bluuebunny/crossref_metadata_2025 huggingface dataset:
Signaling crosstalk underlying synergistic induction of astrocyte differentiation by BMPs and IL‐6 family of cytokines
Authors: Yanagisawa Makoto , Nakashima Kinichi , Takizawa Takumi , Ochiai Wataru , Arakawa Hirokazu , Taga Tetsuya
Published: July 2002

We here show that bone morphogenetic protein (BMP) 7 acted in synergy with the distinct type of cytokines, leukemia inhibitory factor (LIF) and interleukin (IL) 6 that are in the IL‐6 family, to induce astrocyte differentiation from neuroepithelial cells as assessed by expression of glial fibrillary acidic protein (GFAP). In this synergistic action, transcription factors, Smads and STAT3 (for signal transducer and activator of transcription 3) activated by respective group of cytokines, as well as a transcriptional coactivator p300 were essential. Taken together with our previous finding that the synergistic astrocyte induction by BMP2 and LIF is attributed to the complex formation of Smads and STAT3 bridged by p300, it is conceivable that this complex formation is a mechanism utilized in common by two different types of cytokines belonging to the BMP and IL‐6 families in order to synergistically induce astrocyte differentiation.
The solution structure of the disulphide‐linked homodimer of the human trefoil protein TFF1
Authors: Williams Mark A. , Westley Bruce R. , May Felicity E.B. , Feeney James
Published: July 2002

The trefoil factor family protein, TFF1, forms a homodimer, via a disulphide linkage, that has greater activity in wound healing assays than the monomer. Having previously determined a high‐resolution solution structure of a monomeric analogue of TFF1, we now investigate the structure of the homodimer formed by the native sequence. The two putative receptor/ligand recognition domains are found to be well separated, at opposite ends of a flexible linker. This contrasts sharply with the known fixed and compact arrangement of the two trefoil domains of the closely related TFF2, and has significant implications for the mechanism of action and functional specificity of the TFF of proteins.
A new caffeine biosynthetic pathway in tea leaves: utilisation of adenosine released from the S‐adenosyl‐L‐methionine cycle
Authors: Koshiishi Chie , Kato Ayako , Yama Sachiko , Crozier Alan , Ashihara Hiroshi
Published: July 2002

The four‐step caffeine biosynthetic pathway includes three methylation steps that utilise S‐adenosyl‐L‐methionine (SAM) as the methyl donor. In the process SAM is converted to S‐adenosyl‐L‐homocysteine (SAH) which in turn is hydrolysed to L‐homocysteine and adenosine. Significant amounts of radioactivity from [methyl‐14C]methionine and [methyl‐14C]SAM were incorporated into theobromine and caffeine in young tea leaf segments, and very high SAH hydrolase activity was found in cell‐free extracts from young tea leaves. Substantial amounts of radioactivity from [adenosyl‐14C]SAH were also recovered as theobromine and caffeine in tea leaf segments, indicating that adenosine derived from SAH is utilised for the synthesis of the purine ring of caffeine. From the profiles of activity of related enzymes in tea leaf extracts, it is proposed that the major route from SAM to caffeine is a SAM→SAH→adenosine→adenine→AMP→IMP→XMP→xanthosine→7‐methylxanthosine→7‐methylxanthine→theobromine→caffeine pathway. In addition, direct adenosine kinase‐catalysed formation of AMP from adenosine may participate as an alternative minor route. The activity of two of the three N‐methyltransferase activities involved in caffeine biosynthesis and part of the activities of SAH hydrolase, adenosine nucleosidase, adenine phosphoribosyltransferase and adenosine kinase were located in tea chloroplasts. In contrast, no detectable activity of SAM synthetase was associated with the purified chloroplast fraction. This is a first demonstration that the purine skeleton of caffeine is synthesised from adenosine released from the SAM cycle.
Human leukocyte glycosylasparaginase: cell‐to‐cell transfer and properties in correction of aspartylglycosaminuria
Authors: Dunder Ulla , Mononen Ilkka
Published: July 2002

Aspartylglycosaminuria (AGU), a severe lysosomal storage disease, is caused by the deficiency of the lysosomal enzyme, glycosylasparaginase (GA), and accumulation of aspartylglucosamine (GlcNAc‐Asn) in tissues. Here we show that human leukocyte glycosylasparaginase can correct the metabolic defect in Epstein–Barr virus (EBV)‐transformed AGU lymphocytes rapidly and effectively by mannose‐6‐phosphate receptor‐mediated endocytosis or by contact‐mediated cell‐to‐cell transfer from normal EBV‐transformed lymphocytes, and that 2–7% of normal activity is sufficient to correct the GlcNAc‐Asn metabolism in the cells. Cell‐to‐cell contact is obligatory for the transfer of GA since normal transformed lymphocytes do not excrete GA into extracellular medium. The combined evidence indicates that cell‐to‐cell transfer of GA plays a main role in enzyme replacement therapy of AGU by normal lymphocytes.
Alterations in expression of E2F‐1 and E2F‐responsive genes by RB, p53 and p21Sdi1/WAF1/Cip1 expression
Authors: Ookawa Keizou , Tsuchida Shigeki , Kohno Takashi , Yokota Jun
Published: July 2002

