bluuebunny/crossref_metadata_2025 huggingface dataset:
NMR-based screening in drug discovery
Authors: Hajduk Philip J. , Meadows Robert P. , Fesik Stephen W.
Published: July 2002

1. Introduction 211

2. Screening methods 213

2.1 Chemical shifts 213

2.2 Diffusion 214

2.3 Transverse relaxation 218

2.4 Nuclear Overhauser effects 218

3. Strategies for drug discovery and design 221

3.1 Fragment-based methods 221

3.1.1 Linked-fragment approach 221

3.1.2 Directed combinatorial libraries 222

3.1.3 Modification of high-affinity ligands 223

3.1.4 Solvent mapping techniques 223

3.2 High-throughput NMR-based screening 224

3.3 Enzymatic assays 226

4. Discovery of novel ligands 227

4.1 High-affinity ligands for FKBP 227

4.2 Potent inhibitors of stromelysin 229

4.3 Ligands for the DNA-binding domain of the E2 protein 233

4.4 Discovery of Erm methyltransferase inhibitors 233

4.5 Phosphotyrosine mimetics for SH2 domains 236

5. Conclusions 237

6. References 237

A critical step in the drug discovery process is the identification of high-affinity ligands for
macromolecular targets. Traditionally, the identification of such lead compounds has been
accomplished through the high-throughout screening (HTS) of corporate compound
repositories. Conventional HTS methodology has enjoyed widespread application and
success in the pharmaceutical industry and, through recent technological advances in
screening (Fernandes, 1998; Oldenburg et al. 1998; Silverman et al. 1998) and combinatorial
chemistry (Fauchere et al. 1998; Fecik et al. 1998), these programs will continue to have a
prominent role in drug discovery. However, suitable leads cannot always be found using
conventional methods. This is not surprising since typical corporate libraries contain fewer
than 106 compounds compared with the estimated 1050–1080 universe of compounds (Martin,
1997). In addition, most conventional assays are limited to screening libraries of compounds
against proteins with known function, excluding the large number of targets becoming
available from genomics research.

Recently, a number of NMR-based screening methods have been employed to identify
and design lead ligands for protein targets (see Table 1). These NMR-based strategies can
augment ongoing conventional HTS for identifying leads and can be used to aid in lead
optimization. All of these techniques take advantage of the fact that upon complex formation
between a target molecule and a ligand, significant perturbations can be observed in NMR-sensitive parameters of either the target or the ligand. These perturbations can be used
qualitatively to detect ligand binding or quantitatively to assess the strength of the binding
interaction. In addition, some of the techniques allow the identification of the ligand binding
site or which part of the ligand is responsible for interacting with the target. In this article,
the current state of NMR-based screening is reviewed.
Representation is representation of similarities
Authors: Edelman Shimon
Published: July 2002

Advanced perceptual systems are faced with the problem
of securing a principled (ideally, veridical) relationship between the
world and its internal representation. I propose a unified approach
to visual representation, addressing the need for superordinate and
basic-level categorization and for the identification of specific
instances of familiar categories. According to the proposed theory,
a shape is represented internally by the responses of a small number
of tuned modules, each broadly selective for some reference shape,
whose similarity to the stimulus it measures. This amounts to
embedding the stimulus in a low-dimensional proximal shape space
spanned by the outputs of the active modules. This shape space
supports representations of distal shape similarities that are
veridical as Shepard's (1968) second-order isomorphisms
(i.e., correspondence between distal and proximal similarities
among shapes, rather than between distal shapes and their proximal
representations). Representation in terms of similarities to reference
shapes supports processing (e.g., discrimination) of shapes that are
radically different from the reference ones, without the need for the
computationally problematic decomposition into parts required by other
theories. Furthermore, a general expression for similarity between two
stimuli, based on comparisons to reference shapes, can be used to
derive models of perceived similarity ranging from continuous,
symmetric, and hierarchical ones, as in multidimensional scaling
(Shepard 1980), to discrete and nonhierarchical ones, as in the
general contrast models (Shepard & Arabie 1979; Tversky
1977).
Neurobiology of the structure of personality: Dopamine, facilitation of incentive motivation, and extraversion
Authors: Depue Richard A. , Collins Paul F.
Published: July 2002

Extraversion has two central characteristics: (1)
interpersonal engagement, which consists of affiliation
(enjoying and valuing close interpersonal bonds, being warm and
affectionate) and agency (being socially dominant, enjoying leadership
roles, being assertive, being exhibitionistic, and having a sense of
potency in accomplishing goals) and (2) impulsivity, which
emerges from the interaction of extraversion and a second, independent
trait (constraint). Agency is a more general motivational disposition
that includes dominance, ambition, mastery, efficacy, and achievement.
Positive affect (a combination of positive feelings and motivation) is
closely associated with extraversion. Extraversion is accordingly
based on positive incentive motivation.

Parallels between extraversion (particularly its agency component)
and a mammalian behavioral approach system based on positive incentive
motivation implicate a neuroanatomical network and modulatory
neurotransmitters in the processing of incentive motivation. A
corticolimbic-striatal-thalamic network (1) integrates the salient
incentive context in the medial orbital cortex, amygdala, and
hippocampus; (2) encodes the intensity of incentive stimuli in a
motive circuit composed of the nucleus accumbens, ventral pallidum,
and ventral tegmental area dopamine projection system; and (3) creates
an incentive motivational state that can be transmitted to the motor
system.

