bluuebunny/crossref_metadata_2025 huggingface dataset:
A reversibly glycosylated polypeptide (RGP1) possibly involved in plant cell wall synthesis: Purification, gene cloning, and trans-Golgi localization
Authors: Dhugga Kanwarpal S. , Tiwari Suresh C. , Ray Peter M.
Published: July 2002

We purified from pea (Pisum sativum) tissue an ≈40 kDa reversibly glycosylated polypeptide (RGP1) that can be glycosylated by UDP-Glc, UDP-Xyl, or UDP-Gal, and isolated a cDNA encoding it, apparently derived from a single-copy gene (Rgp1). Its predicted translation product has 364 aminoacyl residues and molecular mass of 41.5 kDa. RGP1 appears to be a membrane-peripheral protein. Immunogold labeling localizes it specifically to trans-Golgi dictyosomal cisternae. Along with other evidence, this suggests that RGP1 is involved in synthesis of xyloglucan and possibly other hemicelluloses. Corn (Zea mays) contains a biochemically similar and structurally homologous RGP1, which has been thought (it now seems mistakenly) to function in starch synthesis. The expressed sequence database also reveals close homologs of peaRgp1inArabidopsisand rice (Oryza sativa). Rice possesses, in addition, a distinct but homologous sequence (Rgp2). RGP1 provides a polypeptide marker for Golgi membranes that should be useful in plant membrane studies.
The 2.0-Å resolution crystal structure of a trimeric antibody fragment with noncognate VH–VLdomain pairs shows a rearrangement of VH CDR3
Authors: Pei Xue Y. , Holliger Philipp , Murzin Alexey G. , Williams Roger L.
Published: July 2002

The 2.0-Å resolution x-ray crystal structure of a novel trimeric antibody fragment, a “triabody,” has been determined. The trimer is made up of polypeptides constructed in a manner identical to that previously described for some “diabodies”: a VLdomain directly fused to the C terminus of a VHdomain—i.e., without any linker sequence. The trimer has three Fv heads with the polypeptides arranged in a cyclic, head-to-tail fashion. For the particular structure reported here, the polypeptide was constructed with a VHdomain from one antibody fused to the VLdomain from an unrelated antibody giving rise to “combinatorial” Fvs upon formation of the trimer. The structure shows that the exchange of the VLdomain from antibody B1-8, a Vλdomain, with the VLdomain from antibody NQ11, a Vκdomain, leads to a dramatic conformational change in the VHCDR3 loop of antibody B1-8. The magnitude of this change is similar to the largest of the conformational changes observed in antibody fragments in response to antigen binding. Combinatorial pairing of VHand VLdomains constitutes a major component of antibody diversity. Conformationally flexible antigen-binding sites capable of adapting to the specific CDR3 loop context created upon VH–VLpairing may be employed by the immune system to maximize the structural diversity of the immune response.
Dual roles for DNA sequence identity and the mismatch repair system in the regulation of mitotic crossing-over in yeast
Authors: Datta Abhijit , Hendrix Miyono , Lipsitch Marc , Jinks-Robertson Sue
Published: July 2002

Sequence divergence acts as a potent barrier to homologous recombination; much of this barrier derives from an antirecombination activity exerted by mismatch repair proteins. An inverted repeat assay system with recombination substrates ranging in identity from 74% to 100% has been used to define the relationship between sequence divergence and the rate of mitotic crossing-over in yeast. To elucidate the role of the mismatch repair machinery in regulating recombination between mismatched substrates, we performed experiments in both wild-type and mismatch repair defective strains. We find that a single mismatch is sufficient to inhibit recombination between otherwise identical sequences, and that this inhibition is dependent on the mismatch repair system. Additional mismatches have a cumulative negative effect on the recombination rate. With sequence divergence of up to approximately 10%, the inhibitory effect of mismatches results mainly from antirecombination activity of the mismatch repair system. With greater levels of divergence, recombination is inefficient even in the absence of mismatch repair activity. In both wild-type and mismatch repair defective strains, an approximate log-linear relationship is observed between the recombination rate and the level of sequence divergence.
The problem of the spreading of a liquid film along a solid surface: A new mathematical formulation
Authors: Barenblatt G. I. , Beretta E. , Bertsch M.
Published: July 2002

A new mathematical model is proposed for the spreading of a liquid film on a solid surface. The model is based on the standard lubrication approximation for gently sloping films (with the no-slip condition for the fluid at the solid surface) in the major part of the film where it is not too thin. In the remaining and relatively small regions near the contact lines it is assumed that the so-called autonomy principle holds—i.e., given the material components, the external conditions, and the velocity of the contact lines along the surface, the behavior of the fluid is identical for all films. The resulting mathematical model is formulated as a free boundary problem for the classical fourth-order equation for the film thickness. A class of self-similar solutions to this free boundary problem is considered.
Strong balancing selection at HLA loci: Evidence from segregation in South Amerindian families
Authors: Black Francis L. , Hedrick Philip W.
Published: July 2002