RB, p53 and p21
Sdi1/WAF1/Cip1
interact in the induction of G1 arrest. We established osteosarcoma cell lines in which a tetracycline‐regulatable promoter controls the induction of RB, p53 and p21. By using these cell lines, we investigated whether RB, p53 or p21 regulates, in the same manner or differently, expression and function of E2F‐1 and its responsive genes. E2F‐1 gene products and transcripts of the E2F‐responsive genes decreased in response to RB. Similar changes occurred to p53 and p21 when RB is present. However, in the absence of RB, some of the E2F‐responsive genes decreased in response to p53 but not to p21. Thus, RB is a critical component for regulating the E2F‐responsive genes, while p53 alone affects only a subset of these genes.
Multiple opioid receptor‐like genes are identified in diverse vertebrate phyla
Authors: Li Xia , Keith Duane E. , Evans Christopher J.
Published: July 2002

Polymerase chain reaction was used to determine whether opioid receptor‐like sequences are present in species from the protostome and deuterostome branches of the metazoan kingdom. Multiple opioid receptor‐like sequences were found in all vertebrates, but no specific fragments were obtained from any invertebrates. Delta, mu, kappa and ORL‐1 receptors were identified from bovine DNA, and three different opioid receptor‐like fragments were identified from the other vertebrates analyzed. The data suggest that the opioid receptor gene family has been highly conserved during vertebrate evolution and that, even in the primitive jawless fish, multiple members of the opioid receptor family appear to be present.
Structure and distribution of a broadly expressed atypical sodium channel
Authors: Akopian Armen N , Souslova Veronika , Sivilotti Lucia , Wood John N
Published: July 2002

A cDNA clone isolated from a rat dorsal root ganglion library encodes a 195 kDa voltage‐gated sodium channel‐like protein (SCL‐11) with homology to the mouse (87%) and human (72%) atypical Na+ channels and rat partial clone NaG (98%). Two dominant mRNAs of 4.5 and 7 kb are expressed. The transcripts are present in lung, Schwann cells, pituitary and tissues containing smooth muscle cells. No functional channels could be detected on oocyte injection with cRNA, consistent with the absence of structural features necessary for voltage‐gated sodium channel activity.
Molecular cloning and characterization of a new receptor for galanin
Authors: Howard Andrew D , Tan Carina , Shiao Lin-Lin , Palyha Oksana C , McKee Karen Kulju , Weinberg David H , Feighner Scott D , Cascieri Margaret A , Smith Roy G , Van Der Ploeg Lex H.T , Sullivan Kathleen A
Published: July 2002

Galanin (GAL) is a widely distributed neuropeptide with diverse biological effects including modulation of hormone release, antinociception and modification of feeding behavior. Its effects are mediated through G‐protein‐coupled receptors (GPCR) for which only a single type has been cloned, GAL receptor 1 (GALR1). We describe the cloning of a second galanin receptor type, GALR2, from rat hypothalamus. The GALR2 amino acid sequence is 38% identical to GALR1 and is pharmacologically similar to GALR1 when expressed in COS‐7 cells. GALR2 is encoded by a single gene containing at least one intron and expressed in a diverse range of tissues.
Interactions of lactone, carboxylate and self‐aggregated forms of camptothecin with human and bovine serum albumins
Authors: Fleury Fabrice , Kudelina Irina , Nabiev Igor
Published: July 2002

Pronounced differences in the interactions of monomeric (lactone and carboxylate) and the J‐type self‐aggregated form of camptothecin (CPT), an inhibitor of DNA topoisomerase (topo) I, with human (HSA) and bovine (BSA) serum albumins were observed by using circular dichroism (CD) spectroscopy. HSA binding changes the geometry of the covalent structure of CPT due to hydrophobic contacts of the chromophore within the protein interior. The carbonyl group of the ring D of CPT (Fig. 1A) interacts with the positively charged amino acid residues of HSA. Interaction with HSA induces disaggregation of the J‐type self‐aggregates of CPT. On the other hand, neither heat‐denatured HSA nor native BSA participated in binding of the lactone or carboxylate or self‐aggregate forms of CPT. Analysis of HSA and BSA homology within the IIA and IIIA principle ligand‐binding structural domains suggests that the binding site for the CPT chromophore is located in subdomain IIA. Hydrophobic contacts with Leu‐203, Phe‐211, and Ala‐215 and electrostatic interactions with Lys‐199 and/or Arg‐222 of HSA may play a key role in formation of the drug‐HSA complex.
Disruption of a Synechocystis sp. PCC 6803 gene with partial similarity to phytochrome genes alters growth under changing light qualities
Authors: Wilde Annegret , Churin Yuri , Schubert Hendrik , Börner Thomas
Published: July 2002

A gene that may encode a novel light sensing histidine protein kinase, designated plpA (phytochrome‐like protein), was isolated from the cyanobacterium Synechocystis sp. PCC 6803. The 200 COOH‐terminal amino acids of the gene product show homology with conserved domains of several bacterial histidine kinases and the ethylene response gene etr1 of Arabidopsis, whereas its central region is similar to the chromophore attachment site of plant phytochromes. Interruption or partial deletion of plpA yielded mutants unable to grow under blue light.
In search of a function for the Ras‐like GTPase Rap1
Authors: Bos Johannes L , Franke Barbara , M'Rabet Laura , Reedquist Kris , Zwartkruis Fried
Published: July 2002

