bluuebunny/crossref_metadata_2025 huggingface dataset:
Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria
Authors: Leclerc D. , Wilson A. , Dumas R. , Gafuik C. , Song D. , Watkins D. , Heng H. H. Q. , Rommens J. M. , Scherer S. W. , Rosenblatt D. S. , Gravel R. A.
Published: July 2002

Methionine synthase catalyzes the remethylation of homocysteine to methionine via a reaction in which methylcobalamin serves as an intermediate methyl carrier. Over time, the cob(I)alamin cofactor of methionine synthase becomes oxidized to cob(II)alamin rendering the enzyme inactive. Regeneration of functional enzyme requires reductive methylation via a reaction in which
S
-adenosylmethionine is utilized as a methyl donor. Patients of the
cblE
complementation group of disorders of folate/cobalamin metabolism who are defective in reductive activation of methionine synthase exhibit megaloblastic anemia, developmental delay, hyperhomocysteinemia, and hypomethioninemia. Using consensus sequences to predicted binding sites for FMN, FAD, and NADPH, we have cloned a cDNA corresponding to the “methionine synthase reductase” reducing system required for maintenance of the methionine synthase in a functional state. The gene
MTRR
has been localized to chromosome 5p15.2–15.3. A predominant mRNA of 3.6 kb is detected by Northern blot analysis. The deduced protein is a novel member of the FNR family of electron transferases, containing 698 amino acids with a predicted molecular mass of 77,700. It shares 38% identity with human cytochrome P450 reductase and 43% with the
C. elegans
putative methionine synthase reductase. The authenticity of the cDNA sequence was confirmed by identification of mutations in
cblE
patients, including a 4-bp frameshift in two affected siblings and a 3-bp deletion in a third patient. The cloning of the cDNA will permit the diagnostic characterization of
cblE
patients and investigation of the potential role of polymorphisms of this enzyme as a risk factor in hyperhomocysteinemia-linked vascular disease.
Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons
Authors: Saucedo-Cardenas Odila , Quintana-Hau Juan D. , Le Wei-Dong , Smidt Marten P. , Cox Joke J. , De Mayo Francesco , Burbach J. Peter H. , Conneely Orla M.
Published: July 2002

Nurr1 is a member of the nuclear receptor superfamily of transcription factors that is expressed predominantly in the central nervous system, including developing and mature dopaminergic neurons. Recent studies have demonstrated that Nurr1 is essential for the induction of phenotypic markers of ventral mid-brain dopaminergic neurons whose generation is specified by the floor plate-derived morphogenic signal sonic hedgehog (SHH), but the precise role of Nurr1 in this differentiative pathway has not been established. To provide further insights into the role of Nurr1 in the final differentiation pathway, we have examined the fate of dopamine cell precursors in Nurr1 null mutant mice. Here we demonstrate that Nurr1 functions at the later stages of dopamine cell development to drive differentiation of ventral mesencephalic late dopaminergic precursor neurons. In the absence of Nurr1, neuroepithelial cells that give rise to dopaminergic neurons adopt a normal ventral localization and neuronal phenotype characterized by expression of the homeodomain transcription factor and mesencephalic marker, Ptx-3, at embryonic day 11.5. However, these late precursors fail to induce a dopaminergic phenotype, indicating that Nurr1 is essential for specifying commitment of mesencephalic precursors to the full dopaminergic phenotype. Further, as development progresses, these mid-brain dopamine precursor cells degenerate in the absence of Nurr1, resulting in loss of Ptx-3 expression and a concomitant increase in apoptosis of ventral midbrain neurons in newborn null mutant mice. Taken together, these data indicate that Nurr1 is essential for both survival and final differentiation of ventral mesencephalic late dopaminergic precursor neurons into a complete dopaminergic phenotype.
A cell-autonomous requirement for CXCR4 in long-term lymphoid and myeloid reconstitution
Authors: Kawabata Kenji , Ujikawa Miho , Egawa Takeshi , Kawamoto Hiroshi , Tachibana Kazunobu , Iizasa Hisashi , Katsura Yoshimoto , Kishimoto Tadamitsu , Nagasawa Takashi
Published: July 2002

Mice lacking the chemokine stromal cell-derived factor/pre-B cell growth stimulating factor or its primary physiological receptor CXCR4 revealed defects in B lymphopoiesis and bone marrow myelopoiesis during embryogenesis. We show here that adoptive transfer experiments reveal a deficiency in long-term lymphoid and myeloid repopulation in adult bone marrow by CXCR4−/− fetal liver cells, although stromal cell-derived factor/pre-B cell growth stimulating factor−/− fetal liver cells yield normal multilineage reconstitution. These findings indicate that CXCR4 is required cell autonomously for lymphoid and myeloid repopulation in bone marrow. In addition, CXCR4−/− fetal liver cells generated much more severely reduced numbers of B cells relative to other lineages in bone marrow. Furthermore, the repopulation of c-kit
+
Sca-1
+
lin
low/−
cells by CXCR4−/− fetal liver cells was less affected compared with c-kit
+
Sca-1
−
lin
low/−
cells. By previous studies, it has been shown that c-kit
+
Sca-1
+
lin
low/−
cells are highly purified primitive hematopoietic progenitors and that c-kit
+
Sca-1
−
lin
low/−
cells are more committed hematopoietic progenitors in mice. Thus, CXCR4 may play an essential role in generation and/or expansion of early hematopoietic progenitors within bone marrow.
Vascular endothelial–cadherin is an important determinant of microvascular integrityinvivo
Authors: Corada Monica , Mariotti Massimo , Thurston Gavin , Smith Kelly , Kunkel Robin , Brockhaus Manfred , Lampugnani Maria Grazia , Martin-Padura Ines , Stoppacciaro Antonella , Ruco Luigi , McDonald Donald M. , Ward Peter A. , Dejana Elisabetta
Published: July 2002