The genotypic proportions for major histocompatibility complex loci,
HLA-A
and
HLA-B
, of progeny in families in 23 South Amerindian tribes in which segregation for homozygotes and heterozygotes could occur are examined. Overall, there is a large deficiency of homozygotes compared with Mendelian expectations (for
HLA-A
, 114 observed and 155.50 expected and for
HLA-B
110 observed and 144.75 expected), consistent with strong balancing selection favoring heterozygotes. There is no evidence that these deficiencies were associated with particular alleles or with the age of the individuals sampled. When these families were divided into four mating types, there was strong selection against homozygotes, averaging 0.462 for three of the mating types over the two loci. For the other mating type in which the female parent is homozygous and shares one allele with the heterozygous male parent, there was no evidence of selection against homozygotes. A theoretical model incorporating these findings surprisingly does not result in a stable polymorphism for two alleles but does result in an excess of heterozygotes and a minimum fitness at intermediate allele frequencies. However, for more than two alleles, balancing selection does occur and the model approaches the qualities of the symmetrical heterozygote advantage model as the number of alleles increases.
The prion model for [URE3] of yeast: Spontaneous generation and requirements for propagation
Authors: Masison Daniel C. , Maddelein Marie-Lise , Wickner Reed B.
Published: July 2002

The genetic properties of the non-Mendelian element, [URE3], suggest that it is a prion (infectious protein) form of Ure2p, a mediator of nitrogen regulation in
Saccharomyces cerevisiae
. Into a
ure2
Δ strain (necessarily lacking [URE3]), we introduced a plasmid overproducing Ure2p. This induced the frequent “spontaneous generation” of [URE3], with properties identical to the original [URE3]. Altering the translational frame only in the prion-inducing domain of
URE2
shows that it is Ure2 protein (and not
URE2
RNA) that induces appearance of [URE3]. The proteinase K-resistance of Ure2p is unique to [URE3] strains and is not seen in nitrogen regulation of normal strains. The prion-inducing domain of Ure2p (residues 1–65) can propagate [URE3] in the absence of the C-terminal part of the molecule. In contrast, the C-terminal part of Ure2p cannot be converted to the prion (inactive) form without the prion-inducing domain covalently attached. These experiments support the prion model for [URE3] and extend our understanding of its propagation.
Interleukin 18 together with interleukin 12 inhibits IgE production by induction of interferon-γ production from activated B cells
Authors: Yoshimoto Tomohiro , Okamura Haruki , Tagawa Yoh-Ichi , Iwakura Yoichiro , Nakanishi Kenji
Published: July 2002

Interleukin 18 (IL-18), originally called interferon (IFN)-γ-inducing factor, is a recently cloned cytokine of approximately 18 kDa synthesized by Kupffer cells and activated macrophages. The major activity associated with this molecule is the induction of IFN-γ production from anti-CD3-activated T helper 1 cells in the presence of IL-12. B cells produce IgG1 and IgE when stimulated with anti-CD40 and IL-4. Here we show that a combination of IL-12 and IL-18 induces anti-CD40-activated B cells to produce IFN-γ, which inhibits IL-4-dependent IgE and IgG1 production and enhances IgG2a production without inhibiting the B cell proliferative response. We also show that 24.3% of B cells became positive for cytoplasmic IFN-γ after being stimulated with IL-12 and IL-18. Furthermore, we show that, like splenic T cells stimulated with anti-CD3, IL-12, and IL-18, B cells produced high level of IFN-γ in response to anti-CD40, IL-12, and IL-18. Injection of a mixture of IL-12 and IL-18 into mice inoculated with
Nippostrongylus brasiliensis
or injected with anti-IgD induced IFN-γ-producing cells that inhibit IgE production in them. Furthermore, B cells obtained from normal mice could develop into IFN-γ-producing cells in IFN-γ
−/−
host mice in response to
in vivo
treatment with IL-12 and IL-18. These results indicate that IFN-γ from activated B cells differentially regulates IgG1/IgE and IgG2a responses
in vitro
and
in vivo
, indicating that B cells act as regulatory cells in the immune response. Present results suggested that injection of IL-12 and IL-18 could present a unique approach for the treatment of allergic disorders.
Assaying genome-wide recombination and centromere functions with
Arabidopsis
tetrads
Authors: Copenhaver Gregory P. , Browne William E. , Preuss Daphne
Published: July 2002

During meiosis, crossover events generate new allelic combinations, yet the abundance of these genetic exchanges in individual cells has not been measured previously on a genomic level. To perform a genome-wide analysis of recombination, we monitored the assortment of genetic markers in meiotic tetrads from
Arabidopsis
. By determining the number and distribution of crossovers in individual meiotic cells, we demonstrated (
i
) surprisingly precise regulation of crossover number in each meiosis, (
ii
) considerably reduced recombination along chromosomes carrying ribosomal DNA arrays, and (
iii
) an inversely proportional relationship between recombination frequencies and chromosome size. This use of tetrad analysis also achieved precise mapping of all five
Arabidopsis
centromeres, localizing centromere functions in the intact chromosomes of a higher eukaryote.
Molecular population genetics of the
Arabidopsis CAULIFLOWER
regulatory gene: Nonneutral evolution and naturally occurring variation in floral homeotic function
Authors: Purugganan Michael D. , Suddith Jane I.
Published: July 2002

