bluuebunny/crossref_metadata_2025 huggingface dataset:
A total synthesis of estrone based on a novel cascade of radical cyclizations
Authors: Pattenden Gerald , Gonzalez Miguel A. , McCulloch Stuart , Walter Affo , Woodhead Steven J.
Published: August 2004

Two conceptually different and novel radical-mediated cascade reactions leading to a total synthesis of the steroid (±)-estrone 1 and to a synthesis of 14-epiestrone 40 are described. Treatment of the iododienynone 23 with Bu
3
SnH/2,2′-azobis(isobutyronitrile) (AIBN) triggers a 13-
endo
-dig radical macrocyclization followed by two sequential radical transannulation reactions leading to the crystalline estrane 24 in 50% yield. The x-ray crystal structure of 24 established its
trans
,
syn
, stereochemistry. Transposition of the enone functionality in 24 next led to 38, which was then converted into 39 by reductive methylation. Deprotection of the methyl ether 39 finally gave 14-epiestone 40. When the substituted iodovinylcyclopropane 55 was treated similarly with Bu
3
SnH/AIBN, the resulting radical center underwent a different sequence of cascade macrocyclization-transannulation reactions producing the
trans
,
anti
,
trans
estrane 56 in 12% overall yield. Oxidation of 56, using CrO
3
-H
2
SO
4
next led to the cyclopentanone 57, which, on deprotection using BBr
3
gave (±)-estrone 1. A number of alternative substituted iodopolyenynones and iodovinylcyclopropanes, i.e., 8a, 8b, 33, 49a, and 49b, underwent similar radical-mediated cascade cyclizations leading to other estranes, i.e., 21a, 21b, 35, and 50, and, in one case, to the 6,6,5,6-tetracycle 51, in variable overall yields. The structures and stereochemistries of several estranes were established by using x-ray crystal structure measurements in combination with analysis of their NMR spectroscopic data and correlation with literature precedent.
Gene duplication and speciation in
Drosophila
: Evidence from the
Odysseus
locus
Authors: Ting Chau-Ti , Tsaur Shun-Chern , Sun Sha , Browne William E. , Chen Yung-Chia , Patel Nipam H. , Wu Chung-I
Published: August 2004

The importance of gene duplication in evolution has long been recognized. Because duplicated genes are prone to diverge in function, gene duplication could plausibly play a role in species differentiation. However, experimental evidence linking gene duplication with speciation is scarce. Here, we show that a hybrid-male sterility gene,
Odysseus
(
OdsH
), arose by gene duplication in the
Drosophila
genome.
OdsH
has evolved at a very high rate, whereas its most immediate paralog,
unc-4
, is nearly identical among species in the
Drosophila melanogaster
subgroup. The disparity in their sequence evolution is echoed by the divergence in their expression patterns in both soma and reproductive tissues. We suggest that duplicated genes that have yet to evolve a stable function at the time of speciation may be candidates for “speciation genes,” which is broadly defined as genes that contribute to differential adaptation between species.
Mutations in ClpC2/Hsp100 suppress the requirement for FtsH in thylakoid membrane biogenesis
Authors: Park Sungsoon , Rodermel Steven R.
Published: August 2004

The
Arabidopsis var2
variegation mutant defines a nuclear gene for a chloroplast FtsH metalloprotease. Leaf variegation is expressed only in homozygous recessive plants. The cells in the green leaf sectors of this mutant contain morphologically normal chloroplasts, whereas cells in the white sectors contain abnormal plastids lacking organized lamellar structures.
var2
mutants are hypersusceptible to photoinhibition, and VAR2 degrades unassembled polypeptides and is involved in the D1 repair cycle of photosystem II, likely by affecting turnover of the photodamaged D1 polypeptide. A second-site suppressor screen of
var2
yielded a normal-appearing, nonvariegated line. Map-based cloning revealed that the suppression of variegation in this line is due to a splice site mutation in
ClpC2
, a chloroplast Hsp100 chaperone, that results in sharply reduced ClpC2 protein accumulation. Isolation of
clpC2
single mutants showed that
clpC2
is epistatic to
var2
, and that a lack of ClpC2 does not markedly alter the composition of the thylakoid membrane. Suppression by
clpC2
is not allele-specific. Our results suggest that
clpC2
is a suppressor of thylakoid biogenesis and maintenance and that ClpC2 might act by accelerating photooxidative stress.
Arabidopsis
has two
ClpC
genes (
ClpC1
and
ClpC2
), and mutants with down-regulated expression of both genes have a phenotype different from
clpC2
, suggesting that ClpC1 and ClpC2 act synergistically and/or that they are only partially redundant. The isolation of a
clpC2
mutant represents an important advance in the generation of tools to understand Hsp100 function and insight into the mechanisms of protein quality control in plants.
Major genetic marker of nidoviruses encodes a replicative endoribonuclease
Authors: Ivanov Konstantin A. , Hertzig Tobias , Rozanov Mikhail , Bayer Sonja , Thiel Volker , Gorbalenya Alexander E. , Ziebuhr John
Published: August 2004