Individual differences in the functioning of this network arise
from functional variation in the ventral tegmental area dopamine
projections, which are directly involved in coding the intensity of
incentive motivation. The animal evidence suggests that there are
three neurodevelopmental sources of individual differences in
dopamine: genetic, “experience-expectant,” and
“experience-dependent.” Individual differences in
dopamine promote variation in the heterosynaptic plasticity that
enhances the connection between incentive context and incentive
motivation and behavior.

Our psychobiological threshold model explains the effects of
individual differences in dopamine transmission on behavior, and
their relation to personality traits is discussed.
Regularity of the transfer map for cohomologous cocycles
Authors: NIŢICĂ VIOREL , TÖRÖK ANDREI
Published: July 2002

In this paper we obtain results about the regularity of the transfer map between two cocycles over an Anosov system, with values in either a diffeomorphism or a Lie group. We also explain how certain examples of de la Llave show that our results are essentially optimal.
The development of metacognition in musicians: Implications for education
Authors: Hallam Susan
Published: July 2002

Recent research on musical practice has focused on metacognition and the strategies that musicians adopt in their preparations for performance. This study explored the development of metacognition and performance planning strategies in musicians from novice to professional level. Twenty-two professional musicians and fifty-five novices were interviewed about their practising. The novices were also tape-recorded learning and performing a short piece. The professional musicians demonstrated extensive metacognition in relation to their preparations for performance encompassing technical matters, interpretation, and issues relating to learning itself, e.g. concentration, planning, monitoring and evaluation. Although there were similarities in the strategies adopted there was considerable variation because of individual need. In the novice musicians, there was a complex relationship between the development of expertise and the use of planning strategies.
An Impossibility Theorem for Welfarist Axiologies
Authors: Arrhenius Gustaf
Published: July 2002

A search is under way for a theory that can accommodate our intuitions in population axiology. The object of this search has proved elusive. This is not surprising since, as we shall see, any welfarist axiology that satisfies three reasonable conditions implies at least one of three counter-intuitive conclusions. I shall start by pointing out the failures in three recent attempts to construct an acceptable population axiology. I shall then present an impossibility theorem and conclude with a short discussion of how it might be extended to pluralist axiologies, that is, axiologies that take more values than welfare into account.
SUPPLEMENTARY VARIABLE TECHNIQUE IN STOCHASTIC MODELS
Authors: Alfa Attahiru Sule , Rao T. S. S. Srinivasa
Published: July 2002

In this article, we formalize the framework for the
supplementary variable technique in stochastic models.
Specifically, we show that the use of remaining or elapsed
times (or any metric) as supplementary variables leads
to the notion of forward or backward Chapman–Kolmogorov
equations, respectively. We further show that for a class
of queueing systems, using remaining time as the supplementary
variable makes analysis simpler.
WILLINGNESS TO COMMUNICATE, SOCIAL SUPPORT, AND
LANGUAGE-LEARNING ORIENTATIONS OF IMMERSION STUDENTS
Authors: MacIntyre Peter D. , Baker Susan C. , Clément Richard , Conrod Sarah
Published: July 2002

Willingness to communicate (WTC) has been defined as the intention to initiate
communication, given a choice. It was hypothesized that orientations toward language learning as
well as social support would influence students' WTC in a second language. Grade 9
students of L2 French immersion, living in a relatively unilingual Anglophone community,
participated in the study. WTC was measured in each of four skill areas: speaking, writing,
reading, and comprehension. Five orientations or reasons for studying an L2 were examined:
travel, job related, friendship with Francophones, personal knowledge, and school achievement.
Results showed that endorsement of all five orientations for language learning was positively
correlated with WTC both inside and outside the classroom. Results also showed that social
support, particularly from friends, was associated with higher levels of WTC outside the
classroom but played less of a role inside the classroom. The support of friends was also
associated with higher orientations for travel and for friendship with Francophones. Results are
discussed in terms of an emerging situated model.
EXPLICITNESS, INTAKE, AND THE ISSUE OF AWARENESS
Authors: Rosa Elena , O'Neill Michael D.
Published: July 2002

The conditions (implicit or explicit) under which exposure to L2 input takes place and the
level of awareness raised while processing input may be strongly related to the learning process.
This study investigates how intake was affected both by awareness and by the conditions under
which a problem-solving task was performed. Spanish conditional sentences were presented to
learners through five different degrees of explicitness, which were the result of combining the
factors [±formal instruction] and [±directions to search for rules]. Intake was
measured through a multiple-choice recognition test administered immediately after the
experimental task. Level of awareness was assessed by means of think-aloud protocols collected
during input processing. Results indicate that (a) the degrees of explicitness had a differential
effect on intake, (b) the higher the level of awareness demonstrated, the stronger the effect on
intake, and (c) the conditions under which the task was administered influenced the way
information was processed.
Interpretation of relative clauses by young children: another look
Authors: EISENBERG SARITA
Published: July 2002