The evolution of interspecies differences in morphology requires sufficient within-species variation in developmental regulatory systems on which evolutionary forces can act. Molecular analyses of naturally occurring alleles of the
Arabidopsis thaliana CAULIFLOWER
locus reveal considerable intraspecific diversity at this floral homeotic gene, and the McDonald–Kreitman test suggests that this gene is evolving in a nonneutral fashion, with an excess of intraspecific replacement polymorphisms. The naturally occurring molecular variation within this floral regulatory gene is associated with functionally different alleles, which can be distinguished phenotypically by their differential ability to direct floral meristem development.
Cospeciation of chemoautotrophic bacteria and deep sea clams
Authors: Peek Andrew S. , Feldman Robert A. , Lutz Richard A. , Vrijenhoek Robert C.
Published: July 2002

Vesicomyid clams depend entirely on sulfur-oxidizing endosymbiotic bacteria for their nutriment. Endosymbionts that are transmitted cytoplasmically through eggs, such as these, should exhibit a phylogenetic pattern that closely parallels the phylogeny of host mitochondrial genes. Such parallel patterns are rarely observed, however, because they are obscured easily by small amounts of horizontal symbiont transmission or occasional host switching. The present symbiont genealogy, based on bacterial small subunit (16S) rDNA sequences, was closely congruent with the host genealogy, based on clam mitochondrial cytochrome oxidase subunit I and large subunit (16S) rDNA sequences. This phylogenetic evidence supports the hypothesis of cospeciation and a long term association between the participants in this symbiosis.
An essential role for the phosphatidylinositol transfer protein in the scission of coatomer-coated vesicles from the trans-Golgi network
Authors: Simon Jean-Pierre , Morimoto Takashi , Bankaitis Vytas A. , Gottlieb Theodore A. , Ivanov Ivan E. , Adesnik Milton , Sabatini David D.
Published: July 2002

We identified the phosphatidylinositol transfer protein (PITP) as being responsible for a powerful latent, nucleotide-independent, Golgi-vesiculating activity that is present in the cytosol but is only manifested as an uncontrolled activity in a cytosolic protein subfraction, in which it is separated from regulatory components that appear to normally limit its action to the scission of COPI-coated buds from trans-Golgi network membranes. A specific anti-PITP antibody that recognizes the two mammalian PITP isoforms fully inhibited the capacity of the cytosol to support normal vesicle generation as well as the uncontrolled vesiculating activity manifested by the cytosolic protein subfraction. The phosphatidylinositol- (PI) loaded form of the yeast PITP, Sec14p, but not the phosphatidylcholine- (PC) loaded form of the protein, was capable of substituting for the cytosolic subfraction in promoting the scission of coated buds from the trans-Golgi network. At higher concentration, however, Sec14p, when loaded with PI, but not with PC or phosphatidylglycerol, caused by itself an indiscriminate vesiculation of uncoated Golgi membranes that could be suppressed by PC-Sec14p, which also suppresses the uncontrolled vesiculation caused by the cytosolic subfraction. We propose that, by delivering PI to specific sites in the Golgi membrane near the necks of coated buds, PITP induces local changes in the organization of the lipid bilayer, possibly involving PI metabolites, that triggers the fusion of the ectoplasmic faces of the Golgi membrane necessary for the scission of COPI-coated vesicles.
Regulatory dysfunction of the interleukin-2 receptor during HIV infection and the impact of triple combination therapy
Authors: David Denis , Bani Lynda , Moreau Jean-Louis , Treilhou Marie-Pierre , Nakarai Takayuki , Joussemet Marcel , Ritz Jerome , Dupont Bertrand , Pialoux Gilles , Thèze Jacques
Published: July 2002

The interleukin-2 (IL-2)/IL-2 receptor (IL-2R) system is the main regulatory determinant of T cell reactivity. Although it is well known that IL-2 secretion is impaired during HIV infection, up to now IL-2R expression has not been extensively studied in HIV-infected patients despite the use of IL-2 in clinical therapy trials. We show here that IL-2R expression in HIV patients with high viral load (group 1 in the study) is greatly enhanced on B lymphocytes, CD8 T lymphocytes, and monocytes, but not on CD4 T lymphocytes, compared with noninfected individuals. Paradoxically, this modified IL-2R expression does not lead to increased IL-2 responsiveness, except for B lymphocytes. In patients receiving triple combination therapy (TCT, two reverse transcriptase inhibitors and one protease inhibitor) that has triggered a drastic reduction in plasma viral load and an increase in CD4 counts (group 2 patients), IL-2R expression is significantly lower than in group 1 patients. Moreover, cells involved in cellular immunity and CD4 T lymphocytes have the capacity to respond to IL-2 after TCT. These results allow us to anticipate a beneficial role of IL-2 immunotherapy in combination with TCT.
Structure of the Ets-1 pointed domain and mitogen-activated protein kinase phosphorylation site
Authors: Slupsky Carolyn M. , Gentile Lisa N. , Donaldson Logan W. , Mackereth Cameron D. , Seidel Jeffrey J. , Graves Barbara J. , McIntosh Lawrence P.
Published: July 2002

