine the importance of periodic gene expression to this process. The expression profiles of two genes required for the axial pattern of cell division, BUD3 and BUD10/AXL2/SRO4, are strongly cell cycle regulated. BUD3 is expressed close to the onset of mitosis. BUD10 is expressed in late G1. Through promotor-swap experiments, the expression profile of each gene was altered and the consequences examined. We found that an S/G2 pulse of BUD3 expression controls the timing of Bud3p localization, but that this timing is not critical to Bud3p function. In contrast, a G1 pulse of BUD10 expression plays a direct role in Bud10p localization and function. Bud10p, a membrane protein, relies on the polarized secretory machinery specific to G1 to be delivered to its proper location. Such a secretion-based targeting mechanism for membrane proteins provides cells with flexibility in remodeling their architecture or evolving new forms.
Two Distinct Vps34 Phosphatidylinositol 3–Kinase Complexes Function in Autophagy and Carboxypeptidase Y Sorting inSaccharomyces cerevisiae
Authors: Kihara Akio , Noda Takeshi , Ishihara Naotada , Ohsumi Yoshinori
Published: July 2002

Vps30p/Apg6p is required for both autophagy and sorting of carboxypeptidase Y (CPY). Although Vps30p is known to interact with Apg14p, its precise role remains unclear. We found that two proteins copurify with Vps30p. They were identified by mass spectrometry to be Vps38p and Vps34p, a phosphatidylinositol (PtdIns) 3–kinase. Vps34p, Vps38p, Apg14p, and Vps15p, an activator of Vps34p, were coimmunoprecipitated with Vps30p. These results indicate that Vps30p functions as a subunit of a Vps34 PtdIns 3–kinase complex(es). Phenotypic analyses indicated that Apg14p and Vps38p are each required for autophagy and CPY sorting, respectively, whereas Vps30p, Vps34p, and Vps15p are required for both processes. Coimmunoprecipitation using anti-Apg14p and anti-Vps38p antibodies and pull-down experiments showed that two distinct Vps34 PtdIns 3–kinase complexes exist: one, containing Vps15p, Vps30p, and Apg14p, functions in autophagy and the other containing Vps15p, Vps30p, and Vps38p functions in CPY sorting. The vps34 and vps15 mutants displayed additional phenotypes such as defects in transport of proteinase A and proteinase B, implying the existence of another PtdIns 3–kinase complex(es). We propose that multiple Vps34p–Vps15p complexes associated with specific regulatory proteins might fulfill their membrane trafficking events at different sites.
Disruption of the Bcl6 Gene Results in an Impaired Germinal Center Formation
Authors: Fukuda Tetsuya , Yoshida Takehiko , Okada Seiji , Hatano Masahiko , Miki Tohru , Ishibashi Kazuki , Okabe Shinichiro , Koseki Haruhiko , Hirosawa Shinsaku , Taniguchi Masaru , Miyasaka Nobuyuki , Tokuhisa Takeshi
Published: July 2002

The Bcl6 gene has been identified from the chromosomal translocation breakpoint in B cell lymphomas, and its products are expressed highly in germinal center (GC) B cells. To investigate the function of Bcl6 in lymphocytes, we have generated RAG1-deficient mice reconstituted with bone marrow cells from Bcl6-deficient mice (Bcl6−/−RM). Lymphogenesis in primary lymphoid tissues of Bcl6−/−RM is normal, and Bcl6−/−RM produced control levels of primary IgG1 antibodies specific to T cell–dependent antigens. However, GCs were not found in these mice. This defect was mainly due to the abnormalities of B cells. Therefore, Bcl6 is essential for the differentiation of GC B cells.
B7-1 Engagement of Cytotoxic T Lymphocyte Antigen 4 Inhibits T Cell Activation in the Absence of CD28
Authors: Fallarino Francesca , Fields Patrick E. , Gajewski Thomas F.
Published: July 2002

Ligation of cytotoxic T lymphocyte antigen 4 (CTLA4) appears to inhibit T cell responses. Four mechanisms have been proposed to explain the inhibitory activity of CTLA4: competition for B7-1 and B7-2 binding by CD28; sequestration of signaling molecules away from CD28 via endocytosis; delivery of a signal that antagonizes a CD28 signal; and delivery of a signal that antagonizes a T cell receptor (TCR) signal. As three of these potential mechanisms involve functional antagonism of CD28, an experimental model was designed to determine whether CTLA4 could inhibit T cell function in the absence of CD28. TCR transgenic/recombinase activating gene 2–deficient/CD28–wild-type or CD28-deficient mice were generated and immunized with an antigen-expressing tumor. Primed T cells from both types of mice produced cytokines and proliferated in response to stimulator cells lacking B7 expression. However, whereas the response of CD28+/+ T cells was augmented by costimulation with B7-1, the response of the CD28−/− T cells was strongly inhibited. This inhibition was reversed by monoclonal antibody against B7-1 or CTLA4. Thus, CTLA4 can potently inhibit T cell activation in the absence of CD28, indicating that antagonism of a TCR-mediated signal is sufficient to explain the inhibitory effect of CTLA4.
Induction of Early B Cell Factor (EBF) and Multiple B Lineage Genes by the Basic Helix-Loop-Helix Transcription Factor E12
Authors: Kee Barbara L. , Murre Cornelis
Published: July 2002

