Effects of cell cycle variability on lineage and population measurements of mRNA abundance

Many models of gene expression do not explicitly incorporate a cell cycle description. Here, we derive a theory describing how messenger RNA (mRNA) fluctuations for constitutive and bursty gene expression are influenced by stochasticity in the duration of the cell cycle and the timing of DNA replication. Analytical expressions for the moments show that omitting cell cycle duration introduces an error in the predicted mean number of mRNAs that is a monotonically decreasing function of η, which is proportional to the ratio of the mean cell cycle duration and the mRNA lifetime. By contrast, the error in the variance of the mRNA distribution is highest for intermediate values of η consistent with genome-wide measurements in many organisms. Using eukaryotic cell data, we estimate the errors in the mean and variance to be at most 3% and 25%, respectively. Furthermore, we derive an accurate negative binomial mixture approximation to the mRNA distribution. This indicates that stochasticity in the cell cycle can introduce fluctuations in mRNA numbers that are similar to the effect of bursty transcription. Finally, we show that for real experimental data, disregarding cell cycle stochasticity can introduce errors in the inference of transcription rates larger than 10%

Chemical characterization of a hypoglycemic extract from Cucurbita ficifolia bouche that induces liver glycogen accumulation in diabetic mice

Background: The aqueous extract of Cucurbita ficifolia (C. ficifolia) fruit has demonstrated hypoglycemic effect, which may be attributed to some components in the extract. However, the major secondary metabolites in this fruit have not yet been identified and little is known about its extra-pancreatic action, in particular, on liver carbohydrate metabolism. Therefore, in addition to the isolation and structural elucidation of the principal components in the aqueous extract of C. ficifolia, the aim of this study was to determine whether or not the hypoglycemic effect of the aqueous extract of Cucurbita ficifolia (C. ficifolia) fruit is due to accumulation of liver glycogen in diabetic mice.Materials and Methods: The aqueous extract from fruit of C. ficifolia was fractionated and its main secondary metabolites were purified and chemically characterized (NMR and GC-MS). Alloxan-induced diabetic mice received daily by gavage the aqueous extract (30 days). The liver glycogen content was quantified by spectroscopic method and by PAS stain; ALT and AST by spectrometric method; glycogen synthase, glycogen phosphorylase and GLUT2 by Western blot; the mRNA expression of GLUT2 and glucagon-receptor by RT-PCR; while serum insulin was quantified by ELISA method. A liver histological analysis was also performed by H&E stain.Results: Chemical fingerprint showed five majoritarian compounds in the aqueous extract of C. ficifolia: p-coumaric acid, p-hydroxybenzoic acid, salicin, stigmast-7,2,2-dien-3-ol and stigmast-7-en-3-ol. The histological analysis showed accumulation of liver glycogen. Also, increased glycogen synthase and decreased glycogen phosphorylase were observed. Interestingly, the histological architecture evidenced a liver-protective effect due the extract.Conclusion: Five compounds were identified in C. ficifolia aqueous extract. The hypoglycemic effect of this extract may be partially explained by liver glycogen accumulation. The bioactive compound responsible for the hypoglycemic effect of this extract will be elucidated in subsequent studies.Keywords: Cucurbita ficifolia, Cucurbitaceae, liver glycogen, hypoglycemic plants, p-coumaric acid, salicin, p-hydroxybenzoic aci

Aerostructural Optimization of Nonplanar Lifting Surfaces

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83557/1/AIAA-44727-830.pd

Mechano‐electrical interactions and heterogeneities in wild‐type and drug‐induced long QT syndrome rabbits

Electromechanical reciprocity – comprising electro-mechanical (EMC) and mechano-electric coupling (MEC) – provides cardiac adaptation to changing physiological demands. Understanding electromechanical reciprocity and its impact on function and heterogeneity in pathological conditions – such as (drug-induced) acquired long QT syndrome (aLQTS) – might lead to novel insights in arrhythmogenesis. Our aim is to investigate how electrical changes impact on mechanical function (EMC) and vice versa (MEC) under physiological conditions and in aLQTS. To measure regional differences in EMC and MEC in vivo, we used tissue phase mapping cardiac MRI and a 24-lead ECG vest in healthy (control) and IKr-blocker E-4031-induced aLQTS rabbit hearts. MEC was studied in vivo by acutely increasing cardiac preload, and ex vivo by using voltage optical mapping (OM) in beating hearts at different preloads. In aLQTS, electrical repolarization (heart rate corrected RT-interval, RTn370) was prolonged compared to control (P < 0.0001) with increased spatial and temporal RT heterogeneity (P < 0.01). Changing electrical function (in aLQTS) resulted in significantly reduced diastolic mechanical function and prolonged contraction duration (EMC), causing increased apico-basal mechanical heterogeneity. Increased preload acutely prolonged RTn370 in both control and aLQTS hearts (MEC). This effect was more pronounced in aLQTS (P < 0.0001). Additionally, regional RT-dispersion increased in aLQTS. Motion-correction allowed us to determine APD-prolongation in beating aLQTS hearts, but limited motion correction accuracy upon preload-changes prevented a clear analysis of MEC ex vivo. Mechano-induced RT-prolongation and increased heterogeneity were more pronounced in aLQTS than in healthy hearts. Acute MEC effects may play an additional role in LQT-related arrhythmogenesis, warranting further mechanistic investigations

CHEMICAL CHARACTERIZATION OF A HYPOGLYCEMIC EXTRACT FROM CUCURBITA FICIFOLIA BOUCHE THAT INDUCES LIVER GLYCOGEN ACCUMULATION IN DIABETIC MICE.