In the present paper, we characterize an antibody, mAb BV13, directed to mouse vascular endothelial (VE)-cadherin, a major adhesive protein of interendothelial adherens junctions. When added to cultured endothelial cells, BV13 induces a redistribution of VE-cadherin from intercellular junctions. VE-cadherin redistribution did not change the localization of platelet endothelial cell adhesion molecule or tight junction markers such as zonula occludens 1, cingulin, and junctional adhesion molecule. Intravenous administration of mAb BV13 induced a concentration- and time-dependent increase in vascular permeability in heart and lungs. By electron microscopy, interstitial edema and accumulation of mixed types of inflammatory cells in heart and lungs were observed. Injection of (rhodamine-labeled)Ricinus communisI lectin showed focal spots of exposed basement membrane in the alveolar capillaries and in some larger pulmonary vessels. These data indicate that VE-cadherin is required for vascular integrity and normal organ functions.
Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M
4
muscarinic acetylcholine receptor knockout mice
Authors: Gomeza Jesus , Zhang Lu , Kostenis Evi , Felder Christian , Bymaster Frank , Brodkin Jesse , Shannon Harlan , Xia Bing , Deng Chu-xia , Wess Jürgen
Published: July 2002

Muscarinic acetylcholine receptors (M
1
–M
5
) regulate many key functions of the central and peripheral nervous system. Primarily because of the lack of receptor subtype-selective ligands, the precise physiological roles of the individual muscarinic receptor subtypes remain to be elucidated. Interestingly, the M
4
receptor subtype is expressed abundantly in the striatum and various other forebrain regions. To study its potential role in the regulation of locomotor activity and other central functions, we used gene-targeting technology to create mice that lack functional M
4
receptors. Pharmacologic analysis of M
4
receptor-deficient mice indicated that M
4
receptors are not required for muscarinic receptor-mediated analgesia, tremor, hypothermia, and salivation. Strikingly, M
4
receptor-deficient mice showed an increase in basal locomotor activity and greatly enhanced locomotor responses (as compared with their wild-type littermates) after activation of D1 dopamine receptors. These results indicate that M
4
receptors exert inhibitory control on D1 receptor-mediated locomotor stimulation, probably at the level of striatal projection neurons where the two receptors are coexpressed at high levels. Our findings offer new perspectives for the treatment of Parkinson’s disease and other movement disorders that are characterized by an imbalance between muscarinic cholinergic and dopaminergic neurotransmission.
Activation of a Frizzled-2/β-adrenergic receptor chimera promotes Wnt signaling and differentiation of mouse F9 teratocarcinoma cells via Gαo and Gαt
Authors: Liu Xunxian , Liu Tong , Slusarski Diane C. , Yang-Snyder Julia , Malbon Craig C. , Moon Randall T. , Wang Hsien-yu
Published: July 2002

The
frizzled
gene family of putative Wnt receptors encodes proteins that have a seven-transmembrane-spanning motif characteristic of G protein-linked receptors, though no loss-of-function studies have demonstrated a requirement for G proteins for Frizzled signaling. We engineered a Frizzled-2 chimera responsive to β-adrenergic agonist by using the ligand-binding domains of the β
2
-adrenergic receptor. The expectation was that the chimera would be sensitive both to drug-mediated activation and blockade, thereby circumventing the problem of purifying soluble and active Wnt ligand to activate Frizzled. Expression of the chimera in zebrafish embryos demonstrated isoproterenol (ISO)-stimulated, propranolol-sensitive calcium transients, thereby confirming the β-adrenergic nature of Wnt signaling by the chimeric receptor. Because F9 embryonic teratocarcinoma cells form primitive endoderm after stable transfection of Frizzled-2 chimera and stimulation with ISO, they were subject to depletion of G protein subunits. ISO stimulation of endoderm formation of F9 stem cells expressing the chimeric receptor was blocked by pertussis toxin and by oligodeoxynucleotide antisense to Gαo, Gαt2, and Gβ2. Our results demonstrate the requirement of two pertussis toxin-sensitive G proteins, Gαo and Gαt, for signaling by the Frizzled-2 receptor.
Brominated 7-hydroxycoumarin-4-ylmethyls: Photolabile protecting groups with biologically useful cross-sections for two photon photolysis
Authors: Furuta Toshiaki , Wang Samuel S.-H. , Dantzker Jami L. , Dore Timothy M. , Bybee Wendy J. , Callaway Edward M. , Denk Winfried , Tsien Roger Y.
Published: July 2002

