bluuebunny/crossref_metadata_2025 huggingface dataset:
The instability of stratified flows at large Richardson numbers
Authors: Madja Andrew J. , Shefter Michael
Published: July 2002

In contrast to conventional expectations based on the stability of steady shear flows, elementary time-periodic stratified flows that are unstable at arbitrarily large Richardson numbers are presented here. The fundamental instability is a parametric one with twice the period of the basic state. This instability spontaneously generates local shears on buoyancy time scales near a specific angle of inclination that saturates into a localized regime of strong mixing with density overturning. We speculate that such instabilities may contribute significantly to the step-like microstructure often observed in buoyancy measurements in the ocean.
Geometric and viscous components of the tortuosity of the extracellular space in the brain
Authors: Rusakov Dmitri A. , Kullmann Dimitri M.
Published: July 2002

To understand the function of neuro-active molecules, it is necessary to know how far they can diffuse in the brain. Experimental measurements show that substances confined to the extracellular space diffuse more slowly than in free solution. The diffusion coefficients in the two situations are commonly related by a tortuosity factor, which represents the increase in path length in a porous medium approximating the brain tissue. Thus far, it has not been clear what component of tortuosity is due to cellular obstacles and what component represents interactions with the extracellular medium (“geometric” and “viscous” tortuosity, respectively). We show that the geometric tortuosity of any random assembly of space-filling obstacles has a unique value (≈1.40 for radial flux and ≈1.57 for linear flux) irrespective of their size and shape, as long as their surfaces have no preferred orientation. We also argue that the Stokes–Einstein law is likely to be violated in the extracellular medium. For molecules whose size is comparable with the extracellular cleft, the predominant effect is the viscous drag of the cell walls. For small diffusing particles, in contrast, macromolecular obstacles in the extracellular space retard diffusion. The main parameters relating the diffusion coefficient within the extracellular medium to that in free solution are the intercellular gap width and the volume fraction occupied by macromolecules. The upper limit of tortuosity for small molecules predicted by this theory is ≈2.2 (implying a diffusion coefficient approximately five times lower than that in a free medium). The results provide a quantitative framework to estimate the diffusion of molecules ranging in size from Ca
2+
ions to neurotrophins.
The common marmoset: A new world primate species with limitedMhcclass II variability
Authors: Antunes Susana G. , de Groot Natasja G. , Brok Herbert , Doxiadis Gaby , Menezes Alexandre A. L. , Otting Nel , Bontrop Ronald E.
Published: July 2002

The common marmoset (Callithrix jacchus) is a New World primate species that is highly susceptible to fatal infections caused by various strains of bacteria. We present here a first step in the molecular characterization of the common marmoset’sMhcclass II genes by nucleotide sequence analysis of the polymorphic exon 2 segments. For this study, genetic material was obtained from animals bred in captivity as well as in the wild. The results demonstrate that the common marmoset has, like other primates, apparently functionalMhc-DRand -DQregions, but theMhc-DPregion has been inactivated. At the -DRand -DQloci, only a limited number of lineages were detected. On the basis of the number of alleles found, the -DQAand -Bloci appear to be oligomorphic, whereas only a moderate degree of polymorphism was observed for two of threeMhc-DRBloci. The contact residues in the peptide-binding site of the Caja-DRB1*03 lineage members are highly conserved, whereas the -DRB*W16 lineage members show more divergence in that respect. The latter locus encodes five oligomorphic lineages whose members are not observed in any other primate species studied, suggesting rapid evolution, as illustrated by frequent exchange of polymorphic motifs. All common marmosets tested were found to share one monomorphic type ofCaja-DRB*W12allele probably encoded by a separate locus. Common marmosets apparently lack haplotype polymorphism because the number ofCaja-DRBloci present per haplotype appears to be constant. Despite this, however, an unexpectedly high number of allelic combinations are observed at the haplotypic level, suggesting thatCaja-DRBalleles are exchanged frequently between chromosomes by recombination, promoting an optimal distribution of limitedMhcpolymorphisms among individuals of a given population. This peculiar genetic make up, in combination with the limited variability of the major histocompatability complex class II repertoire, may contribute to the common marmoset’s susceptibility to particular bacterial infections.
Kinetics of T cell receptor β, γ, and δ rearrangements during adult thymic development: T cell receptor rearrangements are present in CD44+CD25+Pro-T thymocytes
Authors: Capone Myriam , Hockett Richard D. , Zlotnik Albert
Published: July 2002

We performed a comprehensive analysis of T cell receptor (TCR) γ rearrangements in T cell precursors of the mouse adult thymus. Using a sensitive quantitative PCR method, we show that TCRγ rearrangements are present in CD44+CD25+Pro-T thymocytes much earlier than expected. TCRγ rearrangements increase significantly from the Pro-T to the CD44−CD25+Pre-T cell transition, and follow different patterns depending on each Vγ gene segment, suggesting that ordered waves of TCRγ rearrangement exist in the adult mouse thymus as has been described in the fetal mouse thymus. Recombinations of TCRγ genes occur concurrently with TCRδ and D-Jβ rearrangements, but before Vβ gene assembly. Productive TCRγ rearrangements do not increase significantly before the Pre-T cell stage and are depleted in CD4+CD8+double-positive cells from normal mice. In contrast, double-positive thymocytes from TCRδ−/− mice display random proportions of TCRγ rearranged alleles, supporting a role for functional TCRγ/δ rearrangements in the γδ divergence process.
Negative regulation of mitosis in fission yeast by the Shk1interacting protein Skb1 and its human homolog, Skb1Hs
Authors: Gilbreth Mary , Yang Peirong , Bartholomeusz Geoffrey , Pimental Ruth A. , Kansra Sanjay , Gadiraju Ramesh , Marcus Stevan
Published: July 2002