Interpretation of relative clauses sentences was investigated by having sixteen children between the ages of 3;5 and 4;6 act out sentences within four conditions that varied the number of potential referents for each noun within the sentence. No difference in interpretation accuracy was found between felicitous and infelicitous conditions or between biased and neutral conditions. This result raises problems for the view that children of this age know the pragmatic principles for interpreting relative clauses.
Prevalence of Toxoplasma gondii specific

immunoglobulin G antibodies among pregnant women in Norway
Authors: JENUM P. A. , KAPPERUD G. , STRAY-PEDERSEN B. , MELBY K. K. , ESKILD A. , ENG J.
Published: July 2002

During one year from June 1992 serum IgG antibodies to

Toxoplasma gondii among 35940

pregnant women were measured in a cross-sectional study

conducted in Norway. The overall

prevalence was 10·9%. The lowest prevalences were

detected in the north (6·7%) and in the

inland counties (8·2%). A significantly higher

prevalence was detected in the southern counties

(13·4%) where a mild, coastal climate prevails.

Women with foreign names had a higher

prevalence (22·6%) than women with Norwegian names

(10·0%). The high prevalence among

women living in the capital city (Oslo) as compared to other

cities and rural areas (13·2% vs.

10·1% and 10·2% respectively), was explained by

the higher proportion of foreign women in

Oslo. Prevalence significantly increased with age in women

over 34 years old. This increase was

only detected among women with Norwegian names. An increase

in prevalence according to

number of children was detected. Women without children had

a prevalence of 8·8% while

women with three children or more had a prevalence of

14·9%. Multivariate analyses showed

that being seropositive was independently associated with

county of residence, age, nationality

and number of children.
Hepatitis A in New South Wales, Australia, from
consumption of oysters: the first reported outbreak
Authors: CONATY S. , BIRD P. , BELL G. , KRAA E. , GROHMANN G. , McANULTY J. M.
Published: July 2002

Between 22 January and 4 April 1997, 467 hepatitis A cases were reported to the New South
Wales Health Department, Australia. To identify the cause of the outbreak, we conducted a
matched case-control study, and an environmental investigation. Among 66 cases and 66
postcode-matched controls, there was a strong association between illness and consumption of
oysters (adjusted odds ratio 42; 95% confidence interval 5–379). More than two-thirds of cases
reported eating oysters, including one third of cases and no controls who reported eating
oysters in the Wallis Lake area. A public warning was issued on 14 February, and Wallis Lake
oysters were withdrawn from sale. Hepatitis A virus was subsequently identified in oyster
samples taken from the lake. Hepatitis A virus poses a special risk to consumers who eat raw
oysters because it can survive for long periods in estuaries and cause severe disease.
Status and distribution of khulan (Equus hemionus) in Mongolia
Authors: Reading Richard P. , Mix Henry M. , Lhagvasuren Badamjaviin , Feh Claudia , Kane David P. , Dulamtseren S. , Enkhbold Sumyain
Published: July 2002

The Asiatic wild ass Equus hemionus, or khulan, once ranged across much of Central Asia, but is now globally threatened. The largest free‐ranging populations are now restricted to a 250‐km wide area (range 100–400 km) across the Gobi Desert region of southern Mongolia. Over the last 23 years the population has moved further north and east into its former range. Surveys conducted in the 1970s and 1980s estimated that the Mongolian population contained fewer than 15 000 animals and was declining as a result of human exploitation and livestock competition. Aerial surveys (one in autumn 1994, two in spring 1997) were flown as line transects over portions of the khulan's range in Mongolia and ground surveys (five in spring, summer, and autumn 1994–97) were conducted by vehicle and foot. Sample sizes and areas surveyed were larger than previous surveys, and our methods were often more systematic. Population size was estimated at 33 000–63 000 wild asses in Mongolia. Animal density ranged from 4.2±1.3 to 19.1±3.2 per 100 km2. Mean group size ranged from four to 35 animals in the south‐western Gobi, four to seven animals in the southern Gobi, and three to 18 in the south‐eastern Gobi. Our data suggest that Mongolia is the most important stronghold for the conservation of E. hemionus. Conservation management continues to be challenging because intensive studies on khulan biology and ecology are just beginning. As a free‐market economy continues to emerge in Mongolia, pressure from resource extraction interests and nomadic livestock herders to remove the khulan's protected status, permit harvesting and halt population growth and expansion, also makes implementation of research and conservation management programs more imperative.
Dimorphism and the functional basis of claw strength in six brachyuran crabs
Authors: Schenk Steve C. , Wainwright Peter C.
Published: July 2002