Photochemical release (uncaging) of bioactive messengers with
three-dimensional spatial resolution in light-scattering media would be
greatly facilitated if the photolysis could be powered by pairs of IR
photons rather than the customary single UV photons. The quadratic
dependence on light intensity would confine the photolysis to the focus
point of the laser, and the longer wavelengths would be much less
affected by scattering. However, previous caged messengers have had
very small cross sections for two-photon excitation in the IR region.
We now show that brominated 7-hydroxycoumarin-4-ylmethyl esters and
carbamates efficiently release carboxylates and amines on photolysis,
with one- and two-photon cross sections up to one or two orders of
magnitude better than previously available. These advantages are
demonstrated on neurons in brain slices from rat cortex and hippocampus
excited by glutamate uncaged from
N
-(6-bromo-7-hydroxycoumarin-4-ylmethoxycarbonyl)-
l
-glutamate
(Bhc-glu). Conventional UV photolysis of Bhc-glu requires less than
one-fifth the intensities needed by one of the best previous caged
glutamates, γ-(α-carboxy-2-nitrobenzyl)-
l
-glutamate
(CNB-glu). Two-photon photolysis with raster-scanned femtosecond IR
pulses gives the first three-dimensionally resolved maps of the
glutamate sensitivity of neurons in intact slices. Bhc-glu and analogs
should allow more efficient and three-dimensionally localized uncaging
and photocleavage, not only in cell biology and neurobiology but also
in many technological applications.
Serine–arginine (SR)-rich splicing factors have an exon-independent function in pre-mRNA splicing
Authors: Hertel Klemens J. , Maniatis Tom
Published: July 2002

Two distinct functions have been proposed for the serine–arginine (SR)-rich family of splicing factors. First, SR proteins are essential splicing factors and are thought to function by mediating protein–protein interactions within the intron during spliceosome assembly. Second, SR proteins bind to exonic enhancer sequences and recruit spliceosome components to adjacent introns. The latter activity is required for splice-site recognition and alternative splicing. Until now it has not been possible to determine whether the requirement for SR proteins in the basic splicing reaction is a secondary consequence of their exon-dependent recruitment function. Here we show that RNA substrates containing only 1 nt of exon sequence can undergo the first step of the splicing reaction
in vitro
and that this activity requires SR proteins. Thus, we provide direct evidence that SR proteins have both exon-independent and exon-dependent functions in pre-mRNA splicing.
Mechanical and chemical unfolding of a single protein: A comparison
Authors: Carrion-Vazquez Mariano , Oberhauser Andres F. , Fowler Susan B. , Marszalek Piotr E. , Broedel Sheldon E. , Clarke Jane , Fernandez Julio M.
Published: July 2002

Is the mechanical unraveling of protein domains by atomic force microscopy (AFM) just a technological feat or a true measurement of their unfolding? By engineering a protein made of tandem repeats of identical Ig modules, we were able to get explicit AFM data on the unfolding rate of a single protein domain that can be accurately extrapolated to zero force. We compare this with chemical unfolding rates for untethered modules extrapolated to 0 M denaturant. The unfolding rates obtained by the two methods are the same. Furthermore, the transition state for unfolding appears at the same position on the folding pathway when assessed by either method. These results indicate that mechanical unfolding of a single protein by AFM does indeed reflect the same event that is observed in traditional unfolding experiments. The way is now open for the extensive use of AFM to measure folding reactions at the single-molecule level. Single-molecule AFM recordings have the added advantage that they define the reaction coordinate and expose rare unfolding events that cannot be observed in the absence of chemical denaturants.
Acyl homoserine-lactone quorum-sensing signal generation
Authors: Parsek Matthew R. , Val Dale L. , Hanzelka Brian L. , Cronan John E. , Greenberg E. P.
Published: July 2002

Acyl homoserine lactones (acyl-HSLs) are important intercellular signaling molecules used by many bacteria to monitor their population density in quorum-sensing control of gene expression. These signals are synthesized by members of the LuxI family of proteins. To understand the mechanism of acyl-HSL synthesis we have purified the
Pseudomonas aeruginosa
RhlI protein and analyzed the kinetics of acyl-HSL synthesis by this enzyme. Purified RhlI catalyzes the synthesis of acyl-HSLs from acyl–acyl carrier proteins and
S
-adenosylmethionine. An analysis of the patterns of product inhibition indicated that RhlI catalyzes signal synthesis by a sequential, ordered reaction mechanism in which
S
-adenosylmethionine binds to RhlI as the initial step in the enzymatic mechanism. Because pathogenic bacteria such as
P. aeruginosa
use acyl-HSL signals to regulate virulence genes, an understanding of the mechanism of signal synthesis and identification of inhibitors of signal synthesis has implications for development of quorum sensing-targeted antivirulence molecules.
Mice that lack the angiogenesis inhibitor, thrombospondin 2, mount an altered foreign body reaction characterized by increased vascularity
Authors: Kyriakides Themis R. , Leach Kathleen J. , Hoffman Allan S. , Ratner Buddy D. , Bornstein Paul
Published: July 2002

