bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural plasticity and tianeptine: cellular and molecular targets
Authors: McEwen B.S. , Magarinos A.M. , Reagan L.P.
Published: December 2002

The hippocampal formation, a structure involved in declarative, spatial and contextual memory, undergoes atrophy in depressive illness along with impairment in cognitive function. Animal model studies have shown that the hippocampus is a particularly sensitive and vulnerable brain region that responds to stress and stress hormones. Studies on models of stress and glucocorticoid actions reveal that the hippocampus shows a considerable degree of structural plasticity in the adult brain. Stress suppresses neurogenesis of dentate gyrus granule neurons, and repeated stress causes remodeling of dendrites in the CA3 region, a region that is particularly important in memory processing. Both forms of structural remodeling of the hippocampus are mediated by adrenal steroids working in concert with excitatory amino acids (EAA) andN-methyl-D-aspartate (NMDA) receptors. EAA and NMDA receptors are also involved in neuronal death that is caused in pyramidal neurons by seizures, head trauma, and ischemia, and alterations of calcium homeostasis that accompany age-related cognitive impairment. Tianeptine (tianeptine) is an effective antidepressant that prevents and even reverses the actions of stress and glucocorticoids on dendritic remodeling in an animal model of chronic stress. Multiple neurotransmitter systems contribute to dendritic remodeling, including EAA, serotonin, and gamma-aminobutyric acid (GABA), working synergistically with glucocorticoids. This review summarizes findings on neurochemical targets of adrenal steroid actions that may explain their role in the remodeling process. In studying these actions, we hope to better understand the molecular and cellular targets of action of tianeptine in relation to its role in influencing structural plasticity of the hippocampus.
A meta-analysis of randomized controlled trials of tianeptine versus SSRI in the short-term treatment of depression
Authors: Kasper S. , Olié J.P.
Published: December 2002

A meta-analysis was performed to compare the efficacy of tianeptine and selective serotonin reuptake inhibitors (SSRI) in the short-term treatment of depression. Consecutive selection and inclusion processes allowed five studies to be selected: two studies on tianeptine versus fluoxetine, two studies on tianeptine versus paroxetine, and one study on tianeptine versus sertraline. A total of 1348 patients were included in the five studies; 681 subjects received an SSRI and 667 tianeptine.

A strict step-by-step methodology was applied in order to legitimize this meta-analysis and to interpret the results. Considering all the patients or those with a Montgomery–Åsberg Depression Rating Scale (MADRS) inclusion score greater than 28, none of the assessed parameters (MADRS total score and responder rate) revealed any significant difference between the two treatment groups. Further analysis based on clinical global impression (CGI) items found no significant difference, except for CGI item 3 (therapeutic index), where a tendency (P=0.06 or 0.07 depending on the methodology) was found in favor of tianeptine. All in all, this study confirmed that tianeptine is at least as effective as SSRI, with a trend for a better acceptability profile in the treatment of depressed patients.
Pathophysiology of depression: the concept of synaptic plasticity
Authors: Duman R.S.
Published: December 2002

Neuronal plasticity or remodeling is most often discussed with regard to cellular and behavioral models of learning and memory. However, neuronal plasticity is a fundamental process by which the brain acquires information and makes the appropriate adaptive responses in future-related settings. Dysfunction of these fundamental processes could thereby contribute to the pathophysiology of mood disorders, and recovery could occur by induction of the appropriate plasticity or remodeling. These possibilities are supported by preclinical and clinical studies demonstrating that there are structural alterations that occur in response to stress and in patients with mood disorders. Moreover, antidepressant treatment may oppose these effects by regulation of signal transduction and gene expression pathways linked to neuronal plasticity. These findings comprise a novel conceptual framework for future studies of the etiology of mood disorders and for the development of novel therapeutic interventions.
The hippocampus and depression
Authors: Sheline Y.I. , Mittler B.L. , Mintun M.A.
Published: December 2002

The effect of depression on the hippocampus has become the focus of a number of structural and functional neuroimaging studies. In the past two decades, advances in neuroimaging techniques now allow the examination of subtle changes in both regional structure and function that are associated with the pathophysiology of depression. Many studies using 3-dimensional magnetic resonance imaging (MRI) volumetric measurement have reported decreases in hippocampal volume among depressed subjects compared with controls, whereas other studies have not found any volume loss. Differences among studies have been discussed. In some studies, the volume loss appears to have functional significance including an association with memory loss. Furthermore, we have found a trend towards loss of 5-HT2Areceptors in the hippocampus using positron emission tomography (PET) to detect regional changes in [18F]altanserin binding. Functional imaging extends the sensitivity and specificity of structural imaging and will lead to a better understanding of affective disorders.
Introduction to ‘Music and Television’ special issue
Authors: Negus Keith , Street John
Published: December 2002

Television has been conspicuously neglected in studies of popular music, and music has been notably absent from most accounts of television. The thought that this neglect might be significant was taken as the starting point for this special edition of the journal. Unlike some subjects (such as popular music and gender/sexuality, for example), where it is readily apparent that a number of people are busily pursuing research and where there is a history of sustained engagement in a range of related theories and debates, it was not clear initially who, if anyone, was seriously thinking about or researching the relationship between music and television. Even work on popular music and video, which once grabbed the imagination of popular music and media scholars, has faded from the academic agenda. We hoped that the call for papers might strike a chord and prompt new thoughts about this area.
‘One night on TV is worth weeks at the Paramount’: musicians and opportunity in early television, 1948–55
Authors: Forman Murray
Published: December 2002