The transcription factors encoded by the E2A and early B cell factor (EBF) genes are required for the proper development of B lymphocytes. However, the absence of B lineage cells in E2A- and EBF-deficient mice has made it difficult to determine the function or relationship between these proteins. We report the identification of a novel model system in which the role of E2A and EBF in the regulation of multiple B lineage traits can be studied. We found that the conversion of 70Z/3 pre-B lymphocytes to cells with a macrophage-like phenotype is associated with the loss of E2A and EBF. Moreover, we show that ectopic expression of the E2A protein E12 in this macrophage line results in the induction of many B lineage genes, including EBF, IL7Rα, λ5, and Rag-1, and the ability to induce κ light chain in response to mitogen. Activation of EBF may be one of the critical functions of E12 in regulating the B lineage phenotype since expression of EBF alone leads to the activation of a subset of E12-inducible traits. Our data demonstrate that, in the context of this macrophage line, E12 induces expression of EBF and together these transcription factors coordinately regulate numerous B lineage–associated genes.
Asymmetric Cell Divisions Sustain Long-Term Hematopoiesis from Single-sorted Human Fetal Liver Cells
Authors: Brummendorf Tim H. , Dragowska Wieslawa , Zijlmans J.Mark J.M. , Thornbury Gayle , Lansdorp Peter M.
Published: July 2002

Hematopoietic stem cells (HSCs) in adult marrow are believed to be derived from fetal liver precursors. To study cell kinetics involved in long-term hematopoiesis, we studied single-sorted candidate HSCs from fetal liver that were cultured in the presence of a mixture of stimulatory cytokines. After 8–10 d, the number of cells in primary cultures varied from <100 to >10,000 cells. Single cells in slow growing colonies were recloned upon reaching a 100–200 cell stage. Strikingly, the number of cells in subclones varied widely again. These results are indicative of asymmetric divisions in primitive hematopoietic cells in which proliferative potential and cell cycle properties are unevenly distributed among daughter cells. The continuous generation of functional heterogeneity among the clonal progeny of HSCs is in support of intrinsic control of stem cell fate and provides a model for the long-term maintenance of hematopoiesis in vitro and in vivo.
High Frequency of Skin-homing Melanocyte-specific Cytotoxic T Lymphocytes in Autoimmune Vitiligo
Authors: Ogg Graham S. , Rod Dunbar P. , Romero Pedro , Chen Ji-Li , Cerundolo Vincenzo
Published: July 2002

Vitiligo is an autoimmune condition characterized by loss of epidermal melanocytes. Using tetrameric complexes of human histocompatibility leukocyte antigen (HLA) class I to identify antigen-specific T cells ex vivo, we observed high frequencies of circulating MelanA-specific, A*0201-restricted cytotoxic T lymphocytes (A2–MelanA tetramer+ CTLs) in seven of nine HLA-A*0201–positive individuals with vitiligo. Isolated A2–MelanA tetramer+ CTLs were able to lyse A*0201-matched melanoma cells in vitro and their frequency ex vivo correlated with extent of disease. In contrast, no A2–MelanA tetramer+ CTL could be identified ex vivo in all four A*0201-negative vitiligo patients or five of six A*0201-positive asymptomatic controls. Finally, we observed that the A2–MelanA tetramer+ CTLs isolated from vitiligo patients expressed high levels of the skin homing receptor, cutaneous lymphocyte-associated antigen, which was absent from the CTLs seen in the single A*0201-positive normal control. These data are consistent with a role of skin-homing autoreactive melanocyte-specific CTLs in causing the destruction of melanocytes seen in autoimmune vitiligo. Lack of homing receptors on the surface of autoreactive CTLs could be a mechanism to control peripheral tolerance in vivo.
Regulatory T Cells in the Control of Autoimmunity: the Essential Role of  Transforming Growth Factor β and Interleukin 4 in the Prevention of Autoimmune Thyroiditis in Rats by Peripheral CD4+CD45RC− Cells and CD4+CD8− Thymocytes
Authors: Seddon Benedict , Mason Don
Published: July 2002