Disruption of the thrombospondin 2 gene (
Thbs2
) in mice results in a complex phenotype characterized chiefly by abnormalities in fibroblasts, connective tissues, and blood vessels. Consideration of this phenotype suggested to us that the foreign body reaction (FBR) might be altered in thrombospondin 2 (TSP2)-null mice. To investigate the participation of TSP2 in the FBR, polydimethylsiloxane (PDMS) and oxidized PDMS (ox-PDMS) disks were implanted in TSP2-null and control mice. Growth of TSP2-null and control skin fibroblasts
in vitro
also was evaluated on both types of disks. Normal fibroblasts grew as a monolayer on both surfaces, but attachment of the cells to ox-PDMS was weak and sensitive to movement. TSP2-null fibroblasts grew as aggregates on both surfaces, and their attachment was further compromised on ox-PDMS. After a 4-week implantation period, both types of PDMS elicited a similar FBR with a collagenous capsule in both TSP2-null and control mice. However, strikingly, the collagenous capsule that formed in TSP2-null mice was highly vascularized and thicker than that formed in normal mice. In addition, abnormally shaped collagen fibers were observed in capsules from mutant mice. These observations indicate that the presence or absence of an extracellular matrix component, TSP2, can influence the nature of the FBR, in particular its vascularity. The expression of TSP2 therefore could represent a molecular target for local inhibitory measures when vascularization of the tissue surrounding an implanted device is desired.
Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation
in vitro
and are attenuated by drugs that enhance the cAMP signaling pathway
Authors: Bach Mary Elizabeth , Barad Mark , Son Hyeon , Zhuo Min , Lu Yun-Fei , Shih Robert , Mansuy Isabelle , Hawkins Robert D. , Kandel Eric R.
Published: July 2002

To study the physiological and molecular mechanisms of age-related memory loss, we assessed spatial memory in C57BL/B6 mice from different age cohorts and then measured
in vitro
the late phase of hippocampal long-term potentiation (L-LTP). Most young mice acquired the spatial task, whereas only a minority of aged mice did. Aged mice not only made significantly more errors but also exhibited greater individual differences. Slices from the hippocampus of aged mice exhibited significantly reduced L-LTP, and this was significantly and negatively correlated with errors in memory. Because L-LTP depends on cAMP activation, we examined whether drugs that enhanced cAMP would attenuate the L-LTP and memory defects. Both dopamine D1/D5 receptor agonists, which are positively coupled to adenylyl cyclase, and a cAMP phosphodiesterase inhibitor ameliorated the physiological as well as the memory defects, consistent with the idea that a cAMP–protein kinase A-dependent signaling pathway is defective in age-related spatial memory loss.
Positron emission tomography provides molecular imaging of biological processes
Authors: Phelps Michael E.
Published: July 2002

Diseases are biological processes, and molecular imaging with positron emission tomography (PET) is sensitive to and informative of these processes. This is illustrated by detection of biological abnormalities in neurological disorders with no computed tomography or MRI anatomic changes, as well as even before symptoms are expressed. PET whole body imaging in cancer provides the means to (
i
) identify early disease, (
ii
) differentiate benign from malignant lesions, (
iii
) examine all organs for metastases, and (
iv
) determine therapeutic effectiveness. Diagnostic accuracy of PET is 8–43% higher than conventional procedures and changes treatment in 20–40% of the patients, depending on the clinical question, in lung and colorectal cancers, melanoma, and lymphoma, with similar findings in breast, ovarian, head and neck, and renal cancers. A microPET scanner for mice, in concert with human PET systems, provides a novel technology for molecular imaging assays of metabolism and signal transduction to gene expression, from mice to patients: e.g., PET reporter gene assays are used to trace the location and temporal level of expression of therapeutic and endogenous genes. PET probes and drugs are being developed together—in low mass amounts, as molecular imaging probes to image the function of targets without disturbing them, and in mass amounts to modify the target's function as a drug. Molecular imaging by PET, optical technologies, magnetic resonance imaging, single photon emission tomography, and other technologies are assisting in moving research findings from
in vitro
biology to
in vivo
integrative mammalian biology of disease.
Interleukin-6 is an essential, corticotropin-releasing hormone-independent stimulator of the adrenal axis during immune system activation
Authors: Bethin Kathleen E. , Vogt Sherri K. , Muglia Louis J.
Published: July 2002

Glucocorticoids play a critical role in control of the cytokine response after immune challenge. Conversely, cytokines modulate glucocorticoid production by the hypothalamic–pituitary–adrenal axis. To define the potency and mechanism of interleukin-6 (IL-6) for augmentation of adrenal function, we exploited mice deficient in corticotropin-releasing hormone (CRH), IL-6, or both. Mice deficient in CRH action demonstrate severely impaired glucocorticoid production in response to psychological and metabolic challenge, but near normal responses to stressors that activate the immune system. In this paper, we demonstrate that IL-6 is essential for activation of the hypothalamic–pituitary–adrenal axis during immunological challenge in the absence of hypothalamic input from CRH. IL-6 receptors are present on pituitary corticotrophs and adrenocortical cells, consistent with the ability of IL-6 to bypass CRH in augmentation of adrenal function. Plasma corticosterone levels after bacterial lipopolysaccharide injection in mice deficient in CRH or IL-6 were significantly lower than in wild-type mice but significantly greater than in mice deficient in both CRH and IL-6. A second model of immune system activation using 2C11, an antibody to the T cell receptor, demonstrated a normal corticosterone response in mice deficient in CRH or IL-6, but a markedly decreased response in mice deficient in both CRH and IL-6. Surprisingly, the relative contribution of IL-6 for modulation of the adrenal response to stress is greater in female than in male mice. This gender-specific difference in IL-6 action in mice suggests the utility of further analysis of IL-6 in determining the female predominance seen in many human inflammatory/autoimmune diseases.
Role of circulating nitrite and
S
-nitrosohemoglobin in the regulation of regional blood flow in humans
Authors: Gladwin Mark T. , Shelhamer James H. , Schechter Alan N. , Pease-Fye Margaret E. , Waclawiw Myron A. , Panza Julio A. , Ognibene Frederick P. , Cannon Richard O.
Published: July 2002

