bluuebunny/crossref_metadata_2025 huggingface dataset:
Horizontal line bisections in upper and lower body space
Authors: BARRETT ANNA M. , CROSSON J. BRENT , CRUCIAN GREGORY P. , HEILMAN KENNETH M.
Published: July 2002

Whereas the ventral cortical visual stream is important
in object recognition, the dorsal stream is specialized
for spatial localization. In humans there are also right
and left hemisphere asymmetries in visual processing: the
left hemisphere being more important in object recognition
and the right in specifying spatial locations. Based on
these dorsal–ventral and right–left where–what
dichotomies, one would expect that the dorsal right hemisphere
systems would be most activated during spatial localization
tasks, and this activation may induce a leftward spatial
bias in lower space. To determine if visual stimuli in
upper and lower body space evoke different hemispheric
activation, we had 12 normal participants bisect horizontal
lines above and below eye level. Participants erred leftward
in lower body space relative to upper body space (M
= 1.3345 mm and 0.4225 mm, respectively; p = .011).
In upper body space, bisection errors did not differ from
zero, but in lower body space, errors tended to deviate
leftward (M = 1.3345 mm, differs from null hypotheses
at p = .0755). Our results are consistent with
dorsal stream/right hemisphere activation when performing
a spatial localization task in lower versus upper
body space. (JINS, 2000, 6, 455–459.)
Components of verbal learning and hippocampal damage assessed
by T2 relaxometry
Authors: WOOD AMANDA G. , SALING MICHAEL M. , O'SHEA MARIE F. , BERKOVIC SAMUEL F. , JACKSON GRAEME D.
Published: July 2002

We studied a group of 31 temporal lobe epilepsy
patients (25 left, 6 right) with unilateral hippocampal
sclerosis evident on magnetic resonance imaging. Single
slice T2 relaxation times were acquired for the left and
right hippocampi. Principal components analysis of preoperative
memory data resulted in two factors that reflect a distinction
between arbitrary and semantic forms of verbal recall.
The former component correlated with left hippocampal T2
relaxation time, while the latter component did not. This
study suggests that variation in left hippocampal integrity
is more related to the acquisition of arbitrary associates
than semantically structured material, and reinforces the
possibility that the left temporal lobe is functionally
heterogeneous with respect to memory. (JINS, 2000,
6, 529–538.)
Rates of forgetting on three measures of verbal learning
using retention intervals ranging from 20 min to 62 days
Authors: TOMBAUGH TOM N. , HUBLEY ANITA M.
Published: July 2002

Previous research has examined age effects in rates
of forgetting at short delay intervals of 20–30 min.
The present study examined age effects in three verbal
memory tasks at longer delay intervals of up to 62 days.
Study participants consisted of 371 community-dwelling
men and women comprising three age groups 20–39,
40–59, and 60–79 years. Age differences in
acquisition and 20-min delayed recall were found on each
of the memory tasks (paragraph, word list, and word pairs).
However, all age groups showed equivalent rates of forgetting
after this short delay interval. When participants were
required to retain information for longer delay intervals
(i.e., 1–62 days), increasing age was associated
with faster rates of forgetting for day 1, but not over
longer delay intervals. Age differences in rates of forgetting
for longer delay intervals and the facilitating effects
of prompted recall are discussed in terms of encoding and
storage versus retrieval processes. (JINS,
2001, 7, 79–91.)
Working memory deficits associated with chronic fatigue
syndrome
Authors: DOBBS BONNIE M. , DOBBS ALLEN R. , KISS IVAN
Published: July 2002

Cognitive impairments are among the most frequently
reported and least investigated components of the chronic
fatigue syndrome (CFS). As part of a multifaceted study
of the CFS, the present study investigated the cognitive
functioning of chronic fatigue patients. The performance
of 20 CFS patients was compared to that of controls (N
= 20) on 4 tests of working memory (WM). Digit Span Forward
was used to assess the storage capacity of WM. Multiple
aspects of central executive functioning were assessed
using several standard measures: Digit Span Backward, and
Trails A and Trails B. More recently developed measures
of WM were used to assess control of processing under temporal
demands (working memory task) and resistance to interference
(a sustained attention task). Deficits were restricted
to more demanding tasks, requiring resistance to interference
and efficient switching between processing routines. The
overall results clearly implicate deficits in the control
aspects of central executive function in CFS. (JINS,
2001, 7, 285–293.)
Interhemispheric Stroop effects in partial and complete
agenesis of the corpus callosum
Authors: BROWN WARREN S. , THRASHER ELLEN D. , PAUL LYNN K.
Published: July 2002

Previous research had demonstrated diminished interhemispheric
Stroop effects in individuals with agenesis of the corpus
callosum (ACC), suggesting an important role for the callosum
in interhemispheric color-word and color-patch interactions.
However, this outcome rested on the results of only 1 ACC
participant, who had normal intelligence and a minimum
of other neuropathology. In the research reported herein,
the role of the corpus callosum in interhemispheric Stroop
interference and facilitation was investigated in 9 individuals
with complete or partial ACC and normal intelligence, and
in non-ACC controls. Congruent, incongruent, or neutral
stimulus pairs were presented either unilaterally (color-patch
and color-word in the same visual field) or bilaterally
(color-patch and color-word in different visual fields).
Both unilateral and bilateral (interhemispheric) Stroop
interference were found for both ACC and non-ACC groups,
with no significant difference in magnitude, indicating
that extracallosal pathways are sufficient for mediating
this phenomenon. It is suggested that the anterior commissure
is a more likely candidate for the interhemispheric transmission
of the semantic information resulting in Stroop interference.
(JINS, 2001, 7, 302–311.)
Improved memory functioning and frontal lobe maturation
between childhood and adolescence: A structural MRI study
Authors: SOWELL ELIZABETH R. , DELIS DEAN , STILES JOAN , JERNIGAN TERRY L.
Published: July 2002