This article addresses a gap in the historical study of music on television by revisiting North American popular music in conjunction with the broadcast medium's early stage of development. Central to its analysis is the fact that music has always been deemed essential to the character and success of television. Emphasising the circulating discourses of ‘opportunity’, the article isolates the ways in which some musicians and others in various sectors of the music industry regarded the new medium as a positive influence at its inception. Among key considerations at the time were issues of musical performance style and aesthetics, repertoire, promotional capabilities, career enhancement, and additional leisure options for audiences.
Chewing gum for the ears: children's television and popular music
Authors: Lury Karen
Published: December 2002

Television is one of the earliest ways that children gain access to popular music. The child's early experience of both music and television does not necessarily separate out ‘music alone’ from his or her evolving musical appreciation. The co-operation of television and popular music encourage particular modes of attention and expression for the child as both viewer and listener. Movement, gesture, and the response of the body to the visual and aural cues of music-television may be seen to inform this appreciation. The child learns, feels and demonstrates that they have done so. This is guided and inspired by what they hear and see.
Authentic boy bands on TV? Performers and impresarios in The Monkees and Making the Band
Authors: Stahl Matthew
Published: December 2002

Boy bands embody contradictory representations of their own individuality and authenticity and the corporate nature of their genesis and presentation. Boy band members, the impresarios and entrepreneurs behind them, and the producers of television shows about them must contend in their work and relationships with the social and symbolic conventions of their historical moment. In this article I analyse representations of boy bands on the American TV shows The Monkees (1966-8) and Making the Band (2000-) in order to highlight shifts in the ways the performers and production personnel have been represented and have sought to represent themselves. The internal push for legitimacy and autonomy of the young stars of these shows, acting from within a perceived but unstable gap between ‘musician’ and ‘employee’, exists in tension with the external push of TV and music producers, network, record label and marketing departments for rational, predictable products and behaviours that fit within an overall business plan. While the rock ideology of authenticity has lost much of the force it had in the 1960s and change in representational conventions seem to indicate a general acceptance of the overt commercialism of chart-busting pop, this article shows that even within the mainstream flows a strong current of concern over issues of authenticity, legitimacy and autonomy.
From fanfare to funfair: the changing sound world of UK television idents
Authors: Brownrigg Mark , Meech Peter
Published: December 2002

Identifying a television channel on-air has become increasingly important in the multi-channel age. For viewers it is a navigational necessity; for broadcasting executives it contributes to corporate branding. But despite the fact that television is an audiovisual medium, the so-called channel idents which appear between programmes are almost always discussed in terms of their visual rather than their audio characteristics. This article aims to go some way to correct this imbalance in arguing that the latter have evolved in a distinctive manner. Initially borrowing the idea of the fanfare from the cinema, UK broadcasters in recent years have developed a softer style, then drawn on dance and other forms of popular music and finally employed sound effects in the production of channel idents.
Television's problem with (classical) music
Authors: Chanan Michael
Published: December 2002

The idea I have in mind is to compare the situation on television today and thirty years ago of what persists in being known as classical music. I write as an academic, but this will not be a normal academic paper. For one thing, I shall not do any special research but base myself instead on memory and autobiographical experience, because thirty years ago, before becoming an academic, I began by writing music criticism and making documentaries on music for television. My intention is to say something as a participant observer about the alteration of the cultural context in which this thing called classical music operates, and about the part that television has played in this.
Reusable XML technologies and the development of language learning materials
Authors: WARD MONICA
Published: December 2002

There are many CALL resources available today but often they need to be adapted
for level or culture. CALL practitioners would like to reuse currently existing material rather than
reinvent the wheel, but often this is not possible. Thus, they end up building CALL material, both
language content and software, from scratch. This is inefficient in terms of CALL practitioners’
time and as Felix (1999) points out, there is no point ‘doing badly’ what has already
been done well. Why can’t we reuse what already exists? Often the language content is
hard-wired in the software and cannot be modified or the CALL material comes as an executable which
is hard or impossible to change. Authoring tools can provide a degree of flexibility, but often
focus on particular parts of the language learning process (e.g. interactive exercises) and the
associated language content cannot, in general, easily be exported into other formats and
presentation software. One solution to this problem is provided by XML technologies. They provide
a strict separation between data and processing. Thus, three types of reuse are possible: reuse of
the data processing engine (i.e. the XSL processing files), reuse of the language content structure
(i.e. the XML data files) and reuse the linguistic resources (i.e. the language content). In this
paper, an example is given of a CALL template that has been developed using XML technologies. The
template provides a structure into which the language content can be slotted and a processing engine
to act upon the data to create CALL material. The template was developed for the production of
CALL materials for Endangered Languages (ELs), but could be used for MCTLs (Most Commonly Taught
Languages) and LCTLs (Less Commonly Taught Languages) also. It has been used to develop a language
learning course for Nawat (a language of El Salvador), Akan (a Ghanaian language) and Irish,
demonstrating the reusability of the language content structure as well as proving the reusability
of the processing engine provided by the template. A further reusable feature is the ability to
create courseware in different media (Internet, CD and print) from the same source language content.
Improving access to target vocabulary using computerized bilingual dictionaries
Authors: LOUCKY JOHN PAUL
Published: December 2002