Coronaviruses are important pathogens that cause acute respiratory diseases in humans. Replication of the ≈30-kb positive-strand RNA genome of coronaviruses and discontinuous synthesis of an extensive set of subgenome-length RNAs (transcription) are mediated by the replicase-transcriptase, a barely characterized protein complex that comprises several cellular proteins and up to 16 viral subunits. The coronavirus replicase-transcriptase was recently predicted to contain RNA-processing enzymes that are extremely rare or absent in other RNA viruses. Here, we established and characterized the activity of one of these enzymes, replicative nidoviral uridylate-specific endoribonuclease (NendoU). It is considered a major genetic marker that discriminates nidoviruses (
Coronaviridae, Arteriviridae
, and
Roniviridae
) from all other RNA virus families. Bacterially expressed forms of NendoU of severe acute respiratory syndrome coronavirus and human coronavirus 229E were revealed to cleave single-stranded and double-stranded RNA in a Mn
2+
-dependent manner. Single-stranded RNA was cleaved less specifically and effectively, suggesting that double-stranded RNA is the biologically relevant NendoU substrate. Double-stranded RNA substrates were cleaved upstream and downstream of uridylates at GUU or GU sequences to produce molecules with 2′-3′ cyclic phosphate ends. 2′-
O
-ribose-methylated RNA substrates proved to be resistant to cleavage by NendoU, indicating a functional link with the 2′-
O
-ribose methyltransferase located adjacent to NendoU in the coronavirus replicative polyprotein. A mutagenesis study verified potential active-site residues and allowed us to inactivate NendoU in the full-length human coronavirus 229E clone. Substitution of D6408 by Ala was shown to abolish viral RNA synthesis, demonstrating that NendoU has critical functions in viral replication and transcription.
Structural evidence for evolution of shark Ig new antigen receptor variable domain antibodies from a cell-surface receptor
Authors: Streltsov V. A. , Varghese J. N. , Carmichael J. A. , Irving R. A. , Hudson P. J. , Nuttall S. D.
Published: August 2004

The Ig new antigen receptors (IgNARs) are single-domain antibodies found in the serum of sharks. Here, we report 2.2- and 2.8-Å structures of the type 2 IgNAR variable domains 12Y-1 and 12Y-2. Structural features include, first, an Ig superfamily topology transitional between cell adhesion molecules, antibodies, and T cell receptors; and, second, a vestigial complementarity-determining region 2 at the “bottom” of the molecule, apparently discontinuous from the antigen-binding paratope and similar to that observed in cell adhesion molecules. Thus, we suggest that IgNARs originated as cell-surface adhesion molecules coopted to the immune repertoire and represent an evolutionary lineage independent of variable heavy chain/variable light chain type antibodies. Additionally, both 12Y-1 and 12Y-2 form unique crystallographic dimers, predominantly mediated by main-chain framework interactions, which represent a possible model for primordial cell-based interactions. Unusually, the 12Y-2 complementarity-determining region 3 also adopts an extended β-hairpin structure, suggesting a distinct selective advantage in accessing cryptic antigenic epitopes.
msari
: Multiple sequence alignments for statistical detection of RNA secondary structure
Authors: Coventry Alex , Kleitman Daniel J. , Berger Bonnie
Published: August 2004

We present a highly accurate method for identifying genes with conserved RNA secondary structure by searching multiple sequence alignments of a large set of candidate orthologs for correlated arrangements of reverse-complementary regions. This approach is growing increasingly feasible as the genomes of ever more organisms are sequenced. A program called
msari
implements this method and is significantly more accurate than existing methods in the context of automatically generated alignments, making it particularly applicable to high-throughput scans. In our tests, it discerned
clustalw
-generated multiple sequence alignments of signal recognition particle or RNaseP orthologs from controls with 89.1% sensitivity at 97.5% specificity and with 74.4% sensitivity with no false positives in 494 controls. We used
msari
to conduct a comprehensive scan for secondary structure in mRNAs of coding genes, and we found many genes with known mRNA secondary structure and compelling evidence for secondary structure in other genes.
msari
uses a method for coping with sequence redundancy that is likely to have applications in a large set of other comparison-based search methods. The program is available for download from
http://theory.csail.mit.edu/MSARi
.
Imaging inflammation of the pancreatic islets in type 1 diabetes
Authors: Denis Maria C. , Mahmood Umar , Benoist Christophe , Mathis Diane , Weissleder Ralph
Published: August 2004

Type 1 diabetes is the clinical manifestation of aberrant leukocytic infiltration of the pancreatic islets; it is usually diagnosed only very late in disease progression, after the critical autoimmune phenomena have mostly played out. A noninvasive means of directly monitoring the evolution of islet infiltrates would have important research and clinical applications. We have exploited fluorescence and MRI of long-circulating magnetofluorescent nanoparticles to visualize micro-vascular leakage, as an indicator of inflammation, in pancreata of mouse models of type 1 diabetes
ex vivo
or
in vivo
. We could detect the onset and evolution of insulitis
in vivo
and in real time, permitting us to study the natural history of diabetes in individual animals.
Approximate protein structural alignment in polynomial time
Authors: Kolodny Rachel , Linial Nathan
Published: August 2004

