Gene profiling of maternal hepatic adaptations to pregnancy

BACKGROUND: Maternal metabolic demands change dramatically during the course of gestation and must be co-ordinated with the needs of the developing placenta and fetus. The liver is critically involved in metabolism and other important functions. However, maternal hepatic adjustments to pregnancy are poorly understood. AIM: The aim of the study was to evaluate the influences of pregnancy on the maternal liver growth and gene expression profile. METHODS: Holtzman Sprague-Dawley rats were mated and sacrificed at various stages of gestation and post-partum. The maternal livers were analysed in gravimetric response, DNA content by PicoGreen dsDNA quantitation reagent, hepatocyte ploidy by flow cytometry and hepatocyte proliferation by ki-67 immunostaining. Gene expression profiling of non-pregnant and gestation d18.5 maternal hepatic tissue was analysed using a DNA microarray approach and partially verified by northern blot or quantitative real-time PCR analysis. RESULTS: During pregnancy, the liver exhibited approximately an 80% increase in size, proportional to the increase in body weight of the pregnant animals. The pregnancy-induced hepatomegaly was a physiological event of liver growth manifested by increases in maternal hepatic DNA content and hepatocyte proliferation. Pregnancy did not affect hepatocyte polyploidization. Pregnancy-dependent changes in hepatic expression were noted for a number of genes, including those associated with cell proliferation, cytokine signalling, liver regeneration and metabolism. CONCLUSIONS: The metabolic demands of pregnancy cause marked adjustments in maternal liver physiology. Central to these adjustments are an expansion in hepatic capacity and changes in hepatic gene expression. Our findings provide insights into pregnancy-dependent hepatic adaptations

Maternal hepatic growth response to pregnancy in the mouse

Pregnancy is characterized by physiological adjustments in the maternal compartment. In this investigation, the influence of pregnancy on maternal liver was examined in CD-1 mice. Dramatic changes were observed in the size of the maternal liver during pregnancy. Livers doubled in weight from the non-pregnant state to day 18 of pregnancy. The pregnancy-induced hepatomegaly was a physiological event of liver growth confirmed by DNA content increase and detection of hepatocyte hyperplasia and hypertrophy. Growth of the liver was initiated following implantation and peaked at parturition. The expression and/or activities of key genes known to regulate liver regeneration, a phenomenon of liver growth compensatory to liver mass loss, were investigated. The results showed that pregnancy-dependent liver growth was associated with interleukin (IL)-6, tumor necrosis factor α, c-Jun and IL-1β, but independent of hepatocyte growth factor, fibroblast growth factor 1, tumor necrosis factor receptor 1, constitutive androstane receptor and pregnane X receptor. Furthermore, maternal liver growth was associated with the activation of hepatic signal transducer and activator of transcription 3, β-catenin and epidermal growth factor receptor, but pregnancy did not activate hepatic c-Met. The findings suggest that the molecular mechanisms regulating pregnancy-induced liver growth and injury-induced liver regeneration exhibit overlapping features but are not identical. In summary, the liver of the mouse adapts to the demands of pregnancy via a dramatic growth response driven by hepatocyte proliferation and size increase

Path-integral analysis of fluctuation theorems for general Langevin processes

We examine classical, transient fluctuation theorems within the unifying framework of Langevin dynamics. We explicitly distinguish between the effects of non-conservative forces that violate detailed balance, and non-autonomous dynamics arising from the variation of an external parameter. When both these sources of nonequilibrium behavior are present, there naturally arise two distinct fluctuation theorems.Comment: 24 pages, one figur

Does stapedotomy improve high frequency conductive hearing?

Objectives: Stapedotomy is performed to address conductive hearing deficits. While hearing thresholds reliably improve at low frequencies (LF), conductive outcomes at high frequencies (HF) are less reliable and have not been well described. Herein, we evaluate post-operative HF air-bone gap (ABG) changes and measure HF air conduction (AC) thresholds changes as a function of frequency. Methods: Retrospective review of patients who underwent primary stapedotomy with incus wire piston prosthesis between January 2016 and May 2020. Pre- and postoperative audiograms were evaluated. LF ABG was calculated as the mean ABG of thresholds at 250, 500, and 1000 Hz. HF ABG was calculated at 4 kHz. Results: Forty-six cases met criteria. Mean age at surgery was 54.0 +/- 11.7 years. The LF mean preoperative ABG was 36.9 +/- 11.0 dB and postoperatively this significantly reduced to 9.35 +/- 6.76 dB, (P \u3c .001). The HF mean preoperative ABG was 31.1 +/- 14.4 dB and postoperatively, this also significantly reduced to 14.5 +/- 12.3 dB, (P \u3c .001). The magnitude of LF ABG closure was over 1.5 times the magnitude of HF ABG closure (P \u3c .001). The gain in AC decreased with increasing frequency (P \u3c .001). Conclusion: Hearing improvement following stapedotomy is greater at low than high frequencies. Postoperative air bone gaps persist at 4 kHz. Further biomechanical and histopathologic work is necessary to localize postoperative high frequency conductive hearing deficits and improve stapedotomy hearing outcomes. Level of Evidence: 4, retrospective study

