Maternal eNOS deficiency determines a fatty liver phenotype of the offspring in a sex dependent manner

Maternal environmental factors can impact on the phenotype of the offspring via the induction of epigenetic adaptive mechanisms. The advanced fetal programming hypothesis proposes that maternal genetic variants may influence the offspring's phenotype indirectly via epigenetic modification, despite the absence of a primary genetic defect. To test this hypothesis, heterozygous female eNOS knockout mice and wild type mice were bred with male wild type mice. We then assessed the impact of maternal eNOS deficiency on the liver phenotype of wild type offspring. Birth weight of male wild type offspring born to female heterozygous eNOS knockout mice was reduced compared to offspring of wild type mice. Moreover, the offspring displayed a sex specific liver phenotype, with an increased liver weight, due to steatosis. This was accompanied by sex specific differences in expression and DNA methylation of distinct genes. Liver global DNA methylation was significantly enhanced in both male and female offspring. Also, hepatic parameters of carbohydrate metabolism were reduced in male and female offspring. In addition, male mice displayed reductions in various amino acids in the liver. Maternal genetic alterations, such as partial deletion of the eNOS gene, can affect liver metabolism of wild type offspring without transmission of the intrinsic defect. This occurs in a sex specific way, with more detrimental effects in females. This finding demonstrates that a maternal genetic defect can epigenetically alter the phenotype of the offspring, without inheritance of the defect itself. Importantly, these acquired epigenetic phenotypic changes can persist into adulthood.     

Toward intensifying design of experiments in upstream bioprocess development: An industrial Escherichia coli feasibility study

In this study, step variations in temperature, pH, and carbon substrate feeding rate were performed within five high cell density Escherichia coli fermentations to assess whether intraexperiment step changes, can principally be used to exploit the process operation space in a design of experiment manner. A dynamic process modeling approach was adopted to determine parameter interactions. A bioreactor model was integrated with an artificial neural network that describes biomass and product formation rates as function of varied fed‐batch fermentation conditions for heterologous protein production. A model reliability measure was introduced to assess in which process region the model can be expected to predict process states accurately. It was found that the model could accurately predict process states of multiple fermentations performed at fixed conditions within the determined validity domain. The results suggest that intraexperimental variations of process conditions could be used to reduce the number of experiments by a factor, which in limit would be equivalent to the number of intraexperimental variations per experiment. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1343–1352, 2016     

Oxidative shielding and the cost of reproduction

Life‐history theory assumes that reproduction and lifespan are constrained by trade‐offs which prevent their simultaneous increase. Recently, there has been considerable interest in the possibility that this cost of reproduction is mediated by oxidative stress. However, empirical tests of this theory have yielded equivocal support. We carried out a meta‐analysis to examine associations between reproduction and oxidative damage across markers and tissues. We show that oxidative damage is positively associated with reproductive effort across females of various species. Yet paradoxically, categorical comparisons of breeders versus non‐breeders reveal that transition to the reproductive state is associated with a step‐change reduction in oxidative damage in certain tissues and markers. Developing offspring may be particularly sensitive to harm caused by oxidative damage in mothers. Therefore, such reductions could potentially function to shield reproducing mothers, gametes and developing offspring from oxidative insults that inevitably increase as a consequence of reproductive effort. According to this perspective, we hypothesise that the cost of reproduction is mediated by dual impacts of maternally‐derived oxidative damage on mothers and offspring, and that mothers may be selected to diminish such damage. Such oxidative shielding may explain why many existing studies have concluded that reproduction has little or no oxidative cost. Future advance in life‐history theory therefore needs to take account of potential transgenerational impacts of the mechanisms underlying life‐history trade‐offs.     

Fetal programming of neuropsychiatric disorders

Starting from the Developmental Origins of Health and Disease (DOHaD) hypotheses proposed by David Barker, namely fetal programming, in the past years, there is a growing evidence of the major role played by epigenetic factors during the intrauterine life and the perinatal period. Furthermore, it has been assessed that these factors can affect the health status in infancy and even in adulthood. In this review, we focus our attention on the fetal programming of the brain, analyzing the most recent literature concerning the epigenetic factors that can influence the development of neuropsychiatric disorders such as bipolar disorders, major depressive disorders, and schizophrenia. The perinatal epigenetic factors have been divided in two main groups: maternal factors and fetal factors. The maternal factors include diet, smoking, alcoholism, hypertension, malnutrition, trace elements, stress, diabetes, substance abuse, and exposure to environmental toxicants, while the fetal factors include hypoxia/asphyxia, placental insufficiency, prematurity, low birth weight, drugs administered to the mother or to the baby, and all factors causing intrauterine growth restriction. A better comprehension of the possible mechanisms underlying the pathogenesis of these diseases may help researchers and clinicians develop new diagnostic tools and treatments to offer these patients a tailored medical treatment strategy to improve their quality of life. Birth Defects Research (Part C) 108:207–223, 2016. © 2016 Wiley Periodicals, Inc.     