We previously provided evidence that the protein encoded by the highly conserved
skb1
gene is a putative regulator of Shk1, a p21
Cdc42/Rac
-activated kinase (PAK) homolog in the fission yeast
Schizosaccharomyces pombe. skb1
null mutants are viable and competent for mating but less elongate than wild-type
S. pombe
cells, whereas cells that overexpress
skb1
are hyperelongated. These phenotypes suggest a possible role for Skb1 as a mitotic inhibitor. Here we show genetic interactions of both
skb1
and
shk1
with genes encoding key mitotic regulators in
S. pombe
. Our results indicate that Skb1 negatively regulates mitosis by a mechanism that is independent of the Cdc2-activating phosphatase Cdc25 but that is at least partially dependent on Shk1 and the Cdc2 inhibitory kinase Wee1. We provide biochemical evidence for association of Skb1 and Shk1 with Cdc2 in
S. pombe
, suggesting that Skb1 and Shk1 inhibit mitosis through interaction with the Cdc2 complex, rather than by an indirect mechanism. These results provide evidence of a previously undescribed role for PAK-related protein kinases as mitotic inhibitors. We also describe the cloning of a human homolog of
skb1
,
SKB1Hs
, and show that it can functionally replace
skb1
in
S. pombe
. Thus, the molecular functions of Skb1-related proteins have likely been substantially conserved through evolution.
Impact of oncogenes in tumor angiogenesis: Mutant K-
ras
up-regulation of vascular endothelial growth factor/vascular permeability factor is necessary, but not sufficient for tumorigenicity of human colorectal carcinoma cells
Authors: Okada Futoshi , Rak Janusz W. , Croix Brad St. , Lieubeau Blandine , Kaya Mitsunori , Roncari Luba , Shirasawa Senji , Sasazuki Takehiko , Kerbel Robert S.
Published: July 2002

Targeted disruption of the single mutant K-
ras
allele in two human colorectal carcinoma cell lines (DLD-1 and HCT-116) leads to loss of tumorigenic competence in nude mice with retention of ability to grow indefinitely in monolayer culture. Because expression of the mutant K-
ras
oncogene in these cell lines is associated with marked up-regulation of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), we sought to determine whether this potent angiogenesis inducer plays a role in K-ras-dependent tumorigenic competence. Transfection of a VEGF
121
antisense expression vector into DLD-1 and HCT-116 cells resulted in suppression of VEGF/VPF production by a factor of 3- to 4-fold. The VEGF/VPF-deficient sublines, unlike the parental population or vector controls, were profoundly suppressed in their ability to form tumors in nude mice for as long as 6 months after cell injection. In contrast,
in vitro
growth of these sublines was unaffected, thus demonstrating the critical importance of VEGF/VPF as an angiogenic factor for HCT-116 and DLD-1 cells. Transfection of a full-length VEGF
121
cDNA into two nontumorigenic mutant K-
ras
knockout sublines resulted in a weak but detectable restoration of tumorigenic ability
in vivo
in a subset of the transfectants, with no consistent change in growth properties
in vitro
. The findings indicate that mutant
ras
-oncogene-dependent VEGF/VPF expression is necessary, but not sufficient, for progressive tumor growth
in vivo
and highlight the relative contribution of oncogenes, such as mutant K-
ras,
to the process of tumor angiogenesis.
Experimental support for a β-propeller domain in integrin α-subunits and a calcium binding site on its lower surface
Authors: Oxvig Claus , Springer Timothy A.
Published: July 2002

Integrins are large, heterodimeric surface molecules of wide importance in cell adhesion. The N-terminal half of all integrin α-subunits contains seven weak sequence repeats of ≈60 amino acids that are important in ligand binding and have been predicted to fold cooperatively into a single β-propeller domain with seven β-sheets. We provide evidence supporting this model with a mouse mAb to human Mac-1 (αMβ2, CD11b/CD18). This antibody, CBRM1/20, binds to amino acid residues that are in different repeats and are 94 residues apart in the primary structure in the loop between strands 1 and 2 of β-sheet 5 and in the loop between strands 3 and 4 of β-sheet 6. The 1–2 loops of β-sheets 5–7 in integrins have EF hand-like Ca
2+
-binding motifs. CBRM1/20 binds to Mac-1 in the presence of Ca
2+
or Sr
2+
with an EC
50
of 0.2 mM. Mg
2+
or Mn
2+
cannot substitute. Antibodies to other epitopes on the Mac-1 β-propeller domain bind in the absence of calcium. mAb CBRM1/20 does not block ligand binding. Thus, the region on the lower surface of the β-propeller domain to which mAb CBRM1/20 binds does not bind ligand and, furthermore, cannot bind other integrin domains, such as those of the β-subunit.
Oxygen sensing in yeast: Evidence for the involvement of the respiratory chain in regulating the transcription of a subset of hypoxic genes
Authors: Kwast Kurt E. , Burke Patricia V. , Staahl Brett T. , Poyton Robert O.
Published: July 2002