Previous studies conducted by our group have provided
evidence for age-related reductions in cortical thickness
in dorsal frontal and parietal regions between childhood
and adulthood, and gray matter volume increases of mesial
temporal and anterior diencephalic structures. The purpose
of this study was to describe neurobehavioral correlates
of these brain maturational changes using morphometric
analyses of brain magnetic resonance images (MRI) and two
tests of cognitive abilities. Participants were 35 normal
children roughly stratified by age (7 to 16 years) and
sex (20 boys and 15 girls) and frontal and mesial temporal
regions were anatomically defined in each subjects'
MRI data. The California Verbal Learning Test–Children's
Version and the Rey-Osterrieth Complex Figure test were
used as measures of verbal and visuospatial memory and
organizational abilities. Analyses designed to show regionally
specific relationships between the brain and behavioral
measures revealed interesting results. Specifically, frontal
lobe gray matter thinning was more strongly predictive
of delayed verbal memory functioning than was the mesial
temporal lobe gray matter volume, and this relationship
did not appear to be mediated by factors indexed in chronological
age. Similar, but less regionally specific relationships
were observed for measures of visuospatial memory abilities
and frontal lobe maturation. Functional imaging studies
in the literature consistently report activation in frontal
regions in adults during retrieval tasks. The relationship
between frontal lobe maturation and delayed recall observed
here may be reflective of the children's development
towards the more adult-like frontal lobe function revealed
in the functional imaging studies. (JINS, 2001,
7, 312–322.)
Limitations of the Paced Auditory Serial Addition Test as
a measure of working memory in patients with multiple sclerosis
Authors: FISK JOHN D. , ARCHIBALD CATHERINE J.
Published: July 2002

The Paced Auditory Serial Addition Test (PASAT)
is a commonly used procedure that combines elements of
both a working memory task and a test of information processing
speed. Patients with multiple sclerosis (MS) have consistently
been found to be impaired on this test and it has been
recommended as a core outcome measure in clinical trials.
The standard score for this task is the number of correct
responses at each stimulus presentation rate but a concern
has been raised that subjects may ignore some test items
in order to chunk the information into manageable portions
and avoid performing several cognitive tasks simultaneously.
To account for this strategy, one can examine the proportion
of correct responses that are consecutive (termed dyads),
since such responses require that the task be performed
according to the instructions. We compared a group of 35
mildly to moderately disabled MS patients and matched healthy
controls on the PASAT. The MS patients made significantly
fewer correct responses at the 2 slowest presentation rates
(2.4, 2.0 s/digit) while their scores at faster rates (1.6,
1.2 s/digit) did not discriminate them from controls as
well. Nevertheless, the MS patients' percentage of
dyads was significantly lower than that of the control
sample across all stimulus presentation rates. While our
study supports the use of the PASAT as a test that distinguishes
MS patients from healthy individuals, our results also
illustrate problems that lie in the interpretation of this
difference in performance. It appears that a chunking strategy
may be common in the PASAT, particularly as task demands
increase, and that this may mask actual performance differences.
If so, the total correct response score alone is limited
as a measure of working memory and information processing
speed. More detailed analyses of PASAT performance, coupled
with other measures of information processing, may help
clarify the underlying cognitive deficits of MS patients.
(JINS, 2001, 7, 363–372.)
Depression in multiple sclerosis: Relationship to planning ability
Authors: ARNETT PETER A. , HIGGINSON CHRISTOPHER I. , RANDOLPH JOHN J.
Published: July 2002

Recent research has demonstrated deficits on effortful executive
tasks involving planning in multiple sclerosis (MS) patients.
Given the high prevalence of depression in MS and the commonly
reported link between depression and performance on executive
tasks, planning impairments in MS may be associated with
depression. We compared the performance of depressed and
nondepressed MS patients on a planning task (Tower of
London–TOL) to evaluate this hypothesis. Compared with
nondepressed MS patients, depressed MS patients made significantly
(p < .05) more moves and took more time per trial
on the TOL. A follow-up regression analysis was conducted that
included the TOL and speeded attentional/working memory task
indices found to be associated with depression in MS from the
authors' prior reports. This analysis revealed that 25%
of the variance in depression scores was predicted by the most
sensitive speeded attentional/working memory task. Furthermore,
this variance overlapped completely with variance predicted
by the TOL–time/trial index. The only clearly nonspeeded
task index, TOL–moves per trial, was associated with unique
variance (8%) in predicting MS depression scores. These results
suggest that slowed information processing speed and, secondarily,
deficient nonspeeded central executive skill, may be core to
the cognitive deficits characteristic of depressed MS patients.
(JINS, 2001, 7, 665–674.)
Inflammatory and hormonal measures predict neuropsychological
functioning in systemic lupus erythematosus and rheumatoid
arthritis patients
Authors: KOZORA ELIZABETH , LAUDENSLAGER MARK , LEMIEUX ANDRINE , WEST STERLING G.
Published: July 2002