This study aims to compare various computerized bilingual dictionaries
(henceforth CBDs) for their relative effectiveness in helping Japanese college students at several
language proficiency levels to access new English target vocabulary. Its rationale was based on
several observations and research claims (see Atkins & Knowles, 1990; Bejoint & Moulin, 1987;
Laufer & Hadar, 1997) that bilingual and bilingualized dictionaries in general, as well as
electronic dictionaries in particular appear to be much more rapid and effective than monolingual
book dictionaries for the acquisition of new L2 vocabulary by language learners. The author has been
testing and analyzing various CBDs in four major categories for the past two years. These include
(i) portable electronic dictionaries (PEDs); (ii) software CBDs; (iii) online dictionary websites;
and (iv) optical character recognition/translation (OCR/OCT) devices, both portable handheld
’Reading Pens‘ (e.g. Quickionary/Quicklink) and also flatbed OCR scanners (Logo Vista)
bundled with translation programs. His research started over ten years ago, however, culminating in
a dissertation entitled ‘Developing and testing vocabulary training methods and materials for
Japanese college students studying English as a foreign language’ (Loucky, 1996; or summary
thereof, Loucky, 1997). This dissertation studied the pre- and post-test vocabulary, comprehension,
listening and total reading levels of over 1,000 Japanese college students at six institutions.
Since then the author has devised a simple yet practical Vocabulary Knowledge Scale (VKS), helping
to more clearly define and test the differences between passive or receptive understanding
vocabulary and active or productive use vocabulary. Computerized technology has now made possible
multimedia programming with the benefits of interactive processing and immediate feedback.
Modern CAI/CAELL along with well-made CBDs, either online or off, can already be found to scan,
pronounce and translate for us in any direction of the four language skills. This study examined
Japanese college students’ use of four kinds of CBDs for more rapid accessing and archiving
of new L2 terms, recommending integration of their use into a more systematic taxonomy of
vocabulary learning strategies.
Evaluation of a team model of digital language exchange
Authors: KUNG SHIAO-CHUAN
Published: December 2002

This paper describes an online collaborative model designed to allow meaningful,
authentic interactions between college English as a Foreign Language (EFL) students and adult native
speakers of English. The program uses technology to bridge the gap between the need of EFL students to
interact with native speakers for successful language learning and the geographical distance of EFL
classrooms. The two groups of participants were brought together in a symbiotic relationship enabled and
shaped by an online collaborative learning environment. This study employed two 4-member teams collaborating
on an electronic bulletin board to address problems such as lack of response and lack of purpose that
current models of online exchange face. Findings indicate that the team model is a viable alternative to
one-to-one or many-to-many correspondence. They also suggest that collaborative activities may play an
important role in fostering meaningful and lasting interactions.
Discovery of breeding grounds of a Siberian Crane Grus leucogeranus flock that winters in Iran, via satellite telemetry
Authors: Kanai Yutaka , Nagendran Meenakshi , Ueta Mutsuyuki , Markin Yuri , Rinne Juhani , Sorokin Alexander G. , Higuchi Hiroyoshi , Archibald George W.
Published: December 2002

Siberian Crane Grus leucogeranus occurs only in Asia, and is Critically Endangered. The western population of the species has been almost extirpated, wintering at just two known sites, in Iran and India. To help conserve species that migrate long distances it is essential to have a comprehensive conservation plan that includes identification of migration routes and key resting areas. One Siberian Crane was satellite-tracked from the south Caspian Sea to its breeding grounds in Russia during the spring of 1996. The crane began migration on 6 March, and completed its migration on 1 May. This destination was formerly unknown as a breeding area for the species. During migration, the crane rested primarily at the eastern end of the Volga River delta. This suggests that the delta may be an important resting site for Siberian Crane.
Factors affecting the response of Seychelles Scops-owl Otus insularis to playback of conspecific calls: consequences for monitoring and management
Authors: Currie David , Millett James , Hill Mike , Jivan Shah Nirmal
Published: December 2002

The endemic Seychelles Scops-owl Otus insularis is a Critically Endangered restricted range species currently only recorded in the upland forest of Mahé, the largest (152 km2) and highest (903 m) island in the granitic Seychelles. We studied the response of colour-ringed individuals to playback of conspecific calls, to determine factors affecting playback reaction, to monitor behaviour and to assess the reliability of current monitoring techniques. Playback of the territorial waugh call was conducted at fixed points (c. 200 m apart) every month along a total transect length of 8.4 km between April 1999 and May 2001. On the basis of responses and movements of marked individuals we identified 12 territories and noted their boundaries. Mean territory length was 2.92 points (approximately 400 m), equivalent to a conservative estimated territory size of c. 12–16 ha. Males were more frequently detected than females/pairs. The probability of detection (males vs. females/pairs) was 0.87 vs. 0.50 on territory; 0.65 vs. 0.26 at fixed points within territories; and 0.58 vs. 0.22 at fixed points along the transect. There was some significant seasonal variation in detection rates at fixed points within territories for both males and pairs, and in general there was a low probability of detecting individuals around June-August and a high probability of detection around April and, to a lesser degree, October. Response times and owl-recorder distances were not influenced by moon phase or time of playback. This study provides the first baseline data on individual responses to the systematic repeated use of playback in Seychelles Scops-owl. We discuss the implications for current monitoring and its application to other similar Otus species.
Interaction of katabatic winds and mesocyclones near the eastern coast of Greenland
Authors: Klein Thomas , Heinemann Günther
Published: December 2002