Rap1 (Krev‐1) is a small GTPase first identified as a transformation suppressor of K‐ras. This GTPase is very similar to Ras, particularly in the effector region, but its function is still elusive. Recent progress in the search for Rap1 function has come from the development of a novel assay to measure Rap1 activation. Using this assay activation of Rap1 was observed in human platelets and neutrophils after stimulation with various agonists. We speculate that Rap1 plays a role in one of the specialised functions of these cells.
Hevamine, a chitinase from the rubber tree Hevea brasiliensis, cleaves peptidoglycan between the C‐1 of N‐acetylglucosamine and C‐4 of N‐acetylmuramic acid and therefore is not a lysozyme
Authors: Bokma Evert , van Koningsveld Gerrit A. , Jeronimus-Stratingh Margot , Beintema Jaap J.
Published: July 2002

Hevamine is a chitinase from the rubber tree Hevea brasiliensis and belongs to the family 18 glycosyl hydrolases. In this paper the cleavage specificity of hevamine for peptidoglycan was studied by HPLC and mass‐spectrometry analysis of enzymatic digests. The results clearly showed that the enzyme cleaves between the C‐1 of a N‐acetylglucosamine and the C‐4 of a N‐acetylmuramate residue. This means that hevamine, and very likely also other family 18 glycosyl hydrolases which cleave peptidoglycan, cannot be classified as lysozymes.
Antibodies to steroids from a small human naive IgM library
Authors: Dörsam Heinz , Rohrbach Petra , Kürschner Timo , Kipriyanov Sergey , Renner Stefanie , Braunagel Michael , Welschof Martin , Little Melvyn
Published: July 2002

Human antibodies specific for digoxigenin, estradiol, testosterone and progesterone have been isolated from a small combinatorial IgM repertoire (4×107) of single chain antibodies (scFv). The affinities of both the anti‐estradiol and anti‐progesterone scFv were approximately 108 M−1. Naive IgM genes appeared to be highly represented, since only the heavy chain variable domain of the anti estradiol antibody contained differences to corresponding germline sequences. The light chain variable domain of the progesterone receptor was also identical to a germline sequence, showing that it is possible for completely naive antibodies to bind steroids with affinities comparable to those obtained after a secondary immune response.
Growth stage dependent effects of electromagnetic fields on DNA synthesis of Jurkat cells
Authors: Nindl G , Swez J.A , Miller J.M , Balcavage W.X
Published: July 2002

A 1.8 mT, bone healing, electromagnetic field (EMF) and power frequency EMFs of 0.1 and 0.4 mT significantly inhibit DNA synthesis in otherwise unstimulated Jurkat (E 6.1) cells. Inhibition is generally most prominent in cells from mid log phase growth. In complete medium the bone healing EMF inhibits [3H] thymidine uptake of the latter cells by almost 50% vs. 20–25% inhibition by 60 Hz fields. Cells in conditioned medium are even more sensitive to EMFs with inhibition up to ca. 60%. The effects of the 0.1 and 0.4 mT power frequency EMFs were very similar suggesting saturation at 0.1 mT or lower.
Nef protein of HIV‐1 induces apoptotic cytolysis of murine lymphoid cells independently of CD95 (Fas) and its suppression by serine/threonine protein kinase inhibitors
Authors: Okada Harue , Takei Ryoichi , Tashiro Masato
Published: July 2002

The Nef protein of HIV‐1 is suggested to play a role in depletion of uninfected CD4+ T cells leading to the development of AIDS. The recombinant soluble Nef protein was shown to bind to cell surfaces of various murine lymphoid cell lines, including T and B lymphocytes, mastocytoma cells and macrophages. Cross‐linking of the cell‐bound Nef protein with anti‐Nef antibodies induced apoptotic cytolysis of the cells. Although primary lymphocytes from young mice resisted Nef binding and Nef‐induced cytolysis, treatment of the cells with concanavalin A or phytohemagglutinin made them susceptible to these activities, indicating that cellular activation is required for the apoptosis. The Nef‐induced apoptosis also occurred with murine cells not expressing CD95 (Fas). These findings were quite similar to those obtained for human blood cells, suggesting that the mouse is applicable for analysis of Nef activities. The Nef‐induced apoptosis was efficiently suppressed by serine/threonine protein kinase inhibitors, H7, fasudil hydrochloride and M3, which did not inhibit CD95 (Fas)‐mediated apoptosis. On the other hand, bisindolylmaleimide, a protein kinase C inhibitor which inhibits CD95 (Fas)‐mediated apoptosis, did not affect Nef‐induced apoptosis. These results suggest that the Nef‐induced apoptosis of murine cells involved a serine/threonine protein kinase‐dependent signal transduction pathway distinct from the CD95 (Fas)‐mediated system.
Yeast RNase H(35) is the counterpart of the mammalian RNase HI, and is evolutionarily related to prokaryotic RNase HII1
Authors: Frank Peter , Braunshofer-Reiter Christa , Wintersberger Ulrike
Published: July 2002

We cloned the Saccharomyces cerevisiae homologue of mammalian RNase HI, which itself is related to the prokaryotic RNase HII, an enzyme of unknown function and previously described as having minor activity in Escherichia coli. Expression of the corresponding yeast 35 kDa protein (named by us RNase H(35)) in E. coli and immunological analysis proves a close evolutionary relationship to mammalian RNase HI. Deletion of the gene (called RNH35) from the yeast genome leads to an about 75% decrease of RNase H activity in preparations from the mutated, still viable cells. Sequence comparison discriminates this new yeast RNase H from earlier described yeast enzymes, RNase H(70) and RNase HI.
Human rab11a: transcription, chromosome mapping and effect on the expression levels of host GTP‐binding proteins
Authors: Gromov Pavel S. , Celis Julio E. , Hansen Claus , Tommerup Niels , Gromova Irina , Madsen Peder
Published: July 2002

