Glucose transport from mother to fetus—A theoretical study

The factors that affect and govern the glucose transfer from maternal blood to the fetus are not completely deciphered. We present a steady state, one dimensional mathematical simulation which integrates the main mechanisms that have been shown to exist: metabolic consumption of the placenta, simple and facilitated diffusion via the two membranes of the microvillous and simple diffusion within the placenta. The model uses all available physiologic data we could collect. Numerical results indicate that the most crucial factor in determining the fetal glucose concentration is the facilitated diffusion process at the basal membrane or, more specifically: the permeability of the basal membrane and the density of the transporter GLUT1 on its faces. The gradient between the maternal and the fetal glucose concentration is important as is the metabolic consumption of the placenta. The diffusion within the placenta and the conditions that prevail at the apical microvillous plasma membrane are much less significant. Intrasyncytial concentration of glucose is close to that of maternal blood. The adjustment of the fetal glucose concentration to abrupt changes of its surrounding is estimated to be quite rapid hence for all practical purposes this steady state model can serve as a reasonable approximation. Parameters that await experimental determination are identified.     

Vitamin D Status during Pregnancy and the Risk of Subsequent Postpartum Depression: A Case-Control Study

Epidemiological studies have provided evidence of an association between vitamin D insufficiency and depression and other mood disorders, and a role for vitamin D in various brain functions has been suggested. We hypothesized that low vitamin D status during pregnancy might increase the risk of postpartum depression (PPD). The objective of the study was thus to determine whether low vitamin D status during pregnancy was associated with postpartum depression. In a case-control study nested in the Danish National Birth Cohort, we measured late pregnancy serum concentrations of 25[OH]D3 in 605 women with PPD and 875 controls. Odds ratios [OR) for PPD were calculated for six levels of 25[OH]D3. Overall, we found no association between vitamin D concentrations and risk of PPD (p = 0.08). Compared with women with vitamin D concentrations between 50 and 79 nmol/L, the adjusted odds ratios for PPD were 1.35 (95% CI: 0.64; 2.85), 0.83 (CI: 0.50; 1.39) and 1.13 (CI: 0.84; 1.51) among women with vitamin D concentrations < 15 nmol/L, 15–24 nmol/L and 25–49 nmol/L, respectively, and 1.53 (CI: 1.04; 2.26) and 1.89 (CI: 1.06; 3.37) among women with vitamin D concentrations of 80–99 nmol/L and ≥ 100 nmol/L, respectively. In an additional analysis among women with sufficient vitamin D (≥ 50 nmol/L), we observed a significant positive association between vitamin D concentrations and PPD. Our results did not support an association between low maternal vitamin D concentrations during pregnancy and risk of PPD. Instead, an increased risk of PPD was found among women with the highest vitamin D concentrations.     

Early PTSD Symptom Trajectories: Persistence,Recovery, and Response to Treatment: Results from the Jerusalem Trauma Outreach and Prevention Study (J-TOPS)

Context

Uncovering heterogeneities in the progression of early PTSD symptoms can improve our understanding of the disorder''s pathogenesis and prophylaxis.

Objectives

To describe discrete symptom trajectories and examine their relevance for preventive interventions.

Design

Latent Growth Mixture Modeling (LGMM) of data from a randomized controlled study of early treatment. LGMM identifies latent longitudinal trajectories by exploring discrete mixture distributions underlying observable data.

Setting

Hadassah Hospital unselectively receives trauma survivors from Jerusalem and vicinity.

Participants

Adult survivors of potentially traumatic events consecutively admitted to the hospital''s emergency department (ED) were assessed ten days and one-, five-, nine- and fifteen months after ED admission. Participants with data at ten days and at least two additional assessments (n = 957) were included; 125 received cognitive behavioral therapy (CBT) between one and nine months.

Approach

We used LGMM to identify latent parameters of symptom progression and tested the effect of CBT on these parameters. CBT consisted of 12 weekly sessions of either cognitive therapy (n = 41) or prolonged exposure (PE, n = 49), starting 29.8±5.7 days after ED admission, or delayed PE (n = 35) starting at 151.8±42.4 days. CBT effectively reduced PTSD symptoms in the entire sample.

Main Outcome Measure

Latent trajectories of PTSD symptoms; effects of CBT on these trajectories.

Results

Three trajectories were identified: Rapid Remitting (rapid decrease in symptoms from 1- to 5-months; 56% of the sample), Slow Remitting (progressive decrease in symptoms over 15 months; 27%) and Non-Remitting (persistently elevated symptoms; 17%). CBT accelerated the recovery of the Slow Remitting class but did not affect the other classes.

Conclusions

The early course of PTSD symptoms is characterized by distinct and diverging response patterns that are centrally relevant to understanding the disorder and preventing its occurrence. Studies of the pathogenesis of PTSD may benefit from using clustered symptom trajectories as their dependent variables.     

Development and characterization of high affinity leptins and leptin antagonists

Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin.     