By examining the morphological basis of force generation in the chelae (claws) of both molluscivorous and non‐molluscivorous crabs, it is possible to understand better the difference between general crab claw design and the morphology associated with durophagy. This comparative study investigates the morphology underlying claw force production and intraspecific claw dimorphism in six brachyuran crabs: Callinectes sapidus (Portunidae), Libinia emarginata (Majidae), Ocypode quadrata (Ocypodidae), Menippe mercenaria (Xanthidae), Panopeus herbstii (Xanthidae), and P. obesus (Xanthidae). The crushers of the three molluscivorous xanthids consistently proved to be morphologically ‘strong,’ having largest mechanical advantages (MAs), mean angles of pinnation (MAPs), and physiological cross‐sectional areas (PCSAs). However, some patterns of variation (e.g. low MA in C. sapidus, indistinguishable force generation potential in the xanthids) suggested that a quantitative assessment of occlusion and dentition is needed to understand fully the relationship between force generation and diet. Interspecific differences in force generation potential seemed mainly to be a function of differences in chela closer muscle cross‐sectional area, due to a sixfold variation in apodeme area. Intraspecific dimorphism was generally defined by tall crushers with long in‐levers, though O. quadrata exhibited an extreme dimorphism suggesting that factors unrelated to a speed–strength dichotomy (e.g. sexual selection) have shaped dimorphism of that species. It is concluded here that: (1) the majority of interspecific claw strength variation is a function of closer muscle cross‐sectional area; (2) variation in claw morphology related to force production and transmission does have some relation to hardness of diet; (3) claw dimorphism in many species does seem to be related to strength and speed trade‐offs; (4) factors besides molluscivory must be considered to understand claw evolution fully; (5) a quantitative assessment of force distribution, lacking in the literature, is essential for a more complete understanding of the relationship between claw design and ecological function.
Nature and autonomy: An organizational view of social and neurobiological aspects of

self-regulation in behavior and development
Authors: RYAN RICHARD M. , KUHL JULIUS , DECI EDWARD L.
Published: July 2002

The concepts of self-regulation and autonomy are examined within an organizational

framework. We begin by retracing the historical origins of the organizational viewpoint in early

debates within the field of biology between vitalists and reductionists, from which the construct

of self-regulation emerged. We then consider human autonomy as an evolved behavioral,

developmental, and experiential phenomenon that operates at both neurobiological and

psychological levels and requires very specific supports within higher order social organizations.

We contrast autonomy or true self-regulation with controlling regulation (a nonautonomous form

of intentional behavior) in phenomenological and functional terms, and we relate the forms of

regulation to the developmental processes of intrinsic motivation and internalization.

Subsequently, we describe how self-regulation versus control may be characterized by distinct

neurobiological underpinnings, and we speculate about some of the adaptive advantages that may

underlie the evolution of autonomy. Throughout, we argue that disturbances of autonomy, which

have both biological and psychological etiologies, are central to many forms of psychopathology

and social alienation.
Coparental and family group-level dynamics during infancy: Early family precursors of
child and family functioning during preschool
Authors: MCHALE JAMES P. , RASMUSSEN JEFFREY L.
Published: July 2002

This study examines longitudinal correlates of coparental and family group-level dynamics
during infancy. Thirty-seven couples observed at play with their 8–11-month-old infants
(15 boys, 22 girls) rated their child's internalizing and externalizing symptoms, and their
own coparenting behavior 3 years later. Teachers also rated child behavior at the 3-year
follow-up. Several significant relationships emerged between observed family process (high
hostility–competitiveness, low family harmony, and high parenting discrepancies in the
triad) at Time 1, and subsequent reports of child and coparenting behavior at Time 2. Larger
parenting discrepancies at Time 1 predicted greater child anxiety as rated by teachers; greater
hostility–competitiveness and lower harmony forecast higher child aggression. Time 1
family process continued to predict Time 2 aggression even after controlling for individual and
marital functioning. Several links were also found between distressed family process and later
parental reports of negative coparenting behavior. These parental reports of coparenting also
explained unique variance in concurrent child behavior ratings. The significance of coparenting
as a distinct family construct is discussed.
Resolving conflict
creatively: Evaluating the developmental effects of a school-based violence prevention program
in neighborhood and classroom context
Authors: ABER J. LAWRENCE , JONES STEPHANIE M. , BROWN JOSHUA L. , CHAUDRY NINA , SAMPLES FAITH
Published: July 2002

This study evaluated
the short-term impact of a school-based violence prevention initiative on developmental
processes thought to place children at risk for future aggression and violence and examined the
influence of classroom and neighborhood contexts on the effectiveness of the violence
prevention initiative. Two waves of developmental data (fall and spring) were analyzed from the
1st year of the evaluation of the Resolving Conflict Creatively Program (RCCP), which includes
5053 children from grades two to six from 11 elementary schools in New York City. Three
distinct profiles of exposure to the intervention were derived from Management Information
System (MIS) data on between classroom differences in teacher Training and Coaching in
RCCP, Classroom Instruction in RCCP, and percentages of students who are Peer Mediators.
Developmental processes that place children at risk were found to increase over the course of the
school year. Children whose teachers had a moderate amount of training and coaching from
RCCP and who taught many lessons showed significantly slower growth in aggression-related
processes, and less of a decrease in competence-related processes, compared to children whose
teachers taught few or no lessons. Contrary to expectation, children whose teachers had a higher
level of training and coaching in the RCCP but taught few lessons showed significantly faster
growth over time in aggressive cognitions and behaviors. The impact of the intervention on
children's social cognitions (but not on their interpersonal behaviors) varied by context.
Specifically the positive effect of High Lessons was dampened for children in high-risk
classrooms and neighborhoods. Implications for future research on developmental
psychopathology in context and for the design of preventive interventions are discussed.
EVOLUTION OF THE ARALIA–PANAX COMPLEX (ARALIACEAE) AS INFERRED FROM NUCLEAR RIBOSOMAL ITS SEQUENCES
Authors: WEN J.
Published: July 2002

