bluuebunny/crossref_metadata_2025 huggingface dataset:
The management of organic acidaemias: The role of transplantation
Authors: Leonard J. V. , Walter J. H. , McKiernan P. J.
Published: December 2002

This workshop addressed the issue of treatment in propionic acid‐aemia (PA) and methylmalonic acidaemia (MMA) and in particular the outcome of conventional management compared with organ transplantation. Although it appears that with medical treatment the mortality for early‐onset disease has improved, long‐term outcome remains poor. However, liver and liver/kidney transplantation is associated with a high perioperative mortality and long‐term complications. It offers only a partial cure. The indications for transplantation remain unclear. It is recommended that a register of PA and MMA patients should be established.
Psychosocial Outcomes of Urban African American Adolescents Born to Teenage Mothers
Authors: Zimmerman Marc A. , Tuttle Lisa , Kieffer Edie , Parker Edith , Caldwell Cleopatra H. , Maton Kenneth I.
Published: December 2002

This is a study of psychosocial outcomes of adolescents born to teenage mothers. Adolescents' problem behaviors, psychological well‐being, social support, school variables, and sexual behaviors are compared across three groups—those born to mothers 17 or younger, mothers 18–19 years old, and mothers 20 or older. Analyses from two samples of African American adolescents from Maryland (n = 205) and Michigan (n = 570) are reported. The results from both samples indicate that mother's age at birth is unrelated to adolescents' psychosocial outcomes. These two studies add to the limited number of analyses that examine adolescent outcomes for children of teen mothers. The results suggest that efforts to understand social structural determinants of healthy and problematic adolescent development may be more informative than examining the effects of mother's age. They also suggest that teen pregnancy prevention programs may be more effective if they are part of a larger prevention strategy that incorporates social structural change efforts and not only a focus on individual level change.
Cross-Linking Study of Cytochrome P450 1A2 in Proteoliposomes
Authors: Myasoedova Ksenia N. , Magretova Natalia N.
Published: December 2002

Proteoliposomes, containing cytochrome P450 1A2, were obtained by the cholate-dialysis technique. The effect of bifunctional cross-linking reagents on the purified hexameric cytochrome P450 1A2 in an aqueous medium and on the proteoliposomal P450 1A2 have been compared. Electrophoretic analysis of the modified proteins demonstrated the same oligomeric (hexameric) organization of the hemoprotein in each case.
Factor V Leiden mutation in Turkish patients with homozygous cystathionine β‐synthase deficiency
Authors: Kalkanoğlu H. S. , Coşkun T. , Aydoğdu S. D. , Tokatli A. , Gürgey A.
Published: December 2002

Venous and arterial thromboembolism can occur in patients with homocystinuria. Resistance to activated protein C, which is caused by a single point mutation in the gene for factor V, renders an individual at risk for thrombosis. It has been suggested that coexistence of hereditary homocystinuria and factor V Leiden mutation might jointly play a role in the development of thrombosis. We analysed six patients with homocystinuria due to cystathionine β‐synthase deficiency for factor V Leiden and prothrombin G20210A mutations. Only one patient was found to have the factor V Leiden mutation in homozygous form and this patient had suffered from severe thrombosis. One patient was found to be heterozygous with no documented thrombosis. None of the patients had prothrombin G20210A mutation. We stress the necessity for screening for known thrombophilic risk factors in patients with cystathonine β‐synthase deficiency. The coexistence of the factor V Leiden mutation can cause severe thrombotic events in patients with homocystinuria.
Hardiness: An examination of its relationship with positive and negative long term changes following trauma
Authors: Waysman Mark , Schwarzwald Joseph , Solomon Zahava
Published: December 2002

Two models positing direct versus moderating effects of hardiness were examined in relation to long term positive and negative changes following exposure to traumatic stress. Participating in the study were 164 Israeli POWs and a matched group of 184 veterans of the 1973 Yom Kippur War. Participants completed a battery of questionnaires that included the Personal Views Survey (hardiness); the Trait, Attitude, and Behavior Change questionnaire; and questions related to their captivity/war experiences. Findings were consistent with a model that posits moderating effects of hardiness on both long term negative and positive changes. The discussion addresses the possible role of hardiness in relation to negative and positive outcomes of traumatic events.
A brief report on the Penn Inventory for posttraumatic stress disorder
Authors: Scragg Peter , Grey Nick , Lee Deborah , Young Kerry , Turner Stuart
Published: December 2002

In this report we provide normative data for the Penn Inventory for posttraumatic stress disorder for men and women who were referred to a specialist outpatient clinic following a range of traumatic events. Data are provided from clinical assessment of 80 people. There was no significant difference between male and female scores. Using the Clinician Administered PTSD Scale to ascertain diagnostic status and Hammarberg's cut‐off criterion of 35, the Penn Inventory showed a sensitivity of .90 for male participants and .89 for female participants and a specificity of .55 for male participants and .67 for female participants. The Penn Inventory correlated highly with other measures of psychological distress. We discuss that the Penn Inventory may be best used as a screening instrument or measure of change of general mental well‐being after trauma, rather than a diagnostic tool for specific traumatic stress symptoms.
Role of major lifetime stressors in patients' and spouses' reactions to cancer
Authors: Silver‐Aylaian Michele , Cohen Lawrence H.
Published: December 2002