Oxygen availability affects the transcription of a number of genes in nearly all organisms. Although the molecular mechanisms for sensing oxygen are not precisely known, heme is thought to play a pivotal role. Here, we address the possibility that oxygen sensing in yeast, as in mammals, involves a redox-sensitive hemoprotein. We have found that carbon monoxide (CO) completely blocks the anoxia-induced expression of two hypoxic genes,
OLE1
and
CYC7
, partially blocks the induction of a third gene
, COX5b
, and has no effect on the expression of other hypoxic or aerobic genes. In addition, transition metals (Co and Ni) induce the expression of
OLE1
and
CYC7
in a concentration-dependent manner under aerobic conditions. These findings suggest that the redox state of an oxygen-binding hemoprotein is involved in controlling the expression of at least two hypoxic yeast genes. By using mutants deficient in each of the two major yeast CO-binding hemoproteins (cytochrome
c
oxidase and flavohemoglobin), respiratory inhibitors, and
cob1
and ρ
0
mutants, we have found that the respiratory chain is involved in the anoxic induction of these two genes and that cytochrome
c
oxidase is likely the hemoprotein “sensor.” Our findings also indicate that there are at least two classes of hypoxic genes in yeast (CO sensitive and CO insensitive) and imply that multiple pathways/mechanisms are involved in modulating the expression of hypoxic yeast genes.
Control of spine formation by electrical activity in the adult rat cerebellum
Authors: Bravin Monica , Morando Laura , Vercelli Alessandro , Rossi Ferdinando , Strata Piergiorgio
Published: July 2002

Dendritic spines are a key structure in neuronal plasticity.
Enhanced activity is commonly associated with an increase in spine size
and density. Purkinje cell dendrites are characterized by a proximal
and a distal compartment on which climbing fibers and parallel fibers,
respectively, impinge. The proximal region has a very low spine
density, whereas the distal region has a high density. Previous
experiments showed that after climbing fiber deletion, Purkinje cells
become hyperactive, and a large number of spines develop on the
proximal dendrites. Here we show that the same hyperspiny
transformation occurs in the proximal dendrites of adult Purkinje cells
by depressing electrical activity with tetrodotoxin. Thus, spines in
different dendritic compartments are created or maintained
independently from the level of Purkinje cell-firing rate and when the
afferent activity is blocked. This conclusion supports the view that
spinogenesis is the expression of an intrinsic program and the two
regions of the dendritic tree respond differently to activity block
because of differences in the inputs that they receive. On tetrodotoxin
treatment, climbing fibers become atrophic and may sprout thin
collateral ramifications directed mainly toward the granular layer. All
changes are reversible on tetrodotoxin removal. Therefore, Purkinje
cells provide a model where spines in different compartments of the
same neuron are differently regulated by the activity of their local
afferents. In addition, electrical activity is also essential to
maintain the full climbing fiber innervation.
Intermolecular interactions between dimeric calcium-sensing receptor monomers are important for its normal function
Authors: Bai Mei , Trivedi Sunita , Kifor Olga , Quinn Stephen J. , Brown Edward M.
Published: July 2002

We recently demonstrated that the G protein-coupled, extracellular calcium-sensing receptor (CaR) forms disulfide-linked dimers. The functional significance of dimerization of this receptor was suggested by our earlier observations that CaRs carrying certain point mutations exert dominant negative effects on the function of the coexpressed wild-type receptor both
in vivo
and when cotransfected in human embryonic kidney cells. In this study, we explored the functional consequences of CaR dimerization. Coexpression in human embryonic kidney cells of specific pairs of mutant CaRs, each with reduced or absent activity because of distinct loss-of-function mutations, results in the formation of heterodimers and partially reconstitutes extracellular calcium-dependent signaling. Moreover, our results suggest that the CaR has at least two functionally separable domains. However, the presence of an abnormal domain in each mutant monomer substantially impairs the function of the CaR heterodimer, resulting in the reconstituted CaRs having characteristics distinct from those of the wild-type CaR. Our study suggests that intermolecular interactions within the dimeric CaR are important for the receptor’s function.
Stable expression of human β1,4-galactosyltransferase in plant cells modifies N-linked glycosylation patterns
Authors: Palacpac Nirianne Q. , Yoshida Shohei , Sakai Hiromi , Kimura Yoshinobu , Fujiyama Kazuhito , Yoshida Toshiomi , Seki Tatsuji
Published: July 2002

β1,4-Galactosyltransferase (UDP galactose: β-
N
-acetylglucosaminide: β1,4-galactosyltransferase; EC
2.4.1.22
) catalyzes the transfer of galactose from UDP-Gal to
N
-acetylglucosamine in the penultimate stages of the terminal glycosylation of N-linked complex oligosaccharides in mammalian cells. Tobacco BY2 cells lack this Golgi enzyme. To determine to what extent the production of a mammalian glycosyltransferase can alter the glycosylation pathway of plant cells, tobacco BY2 suspension-cultured cells were stably transformed with the full-length human galactosyltransferase gene placed under the control of the cauliflower mosaic virus 35S promoter. The expression was confirmed by assaying enzymatic activity as well as by Southern and Western blotting. The transformant with the highest level of enzymatic activity has glycans with galactose residues at the terminal nonreducing ends, indicating the successful modification of the plant cell N-glycosylation pathway. Analysis of the oligosaccharide structures shows that the galactosylated
N
-glycans account for 47.3% of the total sugar chains. In addition, the absence of the dominant xylosidated- and fucosylated-type sugar chains confirms that the transformed cells can be used to produce glycoproteins without the highly immunogenic glycans typically found in plants. These results demonstrate the synthesis in plants of N-linked glycans with modified and defined sugar chain structures similar to mammalian glycoproteins.
Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation
Authors: Jin Shengkan , Gorfajn Barbara , Faircloth Glynn , Scotto Kathleen W.
Published: July 2002