To determine the relative contributions of endothelial-derived
nitric oxide (NO) vs. intravascular nitrogen oxide species in the
regulation of human blood flow, we simultaneously measured forearm
blood flow and arterial and venous levels of plasma nitrite, LMW-SNOs
and HMW-SNOs, and red cell S-nitrosohemoglobin (SNO-Hb). Measurements
were made at rest and during regional inhibition of NO synthesis,
followed by forearm exercise. Surprisingly, we found significant
circulating arterial-venous plasma nitrite gradients, providing a novel
delivery source for intravascular NO. Further supporting the notion
that circulating nitrite is bioactive, the consumption of nitrite
increased significantly with exercise during the inhibition of regional
endothelial synthesis of NO. The role of circulating
S
-nitrosothiols and SNO-Hb in the regulation of basal
vascular tone is less certain. We found that low-molecular-weight
S-nitrosothiols were undetectable and S-nitroso-albumin levels were two
logs lower than previously reported. In fact, S-nitroso-albumin
primarily formed in the venous circulation, even during NO synthase
inhibition. Whereas SNO-Hb was measurable in the human circulation
(brachial artery levels of 170 nM in whole blood), arterial-venous
gradients were not significant, and delivery of NO from SNO-Hb was
minimal. In conclusion, we present data that suggest (
i
)
circulating nitrite is bioactive and provides a delivery gradient of
intravascular NO, (
ii
) S-nitroso-albumin does not
deliver NO from the lungs to the tissue but forms in the peripheral
circulation, and (
iii
) SNO-Hb and
S
-nitrosothiols play a minimal role in the regulation of
basal vascular tone, even during exercise stress.
The human hematopoietic stem cell compartment is heterogeneous for CXCR4 expression
Authors: Rosu-Myles Michael , Gallacher Lisa , Murdoch Barbara , Hess David A. , Keeney Mike , Kelvin David , Dale Leanne , Ferguson Stephen S. G. , Wu Dongmei , Fellows Fraser , Bhatia Mickie
Published: July 2002

The chemokine stromal derived factor-1α (SDF-1α) has been implicated recently in the chemotaxis of primitive human hematopoietic cells, suggesting that pluripotent human stem cells express the SDF-1α receptor, CXCR4. By using flow cytometry and confocal microscopy, we have identified and isolated primitive subsets of human CXCR4+and CXCR4−cells. Distinctions in the progenitor content and response to SDF-1αin vitroindicate that CXCR4+and CXCR4−cells represent discrete populations of primitive blood cells. The i.v. transplantation of these subfractions into immune-deficient mice established that both possess comparable engraftment capacityin vivo. Human myeloid, lymphoid, and primitive CD34+CXCR4+cells were present in chimeric animals transplanted with either subset, indicating that CXCR4+and CXCR4−stem cells have equivalent proliferative and differentiative abilities. Our study indicates that the human stem cell compartment is heterogeneous for CXCR4 expression, suggesting that the relationship between CXCR4 expression and stem cell repopulating function is not obligatory.
Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26S proteasome
Authors: Lange Carol A. , Shen Tianjie , Horwitz Kathryn B.
Published: July 2002

Ligand-dependent down-regulation that leads to rapid and extensive loss of protein is characteristic of several nuclear steroid receptors, including human progesterone receptors (PRs). In breast cancer cells, >95% of PRs are degraded 6 h after the start of progestin treatment. The mechanism for down-regulation is unknown. We examined the role of PR phosphorylation by mitogen-activated protein kinases (MAPKs) in this process. Lactacystin and calpain inhibitor I, specific inhibitors of the 26S proteasome, blocked progestin-induced down-regulation, and ubiquitinated conjugates of PR accumulated in cells. Ligand-dependent PR degradation was also blocked by specific inhibition of p42 and p44 MAPKs. To define the targets of phosphorylation by this kinase, two serine/proline MAPK consensus sites on PR were mutated. We demonstrate that mutation of PR serine-294 to alanine (S294A) specifically and completely prevents ligand-dependent receptor down-regulation. We also find that rapid, ligand-independent degradation of immature PR intermediates occurs by a proteasome-mediated pathway. These results demonstrate that PR destruction, by either of two alternate routes, is mediated by the 26S proteasome. Specifically, down-regulation of mature PRs occurs by a mechanism in which ligand binding activates PR phosphorylation by MAPKs at a unique serine residue, which then targets the receptors for degradation.
Ascorbic acid acts as an inhibitory transmitter in the hypothalamus to inhibit stimulated luteinizing hormone-releasing hormone release by scavenging nitric oxide
Authors: Karanth Sharada , Yu Wen H. , Walczewska Anna , Mastronardi Claudio , McCann Samuel M.
Published: July 2002