Previous studies have shown that induction of autoimmune diabetes by adult thymectomy and split dose irradiation of PVG.RT1u rats can be prevented by their reconstitution with peripheral CD4+CD45RC−TCR-α/β+RT6+ cells and CD4+CD8− thymocytes from normal syngeneic donors. These data provide evidence for the role of regulatory T cells in the prevention of a tissue-specific autoimmune disease but the mode of action of these cells has not been reported previously. In this study, autoimmune thyroiditis was induced in PVG.RT1c rats using a similar protocol of thymectomy and irradiation. Although a cell-mediated mechanism has been implicated in the pathogenesis of diabetes in PVG.RT1u rats, development of thyroiditis is independent of CD8+ T cells and is characterized by high titers of immunoglobulin (Ig)G1 antithyroglobulin antibodies, indicating a major humoral component in the pathogenesis of disease. As with autoimmune diabetes in PVG.RT1u rats, development of thyroiditis was prevented by the transfer of CD4+CD45RC− and CD4+CD8− thymocytes from normal donors but not by CD4+CD45RC+ peripheral T cells. We now show that transforming growth factor (TGF)-β and interleukin (IL)-4 both play essential roles in the mechanism of this protection since administration of monoclonal antibodies that block the biological activity of either of these cytokines abrogates the protective effect of the donor cells in the recipient rats. The prevention of both diabetes and thyroiditis by CD4+CD45RC− peripheral cells and CD4+CD8− thymocytes therefore does not support the view that the mechanism of regulation involves a switch from a T helper cell type 1 (Th1) to a Th2-like response, but rather relies upon a specific suppression of the autoimmune responses involving TGF-β and IL-4. The observation that the same two cytokines were implicated in the protective mechanism, whether thymocytes or peripheral cells were used to prevent autoimmunity, strongly suggests that the regulatory cells from both sources act in the same way and that the thymocytes are programmed in the periphery for their protective role. The implications of this result with respect to immunological homeostasis are discussed.
Cytotoxicity Is Mandatory for CD8+ T Cell–mediated Contact Hypersensitivity
Authors: Kehren Jeanne , Desvignes Cyril , Krasteva Maya , Ducluzeau Marie-Thérèse , Assossou Olga , Horand Françoise , Hahne Michael , Kägi David , Kaiserlian Dominique , Nicolas Jean-François
Published: July 2002

Contact hypersensitivity (CHS) is a T cell–mediated skin inflammation induced by epicutaneous exposure to haptens in sensitized individuals. We have previously reported that CHS to dinitrofluorobenzene in mice is mediated by major histocompatibility complex (MHC) class I–restricted CD8+ T cells. In this study, we show that CD8+ T cells mediate the skin inflammation through their cytotoxic activity. The contribution of specific cytotoxic T lymphocytes (CTLs) to the CHS reaction was examined both in vivo and in vitro, using mice deficient in perforin and/or Fas/Fas ligand (FasL) pathways involved in cytotoxicity. Mice double deficient in perforin and FasL were able to develop hapten-specific CD8+ T cells in the lymphoid organs but did not show CHS reaction. However, they did not generate hapten-specific CTLs, demonstrating that the CHS reaction is dependent on cytotoxic activity. In contrast, Fas-deficient lpr mice, FasL-deficient gld mice, and perforin-deficient mice developed a normal CHS reaction and were able to generate hapten-specific CTLs, suggesting that CHS requires either the Fas/FasL or the perforin pathway. This was confirmed by in vitro studies showing that the hapten-specific CTL activity was exclusively mediated by MHC class I–restricted CD8+ T cells which could use either the perforin or the Fas/FasL pathway for their lytic activity. Thus, cytotoxic CD8+ T cells, commonly implicated in the host defence against tumors and viral infections, could also mediate harmful delayed-type hypersensitivity reactions.
Dynamin 2 Is Required for Phagocytosis in Macrophages
Authors: Gold Elizabeth S. , Underhill David M. , Morrissette Naomi S. , Guo Jian , McNiven Mark A. , Aderem Alan
Published: July 2002

Cells internalize soluble ligands through endocytosis and large particles through actin-based phagocytosis. The dynamin family of GTPases mediates the scission of endocytic vesicles from the plasma membrane. We report here that dynamin 2, a ubiquitously expressed dynamin isoform, has a role in phagocytosis in macrophages. Dynamin 2 is enriched on early phagosomes, and expression of a dominant-negative mutant of dynamin 2 significantly inhibits particle internalization at the stage of membrane extension around the particle. This arrest in phagocytosis resembles that seen with inhibitors of phosphoinositide 3-kinase (PI3K), and inhibition of PI3K prevents the recruitment of dynamin to the site of particle binding. Although expression of mutant dynamin in macrophages inhibited particle internalization, it had no effect on the production of inflammatory mediators elicited by particle binding.
Two Distinct Pathways Leading to Nuclear Apoptosis
Authors: Susin Santos A. , Daugas Eric , Ravagnan Luigi , Samejima Kumiko , Zamzami Naoufal , Loeffler Markus , Costantini Paola , Ferri Karine F. , Irinopoulou Theano , Prévost Marie-Christine , Brothers Greg , Mak Tak W. , Penninger Josef , Earnshaw William C. , Kroemer Guido
Published: July 2002