The Pointed (PNT) domain and an adjacent mitogen-activated protein (MAP) kinase phosphorylation site are defined by sequence conservation among a subset of
ets
transcription factors and are implicated in two regulatory strategies, protein interactions and posttranslational modifications, respectively. By using NMR, we have determined the structure of a 110-residue fragment of murine Ets-1 that includes the PNT domain and MAP kinase site. The Ets-1 PNT domain forms a monomeric five-helix bundle. The architecture is distinct from that of any known DNA- or protein-binding module, including the helix-loop-helix fold proposed for the PNT domain of the
ets
protein TEL. The MAP kinase site is in a highly flexible region of both the unphosphorylated and phosphorylated forms of the Ets-1 fragment. Phosphorylation alters neither the structure nor monomeric state of the PNT domain. These results suggest that the Ets-1 PNT domain functions in heterotypic protein interactions and support the possibility that target recognition is coupled to structuring of the MAP kinase site.
Dissociation between bone resorption and bone formation in osteopenic transgenic mice
Authors: Corral David A. , Amling Michael , Priemel Matthias , Loyer Evelyn , Fuchs Sebastien , Ducy Patricia , Baron Roland , Karsenty Gerard
Published: July 2002

Bone mass is maintained constant in vertebrates through bone remodeling (BR). BR is characterized by osteoclastic resorption of preexisting bone followed by
de novo
bone formation by osteoblasts. This sequence of events and the fact that bone mass remains constant in physiological situation lead to the assumption that resorption and formation are regulated by each other during BR. Recent evidence shows that cells of the osteoblastic lineage are involved in osteoclast differentiation. However, the existence of a functional link between the two activities, formation and resorption, has never been shown
in vivo
. To define the role of bone formation in the control of bone resorption, we generated an inducible osteoblast ablation mouse model. These mice developed a reversible osteopenia. Functional analyses showed that in the absence of bone formation, bone resorption continued to occur normally, leading to an osteoporosis of controllable severity, whose appearance could be prevented by an antiresorptive agent. This study establishes that bone formation and/or bone mass do not control the extent of bone resorption
in vivo
.
Overexpression of peptide-methionine sulfoxide reductase inSaccharomyces cerevisiaeand human T cells provides them with high resistance to oxidative stress
Authors: Moskovitz Jackob , Flescher Eliezer , Berlett Barbara S. , Azare Janeen , Poston J. Michael , Stadtman Earl R.
Published: July 2002

The yeast peptide-methionine sulfoxide reductase (MsrA) was overexpressed in aSaccharomyces cerevisiaenull mutant ofmsrAby using a high-copy plasmid harboring themsrAgene and its promoter. The resulting strain had about 25-fold higher MsrA activity than its parent strain. When exposed to either hydrogen peroxide, paraquat, or 2,2′-azobis-(2-amidinopropane) dihydrochloride treatment, the MsrA overexpressed strain grew better, had lower free and protein-bound methionine sulfoxide and had a better survival rate under these conditions than did themsrAmutant and its parent strain. Substitution of methionine with methionine sulfoxide in a medium lacking hydrogen peroxide had little effect on the growth pattern, which suggests that the oxidation of free methionine in the growth medium was not the main cause of growth inhibition of themsrAmutant. Ultraviolet A radiation did not result in obvious differences in survival rates among the three strains. An enhanced resistance to hydrogen peroxide treatment was shown in human T lymphocyte cells (Molt-4) that were stably transfected with the bovinemsrAand exposed to hydrogen peroxide. The survival rate of the transfected strain was much better than its parent strain when grown in the presence of hydrogen peroxide. These results support the proposition that themsrAgene is involved in the resistance of yeast and mammalian cells to oxidative stress.
Biosynthesis of the
Pseudomonas
polyketide coronafacic acid requires monofunctional and multifunctional polyketide synthase proteins
Authors: Rangaswamy Vidhya , Jiralerspong Sao , Parry Ronald , Bender Carol L.
Published: July 2002

Coronafacic acid (CFA) is the polyketide component of the phytotoxin coronatine, a virulence factor of the plant pathogen
Pseudomonas syringae
. Our current knowledge of polyketide biosynthesis largely is based on the analysis of polyketide synthases (PKSs) in actinomycetes and other Gram-positive bacteria. Consequently, the cloning and characterization of the CFA biosynthetic gene cluster will contribute significantly to our knowledge of polyketide synthesis in
Pseudomonas
. In this report, we describe two genes in the CFA biosynthetic gene cluster that encode PKSs that are structurally and functionally similar to the multifunctional modular PKSs, which catalyze the synthesis of macrolide antibiotics. The CFA PKS genes were overproduced in
Escherichia coli
and shown to cross-react with antisera made to a modular PKS involved in erythromycin synthesis. A scheme for CFA biosynthesis is presented that incorporates the activities of all proteins in the CFA PKS. In this report a gene cluster encoding a pseudomonad polyketide has been completely sequenced and the deduced gene functions have been used to develop a biosynthetic scheme.
Identification of hepatic nuclear factor 1 binding sites in the 5′ flanking region of the human phenylalanine hydroxylase gene: Implication of a dual function of phenylalanine hydroxylase stimulator in the phenylalanine hydroxylation system
Authors: Lei Xiang-Dong , Kaufman Seymour
Published: July 2002