Abnormalities of inflammatory and hormonal measures are common
in SLE patients. Although cognitive dysfunction has been documented
in SLE patients, the biological mechanism of these deficits
has not been clarified. The goal of this study was to explore
the relationship between inflammatory and hormonal activity
and measures of learning, fluency, and attention in systemic
lupus erythematosus patients without neuropsychiatric symptoms
(non-CNS–SLE), patients with rheumatoid arthritis (RA),
and healthy controls (HC). Fifteen non-CNS–SLE patients,
15 RA patients and 15 HC participants similar in age, education,
and gender (female) were compared on tests of cognition,
depression, and plasma levels of interleukin-6 (IL-6),
dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate
(DHEA-S) and cortisol. Non-CNS–SLE patients demonstrated
lower learning and poorer attention. Furthermore, non-CNS–SLE
and RA patients had significantly lower levels of DHEA and DHEA-S
than HC participants. Hierarchical regression analysis demonstrates
that DHEA-S and IL-6 accounts for a unique portion of the variance
in subject performance on measures of learning and attention
after controlling for depression and corticosteroid treatment.
This data highlights the value of hierarchical analyses with
covariates, and provides evidence in humans of a relationship
between peripheral cytokine levels and cognitive function.
(JINS, 2001, 7, 745–754.)
Neuropsychological correlates of adolescent substance abuse:
Four-year outcomes
Authors: TAPERT SUSAN F. , BROWN SANDRA A.
Published: July 2002

Alcohol and other drug use are common in youth,
but neurocognitive sequelae are unclear. This study examines
the relationship between neuropsychological functioning
and protracted substance use in adolescence. One hundred
fifteen adolescents, ages 13 to 19 years, were recruited
from inpatient substance abuse treatment programs and followed
for 4 years. Adolescents were administered a comprehensive
battery of neuropsychological tests and evaluated on substance
use involvement during treatment, and at 6-month, 1-year,
2-year, and 4-year follow-up time points. Protracted substance
abuse over the 4 years of follow-up was associated with
significantly poorer subsequent functioning on tests of
attention. In addition, alcohol and drug withdrawal accounted
for significant variance in visuospatial functioning, above
and beyond demographic, educational, and health variables
in detoxified late adolescents and young adults. Results
suggest that alcohol and drug withdrawal may be a more
powerful marker of protracted neuropsychological impairments
than other indices of youthful alcohol and drug involvement.
(JINS, 1999, 5, 481–493.)
The duality of taxes and tradable permits: A survey with applications in Central and Eastern Europe
Authors: FARROW SCOTT
Published: July 2002

Economic instruments such as taxes and tradable permits have been promoted as efficiency improving policies in the transition economies of Central and Eastern Europe and elsewhere. The little noticed potential for a symmetric equity impact from the two instruments in a world without distortions is first discussed. A specific policy option is suggested in which existing environmental taxes in Central and Eastern Europe can be increased without imposing additional financial burdens in industry if appropriate tax credits are provided. Second, conditions in Central and Eastern Europe are identified that reduce the change of efficiency losses in a general equilibrium setting when distortions exist. The trade-off between efficiency and equity in such a setting is found to depend on country-specific parameters and to be reduced if: (1) a cost-effective policy is implemented, (2) environmental assets can be distributed prior to privatization, and (3) government expenditures can decline.
Form and referential citation in a work by Francis Dhomont
Authors: ROY STÉPHANE
Published: July 2002

It is common to oppose formalist and referentialist approaches to music. However, in Francis Dhomont's work Points de fuite, these approaches appear complementary when we consider the relationship between sounds and sources. Adopting the analytical approach of the American theorist Leonard B. Meyer, we show how the syntactic flow of Points de fuite generates formal implications through the impact of tension and relaxation archetypes. The piece explores metaphors based upon recurrent anecdotal events – the recorded signifiers of the source. These extra-musical elements define the work's structure to such an extent that they eliminate the traditional gap between formalism and
referentialism in music.
Donor Insemination: Telling Children About Their Origins
Authors: Hunter Myra , Salter-Ling Natasha , Glover Lesley
Published: July 2002

Despite growing discussion of the potential benefits of openness in
relation to children conceived by donated gametes, the majority of parents
do not intend to tell a future child about his/her origins. As a result little is
actually known about the experiences and concerns of families who do
choose openness. This is a descriptive study of 83 DI Network members
who did intend to or had told a child conceived, using donor insemination,
about his/her origins. Quantitative and qualitative data focused on their
concerns and experiences of telling. Health professionals face the
challenge of providing the opportunity for discussion of these issues both
before treatment and afterwards during childhood.
Ethnicity and Use of a Child and Adolescent Mental Health Service
Authors: Daryanani Renuka , Hindley Peter , Evans Chris , Fahy Paul , Turk Jeremy
Published: July 2002