Rab11a is a member of therab‐branch of theras‐like small GTP‐binding protein superfamily that is associated with both constitutive and regulated secretory pathways. Using a direct procedure for cDNA cloning of smallras‐related GTPases, that is based on the screening of eukaryotic cDNA expression libraries using [α‐32P]GTP as a probe, we have isolated two cDNA clones encoding rab11a. Both clones share identical coding sequences, but differ in the length and sequence of their 3′ untranslated regions (3′‐UTR). Northern blot hybridisation analysis of various human tissues revealed indeed two mRNA species with lengths of 1.0 and 2.3 kb, respectively. Sequence analysis of the cDNAs identified two different putative polyadenylation signals (AATAAA) at positions 927 and 2302 of the larger transcript. In addition, the 3′‐UTR of the larger transcript exhibited several AU‐rich elements (ARE) that are believed to control gene expression by regulating the rate of mRNA degradation. Southern blots of human DNA digested with several rare restriction enzymes, and separated by pulse‐field gel electrophoresis, yielded the same macro‐restriction fragment pattern when hybridised with probes that discriminate between the two transcripts. Taken together, these findings imply that the two mRNA species originate from a single gene, which we have mapped to 15q21.3‐q22.31, by the use of diferent polyadenylation sites. As expected, both rab11a‐cDNAs yielded the same protein product when transiently expressed in COS‐1 cells, and surprisingly, upregulated the proteome expression profile (de novo synthesis or posttranslational modification of preexisting proteins) of a few other, yet unknown GTP‐binding proteins.
Biochemical and spectroscopic characterization of catechol oxidase from sweet potatoes (Ipomoea batatas) containing a type‐3 dicopper center1
Authors: Eicken Christoph , Zippel Frank , Büldt-Karentzopoulos Klaudia , Krebs Bernt
Published: July 2002

Two catechol oxidases have been isolated from sweet potatoes (Ipomoea batatas) and purified to homogeneity. The two isozymes have been characterized by EXAFS, EPR‐, UV/Vis‐spectroscopy, isoelectric focusing, and MALDI‐MS and have been shown to contain a dinuclear copper center. Both are monomers with a molecular mass of 39 kDa and 40 kDa, respectively. Substrate specificity and NH2‐terminal sequences have been determined. EXAFS data for the 39 kDa enzyme reveal a coordination number of four for each Cu in the resting form and suggest a Cu(II)‐Cu(II) distance of 2.9 Å for the native met form and 3.8 Å for the oxy form.
The role and source of 5′‐deoxyadenosyl radical in a carbon skeleton rearrangement catalyzed by a plant enzyme
Authors: Ollagnier Sandrine , Kervio Eric , Rétey János
Published: July 2002

The last step in the biosynthesis of tropane alkaloids is the carbon skeleton rearrangement of littorine to hyoscyamine. The reaction is catalyzed by a cell‐free extract prepared from cultured hairy roots of Datura stramonium. Adenosylmethionine stimulated the rearrangement 10–20‐fold and showed saturation kinetics with an apparent K
m of 25 μM. It is proposed that S‐adenosylmethionine is the source of a 5′‐deoxyadenosyl radical which initiates the rearrangement in a similar manner as it does in analogous rearrangements catalyzed by coenzyme B12‐dependent enzymes. Possible roles of S‐adenosylmethionine as a radical source in higher plants are discussed.
Mutation S543N in the thumb subdomain of the Taq DNA polymerase large fragment suppresses pausing associated with the template structure
Authors: Ignatov K.B. , Bashirova A.A. , Miroshnikov A.I. , Kramarov V.M.
Published: July 2002

Substitution of Asn for the conserved Ser543 in the thumb subdomain of the Taq DNA polymerase large fragment (Klentaq DNA polymerase) prevents pausing during DNA synthesis and allows the enzyme to circumvent template regions with a complex structure. The mutant enzyme (KlentaqN DNA polymerase) provides specific PCR amplification and sequencing of difficult templates, e.g. those with a high GC% content or strong secondary structure.
A revised model of the active site of alternative oxidase
Authors: Andersson Martin E , Nordlund Pär
Published: July 2002

The plant mitochondrial protein alternative oxidase catalyses dioxygen dependent ubiquinol oxidation to yield ubiquinone and water. A structure of this protein has previously been proposed based on an assumed structural homology to the di‐iron carboxylate family of proteins. However, these authors suggested the protein has a very different topology than the known structures of di‐iron carboxylate proteins. We have re‐examined this model and based on comparison of recent sequences and structural data on di‐iron carboxylate proteins we present a new model of the alternative oxidase which allows prediction of active site residues and a possible membrane binding motif.
Immunochemical detection of oxalate monoalkylamide, an ascorbate‐derived Maillard reaction product in the human lens
Authors: Nagaraj Ramanakoppa H. , Shamsi Farrukh A. , Huber Birgit , Pischetsrieder Monika
Published: July 2002