Phenylalanine hydroxylase stimulator (PHS) is a component of the phenylalanine hydroxylation system that is involved in the regeneration of the cofactor tetrahydrobiopterin. It is also identical to the dimerization cofactor of hepatocyte nuclear factor 1 (HNF1) (DCoH) that is able to enhance the transcriptional activity of HNF1. Moreover, it has the structural potential for binding macromolecules such as proteins and nucleic acids, consistent with its involvement in gene expression. We investigated whether PHS/DCoH could enhance the expression of phenylalanine hydroxylase (PAH). Cotransfection assays showed that DCoH itself could not transactivate the 9-kb human PAH 5′ flanking fragment. However, this 9-kb fragment was transactivated by HNF1 in a dose-dependent manner with a maximum of nearly 8-fold activation; DCoH potentiated this transactivation by another 1.6-fold. The HNF1 binding sites were located at −3.5 kb in a region that is 77.5% identical to the mouse liver-specific hormone-inducible PAH gene enhancer. This study suggests a possible dual function of PHS
in vivo
in the human phenylalanine hydroxylation system: it is involved in the regeneration of the cofactor tetrahydrobiopterin and can also enhance the expression of the human PAH gene.
Are decisions under risk malleable?
Authors: Fong Christina , McCabe Kevin
Published: July 2002

Human decision making under risk and uncertainty may depend on individual involvement in the outcome-generating process. Expected utility theory is silent on this issue. Prospect theory in its current form offers little, if any, prediction of how or why involvement in a process should matter, although it may offer
ex post
interpretations of empirical findings. Well-known findings in psychology demonstrate that when subjects exercise more involvement or choice in lottery procedures, they value their lottery tickets more highly. This often is interpreted as an “illusion of control,” meaning that when subjects are more involved in a lottery, they may believe they are more likely to win, perhaps because they perceive that they have more control over the outcome. Our experimental design eliminates several possible alternative explanations for the results of previous studies in an experiment that varies the degree and type of involvement in lottery procedures. We find that in treatments with more involvement subjects on average place less rather than more value on their lottery tickets. One possible explanation for this is that involvement interacts with loss aversion by causing subjects to weigh losses more heavily than they would otherwise. One implication of our study is that involvement, either independently or in interaction with myopic loss aversion, may help explain the extreme risk aversion of bond investors.
Expression of a Hox gene,
Cnox-2,
and the division of labor in a colonial hydroid
Authors: Cartwright Paulyn , Bowsher Julia , Buss Leo W.
Published: July 2002

We report the isolation and expression of the Hox gene,
Cnox-2
, in
Hydractinia symbiolongicarpus
, a hydrozoan displaying division of labor. We found different patterns of aboral-to-oral
Cnox-2
expression among polyp polymorphs, and we show that experimental conversion of one polyp type to another is accompanied by concordant alteration in
Cnox-2
expression. Our results are consistent with the suggestion that polyp polymorphism, characteristic of hydractiniid hydroids, arose via evolutionary modification of proportioning of head to body column.
Molecular cloning and characterization of prostase, an androgen-regulated serine protease with prostate-restricted expression
Authors: Nelson Peter S. , Gan Lu , Ferguson Camari , Moss Patrick , Gelinas Richard , Hood Leroy , Wang Kai
Published: July 2002

The identification of genes with selective expression in specific organs or cell types provides an entry point for understanding biological processes that occur uniquely within a particular tissue. Using a subtraction approach designed to identify genes preferentially expressed in specific tissues, we have identified prostase, a human serine protease with prostate-restricted expression. The prostase cDNA encodes a putative 254-aa polypeptide with a conserved serine protease catalytic triad and an amino-terminal pre-propeptide sequence, indicating a potential secretory function. The genomic sequence comprises five exons and four introns and contains multiple copies of a chromosome 19q-specific minisatellite repeat. Northern analysis indicates that prostase mRNA is expressed in hormonally responsive normal and neoplastic prostate epithelial tissues, but not in prostate stromal constituents. Prostase shares 35% amino acid identity with prostate-specific antigen (PSA) and 78% identity with the porcine enamel matrix serine proteinase 1, an enzyme involved in enamel matrix degradation and with a putative role in the disruption of intercellular junctions. Radiation-hybrid-panel mapping localized prostase to chromosome 19q13, a region containing several other serine proteases, including protease M, pancreatic/renal kallikrein hK1, and the prostate-specific kallikreins hK2 and hK3 (PSA). The sequence homology between prostase and other well-characterized serine proteases suggests several potential functional roles for the prostase protein that include the degradation of extracellular matrix and the activation of PSA and other proteases.
Transmission bottlenecks as determinants of virulence in rapidly evolving pathogens
Authors: Bergstrom Carl T. , McElhany Paul , Real Leslie A.
Published: July 2002

Transmission bottlenecks occur in pathogen populations when only a
few individual pathogens are transmitted from one infected host to
another in the initiation of a new infection. Transmission bottlenecks
can dramatically affect the evolution of virulence in rapidly evolving
pathogens such as RNA viruses. Characterizing pathogen diversity with
the quasispecies concept, we use analytical and simulation methods to
demonstrate that severe bottlenecks are likely to drive down the
virulence of a pathogen because of stochastic loss of the most virulent
pathotypes, through a process analogous to Muller’s ratchet. We
investigate in this process the roles of host population size, duration
of within-host viral replication, and transmission bottleneck size. We
argue that the patterns of accumulation of deleterious mutation may
explain differing levels of virulence in vertically and horizontally
transmitted diseases.
Cancer incidences in Europe related to mortalities, and ethnohistoric, genetic, and geographic distances
Authors: Sokal Robert R. , Oden Neal L. , Rosenberg Michael S. , Thomson Barbara A.
Published: July 2002