The Aralia–Panax complex consists of three closely related genera of Araliaceae (Aralia L., Panax L. and Sciadodendron Griseb.), widely distributed in temperate, subtropical, and tropical regions of Asia and the Americas. Three major lineages (Panax, Aralia sect. Aralia, and Aralia sect. Dimorphanthus Miq.) are disjunctly distributed in eastern Asia and North America. Comparative sequencing of the internal transcribed spacer (ITS) regions of nuclear ribosomal DNA was carried out in order to examine the phylogenetic and biogeographic relationships of this complex. Results suggest Aralia is paraphyletic, with Panax and the Central American monotypic Sciadodendron nested within. The monophyly of Panax (P. trifolius L. maybe excepted), Aralia sect. Aralia (except A. henryi Harms), and Aralia sect. Humiles Harms is supported. The morphologically isolated A. hispida Vent. is embedded within Aralia sect. Dimorphanthus. The phylogenetic data suggest the need to re-examine the generic delimitation of Aralia. None of the presumed intercontinental species pairs between eastern Asia and eastern North America (e.g. Aralia cordata Thunb. and A. racemosa L., A. spinosa L. and A. stipulata Franch., and Panax ginseng C. A. Mey. and P. quinquefolius L.) have been supported as sister species, and the floristic similarity between eastern Asia and eastern North America seems to have been exaggerated by previous workers. Within Aralia sect. Dimorphanthus, the north temperate series Dimorphanthus was paraphyletic, with the subtropical and tropical series Chinensis J. Wen and series Foliolosae J. Wen nested within. This pattern of differentiation is consistent with the hypothesis of morphological stasis among the closely related disjunct taxa between eastern Asia and eastern North America in series Dimorphanthus. Subtropical/tropical Sciadodendron, and Aralia sect. Pentapanax (Seem.) J. Wen are suggested to have derived from temperate elements, although Araliaceae have a generally subtropical and tropical distribution.
Television
Authors: BOURDIEU PIERRE
Published: July 2002

Television claims to report reality but largely creates its own reality. There is very little autonomy, largely because the competition for ‘market share’ is so intense. The pressure to fill the space is strong; hence, it must be something for everyone. Everyone is looking over their shoulder to see what their rivals are saying; to know what to say, you need to know what everyone else is saying. This leads to homogenization and political conformity. Politics and economics lead to an internal censorship. ‘News’ is selective, favouring the extremes, blood, sex, crime, riots, not what ordinary people experience. Television calls for dramatization and the exaggeration of the importance of events. In debate, the fast, superficial thinker is favoured over the original and profound. Can you refuse to talk on television? There is a desire to be seen that is exploited.
Nimrod: a system for generating automated very short range forecasts
Authors: Golding B W
Published: July 2002

A very short range forecasting system has been developed which integrates nowcasting techniques with Numerical Weather Prediction (NWP) model products to provide forecasts over the UK and surrounding waters up to six hours ahead. There are three main components, producing analyses and forecasts of precipitation, cloud and visibility, respectively. The precipitation rate analysis uses processed radar and satellite data, together with surface reports and NWP fields. The forecast is based on an object advection technique, modified for growth and decay using model products. Related variables, such as precipitation type, are also diagnosed using the NWP fields. The cloud analysis is based largely on satellite imagery and surface reports, the forecast being carried out in a similar way to precipitation rate. The visibility analysis combines surface reports with NWP model fields and satellite imagery: Meteosat during the day and NOAA–AVHRR at night. The forecast is an extrapolation using trends from the NWP model, and relaxing towards the model values themselves. Results show a substantial improvement over both persistence and raw NWP model products. Copyright © 1998 Royal Meteorological Society
Introduction to the environmental Kuznets curve special issue
Authors: BARBIER EDWARD B.
Published: July 2002

This short piece introduces the special issue on environmental Kuznets curves (EKC) — the hypothesized 'inverted-U' relationship between levels of environmental degradation and per capita income. Although the analysis of EKC relationships has been a relatively recent phenomenon, there is widespread interest on the part of academics in this analysis, and on the part of policymakers in the resulting implications for environment and development. The following introduction outlines the contributions to EKC analysis of the papers comprising the special issue. This is done in two ways: first, the empirical results of the special issue papers are compared with previous analyses of the EKC relationships; and second, the additional insights offered by the special issue papers on EKCs are discussed.
ERP correlates of executive control during repeated language switching
Authors: Jackson Georgina M. , Swainson Rachel , Cunnington Ross , Jackson Stephen R.
Published: July 2002

A key aspect of higher cognitive function is the ability to switch rapidly and efficiently between alternative modes of response where this is appropriate behaviourally. Such suppression appears to be highly dependent upon the integrity of the prefrontal cortex, yet other cortical areas are likely to be necessary to implement response switching. Language switching in bilingual speakers is a clear example of a task in which response switching is required. Functional brain imaging studies have demonstrated parietal cortex activation during repeated language switching within a translation task. Here we used event-related dense-sensor EEG recording techniques to examine the time course of language switching during a visually cued naming task in which bilingual participants named digits in either their first or second language. Switch-related modulation of ERP components was evident over parietal and frontal cortices, and in the latter case showed an asymmetry across first and second languages. Correspondence with a frontal ERP component found when suppressing manual responding in a Go/No-Go reaction time task may imply that similar inhibitory mechanisms are involved in both response suppression and language switching.
The fasciated ear2 gene encodes a leucine-rich repeat receptor-like protein that regulates shoot meristem proliferation in maize
Authors: Taguchi-Shiobara Fumio , Yuan Zhuang , Hake Sarah , Jackson David
Published: July 2002