Carbohydrates with reactive aldehyde and ketone groups can undergo Maillard reactions with proteins to form advanced glycation end products. Oxalate monoalkylamide was identified as one of the advanced glycation end products formed from the Maillard reaction of ascorbate with proteins. In these experiments, we have analyzed human lens proteins immunochemically for the presence of oxalate monoalkylamide. Oxalate monoalkylamide was absent in most of the very young lenses but was present in old and cataractous lenses. The highest levels were found in senile brunescent lenses. Incubation experiments using bovine lens proteins revealed that oxalate monoalkylamide could form from the ascorbate degradation products, 2,3‐diketogulonate and L‐threose. These data provide the first evidence for oxalate monoalkylamide in vivo and suggest that ascorbate degradation and its binding to proteins are enhanced during lens aging and cataract formation.
The SNF1 kinase complex from Saccharomyces cerevisiae phosphorylates the transcriptional repressor protein Mig1p in vitro at four sites within or near regulatory domain 1
Authors: Smith Fiona C. , Davies Stephen P. , Wilson Wayne A. , Carling David , Hardie D.Grahame
Published: July 2002

Mig1p is a zinc finger protein required for repression of glucose‐regulated genes in budding yeast. On removal of medium glucose, gene repression is relieved via a mechanism that requires the SNF1 protein kinase complex. We show that Mig1p expressed as a glutathione‐S‐transferase fusion in bacteria is readily phosphorylated by the SNF1 kinase in vitro. Four phosphorylation sites were identified, i.e. Ser‐222, Ser‐278, Ser‐311 and Ser‐381. The latter three are exact matches to the recognition motif we previously defined for SNF1 and lie within regions shown to be required for SNF1‐dependent derepression and nuclear‐to‐cytoplasmic translocation.
Differential down‐regulation of CD95 or CD95L in chronically HIV‐infected cells of monocytic or lymphocytic origin: cellular studies and molecular analysis by quantitative competitive RT‐PCR
Authors: Pinti Marcello , Pedrazzi Jessica , Benatti Francesca , Sorrentino Veronica , Nuzzo Cira , Cavazzuti Valeria , Biswas Priscilla , Petrusca Daniela Nicoleta , Mussini Cristina , De Rienzo Bruno , Cossarizza Andrea
Published: July 2002

We analysed the expression of CD95/CD95L in two widely used models for studying the cellular effects of chronic infection with human immunodeficiency virus type 1 (HIV‐1), i.e. ACH‐2 cells, derived from the lymphocytic cell line A301, and U1, derived from monocytic U937 cells. A301 and ACH‐2 mounted the same amount of plasma membrane CD95, while U1 had a consistent decrease in CD95 expression. Using different antibodies, we failed to detect the plasma membrane form of its ligand, CD95L, but we could see the intracellular presence of that molecule in A301 cells and, to a lesser extent, in ACH‐2 cells, but not in U937 or U1 cells. To confirm the cytofluorimetric data and quantify the expression of CD95L at the RNA level, we developed a quantitative competitive RT‐PCR assay. The HUT78 cell line had about 50 000 copies mRNA/1000 cells, three times more after induction with a phorbol ester and ionomycin. ACH‐2 expressed about 400‐ (basal) or 10‐ (induced) fold less CD95L mRNA than the parental cell line A301; U937 and U1 were below the limit of detection. In cells of lymphoid origin (ACH‐2) chronic HIV infection inhibits the expression of CD95L, the phenomenon occurring at the transcriptional level. In cells of monocytic origin (U1) the infection decreases the plasma membrane expression of CD95. This suggests that HIV could trigger different anti‐apoptotic strategies which likely depend upon the cell line which is infected. In monocytic cells which act as a viral reservoir, the expression of the molecule whose binding triggers apoptosis decreases, while in lymphoid cells, capable of exerting cytotoxicity, the expression of a molecule which induces apoptosis is reduced.
Starvation induces tau hyperphosphorylation in mouse brain: implications for Alzheimer's disease
Authors: Yanagisawa Masahiro , Planel Emmanuel , Ishiguro Koichi , Fujita Shinobu C
Published: July 2002

Hyperphosphorylated tau is the major component of paired helical filaments in neurofibrillary tangles found in Alzheimer's disease brains, and tau hyperphosphorylation is thought to be a critical event in the pathogenesis of this disease. The objective of this study was to reproduce tau hyperphosphorylation in an animal model by inducing hypoglycemia. Food deprivation of mice for 1 to 3 days progressively enhanced tau hyperphosphorylation in the hippocampus, to a lesser extent in the cerebral cortex, but the effect was least in the cerebellum, in correspondence with the regional selectivity of tauopathy in Alzheimer's disease. This hyperphosphorylation was reversible by refeeding for 1 day. We discuss possible mechanisms of this phenomenon, and propose the starved mouse as a simple model to study in vivo tau phosphorylation and dephosphorylation which are altered in Alzheimer's disease.
Factors important for fusogenic activity of peptides: molecular modeling study of analogs of fusion peptide of influenza virus hemagglutinin
Authors: Efremov Roman G. , Nolde Dmitry E. , Volynsky Pavel E. , Chernyavsky Andrei A. , Dubovskii Peter V. , Arseniev Alexander S.
Published: July 2002

Nine analogs of fusion peptide of influenza virus hemagglutinin whose membrane perturbation activity has been thoroughly tested [Murata et al. (1992) Biochemistry 31, 1986–1992; Murata et al. (1993) Biophys. J. 64, 724–734] were characterized by molecular modeling techniques with the aim of delineating any specific structural and/or hydrophobic properties inherent in peptides with fusogenic activity. It was shown that, regardless of characteristics common to all analogs (peripheral disposition at the water‐lipid interface, amphiphilic nature, α‐helical structure, etc.), only fusion active peptides reveal a specific ‘tilted oblique‐oriented’ pattern of hydrophobicity on their surfaces and a certain depth of penetration to the non‐polar membrane core. The conclusion was reached that these factors are among the most important for the specific destabilization of a bilayer, which is followed by membrane fusion.
Prevalence of ovarian endometriosis in epithelial ovarian cancer
Authors: Jimbo H , Yoshikawa H , Onda T , Yasugi T , Sakamoto A , Taketani Y
Published: July 2002