Satellite images occasionally show the existence of mesocyclones (MCs) close to the eastern coast of Greenland, especially in the region of Angmagssalik/Tasiilaq. The forcing mechanisms of such MCs are investigated by means of numerical simulations with a three‐dimensional mesoscale model. The special characteristics of the East Greenland topography are shown to be a key factor for the development of the MCs. The channeling of the flow in large valleys along the East Greenland coast leads to a convergence, implying a vertical stretching of the flow through the valleys and the generation of cyclonic vorticity. This convergence can be strong during intense katabatic storms, so‐called Piteraqs, which are a much‐feared phenomenon in that area of Greenland. During these situations the synoptic environment enforces the katabatic flow. The results of the simulations suggest a close relationship between the occurrence of Piteraqs and the generation of mesoscale vortices close to the East Greenland coast. An improved understanding of these processes will help forecasters to advise aircraft and ship operations near the coast of East Greenland. Copyright © 2002 Royal Meteorological Society.
A one‐dimensional Kalman filter for the correction of near surface temperature forecasts
Authors: Galanis George , Anadranistakis Manolis
Published: December 2002

A one‐dimensional Kalman filter is proposed for the correction of maximum and minimum near surface (2 m) temperature forecasts obtained by a Numerical Weather Prediction model. In our study we used only one parameter (observed temperature), employing in this way scalar system and observation equations, and a limited time interval (7 days). As a result, our algorithm can be easily run on any PC with only minor technical support. The corresponding results are rather impressive, since the systematic error of our time series almost disappears, and they show the merit of post‐processing even when only a simple method is applied. Copyright © 2002 Royal Meteorological Society.
Enhancing swimming pool management decisions with climate information
Authors: Changnon David , Sparks Jesse , Burgoyne Andrew , Hahn Chad , Seymour Ross
Published: December 2002

Historical climate conditions were examined to determine whether climate information could improve decisions concerning the seasonal maintenance and operations of regional outdoor swimming pools in heavily urbanised northeastern Illinois. Key weather‐sensitive issues defined for pool companies concern time periods for maintenance (including pool painting), weather limits to pools being open, and hot days which extend hours of pool operation. The specific conditions included the frequency of spring and fall painting periods (defined as dry conditions for two or more days with Tmax ≥18°C (65°F) and Tmin ≥4°C (40°F)); summer inclement weather days (days with precipitation ≥2.54 mm (0.10 inch) with not more than 2 consecutive hours of dry conditions during open swimming hours and/or Tmax ≤21°C (70°F)); and hot days (Tmax ≥32°C (90°F)) were examined.

Climatic records for the region going back 42 years revealed that there were nearly twice as many fall painting periods as those in the spring, indicating that greater emphasis should be placed on pool painting after the swimming season. The average number of inclement weather days was more than twice the number the company budgeted for at the beginning of each swimming season. Plans to extend swimming hours on hot days involves a risky decision since the number of hot days varies dramatically from year‐to‐year in the Chicago region. Studies showed that winter negative sea‐surface temperature anomalies in the central Pacific were related to an above average number of spring painting periods. Also, a higher number of hot summer days occur following El Niño‐classified winters. Results reveal that decision‐makers in the swimming pool management industry can improve several management decisions by including climate information. Copyright © 2002 Royal Meteorological Society.
Interactions among prions and prion “strains” in yeast
Authors: Bradley Michael E. , Edskes Herman K. , Hong Joo Y. , Wickner Reed B. , Liebman Susan W.
Published: December 2002

Prions are “infectious” proteins. When Sup35, a yeast translation termination factor, is aggregated in its [
PSI
+
] prion form its function is compromised. When Rnq1 is aggregated in its [
PIN
+
] prion form, it promotes the
de novo
appearance of [
PSI
+
]. Heritable variants (strains) of [
PSI
+
] with distinct phenotypes have been isolated and are analogous to mammalian prion strains with different pathologies. Here, we describe heritable variants of the [
PIN
+
] prion that are distinguished by the efficiency with which they enhance the
de novo
appearance of [
PSI
+
]. Unlike [
PSI
+
] variants, where the strength of translation termination corresponds to the level of soluble Sup35, the phenotypes of these [
PIN
+
] variants do not correspond to levels of soluble Rnq1. However, diploids and meiotic progeny from crosses between either different [
PSI
+
], or different [
PIN
+
] variants, always have the phenotype of the parental variant with the least soluble Sup35 or Rnq1, respectively. Apparently faster growing prion variants cure cells of slower growing or less stable variants of the same prion. We also find that
YDJ1
overexpression eliminates some but not other [
PIN
+
] variants and that prions are destabilized by meiosis. Finally, we show that, like its affect on [
PSI
+
] appearance, [
PIN
+
] enhances the
de novo
appearance of [
URE3
]. Surprisingly, [
PSI
+
] inhibited [
URE3
] appearance. These results reinforce earlier reports that heterologous prions interact, but suggest that such interactions can not only positively, but also negatively, influence the
de
novo
generation of prions.
Does heterochromatin protein 1 always follow code?
Authors: Li Yuhong , Kirschmann Dawn A. , Wallrath Lori L.
Published: December 2002