We have previously shown that geographic differences in cancer mortalities in Europe are related to (in order of importance): geographic distances (reflecting environmental differences), ethnohistoric distances (encompassing cultural and genetic attributes), and genetic distances of the populations in the areas studied. In this study, we analyzed the relations of the same three factors to European incidences of 45 male and 47 female cancers. Differences in cancer incidences are correlated moderately, first with geographic distances, and then with genetic distances, but not at all with ethnohistoric distances. Comparing these findings to the earlier ones for cancer mortalities, we note the reversal in the importance of ethnohistory and genetics, and the generally lower correlations of incidence differences with the three putatively causal distance matrices. A path diagram combining both studies demonstrates the lack of cultural carcinogenic effects, but suggests cultural influences on procedures such as the registration of deaths in different political entities. Additionally, the relatively large correlation between ethnohistoric distances and mortality differences is caused by common factors behind the correlation of ethnohistoric and geographic distances. Geographic proximity results in similar ethnohistories. The direct effects of genetic distances are negligible and only their common effects with geographic distances play a role, accounting for the weak to negligible influence of genetics on incidence and mortality differences. Apparently, the genetic systems available to us do not substantially affect cancer incidence or mortality. We present indirect evidence that international differences in the quality of cancer rate data are greater in mortalities than in incidences.
Structure-based design of an osteoclast-selective, nonpeptide Src homology 2 inhibitor with
in vivo
antiresorptive activity
Authors: Shakespeare William , Yang Michael , Bohacek Regine , Cerasoli Franklin , Stebbins Karin , Sundaramoorthi Raji , Azimioara Mihai , Vu Chi , Pradeepan Selvi , Metcalf Chester , Haraldson Chad , Merry Taylor , Dalgarno David , Narula Surinder , Hatada Marcos , Lu Xiaode , van Schravendijk Marie Rose , Adams Susan , Violette Shelia , Smith Jeremy , Guan Wei , Bartlett Catherine , Herson Jay , Iuliucci John , Weigele Manfred , Sawyer Tomi
Published: July 2002

Targeted disruption of the pp60
src
(Src) gene has implicated this tyrosine kinase in osteoclast-mediated bone resorption and as a therapeutic target for the treatment of osteoporosis and other bone-related diseases. Herein we describe the discovery of a nonpeptide inhibitor (AP22408) of Src that demonstrates
in vivo
antiresorptive activity. Based on a cocrystal structure of the noncatalytic Src homology 2 (SH2) domain of Src complexed with citrate [in the phosphotyrosine (pTyr) binding pocket], we designed 3′,4′-diphosphonophenylalanine (Dpp) as a pTyr mimic. In addition to its design to bind Src SH2, the Dpp moiety exhibits bone-targeting properties that confer osteoclast selectivity, hence minimizing possible undesired effects on other cells that have Src-dependent activities. The chemical structure AP22408 also illustrates a bicyclic template to replace the post-pTyr sequence of cognate Src SH2 phosphopeptides such as Ac-pTyr-Glu-Glu-Ile (1). An x-ray structure of AP22408 complexed with Lck (S164C) SH2 confirmed molecular interactions of both the Dpp and bicyclic template of AP22408 as predicted from molecular modeling. Relative to the cognate phosphopeptide, AP22408 exhibits significantly increased Src SH2 binding affinity (IC
50
= 0.30 μM for AP22408 and 5.5 μM for 1). Furthermore, AP22408 inhibits rabbit osteoclast-mediated resorption of dentine in a cellular assay, exhibits bone-targeting properties based on a hydroxyapatite adsorption assay, and demonstrates
in vivo
antiresorptive activity in a parathyroid hormone-induced rat model.
Regional Congress of Psychology for Professionals in the Americas
Authors: Knowles Michael C.
Published: July 2002

Mexico City was the venue of the first Regional Congress of Psychology for Professionals in the Americas which was held from 27 July to 2 August 1997. This imaginative initiative was organized by the Instituto Mexicano de Investigacion de Familia y Problacion (IMIFAP) and the Associacion Mexicana de Psicologia Social (AMEPSO), and had the international support of the International Association of Applied Psychology (IAAP), the International Union of Psychological Science, the Interamerica Society of Psychology (SIP), and the International Association of Cross‐Cultural Psychology (IACCP). With a view to not only stimulating the development of professional psychology in Latin America but also strengthening the interface of the science and practice of psychology internationally, the Congress was an outstanding success as evidenced by the depth and quality of its scientific programme, the rich variety of its programme of social and cultural events, and its huge attendance.
Language and Ethnic Mobilization among the Komi in the Post-Soviet Period
Authors: Tsypanov Evgenii
Published: July 2002