Apaf-1−/− or caspase-3−/− cells treated with a variety of apoptosis inducers manifest apoptosis-associated alterations including the translocation of apoptosis-inducing factor (AIF) from mitochondria to nuclei, large scale DNA fragmentation, and initial chromatin condensation (stage I). However, when compared with normal control cells, Apaf-1−/− or caspase-3−/− cells fail to exhibit oligonucleosomal chromatin digestion and a more advanced pattern of chromatin condensation (stage II). Microinjection of such cells with recombinant AIF only causes peripheral chromatin condensation (stage I), whereas microinjection with activated caspase-3 or its downstream target caspase-activated DNAse (CAD) causes a more pronounced type of chromatin condensation (stage II). Similarly, when added to purified HeLa nuclei, AIF causes stage I chromatin condensation and large-scale DNA fragmentation, whereas CAD induces stage II chromatin condensation and oligonucleosomal DNA degradation. Furthermore, in a cell-free system, concomitant neutralization of AIF and CAD is required to suppress the nuclear DNA loss caused by cytoplasmic extracts from apoptotic wild-type cells. In contrast, AIF depletion alone suffices to suppress the nuclear DNA loss contained in extracts from apoptotic Apaf-1−/− or caspase-3−/− cells. As a result, at least two redundant parallel pathways may lead to chromatin processing during apoptosis. One of these pathways involves Apaf-1 and caspases, as well as CAD, and leads to oligonucleosomal DNA fragmentation and advanced chromatin condensation. The other pathway, which is caspase-independent, involves AIF and leads to large-scale DNA fragmentation and peripheral chromatin condensation.
Complement C3 Activation Is Required for Antiphospholipid Antibody-induced Fetal Loss
Authors: Holers V. Michael , Girardi Guillermina , Mo Lian , Guthridge Joel M. , Molina Hector , Pierangeli Silvia S. , Espinola Ricardo , Xiaowei Liu E. , Mao Dailing , Vialpando Christopher G. , Salmon Jane E.
Published: July 2002

The antiphospholipid syndrome (APS) is characterized by recurrent fetal loss, vascular thrombosis, and thrombocytopenia occurring in the presence of antiphospholipid (aPL) antibodies. The pathogenesis of fetal loss and tissue injury in APS is incompletely understood, but is thought to involve platelet and endothelial cell activation as well as procoagulant effects of aPL antibodies acting directly on clotting pathway components. Recent studies have shown that uncontrolled complement activation in the placenta leads to fetal death in utero. We hypothesized that aPL antibodies activate complement in the placenta, generating split products that mediate placental injury and lead to fetal loss and growth retardation. To test this hypothesis, we used a murine model of APS in which pregnant mice are injected with human IgG containing aPL antibodies. We found that inhibition of the complement cascade in vivo, using the C3 convertase inhibitor complement receptor 1–related gene/protein y (Crry)-Ig, blocks fetal loss and growth retardation. Furthermore, mice deficient in complement C3 were resistant to fetal injury induced by aPL antibodies. While antigenic epitopes recognized by aPL antibodies are important in the pathogenesis of APS, our data show that in vivo complement activation is required for aPL antibody-induced fetal loss and growth retardation.
Mechanism of ATP-sensitive K Channel Inhibition by Sulfhydryl Modification
Authors: Trapp Stefan , Tucker Stephen J. , Ashcroft Frances M.
Published: July 2002

ATP-sensitive potassium (KATP) channels are reversibly inhibited by intracellular ATP. Agents that interact with sulfhydryl moieties produce an irreversible inhibition of KATP channel activity when applied to the intracellular membrane surface. ATP appears to protect against this effect, suggesting that the cysteine residue with which thiol reagents interact may either lie within the ATP-binding site or be inaccessible when the channel is closed. We have examined the interaction of the membrane-impermeant thiol-reactive agent p-chloromercuriphenylsulphonate (pCMPS) with the cloned β cell KATP channel. This channel comprises the pore-forming Kir6.2 and regulatory SUR1 subunits. We show that the cysteine residue involved in channel inhibition by pCMPS resides on the Kir6.2 subunit and is located at position 42, which lies within the NH2 terminus of the protein. Although ATP protects against the effects of pCMPS, the ATP sensitivity of the KATP channel was unchanged by mutation of C42 to either valine (V) or alanine (A), suggesting that ATP does not interact directly with this residue. These results are consistent with the idea that C42 is inaccessible to the intracellular solution, and thereby protected from interaction with pCMPS when the channel is closed by ATP. We also observed that the C42A mutation does not affect the ability of SUR1 to endow Kir6.2 with diazoxide sensitivity, and reduces, but does not prevent, the effects of MgADP and tolbutamide, which are mediated via SUR1. The Kir6.2-C42A (or V) mutant channel may provide a suitable background for cysteine-scanning mutagenesis studies.
A critical examination of the peer review process
Authors: van Rooyen Susan
Published: July 2002

This paper examines the process of peer review in scientific publication. It outlines the background to Locknet (the international network for research into the preparation, publication and dissemination of health research). It looks at the objectives of the peer review process, ethical and quality issues raised, and the problems of improving the quality of peer review. It also briefly explores some of the research recently undertaken into peer review.
The real and the symmetric nonnegative inverse eigenvalue problems are different
Authors: Johnson Charles , Laffey Thomas , Loewy Raphael
Published: July 2002