Alignment of protein structures is a fundamental task in computational molecular biology. Good structural alignments can help detect distant evolutionary relationships that are hard or impossible to discern from protein sequences alone. Here, we study the structural alignment problem as a family of optimization problems and develop an approximate polynomial-time algorithm to solve them. For a commonly used scoring function, the algorithm runs in
O
(
n
10
/ε
6
) time, for globular protein of length
n
, and it detects alignments that score within an additive error of ε from all optima. Thus, we prove that this task is computationally feasible, although the method that we introduce is too slow to be a useful everyday tool. We argue that such approximate solutions are, in fact, of greater interest than exact ones because of the noisy nature of experimentally determined protein coordinates. The measurement of similarity between a pair of protein structures used by our algorithm involves the Euclidean distance between the structures (appropriately rigidly transformed). We show that an alternative approach, which relies on internal distance matrices, must incorporate sophisticated geometric ingredients if it is to guarantee optimality and run in polynomial time. We use these observations to visualize the scoring function for several real instances of the problem. Our investigations yield insights on the computational complexity of protein alignment under various scoring functions. These insights can be used in the design of scoring functions for which the optimum can be approximated efficiently and perhaps in the development of efficient algorithms for the multiple structural alignment problem.
Sexual selection explains Rensch's rule of size dimorphism in shorebirds
Authors: Székely Tamás , Freckleton Robert P. , Reynolds John D.
Published: August 2004

Sexual size dimorphism shows a remarkably widespread relationship to body size in the animal kingdom: within lineages, it decreases with size when females are the larger sex, but it increases with size when males are the larger sex. Here we demonstrate that this pattern, termed Rensch's rule, exists in shorebirds and allies (Charadriides), and it is determined by two components of sexual selection: the intensity of sexual selection acting on males and the agility of the males' display. These effects are interactive so that the effect of sexual selection on size dimorphism depends on male agility. As a control, we also examine dimorphism in bill length, which is a functionally selected trait. As such, dimorphism in bill length neither exhibits Rensch's rule nor is associated with sexual selection and display. Our results show that variation among taxa in the direction and magnitude of sexual size dimorphism, as manifested as Rensch's rule, can be explained by the interaction between the form and strength of sexual selection acting on each sex in relation to body size.
The T cell antigen receptor expressed by Vα14iNKT cells has a unique mode of glycosphingolipid antigen recognition
Authors: Sidobre Stéphane , Hammond Kirsten J. L. , Bénazet-Sidobre Lise , Maltsev Sergei D. , Richardson Stewart K. , Ndonye Rachel M. , Howell Amy R. , Sakai Teruyuki , Besra Gurdyal S. , Porcelli Steven A. , Kronenberg Mitchell
Published: August 2004

Natural killer (NK) T cells with an invariant Vα14 rearrangement (Vα14i) are the largest population of lipid antigen-specific T lymphocytes identified in animals. They react to the glycolipid α-galactosyl ceramide (α-GalCer) presented by CD1d, and they may have important regulatory functions. It was previously shown that the Vα14iT cell antigen receptor (TCR) has a high affinity for the α-GalCer/CD1d complex, driven by a long half-life (t1/2). Although this result could have reflected the unique attributes of α-GalCer, using several related glycolipid compounds, we show here that the threshold for full activation of Vα14iNKT cells by these glycosphingolipids requires a relatively high-affinity TCR interaction with a longt1/2. Furthermore, our data are consistent with the view that the mechanism of recognition of these compounds presented by CD1d to the Vα14iNKT cell TCR is likely to fit a lock-and-key model. Overall, these findings emphasize the distinct properties of glycosphingolipid antigen recognition by Vα14iNKT cells.
Rho overexpression leads to mitosis-associated detachment of cells from epithelial sheets: A link to the mechanism of cancer dissemination
Authors: Vasiliev J. M. , Omelchenko T. , Gelfand I. M. , Feder H. H. , Bonder E. M.
Published: August 2004

Dissemination of neoplastic cells from the primary tumor (invasion and metastasis) is a fundamentally dangerous step in multistage carcinogenesis. Recent evidence suggests that Rho GTPase-mediated signaling is linked to dissemination of cells from several different types of human tumors. The Rho family of proteins is typically associated with the regulation of cytoskeletal activity, including actin assembly, microtubule dynamics, and myosin II-dependent contractility of the actin-rich cortex. We examined the effect of overexpression of constitutively active RhoA on islands and monolayers of epithelial cells. Although newly plated cells initially formed small spread islands, there was also a significant population of cells that detached from the substrate, floated in the medium, and then could reattach to the substrate to form new colonies. Detachment of cells from transfected epithelial islands or monolayers occurred in correlation to the plane of cytokinesis after misorientation of the mitotic spindle axis. We suggest that these alterations result from Rho-induced increase of contractility of the cortex of dividing cells, which, during cytokinesis, produces a cell that has budded out of an existing layer of cells. Cell division-mediated detachment of cells from tissue structures may be an important mechanism of tumor dissemination and metastasis.
A zeaxanthin-independent nonphotochemical quenching mechanism localized in the photosystem II core complex
Authors: Finazzi Giovanni , Johnson Giles N. , Dallosto Luca , Joliot Pierre , Wollman Francis-André , Bassi Roberto
Published: August 2004