During the second half of 1991, the final stage of the disintegration of the Soviet Union brought momentous political changes to the citizenry of the country. From the beginning of the post-Soviet period, the new Russian government commenced economic reforms which resulted in the freeing of retail prices, the devaluation of the ruble, and the disastrous depreciation of household savings. In daily life across the state, these events represented a turning point for Russian citizens, including those in the Komi Republic.
The Carabinieri Stood by: The Italian State and the “Slavic Threat” in 1919–1922
Authors: Hametz Maura
Published: July 2002

On 2 August 1919 in the Upper Adriatic port city of Trieste (as it was called in Italian) or Trst (as it was referred to in Slavic languages), nationalist youths harassed socialist children returning from a group outing. The incident escalated into a riot. Police opened fire, and one nationalist was killed. On 12 July 1920, a nationalist mob incited by Fascists looted and burned Narodni Dom, the Slovene cultural center. The carabinieri, Italy's state police, collaborated in the attack, or at the very least stood by and watched as the building was torched using gasoline obtained from the nearby barracks. The next day, Italian nationalist demonstrators torched the Croatian-managed Adriatic Bank. Police at the scene stood on the sidelines and watched the bank burn. In the autumn of 1920, Fascist squads attacked a funeral procession mourning a socialist worker killed in a general strike. The socialists erected barricades in the streets of the San Giacomo quarter, a working class neighborhood. Police leveled the undefended barricades and intimidated the quarter's residents during a house-to-house search. In 1921, a firebomb exploded in the offices of Il Lavoratore, the local socialist newspaper. Police watched the premises burn. In all five instances, the forces of public security in Trieste stood by, unable or unwilling to stem violence and restore order in the city newly annexed to Italy from the Habsburg empire. The Italian liberal authorities officially disavowed mistreatment of ethnic minorities and members of the political opposition, but they found themselves unable to deal effectively with the clash among ethnic groups and political parties precipitated by the transfer of the territory to Italian sovereignty. They sympathized with those adopting extra-legal and violent strategies that they perceived as useful to further state political agendas and promote assimilation, or at least quiescence, of the border population.
The Midweek Match: Premiership Football and the Urban Economy
Authors: Johnstone Sam , Southern Alan , Taylor Rogan
Published: July 2002

The financial aspect of Premiership football is currently attracting huge attention. Hardly a week goes by without some new story breaking about the game, whether it is a record transfer, a wage or television deal, or the building of a new stadium. Yet there has been little, if any, investigation into just how the newfound wealth from Premiership football impacts on the locality. In this article, the authors present an initial indication of how the two Premiership clubs situated in Merseyside are linked into the local economy. It is based on a survey of club suppliers an d local businesses located around the two grounds of Everton and Liverpool Football Clubs. It shows Premiership football to be more than a dependent consumer service activity in the local economy with a potential for exploitation in terms of supplier networks, tourism an d image boosting. The authors argue that this is a subject area that requires further research and understanding, an d more serious attention as a feature of local economic policy.
Options for Managing Psychotropic Medications in Drug‐Abusing Patients Participating in Behavioral Therapies Clinical Trials
Authors: Rounsaville Bruce J. , Weiss Roger , Carroll Kathleen
Published: July 2002

This manuscript reviews strengths and weaknesses of common design options for managing non‐study medications in randomized clinical trials of behavioral treatments for drug abusers. While the principal focus of these trials is on the relative efficacy of different behavioral interventions, drug abusers entering these trials are often either using or in need of prescribed psychotropic medications, which can have a major independent impact on treatment outcome. Options reviewed range from tight to minimal restriction on use of ancillary medications. Generally, major tradeoffs pertain to the balance between internal validity and generalizability. However, experimental rigor can be maintained while allowing subjects to use ancillary medications if steps are taken to monitor and minimize the variability in treatment delivery.
From Epidemiologic Exposure and Risk Assessment to Probabilistic Models: Experience with the Investigation of Health Effects of Soil Contamination in Germany
Authors: Wichmann H.-Erich , Trepka Mary Jo , Heinrich Joachim , Ihme Wolfgang , Mekel Odile , Lin Jouhai
Published: July 2002

Exposure and risk assessment can be based on direct epidemiological investigations that study exposed individuals or on models. Examples from situations in Germany for both approaches are presented and discussed here. Epidemiological studies for the health risk assessment of contaminated soil typically have one or more of the following problems: the number of exposed persons is too small: critical confounders cannot be measured and controlled for appropriately; or the expected effects are not large enough to be detected. Therefore, at least for most situations in Germany, epidemiological investigations designed to measure health risks infrequently provide clear answers. In contrast, direct epidemiological investigations are more likely to be able to quantify exposure. If the soil concentrations are high, one is able to identify the location of relevant “hot spots” using biological and environmental monitoring. Further, epidemiology can be used to get information about the distribution of exposure in specific populations, such as young children or amateur gardeners. Exposure assessment by modeling provides answers in situations in which no reasonable answers can be expected using epidemiological means. The model gives quantitative estimates for average and reasonable worst-case situations. The latter can be determined by modeling probability distributions.
Exposure and Risk Assessment with Respect to Contaminated Soil: Significance of Biomarkers and Bioavailability
Authors: Rangan Urvashi , Hedli Christine , Gallo Michael , Lioy Paul , Snyder Robert
Published: July 2002