We show that there exist real numbers

λ
1

,

λ
2

,
…
,

λ
n

\lambda _1,\lambda _2,\dotsc ,\lambda _n

that occur as the eigenvalues of an entry-wise nonnegative

n
n

-by-

n
n

matrix but do not occur as the eigenvalues of a symmetric nonnegative

n
n

-by-

n
n

matrix. This solves a problem posed by Boyle and Handelman, Hershkowitz, and others. In the process, recent work by Boyle and Handelman that solves the nonnegative inverse eigenvalue problem by appending 0’s to given spectral data is refined.
Primes of the form 𝑝=1+𝑚²+𝑛² in short intervals
Authors: Wu J.
Published: July 2002

In this note, we prove that for every

θ
≥

115
121

\theta \ge {\frac {115}{121}}

and

x
≥

x

0

(
θ
)

x\ge x_{0}(\theta )

, the short interval

(
x
,
x
+

x

θ

]

(x, x+x^{\theta }]

contains at least one prime number of the form

p
=
1
+

m

2

+

n

2

p=1+m^{2}+n^{2}

with

(
m
,
n
)
=
1

(m,n)=1

. This improves a similar result due to Huxley and Iwaniec, which requires

θ
≥

99
100

\theta \ge {\frac {99}{100}}

.
Maximal subgroups in finite and profinite groups
Authors: Borovik Alexandre , Pyber Laszlo , Shalev Aner
Published: July 2002

We prove that if a finitely generated profinite group

G
G

is not generated with positive probability by finitely many random elements, then every finite group

F
F

is obtained as a quotient of an open subgroup of

G
G

. The proof involves the study of maximal subgroups of profinite groups, as well as techniques from finite permutation groups and finite Chevalley groups. Confirming a conjecture from Ann. of Math. 137 (1993), 203–220, we then prove that a finite group

G
G

has at most

|

G

|

c

|G|^c

maximal soluble subgroups, and show that this result is rather useful in various enumeration problems.
Derivations, isomorphisms, and second cohomology of generalized Witt algebras
Authors: Oković Dragomir , Zhao Kaming
Published: July 2002

Generalized Witt algebras, over a field

F
F

of characteristic

0
0

, were defined by Kawamoto about 12 years ago. Using different notations from Kawamoto’s, we give an essentially equivalent definition of generalized Witt algebras

W
=
W
(
A
,
T
,
φ
)

W=W(A,T,\varphi )

over

F
F

, where the ingredients are an abelian group

A
A

, a vector space

T
T

over

F
F

, and a map

φ
:
T
×
A
→
K

\varphi :T\times A\to K

which is linear in the first variable and additive in the second one. In this paper, the derivations of any generalized Witt algebra

W
=

W=

W
(
A
,
T
,
φ
)

W(A,T,\varphi )

, with the right kernel of

φ
\varphi

being

0
0

, are explicitly described; the isomorphisms between any two simple generalized Witt algebras are completely determined; and the second cohomology group

H
2

(
W
,
F
)

H^2(W,F)

for any simple generalized Witt algebra is computed. The derivations, the automorphisms and the second cohomology groups of some special generalized Witt algebras have been studied by several other authors as indicated in the references.
The homological degree of a module
Authors: Vasconcelos Wolmer
Published: July 2002

A homological degree of a graded module

M
M

is an extension of the usual notion of multiplicity tailored to provide a numerical signature for the module even when

M
M

is not Cohen–Macaulay. We construct a degree,

hdeg
⁡
(
M
)

\operatorname {hdeg}(M)

, that behaves well under hyperplane sections and the modding out of elements of finite support. When carried out in a local algebra this degree gives a simulacrum of complexity à la Castelnuovo–Mumford’s regularity. Several applications for estimating reduction numbers of ideals and predictions on the outcome of Noether normalizations are given.
The Dixmier-Moeglin equivalence in quantum coordinate rings and quantized Weyl algebras
Authors: Goodearl K. , Letzter E.
Published: July 2002

We study prime and primitive ideals in a unified setting applicable to quantizations (at nonroots of unity) of

n
×
n

n\times n

matrices, of Weyl algebras, and of Euclidean and symplectic spaces. The framework for this analysis is based upon certain iterated skew polynomial algebras

A
A

over infinite fields

k
k

of arbitrary characteristic. Our main result is the verification, for

A
A

, of a characterization of primitivity established by Dixmier and Moeglin for complex enveloping algebras. Namely, we show that a prime ideal

P
P

of

A
A

is primitive if and only if the center of the Goldie quotient ring of

A

/

P

A/P

is algebraic over

k
k

, if and only if

P
P

is a locally closed point – with respect to the Jacobson topology – in the prime spectrum of

A
A

. These equivalences are established with the aid of a suitable group

H

\mathcal {H}

acting as automorphisms of

A
A

. The prime spectrum of

A
A

is then partitioned into finitely many “

H

\mathcal {H}

-strata” (two prime ideals lie in the same

H

\mathcal {H}

-stratum if the intersections of their

H

\mathcal {H}

-orbits coincide), and we show that a prime ideal

P
P

of

A
A

is primitive exactly when

P
P

is maximal within its

H

\mathcal {H}

-stratum. This approach relies on a theorem of Moeglin-Rentschler (recently extended to positive characteristic by Vonessen), which provides conditions under which