Objective: The objective of this study was to examine the occurrence of ovarian endometriosis in epithelial ovarian cancer in Japan. Method: The presence of ovarian endometriosis was determined by reviewing the sections of resected specimens in 172 epithelial ovarian cancers. Results: The incidence of ovarian endometriosis in ovarian cancer (14.5%) was higher than that in Western countries. The rank order of incidence of endometriosis in each histologic type was clear cell (40.6%)>endometrioid (23.1%)>serous (8.7%)>mucinous (2.9%). The incidence in serous type was higher when compared with that reported in Western countries. The higher incidence of endometriosis in Japan can be explained by a greater proportion of clear cell type, comprising 18.6% of all the cases and a higher incidence of endometriosis in the serous type. Conclusion: The association of ovarian endometriosis with epithelial ovarian cancer was more frequently found in Japan.
Birth weight, gestational age and medications during pregnancy
Authors: Czeizel A.E , Tóth M
Published: July 2002

Objective: To determine the effect of medication on birth weight and gestational age in 29 004 healthy newborn infants born to mothers with or without treatment of drugs. Method: Birth weight and gestational age were evaluated in healthy control newborn infants in the population‐based dataset of the Hungarian Case‐Control Surveillance of Congenital Abnormalities (1980–1991) using multiple regression analysis. Results: Of 114 drugs used in more than 100 pregnant women, 19 had a positive or negative impact. Conclusions: Further studies should be carried out to identify the possible mechanisms of medication and/or the maternal disorder for which this medication was given.
Today's treatments: medical, surgical and in partnership
Authors: Donnez J
Published: July 2002

Objective: To provide an overview of the medical, surgical and combined therapy options for endometriosis. Results: Available medical options include danazol, progestogens, gestrinone, oral contraceptive agents, analgesics and gonadotropin‐releasing hormone (GnRH) agonists. Used in the short‐term, most of these agents relieve pain in a large proportion of patients and produce disease regression, however, they do not prevent recurrence, and are associated with side‐effects. However, few data confirm any benefit of short‐term medical therapy on fertility. One of the most promising medical approaches appears to be GnRH agonists with add‐back hormone replacement therapy. Surgery may relieve pain, eradicate visible disease and improve fertility. A combined approach may facilitate surgery and relieve pain, although any fertility benefit is as yet unproven. Conclusion: Both short‐term medical treatment and surgery relieve endometriosis‐associated pain and decrease endometriotic implants. However, all approaches have side effects which must be balanced against the benefits when defining suitable treatment for a particular patient.
An empirical test of the causal relationships in the Baldrige Health Care Pilot Criteria
Authors: Meyer Susan M , Collier David A
Published: July 2002

This research is the first to empirically test the causal relationships in the Malcolm Baldrige National Quality Award (MBNQA) Health Care Pilot Criteria. The Baldrige model of quality management for the health care industry is tested here using data from 220 US hospitals. Results of confirmatory structural equation modeling show that many of the hypothesized causal relationships in the Baldrige model are statistically significant. For example, Leadership (Baldrige Category 1.0) is identified as a driver of all components in the Baldrige System, including Information and Analysis, Strategic Planning, Human Resource Development and Management, and Process Management. This study also clarifies and improves understanding of within‐System performance relationships. Baldrige components of Leadership and Information and Analysis are significantly linked with Organizational Performance Results while Human Resource Development and Management and Process Management significantly link with Customer Satisfaction. In addition, a comprehensive “measurement model” grounded in the Baldrige Health Care Criteria for the 28 dimensions of measurement is developed, tested, and found to be valid and reliable. This valid and reliable measurement model allows a fair test of the “structural model”, which tests the relationships among the Baldrige model constructs. Ten major findings and future research ideas are discussed.
The effect of component placement on knee kinetics after arthroplasty with an unconstrained prosthesis
Authors: Miller M. C. , Zhang A. X. , Petrella Anthony J. , Berger Richard A. , Rubash Harry E.
Published: July 2002

The mechanical success of a total knee replacement demands stable patellar tracking without subluxation and, stable tracking, in turn, can depend largely on the medial‐lateral forces restraining the patella. Patellar button medialization has been advocated as a means of reducing subluxation, and experimental evidence has shown femoral component rotation also affects medial—lateral forces. Surgeons have choices in femoral component rotation and patellar button medialization and must frequently make intra‐operative decisions concerning component placement because of anatomical variations among patients. Thus, in seeking to minimize medial—lateral patellar force, we examined the effects of patellar button medialization and external femoral component rotation. The study used an unconstrained total knee system implanted in nine cadaveric specimens tested on a knee simulator operating through flexion angles up to 100°. Tests included all combinations of external femoral component rotation of 0°, 2.5°, and 5° and patellar placement at the geometric center and at 3.75 mm medial to the geometric center. A video‐based motion analysis system tracked patellar and tibial kinematics while a six‐component load cell measured patellofemoral loads. Repeated measures analysis of variance revealed a statistically significant decrease in the average medial‐lateral force with button medialization but no significant change with femoral component rotation. Neither femoral component rotation nor patellar button medialization had an effect on the normal component of the patellar reaction force. External femoral component rotation did cause significant increases in lateral patellar tilt, in tibial varus angle, and in external tibial rotation. Button medialization caused significant increases in lateral patellar tracking, lateral patellar tilt and external tibial rotation. The results in medial‐lateral patellar forces quantify the benefit of patellar button medialization and discount any benefit of femoral rotation. The change in tibial kinematics with patellar button medialization and femoral component rotation cannot be measured in vivo with current technology, and the precise clinical implications are unknown. © 2001 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.
Alteration of fracture stability influences chondrogenesis, osteogenesis and immigration of macrophages
Authors: Hankemeier S. , Grässel S. , Plenz G. , Spiegel H. U. , Bruckner P. , Probst A.
Published: July 2002

