Developing a Life Story Pasupathi, M.; Mansour, E.; Brubaker, J.R.
Human development,
01/2007, Letnik:
50, Številka:
2/3
Journal Article
Recenzirano
In this paper, we consider how the life story develops through the creation of selfevent connections in narrating experiences. We first outline the ways in which such connections have been implied by ...existing work on the life story, and then consider the varieties of such connections that we see in our own work. That work suggests that selfevent connections can construct both a stable sense of self as well as a sense of how the self has changed across time. Moreover, different types of connections have different implications for the development of the life story. We also consider developmental and other factors which make one or another type of connection more likely. Finally, we consider two issues for future work, as well as some methodological considerations involved in testing those proposals.
Chemokine receptors CXCR4 and CCR5 regulate WBC trafficking and are engaged by the HIV-1 envelope glycoprotein gp120 during infection. We combine a selection of human CXCR4 and CCR5 libraries ...comprising nearly all of ∼7000 single amino acid substitutions with deep sequencing to define sequence-activity landscapes for surface expression and ligand interactions. After consideration of sequence constraints for surface expression, known interaction sites with HIV-1-blocking Abs were appropriately identified as conserved residues following library sorting for Ab binding, validating the use of deep mutational scanning to map functional interaction sites in G protein-coupled receptors. Chemokine CXCL12 was found to interact with residues extending asymmetrically into the CXCR4 ligand-binding cavity, similar to the binding surface of CXCR4 recognized by an antagonistic viral chemokine previously observed crystallographically. CXCR4 mutations distal from the chemokine binding site were identified that enhance chemokine recognition. This included disruptive mutations in the G protein-coupling site that diminished calcium mobilization, as well as conservative mutations to a membrane-exposed site (CXCR4 residues H79
and W161
) that increased ligand binding without loss of signaling. Compared with CXCR4-CXCL12 interactions, CCR5 residues conserved for gp120 (HIV-1 BaL strain) interactions map to a more expansive surface, mimicking how the cognate chemokine CCL5 makes contacts across the entire CCR5 binding cavity. Acidic substitutions in the CCR5 N terminus and extracellular loops enhanced gp120 binding. This study demonstrates how comprehensive mutational scanning can define functional interaction sites on receptors, and novel mutations that enhance receptor activities can be found simultaneously.
Although environmental lead exposure is associated with significant deficits in cognition, executive functions, social behaviors, and motor abilities, the neuroanatomical basis for these impairments ...remains poorly understood. In this study, we examined the relationship between childhood lead exposure and adult brain volume using magnetic resonance imaging (MRI). We also explored how volume changes correlate with historic neuropsychological assessments.
Volumetric analyses of whole brain MRI data revealed significant decreases in brain volume associated with childhood blood lead concentrations. Using conservative, minimum contiguous cluster size and statistical criteria (700 voxels, unadjusted p < 0.001), approximately 1.2% of the total gray matter was significantly and inversely associated with mean childhood blood lead concentration. The most affected regions included frontal gray matter, specifically the anterior cingulate cortex (ACC). Areas of lead-associated gray matter volume loss were much larger and more significant in men than women. We found that fine motor factor scores positively correlated with gray matter volume in the cerebellar hemispheres; adding blood lead concentrations as a variable to the model attenuated this correlation.
Childhood lead exposure is associated with region-specific reductions in adult gray matter volume. Affected regions include the portions of the prefrontal cortex and ACC responsible for executive functions, mood regulation, and decision-making. These neuroanatomical findings were more pronounced for males, suggesting that lead-related atrophic changes have a disparate impact across sexes. This analysis suggests that adverse cognitive and behavioral outcomes may be related to lead's effect on brain development producing persistent alterations in structure. Using a simple model, we found that blood lead concentration mediates brain volume and fine motor function.