This study examined the role of number of major lifetime stressors (e.g., rape, abuse), and the perceived resolution of those stressors, in cancer patients' (n = 54) and spouses' (n = 30) appraisals and current mood. We hypothesized that a high number of lifetime stressors, and low resolution ratings, would be associated with more distress and more negative appraisals of the cancer. Hierarchical regression analyses showed that number of lifetime stressors was a positive predictor of patients' ratings of the cancer's threat, and a positive predictor of their spouses' anger. Mean resolution ratings were a significant positive predictor of spouses' positive affect. The findings suggest that experience with previous stressors affects an individual's reactions to cancer.
A study of the validity of a Screening Instrument for Traumatic Stress in Earthquake Survivors in Turkey
Authors: Başloǧlu Metin , Şalcioǧlu Ebru , Livanou Maria , Özeren Melih , Aker Tamer , Kihç Cengiz , Mestçioǧlu Özlem
Published: December 2002

The validity of a Traumatic Stress Symptom Checklist (TSSC), which was developed as part of a Screening Instrument for Traumatic Stress in Earthquake Survivors (SITSES), was examined in 130 survivors of the recent earthquake in Turkey. Data were obtained on the TSSC, which consists of 17 DSM‐IV posttraumatic stress disorder (PTSD) items and 6 symptoms of depression. The Clinician‐Administered PTSD Scale and the Major Depressive Episode module of the Semistructured Clinical Interview for DSM‐IV were used for comparison with the TSSC. The results indicated that the TSSC has high internal consistency and satisfactory sensitivity and specificity in predicting the diagnosis of PTSD and major depression. The SITSES appeared to be a useful instrument in screening earthquake survivors for PTSD, major depression, illness severity, and risk factors associated with traumatic stress responses.
Multivariate prediction of posttraumatic symptoms in psychiatric inpatients
Authors: Carlson Eve B. , Dalenberg Constance , Armstrong Judith , Daniels Jill Walker , Loewenstein Richard , Roth David
Published: December 2002

Based on a conceptual framework for the long‐term effects of childhood abuse, this study examined the capacity of childhood family environment (caretaker dysfunction, neglect, perceived social support), violent abuse (physical and sexual), and individual variables (other abuse) to predict adult psychiatric symptoms of PTSD, dissociation, and depression. Complete interview data were obtained from 178 psychiatric inpatients who varied greatly on abuse status and severity. Results of multiple regressions of predictor variables onto the three outcome variables showed that the predictor variables accounted for 15% (for depression) to 42% (for PTSD) of the variance in these symptoms and that violent abuse uniquely accounted for a significant proportion of the variance in outcomes for all three of the symptom groups studied.
Information processing of an acquaintance rape scenario among high‐ and low‐dissociating college women
Authors: Sandberg David A. , Lynn Steven Jay , Matorin Abigail I.
Published: December 2002

To assess the impact of dissociation on information processing, 66 college women with high and low levels of trait dissociation were studied with regard to how they unitized videotape segments of an acquaintance rape scenario (actual assault not shown) and a nonthreatening control scenario. Unitization is a paradigm that measures how actively people process stimuli by recording how many times they press a button to indicate that they have seen a significant or meaningful event. Trait dissociation was negatively correlated with participants' unitization of the acquaintance rape videotape, unitization was positively correlated with danger cue identification, and state dissociation was negatively correlated with dangerousness ratings.
Multivariate assessment of explicit memory function in combat veterans with posttraumatic stress disorder
Authors: Gilbertson Mark W. , Gurvits Tamara V. , Lasko Natasha B. , Orr Scott P. , Pitman Roger K.
Published: December 2002

Declarative memory impairment is a frequent complaint of patients suffering from posttraumatic stress disorder (PTSD). We assessed memory, attention, visual spatial skills, and executive function in Vietnam combat veterans with (n = 19) and without (n = 13) PTSD. Although PTSD subjects demonstrated a “generalized impairment” relative to non‐PTSD subjects on a majority of tasks, only attention and memory provided unique and independent prediction of PTSD versus non‐PTSD status. Our findings suggest that memory functioning represents a neurocognitive domain of specific relevance to the development of PTSD in trauma‐exposed individuals, which can be distinguished from generalized attentional impairment as well as the effects of trauma exposure severity, IQ, comorbid depression, history of alcohol use, and history of developmental learning problems.
Controllability of Matrix Differential Equations Related to Lie Algebra Actions
Authors: Przybylska Maria
Published: December 2002

We investigate the problem of controllability of a certain class of matrix differential equations. All elements from this class can be written by means of particular actions of a Lie algebra on a matrix differential manifold.
Dissipation and Conditions of Equilibrium for an Open Microeconomic System
Authors: Tsirlin Anatolii , Amelkin Sergey
Published: December 2002

An analogy between microeconomic and irreversible thermodynamic systems is shown. The concepts of economic irreversibility, dissipation of capital are introduced and conditions of minimal dissipation are obtained. Problems of optimal control of prices in the processes of resources exchange are solved and the extremal principle for the determination of stationary state of an open microeconomic system is formulated.
Can Information Measure be One of Markers to Estimate Disease Progression in HIV-1-Infected Patients?
Authors: Sato Keiko , Ohya Masanori
Published: December 2002