Global Dissemination of a Single Mutation Conferring White Pericarp in Rice

Here we report that the change from the red seeds of wild rice to the white seeds of cultivated rice (Oryza sativa) resulted from the strong selective sweep of a single mutation, a frame-shift deletion within the Rc gene that is found in 97.9% of white rice varieties today. A second mutation, also within Rc, is present in less than 3% of white accessions surveyed. Haplotype analysis revealed that the predominant mutation originated in the japonica subspecies and crossed both geographic and sterility barriers to move into the indica subspecies. A little less than one Mb of japonica DNA hitchhiked with the rc allele into most indica varieties, suggesting that other linked domestication alleles may have been transferred from japonica to indica along with white pericarp color. Our finding provides evidence of active cultural exchange among ancient farmers over the course of rice domestication coupled with very strong, positive selection for a single white allele in both subspecies of O. sativa

Effects of intersegmental transfers on target location by proteins

We study a model for a protein searching for a target, using facilitated diffusion, on a DNA molecule confined in a finite volume. The model includes three distinct pathways for facilitated diffusion: (a) sliding - in which the protein diffuses along the contour of the DNA (b) jumping - where the protein travels between two sites along the DNA by three-dimensional diffusion, and finally (c) intersegmental transfer - which allows the protein to move from one site to another by transiently binding both at the same time. The typical search time is calculated using scaling arguments which are verified numerically. Our results suggest that the inclusion of intersegmental transfer (i) decreases the search time considerably (ii) makes the search time much more robust to variations in the parameters of the model and (iii) that the optimal search time occurs in a regime very different than that found for models which ignore intersegmental transfers. The behavior we find is rich and shows surprising dependencies, for example, on the DNA length.Comment: 40 pages, 14 figure

Achieving high-sensitivity for clinical applications using augmented exome sequencing

daSNVs in ACMG genes where inadequate coverage was observed among at least one platform, using WES/ACE data normalized to both 12 Gb and 100× mean coverage. (XLSX 312 kb

Synergistic malaria vaccine combinations identified by systematic antigen screening.

A highly effective vaccine would be a valuable weapon in the drive toward malaria elimination. No such vaccine currently exists, and only a handful of the hundreds of potential candidates in the parasite genome have been evaluated. In this study, we systematically evaluated 29 antigens likely to be involved in erythrocyte invasion, an essential developmental stage during which the malaria parasite is vulnerable to antibody-mediated inhibition. Testing antigens alone and in combination identified several strain-transcending targets that had synergistic combinatorial effects in vitro, while studies in an endemic population revealed that combinations of the same antigens were associated with protection from febrile malaria. Video microscopy established that the most effective combinations targeted multiple discrete stages of invasion, suggesting a mechanistic explanation for synergy. Overall, this study both identifies specific antigen combinations for high-priority clinical testing and establishes a generalizable approach that is more likely to produce effective vaccines

Emergent global patterns of ecosystem structure and function from a mechanistic general ecosystem model

Anthropogenic activities are causing widespread degradation of ecosystems worldwide, threatening the ecosystem services upon which all human life depends. Improved understanding of this degradation is urgently needed to improve avoidance and mitigation measures. One tool to assist these efforts is predictive models of ecosystem structure and function that are mechanistic: based on fundamental ecological principles. Here we present the first mechanistic General Ecosystem Model (GEM) of ecosystem structure and function that is both global and applies in all terrestrial and marine environments. Functional forms and parameter values were derived from the theoretical and empirical literature where possible. Simulations of the fate of all organisms with body masses between 10 µg and 150,000 kg (a range of 14 orders of magnitude) across the globe led to emergent properties at individual (e.g., growth rate), community (e.g., biomass turnover rates), ecosystem (e.g., trophic pyramids), and macroecological scales (e.g., global patterns of trophic structure) that are in general agreement with current data and theory. These properties emerged from our encoding of the biology of, and interactions among, individual organisms without any direct constraints on the properties themselves. Our results indicate that ecologists have gathered sufficient information to begin to build realistic, global, and mechanistic models of ecosystems, capable of predicting a diverse range of ecosystem properties and their response to human pressures