Illumination of dark-adapted barley plants with low light transiently induced a large nonphotochemical quenching of chlorophyll fluorescence. This reaction was identified as a form of high-energy-state quenching. Its appearance was not accompanied by zeaxanthin synthesis but was associated with a reversible inactivation of a fraction of photosystem II (PSII) centers. Both the fluorescence quenching and PSII inactivation relaxed in parallel with the activation of the Calvin cycle. We interpret the induction of this phenomenon as due to the generation of a quenched state in the PSII core complex. This reaction is probably caused by the transient overacidification of the thylakoid lumen, whereas its dissipation results from the relaxation of both the pH gradient across the thylakoid membrane and redox pressure upon activation of carbon fixation. At saturating light intensities, inactivation of PSII was still observed at the onset of illumination, although its recovery did not result in dissipation of high-energy quenching, which presents typical characteristics of an antenna-associated quenching at steady state. Reaction-center quenching seems therefore to be a common transient feature during illumination, being replaced by other phenomena (photochemical or antenna quenching and photoinhibition), depending on the balance between light and carbon fixation fluxes.
Spatial patterns of gene expression in the olfactory bulb
Authors: Lin David M. , Yang Yee Hwa , Scolnick Jonathan A. , Brunet Lisa J. , Marsh Heather , Peng Vivian , Okazaki Yasushi , Hayashizaki Yoshihide , Speed Terence P. , Ngai John
Published: August 2004

How olfactory sensory neurons converge on spatially invariant glomeruli in the olfactory bulb is largely unknown. In one model, olfactory sensory neurons interact with spatially restricted guidance cues in the bulb that orient and guide them to their target. Identifying differentially expressed molecules in the olfactory bulb has been extremely difficult, however, hindering a molecular analysis of convergence. Here, we describe several such genes that have been identified in a screen that compiled microarray data to create a three-dimensional model of gene expression within the mouse olfactory bulb. The expression patterns of these identified genes form the basis of a nascent spatial map of differential gene expression in the bulb.
Risk factors for disability pension over 11 years in a cohort of young persons initially sick-listed with low back, neck, or shoulder diagnoses
Authors: Borg Karin , Hensing Gunnel , Alexanderson Kristina
Published: August 2004

Aim: A study was undertaken to ascertain whether the differences in risk in relation to gender and citizenship observed in a previous study of the same cohort would remain if more recent data on sickness absence were used. Methods: This was an 11-year prospective population-based cohort study. The dataset includes all individuals in a Swedish city who, in 1985, were aged 25 - 34 and had a sick-leave spell≥28 days with neck, shoulder, or back diagnoses (n=213). The data covered the following: for 1985 - 96, disability pension, emigration, and death; for 1982 - 96, sickness absence; for 1985, sex and citizenship. The data were subjected to Cox regression analyses with a time-dependent covariate. Results: Disability pension was granted to 22% (n=46) of the cohort. The relative risk for disability pension increased by 9.3 with each sick-leave spell≥90 days during the two previous years. The risk was higher for women than men, and also higher for foreign citizens than Swedes. Conclusion: Many studies have revealed a gender difference in the risk of being on disability pension, and it was found that this difference was still apparent when sick leave during the follow-up period is taken into account. Thus, the reason for the gender differences ought to be found among other factors than prior levels of sickness absence.
Socioeconomic status and risk of childhood leukaemia in Denmark
Authors: Raaschou-Nielsen Ole , Obel Josephine , Dalton Susanne , Tjønneland Anne , Hansen Johnni
Published: August 2004

Aims: The aim of this study was to assess the influence of socioeconomic status on the risk of childhood leukaemia. Methods: A matched case-control design was used. The study population comprised all children (0 - 14 years old) born and reported to the Danish Cancer Registry between 1976 and 1991 for a diagnosis of leukaemia (n=377). Controls were selected from the Central Population Registry and matched by sex, age, and time of birth. Each child was assigned three categories of socioeconomic status, one corresponding to the annual average income in the municipality of residence at the time of birth, another corresponding to that at the time of diagnosis, and, finally, each family was assigned one of five social classes by use of the job titles of the parents. Conditional logistic regression was used to estimate the effect of socioeconomic status on the risk of childhood leukaemia. Results: Children born in low-income municipalities had a significantly increased risk of leukaemia (RR=2.71; 95% CI=1.41 - 5.21; p=0.003), which was higher among those who received their diagnosis before age five (RR=3.43; 95% CI=1.52 - 7.74; p=0.003). Neither individual social class nor the socioeconomic status of the residential area at the time of diagnosis was convincingly associated with the risk of childhood leukaemia. Conclusions: The results suggest that socioeconomic factors associated with community characteristics rather than individual lifestyle are related to the risk of childhood leukaemia and that these factors act early in life.
Health professionals' knowledge, attitudes, and experiences in relation to immigrant patients: a questionnaire study at a Danish hospital
Authors: Michaelsen Jette J. , Krasnik Allan , Nielsen Anette S. , Norredam Marie , Torres Ana Maria
Published: August 2004