To estimate prognosis in patients with human immunodeficiency virus type 1 (HIV-1) infection, we analyzed sequences of V3 region obtained at several points in time following seroconversion of each patient by means of a genetic measure called the entropy evolution rate. Phylogenetic analysis with the entropy evolution rate indicated that sequences in V3 are classified according to disease progression. The branch lengths tend to be longer as disease progressed, from the asymptomatic stage of infection to the symptomatic stage. The branch lengths tend to be longer as disease progressed, from the asymptomatic stage of infection to the symptomatic stage. Viral sequences of each patient who did not develop AIDS during follow up were closely related to each other throughout all time points, and those branch lengths were relatively short. That is, the branch lengths reflected disease progression. Our results indicated that the entropy evolution rate can be one of surrogate the markers to estimate the stage of disease.
Is genotype determination useful in predicting the clinical phenotype in lysosomal storage diseases?
Authors: Maire I.
Published: December 2002

Understanding the relationship between genotype and clinical phenotype will clearly aid in the prognosis, treatment and counselling of patients with lysosomal storage diseases (LSDs). This, however, will require the establishment of widely accepted indices with which to score the severity of LSDs, as these diseases are characterized by their marked clinical heterogeneity. Even in the complete absence of a functional enzyme, presentation may be variable, depending on the patient's genetic background and on a range of epigenetic and environmental factors. Further difficulties in predicting disease severity and progression from the genotype arise from the rarity of these disorders, the low enzyme levels required for a normal phenotype and the relative lack of understanding of the pathophysiology of LSDs.
IGF‐1 and bFGF reduce glutaric acid and 3‐hydroxyglutaric acid toxicity in striatal cultures
Authors: Bjugstad K. B. , Zawada W. M. , Goodman S. I. , Freed C. R.
Published: December 2002

Glutaric acid (GA) and 3‐hydroxyglutaric acid (3GA) are thought to contribute to the degeneration of the caudate and putamen that is seen in some children with glutaric acidaemia type I, a metabolic disorder caused by a glutaryl‐CoA dehydrogenase deficiency. This study assessed the neurotoxicity of GA and 3GA (0–50 mmol/L) compared to quinolinic acid (QUIN) in striatal and cortical cultures. All three acids were neurotoxic in a dose‐dependent manner; however, GA and 3GA were both more toxic than QUIN. The neurotoxic effects of low concentrations of GA or 3GA were additive to QUIN toxicity. A series of hormones and growth factors were tested for protection against GA and 3GA toxicity. Insulin (5–500 μU/ml), basic fibroblast growth factor (bFGF; 10 ng/ml), insulin‐like growth factor (IGF‐1; 50 ng/ml), brain‐derived neurotrophic factor (BDNF; 10 ng/ml), glial‐derived neurotrophic factor (GDNF; 10 ng/ml), and two glutamate antagonists were evaluated in brain cultures to which 7 mmol/L GA or 3GA were added. GA and 3GA neurotoxicities were prevented by bFGF. Attenuation of 3GA‐induced neurotoxicity was seen with insulin (5 μU/ml) and IGF‐1. BDNF and GDNF had no effects on neuronal survival. Glutamate antagonists MK801 (10 μmol/L) and NBQX (10 μmol/L) failed to prevent GA or 3GA neurotoxicity. We conclude that GA and 3GA are neurotoxic in cultures of embryonic rat striatum and cortex. Striatal neurons were rescued from death by bFGF and IGF‐1 but not by glutamate antagonist, suggesting that toxicity in this embryonic system is not necessarily mediated by glutamate receptors.
Detection of β‐ureidopropionase deficiency with HPLC–electrospray tandem mass spectrometry and confirmation of the defect at the enzyme level
Authors: Van Kuilenburg A. B. P. , Van Lenthe H. , Assmann B. , Göhlich‐Ratmann G. , Hoffmann G. F. , Bräutigam C. , Wevers R. A. , Van Gennip A. H.
Published: December 2002

The pyrimidine bases uracil and thymine are degraded via the consecutive action of three enzymes to β‐alanine and β‐aminoisobutyric acid, respectively. To date, a number of patients have been described with a deficiency of dihydropyrimidine dehydrogenase and dihydropyrimidinase, the first two enzymes of the pyrimidine degradation pathway. In this study, we demonstrate that the first patient presenting with N‐carbamyl‐β‐amino aciduria, due to a deficiency of β‐ureidopropionase, was easily diagnosed at the metabolite level using HPLC–tandem mass spectrometry. Urinary analysis showed strongly elevated levels of N‐carbamyl‐β‐alanine and N‐carbamyl‐β‐aminoisobutyric acid, with normal or moderately increased levels of the pyrimidine bases and the dihydropyrimidines, respectively. The deficiency of β‐ureidopropionase was confirmed by measuring all three enzymes of the pyrimidine degradation pathway. No activity of β‐ureidopropionase could be detected in a liver biopsy of the patient, while a normal activity of dihydropyrimidine dehydrogenase and dihydropyrimidinase was present. Thus, HPLC–tandem mass specrometry proved to be a powerful tool for the initial diagnosis of patients with deficiency of β‐ureidopropionase.
Cognitive functioning and the early development of PTSD
Authors: Bustamante Victoria , Mellman Thomas A. , David Daniella , Fins Ana I.
Published: December 2002