We investigate a mechanism for producing double-lows and double-highs in the semi-diurnal tide by selective amplification of higher harmonics in a resonant gulf. A double low water is observed at ...Providence, RI, near the head of Narragansett Bay on days when there is a flattening of the low water tidal curve at Newport, at the mouth of the bay. The flattening is caused by an unusually large quarter-diurnal component to the tide at Newport. The quarter diurnal component has the right phase (a maximum close to the time of the minimum in the semi-diurnal tide) to produce a prolonged flattening of the tidal curve around low water. The natural period of Narragansett Bay (for quarter-wavelength resonance) is close to 4 h and the quarter diurnal tide is amplified, relative to the semi-diurnal tide, within the bay. The selective amplification of the higher harmonic further prolongs the flattening effect at Providence and, occasionally, is sufficient to create a double low water at the head of the bay from quarter and semi-diurnal tides alone. More often, though, a sixth-diurnal harmonic produced within the bay, added to the flattened low water at Providence, creates the double low water. This mechanism of selective amplification of tidal harmonics could be relevant to double tides elsewhere.
Childhood lead exposure is associated with decreased cognitive abilities and executive functioning localized within the prefrontal cortex. Several studies have observed stronger associations between ...blood lead measurements obtained later in life than earlier measures, but there are no imaging studies investigating the developmental trajectory of blood lead levels taken during childhood on adult gray matter volume. In this study, we recruited 157 adults (20.8
±
1.5 years of age) from the Cincinnati Lead Study to undergo high resolution volumetric magnetic resonance imaging. Adjusted voxel-wise regression analyses were performed for associations between adult gray matter volume loss and yearly mean blood lead levels from 1 to 6 years of age in the entire cohort and by sex. We observed significant inverse associations between gray matter volume loss and annual mean blood lead levels from 3 to 6 years of age. The extent of prefrontal gray matter associated with yearly mean blood lead levels increased with advancing age of the subjects. The inverse associations between gray matter volume loss and yearly mean blood lead measurements were more pronounced in the frontal lobes of men than women. Analysis of women yielded significantly weaker associations between yearly mean blood lead levels and gray matter volume at all ages than either men or the combined cohort of men and women together. These results suggest that blood lead concentrations obtained during later childhood demonstrate greater loss in gray matter volume than childhood mean or maximum values. The relationship between childhood blood lead levels and gray matter volume loss was predominantly observed in the frontal lobes of males. This study demonstrates that maximum blood lead levels do not fully account for gray matter changes associated with childhood lead exposure, particularly in the frontal lobes of young men.
. Oral administration of bovine antibodies active against enterotoxigenic Escherichia coli (ETEC) have demonstrated safety and efficacy against diarrhea in human challenge trials. The efficacy of ...bovine serum immunoglobulins (BSIgG) against recombinant colonization factor CS6 or whole cell ETEC strain B7A was assessed against challenge with the CS6-expressing B7A.
. This was a randomized, double-blind, placebo-controlled trial in which healthy adults received oral hyperimmune BSIgG anti-CS6, anti-B7A whole cell killed or non-hyperimmune BSIgG (placebo) in a 1:1:1 ratio then challenged with ETEC B7A. Two days pre-challenge, volunteers began a thrice daily, seven day course of immunoprophylaxis. On day 3, subjects received 1 × 10
10
CFUs of B7A. Subjects were observed for safety and the primary endpoint of moderate-severe diarrhea (MSD).
. A total of 59 volunteers received product and underwent ETEC challenge. The BSIgG products were well-tolerated across all subjects. Upon challenge, 14/20 (70%) placebo recipients developed MSD, compared to 12/19 (63%; p = .74) receiving anti-CS6 BSIgG and 7/20 (35%; p = .06) receiving anti-B7A BSIgG. Immune responses to the ETEC infection were modest across all groups.
. Bovine-derived serum antibodies appear safe and well tolerated. Antibodies derived from cattle immunized with whole cell B7A provided 50% protection against MSD following B7A challenge; however, no protection was observed in subjects receiving serum antibodies targeting CS6. The lack of observed efficacy in this group may be due to low CS6 surface expression on B7A, the high dose challenge inoculum and/or the use of serum derived antibodies versus colostrum-derived antibodies.
Aims To describe the oral disposition of the dietary flavonoid chrysin in healthy volunteers.
Methods Oral 400 mg doses of chrysin were administered to seven subjects. Chrysin and metabolites were ...assayed in plasma, urine and faeces by h.p.l.c.
