Electric Field-Driven Water Dipoles: Nanoscale Architecture of Electroporation

<div><p>Electroporation is the formation of permeabilizing structures in the cell membrane under the influence of an externally imposed electric field. The resulting increased permeability of the membrane enables a wide range of biological applications, including the delivery of normally excluded substances into cells. While electroporation is used extensively in biology, biotechnology, and medicine, its molecular mechanism is not well understood. This lack of knowledge limits the ability to control and fine-tune the process. In this article we propose a novel molecular mechanism for the electroporation of a lipid bilayer based on energetics analysis. Using molecular dynamics simulations we demonstrate that pore formation is driven by the reorganization of the interfacial water molecules. Our energetics analysis and comparisons of simulations with and without the lipid bilayer show that the process of poration is driven by field-induced reorganization of water dipoles at the water-lipid or water-vacuum interfaces into more energetically favorable configurations, with their molecular dipoles oriented in the external field. Although the contributing role of water in electroporation has been noted previously, here we propose that interfacial water molecules are the main players in the process, its initiators and drivers. The role of the lipid layer, to a first-order approximation, is then reduced to a relatively passive barrier. This new view of electroporation simplifies the study of the problem, and opens up new opportunities in both theoretical modeling of the process and experimental research to better control or to use it in new, innovative ways.</p></div

Maternal anemia and severe maternal morbidity in a united states cohort

BACKGROUND: Maternal anemia is a common pregnancy complication and often leads to additional treatments and interventions. Identifying the frequency with which women with antenatally diagnosed anemia experience severe morbidity at the time of labor and delivery admission will guide future recommendations regarding screening and interventions for anemia in pregnancy. OBJECTIVE: The objective of this study was to evaluate the association of antenatally diagnosed anemia with severe maternal morbidity (SMM) as defined by the Center for Disease Control in a large, contemporary United States cohort. Neonatal outcomes were also examined. STUDY DESIGN: This was a secondary analysis of the Consortium on Safe Labor database from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, which collected data on 228,438 deliveries in 19 U.S. hospitals from 2002 to 2008. This analysis included women with viable, singleton gestations with exclusion of stillbirth and severe congenital anomalies. Women with a diagnosis of antenatal anemia were compared to those without. Diagnosis of antenatal anemia was obtained via electronic medical record abstraction and international classification of disease coding per each hospital protocol within the CSL. The primary maternal outcome consisted of a composite of SMM as defined by the CDC including: maternal death, eclampsia, thrombosis, transfusion, hysterectomy, and maternal intensive care unit (ICU) admission. The primary neonatal outcome was a composite that included 5 minute Apgar RESULTS: A total of 166,566 women met inclusion criteria. 56,734 women could not be analyzed due to an unknown diagnosis of anemia. Of those included, 10,217 (6.1%) were diagnosed with anemia during the pregnancy. Women with anemia were more likely to be younger, non-Hispanic Black, single, multiparous, and have higher pre-pregnancy body mass index compared to those without anemia. The frequency of the primary maternal composite outcome, the neonatal composite outcome, and other secondary outcomes including the SMM composite not including transfusion, maternal death, transfusion in labor and postpartum, hysterectomy, postpartum hemorrhage, infectious morbidity, cesarean delivery, and preterm delivery were more common in women with anemia (p CONCLUSION: Women with antepartum anemia experience increased rates of SMM and other serious adverse outcomes. Diagnosis and treatment of anemia during the antepartum period may lead to identification and treatment of women at higher risk of maternal morbidity and mortality

Energetic comparison of vertical vs. planar dipole configurations.

<p>Total energies of dipole configurations (I) and (II). Dashed line–sum of dipole-dipole interaction and dipole-electric field interaction terms for a horizontal layer of oriented dipoles (configuration (I)), solid line–sum of dipole-dipole interaction, dipole-electric field interaction, and the total solvation energy required to remove the dipoles from the bulk water for the vertical stack of dipoles (configuration (II)).</p

Protrusion molecules identification.

<p>XZ-projection of the water molecules positions in a typical WVW simulation at the times (a) just before protrusion begins to grow and (b) just before it begins to interact with/attract water molecules from the other side of the gap. Protrusion molecules are colored in red and the rest of the water molecules are shown as blue.</p

Correlation between protrusion height and total interaction energy in WLW.

<p>A graph (a) and a histogram of the correlation coefficient (b) demonstrating positive correlation between the protrusion height growth and the increase in the total interaction energy between the protrusion waters and the lipids in WLW simulations.</p

Constituent terms of total interaction energy.

<p>Comparison of constituent terms of the total interaction energy per protrusion molecule between WLW (red curve) and WVW (blue curve) simulations: (a) dipole–external electric field interaction energy, (b) electrostatic interaction energy, (c) Lennard-Jones interaction energy.</p

Comparisons of WLW and WVW systems.

<p>Snapshots of the time evolution of water-lipid-water (WLW) and water-vacuum-water (WVW) configurations under an external electric field of 500 MV/m. (a) WLW configuration at times 5.8, 6.7, and 7.3 ns from the start of the simulation with both water molecules (oxygen–red, hydrogen-gray) and lipid molecules (phosphorus-yellow, nitrogen-blue, lipid tail groups–silver) displayed. (b) same WLW data as in (a) but with only water molecules shown. (c) WVW configuration at times 1.157, 1.160, and 1.194 ns.</p