Ecteinascidin 743 (ET-743), a highly promising marine-based antitumor agent presently in phase II clinical trials, has been shown to interfere with the binding of minor-groove-interacting transcription factors, particularly NF-Y, with their cognate promoter elements
in vitro
. We have shown that NF-Y is a central mediator of activation of transcription of the human P glycoprotein gene (MDR1) by a variety of inducers and that NF-Y functions by recruiting the histone acetyltransferase PCAF to the MDR1 promoter. In the present study, we tested whether ET-743 could block activation of the MDR1 promoter by agents that mediate their effect through the NF-Y/PCAF complex. We report that physiologically relevant concentrations of ET-743 abrogate transcriptional activation of both the endogenous MDR1 gene and MDR1 reporter constructs by the histone deacetylase inhibitors as well as by UV light, with minimal effect on constitutive MDR1 transcription. Notably, this inhibition does not alter the promoter-associated histone hyperacetylation induced by histone deacetylase inhibitors, suggesting an
in vivo
molecular target downstream of NF-Y/PCAF binding. ET-743 is therefore the prototype for a distinct class of transcription-targeted chemotherapeutic agents and may be an efficacious adjuvant to the treatment of multidrug-resistant tumors.
Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743
Authors: Minuzzo Mario , Marchini Sergio , Broggini Massimo , Faircloth Glynn , D'Incalci Maurizio , Mantovani Roberto
Published: July 2002

Ecteinascidin-743 (ET-743) is a tetrahydroisoquinoline alkaloid isolated from the tunicate
Ecteinascidia turbinata
currently under phase II clinical trials for its potent anticancer activity. ET-743 binds DNA in the minor groove and forms covalent adducts with some sequence specificity. It selectively inhibits
in vitro
binding of the CCAAT box factor NF-Y. In this study, we assayed ET-743 function
in vivo
on the HSP70 promoter. On heat induction, the drug blocks transcription rapidly at pharmacological concentrations and in a CCAAT-dependent manner, whereas the activity of the CCAAT-less simian virus 40 promoter is not affected. The effect is exerted at the mRNA level. The distamycin-like alkylating tallimustine is inactive in these assays. Binding of NF-Y and of the heat-shock factor is normal in ET-743-treated cells. Run-on analysis of several endogenous genes further proves that the drug has rapid, profound, and selective negative effects on transcription. Thus, this marine-derived compound is a promoter-specific, transcription-interfering agent.
Selenium-dependent metabolism of purines: A selenium-dependent purine hydroxylase and xanthine dehydrogenase were purified from
Clostridium purinolyticum
and characterized
Authors: Self William T. , Stadtman Thressa C.
Published: July 2002

During purification of the selenium-dependent xanthine dehydrogenase (XDH) from
Clostridium purinolyticum
, another hydroxylase was uncovered that also contained selenium and exhibited similar spectral properties. This enzyme was purified to homogeneity. It uses purine, 2OH-purine, and hypoxanthine as substrates, and based on its substrate specificity, this selenoenzyme is termed purine hydroxylase (PH). The product of hydroxylation of purine by PH is xanthine. A concomitant release of selenium from the enzyme and loss of catalytic activity on treatment with cyanide indicates that selenium is essential for PH activity. Selenium-dependent XDH, also purified from
C. purinolyticum
, was found to be insensitive to oxygen during purification and to use both potassium ferricyanide and 2,6-dichloroindophenol as electron acceptors. Selenium is required for the xanthine-dependent reduction of 2,6-dichloroindophenol by XDH. Kinetic analyses of both enzymes revealed that xanthine is the preferred substrate for XDH and purine and hypoxanthine are preferred by PH. This characterization of these selenium-requiring hydroxylases involved in the interconversion of purines describes an extension of the pathway for purine fermentation in the purinolytic clostridia.
Phenotypic variation and intracellular parasitism by
Histoplasma
capsulatum
Authors: Kügler Silke , Sebghati Tricia Schurtz , Eissenberg Linda Groppe , Goldman William E.
Published: July 2002

The success of
Histoplasma capsulatum
as an
intracellular pathogen depends completely on successful conversion of
the saprophytic mycelial (mold) form of this fungus to a parasitic
yeast form. It is therefore not surprising that yeast phase-specific
genes and gene products are proving to be important for survival and
proliferation of
H. capsulatum
within macrophages. In
this study, we have focused on the role and regulation of two
yeast-specific characteristics: α-(1,3)-glucan, a cell wall
polysaccharide modulated by cell-density (quorum) sensing, and a
secreted calcium-binding protein (CBP) that is essential for
pathogenicity.
In vivoHIV-1 infection of CD45RA+CD4+T cells is established primarily by syncytium-inducing variants and correlates with the rate of CD4+T cell decline
Authors: Blaak Hetty , van't Wout Angélique B. , Brouwer Margreet , Hooibrink Berend , Hovenkamp Egbert , Schuitemaker Hanneke
Published: July 2002

