Biomedical subjects

A Sanson

Publications and source records attributed to A Sanson.

At least 19 recordsLinked to original sources

PubMed2005

A cylinder-shaped double ribbon structure formed by an amyloid hairpin peptide derived from the beta-sheet of murine PrP: an X-ray and molecular dynamics simulation study.

A structural model of the murine PrP small beta-sheet was obtained by synthesizing the RGYMLGSADPNGNQVYYRG peptide comprising the two beta-strands 127-133 and 159-164 linked by a four-residue sequence of high turn propensity. The DPNG turn sequence is a "short circuit" replacing the original protein sequence between the two strands. This 19-residue peptide spontaneously forms very long single fibrils as observed by electron microscopy. The X-ray diffraction patterns of a partially oriented sample reveals an average arrangement of the hairpin peptides into a structure which can be geometrically approximated by an empty-core cylinder. The hairpins are oriented perpendicular to the cylinder axis and a 130 A helix period is observed. Based on X-ray diffraction constraints and on more indirect general protein structure considerations, a precise and consistent fibril model was built. The structure consists of two beta-sheet ribbons wound around a cylinder and assembled into a single fibril with a hairpin orientation perpendicular to the fibril axis. Subsequent implicit and explicit solvent molecular dynamics simulations provided the final structure at atomic resolution and further insights into the stabilizing interactions. Particularly important are the zipper-like network of polar interactions between the edges of the two ribbons, including the partially buried water molecules. The hydrophobic core is not optimally compact explaining the low density of this region seen by X-ray diffraction. The present findings provide also a simple model for further investigating the sequence-stability relationship using a mutational approach with a quasi-independent consideration of the polar and apolar interactions.

Amino Acid Sequence↗

PubMed2002

Local thermal expansion in a cuprite structure: the case of Ag(2)O.

The local thermal behavior of the Ag(2)O framework structure has been studied by extended x-ray absorption fine structure. The average Ag-O nearest-neighbor distance expands upon heating, while the Ag-Ag next-nearest-neighbor distance contracts. An original implementation of the cumulant analysis shows that the Ag-O expansion is a joint effect of potential anharmonicity and geometrical deformation of the Ag(4)O basic tetrahedral units. Accordingly, the negative thermal expansion of the lattice parameter in Ag(2)O cannot be explained uniquely in terms of rigid unit modes.

Journal Article↗

PubMed2001

On the cumulant analysis of EXAFS in crystalline solids.

The analysis of temperature-dependent EXAFS spectra based on the cumulant expansion is critically reviewed, seeking for accurate relations between EXAFS parameters and physical properties of crystals. The treatment is based on the distinction between the real and effective distribution of distances, and is divided into three logical steps. (a) The connection between lattice dynamics and cumulants C(n)* of the real distribution is studied and the extent of the usual approximations are numerically evaluated. Atomic vibrations perpendicular to the bond direction make the EXAFS thermal expansion larger than the crystallographic one; the difference is connected to a shift of the effective pair potential rather than to its asymmetry. Peculiar information on lattice dynamics of crystals can be obtained from accurate EXAFS measurements and their cumulant analysis. (b) The differences between cumulants of the real and effective distribution (C(n)* and C(n), respectively) are calculated for various physically realistic distributions. The largest discrepancy concerns the first cumulant: C(1)* measures the thermal expansion of the interatomic bond, while C(1) is a better estimate of the crystallographic thermal expansion. (c) The convergence properties of the cumulant series are discussed and some phenomenological procedures are suggested to monitor and possibly work out the connected failures of the cumulant method. Benefits and risks of the use of an effective pair potential are at last debated.

Journal Article↗

PubMed2001

Investigating the conformational coupling between the transmembrane and cytoplasmic domains of a single-spanning membrane protein. A 1H-NMR study.