The evaluation of health risk from chemical exposure is evolving in concept and practice. The ability to sensitively detect levels of chemicals in the environment has served as the traditional foundation for determining exposure levels and consequent health risks. More recently, however, other parameters have been constructed to probe the pathway between environmental levels of a chemical and the biological effects of subsequent exposure. Among these, two that are discussed in this paper are bioavailability and biomarker determinations. Chemicals in the environment often are associated with a medium such as airborne particulate, water, or soil. The interaction between the chemical and its medium is dependent on the physicochemical properties of the system. In some cases, such as 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) in soil, the chemical becomes partially and irreversibly bound to the medium. Animalingestion studies of TCDD-contaminated soil suggest that some of the TCDD remains bound to the soil and does not cross the gastrointestinal barrier during digestion, and therefore only a fraction of the TCDD enters the blood and becomes bioavailable. The characterization of bioavailability provides for more accurate exposure assessment. Biomarker information potentially can validate exposure assessment information from bioavailability studies, elucidate specific biological effects from chemical exposure, and investigate genetic susceptibility issues that may increase the likelihood that an individual or population will experience increased health risks. Benzene-induced chromosome damage is discussed as an example of a significant biomarker that has demonstrated the potential for providing information useful for accurately prediction health risk.
Contractile protein synthesis rates in vivo in the rat jejunum: modulating role of adrenalectomy and thyroidectomy on ethanol‐induced changes
Authors: MARWAY JASPAUL S. , MIELL JOHN P. , JONES JENNY , BONNER ADRIAN B. , PREECE MICHAEL A. , HASHIM IBRAHIM , PREEDY VICTOR R.
Published: July 2002

Abstract Acute ethanol toxicity has many deleterious effects on the gastrointestinal tract and, in particular, inhibits small intestinal protein synthesis. The mechanism(s) of the ethanol‐induced inhibition of protein synthesis are unknown. This study was designed to investigate the role of adrenal and thyroid hormones on the ethanol‐induced inhibition of whole jejunal protein synthesis in adrenalectomised and thyroidectomised male Wistar rats. Acute ethanol dosage significantly reduced protein synthesis in all subcellular protein fractions of the whole jejunum, in sham‐thyroidectomized, thyroidectomized, sham‐ardrenalectomized and adrenalectomized rats. Synthesis rates relative to RNA and DNA were also highly significantly reduced in all treatment groups in ethanol‐dosed rats. However in most protein fractions the inhibition of protein synthesis was greater in thyroidectomized compared to sham‐thyroidectomized rats, whereas the reverse was true in adrenalectomized rats. Neither adrenalectomy or thyroidectomy completely abolished ethanol‐induced inhibition in protein synthesis, suggesting that ethanol or its metabolites, e.g. acetaldehyde, acts directly on the tissue. However, the ethanol‐induced inhibition of protein synthesis was greater in thyroidectomized rats demonstrating that contractile and non‐contractile proteins synthesis in the jejunum is under control of complex regulatory processes.
Two Systems for Phosphate Uptake in Yarrowia lipolytica Cells Grown at Acidic Conditions
Authors: Zvyagilskaya Renata , Allard Peter , Persson Bengt L.
Published: July 2002

Inorganic phosphate (Pi) is accumulated by Yarrowia lipolytica cells grown at acidic pH conditions by two kinetically discrete H+/Pi‐ cotransport systems with apparent Km values for Pi of 12‐18 muM and 2‐3 mM Pi at pH 5.5, respectively. One of these is derepressible and operates at low external Pi concentrations; the other is most likely constitutively expressed and comes into play at high Pi concentrations. The derepression of the high‐affinity Pi transport system is under the control of available extracellular Pi as well as the amount of intracellular polyphosphates stores. Characteristics of the Pi transport behavior in Yarrowia lipolytica are discussed.
Identification of Novel Vesicles in the Cytosol to Vacuole Protein Degradation Pathway
Authors: Huang Pei-Hsin , Chiang Hui-Ling
Published: July 2002

The key gluconeogenic enzyme, fructose1,6-bisphosphatase (FBPase), is induced when Saccharomyces cerevisiae are starved of glucose. FBPase is targeted from the cytosol to the yeast vacuole for degradation when glucose-starved cells are replenished with fresh glucose. Several vid mutants defective in the glucose-induced degradation of FBPase in the vacuole have been isolated. In some vid mutants, FBPase is found in punctate structures in the cytoplasm. When extracts from these cells are fractionated, a substantial amount of FBPase is sedimentable in the high speed pellet, suggesting that FBPase is associated with intracellular structures in these vid mutants. In this paper we investigated whether FBPase association with intracellular structures also existed in wild-type cells. We report the purification of novel FBPase-associated vesicles from wild-type cells to near homogeneity. Kinetic studies indicate that FBPase association with these vesicles is stimulated by glucose and occurs only transiently, suggesting that these vesicles are intermediate in the FBPase degradation pathway. Fractionation analysis demonstrates that these vesicles are distinct from known organelles such as the vacuole, ER, Golgi, mitochondria, peroxisomes, endosomes, COPI, or COPII vesicles. Under EM, these vesicles are 30–40 nm in diam. Proteinase K experiments indicate that the majority of FBPase is sequestered inside the vesicles. We propose that FBPase is imported into these vesicles before entering the vacuole.