Cross‐sectional studies of chronic PTSD reveal deficits in verbal memory. We studied cognitive functioning and its relationship to current and subsequent PTSD severity during an early phase of trauma response. Thirty‐eight participants with traumatic injuries and only posttrauma incident psychopathology were evaluated shortly after admission to a Level I Trauma Center. Neuropsychological measures were obtained at baseline and assessment of PTSD and other psychiatric disorders was conducted at baseline and follow‐up, 6 weeks later. Significant negative correlations were found for follow‐up PTSD severity with delayed recall and retroactive interference. These relationships were not significant for, and were independent of, baseline PTSD severity. Relative deficits in select areas of verbal memory after a trauma may confer greater risk for developing PTSD.
The long‐term mental health consequences of child sexual abuse: An exploratory study of the impact of multiple traumas in a sample of women
Authors: Banyard Victoria L. , Williams Linda M. , Siegel Jane A.
Published: December 2002

The current study examined exposure to multiple traumas as mediators of the relationship between childhood sexual abuse and negative adult mental health outcomes. Participants were 174 women interviewed in the third wave of a longitudinal study of the consequences of child sexual abuse. Child sexual abuse victims reported a lifetime history of more exposure to various traumas and higher levels of mental health symptoms. Exposure to traumas in both childhood and adulthood other than child sexual abuse mediated the relationship between child sexual abuse and psychological distress in adulthood. There were also some significant direct effects for child sexual abuse on some outcome measures. Results point to the importance of understanding the interconnected nature of trauma exposure for some survivors.
Real-Time Measurement of Intracellular Reactive Oxygen Species Using Mito Tracker Orange (CMH2TMRos)
Authors: Kweon Soo-Mi , Kim Hyun-Jung , Lee Zee-Won , Kim Soo-Jung , Kim Seung-IL , Paik Sang-Gi , Ha Kwon-Soo
Published: December 2002

We have investigated a novel method to monitor real changes of intracellular ROS by the use of CMH2TMRos (a reduced form of MitoTracker orange) in Swiss 3T3 fibroblasts. Arachidonic acid induced a rapid increase of CMTMRos fluorescence with a maximal elevation at 120–150 sec, which was determined by scanning every 10 sec with a confocal microscope. The fluorescence increase by arachidonic acid was completely inhibited by 2-MPG but not by catalase, indicating a major contribution of superoxide to the oxidation of CMH2TMRos. Incubation with glucose oxidase, exogenous H2O2, KO2 and lysophosphatidic acid also increased the CMTMRos fluorescence, which was blocked by 2-MPG. These results suggested that CMH2TMRos is a useful fluorophore for real-time monitoring of intracellular ROS and also indicated that CMH2TMRos detects primarily superoxide in cells even though the fluorophore can be oxidized by both superoxide and H2O2.
Possible Basic and Specific Functions of Plant Uncoupling Proteins (pUCP)
Authors: Ježek Petr , Borecký Jirí , Zácková Markêta , Costa Alexandre D. T. , Arruda Paulo
Published: December 2002

Evidence has been provided that the plant uncoupling proteins (pUCP) play basic physiological roles similar to the other uncoupling protein subfamily members (mammalian UCP1,2,3,4 and BMCP) and are effective in the situations of slight uncoupling that leads to: (1) accelerated respiration and metabolic rates that are beneficial to plant growth and development; (2) decreased formation of reactive oxygen species in mitochondria; and, (3) mild thermogenesis, inevitably accompanying the previous two phenomena. Hypothetically, specific physiological roles of pUCP such as cut off of ATP synthesis could be manifested in connection with climacteric respiratory rise during fruit ripening, seed dormancy, and plant senescence. pUCP might also facilitate growth under low temperatures, e.g., during seed germination or in roots. The existence of these specific roles is suggested by the immunochemical and functional localization of pUCP in mitochondria of fruits, seeds and roots of various plant species.
Representing High-Dimensional Data Sets as Closed Surfaces
Authors: Sangole Archana , Knopf George K.
Published: December 2002

Scientific data visualization provides scientists and engineers with a deeper insight and greater understanding about physical phenomena through the use of graphical tools. Individuals are able to identify patterns embedded in data sets using visual cues such as color and shape, rather than directly searching through a vast volume of numbers. The visualization algorithm described in this paper utilizes a spherical self-organizing feature map (SOFM) to automatically cluster and develop a well-defined topology of arbitrary data vectors, based on a pre-defined measure of similarity, and generate a three-dimensional color-coded surface model that reflects cluster variations. Implementation of this self-organizing surface geometry for data visualization applications is illustrated by examining the graphical forms created for a small synthetic test data set and a large environmental data-base. The proposed methodology provides the researcher with a new tool to encode information into shape and easily transfer the geometric model to an immersive virtual reality (IVR) environment for interactive information analysis.
Sensitivity Encoding to Support Information Space Navigation: A Design Guideline
Authors: Spence Robert
Published: December 2002

This article identifies, illustrates and offers justification for a guideline intended to support interaction design for navigation in electronic information spaces. The essence of the guideline is the concept of ‘sensitivity encoding', a feature of a data display intended to provide guidance regarding potentially beneficial movement in information space. That navigation's objective may be the formation of a mental model, movement towards an objective, or both.
A possible substrate for dopamine-related changes in mood and behavior: Prefrontal and limbic effects of a D3-preferring dopamine agonist
Authors: Black Kevin J. , Hershey Tamara , Koller Jonathan M. , Videen Tom O. , Mintun Mark A. , Price Joseph L. , Perlmutter Joel S.
Published: December 2002