The ability to initiate organs throughout the lifecycle is a unique feature of plant development that is executed by groups of stem cells called meristems. The balance between stem cell proliferation and organ initiation is carefully regulated and ensures that organs can be initiated in regular geometric patterns. To understand how this regulation is achieved, we isolated a novel mutant of maize,fasciated ear2 (fea2), which causes a massive overproliferation of the ear inflorescence meristem and a more modest effect on floral meristem size and organ number. We cloned thefea2 gene using transposon tagging, and it encodes a membrane localized leucine-rich repeat receptor-like protein that is most closely related to CLAVATA2 from Arabidopsis. These findings provide evidence that the CLAVATA pathway for regulation of meristem size is functionally conserved throughout the angiosperms. A possible connection of fea2 to the control of crop yields is discussed.
Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability
Authors: Sears Rosalie , Nuckolls Faison , Haura Eric , Taya Yoichi , Tamai Katsuyuki , Nevins Joseph R.
Published: July 2002

Our recent work has shown that activation of the Ras/Raf/ERK pathway extends the half-life of the Myc protein and thus enhances the accumulation of Myc activity. We have extended these observations by investigating two N-terminal phosphorylation sites in Myc, Thr 58 and Ser 62, which are known to be regulated by mitogen stimulation. We now show that the phosphorylation of these two residues is critical for determining the stability of Myc. Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK. Conversely, phosphorylation of Thr 58, likely mediated by GSK-3 but dependent on the prior phosphorylation of Ser 62, is associated with degradation of Myc. Further analysis demonstrates that the Ras-dependent PI-3K pathway is also critical for controlling Myc protein accumulation, likely through the control of GSK-3 activity. These observations thus define a synergistic role for multiple Ras-mediated phosphorylation pathways in the control of Myc protein accumulation during the initial stage of cell proliferation.
Transcriptional regulation of the Drosophila gene zen by competing Smad and Brinker inputs
Authors: Rushlow Christine , Colosimo Pamela F. , Lin Meng-chi , Xu Mu , Kirov Nikolai
Published: July 2002

The establishment of expression domains of developmentally regulated genes depends on cues provided by different concentrations of transcriptional activators and repressors. Here we analyze the regulation of the Drosophila gene zen, which is a target of the Decapentaplegic (Dpp) signaling pathway during cellular blastoderm formation. We show that low levels of the Dpp signal transducer p-Mad (phosphorylated Mad), together with the recently discovered negative regulator Brinker (Brk), define the spatial limits of zen transcription in a broad dorsal-on/ventral-off domain. The subsequent refinement of this pattern to the dorsal-most cells, however, correlates with high levels of p-Mad that accumulate in the same region during late blastoderm. Examination of the zenregulatory sequences revealed the presence of multiple Mad and Brk binding sites, and our results indicate that a full occupancy of the Mad sites due to high concentrations of nuclear Mad is the primary mechanism for refinement of zen. Interestingly, several Mad and Brk binding sites overlap, and we show that Mad and Brk cannot bind simultaneously to such sites. We propose a model whereby competition between Mad and Brk determines spatially restricted domains of expression of Dpp target genes.
Circadian Rhythms Confer a Higher Level of Fitness to Arabidopsis Plants
Authors: Green Rachel M. , Tingay Sonia , Wang Zhi-Yong , Tobin Elaine M.
Published: July 2002

Circadian rhythms have been demonstrated in organisms across the taxonomic spectrum. In view of their widespread occurrence, the adaptive significance of these rhythms is of interest. We have previously shown that constitutive expression of theCCA1 (CIRCADIAN CLOCK ASSOCIATED 1) gene in Arabidopsis plants (CCA1-ox) results in loss of circadian rhythmicity. Here, we demonstrate that these CCA1-ox plants retain the ability to respond to diurnal changes in light. Thus, transcript levels of several circadian-regulated genes, as well as CCA1 itself and the closely related LHY, oscillate robustly if CCA1-ox plants are grown under diurnal conditions. However, in contrast with wild-type plants in which transcript levels change in anticipation of the dark/light transitions, the CCA1-ox plants have lost the ability to anticipate this daily change in their environment. We have used CCA1-ox lines to examine the effects of loss of circadian regulation on the fitness of an organism. CCA1-ox plants flowered later, especially under long-day conditions, and were less viable under very short-day conditions than their wild-type counterparts. In addition, we demonstrate that two other circadian rhythm mutants, LHY-ox and elf3, have low-viability phenotypes. Our findings demonstrate the adaptive advantage of circadian rhythms in Arabidopsis.
Uptake Kinetics of Arsenic Species in Rice Plants
Authors: Abedin Mohammed Joinal , Feldmann Jörg , Meharg Andy A.
Published: July 2002