This study investigated possible associations between ethnic background of referred children and non-attendance, referrer type, problem type, age and gender. The sample consisted of 769 children offered outpatient appointments. Ethnic background influenced referrer type. Over-referrals against expectations were: White children more by GPs than expected, Black and South Asian children by specialist doctors, Black children by education services and Mixed Race children by social services. There was neither a significant difference in ethnic background between attendees and non-attendees nor were gender, age or problem types related to ethnic group. Clinicians should be aware that referral routes may appropriately, or inappropriately, be different for different ethnic groups. Differences found may be due to genuine variations in morbidity, thus leading to presentation to different referrers.
Addressing the Population Burden of Child and Adolescent Mental Health
Problems: A Primary Care Model
Authors: Appleton Peter L. , Hammond-Rowley Sara
Published: July 2002

A model for primary care child and adolescent mental health (CAMH)
services is presented, the overall goal of which is to reduce population
burden of CAMH problems. The theoretical orientation of the model is
based on ecological systems theories. Features of the model include: local
population outcome measures; small area service focus; primary-care-based CAMH specialists; a locally comprehensive service framework
based in primary care (schools and general practices); and an explicit
process of community engagement. The model is illustrated by reference to
a primary care CAMH service (currently the subject of a controlled trial) in
Flintshire, North Wales.
Tense morphology and verb-second in Swedish L1 children, L2 children and children with SLI
Authors: Håkansson Gisela
Published: July 2002

This paper compares the development of tense morphology and verb-second in different learner populations. Three groups of Swedish pre-school children are investigated longitudinally; ten L1 children, ten L2 children and ten children diagnosed with Specific Language Impairment (SLI). Data was collected twice, with an interval of six months. The results at Time I reveal a significant difference between normally developing L1 children on the one hand and L2 children and children with SLI on the other. The L1 children use verb-second correctly in topicalized declaratives, whereas both L2 children and children with SLI use structures with the verb in third position (XSV structures) as an intermediate step towards verb-second. There is a clear development between the two data collection sessions for the L2 children and the children with SLI, diminishing the difference between them and the unimpaired L1 children. The similarity that is found between L2 children and children with SLI in this study bears important implications for the discussion of the role of transfer in L2 research and for the question of a defective linguistic representation in SLI research.
The problem of age in second-language acquisition: Influences from language, structure, and task
Authors: Bialystok Ellen , Miller Barry
Published: July 2002

Three groups of participants were given a grammaticality judgement test based on five structures of English grammar in both an oral and written form. The first group consisted of native speakers of Chinese, the second, native speakers of Spanish, and the third, native English speakers. The two learner groups were divided into those who had begun learning English at a younger (less than 15 years) or older (more than 15 years) age. Performance was measured for both accuracy of judgement and time taken to respond. The results showed that performance patterns were different for the two learner groups, that the linguistic structure tested in the item affected participants' ability to respond correctly, and that task modality produced reliable response differences for the two learner groups. Although there were proficiency differences in the grammaticality judgement task between the younger and older Spanish learners, there were no such differences for the Chinese group. Furthermore, age of learning influenced achieved proficiency through all ages tested rather than defining a point of critical period. The results are interpreted as failing to provide sufficient evidence to accept the hypothesis that there is a critical period for second language acquisition.
Electoral System Effects on Gender Representation: The Case of Mixed Systems
Authors: Vengroff Richard , Creevey Lucy , Krisch Henry
Published: July 2002

Electoral systems as endogenous re-distributive institutions (Tsebelis, 1990) help to define the rules of the game. In this manner they have an important impact among regional, class, ethnic, gender, and other sub-groups of the general population on the distribution and variation in outcome of who is nominated for, and elected to, national office. In particular, there is a well-established and growing literature on the impact of electoral systems and electoral system reform on the representation of women in national legislative bodies (Darcy, Welch, and Clarke 1994; Matland and Taylor 1997; Caul 1998; Rule 1987; Matland 1998). In general, these studies have concluded that more women are elected in proportional rather than in plurality or majority electoral systems. However, a major difficulty in interpreting these findings is created by the historical, cultural, economic, and institutional differences among cases chosen for comparison.
A Caenorhabditis elegans cohesion protein with functions in meiotic chromosome pairing and disjunction
Authors: Pasierbek Pawel , Jantsch Michael , Melcher Martin , Schleiffer Alexander , Schweizer Dieter , Loidl Josef
Published: July 2002

We have studied four Caenorhabditis elegans homologs of the Rad21/Scc1/Rec8 sister-chromatid cohesion protein family. Based on the RNAi phenotype and protein localization, it is concluded that one of them, W02A2.6p, is the likely worm ortholog of yeast Rec8p. The depletion of C. elegans W02A2.6p (called REC-8) by RNAi, induced univalent formation and splitting of chromosomes into sister chromatids at diakinesis. Chromosome synapsis at pachytene was defective, but primary homology recognition seemed unaffected, as a closer-than-random association of homologous fluorescence in situ hybridization (FISH) signals at leptotene/zygotene was observed. Depletion of REC-8 also induced chromosome fragmentation at diakinesis. We interpret these fragments as products of unrepaired meiotic double-stranded DNA breaks (DSBs), because fragmentation was suppressed in a spo-11 background. Thus, REC-8 seems to be required for successful repair of DSBs. The occurrence of DSBs in REC-8-depleted meiocytes suggests that DSB formation does not depend on homologous synapsis. Anti-REC-8 immunostaining decorated synaptonemal complexes (SCs) at pachytene and chromosomal axes in bivalents and univalents at diakinesis. Between metaphase I and metaphase II, REC-8 is partially lost from the chromosomes. The partial loss of REC-8 from chromosomes between metaphase I and metaphase II suggests that worm REC-8 might function similarly to yeast Rec8p. The loss of yeast Rec8p from chromosome arms at meiosis I and centromeres at meiosis II coordinates the disjunction of homologs and sister chromatids at the two meiotic divisions.
Robertson's Mutator transposons in A. thaliana are regulated by the chromatin-remodeling gene Decrease in DNA Methylation (DDM1)
Authors: Singer Tatjana , Yordan Cristina , Martienssen Robert A.
Published: July 2002