Switch from non-syncytium-inducing (NSI) to syncytium-inducing (SI) HIV type 1 (HIV-1) is associated with accelerated CD4+T cell depletion, which might partially be explained by higher virulence of SI variants compared with NSI variants. Because NSI and SI variants use different coreceptors for entry of target cells, altered tropism might offer an explanation for increased pathogenesis associated with SI HIV-1 infection. To investigate whether SI and NSI HIV-1 variants infect different CD4+T cell subsetsin vivo, the distribution of SI and NSI variants over CD4+memory (CD45RA−RO+) and naive (CD45RA+RO−) cells was studied by using limiting dilution cultures. In contrast to NSI variants that were mainly present in CD45RO+cells, SI variants were equally distributed over CD45RO+and CD45RA+cells. Infection of memory cells by both NSI and SI HIV-1 and infection of naive cells primarily by SI HIV-1 corresponded closely with the differential cell surface expression of CXCR4 and CCR5. The frequency of SI-infected CD45RA+CD4+T cells, but not the frequency of NSI- or SI-infected CD45RO+CD4+T cells, correlated with the rate of CD4+T cell depletion. Infection of naive cells by SI HIV-1 may interfere with CD4+T cell production and thus account for rapid CD4+T cell depletion.
The Induction of Cyclooxygenase‐2 in IL‐1β‐Treated Endothelial Cells is Inhibited by Prostaglandin E2 through cAMP
Authors: Akarasereenont Pravit , Techatrisak Kitirat , Chotewuttakorn Sirikul , Thaworn Athiwat
Published: July 2002

Prostaglandins (PGS) have numerous cardiovascular and inflammatory effects. Cyclooxygenase (COX), which exists as COX‐1 and COX‐2 isoforms, is the first enzyme in the pathway in which arachidonic acid is converted to PGs. Prostaglandin E2 (PGE2) exerts a variety of biological activities for the maintenance of local homeostasis in the body. Elucidation of PGE2 involvement in the signalling molecules such as COX could lead to potential therapeutic interventions. Here, we have investigated the effects of PGE2 on the induction of COX‐2 in human umbilical vein endothelial cells (HUVEC) treated with interleukin‐1β (IL‐1β 1 ng/ml). COX activity was measured by the production of 6‐keto‐PGF1α, PGE2, PGF2α and thromboxane B2 (TXB2) in the presence of exogenous arachidonic acids (10 μM for 10 min) using enzyme immunoassay (EIA). COX‐1 and COX‐2 protein was measured by immunoblotting using specific antibody. Untreated HUVEC contained only COX‐1 protein while IL‐1β treated HUVEC contained COX‐1 and COX‐2 protein. PGE2 (3 μM for 24 h) did not affect on COX activity and protein in untreated HUVEC. Interestingly, PGE2 (3 μM for 24 h) can inhibit COX‐2 protein, but not COX‐1 protein, expressed in HUVEC treated with IL1 β. This inhibition was reversed by coincubation with forskolin (100 μM). The increased COX activity in HUVEC treated with IL‐1β was also inhibited by PGE2 (0.03, 0.3 and 3 μM for 24 h) in a dose‐dependent manner. Similarly, forskolin (10, 50 or 100 μM) can also reverse the inhibition of PGE2 on increased COX activity in IL‐1β treated HUVEC. The results suggested that (i) PGE2 can initiate negative feedback regulation in the induction of COX‐2 elicited by IL‐1β in endothelial cells, (ii) the inhibition of PGE2 on COX‐2 protein and activity in IL‐1β treated HUVEC is mediated by cAMP and (iii) the therapeutic use of PGE2 in the condition which COX‐2 has been involved may have different roles.
Fisher's Last Stand on the Quantity Theory: the Role of Money in the Recovery
Authors: Steindl Frank G.
Published: July 2002

In his recent article, Robert Dimand details for the profession the existence of four obscure papers by Irving Fisher (1935, 1936, 1937, 1940). He also brings to our attention two brief Econometrica contributions (Fisher 1946, 1947), neither of which is listed in the American Economic Association's Index of Economic Journals, as he points out. For this, and for his careful discussion of the content of those papers, we are indeed in his debt.
Transplacental Uptake of Glucose Is Decreased in Embryonic Lethal Connexin26-deficient Mice
Authors: Gabriel Heinz-Dieter , Jung Dirk , Bützler Christoph , Temme Achim , Traub Otto , Winterhager Elke , Willecke Klaus
Published: July 2002

Mice that harbor a targeted homozygous defect in the gene coding for the gap junctional protein connexin26 died in utero during the transient phase from early to midgestation. From day 10 post coitum onwards, development of homozygous embryos was retarded, which led to death around day 11 post coitum. Except for growth retardation, no gross morphological alterations were detected between homozygous connexin26-defective embryos and wild-type littermates.

At day 9 postcoitum, when chorioallantoic placenta started to function, connexin26 was weakly expressed in the yolk sac epithelium, between syncytiotrophoblasts I and II in the labyrinth region of the placenta, and in the skin of the embryo. At day 10 post coitum, expression of connexin26 in the placenta was much stronger than at the other locations. To analyze involvement of connexin26 in the placental transfer of nutrients, we have measured embryonic uptake of the nonmetabolizable glucose analogue 3-O-[14C]methylglucose, injected into the maternal tail vein. At day 10 post coitum, viable, homozygous connexin26-defective embryos accumulated only ∼40% of the radioactivity measured in wild-type and heterozygous littermates of the same size. We conclude that the uptake of glucose, and presumably other nutrients as well, from maternal blood into connexin26-deficient mouse embryos was severely impaired and apparently not sufficient to support the rapid organogenesis during midgestation. Our results suggest that connexin26 gap junction channels likely fulfill an essential role in the transfer of maternal nutrients and embryonic waste products between syncytiotrophoblast I and II in the labyrinth layer of the mouse placenta.
Glypican-3–Deficient Mice Exhibit Developmental Overgrowth and Some of the Abnormalities Typical of Simpson-Golabi-Behmel Syndrome
Authors: Cano-Gauci Danielle F. , Song Howard H. , Yang Huiling , McKerlie Colin , Choo Barbara , Shi Wen , Pullano Rose , Piscione Tino D. , Grisaru Silviu , Soon Shawn , Sedlackova Larisa , Tanswell A. Keith , Mak Tak W. , Yeger Herman , Lockwood Gina A. , Rosenblum Norman D. , Filmus Jorge
Published: July 2002