Because ascorbic acid (AA) is concentrated in synaptic vesicles containing glutamic acid, we hypothesized that AA might act as a neurotransmitter. Because AA is an antioxidant, it might therefore inhibit nitric oxidergic (NOergic) activation of luteinizing hormone-releasing hormone (LH-RH) release from medial basal hypothalamic explants by chemically reducing NO. Cell membrane depolarization induced by increased potassium concentration [K
+
] increased medium concentrations of both AA and LH-RH. An inhibitor of NO synthase (NOS),
N
G
-monomethyl-
l
-arginine (NMMA), prevented the increase in medium concentrations of AA and LH-RH induced by high [K
+
], suggesting that NO mediates release of both AA and LH-RH. Calcium-free medium blocked not only the increase in AA in the medium but also the release of LH-RH. Sodium nitroprusside, which releases NO, stimulated LH-RH release and decreased the concentration of AA in the incubation medium, presumably because the NO released oxidized AA to dehydro-AA. AA (10
−5
to 10
−3
M) had no effect on basal LH-RH release but completely blocked high [K
+
]- and nitroprusside-induced LH-RH release.
N
-Methyl-
d
-aspartic acid (NMDA), which mimics the action of the excitatory amino acid neurotransmitter glutamic acid, releases LH-RH by releasing NO. AA (10
−5
to 10
−3
M) inhibited the LH-RH-releasing action of NMDA. AA may be an inhibitory neurotransmitter that blocks NOergic stimulation of LH-RH release by chemically reducing the NO released by the NOergic neurons.
Cost-benefit analysis potential in feeding behavior of a predatory snail by integration of hunger, taste, and pain
Authors: Gillette Rhanor , Huang Rong-Chi , Hatcher Nathan , Moroz Leonid L.
Published: July 2002

Hunger/satiation state interacts with appetitive and noxious stimuli to determine feeding and avoidance responses. In the predatory marine snail
Pleurobranchaea californica
, food chemostimuli induced proboscis extension and biting at concentration thresholds that varied directly with satiation state. However, food stimuli also tended to elicit avoidance behavior (withdrawal and avoidance turns) at concentration thresholds that were relatively low and fixed. When the feeding threshold for active feeding (proboscis extension with biting) was exceeded, ongoing avoidance and locomotion were interrupted and suppressed. Noxious chemostimuli usually stimulated avoidance, but, in animals with lower feeding thresholds for food stimuli, they often elicited feeding behavior. Thus, sensory pathways mediating appetitive and noxious stimuli may have dual access to neural networks of feeding and avoidance behavior, but their final effects are regulated by satiation state. These observations suggest that a simple cost-benefit computation regulates behavioral switching in the animal's foraging behavior, where food stimuli above or below the incentive level for feeding tend to induce feeding or avoidance, respectively. This decision mechanism can weigh the animal's need for nutrients against the potential risk from other predators and the cost of relative energy outlay in an attack on prey. Stimulation of orienting and attack by low-level noxious stimuli in the hungriest animals may reflect risk-taking that can enhance prey capture success. A simple, hedonically structured neural network model captures this computation.
The new animal phylogeny: Reliability and implications
Authors: Adoutte André , Balavoine Guillaume , Lartillot Nicolas , Lespinet Olivier , Prud'homme Benjamin , de Rosa Renaud
Published: July 2002

DNA sequence analysis dictates new interpretation of phylogenic
trees. Taxa that were once thought to represent successive grades of
complexity at the base of the metazoan tree are being displaced to much
higher positions inside the tree. This leaves no evolutionary
“intermediates” and forces us to rethink the genesis of
bilaterian complexity.
Distinct role of gp130 activation in promoting self-renewal divisions by mitogenically stimulated murine hematopoietic stem cells
Authors: Audet Julie , Miller Cindy L. , Rose-John Stefan , Piret James M. , Eaves Connie J.
Published: July 2002

Previous studies have demonstrated hematopoietic stem cell amplificationin vitroafter the activation of three cell-surface receptors: flt3/flk2, c-kit, and gp130. We now show flt3-ligand and Steel factor alone will stimulate >85% of c-kit+Sca-1+lin−adult mouse bone marrow cells to proliferate in single-cell serum-free cultures, but concomitant retention of their stem cell activity requires additional exposure to a ligand that will activate gp130. Moreover, this response is restricted to a narrow range of gp130-activating ligand concentrations, above and below which hematopoietic stem cell activity is lost. These findings indicate a unique contribution of gp130 signaling to the maintenance of hematopoietic stem cell function when these cells are stimulated to divide with additional differential effects dictated by the intensity of gp130 activation.
Deception in Intimate Relationships
Authors: Peterson Candida
Published: July 2002

This study examined the use of deceptive communication in intimate couple relationships. A total of 80 romantically involved male and female Australian university students read and responded to scenarios depicting men and women perpetrating deceit in couple relationships. Six types of deception were examined, namely: omission, distortion, half‐truths, blatant lies, white lies, and failed lies. Respondents rated their own and their partners' use of each type of deception in terms of frequency, morality, and relationship effects. Self‐reports of satisfaction with the couple relationship were also obtained. Results indicated that each deceptive strategy apart from the white lie was judged as morally reprehensible on dimensions of blame, guilt, and dishonesty. Respondents used white lies most often, and blatant lies least often, and perceived their partners as behaving similarly. Diminished relationship satisfaction was associated with respondents' frequent use of strategies of blatant lying, partial truthfulness, and attempted deceit and with partners' frequent use of each type of deception apart from the white lie. Frequent use of deception by self and partner was correlated with believing that each type of deception was preferable to having an argument, supporting the suggestion from previous research that couples elect dishonesty as a method of conflict avoidance. However, the strength of a respondent's preference for deception rather than arguing did not independently predict satisfaction once the effects of frequent use of the six deception strategies by self and partner were taken into account.
The Microanalysis of Memory Span and Its Development in Childhood
Authors: Cowan Nelson , Saults J. Scott , Nugent Lara D. , Elliott Emily M.
Published: July 2002