Heterochromatin protein 1 (HP1) is a conserved chromosomal protein that participates in chromatin packaging and gene silencing. A loss of HP1 leads to lethality in
Drosophila
and correlates with metastasis in human breast cancer cells. On
Drosophila
polytene chromosomes HP1 is localized to centric regions, telomeric regions, in a banded pattern along the fourth chromosome, and at many sites scattered throughout the euchromatic arms. Recently, one mechanism of HP1 chromosome association was revealed; the amino-terminal chromo domain of HP1 interacts with methylated lysine nine of histone H3, consistent with the histone code hypothesis. Compelling data support this mechanism of HP1 association at centric regions. Is this the only mechanism by which HP1 associates with chromosomes? Interest is now shifting toward the role of HP1 within euchromatic domains. Accumulating evidence in
Drosophila
and mammals suggests that HP1 associates with chromosomes through interactions with nonhistone chromosomal proteins at locations other than centric heterochromatin. Does HP1 play a similar role in chromatin packaging and gene regulation at these sites as it does in centric heterochromatin? Does HP1 associate with the same proteins at these sites as it does in centric heterochromatin? A first step toward answering these questions is the identification of sequences associated with HP1 within euchromatic domains. Such sequences are likely to include HP1 “target genes” whose discovery will aid in our understanding of HP1 lethality in
Drosophila
and metastasis of breast cancer cells.
Histone H3 variants specify modes of chromatin assembly
Authors: Ahmad Kami , Henikoff Steven
Published: December 2002

Histone variants have been known for 30 years, but their functions and the mechanism of their deposition are still largely unknown.
Drosophila
has three versions of histone H3. H3 packages the bulk genome, H3.3 marks active chromatin and may be essential for gene regulation, and Cid is the characteristic structural component of centromeric chromatin. We have characterized the properties of these histones by using a
Drosophila
cell-line system that allows precise analysis of both DNA replication and histone deposition. The deposition of H3 is restricted to replicating DNA. In striking contrast, H3.3 and Cid deposit throughout the cell cycle. Deposition of H3.3 occurs without any corresponding DNA replication. To confirm that the deposition of Cid is also replication-independent (RI), we examined centromere replication in cultured cells and neuroblasts. We found that centromeres replicate out of phase with heterochromatin and display replication patterns that may limit H3 deposition. This confirms that both variants undergo RI deposition, but at different locations in the nucleus. How variant histones accomplish RI deposition is unknown, and raises basic questions about the stability of nucleosomes, the machinery that accomplishes nucleosome assembly, and the functional organization of the nucleus. The different
in vivo
properties of H3, H3.3, and Cid set the stage for identifying the mechanisms by which they are differentially targeted. Here we suggest that local effects of “open” chromatin and broader effects of nuclear organization help to guide the two different H3 variants to their target sites.
Self-perpetuating epigenetic pili switches in bacteria
Authors: Hernday Aaron , Krabbe Margareta , Braaten Bruce , Low David
Published: December 2002

Bacteria have developed an epigenetic phase variation mechanism to control cell surface pili–adhesin complexes between heritable expression (phase ON) and nonexpression (phase OFF) states. In the pyelonephritis-associated pili (
pap
) system, global regulators [catabolite gene activator protein (CAP), leucine-responsive regulatory protein (Lrp), DNA adenine methylase (Dam)] and local regulators (PapI and PapB) control phase switching. Lrp binds cooperatively to three
pap
DNA binding sites, sites 1–3, proximal to the
papBA
pilin promoter in phase OFF cells, whereas Lrp is bound to sites 4–6 distal to
papBA
in phase ON cells. Two Dam methylation targets, GATC
prox
and GATC
dist
, are located in Lrp binding sites 2 and 5, respectively. In phase OFF cells, binding of Lrp at sites 1–3 inhibits methylation of GATC
prox
, forming the phase OFF DNA methylation pattern (GATC
dist
methylated, GATC
prox
nonmethylated). Binding of Lrp at sites 1–3 blocks
pap
pili transcription and reduces the affinity of Lrp for sites 4–6. Together with methylation of GATC
dist
, which inhibits Lrp binding at sites 4–6, the phase OFF state is maintained. We hypothesize that transition to the phase ON state requires DNA replication to dissociate Lrp and generate a hemimethyated GATC
dist
site. PapI and methylation of GATC
prox
act together to increase the affinity of Lrp for sites 4–6. Binding of Lrp at the distal sites protects GATC
dist
from methylation, forming the phase ON methylation pattern (GATC
dist
nonmethyated, GATC
prox
methylated). Lrp binding at sites 4–6 together with cAMP-CAP binding 215.5 bp upstream of the papBA transcription start, is required for activation of pilin transcription. The first gene product of the
papBA
transcript, PapB, helps maintain the switch in the ON state by activating
papI
transcription, which in turn maintains Lrp binding at sites 4–6.
Digital karyotyping
Authors: Wang Tian-Li , Maierhofer Christine , Speicher Michael R. , Lengauer Christoph , Vogelstein Bert , Kinzler Kenneth W. , Velculescu Victor E.
Published: December 2002