Robertson's Mutator transposable elements in maize undergo cycles of activity and then inactivity that correlate with changes in cytosine methylation. Mutator-like elements are present in theArabidopsis genome but are heavily methylated and inactive. These elements become demethylated and active in the chromatin-remodeling mutant ddm1 (Decrease inDNA Methylation), which leads to loss of heterochromatic DNA methylation. Thus, DNA transposons in plants appear to be regulated by chromatin remodeling. In inbred ddm1strains, transposed elements may account, in part, for mutant phenotypes unlinked to ddm1. Gene silencing and paramutation are also regulated by DDM1, providing support for the proposition that epigenetic silencing is related to transposon regulation.
A nonproteolytic function of the proteasome is required for the dissociation of Cdc2 and cyclin B at the end of M phase
Authors: Nishiyama Atsuya , Tachibana Kazunori , Igarashi Yuko , Yasuda Hideyo , Tanahashi Nobuyuki , Tanaka Keiji , Ohsumi Keita , Kishimoto Takeo
Published: July 2002

Inactivation of cyclin B–Cdc2 kinase at the exit from M phase depends on the specific proteolysis of the cyclin B subunit, whereas the Cdc2 subunit remains present at nearly constant levels throughout the cell cycle. It is unknown how Cdc2 escapes degradation when cyclin B is destroyed. In Xenopus egg extracts that reproduce the exit from M phase in vitro, we have found that dissociation of the cyclin B–Cdc2 complex occurred under conditions where cyclin B was tethered to the 26S proteasome but not yet degraded. The dephosphorylation of Thr 161 on Cdc2 was unlikely to be necessary for the dissociation of the two subunits. However, the dissociation was dependent on the presence of a functional destruction box in cyclin B. Cyclin B ubiquitination was also, by itself, not sufficient for separation of Cdc2 and cyclin B. The 26S proteasome, but not the 20S proteasome, was capable of dissociating the two subunits. These results indicate that the cyclin B and Cdc2 subunits are separated by the proteasome through a mechanism that precedes proteolysis of cyclin B and is independent of proteolysis. As a result, cyclin B levels decrease on exit from M phase but Cdc2 levels remain constant.
Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin
Authors: Oldham Sean , Montagne Jacques , Radimerski Thomas , Thomas George , Hafen Ernst
Published: July 2002

The adaptation of growth in response to nutritional changes is essential for the proper development of all organisms. Here we describe the identification of the Drosophila homolog of the target of rapamycin (TOR), a candidate effector for nutritional sensing. Genetic and biochemical analyses indicate that dTOR impinges on the insulin signaling pathway by autonomously affecting growth through modulating the activity of dS6K. However, in contrast to other components in the insulin signaling pathway, partial loss of dTOR function preferentially reduces growth of the endoreplicating tissues. These results are consistent with dTOR residing on a parallel amino acid sensing pathway.
A novel embryonic poly(A) binding protein, ePAB, regulates mRNA deadenylation in Xenopus egg extracts
Authors: Voeltz Gia K. , Ongkasuwan Julina , Standart Nancy , Steitz Joan A.
Published: July 2002

An in vitro system that recapitulates the in vivo effect of AU-rich elements (AREs) on mRNA deadenylation has been developed fromXenopus activated egg extracts. ARE-mediated deadenylation is uncoupled from mRNA body decay, and the rate of deadenylation increases with the number of tandem AUUUAs. A novel ARE-binding protein called ePAB (for embryonicpoly(A)-binding protein) has been purified from this extract by ARE affinity selection. ePAB exhibits 72% identity to mammalian and Xenopus PABP1 and is the predominant poly(A)-binding protein expressed in the stage VI oocyte and during Xenopus early development. Immunodepletion of ePAB increases the rate of both ARE-mediated and default deadenylation in vitro. In contrast, addition of even a small excess of ePAB inhibits deadenylation, demonstrating that the ePAB concentration is critical for determining the rate of ARE-mediated deadenylation. These data argue that ePAB is the poly(A)-binding protein responsible for stabilization of poly(A) tails and is thus a potential regulator of mRNA deadenylation and translation during early development.
Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells
Authors: Hitoshi Seiji , Alexson Tania , Tropepe Vincent , Donoviel Dorit , Elia Andrew J. , Nye Jeffrey S. , Conlon Ronald A. , Mak Tak W. , Bernstein Alan , van der Kooy Derek
Published: July 2002