Dopamine can induce fascinating, complex human behavioral states, including disinhibition, euphoria, or elaborate stereotypies, whereas dopamine deficiency can cause anxiety or sadness. Limited data suggest that these phenomena may involve dysfunction of orbital frontal cortex, cingulate cortex, or ventral striatum. The dopamine D3 receptor (D3R) has an anatomic distribution that suggests it could mediate these effects, but almost no data directly demonstrate the regional functional effects of D3R activation. We used quantitative positron emission tomography (PET), [15O]water, and the D3-preferring dopamine agonist pramipexole to identify D3-mediated regional cerebral blood flow (rCBF) responses in living primates. We studied seven normal baboons ventilated with 70% nitrous oxide, and analyzed results voxelwise in a common atlas space. At clinically relevant doses, pramipexole produced statistically robust decreases in rCBF in bilateral orbitofrontal cortex, thalamus, operculum, posterior and anterior (subgenual) cingulate cortex, and insula (in decreasing order of significance). Cortical areas related to movement were relatively unaffected, and rCBF did not change in cerebellum or visual cortex. The dose-response curve and duration of pramipexole's effects suggest that these rCBF responses indicate functional effects of a D3-preferring agonist. A D2-preferring agonist studied under the same conditions produced a quantitatively different pattern of responses. We conclude that a dopamine D3 receptor agonist preferentially affects brain activity in prefrontal and limbic cortex, and speculate that dopamine's effects on these regions via D3Rs may mediate some of the known psychiatric complications of dopamine deficiency or excess.
Hyperinsulinism induced by targeted suppression of beta cell K
ATP
channels
Authors: Koster J. C. , Remedi M. S. , Flagg T. P. , Johnson J. D. , Markova K. P. , Marshall B. A. , Nichols C. G.
Published: December 2002

ATP-sensitive K
+
(K
ATP
) channels couple cell metabolism to electrical activity. To probe the role of K
ATP
in glucose-induced insulin secretion, we have generated transgenic mice expressing a dominant-negative, GFP-tagged K
ATP
channel subunit in which residues 132–134 (Gly-Tyr-Gly) in the selectivity filter were replaced by Ala-Ala-Ala, under control of the insulin promoter. Transgene expression was confirmed by both beta cell-specific green fluorescence and complete suppression of channel activity in those cells (≈70%) that did fluoresce. Transgenic mice developed normally with no increased mortality and displayed normal body weight, blood glucose levels, and islet architecture. However, hyperinsulinism was evident in adult mice as (
i
) a disproportionately high level of circulating serum insulin for a given glucose concentration (≈2-fold increase in blood insulin), (
ii
) enhanced glucose-induced insulin release from isolated islets, and (
iii
) mild yet significant enhancement in glucose tolerance. Enhanced glucose-induced insulin secretion results from both increased glucose sensitivity and increased release at saturating glucose concentration. The results suggest that incomplete suppression of K
ATP
channel activity can give rise to a maintained
hyper
insulinism.
Analysis of chromosomal instability in human colorectal adenomas with two mutational hits at
APC
Authors: Sieber O. M. , Heinimann K. , Gorman P. , Lamlum H. , Crabtree M. , Simpson C. A. , Davies D. , Neale K. , Hodgson S. V. , Roylance R. R. , Phillips R. K. S. , Bodmer W. F. , Tomlinson I. P. M.
Published: December 2002

In vitro
data show that the adenomatous polyposis coli (APC) protein associates with the mitotic spindle and that mouse embryonic stem cells with biallelic
Apc
mutations are karyotypically unstable. These findings led to suggestions that APC acts in chromosomal segregation and that APC inactivation leads to chromosomal instability (CIN). An alternative hypothesis based on allelic loss studies in colorectal adenomas proposes that CIN precedes and contributes to genetic changes at
APC
. We determined whether colorectal adenomas with two mutations at
APC
show features consistent with these models by studying 55 lesions (average size 5 mm; range 1–13 mm) from patients with familial adenomatous polyposis. A variety of methods was used depending on available material, including flow cytometry, comparative genomic hybridization, and loss of heterozygosity (LOH) analysis. Selected adenomas were assessed for proliferative activity by Ki-67 immunocytochemistry. Seventeen of 20 (85%) tumors were diploid, two were near-diploid, and one was hypotetraploid. Just one (near-diploid) tumor showed increased proliferative activity. LOH was found occasionally on chromosome 15q (2 of 49 tumors), but not on chromosome 18q (0 of 48). In 20 adenomas, LOH at
APC
was associated with loss at 5q but not 5p markers, with the former encompassing a minimum of 20 Mb. However, three of these lesions analyzed by comparative genomic hybridization displayed normal profiles, suggesting, together with other data, that the mechanism of LOH at
APC
is probably somatic recombination. Our results therefore do not support the hypothesis that CIN precedes
APC
mutations in tumorigenesis. Regarding the model in which
APC
mutations lead directly to CIN, if
APC
mutations do have this effect
in vivo
, it must be subtle. Alternatively, CIN associated with
APC
mutations might be essentially an
in vitro
phenomenon.
Intrinsic susceptibility of mouse trophoblasts to natural killer cell-mediated attackinvivo
Authors: Erlebacher Adrian , Lukens Amanda K. , Glimcher Laurie H.
Published: December 2002