PMP1 is a 38-residue single-spanning membrane protein whose C-terminal cytoplasmic domain, Y25-F38, is highly positively charged. The conformational coupling between the transmembrane span and the cytoplasmic domain of PMP1 was investigated from 1H-nuclear magnetic resonance data of two synthetic fragments: F9-F38, i.e. 80% of the whole sequence, and Y25-F38, the isolated cytoplasmic domain. Highly disordered in aqueous solution, the Y25-F38 peptide adopts a well-defined conformation in the presence of dodecylphosphocholine micelles. Compared with the long PMP1 fragment, this structure exhibits both native and non-native elements. Our results make it possible to assess the influence of a hydrophobic anchor on the intrinsic conformational propensity of a cytoplasmic domain.

Amino Acid Sequence↗

PubMed2001

Concerted influence of key amino acids on the lipid binding properties of a single-spanning membrane protein: NMR and mutational analysis.

Finding the combinations of key amino acids involved in the interaction network underlying the interfacial features of membrane proteins would contribute to a better understanding of their sequence-structure-function relationships and the role of anionic phospholipids. To further address these questions, we performed mutational analysis associated with NMR experiments on synthetic fragments of the single-spanning membrane protein PMP1 that exhibit binding specificity for phosphatidylserine (PS). The aromatic and glutamine residues of the helix part of the PMP1 cytoplasmic domain were mutated. (1)H NMR experiments were carried out using perdeuterated DPC micelles as a membrane-like environment, in the absence and presence of small amounts of either POPC or POPS lipids. From intermolecular NOEs and chemical shift data, specific and nonspecific aspects of peptide-phospholipid interactions were distinguished. The major finding of our study is to reveal the concerted influence of a tryptophan and a glutamine residue on the interfacial conformation and lipid binding specificity of the PMP1 cytoplasmic domain.

Amino Acid Sequence↗

PubMed2001

Association of a polymorphism of the dopamine transporter gene with externalizing behavior problems and associated temperament traits: a longitudinal study from infancy to the mid-teens.

There have been reports that a variable number of tandem repeats (VNTR) polymorphism situated in the 3' untranslated region of the dopamine transporter gene is associated with attention-deficit hyperactivity disorder. On the basis of these findings, we predicted an association of this polymorphism with hyperactivity, other externalizing behavior problems, and related temperament traits in a general population sample. The association was investigated using children participating in a longitudinal study of childhood temperament and development. DNA was taken from 660 children who had been assessed for temperament from 4-8 months to 15-16 years, and for behavior problems from 3-4 to 15-16 years. No significant associations were found at any age. There are a number of methodological differences from earlier studies that might explain the lack of associations with hyperactivity. It is also possible that the earlier findings are not replicable.

Adolescent↗

PubMed2001

A GDP/GTP exchange factor involved in linking a spatial landmark to cell polarity.

In both animal and yeast cells, signaling pathways involving small guanosine triphosphatases (GTPases) regulate polarized organization of the actin cytoskeleton. In the budding yeast Saccharomyces cerevisiae, the Ras-like GTPase Bud1/Rsr1 and its guanosine 5'-diphosphate (GDP)/guanosine 5'-triphosphate (GTP) exchange factor Bud5 are involved in the selection of a specific site for growth, thus determining cell polarity. We found that Bud5 is localized at the cell division site and the presumptive bud site. Its localization is dependent on potential cellular landmarks, such as Bud3 and Axl2/Bud10 in haploid cells and Bud8 and Bud9 in diploid cells. Bud5 also physically interacts with Axl2/Bud10, a transmembrane glycoprotein, suggesting that a receptor-like transmembrane protein recruits a GDP/GTP exchange factor to connect an intrinsic spatial signal to oriented cell growth.

Cell Division↗

PubMed2001

15N NMR relaxation as a probe for helical intrinsic propensity: the case of the unfolded D2 domain of annexin I.