Mechanical conditions at the fracture line determine the mode of fracture healing (osteonal versus non‐osteonal bone union). The aim of this study was to investigate the influence of differing degrees of fracture stability on the time course of chondrogenesis, enchondral ossification and immigration of macrophages into the fracture callus.

Using a fracture model of the rat's tibia, histological (Azan staining), immunohistological (antibodies directed against the macrophage‐specific surface antigen ED2), and molecular biological techniques (expression of the mRNA of the cartilage‐specific collagen IX, osteocalcin — a marker for mature osteoblasts — and the macrophage‐specific macrosialin) were employed.

In terms of histology and molecular biology (collagen IX mRNA expression) chondrogenesis in the fracture gap continued for longer in less stable fractures. In more stable fractures bone formation — identified by osteocalcin mRNA expression — increased from day 12 onwards. The expression of the macrophage‐specific surface antigen ED2 and the mRNA of macrosialin was more pronounced but of shorter duration in the more stable fractures.

This study shows that differing degrees of fracture stability not only influence the interplay between osteogenesis and chondrogenesis but also alter the kinetics of macrophage immigration into the fracture callus. These findings could aid in better understanding the cytobiologic mechanisms of callus formation and may suggest that macrophages are an important factor not only in soft tissue healing but also in bone healing. © 2001 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.
Age‐related changes in the localization of P2X (nucleotide) receptors in the rat adrenal gland
Authors: Afework Mekbeb , Burnstock Geoffrey
Published: July 2002

Observation of the changes in the occurrence and distribution of nucleotide (P2X) receptors in the adrenal gland during development and ageing, and correlation with the changes in adrenal status at similar stages may give morphological insights into the functions of purine nucleotides in the gland. Age‐related changes in the localization of all seven subtypes of the P2X receptor in the adrenal gland of rat were therefore investigated immunohistochemically. In the adrenal glands of prenatal rats, immunoreactivity to P2X receptor subtypes was not observed. In glands of the postnatal rat at the developmental stages studied, only immunoreactivity for the P2X5 receptor subtype was observed. A small number of faintly P2X5‐immunoreactive chromaffin cells were found in the adrenal glands of 1‐day‐old rats; the frequency of localization and intensity of staining of immunoreactive cells had increased by day 4 and was further increased at day 7. P2X5 immunoreactivity was not observed in the adrenal glands from 14‐ and 21‐day‐old rats. At 8 weeks of age, immunoreactivity with a specific distribution for each of the seven receptor subtypes was observed. Except for the P2X4 receptor, adrenal glands at 24 months showed a similar pattern of immunoreactivity for the receptor subtypes as that observed at 8 weeks. Immunoreactivity for P2X4 was first observed in the adrenal cortical cells of the zona reticularis at 8 weeks, but was absent in 24‐month‐old rats. However, several P2X4‐immunoreactive chromaffin cells appeared at 24 months. Such immunoreactive cells were not seen in rats of any of the other ages studied. It was concluded that the greater expression of P2X5 receptor at an early developmental stage and of P2X4 in ageing might reflect functional roles for purines in cellular proliferation and/or differentiation, and in cellular degeneration, respectively, in adrenal glands of rat.
Reconstruction of the transected cat spinal cord following NeuroGel™ implantation: axonal tracing, immunohistochemical and ultrastructural studies
Authors: Woerly Stéphane , van Doan Diep , Sosa Norma , de Vellis Jean , Espinosa Araceli
Published: July 2002

This study examined the ability of NeuroGel™, a biocompatible porous poly [N‐(2‐hydroxypropyl) methacrylamide] hydrogel, to establish a permissive environment across a 3 mm gap in the cat spinal cord in order to promote tissue reconstitution and axonal regeneration across the lesion. Animals with NeuroGel™ implants were compared to transection‐only controls and observed for 21 months. The hydrogel formed a stable bridge between the cord segments. Six months after reconstructive surgery, it was densely infiltrated by a reparative tissue composed of glial cells, capillary vessels and axonal fibres. Axonal labelling and double immunostaining for neurofilaments and myelin basic protein, showed that descending supraspinal axons of the ventral funiculus and afferent fibres of the dorsal column regenerated across the reconstructed lesion. Fifteen months after reconstructive surgery, axons had grown, at least, 12 mm into the distal cord tissue, and in the rostral cord there was labelling of neurons of the intermediate gray matter. Electron microscopy showed that after 9 months, most of the regenerating axons were myelinated, principally by Schwann cells. Newly formed neurons presumably from precursor cells of the ependyma and/or migrating neurons were observed within the reparative tissue after 21 months. Results indicate that functional deficit, as assessed by treadmill training, and morphological changes following double transection of the spinal cord can be modified by the implantation of NeuroGel™. This technology offers the potential to promote the formation of a neural tissue equivalent via a reparative neohistogenesis process, that facilitates and supports regenerative growth of axons.
Changes in the immune system in depression and dementia: causal or co‐incidental effects?
Authors: Leonard Brian E.
Published: July 2002