Aims: A study was undertaken to identify variations in knowledge, attitudes, experiences, and communication among different categories of hospital staff with regard to immigrant patients in order to identify potential barriers for effective diagnosis, treatment, and care of immigrant patients. Methods: The study is based on a questionnaire mailed to doctors, nurses, and assistant nurses at Bispebjerg Hospital, a major general hospital in Copenhagen. Among the 1,012 persons included the total response rate was 58%. Results: A majority of all three professional groups obtain their knowledge on immigrants through the media and patient contact, and less through travels, courses, and colleagues. Doctors and nurses showed the most positive attitudes towards different statements about immigrants, and assistant nurses the most negative. Doctors and nurses also had most frequent contacts with immigrant patients and found their communication more satisfactory compared with assistant nurses. Many health workers expressed complaints about immigrants' inappropriate use of health services. That doctors and nurses had more positive attitudes towards immigrants than assistant nurses could be explained by their higher education providing a more "fundamental safety feeling'', or a feeling of not being in a competitive situation with immigrants. Assistant nurses had the least satisfactory communication with immigrant patients, possibly because they had less frequent contacts compared with doctors and nurses. Conclusions: The study provides a foundation for new interventions and priorities within the healthcare system regarding immigrant patients.
Stability and change of volume and intensity of physical activity as predictors of hypertension
Authors: Hernelahti Miika , Kujala Urho M. , Kaprio Jaakko
Published: August 2004

Aims: Controversy exists concerning intensity of physical activity and risk of hypertension. Also, the association between long-term changes in physical activity and hypertension is poorly known. Therefore we investigated how the stability and change of volume and intensity of physical activity are associated with the risk of hypertension in Finnish men and women. Methods: A total of 3,931 men and 4,381 women responded to three questionnaires on health and lifestyle. Baseline data were gathered from two questionnaires, in 1975 and 1981. The subjects were 24 - 51 years of age, healthy, and non-hypertensive at baseline (1981). At the end of the follow-up, in 1990, the subjects responded to a third questionnaire, according to which we assessed the cumulative incidence of hypertension between 1982 and 1990. Results: The cumulative incidence of hypertension from 1982 to 1990 was 10.2% in men and 8.0% in women. In men, the risk of hypertension was higher among those who were persistently not participating in vigorous physical activity (i.e. in both 1975 and 1981) (odds ratio, 1.60; 95% confidence interval, 1.15 to 2.24; p=0.006) than among those persistently participating, when all confounding factors were adjusted for. Among those participating in vigorous activity only in 1975 or in 1981 the risk was not significantly increased compared with those participating persistently. Volume of physical activity was not associated with hypertension. In women, there was no association between physical activity and incidence of hypertension. Conclusions: Compared with inactivity, persistent vigorous physical activity predicts a low risk of hypertension in men.
Achievements and shortcomings of Finnish asthma care
Authors: Ikäheimo Pekka , Tuuponen Tuili , Hartikainen Sirpa , Kiuttu Jorma , Klaukka Timo
Published: August 2004

Background: The Finnish National Asthma Programme was launched in 1994. Aim: A postal self-completion questionnaire study was undertaken to evaluate how the guideline is working in the Finnish healthcare system. Methods: A postal inquiry was sent to a random sample of 6,000 subjects aged 16+ years who were entitled to special reimbursement for anti-asthmatic medication and 4,657 subjects with self-reported asthma were included. Results: The subjects comprised 38% men (n=1,781) and 62% women (n=2,876). In all, 62% of all the subjects and 78% of those with severe asthma had visited a doctor on account of asthma in the past 12 months. Some 83% of the respondents had a given physician who was responsible for treating their asthma, and 75% of these were under observation by a primary healthcare physician. Visits to asthma nurses were relatively rare. Inhaled glucocorticoids were used by 83% of the subjects, but short-acting beta-2-agonists were still the most commonly used asthma drug in monotherapy regardless of the severity of asthma. Inhaled glucocorticoids and a short-acting beta-2-agonist was the most frequent combination. Every tenth subject used this combination supplemented by a long-acting beta-2-agonist. Conclusion: Asthma care in Finland seems to be compatible with the national guidelines in terms of continuity and the common use of inhaled glucocorticoids. The primary care sector has adopted the main responsibility for the treatment of asthma. The common use of short-acting beta-2-agonists is an exception to an otherwise positive trend.
Development in self-rated health among older people as determinant of social relations
Authors: Lund Rikke , Avlund Kirsten , Modvig Jens , Due Pernille , Holstein Bjørn E.
Published: August 2004