H

\mathcal {H}

acts transitively on the set of rational ideals within each

H

\mathcal {H}

-stratum. In addition, we give detailed descriptions of the strata that can occur in the prime spectrum of

A
A

. For quantum coordinate rings of semisimple Lie groups, results analogous to those obtained in this paper already follow from work of Joseph and Hodges-Levasseur-Toro. For quantum affine spaces, analogous results have been obtained in previous work of the authors.
The Hexagonal Honeycomb Conjecture
Authors: Morgan Frank
Published: July 2002

It is conjectured that the planar hexagonal honeycomb provides the least-perimeter way to enclose and separate infinitely many regions of unit area. Various natural formulations of the question are not known to be equivalent. We prove existence for two formulations. Many questions remain open.
On error estimates of the projection methods for the Navier-Stokes equations: Second-order schemes
Authors: Shen Jie
Published: July 2002

We present in this paper a rigorous error analysis of several projection schemes for the approximation of the unsteady incompressible Navier-Stokes equations. The error analysis is accomplished by interpreting the respective projection schemes as second-order time discretizations of a perturbed system which approximates the Navier-Stokes equations. Numerical results in agreement with the error analysis are also presented.
Probability laws related to the Jacobi theta and Riemann zeta functions, and Brownian excursions
Authors: Biane Philippe , Pitman Jim , Yor Marc
Published: July 2002

This paper reviews known results which connect Riemann’s integral representations of his zeta function, involving Jacobi’s theta function and its derivatives, to some particular probability laws governing sums of independent exponential variables. These laws are related to one-dimensional Brownian motion and to higher dimensional Bessel processes. We present some characterizations of these probability laws, and some approximations of Riemann’s zeta function which are related to these laws.
On the modularity of elliptic curves over 𝐐: Wild 3-adic exercises
Authors: Breuil Christophe , Conrad Brian , Diamond Fred , Taylor Richard
Published: July 2002

We complete the proof that every elliptic curve over the rational numbers is modular.
𝐶* tensor categories from quantum groups
Authors: Wenzl Hans
Published: July 2002

Let

g

\mathfrak g

be a semisimple Lie algebra and let

d
d

be the ratio between the square of the lengths of a long and a short root. Moreover, let

F

\mathcal F

be the quotient category of the category of tilting modules of

U
q

g

U_q\mathfrak g

modulo the ideal of tilting modules with zero

q
q

-dimension for

q
=

e

±
π
i

/

d
l

q=e^{\pm \pi i/dl}

. We show that for

l
l

a sufficiently large integer, the morphisms of

F

\mathcal F

are Hilbert spaces satisfying functorial properties. As an application, we obtain a subfactor of the hyperfinite II

1

_1

factor for each object of

F

\mathcal F

.
Inhibition of Anchorage-independent Growth of Transformed NIH3T3 Cells by Epithelial Protein Lost in Neoplasm (EPLIN) Requires Localization of EPLIN to Actin Cytoskeleton
Authors: Song Yuhong , Maul Raymond S. , Gerbin C. Sachi , Chang David D.
Published: July 2002

Epithelial protein lost in neoplasm (EPLIN) is a cytoskeleton-associated protein characterized by the presence of a single centrally located lin-11, isl-1, and mec-3 (LIM) domain. We have reported previously that EPLIN is down-regulated in transformed cells. In this study, we have investigated whether ectopic expression of EPLIN affects transformation. In untransformed NIH3T3 cells, retroviral-mediated transduction of EPLIN did not alter the cell morphology or growth. NIH3T3 cells expressing EPLIN, however, failed to form colonies when transformed by the activated Cdc42 or the chimeric nuclear oncogene EWS/Fli-1. This suppression of anchorage-independent growth was not universal because EPLIN failed to inhibit the colony formation of Ras-transformed cells. Interestingly, the localization of EPLIN to the actin cytoskeleton was maintained in the EWS/Fli-1– or Cdc42-transformed cells, but not in Ras-transformed cells where it was distributed heterogeneously in the cytoplasm. Using truncated EPLIN constructs, we demonstrated that the NH2-terminal region of EPLIN is necessary for both the localization of EPLIN to the actin cytoskeleton and suppression of anchorage-independent growth of EWS/Fli-1–transformed cells. The LIM domain or the COOH-terminal region of EPLIN could be deleted without affecting its cytoskeletal localization or ability to suppress anchorage-dependent growth. Our study indicates EPLIN may function in growth control by associating with and regulating the actin cytoskeleton.
Dephosphorylation of Cell Cycle–regulated Proteins Correlates with Anoxia-induced Suspended Animation inCaenorhabditis elegans
Authors: Padilla Pamela A. , Nystul Todd G. , Zager Richard A. , Johnson Ali C.M. , Roth Mark B.
Published: July 2002