Alterations in the genetic content of a cell are the underlying cause of many human diseases, including cancers. We have developed a method, called digital karyotyping, that provides quantitative analysis of DNA copy number at high resolution. This approach involves the isolation and enumeration of short sequence tags from specific genomic loci. Analysis of human cancer cells by using this method identified gross chromosomal changes as well as amplifications and deletions, including regions not previously known to be altered. Foreign DNA sequences not present in the normal human genome could also be readily identified. Digital karyotyping provides a broadly applicable means for systematic detection of DNA copy number changes on a genomic scale.
The role of chromosomal instability in tumor initiation
Authors: Nowak Martin A. , Komarova Natalia L. , Sengupta Anirvan , Jallepalli Prasad V. , Shih Ie-Ming , Vogelstein Bert , Lengauer Christoph
Published: December 2002

Chromosomal instability (CIN) is a defining characteristic of most human cancers. Mutation of CIN genes increases the probability that whole chromosomes or large fractions of chromosomes are gained or lost during cell division. The consequence of CIN is an imbalance in the number of chromosomes per cell (aneuploidy) and an enhanced rate of loss of heterozygosity. A major question of cancer genetics is to what extent CIN, or any genetic instability, is an early event and consequently a driving force for tumor progression. In this article, we develop a mathematical framework for studying the effect of CIN on the somatic evolution of cancer. Specifically, we calculate the conditions for CIN to initiate the process of colorectal tumorigenesis before the inactivation of tumor suppressor genes.
An mRNA structure that controls gene expression by binding FMN
Authors: Winkler Wade C. , Cohen-Chalamish Smadar , Breaker Ronald R.
Published: December 2002

The
RFN
element is a highly conserved domain that is found frequently in the 5′-untranslated regions of prokaryotic mRNAs that encode for flavin mononucleotide (FMN) biosynthesis and transport proteins. We report that this domain serves as the receptor for a metabolite-dependent riboswitch that directly binds FMN in the absence of proteins. Our results also indicate that in
Bacillus subtilis
, the riboswitch most likely controls gene expression by causing premature transcription termination of the
ribDEAHT
operon and precluding access to the ribosome-binding site of
ypaA
mRNA. Sequence and structural analyses indicate that the
RFN
element is a natural FMN-binding aptamer, the allosteric character of which is harnessed to control gene expression.
Slaving: Solvent fluctuations dominate protein dynamics and functions
Authors: Fenimore P. W. , Frauenfelder H. , McMahon B. H. , Parak F. G.
Published: December 2002

Protein motions are essential for function. Comparing protein processes with the dielectric fluctuations of the surrounding solvent shows that they fall into two classes: nonslaved and slaved. Nonslaved processes are independent of the solvent motions; their rates are determined by the protein conformation and vibrational dynamics. Slaved processes are tightly coupled to the solvent; their rates have approximately the same temperature dependence as the rate of the solvent fluctuations, but they are smaller. Because the temperature dependence is determined by the activation enthalpy, we propose that the solvent is responsible for the activation enthalpy, whereas the protein and the hydration shell control the activation entropy through the energy landscape. Bond formation is the prototype of nonslaved processes; opening and closing of channels are quintessential slaved motions. The prevalence of slaved motions highlights the importance of the environment in cells and membranes for the function of proteins.
Studies on the function of oligosaccharyl transferase subunits: A glycosylatable photoprobe binds to the luminal domain of Ost1p
Authors: Yan Qi , Lennarz William J.
Published: December 2002

Oligosaccharyl transferase (OT) is a complex multisubunit enzyme that, in the case of
Saccharomyces cerevisiae
, contains nine different transmembrane proteins. One of our goals is to identify the OT subunit(s) responsible for recognizing the consensus sequence, -Asn-X-Thr/Ser-, and catalyzing the oligosaccharide transfer reaction. By using a substrate-based photoprobe, earlier we found that Ost1p was specifically linked to the radiolabeled photoprobe. We have now examined Ost1p in more detail. Deletion of the cytoplasmic tail of Ost1p caused no defects in growth and glycosylation. In addition, replacement of the transmembrane domain with other hydrophobic amino acids did not impair growth. In contrast, a construct containing only the luminal domain of Ost1p did not support cell growth. Given these observations, we concentrated on studying the luminal domain of Ost1p and localized the photoprobe attachment region within a sequence of nine amino acid residues. Because mutations in the photoprobe attachment region did not cause any severe growth or glycosylation defects, we conclude that this region is not involved in the recognition of the N-glycosylation site. By further mutagenesis of the conserved residues of Ost1p we conclude that the luminal domain mediates interactions with other subunits of OT and becomes labeled because of its proximity to the recognition and/or catalytic subunit in the OT complex, Stt3p.
Loci on chromosomes 14 and 2, distinct from ABCG5/ABCG8, regulate plasma plant sterol levels in a C57BL/6J × CASA/Rk intercross
Authors: Sehayek Ephraim , Duncan Elizabeth M. , Lutjohann Dieter , von Bergmann Klaus , Ono Jennie G. , Batta Ashok K. , Salen Gerald , Breslow Jan L.
Published: December 2002