It is not clear from the literature why, as children develop, there are important increases in memory span, the number of just‐presented items that the participant can repeat in the correct serial order. To understand this, some recent results on capacity limits and processing rates were re‐analyzed. We first describe results using a conventional measure of performance in immediate memory tasks that is affected by the list length (proportion correct). Next we describe results using a less conventional measure (number correct) that is unaffected by list length under circumstances in which attention to the list during its presentation is curtailed. This measure can estimate an individual's limited‐capacity storage ability. Last, we examine measures of spoken response timing that do and do not change with list length. We show that unconventional measures that do not change with list length, but do change with development, are especially useful in assessing basic changes in information processing parameters, including increases in memory capacity and processing speed.
Current Trends in Education in Russia: Preliminary Outcomes Indicative of Students' Cognitive Development
Authors: Grigorenko Elena L.
Published: July 2002

Using a sample school population (N = 333) in Voronezh, Russia, this study investigated the comparative effect of two different types of Russian public schooling—traditional and innovative—on students' analytical, creative, and practical abilities. These abilities were assessed through (1) ratings by parents and teachers and (2) student performances on tests and other evaluative exercises, as well as student self‐reports. The study found that innovative schools appear to do a better job of developing students' cognitive abilities (analytical, creative, and practical) than do more traditional institutions; in particular, the innovative schools significantly enhanced students' creative abilities. This study begins to illuminate the impact of massive societal change, and accompanying educational responses, on the cognitive development of Russian youth.
'Urban Bias', the Political Economy of Development and Urban Policies for Developing Countries
Authors: Pugh Cedric
Published: July 2002

Theories of urban overdevelopment and 'urban bias' have a long, but discontinuous history, dating from the 1920s when policy-makers in the former Soviet Union considered urban-rural sectoral balance in planned economic development. The idea of urban bias has had continuing relevance in macroeconomic and trade policies (especially in many developing countries) since the 1960s. Although theories of urban-rural economic balance and urban bias have fundamental significance for urban economic development, much of the relevance is either unacknowledged or misunderstood. However, it is appropriate to review the circumstances of the theory of urban bias from the perspective of the 1990s. The results of some modern research shed light on the outstanding issues from past controversies; in the context of developing countries, the World Bank and other leading policy-makers have been advocating a closer relationship between macroeconomic and urban policy development; and economic policies for structural adjustment have been indirectly removing some of the structures which supported the political economy of urban bias. Thus, even if urban bias and urban overdevelopment have some arcane elements in their history and their association with development economics, the subject has importance in post-1990 contexts. This article gives an exposition, an interpretation and a review of the relationships between urban bias, the political economy of development and urban processes and policies for developing countries.
Age and Experiential Differences in Strategy Generation and Information Requests for Solving Everyday Problems
Authors: Berg Cynthia A. , Meegan Sean P. , Klaczynski Paul
Published: July 2002

The role of experience in understanding age differences in strategy generation and information requests for solving everyday problems was explored in young and older adults. Participants received three hypothetical problems dealing with going to doctor’s offices and going to dinner parties and were probed extensively for their strategies and information they would like to solve the problems. Experience with these two domains was assessed by participants’ reports of their experience, script knowledge, and the presence of experience in problem definitions. No age differences were found in these experience measures. Age differences were found in the number of strategies generated and the amount of information requested to solve the problem. Two patterns of everyday problem solving were uncovered: an exhaustive style (involving inferential problem definition, elaborate strategy generation, and information requests); and an experiential style (involving experiential problem definition, less strategy generation, and fewer information requests). The results are interpreted within a model that uses individuals’ problem definitions to understand multiple aspects of everyday problem-solving performance.
Towards Modelling the Effects of National Culture on it Implementation and Acceptance
Authors: Veiga John F. , Floyd Steven , Dechant Kathleen
Published: July 2002

Two of the most significant forces shaping organizations are globalization and the continued, rapid and, some would say, radical changes taking place in information technology (IT). To date, the extant literature has centred on the technology acceptance model (TAM) because it is arguably one of the most widely cited and influential models used for explaining the acceptance of IT. However, this literature has remained relatively silent with respect to the role that differences in national culture might play in IT acceptance as globalization continues. In order to begin to address this deficit, this paper offers a series of research propositions that explore the potential impact of differences in national culture on IT implementation and acceptance. Specifically, the paper explores the effects of culturally induced beliefs – including individualism-collectivism, uncertainty avoidance, long-/short-term orientation and power distance – on the implementation processes that impact on key variables in the TAM. The paper then discusses the potential importance of the revisions it has made for both researchers interested in employing the model for predicting IT acceptance in cross-cultural contexts and for managers faced with introducing new IT in a global organization.
Australian Universities in Crisis
Authors: Maddox Graham
Published: July 2002

That this book, having been recommended for publication by the editors of Melbourne University Press, was subsequently rejected through the intervention of the University authorities, is a symptom of the very malaise which the contributors address. Since the Dawkins 'reforms' to Australian higher education the university system has come under increasing surveillance by government functionaries, and university 'managements' have been subverted through their desire to win favour from government and to display their 'competitive edge' against other 'institutions'. The 'reforms' have mandated the wholesale introduction of business techniques, and a pervading business ethos, which is quite inappropriate to the traditional function of universities. The very word 'traditional' is rejected as contrary to the commitment to change required of expanding businesses. That universities have a role in conserving and transmitting a public culture is all but repudiated by university managements in their desire to appear at the 'cutting edge' of government privatization agenda. The authors of this book affirm a public role for universities, and reassert the conviction that they must protect a threatened independence in the search for truth, and in the responsibility to 'speak truth to power'. Since 'managements' are now unlikely to uphold these duties, it becomes the responsibility of the members of the community of scholars to maintain independence of thought and to expound the truth.
Asia's Leap into E-commerce: Analysis of Developments in Some Countries
Authors: Bajaj Kamlesh K.
Published: July 2002