Some metazoans have evolved the capacity to survive severe oxygen deprivation. The nematode, Caenorhabditis elegans, exposed to anoxia (0 kPa, 0% O2) enters into a recoverable state of suspended animation during all stages of the life cycle. That is, all microscopically observable movement ceases including cell division, developmental progression, feeding, and motility. To understand suspended animation, we compared oxygen-deprived embryos to nontreated embryos in both wild-type and hif-1 mutants. We found that hif-1 mutants survive anoxia, suggesting that the mechanisms for anoxia survival are different from those required for hypoxia. Examination of wild-type embryos exposed to anoxia show that blastomeres arrest in interphase, prophase, metaphase, and telophase but not anaphase. Analysis of the energetic state of anoxic embryos indicated a reversible depression in the ATP to ADP ratio. Given that a decrease in ATP concentrations likely affects a variety of cellular processes, including signal transduction, we compared the phosphorylation state of several proteins in anoxic embryos and normoxic embryos. We found that the phosphorylation state of histone H3 and cell cycle–regulated proteins recognized by the MPM-2 antibody were not detectable in anoxic embryos. Thus, dephosphorylation of specific proteins correlate with the establishment and/or maintenance of a state of anoxia-induced suspended animation.
VISTA : visualizing global DNA sequence alignments of
arbitrary length
Authors: Mayor Chris , Brudno Michael , Schwartz Jody R. , Poliakov Alexander , Rubin Edward M. , Frazer Kelly A. , Pachter Lior S. , Dubchak Inna
Published: July 2002

Summary: VISTA is a program for visualizing global DNA sequence alignments of arbitrary length. It has a clean output, allowing for easy identification of similarity, and is easily configurable, enabling the visualization of alignments of various lengths at different levels of resolution. It is currently available on the web, thus allowing for easy access by all researchers.

Availability: VISTA server is available on the web at http://www-gsd.lbl.gov/vista. The source code is available upon request.

Contact: vista@lbl.gov

To whom correspondence should be addressed.
Prediction whether a human cDNA sequence contains initiation
codon by combining statistical information and similarity with
protein sequences
Authors: Nishikawa Tetsuo , Ota Toshio , Isogai Takao
Published: July 2002

Motivation: In the previous works, we developed ATGpr, a computer program for predicting the fullness of a cDNA, i.e. whether it contains an initiation codon or not. Statistical information of short nucleotide fragments was fully exploited in the prediction algorithm. However, sequence similarities to known proteins, which are becoming increasingly available due to recent rapid growth of protein database, were not used in the prediction. In this work, we present a new prediction algorithm based on both statistical and similarity information, which provides better performance in sensitivity and specificity.

Results: We evaluated the accuracy of ATGpr for predicting fullness of cDNA sequences from human clustered ESTs of UniGene, and we obtained specificity, sensitivity, and correlation coefficient of this prediction. Specificity and sensitivity crossed at 46% over the ATGpr score threshold of 0.33 and the maximum correlation coefficient of 0.34 was obtained at this threshold. Without ATGpr we found it effective to use alignments with known proteins for predicting the fullness of cDNA sequences. That is, specificity increased monotonously as similarity (identity of the alignments) increased. Specificity was achieved greater than 80% if identity was greater than 40%. For more effective prediction of fullness of cDNA sequences we combined the similarity (identity of query sequence) with known proteins and ATGpr score. As a result, specificity became greater than 80% if identity was greater than 20%.

Availability: The prediction program, called ATGpr_ sim, is available at http://www.hri.co.jp/atgpr/ATGpr˙sim.html

Contact: nisikawa@crl.hitachi.co.jp

To whom correspondence should be addressed.

** Present address: Biosystems Research Department, Central Research Laboratory, Hitachi Ltd, 1-280 Higashi-Koigakubo, Kokubunji-shi, Tokyo, 185-8601, Japan.

*** Present address: Kyowa Hakko Kogyo Co. Ltd, Tokyo Research Laboratories, 3-6-6 Asahi-machi, Machida-shi, Tokyo, 194-8533, Japan.
A graph layout algorithm for drawing metabolic pathways
Authors: Becker Moritz Y. , Rojas Isabel
Published: July 2002

Motivation: A large amount of data on metabolic pathways is available in databases. The ability to visualise the complex data dynamically would be useful for building more powerful research tools to access the databases. Metabolic pathways are typically modelled as graphs in which nodes represent chemical compounds, and edges represent chemical reactions between compounds. Thus, the problem of visualising pathways can be formulated as a graph layout problem. Currently available visual interfaces to biochemical databases either use static images or cannot cope well with more complex, non-standard pathways.

Results: This paper presents a new algorithm for drawing pathways which uses a combination of circular, hierarchic and force-directed graph layout algorithms to compute positions of the graph elements representing main compounds and reactions. The algorithm is particularly designed for cyclic or partially cyclic pathways or for combinations of complex pathways. It has been tested on five sample pathways with promising results.

Availability: On request from the authors.