Plasma plant sterol levels differ among humans due to genetic and dietary factors. A disease characterized by high plasma plant sterol levels, β-sitosterolemia, was recently found to be due to mutations at the ABCG5/ABCG8 locus. To detect variants at this and other loci, a genetic cross was carried out between two laboratory mouse strains. Parental C57BL/6J had almost twice the campesterol and sitosterol levels compared with parental CASA/Rk mice, and F
1
mice had levels halfway between the parentals. An intercross between F
1
s was performed and plasma plant sterol levels measured in 102 male and 99 female F
2
mice. Plasma plant sterols in F
2
s displayed a unimodal distribution, suggesting the effects of several rather a single major gene. In the F
2
mice, a full genome scan revealed significant linkages on chromosomes 14 and 2. With regard to chromosome 14, analysis showed a single peak for linkage at 17 cM with a logarithm of odds (LOD) score of 9.9, designated plasma plant sterol 14 (
Plast14
). With regard to chromosome 2, analysis showed two significant peaks for linkage at 18 and 65 cMs with LOD scores of 4.1 and 3.65, respectively, designated
Plast2a
and
Plast2b
, respectively. Four interactions between loci, predominantly of an additive nature, were also demonstrated, the most significant between
Plast14
and
Plast2b
(LOD 16.44). No significant linkage or gene interaction was detected for the ABCG5/ABCG8 locus on chromosome 17. Therefore, other genes besides ABCG5/ABCG8 influence plasma plant sterol levels and now become candidates to explain differences in plasma plant sterol levels between humans.
Catalysis at a dinuclear [CuSMo(O)OH] cluster in a CO dehydrogenase resolved at 1.1-Å resolution
Authors: Dobbek Holger , Gremer Lothar , Kiefersauer Reiner , Huber Robert , Meyer Ortwin
Published: December 2002

The CO dehydrogenase of the eubacterium
Oligotropha carboxidovorans
is a 277-kDa Mo- and Cu-containing iron-sulfur flavoprotein. Here, the enzyme's active site in the oxidized or reduced state, after inactivation with potassium cyanide or with n-butylisocyanide bound to the active site, has been reinvestigated by multiple wavelength anomalous dispersion measurements at atomic resolution, electron spin resonance spectroscopy, and chemical analyses. We present evidence for a dinuclear heterometal [CuSMo(

O)OH] cluster in the active site of the oxidized or reduced enzyme, which is prone to cyanolysis. The cluster is coordinated through interactions of the Mo with the dithiolate pyran ring of molybdopterin cytosine dinucleotide and of the Cu with the Sγ of Cys-388, which is part of the active-site loop VAYRC
388
SFR. The previously reported active-site structure [Dobbek, H., Gremer, L., Meyer, O. & Huber, R. (1999)
Proc. Natl. Acad. Sci. USA
96, 8884–8889] of an Mo with three oxygen ligands and an SeH-group bound to the Sγ atom of Cys-388 could not be confirmed. The structure of CO dehydrogenase with the inhibitor n-butylisocyanide bound has led to a model for the catalytic mechanism of CO oxidation which involves a thiocarbonate-like intermediate state. The dinuclear [CuSMo(

O)OH] cluster of CO dehydrogenase establishes a previously uncharacterized class of dinuclear molybdoenzymes containing the pterin cofactor.
Secondary and tertiary structures of gaseous protein ions characterized by electron capture dissociation mass spectrometry and photofragment spectroscopy
Authors: Oh HanBin , Breuker Kathrin , Sze Siu Kwan , Ge Ying , Carpenter Barry K. , McLafferty Fred W.
Published: December 2002

Over the last decade a variety of MS measurements, such as H/D exchange, collision cross sections, and electron capture dissociation (ECD), have been used to characterize protein folding in the gas phase, in the absence of solvent. To the extensive data already available on ubiquitin, here photofragmentation of its ECD-reduced (M + nH)
(n−1)+•
ions shows that only the 6+ to 9+, not the 10+ to 13+ ions, have tertiary noncovalent bonding; this is indicated as hydrogen bonding by the 3,050–3,775 cm
−1
photofragment spectrum. ECD spectra and H/D exchange of the 13+ ions are consistent with an all α-helical secondary structure, with the 11+ and 10+ ions sufficiently destabilized to denature small bend regions near the helix termini. In the 8+ and 9+ ions these terminal helical regions are folded over to be antiparallel and noncovalently bonded to part of the central helix, whereas this overlap is extended in the 7+, 6+, and, presumably, 5+ ions to form a highly stable three-helix bundle. Thermal denaturing of the 7+ to 9+ conformers both peels and slides back the outer helices from the central one, but for the 6+ conformer, this instead extends the protein ends away to shrink the three-helix bundle. Thus removal of H
2
O from a native protein negates hydrophobic interactions, preferentially stabilizes the α-helical secondary structure with direct solvation of additional protons, and increases tertiary interhelix dipole-dipole and hydrogen bonding.
Therapeutic intervention in experimental allergic encephalomyelitis by administration of uric acid precursors
Authors: Scott Gwen S. , Spitsin Sergei V. , Kean Rhonda B. , Mikheeva Tatiana , Koprowski Hilary , Hooper D. Craig
Published: December 2002