Neural stem cells, which exhibit self-renewal and multipotentiality, are generated in early embryonic brains and maintained throughout the lifespan. The mechanisms of their generation and maintenance are largely unknown. Here, we show that neural stem cells are generated independent of RBP-Jκ, a key molecule in Notch signaling, by using RBP-Jκ−/− embryonic stem cells in an embryonic stem cell-derived neurosphere assay. However, Notch pathway molecules are essential for the maintenance of neural stem cells; they are depleted in the early embryonic brains ofRBP-Jκ−/− or Notch1−/− mice. Neural stem cells also are depleted in embryonic brains deficient for the presenilin1 (PS1) gene, a key regulator in Notch signaling, and are reduced in PS1+/− adult brains. Both neuronal and glial differentiation in vitro were enhanced by attenuation of Notch signaling and suppressed by expressing an active form of Notch1. These data are consistent with a role for Notch signaling in the maintenance of the neural stem cell, and inconsistent with a role in a neuronal/glial fate switch.
Y4 receptor knockout rescues fertility in ob/ob mice
Authors: Sainsbury Amanda , Schwarzer Christoph , Couzens Michelle , Jenkins Arthur , Oakes Samantha R. , Ormandy Christopher J. , Herzog Herbert
Published: July 2002

Hypothalamic neuropeptide Y (NPY) has been implicated in the regulation of energy balance and reproduction, and chronically elevated NPY levels in the hypothalamus are associated with obesity and reduced reproductive function. However, it is not known which one of the five cloned Y receptors mediates these effects. Here we show that crossing the Y4 receptor knockout mouse (Y4−/−) onto theob/ob background restores the reduced plasma testosterone levels of ob/ob mice as well as the reduced testis and seminal vesicle size and morphology to control values. Fertility in the sterileob/ob mice was greatly improved by Y4 receptor deletion, with 100% of male and 50% of femaleY4−/−,ob/ob double knockout mice producing live offspring. Development of the mammary ducts and lobuloalveoli was significantly enhanced in pregnant Y4−/− andY4−/−,ob/ob females. Consistent with the improved fertility and enhanced mammary gland development, gonadotropin releasing hormone (GnRH) expression was significantly increased inY4−/− and Y4−/−,ob/obanimals. Y4−/− mice displayed lower body weight and reduced white adipose tissue mass accompanied by increased plasma levels of pancreatic polypeptide (PP). However, Y4 deficiency had no beneficial effects to reduce body weight or excessive adiposity of ob/ob mice. These data suggest that central Y4 receptor signaling specifically inhibits reproductive function under conditions of elevated central NPY-ergic tonus.
Genes for Cognitive Function: Developments on the X
Authors: Gécz Jozef , Mulley John
Published: July 2002

Developments in human genome research enabled the first steps toward a molecular understanding of cognitive function. That there are numerous genes on the X chromosome affecting intelligence at the lower end of the cognitive range is no longer in doubt. Naturally occurring mutations have so far led to the identification of seven genes accounting for a small proportion of familial nonspecific X-linked mental retardation. These new data indicate that normal expression of many more X-linked and autosomal genes contribute to cognitive function. The emerging knowledge implicating genes in intracellular signaling pathways provides the insight to identify as candidates other X-linked and autosomal genes regulating the normal development of cognitive function. Recent advances in unravelling the underlying molecular complexity have been spectacular but represent only the beginning, and new technologies will need to be introduced to complete the picture.
Extensive Genome-wide Linkage Disequilibrium in Cattle
Authors: Farnir Frédéric , Coppieters Wouter , Arranz Juan-José , Berzi Paulette , Cambisano Nadine , Grisart Bernard , Karim Latifa , Marcq Fabienne , Moreau Laurence , Mni Myriam , Nezer Carine , Simon Patricia , Vanmanshoven Pascal , Wagenaar Danny , Georges Michel
Published: July 2002

A genome-wide linkage disequilibrium (LD) map was generated using microsatellite genotypes (284 autosomal microsatellite loci) of 581 gametes sampled from the dutch black-and-white dairy cattle population. LD was measured between all marker pairs, both syntenic and nonsyntenic. Analysis of syntenic pairs revealed surprisingly high levels of LD that, although more pronounced for closely linked marker pairs, extended over several tens of centimorgan. In addition, significant gametic associations were also shown to be very common between nonsyntenic loci. Simulations using the known genealogies of the studied sample indicate that random drift alone is likely to account for most of the observed disequilibrium. No clear evidence was obtained for a direct effect of selection (“Bulmer effect”). The observation of long range disequilibrium between syntenic loci using low-density marker maps indicates that LD mapping has the potential to be very effective in livestock populations. The frequent occurrence of gametic associations between nonsyntenic loci, however, encourages the combined use of linkage and linkage disequilibrium methods to avoid false positive results when mapping genes in livestock.
Systematic Management and Analysis of Yeast Gene Expression Data
Authors: Aach John , Rindone Wayne , Church George M.
Published: July 2002