Chlorophyll a is the crucial redox sensor and transmembrane signal transmitter in the cytochrome b6f complex. Components and mechanisms of state transitions from the hydrophobic mismatch viewpoint

The cytochrome (cyt) b₆f complex is involved in the transmembrane redox signaling that triggers state transitions in cyanobacteria and chloroplasts. However, the components and molecular mechanisms are still unclear. In an attempt to solve this long-standing problem, we first focused on the unknown role of a single chlorophyll a (Chla) in cyt b₆f with a new approach based on Chla structural properties. Various b₆f X-ray crystal structures were analyzed to identify their differences, which correlate with differences in Chla molecular volume. We found that the distance of the Rieske [2Fe-2S] cluster to Chla correlates with the distance between a pair of residues at the Q_o-site and the distance between a pair of residues at the opposite membrane side. These correlations were accompanied by the rotation of a key peripheral residue and by changes in the hydrophobic thickness of cyt b₆f. Parallel analysis of cyt bc₁ crystal structures allowed us to conclude that Chla acts as the crucial redox sensor and transmembrane signal transmitter in b₆f for changes in the plastoquinone pool redox state. The hydrophobic mismatch induced by the changed hydrophobic thickness of cyt b₆f is the driving force for the structural reorganizations of the photosynthetic apparatus during induction and the progression of state transitions in cyanobacteria and chloroplasts. A mechanism for LHCII kinase activation in chloroplasts is also proposed. Our understanding of the dynamic structural changes in bc-complexes during turnover at the Q_o-site and state transitions is augmented by the time-sequence ordering of 56 bc crystal structures.     

Numerical investigations of rib fracture failure models in different dynamic loading conditions

Rib fracture is one of the most common thoracic injuries in vehicle traffic accidents that can result in fatalities associated with seriously injured internal organs. A failure model is critical when modelling rib fracture to predict such injuries. Different rib failure models have been proposed in prediction of thorax injuries. However, the biofidelity of the fracture failure models when varying the loading conditions and the effects of a rib fracture failure model on prediction of thoracic injuries have been studied only to a limited extent. Therefore, this study aimed to investigate the effects of three rib failure models on prediction of thoracic injuries using a previously validated finite element model of the human thorax. The performance and biofidelity of each rib failure model were first evaluated by modelling rib responses to different loading conditions in two experimental configurations: (1) the three-point bending on the specimen taken from rib and (2) the anterior–posterior dynamic loading to an entire bony part of the rib. Furthermore, the simulation of the rib failure behaviour in the frontal impact to an entire thorax was conducted at varying velocities and the effects of the failure models were analysed with respect to the severity of rib cage damages. Simulation results demonstrated that the responses of the thorax model are similar to the general trends of the rib fracture responses reported in the experimental literature. However, they also indicated that the accuracy of the rib fracture prediction using a given failure model varies for different loading conditions.     

Computational evaluation of load carriage effects on gait balance stability

Evaluating the effects of load carriage on gait balance stability is important in various applications. However, their quantification has not been rigorously addressed in the current literature, partially due to the lack of relevant computational indices. The novel Dynamic Gait Measure (DGM) characterizes gait balance stability by quantifying the relative effects of inertia in terms of zero-moment point, ground projection of center of mass, and time-varying foot support region. In this study, the DGM is formulated in terms of the gait parameters that explicitly reflect the gait strategy of a given walking pattern and is used for computational evaluation of the distinct balance stability of loaded walking. The observed gait adaptations caused by load carriage (decreased single support duration, inertia effects, and step length) result in decreased DGM values (p < 0.0001), which indicate that loaded walking motions are more statically stable compared with the unloaded normal walking. Comparison of the DGM with other common gait stability indices (the maximum Floquet multiplier and the margin of stability) validates the unique characterization capability of the DGM, which is consistently informative of the presence of the added load.     

Covalent vs. Non‐Covalent Inhibition: Tackling Drug Resistance in EGFR – A Thorough Dynamic Perspective

A persistent challenge in the treatment of non‐small cell lung cancer (NSCLC) with EGFR is the emergence of drug‐resistant caused by somatic mutations. The EGFR L858R/T790 M double mutant (EGFR^DM) was found to be the most alarming variant. Despite the development of a wide range of inhibitors, none of them could inhibit EGFR^DM effectively. Recently, 11h and 45a , have been found to be potent inhibitors against EGFR^DM through two distinctive mechanisms, non‐covalent and covalent binding, respectively. However, the structural and dynamic implications of the two modes of inhibitions remain unexplored. Herein, two molecular dynamics simulation protocols, coupled with free‐energy calculations, were applied to gain insight into the atomistic nature of each binding mode. The comparative analysis confirmed that there is a significant difference in the binding free energy between 11h and 45a (ΔΔG_bind=?21.17 kcal/mol). The main binding force that governs the binding of both inhibitors is vdW, with a higher contribution for 45a . Two residues ARG841 and THR854 were found to have curtailed role in the binding of 45a to EGFR^DM by stabilizing its flexible alcohol chain. The 45a binding to EGFR^DM induces structural rearrangement in the active site to allow easier accessibility of 45a to target residue CYS797. The findings of this work can substantially shed light on new strategies for developing novel classes of covalent and non‐covalent inhibitors with increased specificity and potency.