Uric acid (UA) is a purine metabolite that selectively inhibits peroxynitrite-mediated reactions implicated in the pathogenesis of multiple sclerosis (MS) and other neurodegenerative diseases. Serum UA levels are inversely associated with the incidence of MS in humans because MS patients have low serum UA levels and individuals with hyperuricemia (gout) rarely develop the disease. Moreover, the administration of UA is therapeutic in experimental allergic encephalomyelitis (EAE), an animal model of MS. Thus, raising serum UA levels in MS patients, by oral administration of a UA precursor such as inosine, may have therapeutic value. We have assessed the effects of inosine, as well as inosinic acid, on parameters relevant to the chemical reactivity of peroxynitrite and the pathogenesis of EAE. Both had no effect on chemical reactions associated with peroxynitrite, such as tyrosine nitration, or on the activation of inflammatory cells
in vitro
. Moreover, when mice treated with the urate oxidase inhibitor potassium oxonate were fed inosine or inosinic acid, serum UA levels were elevated markedly for a period of hours, whereas only a minor, transient increase in serum inosine was detected. Administration of inosinic acid suppressed the appearance of clinical signs of EAE and promoted recovery from ongoing disease. The therapeutic effect on animals with active EAE was associated with increased UA, but not inosine, levels in CNS tissue. We, therefore, conclude that the mode of action of inosine and inosinic acid in EAE is via their metabolism to UA.
Overcredibility of molecular phylogenies obtained by Bayesian phylogenetics
Authors: Suzuki Yoshiyuki , Glazko Galina V. , Nei Masatoshi
Published: December 2002

Bayesian phylogenetics has recently been proposed as a powerful method for inferring molecular phylogenies, and it has been reported that the mammalian and some plant phylogenies were resolved by using this method. The statistical confidence of interior branches as judged by posterior probabilities in Bayesian analysis is generally higher than that as judged by bootstrap probabilities in maximum likelihood analysis, and this difference has been interpreted as an indication that bootstrap support may be too conservative. However, it is possible that the posterior probabilities are too high or too liberal instead. Here, we show by computer simulation that posterior probabilities in Bayesian analysis can be excessively liberal when concatenated gene sequences are used, whereas bootstrap probabilities in neighbor-joining and maximum likelihood analyses are generally slightly conservative. These results indicate that bootstrap probabilities are more suitable for assessing the reliability of phylogenetic trees than posterior probabilities and that the mammalian and plant phylogenies may not have been fully resolved.
Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: Acetyl–CoA carboxylase inhibition and AMP-activated protein kinase activation
Authors: Tomas Eva , Tsao Tsu-Shuen , Saha Asish K. , Murrey Heather E. , Zhang Cheng cheng , Itani Samar I. , Lodish Harvey F. , Ruderman Neil B.
Published: December 2002

gACRP30, the globular subunit of adipocyte complement-related protein of 30 kDa (ACRP30), improves insulin sensitivity and increases fatty acid oxidation. The mechanism by which gACRP30 exerts these effects is unknown. Here, we examined if gACRP30 activates AMP-activated protein kinase (AMPK), an enzyme that has been shown to increase muscle fatty acid oxidation and insulin sensitivity. Incubation of rat extensor digitorum longus (EDL), a predominantly fast twitch muscle, with gACRP30 (2.5 μg/ml) for 30 min led to 2-fold increases in AMPK activity and phosphorylation of both AMPK on Thr-172 and acetyl CoA carboxylase (ACC) on Ser-79. Accordingly, concentration of malonyl CoA was diminished by 30%. In addition, gACRP30 caused a 1.5-fold increase in 2-deoxyglucose uptake. Similar changes in malonyl CoA and ACC were observed in soleus muscle incubated with gACRP30 (2.5 μg/ml), although no significant changes in AMPK activity or 2-deoxyglucose uptake were detected. When EDL was incubated with full-length hexameric ACRP30 (10 μg/ml), AMPK activity and ACC phosphorylation were not altered. Administration of gACRP30 (75 μg) to C57 BL/6J mice
in vivo
led to increased AMPK activity and ACC phosphorylation and decreased malonyl CoA concentration in gastrocnemius muscle within 15–30 min. Both
in vivo
and
in vitro
, activation of AMPK was the first effect of gACRP30 and was transient, whereas alterations in malonyl CoA and ACC occurred later and were more sustained. Thus, gACRP30 most likely exerts its actions on muscle fatty acid oxidation by inactivating ACC via activation of AMPK and perhaps other signal transduction proteins.