Protecting the fetus and placenta from the maternal immune system has long been considered a function of placental trophoblasts. Here, we present two related lines of evidence that contradict this assumption. First, we show that transformed mouse trophoblast cell lines akin to human choriocarcinomas form tumors in syngeneic and immunodeficient mice, yet are rejected in immunocompetent allogeneic mice. Second, we show that wild-type trophoblasts are rapidly killed after i.v. injection into allogeneic mice. In both cases, the pattern of trophoblast killing in different strains of immunodeficient mice indicated that rejection involved host natural killer cells, and this was corroborated byin vitrokilling assays. The apparent intrinsic susceptibility of mouse trophoblasts to immune attack strongly suggests that it is instead some property of the pregnant uterus that is of primary importance in preventing rejection of the fetus.
G
2
arrest in
Xenopus
oocytes depends on phosphorylation of cdc25 by protein kinase A
Authors: Duckworth Brian C. , Weaver Jennifer S. , Ruderman Joan V.
Published: December 2002

Xenopus
oocytes, which are arrested in G
2
of meiosis I, contain complexes of cyclin B–cdc2 (M phase-promoting factor) that are kept repressed by inhibitory phosphorylations on cdc2 at Thr-14 and Tyr-15. Progesterone induces a cytoplasmic signaling pathway that leads to activation of cdc25, the phosphatase that removes these phosphorylations, catalyzing entry into M phase. It has been known for 25 years that high levels of cAMP and protein kinase A (PKA) are required to maintain the G
2
arrest and that a drop in PKA activity is required for M phase-promoting factor activation, but no physiological targets of PKA have been identified. We present evidence that cdc25 is a critical target of PKA. (
i
)
In vitro
, cdc25 Ser-287 serves as a major site of phosphorylation by PKA, resulting in sequestration by 14-3-3. (
ii
) Endogenous cdc25 is phosphorylated on Ser-287 in oocytes and dephosphorylated in response to progesterone just before cdc2 dephosphorylation and M-phase entry. (
iii
) High PKA activity maintains phosphorylation of Ser-287
in vivo
, whereas inhibition of PKA by its heat-stable inhibitor (PKI) induces dephosphorylation of Ser-287. (
iv
) Overexpression of mutant cdc25 (S287A) bypasses the ability of PKA to maintain oocytes in G
2
arrest. These findings argue that cdc25 is a physiologically relevant target of PKA in oocytes. In the early embryonic cell cycles, Ser-287 is phosphorylated during interphase and dephosphorylated just before cdc2 activation and mitotic entry. Thus, in addition to its role in checkpoint arrest, cdc25 Ser-287 serves as a site for regulation during normal, unperturbed cell cycles.
Bacillus thuringiensis
-toxin resistance management: Stable isotope assessment of alternate host use by
Helicoverpa
zea
Authors: Gould F. , Blair N. , Reid M. , Rennie T. L. , Lopez J. , Micinski S.
Published: December 2002

Data have been lacking on the proportion of
Helicovera zea
larvae that develop on noncotton host plants that can serve as a refuge from selection pressure for adaptation to transgenic cotton varieties that produce a toxin from the bacterium
Bacillus thuringiensis
. We found that individual
H. zea
moths that develop as larvae on cotton and other plants with C
3
physiology have a different ratio of
13
C to
12
C than moths that develop on plants with C
4
physiology, such as corn. We used this finding in determining the minimum percentage of moths that developed on noncotton hosts in two cotton-growing areas. Our results indicate that local corn can serve as a refuge for
H. zea
in midsummer. Our results contrast dramatically with the prevailing hypothesis that the large majority of late-season moths are produced from larvae feeding on cotton, soybean, and other C
3
plants. Typically, <50% of moths captured in August through October have isotope ratios indicative of larval feeding on C
3
plants. In one October sample, 100% of the moths originated from C
4
hosts even though C
4
crops were harvested at least 1 mo earlier, and no common wild C
4
hosts were available. These findings support other research indicating that many late-season
H. zea
moths captured in Louisiana and Texas are migrants whose larvae developed on corn in more northern locations. Our isotope data on moths collected in Texas early in the season indicate that the majority of overwintering
H. zea
do not originate from cotton-feeding larvae and may be migrants from Mexico. Non-Bt corn in Mexico and the U.S. corn belt appears to serve as an important refuge for
H. zea
.
Neural correlates of perceptual learning: A functional MRI study of visual texture discrimination
Authors: Schwartz Sophie , Maquet Pierre , Frith Chris
Published: December 2002