We report steps toward the systematic management, standardization, and analysis of functional genomics data. We developed the ExpressDB database for yeast RNA expression data and loaded it with ∼17.5 million pieces of data reported by 11 studies with three different kinds of high-throughput RNA assays. A web-based tool supports queries across the data from these studies. We examined comparability of data by converting data from 9 studies (217 conditions) into mRNA relative abundance estimates (ERAs) and by clustering of conditions by ERAs. We report on generation of ERAs and condition clustering for non-microarray data (5 studies, 63 conditions) and describe initial attempts to generate microarray-based ERAs (4 studies, 154 conditions), which exhibit increased error, on our web sitehttp://arep.med.harvard.edu/ExpressDB. We recommend standards for data reporting, suggest research into improving comparability of microarray data through quantifying and standardizing control condition RNA populations, and also suggest research into the calibration of different RNA assays. We introduce a model for a database that integrates different kinds of functional genomics data, Biomolecule Interaction, Growth and Expression Database (BIGED).
A Human Genomic Library Enriched in Transcriptionally Active Sequences (aDNA Library)
Authors: Pelling Anna L. , Thorne Alan W. , Crane-Robinson Colyn
Published: July 2002

Core histone hyperacetylation, in particular of H4, is concentrated in the promoter–upstream regions of active genes and in certain cases is locuswide. Antibodies to hyperacetylated H4 were used to immunoprecipitate dinucleosomal chromatin derived from K562 human erythroleukemic cells by micrococcal nuclease digestion. The extracted DNA was made into a genomic library and was expected to contain sequences from genes active in K562 cells (an active, ‘aDNA’ library). Clones (180) were randomly selected from the library; 24 of 103 tested (23%) contained highly repeated sequences, as determined by their hybridization to total genomic DNA, and were not analyzed further. An additional 10 clones (6%) were shown to contain no insert DNA. The remaining 146 were sequenced and compared with the nucleic acid databases and in all six frames to the protein databases: Sixeen clones could be assigned to known genes, the majority of which (12) were tissue specific. All but 2 of these 16 corresponded to segments 5′ of the coding sequences, as expected if H4 acetylation is concentrated at promoter regions. Thirty-three clones (23%) displayed high sequence identity to cDNAs in the expressed sequence tag database (dbEST). Northern blots and reverse transcription (RT)—PCR were used to determine the proportion of clones representing sequences expressed in K562 cells: Although only 1 of 34 tested clones showed a band in Northern hybridization, RT–PCR demonstrated that at least 12 of 40 tested clones (30%) were present in the mRNA population. Because a further 8 of these 40 clones were identified as gene fragments by database sequence comparisons, it follows that about half of this subset of 40 clones is derived from genes. The aDNA library is thus very gene rich and not skewed toward the most highly expressed sequences, as in mRNA libraries. The aDNA library is also rich in promoters and could be a valuable source of such sequences, particularly those that lack CpG islands or other features that allow their specific selection.
An Efficient Method for High-Fidelity BAC/PAC Retrofitting with a Selectable Marker for Mammalian Cell Transfection
Authors: Wang Zunde , Engler Peter , Longacre Angelika , Storb Ursula
Published: July 2002

Large-scale genomic sequencing projects have provided DNA sequence information for many genes, but the biological functions for most of them will only be known through functional studies. Bacterial artificial chromosomes (BACs) and P1-derived artificial chromosomes (PACs) are large genomic clones stably maintained in bacteria and are very important in functional studies through transfection because of their large size and stability. Because most BAC or PAC vectors do not have a mammalian selection marker, transfecting mammalian cells with genes cloned in BACs or PACs requires the insertion into the BAC/PAC of a mammalian selectable marker. However, currently available procedures are not satisfactory in efficiency and fidelity. We describe a very simple and efficient procedure that allows one to retrofit dozens of BACs in a day with no detectable deletions or unwanted recombination. We use a BAC/PAC retrofitting vector that, on transformation into competent BAC or PAC strains, will catalyze the specific insertion of itself into BAC/PAC vectors through in vivo cre/loxP site-specific recombination.
Genome-Scale Compositional Comparisons in Eukaryotes
Authors: Gentles Andrew J. , Karlin Samuel
Published: July 2002

We examined dinucleotide relative abundances and their biases in recent sequences of eukaryotic genomes and chromosomes, including human chromosomes 21 and 22, Saccharomyces cerevisiae, Arabidopsis thaliana, and Drosophila melanogaster. We found that dinucleotide relative abundances are remarkably constant across human chromosomes and within the DNA of a particular species. The dinucleotide biases differ between species, providing a genome signature that is characteristic of the bulk properties of an organism's DNA. We detail the relations between species genome signatures and suggest possible mechanisms for their origin and maintenance.
Human–Ovine Comparative Sequencing of a 250-kb Imprinted Domain Encompassing the Callipyge (clpg) Locus and Identification of Six Imprinted Transcripts: DLK1, DAT, GTL2, PEG11, antiPEG11, and MEG8
Authors: Charlier Carole , Segers Karin , Wagenaar Danny , Karim Latifa , Berghmans Stéphane , Jaillon Olivier , Shay Tracy , Weissenbach Jean , Cockett Noelle , Gyapay Gabor , Georges Michel
Published: July 2002

Two ovine BAC clones and a connecting long-range PCR product, jointly spanning ∼250 kb and representing most of theMULGE5-OY3 marker interval known to contain the clpglocus, were completely sequenced. The resulting genomic sequence was aligned with its human ortholog and extensively annotated. Six transcripts, four of which were novel, were predicted to originate from within the analyzed region and their existence confirmed experimentally: DLK1, DAT, GTL2, PEG11, antiPEG11, and MEG8. RT-PCR experiments performed on a range of tissues sampled from an 8-wk-old animal demonstrated the preferential expression of all six transcripts in skeletal muscle, which suggests that they are under control of common regulatory elements. The six transcripts were also shown to be subject to parental imprinting: DLK1, DAT, andPEG11 were shown to be paternally expressed and GTL2,antiPEG11, and MEG8 to be maternally expressed.