Results Peak plasma chrysin concentrations were only 3–16 ng ml−1 with AUCs of 5–193 ng ml−1 h. Plasma chrysin sulphate concentrations were 30‐fold higher (AUC 450–4220 ng ml−1 h). In urine, chrysin and chrysin glucuronide accounted for 0.2–3.1 mg and 2–26 mg, respectively. Most of the dose appeared in faeces as chrysin. Parallel experiments in rats showed high bile concentrations of chrysin conjugates.
Conclusions These findings, together with previous data using Caco‐2 cells, suggest that chrysin has low oral bioavailability, mainly due to extensive metabolism and efflux of metabolites back into the intestine for hydrolysis and faecal elimination.
To describe the oral disposition of the dietary flavonoid chrysin in healthy volunteers.
Oral 400 mg doses of chrysin were administered to seven subjects. Chrysin and metabolites were assayed in ...plasma, urine and faeces by h.p.l.c.
Peak plasma chrysin concentrations were only 3-16 ng ml(-1) with AUCs of 5-193 ng ml(-1) h. Plasma chrysin sulphate concentrations were 30-fold higher (AUC 450-4220 ng ml(-1) h). In urine, chrysin and chrysin glucuronide accounted for 0.2-3.1 mg and 2-26 mg, respectively. Most of the dose appeared in faeces as chrysin. Parallel experiments in rats showed high bile concentrations of chrysin conjugates.
These findings, together with previous data using Caco-2 cells, suggest that chrysin has low oral bioavailability, mainly due to extensive metabolism and efflux of metabolites back into the intestine for hydrolysis and faecal elimination.
Abstract
Electron paramagnetic resonance (EPR) has become an important tool to probe conformational changes in nucleic acids. An array of EPR labels for nucleic acids are available, but they often ...come at the cost of long tethers, are dependent on the presence of a particular nucleotide or can be placed only at the termini. Site directed incorporation of Cu2+-chelated to a ligand, 2,2′dipicolylamine (DPA) is potentially an attractive strategy for site-specific, nucleotide independent Cu2+-labelling in DNA. To fully understand the potential of this label, we undertook a systematic and detailed analysis of the Cu2+-DPA motif using EPR and molecular dynamics (MD) simulations. We used continuous wave EPR experiments to characterize Cu2+ binding to DPA as well as optimize Cu2+ loading conditions. We performed double electron-electron resonance (DEER) experiments at two frequencies to elucidate orientational selectivity effects. Furthermore, comparison of DEER and MD simulated distance distributions reveal a remarkable agreement in the most probable distances. The results illustrate the efficacy of the Cu2+-DPA in reporting on DNA backbone conformations for sufficiently long base pair separations. This labelling strategy can serve as an important tool for probing conformational changes in DNA upon interaction with other macromolecules.
Fast sampling ADCPs (Acoustic Doppler Current Profilers) have been used to observe the cycle of turbulent properties in a partially stratified estuary over a springs-neaps cycle in parallel with ...measurements of water column
T
/
S
from an anchored vessel. Using the variance method, estimates of the Reynolds stress
τ
, the rate of turbulent kinetic energy production
P and the eddy viscosity
N
z
are derived from measurements of the along beam velocities with a vertical resolution of 0.5
m. Combined with vertical profile measurements of temperature and salinity, the results reveal the important influence of tidal straining in controlling the structure and intensity of turbulent stresses and TKE production on both ebb and flood phases of the tide.
Over the
M
2 cycle at neaps,
τ
and
P both showed a significant response to water column structure with higher values restricted to the lower part of the water column at times when the water column was stratified by tidal straining. Conversely at the end of the flood, when stratification was minimal due to the de-stabilising effect of straining in supplementing tidal mixing, significant stresses and relatively high production levels extended upwards to near the surface. At springs, strain-induced stratification is relatively weaker but the influence of straining is still apparent in the development of some stability at the end of the ebb and in relatively high values of
N
z
on the flood due to the action of tidal straining in inducing a negative buoyancy flux. This asymmetry between mixing conditions on the ebb and the flood is apparent in plots of
N
z
versus the local gradient Richardson number
Ri
.
N
z
generally increases rapidly for
Ri
<1 but there is considerable scatter and only limited conformity to functional relations like that of Munk and Anderson.
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