Arsenic (As) finds its way into soils used for rice (Oryza sativa) cultivation through polluted irrigation water, and through historic contamination with As-based pesticides. As is known to be present as a number of chemical species in such soils, so we wished to investigate how these species were accumulated by rice. As species found in soil solution from a greenhouse experiment where rice was irrigated with arsenate contaminated water were arsenite, arsenate, dimethylarsinic acid, and monomethylarsonic acid. The short-term uptake kinetics for these four As species were determined in 7-d-old excised rice roots. High-affinity uptake (0–0.0532 mm) for arsenite and arsenate with eight rice varieties, covering two growing seasons, rice var. Boro (dry season) and rice var. Aman (wet season), showed that uptake of both arsenite and arsenate by Boro varieties was less than that of Aman varieties. Arsenite uptake was active, and was taken up at approximately the same rate as arsenate. Greater uptake of arsenite, compared with arsenate, was found at higher substrate concentration (low-affinity uptake system). Competitive inhibition of uptake with phosphate showed that arsenite and arsenate were taken up by different uptake systems because arsenate uptake was strongly suppressed in the presence of phosphate, whereas arsenite transport was not affected by phosphate. At a slow rate, there was a hyperbolic uptake of monomethylarsonic acid, and limited uptake of dimethylarsinic acid.
Antisense Acid Invertase (TIV1) Gene Alters Soluble Sugar Composition and Size in Transgenic Tomato Fruit
Authors: Klann E. M. , Hall B. , Bennett A. B.
Published: July 2002

Invertase (β-fructosidase, EC 3.2.1.26) hydrolyzes sucrose to hexose sugars and thus plays a fundamental role in the energy requirements for plant growth and maintenance. Transgenic plants with altered extracellular acid invertase have highly disturbed growth habits. We investigated the role of intracellular soluble acid invertase in plant and fruit development. Transgenic tomato (Lycopersicon esculentum Mill.) plants expressing a constitutive antisense invertase transgene grew identically to wild-type plants. Several lines of transgenic fruit expressing a constitutive antisense invertase gene had increased sucrose and decreased hexose sugar concentrations. Each transgenic line with fruit that had increased sucrose concentrations also had greatly reduced levels of acid invertase in ripe fruit. Sucrose-accumulating fruit were approximately 30% smaller than control fruit, and this differential growth correlated with high rates of sugar accumulation during the last stage of development. These data suggest that soluble acid invertase controls sugar composition in tomato fruit and that this change in composition contributes to alterations in fruit size. In addition, sucrose-accumulating fruit have elevated rates of ethylene evolution relative to control fruit, perhaps as a result of the smaller fruit size of the sucrose-accumulating transgenic lines.
Symplasmic Constriction and Ultrastructural Features of the Sieve Element/Companion Cell Complex in the Transport Phloem of Apoplasmically and Symplasmically Phloem-Loading Species1
Authors: Kempers Ronald , Ammerlaan Ankie , van Bel Aart J.E.
Published: July 2002

The ultrastructural features of the sieve element/companion cell complexes were screened in the stem phloem of two symplasmically loading (squash, [Cucurbita maxima L.] and Lythrum salicaria L.) and two apoplasmically loading (broad bean [Vicia faba L.] andZinnia elegans L.) species. The distinct ultrastructural differences between the companion cells in the collection phloem of symplasmically and apoplasmically phloem-loading species continue to exist in the transport phloem. Plasmodesmograms of the stem phloem showed a universal symplasmic constriction at the interface between the sieve element/companion cell complex and the phloem parenchyma cells. This contrasts with the huge variation in symplasmic continuity between companion cells and adjoining cells in the collection phloem of symplasmically and apoplasmically loading species. Further, the ultrastructure of the companion cells in the transport phloem faintly reflected the features of the companion cells in the loading zone of the transport phloem. The companion cells of squash contained numerous small vacuoles (or vesicles), and those of L. salicariacontained a limited number of vacuoles. The companion cells of broad bean and Z. elegans possessed small wall protrusions. Implications of the present findings for carbohydrate processing in intact plants are discussed.
Re-Aeration following Hypoxia or Anoxia Leads to Activation of the Antioxidative Defense System in Roots of Wheat Seedlings1
Authors: Biemelt Sophia , Keetman Ulrich , Albrecht Gerd
Published: July 2002

The response of the ascorbate-glutathione cycle was investigated in roots of young wheat (Triticum aestivum L.) seedlings that were deprived of oxygen either by subjecting them to root hypoxia or to entire plant anoxia and then re-aerated. Although higher total levels of ascorbate and glutathione were observed under hypoxia, only the total amount of ascorbate was increased under anoxia. Under both treatments a significant increase in the reduced form of ascorbate and glutathione was found, resulting in increased reduction states. Upon the onset of re-aeration the ratios started to decline rapidly, indicating oxidative stress. Hypoxia caused higher activity of ascorbate peroxidase, whereas activities of monodehydroascorbate reductase, dehydroascorbate reductase, and glutathione reductase were diminished or only slightly influenced. Under anoxia, activities of ascorbate peroxidase and glutathione reductase decreased significantly to 39 and 62%, respectively. However, after re-aeration of hypoxically or anoxically pretreated roots, activity of enzymes approached the control levels. This corresponds with the restoration of the high reduction state of ascorbate and glutathione within 16 to 96 h of re-aeration, depending on the previous duration of anoxia. Apparently, anoxia followed by re-aeration more severely impairs entire plant metabolism compared with hypoxia, thus leading to decreased viability.
High Expression of the Tonoplast Aquaporin ZmTIP1in Epidermal and Conducting Tissues of Maize1
Authors: Barrieu François , Chaumont François , Chrispeels Maarten J.
Published: July 2002