[The sequence data described in this paper have been submitted to the GenBank data library under accession no. AF354168.]
Prokaryotic Homologs of the Eukaryotic DNA-End-Binding Protein Ku, Novel Domains in the Ku Protein and Prediction of a Prokaryotic Double-Strand Break Repair System
Authors: Aravind L. , Koonin Eugene V.
Published: July 2002

Homologs of the eukaryotic DNA-end-binding protein Ku were identified in several bacterial and one archeal genome using iterative database searches with sequence profiles. Identification of prokaryotic Ku homologs allowed the dissection of the Ku protein sequences into three distinct domains, the Ku core that is conserved in eukaryotes and prokaryotes, a derived von Willebrand A domain that is fused to the amino terminus of the core in eukaryotic Ku proteins, and the newly recognized helix–extension–helix (HEH) domain that is fused to the carboxyl terminus of the core in eukaryotes and in one of the Ku homologs from the Actinomycete Streptomyces coelicolor. The version of the HEH domain present in eukaryotic Ku proteins represents the previously described DNA-binding domain called SAP. The Ku homolog from S. coelicolor contains a distinct version of the HEH domain that belongs to a previously unnoticed family of nucleic-acid-binding domains, which also includes HEH domains from the bacterial transcription termination factor Rho, bacterial and eukaryotic lysyl-tRNA synthetases, bacteriophage T4 endonuclease VII, and several uncharacterized proteins. The distribution of the Ku homologs in bacteria coincides with that of the archeal-eukaryotic-type DNA primase and genes for prokaryotic Ku homologs form predicted operons with genes coding for an ATP-dependent DNA ligase and/or archeal-eukaryotic-type DNA primase. Some of these operons additionally encode an uncharacterized protein that may function as nuclease or an Slx1p-like predicted nuclease containing a URI domain. A hypothesis is proposed that the Ku homolog, together with the associated gene products, comprise a previously unrecognized prokaryotic system for repair of double-strand breaks in DNA.
Functional Versatility and Molecular Diversity of the Metabolic Map of Escherichia coli
Authors: Tsoka Sophia , Ouzounis Christos A.
Published: July 2002

We have analyzed the known metabolic enzymes of Escherichia coli in relation to their biochemical reaction properties and their involvement in biochemical pathways. All enzymes involved in small-molecule metabolism and their corresponding protein sequences have been extracted from the EcoCyc database. These 548 metabolic enzymes are clustered into 405 protein families according to sequence similarity. In this study, we examine the functional versatility within enzyme families in terms of their reaction capabilities and pathway participation. In addition, we examine the molecular diversity of reactions and pathways according to their presence across enzyme families. These complex, many-to-many relationships between protein sequence and biochemical function reveal a significant degree of correlation between enzyme families and reactions. Pathways, however, appear to require more than one enzyme type to perform their complex biochemical transformations. Finally, the distribution of enzyme family members across different pathways provides support for the “recruitment” hypothesis of biochemical pathway evolution.
Using Quality Measures to Facilitate Allele Calling in High-Throughput Genotyping
Authors: Pálsson Birgir , Pálsson Frosti , Perlin Mark , Gudbjartsson Hákon , Stefánsson Kári , Gulcher Jeffrey
Published: July 2002

Currently, the main limitation in high-throughput microsatellite genotyping is the required manual editing of allele calls. Even though programs for automated allele calling have been available for several years, they have limited capability because accurate data could only be assured by manual inspection of the electropherograms for confirmation. Here we describe the development of a parametric approach to allele call quality control that eliminates much of the time required for manual editing of the data. This approach was implemented in an editing tool, Decode-GT, that works downstream of the allele calling program, TrueAllele (TA). Decode-GT reads the output data from TA, displays the underlying electropherograms for the genotypes, and sorts the allele calls into three categories: good, bad, and ambiguous. It discards the bad calls, accepts the good calls, and suggests that the user inspect the ambiguous calls, thereby reducing dependence on manual editing. For the categorization we use the following parameters: (1) the quality value for each allele call from TrueAllele; (2) the peak height of the alleles; and (3) the size of the peak shift needed to move peaks into the nearest bin. Here we report how we optimized the parameters such that the size of the ambiguous category was minimized, and both the number of miscalled genotypes in the good category and the useable genotypes in the bad category were negligible. This approach reduces the manual editing time and results in <1% miscalls.
Frequent Alternative Splicing of Human Genes
Authors: Mironov Andrey A. , Fickett James Wildon , Gelfand Mikhail S.
Published: July 2002

Alternative splicing can produce variant proteins and expression patterns as different as the products of different genes, yet the prevalence of alternative splicing has not been quantified. Here the spliced alignment algorithm was used to make a first inventory of exon-intron structures of known human genes using EST contigs from the TIGR Human Gene Index. The results on any one gene may be incomplete and will require verification, yet the overall trends are significant. Evidence of alternative splicing was shown in 35% of genes and the majority of splicing events occurred in 5′ untranslated regions, suggesting wide occurrence of alternative regulation. Most of the alternative splices of coding regions generated additional protein domains rather than alternating domains.