It is now widely accepted that psychological stress and psychiatric illness can compromise immune function. Furthermore the mechanisms whereby such changes occur are probably associated with the activities of the cytokines and other inflammatory mediators of the immune system which are known to initiate changes in behaviour. This review aims to summarise the experimental and clinical evidence that implicates the pro‐inflammatory cytokines in the pathological changes seen in major depression and in Alzheimer's disease (AD). In major depression, evidence is provided to show that both activation (e.g., macrophage activity, acute phase proteins) and inhibition (e.g., natural killer cell activity) of the immune system occur. Many of the behavioural changes seen in depression are simulated by three pro‐inflammatory cytokines (IL‐1, IL‐6 and TNF‐alpha), which may produce their impact on the brain by activating cyclooxygenase, nitric acid synthase and corticotrophin releasing factor. Effective antidepressant treatments largely attenuate the immune changes thereby raising the possibility that the normalisation of central biogenic amine function that are conventionally implicated in the cause of depression may be secondary to those of the pro‐inflammatory cytokines.

With respect to AD, while the cause(s) are unknown, there is both experimental and clinical evidence to suggest that inflammatory processes in the brain caused in particular by TNF‐alpha together with the subsequent rise in free radicals, are instrumental in causing the pathological changes which underlie the disease. Evidence in favour of the inflammatory hypothesis is supported by the finding that nonsteroidal anti‐inflammatory drugs slow down the progression of the disease.

Although, more research is needed into the inter‐relationships between the various pro‐inflammatory cytokines and the behavioural changes invoked in major depression and AD, the immunological hypothesis has been important in stimulating new concepts regarding the causes of the pathological changes in these diseases and how effective drug treatments may attenuate them.
The role of integrin receptors in aspects of glioma invasion in vitro
Authors: Rooprai Harcharan K. , Vanmeter Timothy , Panou Chryssoula , Schnüll Stefan , Trillo‐Pazos Gusta , Davies Derek , Pilkington Geoffrey J.
Published: July 2002

Integrins are heterodimers consisting of non‐covalently associated alpha and beta subunits. They mediate adherence of normal and tumour cells to the extracellular matrix, a property which is essential for migration of neoplastic astrocytes as they invade into the normal brain parenchyma. Flow cytometry and immunocytochemical analysis of cultured cells derived from 10 gliomas (1 pilocytic astrocytoma, 1 astrocytoma, 1 oligoastrocytoma, 1 anaplastic oligoastrocytoma, 4 anaplastic astrocytomas and 2 glioblastoma multiforme) revealed that the β1 integrin subunit was generally expressed more strongly than α4 or αv integrin subunits. Subsequent studies with function‐blocking antibodies against the β1 subunit inhibited adhesion, motility and invasion of the gliomas in vitro, to varying degrees, on all extracellular matrix substrates investigated (laminin, collagen type IV, fibronectin and vitronectin), the inhibition by β1 subunit was greatest on collagen type IV. These studies therefore substantiate the case for a role of the β1 integrin subunit in neoplastic glial cell invasion of the brain.
An empirical analysis of differences in Black and White asset and liability combinations
Authors: Badu Yaw A. , Daniels Kenneth N. , Salandro Daniel P.
Published: July 2002

This study analyzes data from the 1992 Survey of Consumer Finances and finds significant differences in asset and liability combinations between Black and White households. In addition, White households are identified as having significantly greater net worth and financial assets relative to Black households. We are unable to show that the net worth of Black households is constrained by barriers in financial markets. Our study investigates how this difference in net worth could engender different financing decisions. We find that Black households are significantly more risk averse in their choice of assets. Further, we find that Black households typically pay higher rates for several types of credit instruments, even though they self identify as conducting significantly more extensive searches in the financial markets. © 2000 Elsevier Science Inc. All rights reserved.
Foreign trade and exchange‐rate risk in the G‐7 countries: Cointegration and error‐correction models
Authors: Arize A.C.
Published: July 2002

This paper examines the impact of real exchange‐rate volatility on the trade flows of G‐7 countries in the context of a multivariate error‐ correction model. The advantages of this statistical approach vis‐a‐vis earlier approaches are that it provides more efficient short‐run and long‐ run coefficient estimates and avoids the problems of spurious regressions. The major results show that increases in the volatility of the real effective exchange rate, approximating exchange‐rate uncertainty, exert a significant negative effect upon export demand in both the short‐run and the long‐run in each of the G‐7 countries. These effects may result in significant allocation of resources by market participants.
Building an infrastructure to enable delivery of genomic medicine
Authors: Hooker Gillian W.
Published: January 2021

To meaningfully address health disparities in access to genomic testing, major developments in the infrastructure to support delivery of care are needed. The current value chain for delivering genomic medicine is fragmented, with poor communication between the stakeholders who order, perform, and reimburse for genetic tests. Standards, connectivity, and scaled expertise are needed to reach more people equitably and achieve healthcare returns on society's investments in genomics. As the costs of genetically‐targeted therapeutics and treatments rise, a mature infrastructure to support the delivery of genetic tests becomes critical.