Visual texture discrimination has been shown to induce long-lasting behavioral improvement restricted to the trained eye and trained location in visual field [Karni, A. & Sagi, D. (1991)
Proc. Natl. Acad. Sci. USA
88, 4966–4970]. We tested the hypothesis that such learning involves durable neural modifications at the earliest cortical stages of the visual system, where eye specificity, orientation, and location information are mapped with highest resolution. Using functional magnetic resonance imaging in humans, we measured neural activity 24 h after a single session of intensive monocular training on visual texture discrimination, performed in one visual quadrant. Within-subject comparisons between trained and untrained eye for targets presented within the same quadrant revealed higher activity in a corresponding retinotopic area of visual cortex. Functional connectivity analysis showed that these learning-dependent changes were not associated with an increased engagement of other brain areas remote from early visual cortex. We suggest that these new data are consistent with recent proposals that the cellular mechanisms underlying this type of perceptual learning may involve changes in local connections within primary visual cortex. Our findings provide a direct demonstration of learning-dependent reorganization at early processing stages in the visual cortex of adult humans.
Discovery of sulfated metabolites in mycobacteria with a genetic and mass spectrometric approach
Authors: Mougous Joseph D. , Leavell Michael D. , Senaratne Ryan H. , Leigh Clifton D. , Williams Spencer J. , Riley Lee W. , Leary Julie A. , Bertozzi Carolyn R.
Published: December 2002

The study of the metabolome presents numerous challenges, first among them being the cataloging of its constituents. A step in this direction will be the development of tools to identify metabolites that share common structural features. The importance of sulfated molecules in cell–cell communication motivated us to develop a rapid two-step method for identifying these metabolites in microorganisms, particularly in pathogenic mycobacteria. Sulfurcontaining molecules were initially identified by mass spectral analysis of cell extracts from bacteria labeled metabolically with a stable sulfur isotope (
34
SO

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). To differentiate sulfated from reduced-sulfur-containing molecules, we employed a mutant lacking the reductive branch of the sulfate assimilation pathway. In these sulfur auxotrophs, heavy sulfate is channeled exclusively into sulfated metabolites. The method was applied to the discovery of several new sulfated molecules in
Mycobacterium tuberculosis
and
Mycobacterium smegmatis
. Because a sulfur auxotrophic strain is the only requirement of the approach, many microorganisms can be studied in this manner. Such genetic engineering in combination with stable isotopic labeling can be applied to various metabolic pathways and their products.
Engineered calmodulins reveal the unexpected eminence of Ca
2+
channel inactivation in controlling heart excitation
Authors: Alseikhan Badr A. , DeMaria Carla D. , Colecraft Henry M. , Yue David T.
Published: December 2002

Engineered calmodulins (CaMs), rendered Ca
2+
-insensitive by mutations, function as dominant negatives in heterologous systems, and have revealed mechanisms of ion channel modulation by Ca
2+
/CaM. The use of these CaMs in native mammalian cells now emerges as a strategy to unmask the biology of such Ca
2+
feedback. Here, we developed recombinant adenoviruses bearing engineered CaMs to facilitate their expression in adult heart cells, where Ca
2+
regulation may be essential for moment-to-moment control of the heartbeat. Engineered CaMs not only eliminated the Ca
2+
-dependent inactivation of native calcium channels, but exposed an unexpectedly large impact of removing such feedback: the unprecedented (4- to 5-fold) prolongation of action potentials. This striking result recasts the basic paradigm for action-potential control and illustrates the promise of virally delivered engineered CaM to investigate the biology of numerous other CaM-signaling pathways.
A molecular switch underlies a human telomerase disease
Authors: Comolli Luis R. , Smirnov Ivan , Xu Lifeng , Blackburn Elizabeth H. , James Thomas L.
Published: December 2002

Telomerase is a ribonucleoprotein (RNP) required for maintenance of telomeres. Although up-regulated telomerase activity is closely linked to the cellular immortality characteristic of late stage carcinogenesis, recently, mutations in the telomerase RNA gene in humans have been associated with dyskeratosis congenita and aplastic anemia, both typified by impaired haemopoietic function. These mutations include base changes in a highly conserved putative telomerase RNA pseudoknot. Here, by using
in vitro
telomerase assays, NMR, and UV absorbance melting analyses of model oligonucleotides designed to form a “trans-pseudoknot,” we describe functional, structural, and energetic properties of this structure. We demonstrate that the pseudoknot domain exists in two alternative states of nearly equal stability in solution: one is the previously proposed pseudoknot formed by pairing P3 with the loop domain of P2b, and the other is a structured P2b loop alone. We show that the two-base mutation (GC107/8 → AG) present in one gene copy in a family with dyskeratosis congenita abrogates telomerase activity. This mutation hyperstabilizes the P2b intraloop structure, blocking pseudoknot formation. Conversely, when the P3 pseudoknot pairing is hyperstabilized by deleting a conserved bulge in P3, telomerase activity also decreases. We propose that the P2b/P3 pseudoknot domain acts as a molecular switch, and interconversion between its two states is important for telomerase function. Phylogenetic covariation in the P2b and P3 sequences of 35 species provides a compelling set of “natural” compensatory base pairing changes supporting the existence of the crucial molecular switch.
SadA, a novel adhesion receptor in Dictyostelium
Authors: Fey Petra , Stephens Stephen , Titus Margaret A. , Chisholm Rex L.
Published: December 2002