Glypicans are a family of heparan sulfate proteoglycans that are linked to the cell surface through a glycosyl–phosphatidylinositol anchor. One member of this family, glypican-3 (Gpc3), is mutated in patients with the Simpson-Golabi-Behmel syndrome (SGBS). These patients display pre- and postnatal overgrowth, and a varying range of dysmorphisms. The clinical features of SGBS are very similar to the more extensively studied Beckwith-Wiedemann syndrome (BWS). Since BWS has been associated with biallelic expression of insulin-like growth factor II (IGF-II), it has been proposed that GPC3 is a negative regulator of IGF-II. However, there is still no biochemical evidence indicating that GPC3 plays such a role.

Here, we report that GPC3-deficient mice exhibit several of the clinical features observed in SGBS patients, including developmental overgrowth, perinatal death, cystic and dyplastic kidneys, and abnormal lung development. A proportion of the mutant mice also display mandibular hypoplasia and an imperforate vagina. In the particular case of the kidney, we demonstrate that there is an early and persistent developmental abnormality of the ureteric bud/collecting system due to increased proliferation of cells in this tissue element.

The degree of developmental overgrowth of the GPC3-deficient mice is similar to that of mice deficient in IGF receptor type 2 (IGF2R), a well characterized negative regulator of IGF-II. Unlike the IGF2R-deficient mice, however, the levels of IGF-II in GPC3 knockouts are similar to those of the normal littermates.
Spindle Checkpoint Protein Bub1 Is Required for Kinetochore Localization of Mad1, Mad2, Bub3, and Cenp-E, Independently of Its Kinase Activity
Authors: Sharp-Baker Hilary , Chen Rey-Huei
Published: July 2002

The spindle checkpoint inhibits the metaphase to anaphase transition until all the chromosomes are properly attached to the mitotic spindle. We have isolated a Xenopus homologue of the spindle checkpoint component Bub1, and investigated its role in the spindle checkpoint in Xenopus egg extracts. Antibodies raised against Bub1 recognize a 150-kD phosphoprotein at both interphase and mitosis, but the molecular mass is reduced to 140 upon dephosphorylation in vitro. Bub1 is essential for the establishment and maintenance of the checkpoint and is localized to kinetochores, similar to the spindle checkpoint complex Mad1–Mad2. However, Bub1 differs from Mad1–Mad2 in that Bub1 remains on kinetochores that have attached to microtubules; the protein eventually dissociates from the kinetochore during anaphase. Immunodepletion of Bub1 abolishes the spindle checkpoint and the kinetochore binding of the checkpoint proteins Mad1, Mad2, Bub3, and CENP-E. Interestingly, reintroducing either wild-type or kinase-deficient Bub1 protein restores the checkpoint and the kinetochore localization of these proteins. Our studies demonstrate that Bub1 plays a central role in triggering the spindle checkpoint signal from the kinetochore, and that its kinase activity is not necessary for the spindle checkpoint in Xenopus egg extracts.
Regulation of B Cell Development by Variable Gene Complexity in Mice Reconstituted with Human Immunoglobulin Yeast Artificial Chromosomes
Authors: Green Larry L. , Jakobovits Aya
Published: July 2002

The relationship between variable (V) gene complexity and the efficiency of B cell development was studied in strains of mice deficient in mouse antibody production and engineered with yeast artificial chromosomes (YACs) containing different sized fragments of the human heavy (H) chain and κ light (L) chain loci. Each of the two H and the two κ chain fragments encompasses, in germline configuration, the same core variable and constant regions but contains different numbers of unique VH (5 versus 66) or Vκ genes (3 versus 32). Although each of these YACs was able to substitute for its respective inactivated murine counterpart to induce B cell development and to support production of human immunoglobulins (Igs), major differences in the efficiency of B cell development were detected. Whereas the YACs with great V gene complexity restored efficient development throughout all the different recombination and expression stages, the YACs with limited V gene repertoire exhibited inefficient differentiation with significant blocks at critical stages of B cell development in the bone marrow and peripheral lymphoid tissues. Our analysis identified four key checkpoints regulated by VH and Vκ gene complexity: (a) production of functional μ chains at the transition from the pre B-I to the pre B-II stage; (b) productive VκJκ recombination at the small pre B-II stage; (c) formation of surface Ig molecules through pairing of μ chains with L chains; and (d) maturation of B cells. These findings demonstrate that V gene complexity is essential not only for production of a diverse repertoire of antigen-specific antibodies but also for efficient development of the B cell lineage.
Overexpression of Acid Ceramidase Protects from Tumor Necrosis Factor–Induced Cell Death
Authors: Strelow Astrid , Bernardo Katussevani , Adam-Klages Sabine , Linke Thomas , Sandhoff Konrad , Krönke Martin , Adam Dieter
Published: July 2002