The Internet is creating a global digital economy with new opportunities. Developing countries have to catch up with the developed world by establishing the required information infrastructure to overcome the dangers of isolation and polarisation. The growth path is through the development of IT industries and greater application of IT in society. These IT industries must be compatible with local conditions and conducive to industrialisation.
Neurological aspects of opium addiction in imprisoned women
Authors: TAITSLIN V. I. , MATUZOK E. G.
Published: July 2002

The study covered 52 women, aged 19–30 years, who had previously taken home‐made poppy preparations. In seven of them we diagnosed opium use (F 11.11 according to ICD‐10) and 45 had opium abuse (F 11.21). All were detained in penitentiaries for 2–23 months. The control group consisted of 20 healthy females. A significant frequency of brain stem and extrapyramidal disturbances was found in the opium abuse group. Brain stem signs included tendon anisoreflexia (100–2%), nystagmus (87 5%), ataxia (87 5%) and corneal hyporeflexia (48 7%). Among the most frequent extrapyramidal disturbances were a positive pushing test (90 4%); test with pendular swinging of the legs (85 5%) and hand tremor (82 7%). Statistical analysis revealed a relationship between the degree of extrapyramidal system damage and duration of opiate dependence.
Quality of life measures in alcohol dependent subjects and changes with abstinence and continued heavy drinking
Authors: FOSTER J. H. , MARSHALL E. J. , HOOPER R. , PETERS T. J.
Published: July 2002

This study evaluates the quality of life status of 39 male and 21 female Caucasian subjects admitted to a voluntary sector community alcohol detoxification unit. Baseline data including socio‐demographics, severity of alcohol dependence and alcohol problems were collected 4–5 days following admission. In addition, the following measures were obtained: Rotterdam Symptoms Checklist, the Beck Depression Inventory, the General Health Questionnaire 12, Chubon's Life Situation Survey and the Nottingham Health Profile. Subjects were followed up at 12 weeks, and subdivided into two groups: relapsers and non‐relapsers. A relapse was defined as drinking 21 or more units per week for men and 14 units or more per week for women over 7 consecutive days (1 unit is the equivalent of 8–10 g of absolute ethanol). Fifty‐eight (97%) subjects were successfully followed‐up, with 36 (62%) of the group relapsing to heavy drinking within 12 weeks. The results show that alcohol dependence is associated with a poor quality of life. Subjects rated poorly on the standardized questionnaires compared with the normative values for their reference populations. Relapsers and non‐relapsers differed significantly in their life situation, depression, physical and psychological symptom total scores and the Nottingham Health Profile sub‐score energy at 12 weeks compared with baseline, and these changes were investigated for each group. Within the relapse group a linear regression showed no association between any of the quality of life measures and time to relapse. Individual sub‐score analysis of the Nottingham Health Profile results point to the importance of sleep, social isolation, pain, physical mobility and anergia in alcohol dependency. There was little change as a result of either not remitting or returning to heavy drinking and overall these findings confirm that alcohol dependent subjects have a poor quality of life.
Book and Media Reviews
Authors: COOK CHRIS
Published: July 2002

Books reviewed in this article:

Book reviews in this column will primarily be of titles focusing completely, or in part, on biological aspects of addiction. However, significant titles of general relevance to the addictions field will also be included, even if they are not “biological”, as will titles of general methodological and clinical relevance, even if they are not on “addictions”. Similar considerations will apply to other media (software, audio tapes and CDs, videos, etc). However, specific “addictions” software applications seem to be relatively uncommon and, as these items are rarely reviewed elsewhere, we will endeavour to include reviews of some of the older programmes that are still useful, as well as new titles that appear. I would appreciate suggestions of any items suitable for reviews, but especially software and other media of specific relevance to the addictions. Please contact: Professor Chris Cook, Kent Institute of Medicine and Health Sciences, University of Kent at Canterbury, Kent CT2 7NR, UK. Email: c.c.h.cook@ukc.ac.uk

Alcohol Misuse: A European Perspective TIMOTHY J. PETERS (Ed.)

Harrison's Principles of Internal Medicine A. S. FAUCI, E. BRAUNWALD, K. J. ISSEL‐BACHER et al.

Understanding Accreditation in Laboratory Medicine (Management and Technology in Laboratory Medicine) DAVID BURNETT

A Sceptic's Medical Dictionary MICHAEL O'DONNELL

Aliens and Alienists: Ethnic Minorities and Psychiatry, 3rd edition R. LITTLEWOOD & M. LIPSEDGE

Cambridge Handbook of Psychology, Health and Medicine ANDREW BAUM, STANTON NEWMAN, JOHN WEINMAN, CHRIS MCMANUS & ROBERT WEST (Eds)

Software
 
‘Electronic dtb/eBNF’ UK, CD‐ROM Drug and Therapeutics Bulletin January 1993–September 1997/British National Formulary No. 34 September 1997