Aquaporins are integral membrane proteins of the tonoplast and the plasma membrane that facilitate the passage of water through these membranes. Because of their potentially important role in regulating water flow in plants, studies documenting aquaporin gene expression in specialized tissues involved in water and solute transport are important. We used in situ hybridization to examine the expression pattern of the tonoplast aquaporinZmTIP1 in different organs of maize (Zea mays L.). This tonoplast water channel is highly expressed in the root epidermis, the root endodermis, the small parenchyma cells surrounding mature xylem vessels in the root and the stem, phloem companion cells and a ring of cells around the phloem strand in the stem and the leaf sheath, and the basal endosperm transfer cells in developing kernels. We postulate that the high level of expression ofZmTIP1 in these tissues facilitates rapid flow of water through the tonoplast to permit osmotic equilibration between the cytosol and the vacuolar content, and to permit rapid transcellular water flow through living cells when required.
Identification of a Functional Homolog of the Yeast Copper Homeostasis Gene ATX1 from Arabidopsis1
Authors: Himelblau Edward , Mira Helena , Lin Su-Ju , Cizewski Culotta Valeria , Peñarrubia Lola , Amasino Richard M.
Published: July 2002

A cDNA clone encoding a homolog of the yeast (Saccharomyces cerevisiae) gene Anti-oxidant 1(ATX1) has been identified from Arabidopsis. This gene, referred to as CopperCHaperone(CCH), encodes a protein that is 36% identical to the amino acid sequence of ATX1 and has a 48-amino acid extension at the C-terminal end, which is absent from ATX1 homologs identified in animals. ATX1-deficient yeast (atx1) displayed a loss of high-affinity iron uptake. Expression of CCH in the atx1 strain restored high-affinity iron uptake, demonstrating thatCCH is a functional homolog of ATX1. When overexpressed in yeast lacking the superoxide dismutase geneSOD1, both ATX1 and CCHprotected the cell from the reactive oxygen toxicity that results from superoxide dismutase deficiency. CCH was unable to rescue the sod1 phenotype in the absence of copper, indicating that CCH function is copper dependent. In Arabidopsis CCH mRNA is present in the root, leaf, and inflorescence and is up-regulated 7-fold in leaves undergoing senescence. In plants treated with 800 nL/L ozone for 30 min,CCH mRNA levels increased by 30%. In excised leaves and whole plants treated with high levels of exogenous CuSO4,CCH mRNA levels decreased, indicating thatCCH is regulated differently than characterized metallothionein proteins in Arabidopsis.
pH-Regulated Leaf Cell Expansion in Droughted Plants Is Abscisic Acid Dependent
Authors: Bacon Mark A. , Wilkinson Sally , Davies William J.
Published: July 2002

Elongation rates of barley (Hordeum vulgare L. cv Hanna) leaves decreased with decreasing soil water content, whereas the pH of xylem sap increased from 5.9 to 6.9 over 6 d as the soil dried. The reduction in leaf-elongation rate (LER) was correlated with the increase in sap pH. Artificial sap buffered to different pH values was fed via the subcrown internode to derooted seedlings. Although leaves elongated at in planta rates when fed artificial sap at a well-watered pH of 6.0, LER declined with increasing sap pH. This effect persisted in the light and in the dark. pH had no effect on the relative water content or the bulk abscisic acid (ABA) concentration of the growing zone of these leaves. LERs of the ABA-deficient mutant Az34 were uniformly high over the pH range tested, whereas those of its isogenic wild-type cultivar Steptoe were reduced as the artificial sap pH was increased from 6.0 to 7.0. However, supplying a well-watered concentration of ABA (3 × 10−8  m) in the artificial xylem sap restored the pH response of the Az34 mutant. The results suggest that increased xylem sap pH acts as a drought signal to reduce LER via an ABA-dependent mechanism.
Interactions between Senescence and Leaf Orientation Determine in Situ Patterns of Photosynthesis and Photoinhibition in Field-Grown Rice1
Authors: Murchie Erik H. , Chen Yi-zhu , Hubbart Stella , Peng Shaobing , Horton Peter
Published: July 2002

Photosynthesis and photoinhibition in field-grown rice (Oryza sativa L.) were examined in relation to leaf age and orientation. Two varieties (IR72 and IR65598-112-2 [BSI206]) were grown in the field in the Philippines during the dry season under highly irrigated, well-fertilized conditions. Flag leaves were examined 60 and 100 d after transplanting. Because of the upright nature of 60-d-old rice leaves, patterns of photosynthesis were determined by solar movements: light falling on the exposed surface in the morning, a low incident angle of irradiance at midday, and light striking the opposite side of the leaf blade in the afternoon. There was an early morning burst of CO2 assimilation and high levels of saturation of photosystem II electron transfer as incident irradiance reached a maximum level. However, by midday the photochemical efficiency increased again almost to maximum. Leaves that were 100 d old possessed a more horizontal orientation and were found to suffer greater levels of photoinhibition than younger leaves, and this was accompanied by increases in the de-epoxidation state of the xanthophyll cycle. Older leaves had significantly lower chlorophyll content but only slightly diminished photosynthesis capacity.