Tumor necrosis factor (TNF) signals cell death and simultaneously induces generation of ceramide. To evaluate the contribution of ceramide to TNF-dependent cell death, we generated clones of the TNF-sensitive cell line L929 that constitutively overexpress human acid ceramidase (AC). Ceramidase, in concert with sphingosine kinase, metabolizes ceramide to sphingosine-1-phosphate (SPP), an inducer of proliferation. In response to TNF, parental L929 cells display a significant increase in intracellular ceramide correlated with an “atypical apoptosis” characterized by membrane blebbing, DNA fragmentation and degradation of poly(ADP-ribose) polymerase despite a lack of caspase activity. These features are strongly reduced or absent in AC-overexpressing cells. Pharmacological suppression of AC with N-oleoylethanolamine restored the accumulation of intracellular ceramide as well as the sensitivity of the transfectants to TNF, implying that an enhanced metabolization of intracellular ceramide by AC shifts the balance between intracellular ceramide and SPP levels towards cell survival. Correspondingly, inhibition of ceramide production by acid sphingomyelinase also increased survival of TNF-treated L929 cells.
E‐citations: actionable identifiers and scholarly referencing
Authors: Paskin Norman
Published: July 2002

This document discusses the role of ‘actionable’ identifiers such as the Digital Object Identifier (DOI) in enabling scholarly citations in a digital environment. Citation is a subset of the general wider concept of linkage, but an interesting one for two reasons: it is a practical example being worked on today, and it demonstrates that linkage only between digital entities is insufficient for scholarly citation. It also points the way to future extensions of the concept of linkage, with new uses being made of internet resources, and tools which can support these new patterns of citation.
A limited study of online access and user preferences
Authors: Goldfinch E. P.
Published: July 2002

This paper describes a survey designed to establish the online requirements for readers and potential readers of scientific journals in a limited specialist field. Questionnaires were distributed with publication catalogues, distributed on a worldwide basis, and also included on the Nuclear Technology Publishing website. The questions covered the needs for availability of paper abstracts, full papers and CD‐ROM products. Additionally, the questions explored methods by which individual scientists access the internet and the online service facilities that are used. Many of the results are expected, but one surprising result is that a significant majority of scientists responding to the questionnaire appear to prefer to gain access to publications through the journal publishers' websites rather than through the popular service providers.
Reviews
Authors: Braid Andrew , Pilling Stella , Dryburgh Alastair , Watkins Judy
Published: July 2002

Making Sense of Standards and Technologies for Serials Management: A Guide to Practice and Future Developments for Librarians, Publishers and Systems Developers edited by Rosemary Russell. London: Library Association Publishing, in association with the UK Office for Library and Information Networking, University of Bath, April 2000. Pp. 192. Hardback, £39.95. ISBN 1‐85604‐338‐X

Blown to Bits: How the New Economics of Information Transforms Strategy by Philip Evans and Thomas S. Wurster. Harvard Business School Press, 2000. Pp. 274, Hardback, £18.99. ISBN 0‐87584‐877‐X

The Legal and Regulatory Environment for Electronic Information, 3rd edn by Charles Oppenheim. Infonortics In‐depth Briefings, 1999. Pp. 231. Hardback, £55.00. ISBN 1‐873699‐53‐0
Linking at the US National Library of Medicine
Authors: Smith Kent A. , Sequeira Ed
Published: July 2002

The development of services provided by the National Library of Medicine (NLM), which dates back to 1836, is described. MEDLINE, a database of 10‐plus million references and abstracts to the world's biomedical literature, was put on the World Wide Web for free searching in 1997 as a system called PubMed, whose use has grown to over 250 million searches per year. PubMed features a variety of links between MEDLINE references and related information – full‐text journal articles, DNA sequence data, medical knowledge bases, etc. – at websites within and outside NLM. PubMed is a major component of a larger NLM system, Entrez, which integrates access to a number of genome‐related databases with linking features similar to those of PubMed. The newest linked service, which became a reality in February 2000, is PubMed Central, the National Institutes of Health's free repository for primary research reports in all the life sciences.
JIME: an interactive journal for interactive media
Authors: Shum Simon Buckingham , Sumner Tamara
Published: July 2002

How can new media positively transform scholarly practices? In this article, we describe the Journal of Interactive Media in Education (JIME). JIME's peer‐review process is designed to promote multidisciplinary dialogue through the use of a purpose‐designed web document–discussion interface. This innovative peer‐review model and the resulting enriched digital documents illustrate some of the possibilities for promoting knowledge construction and preserving intellectual products in digital scholarly publications. We present JIME's technical infrastructure, editorial policy, and peer‐review process, and discuss how these features are used to support the journal's goals. Finally, we conclude by considering what aspects of our approach might be suitable for e‐journals in other disciplines.
The importance of aggregators
Authors: Inger Simon
Published: July 2002

This paper tries to clarify the varying roles of a group of companies collectively termed aggregators. The three classes of aggregator with distinct business models are described. All bring about different benefits to publishers and libraries alike.
ALPSP Affairs
Authors: Thorn Sue
Published: July 2002

The ALPSP Electronic Developments Committee has now been in existence for two years; this article reviews its origins, its activities to date and possible future directions.
Scholarly communities on the World Wide Web
Authors: Charkin Richard
Published: July 2002