The isolated D2 domain of annexin I is unable to adopt a tertiary fold but exhibits both native and non-native residual structures. It thus constitutes an attractive model for the investigation of dynamics of partially folded states in the context of protein folding and stability. 15N relaxation parameters of the D2 domain have been acquired at three different magnetic fields, 500, 600 and 800 MHz. This enables the estimation of the contribution of conformational exchange to the relaxation parameters on the micro- to millisecond time scale, thus providing a suitable data set for the description of motions on the pico- and nanosecond time scale. The analysis of the seven spectral densities obtained (J(0), J(50 MHz), J(60 MHz), J(80 MHz), , , ) provides complementary and meaningful results on the conformational features of the D2 domain structure previously depicted by chemical shift and NOE data. Especially, residual helix segments exhibit distinct dynamical behaviors that are related to their intrinsic helical propensity. Beside the spectral density analysis, a series of models derived from the Lipari and Szabo model-free approach are investigated. Two models containing three parameters are able to reproduce equally well the experimental data within experimental errors but provide different values of order parameters and correlation times. The inability to find a unique model to describe the data emphasizes the difficulty to use and interpret the model-free parameters in the case of partially or fully unfolded proteins consisting of a wide range of interconverting conformers.

Annexin A1↗

PubMed2001

Longitudinal predictors of behavioural adjustment in pre-adolescent children.

OBJECTIVES: Longitudinal data from infancy onwards, from the Australian Temperament Project, a prospective study of the temperament and development of a large and representative sample of Victorian children, were examined to identify predictors of psychological disorder at 11-12 years of age. METHOD: Those children scoring in the at-risk range for psychological disorder according to parents, teachers and self-reports using the Child Behaviour Questionnaire were selected at 11-12 years of age for in-depth assessment and comparison with a group of children with no history of adjustment problems. Analyses of group differences using longitudinal data gathered from infancy to 12 years focused on parent and teacher reports on child temperament and behaviour, and various facets of home and school adjustment. RESULTS: The strongest predictors of adjustment at 12 years were previous behaviour problems, along with some specific temperament factors involving self-regulation capacities and mother's overall rating of child difficulty. Results based on parallel teacher data including peer adjustment, and social and academic competence measures were consistent with parent data. CONCLUSIONS: Our research confirms the persistence of early appearing behaviour problems in a community sample and the longitudinal influence of temperament factors in childhood. The study supports the need for a focus on early intervention and prevention strategies in the child mental health field.

Adolescent↗

PubMed2000

A longitudinal study of the role of childhood temperament in the later development of eating concerns.

OBJECTIVE: This study examined the relationship between childhood temperament and the later development of eating and body concerns in early adolescent children. METHOD: The Australian Temperament Project has followed a cohort of children from birth, assessing temperament factors such as Negative Emotionality, Persistence, Approach/Withdrawal, and Activity. Using a longitudinal design, the study reports on the relationship between temperament measured from infancy onward and eating and body concerns at 12-13 years of age. Participants (597 girls, 631 boys) completed the Eating Disorders Inventory subscales Drive For Thinness, Body Dissatisfaction, and Bulimia, and an estimate of their current size. Parents described their child's temperament and body size. RESULTS: High Negative Emotionality and low Persistence were the factors most associated with risk status over time, particularly in girls. DISCUSSION: While it is unlikely that temperamental characteristics per se lead to disordered eating, it is argued that in combination with other risk factors, certain temperamental characteristics may increase vulnerability.

Adolescent↗

PubMed2000

PMP1 18-38, a yeast plasma membrane protein fragment, binds phosphatidylserine from bilayer mixtures with phosphatidylcholine: a (2)H-NMR study.