Aim: The purpose of this study was to analyse whether development in self-rated health (SRH) over four years was associated with the structure of and satisfaction with social relations, at four and eight years follow-up, among elderly women and men. Methods: A longitudinal questionnaire-based study was undertaken of non-institutionalized Danes, aged 70 - 95 years, with baseline in 1986. The response rate at baseline was 69%, n=1,231. First follow-up was carried out in 1990, with 91% of eligible individuals participating (n=911). Second follow-up took place in 1994, where 83% of eligible individuals participated (n=542). The association was studied between development in SRH from 1986 to 1990 and social relations in 1990 and in 1994. Results: A sustained poor SRH predicted low contact frequency OR=1.7 (1.1 - 2.6), small contact diversity OR=1.6 (1.0 - 2.6) and low contact satisfaction OR=3.4 (2.3 - 5.2) in the two-point analyses. Furthermore, a deterioration in SRH predicted poor contact satisfaction OR=2.8 (1.7 - 4.5). All analyses were adjusted for age, gender, mental health, functional ability, cohabitation status, and a measure of social relations at baseline. Results for the three-point analyses were similar to those for the two-point analyses. The associations were weaker for contact satisfaction OR=2.8 (1.7 - 4.7), but stronger for contact frequency OR=2.5 (1.4 - 4.4) and diversity OR=2.1 (1.2 - 3.6). Conclusion: Sustained poor SRH and, to some degree, deterioration in SRH were predictors of poor social relations after four and eight years.
Old Yellow Enzyme Protects the Actin Cytoskeleton from Oxidative Stress
Authors: Haarer Brian K. , Amberg David C.
Published: August 2004

Old Yellow Enzyme (OYE) has long served as a paradigm for the study of flavin-containing NADPH oxido-reductases and yet its physiological role has remained a mystery. A two-hybrid interaction between Oye2p and actin led us to investigate a possible function in the actin cytoskeleton. We found that oye deletion strains have an overly elaborate actin cytoskeleton that cannot be attributed to changes in actin concentration but likely reflect stabilization of actin filaments, resulting in excessive actin assembly. Cells expressing the actin mutant act1-123p, which has a weakened interaction with Oye2p, show comparable defects in actin organization to the oye deletion strain that can be suppressed by overexpression of Oye2p. Similarly, mutation of either conserved cysteine of the potential disulfide pair Cys285-Cys374 in actin completely suppresses the actin organization defect of the oyeΔ phenotype. Strains lacking Oye function are also sensitive to oxidative stress as induced by H2O2, menadione, and diamide treatment. Mutation of either Cys285 or Cys374 of actin suppresses the sensitivity of oyeΔ strains to oxidative stress and in fact confers super-resistance to oxidative stress in otherwise wild-type strains. These results suggest that oxidative damage to actin, like that which has been observed in irreversibly sickled red blood cells, may be a general phenomenon and that OYE functions to control the redox state of actin thereby maintaining the proper plasticity of the actin cytoskeleton. In addition to uncovering a long sought biological function for Old Yellow Enzyme, these results establish that cellular sensitivity to oxidative stress can in part be directly attributed to a specific form (C285-C374 disulfide bond formation) of oxidative damage to actin.
The LC7 Light Chains ofChlamydomonasFlagellar Dyneins Interact with Components Required for Both Motor Assembly and Regulation
Authors: DiBella Linda M. , Sakato Miho , Patel-King Ramila S. , Pazour Gregory J. , King Stephen M.
Published: August 2004

Members of the LC7/Roadblock family of light chains (LCs) have been found in both cytoplasmic and axonemal dyneins. LC7a was originally identified within Chlamydomonas outer arm dynein and associates with this motor's cargo-binding region. We describe here a novel member of this protein family, termed LC7b that is also present in the Chlamydomonas flagellum. Levels of LC7b are reduced ∼20% in axonemes isolated from strains lacking inner arm I1 and are ∼80% lower in the absence of the outer arms. When both dyneins are missing, LC7b levels are diminished to <10%. In oda9 axonemal extracts that completely lack outer arms, LC7b copurifies with inner arm I1, whereas in ida1 extracts that are devoid of I1 inner arms it associates with outer arm dynein. We also have observed that some LC7a is present in both isolated axonemes and purified 18S dynein from oda1, suggesting that it is also a component of both the outer arm and inner arm I1. Intriguingly, in axonemal extracts from the LC7a null mutant, oda15, which assembles ∼30% of its outer arms, LC7b fails to copurify with either dynein, suggesting that it interacts with LC7a. Furthermore, both the outer arm γ heavy chain and DC2 from the outer arm docking complex completely dissociate after salt extraction from oda15 axonemes. EDC cross-linking of purified dynein revealed that LC7b interacts with LC3, an outer dynein arm thioredoxin; DC2, an outer arm docking complex component; and also with the phosphoprotein IC138 from inner arm I1. These data suggest that LC7a stabilizes both the outer arms and inner arm I1 and that both LC7a and LC7b are involved in multiple intradynein interactions within both dyneins.
Conformational Defects Slow Golgi Exit, Block Oligomerization, and Reduce Raft Affinity of Caveolin-1 Mutant Proteins
Authors: Ren Xiaoyan , Ostermeyer Anne G. , Ramcharan Lynne T. , Zeng Youchun , Lublin Douglas M. , Brown Deborah A.
Published: August 2004