Contact: mywyb2@cam.ac.uk

* To whom correspondence should be addressed at: Trinity College, University of Cambridge, Cambridge CB2 1TQ, UK.
Models@Home: distributed computing in bioinformatics using a
screensaver based approach
Authors: Krieger Elmar , Vriend Gert
Published: July 2002

Motivation: Due to the steadily growing computational demands in bioinformatics and related scientific disciplines, one is forced to make optimal use of the available resources. A straightforward solution is to build a network of idle computers and let each of them work on a small piece of a scientific challenge, as done by Seti@Home (http://setiathome.berkeley.edu), the world’s largest distributed computing project.

Results: We developed a generally applicable distributed computing solution that uses a screensaver system similar to Seti@Home. The software exploits the coarse-grained nature of typical bioinformatics projects. Three major considerations for the design were: (1) often, many different programs are needed, while the time is lacking to parallelize them. Models@Home can run any program in parallel without modifications to the source code; (2) in contrast to the Seti project, bioinformatics applications are normally more sensitive to lost jobs. Models@Home therefore includes stringent control over job scheduling; (3) to allow use in heterogeneous environments, Linux and Windows based workstations can be combined with dedicated PCs to build a homogeneous cluster. We present three practical applications of Models@Home, running the modeling programs WHAT IF and YASARA on 30 PCs: force field parameterization, molecular dynamics docking, and database maintenance.

Availability: Models@Home is freely available including source code and detailed instructions from http://www.cmbi.nl/models.

Contact: elmar.krieger@cmbi.kun.nl

* To whom correspondence should be addressed.
Adaptive quality-based clustering of gene expression profiles
Authors: De Smet Frank , Mathys Janick , Marchal Kathleen , Thijs Gert , De Moor Bart , Moreau Yves
Published: July 2002

Motivation: Microarray experiments generate a considerable amount of data, which analyzed properly help us gain a huge amount of biologically relevant information about the global cellular behaviour. Clustering (grouping genes with similar expression profiles) is one of the first steps in data analysis of high-throughput expression measurements. A number of clustering algorithms have proved useful to make sense of such data. These classical algorithms, though useful, suffer from several drawbacks (e.g. they require the predefinition of arbitrary parameters like the number of clusters; they force every gene into a cluster despite a low correlation with other cluster members). In the following we describe a novel adaptive quality-based clustering algorithm that tackles some of these drawbacks.

Results: We propose a heuristic iterative two-step algorithm: First, we find in the high-dimensional representation of the data a sphere where the ‘density’ of expression profiles is locally maximal (based on a preliminary estimate of the radius of the cluster—quality-based approach). In a second step, we derive an optimal radius of the cluster (adaptive approach) so that only the significantly coexpressed genes are included in the cluster. This estimation is achieved by fitting a model to the data using an EM-algorithm. By inferring the radius from the data itself, the biologist is freed from finding an optimal value for this radius by trial-and-error. The computational complexity of this method is approximately linear in the number of gene expression profiles in the data set. Finally, our method is successfully validated using existing data sets.

Availability: http://www.esat.kuleuven.ac.be/~thijs/Work/Clustering.html

Contact: frank.desmet@esat.kuleuven.ac.be

* To whom correspondence should be addressed.
PRICE, QUALITY, AND SERVICE ON THE INTERNET: SENSE AND NONSENSE
Authors: Koch James V. , Cebula Richard J.
Published: July 2002

Faster, frictionless, cheaper, better: these are said to be the hallmarks of economic activity on the Internet. Search theory suggests use of the Net could reduce the prices consumers pay, but product branding, price discrimination based on data mining, and auctions may raise prices. The Net has lowered most prices, but raised others, even when shop bots are used. Price dispersion is greater on the Net, and Net sellers change their prices more often. The role of intermediaries has not been reduced. The quality of service is idiosyncratic and highly variable. The Net is a new and distinctive avenue of commerce, but those who argue it has invalidated conventional economic principles are well off base.
Reputational Capital and Academic Pay
Authors: Moore William J. , Newman Robert J. , Turnbull Geoffrey K.
Published: July 2002

This article examines how research productivity, administrative service, and teaching affect reputational capital in the market for academic economists. Also, we investigate the issue of the durability of reputational capital, estimating the penalties associated with gaps in research output. Our results reveal that (1) the market makes a distinction between the quantity and the quality of an individual's research output, (2) a smaller number of frequently cited papers enhances reputational capital more than a greater number of less frequently cited papers, (3) reputational capital does not depreciate rapidly during research breaks, and (4) the market does not discount co‐authored papers.
Core Journals in Economics
Authors: Liner Gaines H.
Published: July 2002

This article ranks core journals in economics using the textbook citation method. Rankings are produced from citations in graduate‐level microeconomics, macroeconomics, and econometrics textbooks. Textbooks used in the study were chosen through responses from a survey of professors in top‐tier economics departments. The top nine journals or core journals from this study correlate closely in rank with the results of two comparison studies. Second‐tier journals identified in this study correlate less closely in rank with second‐tier journals in comparison studies.