PMP1 is a 38-residue plasma membrane protein of the yeast Saccharomyces cerevisiae that regulates the activity of the H(+)-ATPase. The cytoplasmic domain conformation results in a specific interfacial distribution of five basic side chains, thought to strongly interact with anionic phospholipids. We have used the PMP1 18-38 fragment to carry out a deuterium nuclear magnetic resonance ((2)H-NMR) study for investigating the interactions between the PMP1 cytoplasmic domain and phosphatidylserines. For this purpose, mixed bilayers of 1-palmitoyl, 2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1-palmitoyl, 2-oleoyl-sn-glycero-3-phosphoserine (POPS) were used as model membranes (POPC/POPS 5:1, m/m). Spectra of headgroup- and chain-deuterated POPC and POPS phospholipids, POPC-d4, POPC-d31, POPS-d3, and POPS-d31, were recorded at different temperatures and for various concentrations of the PMP1 fragment. Data obtained from POPS deuterons revealed the formation of specific peptide-POPS complexes giving rise to a slow exchange between free and bound PS lipids, scarcely observed in solid-state NMR studies of lipid-peptide/protein interactions. The stoichiometry of the complex (8 POPS per peptide) was determined and its significance is discussed. The data obtained with headgroup-deuterated POPC were rationalized with a model that integrates the electrostatic perturbation induced by the cationic peptide on the negatively charged membrane interface, and a "spacer" effect due to the intercalation of POPS/PMP1f complexes between choline headgroups.

Amino Acid Sequence↗

PubMed2000

Dimensions of early childhood behavior problems: stability and predictors of change from 18 to 30 months.

The prevalence, structure, stability, and predictors of change in early behavior problems were examined in a population-based sample of Norwegian children at 18 and 30 months of age (N = 750). A clear factor structure involving four dimensions emerged at both assessment times: Two factors were characterized by externalizing behaviors and were labeled Social Adjustment and Overactive-Inattentive; one factor tapped internalizing problems and was labeled Emotional Adjustment; and the fourth, related to general immaturity, was labeled Regulation. Specific patterns of child and family risk factors were associated with stability and change over the two time points for each factor. Children with stable problems had the most problematic characteristics on all significant predictors, followed by children with problems at one, but not both, time points. The data suggest that it is possible to identify risk factors for stable problems at 18 months, allowing some prediction of those children whose problems will persist over early childhood. Since specific risk factors emerged for specific types of behavior problems, the results may provide some much-needed guidance to early intervention efforts.

Age Factors↗

PubMed2000

Association of a functional polymorphism of the serotonin transporter gene with anxiety-related temperament and behavior problems in children: a longitudinal study from infancy to the mid-teens.

A polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) has been associated with anxiety-related personality traits in adults. Initial studies showed that the short allele was associated with higher neuroticism, anxiety and harm avoidance. However, most attempts to replicate these findings have been negative. Because the association of candidate polymorphisms with behavioral traits may vary with stage of development, we investigated the association using participants in a longitudinal study of childhood temperament. DNA was available for 660 children who had been assessed for temperament from 4-8 months to 15-16 years, and for behaviour problems from 3-4 years to 15-16 years. No significant associations were found at most ages. However, at ages 13-14 years and 15-16 years, the long/long genotype was associated with higher anxiety. These findings do not support an association of the short allele with anxiety-related traits in early life.

Adolescent↗

PubMed2000

Does shy-inhibited temperament in childhood lead to anxiety problems in adolescence?

OBJECTIVE: To assess the relationships between shy-inhibited temperament in childhood and anxiety problems in early adolescence using a prospective, longitudinal data set from a large community sample. METHOD: Relationships between shyness ratings on age-appropriate temperament scales and anxiety problems were analyzed, looking both forward and backward in time from infancy to adolescence. RESULTS: Forty-two percent of children rated as shy on 6 or more occasions over 8 surveys in childhood had anxiety problems in adolescence, compared with 11% who were never shy. Persistence of shyness and its presence in middle childhood increased risk for anxiety. A highly reactive temperament added to shyness did not increase the risk for anxiety. Few children with an anxiety diagnosis in early adolescence had a history of shyness. CONCLUSIONS: Prediction from childhood shyness to adolescent anxiety disorder is modest but clinically meaningful in a community sample. However, most shy children did not develop an anxiety disorder and most adolescents with anxiety disorders had not been especially shy.

Adolescent↗

PubMed1999

Localization of Bud2p, a GTPase-activating protein necessary for programming cell polarity in yeast to the presumptive bud site.