Little is known about cell–substrate adhesion and how motile and adhesive forces work together in moving cells. The ability to rapidly screen a large number of insertional mutants prompted us to perform a genetic screen in Dictyostelium to isolate adhesion-deficient mutants. The resulting substrate adhesion–deficient (sad) mutants grew in plastic dishes without attaching to the substrate. The cells were often larger than their wild-type parents and displayed a rough surface with many apparent blebs. One of these mutants, sadA−, completely lacked substrate adhesion in growth medium. The sadA− mutant also showed slightly impaired cytokinesis, an aberrant F-actin organization, and a phagocytosis defect. Deletion of the sadA gene by homologous recombination recreated the original mutant phenotype. Expression of sadA–GFP in sadA-null cells restored the wild-type phenotype. In sadA–GFP-rescued mutant cells, sadA–GFP localized to the cell surface, appropriate for an adhesion molecule. SadA contains nine putative transmembrane domains and three conserved EGF-like repeats in a predicted extracellular domain. The EGF repeats are similar to corresponding regions in proteins known to be involved in adhesion, such as tenascins and integrins. Our data combined suggest that sadA is the first substrate adhesion receptor to be identified in Dictyostelium.
Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis
Authors: Karbowski Mariusz , Lee Yang-Ja , Gaume Brigitte , Jeong Seon-Yong , Frank Stephan , Nechushtan Amotz , Santel Ansgar , Fuller Margaret , Smith Carolyn L. , Youle Richard J.
Published: December 2002

We find that Bax, a proapoptotic member of the Bcl-2 family, translocates to discrete foci on mitochondria during the initial stages of apoptosis, which subsequently become mitochondrial scission sites. A dominant negative mutant of Drp1, Drp1K38A, inhibits apoptotic scission of mitochondria, but does not inhibit Bax translocation or coalescence into foci. However, Drp1K38A causes the accumulation of mitochondrial fission intermediates that are associated with clusters of Bax. Surprisingly, Drp1 and Mfn2, but not other proteins implicated in the regulation of mitochondrial morphology, colocalize with Bax in these foci. We suggest that Bax participates in apoptotic fragmentation of mitochondria.
The Cdc37 protein kinase–binding domain is sufficient for protein kinase activity and cell viability
Authors: Lee Paul , Rao Jie , Fliss Albert , Yang Emy , Garrett Stephen , Caplan Avrom J.
Published: December 2002

Cdc37 is a molecular chaperone required for folding of protein kinases. It functions in association with Hsp90, although little is known of its mechanism of action or where it fits into a folding pathway involving other Hsp90 cochaperones. Using a genetic approach with Saccharomyces cerevisiae, we show that CDC37 overexpression suppressed a defect in v-Src folding in yeast deleted for STI1, which recruits Hsp90 to misfolded clients. Expression of CDC37 truncation mutants that were deleted for the Hsp90-binding site stabilized v-Src and led to some folding in both sti1Δ and hsc82Δ strains. The protein kinase–binding domain of Cdc37 was sufficient for yeast cell viability and permitted efficient signaling through the yeast MAP kinase–signaling pathway. We propose a model in which Cdc37 can function independently of Hsp90, although its ability to do so is restricted by its normally low expression levels. This may be a form of regulation by which cells restrict access to Cdc37 until it has passed through a triage involving other chaperones such as Hsp70 and Hsp90.
A divide-and-conquer approach to fragment assembly
Authors: Otu Hasan H. , Sayood Khalid
Published: December 2002

Motivation: One of the major problems in DNA sequencing is assembling the fragments obtained by shotgun sequencing. Most existing fragment assembly techniques follow the overlap—layout—consensus approach. This framework requires extensive computation in each phase and becomes inefficient with increasing number of fragments.

Results: We propose a new algorithm which solves the overlap, layout, and consensus phases simultaneously. The fragments are clustered with respect to their Average Mutual Information (AMI) profiles using the k-means algorithm. This removes the unnecessary burden of considering the collection of fragments as a whole. Instead, the orientation and overlap detection are solved efficiently, within the clusters. The algorithm has successfully reconstructed both artificial and real data.

Availability: Available on request from the authors.

Contact: otu@eecomm.unl.edu

* To whom correspondence should be addressed.
Psychopathology in the Postgenomic Era
Authors: Plomin Robert , McGuffin Peter
Published: December 2002

We are rapidly approaching the postgenomic era in which we will know all of the 3 billion DNA bases in the human genome sequence and all of the variations in the genome sequence that are ultimately responsible for genetic influence on behavior. These ongoing advances and new techniques will make it easier to identify genes associated with psychopathology. Progress in identifying such genes has been slower than some experts expected, probably because many genes are involved for each phenotype, which means the effect of any one gene is small. Nonetheless, replicated linkages and associations are being found, for example, for dementia, reading disability, and hyperactivity. The future of genetic research lies in finding out how genes work (functional genomics). It is important for the future of psychology that pathways between genes and behavior be examined at the top-down psychological level of analysis (behavioral genomics), as well as at the bottom-up molecular biological level of cells or the neuroscience level of the brain. DNA will revolutionize psychological research and treatment during the coming decades.
Neuroimaging Studies of Language Production and Comprehension
Authors: Gernsbacher Morton Ann , Kaschak Michael P.
Published: December 2002

The 1990s were dubbed the “Decade of the Brain.” During this time there was a marked increase in the amount of neuroimaging work observing how the brain accomplishes many tasks, including the processing of language. In this chapter we review the past 15 years of neuroimaging research on language production and comprehension. The findings of these studies indicate that the processing involved in language use occurs in diffuse brain regions. These regions include Broca's and Wernicke's areas, primary auditory and visual cortex, and frontal regions in the left hemisphere, as well as in the right hemisphere homologues to these regions. We conclude the chapter by discussing the future of neuroimaging research into language production and comprehension.