‘Communities’ has become a buzzword in the strategy departments of publishing companies. It is clear – and becoming clearer – that the Internet is not merely a potential information delivery route but a vehicle for bringing together communities. One of the problems, however, is that much of the scholarly activity on the Web is driven by people with a traditional information delivery role – writers, publishers, booksellers and subscription agents and librarians. Nobody questions the importance of these roles but community creation is different and requires skills which are frequently closer to caterers or advertising agencies or hoteliers. Time will tell how communities will develop. Whatever happens it is clear that the world of scholarly publishing is going to change beyond recognition in the next decade – and most of that change is for the better.
Copyright and licensing — the changing scene
Authors: Morris Sally
Published: July 2002

A rapid survey of the key current issues and changes in the copyright and licensing environment. Briefly discusses the reasons why there is so much change, and in particular the changing attitudes of both authors and customers towards publishers. Surveys the new contractual problems confronting publishers; the requirements for doing business electronically in future; major legal changes; and developments in licensing. Concludes by considering how publishers can influence what happens.
Charging mechanisms for digitised texts
Authors: Bide Mark , Oppenheim Charles , Ramsden Anne
Published: July 2002

This article is an edited and condensed version of the report of a study carried out under the auspices of the Joint Information Systems Committee (JISC) and the Publishers Association (PA). It develops the conclusions of an earlier analysis (Bide, Oppenheim & Ramsden, 1997) and builds upon discussions between representatives of JISC and the PA held in the summer of 1997. The full report is available on the UKOLN server at www.ukoln.ac.uk/services/elib/papers/pa/charging/
Optimizing your association's revenue through Internet advertising
Authors: Byrne James A.
Published: July 2002

This article outlines the Internet advertising experiences of ACS Publications. It describes how ACS Publications has successfully designed a group of Websites that have increased total advertising revenue for the American Chemical Society. Detailed accounts of each ACS Website, advertising strategy, and Website development are all discussed in this article.
A bill of rights for authors?
Authors: Wilson David Gordon
Published: July 2002

An enquiry of several mid‐ or late‐career much‐published engineers and scientists about their experiences having their papers and books published will usually produce a surprising number of ‘horror stories’. If one discounts the tendency of many people to prefer transmitting, and possibly embellishing, bad news rather than good, one is still left with the strong impression that serious ethical lapses can take place in the reviewing and editing processes. The most serious problems are very long delays – periods of two years are often experienced – before acceptances or rejections of manuscripts are made known. All too often, such a delay is coupled with the appearance of a publication on the same topic by a (suspected) later‐starting rival. In several cases, authors have claimed proof that these rivals were reviewers of their papers. In some cases, the reviewer has even ‘lifted’ material from the submitted manuscript. This is a very difficult area for editors and publishers to police. A group of aggrieved authors in the US drew up a ‘bill of rights’ and negotiated, with some success, with the then‐editor of Science for its acceptance.
Analytic continuation of multiple zeta functions
Authors: Zhao Jianqiang
Published: July 2002

In this paper we shall define the analytic continuation of the multiple (Euler-Riemann-Zagier) zeta functions of depth

d
d

:
\[
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="zeta left-parenthesis s 1 comma ellipsis comma s Subscript d Baseline right-parenthesis colon equals sigma-summation Underscript 0 greater-than n 1 greater-than n 2 greater-than midline-horizontal-ellipsis greater-than n Subscript d Baseline Endscripts StartFraction 1 Over n 1 Superscript s 1 Baseline n 2 Superscript s 2 Baseline midline-horizontal-ellipsis n Subscript d Superscript s Super Subscript d Superscript Baseline EndFraction comma">

ζ
(

s
1

,
…
,

s
d

)
:=

∑

0
>

n
1

>

n
2

>
⋯
>

n
d

1

n
1

s
1

n
2

s
2

⋯

n
d

s
d

,

\zeta (s_1,\dots ,s_d):= \sum _{0>n_1 > n_2>\cdots >n_d} \frac {1}{n_1^{s_1}n_2^{s_2}\cdots n_d^{s_d}},

\]
where

Re
⁡
(

s
d

)
>
1

\operatorname {Re}(s_d)>1

and

∑

j
=
1

d

Re
⁡
(

s
j

)
>
d

\sum _{j=1}^d\operatorname {Re}(s_j)>d

. We shall also study their behavior near the poles and pose some open problems concerning their zeros and functional equations at the end.
Weighted ergodic theorems for mean ergodic 𝐿₁-contractions
Authors: Çömez Doğan , Lin Michael , Olsen James
Published: July 2002

It is shown that any bounded weight sequence which is good for all probability preserving transformations (a universally good weight) is also a good weight for any

L

1

L_{1}

-contraction with mean ergodic (ME) modulus, and for any positive contraction of

L

p

L_{p}

with

1
>
p
>
∞

1 > p >\infty

. We extend the return times theorem by proving that if

S
S

is a Dunford-Schwartz operator (not necessarily positive) on a Lebesgue space, then for any

g
g

bounded measurable

{

S

n

g
(
ω
)
}

\{S^{n} g(\omega )\}

is a universally good weight for a.e.

ω
.

\omega .

We prove that if a bounded sequence has "Fourier coefficents", then its weighted averages for any

L

1

L_{1}

-contraction with mean ergodic modulus converge in

L

1

L_{1}

-norm. In order to produce weights, good for weighted ergodic theorems for

L

1

L_{1}

-contractions with quasi-ME modulus (i.e., so that the modulus has a positive fixed point supported on its conservative part), we show that the modulus of the tensor product of

L

1

L_{1}

-contractions is the product of their moduli, and that the tensor product of positive quasi-ME

L

1

L_{1}

-contractions is quasi-ME.