Yeast cells of different cell type exhibit distinct budding patterns that reflect the organization of the actin cytoskeleton. Bud1p (Rsr1p), a Ras-like GTPase, and Bud2p, a GTPase-activating protein for Bud1p, are essential for proper budding pattern. We show that Bud2p is localized at the presumptive bud site in G(1) cells in all cell types and that this localization is independent of Bud1p. Bud2p subsequently localizes to the mother-bud neck after bud emergence; this localization depends on the integrity of the septins. These observations indicate that Bud2p becomes positioned in G(1) cells by recognizing cell type-specific landmarks at the presumptive bud site.

Cell Cycle Proteins↗

PubMed1999

Dodecylphosphocholine micelles as a membrane-like environment: new results from NMR relaxation and paramagnetic relaxation enhancement analysis.

To further examine to what extent a dodecyl-phosphocholine (DPC) micelle mimics a phosphatidylcholine bilayer environment, we performed 13C, 2H, and 31P NMR relaxation measurements. Our data show that the dynamic behavior of DPC phosphocholine groups at low temperature (12 degrees C) corresponds to that of a phosphatidylcholine interface at high temperature (51 degrees C). In the presence of helical peptides, a PMP1 fragment, or an annexin fragment, the DPC local dynamics are not affected whereas the DPC aggregation number is increased to match an appropriate area/volume ratio for accommodating the bound peptides. We also show that quantitative measurements of paramagnetic relaxation enhancements induced by small amounts of spin-labeled phospholipids on peptide proton signals provide a meaningful insight on the location of both PMP1 and annexin fragments in DPC micelles. The paramagnetic contributions to the relaxation were extracted from intra-residue cross-peaks of NOESY spectra for both peptides. The location of each peptide in the micelles was found consistent with the corresponding relaxation data. As illustrated by the study of the PMP1 fragment, paramagnetic relaxation data also allow us to supply the missing medium-range NOEs and therefore to complete a standard conformational analysis of peptides in micelles.

Amino Acid Sequence↗

PubMed1999

Relationships between learning difficulties and psychological problems in preadolescent children from a longitudinal sample.

OBJECTIVES: To examine the relationships between learning difficulties and behavior problems in preadolescent children both concurrently and longitudinally, using data from the Australian Temperament Project, and to examine associations between DSM-diagnosed disorders and types of learning difficulties. METHOD: Clinical and comparison groups of 11- to 12-year-old children were assessed on behavioral and learning indices and completed a structured diagnostic interview. Longitudinal data were available from earlier surveys of the development of these children. RESULTS: Children in the clinical group were disadvantaged on all learning and behavioral indices, and their problems in many cases had been evident from 7 to 8 years of age. There were specific associations between types of learning difficulties and both internalizing and externalizing disorders. Numeracy difficulties were strongly associated with DSM diagnoses for both boys and girls, and externalizing problems tended to co-occur with a combination of learning problems. CONCLUSIONS: Behavioral maladjustment in many domains is strongly associated with learning difficulties even after intelligence and socioeconomic factors are controlled. The odds ratios for persistence of difficulties throughout elementary school are extremely high for children with clinical problems.

Child↗

PubMed1999

Psychological disorders and their correlates in an Australian community sample of preadolescent children.

The nature and correlates of psychological disorders of preadolescent children from the longitudinal Australian Temperament Project (ATP) are reported. Almost half of the children identified via checklists completed by mothers, teachers, and the children themselves as being in the at-risk range for disorder received a DSM-III-R diagnosis. Nine per cent of comparison, or low-risk, children also received a diagnosis. Internalising disorders were the most common, and 44% of cases had multiple problems. Children rated as problematic by all three informants or by child plus teacher were the most likely to receive a diagnosis. The at-risk group had more difficult temperament, poorer family and peer relationships, lower levels of social skills, and were of lower SES than the comparison group. There were minimal differences on these variables between at-risk children who did, or did not, receive a DSM-III-R diagnosis. It is argued that especially for boys, checklists from multiple informants are effective tools for identifying clinically significant disorders.

Australia↗