Simulating electrostatic energies in proteins: perspectives and some recent studies of pKas, redox, and other crucial functional properties

Electrostatic energies provide what is arguably the most effective tool for structure-function correlation of biological molecules. Here, we provide an overview of the current state-of-the-art simulations of electrostatic energies in macromolecules, emphasizing the microscopic perspective but also relating it to macroscopic approaches. We comment on the convergence issue and other problems of the microscopic models and the ways of keeping the microscopic physics while moving to semi-macroscopic directions. We discuss the nature of the protein dielectric "constants" reiterating our long-standing point that the dielectric "constants" in semi-macroscopic models depend on the definition and the specific treatment. The advances and the challenges in the field are illustrated considering different functional properties including pK(a)'s, redox potentials, ion and proton channels, enzyme catalysis, ligand binding, and protein stability. We emphasize the microscopic overcharging approach for studying pK(a) 's of internal groups in proteins and give a demonstration of power of this approach. We also emphasize recent advances in coarse grained models with a physically based electrostatic treatment and provide some examples including further directions in treating voltage activated ion channels.     

Maternal Vitamin D Status and Offspring Bone Fractures: Prospective Study over Two Decades in Aarhus City,Denmark

Background

Studies investigating the association between maternal vitamin D status and offspring bone mass measured by dual-energy X-ray absorptiometry (DXA) during childhood have shown conflicting results.

Purpose

We used occurrence of bone fractures up to the age of 18 as a measure reflecting offspring bone mass and related that to maternal vitamin D status.

Methods

The Danish Fetal Origins 1988 Cohort recruited 965 pregnant women during 1988–89 at their 30^th gestation week antenatal midwife visit. A blood sample was drawn and serum was stored, which later was analyzed for the concentration of 25-hydroxyvitamin D (25(OH)D) by the liquid chromatography coupled with a tandem mass spectrometric method (LC-MS/MS). Outcome was diagnosis of first time bone fractures extracted from the Danish National Patient Register.

Results

Vitamin D status was available for 850 women. The median (5^th–95^th percentile) 25(OH)D was 76.2 (23.0–152.1) nmol/l. During follow up 294 children were registered with at least one bone fracture diagnosis. Multivariable Cox regression models using age as the underlying time scale indicated no overall association between maternal vitamin D status and first time bone fractures. However, there was a significantly increased hazard ratio (HR) during childhood for those who had maternal blood drawn in Dec/Jan/Feb compared with Jun/Jul/Aug (HR: 1.75, 95%CI: 1.11–2.74). Adjustment for vitamin D status strengthened this association (1.82, 1.12–2.97), which indicated a potential seasonal impact on offspring fractures independent of maternal vitamin D status. In a sensitivity analysis we found a borderline significant inverse association between continuous concentrations of 25(OH)D and offspring forearm fractures (P = 0.054).

Conclusion

Overall, our results did not substantiate an association between maternal vitamin D status and offspring bone fractures. Further studies on this subject are needed, but the study populations must be large enough to allow for subdivision of fractures.     

Postnatal leptin is necessary for maturation of numerous organs in newborn rats

The postnatal leptin surge, described particularly in rodents, has been demonstrated to be crucial for hypothalamic maturation and brain development. In the present study, the possible general effects of this hormone on maturation of numerous peripheral organs have been explored. To test this hypothesis, we used a leptin antagonist (L39A/D40A/F41A) to investigate the effects of the blockage of postnatal leptin action on neonatal growth and maturation of organs involved in metabolism regulation, reproduction and immunity. For that purpose, newborn female pups were subcutaneously injected from days 2-13 with either saline or leptin antagonist and sacrificed at weaning. Organs were submitted to histological and immunohistochemical analyses. Leptin antagonist treatment clearly impaired the maturation of pancreas, kidney, thymus and ovary. All these alterations, at the organ level, occurred without changes in the whole-body mass of the animals. Leptin antagonist treatment induced: (1) a reduction in b cell area and a concomitant increase of a cells in Langherans islets in the pancreas, (2) a reduction in the number of glomeruli and a persistence of immature glomeruli in kidney, (3) an increase in the thymic cortical layer thickness, reflecting an unmatured stage, (4) a drastic reduction of the pool of primordial follicles, in ovaries. All these results strongly argue for a crucial role of leptin for the achievement of organ maturation, opening new perspectives in the field of leptin physiology and organ development.     

The empirical valence bond as an effective strategy for computer-aided enzyme design

The ability of the empirical valence bond (EVB) to be used in screening active site residues in enzyme design is explored in a preliminary way. This validation is done by comparing the ability of this approach to evaluate the catalytic contributions of various residues in chorismate mutase. It is demonstrated that the EVB model can serve as an accurate tool in the final stages of computer-aided enzyme design (CAED). The ability of the model to predict quantitatively the catalytic power of enzymes should augment the capacity of current approaches for enzyme design.