Caveolin-1, a structural protein of caveolae, is cleared unusually slowly from the Golgi apparatus during biosynthetic transport. Furthermore, several caveolin-1 mutant proteins accumulate in the Golgi apparatus. We examined this behavior further in this mutant study. Golgi accumulation probably resulted from loss of Golgi exit information, not exposure of cryptic retention signals, because several deletion mutants accumulated in the Golgi apparatus. Alterations throughout the protein caused Golgi accumulation. Thus, most probably acted indirectly, by affecting overall conformation, rather than by disrupting specific Golgi exit motifs. Consistent with this idea, almost all the Golgi-localized mutant proteins failed to oligomerize normally (even with an intact oligomerization domain), and they showed reduced raft affinity in an in vitro detergent-insolubility assay. A few mutant proteins formed unstable oligomers that migrated unusually slowly on blue native gels. Only one mutant protein, which lacked the first half of the N-terminal hydrophilic domain, accumulated in the Golgi apparatus despite normal oligomerization and raft association. These results suggested that transport of caveolin-1 through the Golgi apparatus is unusually difficult. The conformation of caveolin-1 may be optimized to overcome this difficulty, but remain very sensitive to mutation. Disrupting conformation can coordinately affect oligomerization, raft affinity, and Golgi exit of caveolin-1.
Optical properties of the scales ofMorpho rhetenorbutterflies: theoretical and experimental investigation of the back-scattering of light in the visible spectrum
Authors: Plattner Luca
Published: August 2004

A study of the optical properties of the largely periodic microstructure occurring on the wings of the iridescent tropical butterflyMorpho rhetenorand responsible for its structural colouration is reported. An extensive measurement of the back-scattering of visible light from butterfly scales was performed for various angles of incidence. Efficient low-pass filter behaviour was observed for all angles of incidence and polarizations, with near-complete transmission at wavelengths above the threshold of 550 nm. The angular spread of the back-scattered light was found to be organized in lobes with total extinction of the specular reflection for all conditions of incidence. Retro-reflector behaviour was also observed for angles of incidence of 30° and above. Additionally, the role of periodic geometrical features found in the microstructure for the generation of its spectral response was analysed theoretically. Using finite-difference timedomain and near-field to far-field transformation techniques, the back-scattering of visible light by models was computed numerically and the relevance of geometrical features for the production of structural colour and diffraction was demonstrated.
Retinally-generated saccadic suppression of a locust looming-detector neuron: investigations using a robot locust
Authors: Santer Roger D. , Stafford Richard , Rind F. Claire
Published: August 2004

A fundamental task performed by many visual systems is to distinguish apparent motion caused by eye movements from real motion occurring within the environment. During saccadic eye movements, this task is achieved by inhibitory signals of central and retinal origin that suppress the output of motion-detecting neurons. To investigate the retinally-generated component of this suppression, we used a computational model of a locust looming-detecting pathway that experiences saccadic suppression. This model received input from the camera of a mobile robot that performed simple saccade-like movements, allowing the model's response to simplified real stimuli to be tested. Retinally-generated saccadic suppression resulted from two inhibitory mechanisms within the looming-detector's input architecture. One mechanism fed inhibition forward through the network, inhibiting the looming-detector's initial response to movement. The second spread inhibition laterally within the network, suppressing the looming-detector's maintained response to movement. These mechanisms prevent a loomingdetector model response to whole-field visual stimuli. In the locust, this mechanism of saccadic suppression may operate in addition to centrally-generated suppression. Because lateral inhibition is a common feature of early visual processing in many organisms, we discuss whether the mechanism of retinally-generated saccadic suppression found in the locust looming-detector model may also operate in these species.
Well–being and affective style: neural substrates and biobehavioural correlates
Authors: Davidson Richard J.
Published: August 2004

One of the most salient features of emotion is the pronounced variability among individuals in their reactions to emotional incentives and in their dispositional mood. Collectively, these individual differences have been described as affective style. Recent research has begun to dissect the constituents of affective style. The search for these components is guided by the neural systems that instantiate emotion and emotion regulation. In this article, this body of research and theory is applied specifically to positive affect and well–being. The central substrates and peripheral biological correlates of well–being are described. A resilient affective style is associated with high levels of left prefrontal activation, effective modulation of activation in the amygdala and fast recovery in response to negative and stressful events. In peripheral biology, these central patterns are associated with lower levels of basal cortisol and with higher levels of antibody titres to influenza vaccine. The article concludes with a consideration of whether these patterns of central and peripheral biology can be modified by training and shifted toward a more salubrious direction.
Intelligence and culture: how culture shapes what intelligence means, and the implications for a science of well–being
Authors: Sternberg Robert J. , Grigorenko Elena L.
Published: August 2004

This paper discusses the relationship between culture and intelligence. The main message of the paper is that intelligence cannot fully or even meaningfully be understood outside its cultural context. Behaviour that is considered intelligent in one culture may be considered unintelligent in another culture, andvice versa. Moreover, people in different cultures have different implicit (folk) theories of intelligence, so may not even mean the same thing by the word. The relationships between different aspects of intelligence can vary across cultures, with correlations that are positive in one setting proving to be negative in another. The paper opens with a general discussion of issues regarding the relationship between the two concepts. It then describes the theory of successful intelligence, which motivates our work on the interface between culture and intelligence. Finally, the article draws some conclusions.
The developmental origins of well–being
Authors: Barker D. J. P.
Published: August 2004

Low birthweight is now known to be associated with increased rates of coronary heart disease and the related disorders, stroke, hypertension and adult–onset diabetes. These associations have been extensively replicated in studies in different countries and are not the result of confounding variables. They extend across the normal range of birthweight and depend on lower birthweights in relation to the duration of gestation rather than the effects of premature birth. The associations are thought to be consequences of developmental plasticity, the phenomenon by which one genotype can give rise to a range of different physiological or morphological states in response to different environmental conditions during development. Recent observations have shown that impaired growth in infancy and rapid childhood weight gain exacerbate the effects of impaired prenatal growth. A new vision of optimal early human development is emerging, which takes account of health and well–being throughout life.
Introduction: why do we need a science of well–being?
Authors: Huppert Felicia A. , Baylis Nick , Keverne Barry
Published: August 2004

Introduction: why do we need a science of well–being?
Well–being: towards an integration of psychology, neurobiology and social science
Authors: Huppert Felicia A. , Baylis Nick
Published: August 2004

The study of well–being is a rapidly evolving field, and an exquisite example of a truly multidisciplinary endeavour. Two of the strongest strands have emerged from recent research on positive psychology and on social capital, but the field reaches well beyond these domains. We summarize some of the major themes that unite these different approaches and disciplines, highlighting both commonalities and controversies. The five themes on which we focus are: (i) evolution and development; (ii) the nature of wellbeing; (iii) well–being and capabilities; (iv) the relationship between health and well–being; and (v) the implications of the findings of the research for intervention strategies and public policies.
Positive health: connecting well–being with biology
Authors: Ryff Carol D. , Singer Burton H. , Dienberg Love Gayle
Published: August 2004

Two key types of well–being, eudaimonic and hedonic, are reviewed. The first addresses ideas of self–development, personal growth and purposeful engagement, while the second is concerned with positive feelings such as happiness and contentment. How well–being varies by age and socio–economic standing is briefly summarized, followed by examination of its biological correlates (neuroendocrine, immune, cardiovascular, rapid eye movement (REM) sleep). Preliminary findings on a sample of ageing women showed that those with higher levels of eudaimonic well–being had lower levels of daily salivary cortisol, pro–inflammatory cytokines, cardiovascular risk, and longer duration REM sleep compared with those showing lower levels of eudaimonic well–being. Hedonic well–being, however, showed minimal linkage to biomarker assessments. Future research directions building on these initial findings are discussed.
Neuronal accumulation of abnormal prion protein in sheep carrying a scrapie-resistant genotype (PrPARR/ARR)
Authors: Buschmann Anne , Lühken Gesine , Schultz Julia , Erhardt G. , Groschup Martin H.
Published: August 2004

The susceptibility of sheep to scrapie infection is influenced by prion gene alleles, which are modulated by polymorphic variations corresponding to amino acid positions 136, 154 and 173 of the prion protein (PrP). As no unquestioned report of a diseased sheep carrying homozygous alleles encoding alanine, arginine and arginine (PrPARR) at these sites has been published to date, sheep of this genotype are believed to be scrapie resistant. After the introduction of large-scale rapid testing for scrapie, a number of so-called ‘atypical’ scrapie cases have been found in Germany and elsewhere. Among those cases were two supposedly scrapie-resistant sheep. Brain samples from these animals tested positive for abnormal PrP (PrPSc) in one of four rapid tests available. Moreover, scrapie-associated fibril (SAF)-immunoblotting and immunohistochemistry, which are the generally accepted diagnostic techniques for scrapie, revealed prominent PrPSc deposition in the cerebellum. SAF immunoblotting also revealed PrPSc deposition in the obex, frontal cortex and brainstem. Transmission experiments to investigate the infectivity of scrapie propagated from these sheep have been initiated.
Splicing of Cauliflower mosaic virus 35S RNA serves to downregulate a toxic gene product
Authors: Froissart Rémy , Uzest Maryline , Ruiz-Ferrer Virginia , Drucker Martin , Hébrard Eugénie , Hohn Thomas , Blanc Stéphane
Published: August 2004

Alternative splicing usually leads to an increase in the number of gene products that can be derived from a single transcript. Here, a different and novel use of alternative splicing – as a means to control the amount of a potentially toxic gene product in the plant pararetrovirus Cauliflower mosaic virus (CaMV) – is reported. About 70 % of the CaMV 35S RNA, which serves as a substrate for both reverse transcription and polycistronic mRNA, is spliced into four additional RNA species. Splicing occurs between four donor sites – one in the 5′ untranslated region and three within open reading frame (ORF) I – and one unique acceptor site at position 1508 in ORF II. A previous study revealed that the acceptor site is vital for CaMV infectivity and expression of ORFs III and IV from one of the spliced RNA species suggested that splicing may facilitate expression of downstream CaMV ORFs. However, it is shown here that deleting the splice acceptor site and replacing ORF II with a cargo ORF that lacks splice acceptor sites does not interfere with virus proliferation. Furthermore, it is demonstrated that whenever P2 cannot accumulate in infected tissues, the splice acceptor site at position 1508 is no longer vital and has little effect on virus replication. This suggests that the vital role of splicing in CaMV is regulation of P2 expression and that P2 exhibits biological properties that, whilst indispensable for virus–vector interactions, can block in planta virus infection if this regulation is abolished.