Background: The aqueous extract of Cucurbita ficifolia (C. ficifolia) fruit has demonstrated hypoglycemic effect, which may be attributed to some components in the extract. However, the major secondary metabolites in this fruit have not yet been identified and little is known about its extra-pancreatic action, in particular, on liver carbohydrate metabolism. Therefore, in addition to the isolation and structural elucidation of the principal components in the aqueous extract of C. ficifolia, the aim of this study was to determine whether or not the hypoglycemic effect of the aqueous extract of Cucurbita ficifolia (C. ficifolia) fruit is due to accumulation of liver glycogen in diabetic mice. Materials and Methods: The aqueous extract from fruit of C. ficifolia was fractionated and its main secondary metabolites were purified and chemically characterized (NMR and GC-MS). Alloxan-induced diabetic mice received daily by gavage the aqueous extract (30 days). The liver glycogen content was quantified by spectroscopic method and by PAS stain; ALT and AST by spectrometric method; glycogen synthase, glycogen phosphorylase and GLUT2 by Western blot; the mRNA expression of GLUT2 and glucagon-receptor by RT-PCR; while serum insulin was quantified by ELISA method. A liver histological analysis was also performed by H&E stain. Results: Chemical fingerprint showed five majoritarian compounds in the aqueous extract of C. ficifolia: p-coumaric acid, p-hydroxybenzoic acid, salicin, stigmast-7,2,2-dien-3-ol and stigmast-7-en-3-ol. The histological analysis showed accumulation of liver glycogen. Also, increased glycogen synthase and decreased glycogen phosphorylase were observed. Interestingly, the histological architecture evidenced a liver-protective effect due the extract. Conclusion: Five compounds were identified in C. ficifolia aqueous extract. The hypoglycemic effect of this extract may be partially explained by liver glycogen accumulation. The bioactive compound responsible for the hypoglycemic effect of this extract will be elucidated in subsequent studies

Ocean Drilling Perspectives on Meteorite Impacts

Extraterrestrial impacts that reshape the surfaces of rocky bodies are ubiquitous in the solar system. On early Earth, impact structures may have nurtured the evolution of life. More recently, a large meteorite impact off the Yucatán Peninsula in Mexico at the end of the Cretaceous caused the disappearance of 75% of species known from the fossil record, including non-avian dinosaurs, and cleared the way for the dominance of mammals and the eventual evolution of humans. Understanding the fundamental processes associated with impact events is critical to understanding the history of life on Earth, and the potential for life in our solar system and beyond. Scientific ocean drilling has generated a large amount of unique data on impact pro- cesses. In particular, the Yucatán Chicxulub impact is the single largest and most sig- nificant impact event that can be studied by sampling in modern ocean basins, and marine sediment cores have been instrumental in quantifying its environmental, cli- matological, and biological effects. Drilling in the Chicxulub crater has significantly advanced our understanding of fundamental impact processes, notably the formation of peak rings in large impact craters, but these data have also raised new questions to be addressed with future drilling. Within the Chicxulub crater, the nature and thickness of the melt sheet in the central basin is unknown, and an expanded Paleocene hemipelagic section would provide insights to both the recovery of life and the climatic changes that followed the impact. Globally, new cores collected from today’s central Pacific could directly sample the downrange ejecta of this northeast-southwest trending impact. Extraterrestrial impacts have been controversially suggested as primary drivers for many important paleoclimatic and environmental events throughout Earth history. However, marine sediment archives collected via scientific ocean drilling and geo- chemical proxies (e.g., osmium isotopes) provide a long-term archive of major impact events in recent Earth history and show that, other than the end-Cretaceous, impacts do not appear to drive significant environmental changes

Replication and Transmission of H9N2 Influenza Viruses in Ferrets: Evaluation of Pandemic Potential

H9N2 avian influenza A viruses are endemic in poultry of many Eurasian countries and have caused repeated human infections in Asia since 1998. To evaluate the potential threat of H9N2 viruses to humans, we investigated the replication and transmission efficiency of H9N2 viruses in the ferret model. Five wild-type (WT) H9N2 viruses, isolated from different avian species from 1988 through 2003, were tested in vivo and found to replicate in ferrets. However these viruses achieved mild peak viral titers in nasal washes when compared to those observed with a human H3N2 virus. Two of these H9N2 viruses transmitted to direct contact ferrets, however no aerosol transmission was detected in the virus displaying the most efficient direct contact transmission. A leucine (Leu) residue at amino acid position 226 in the hemagglutinin (HA) receptor-binding site (RBS), responsible for human virus-like receptor specificity, was found to be important for the transmission of the H9N2 viruses in ferrets. In addition, an H9N2 avian-human reassortant virus, which contains the surface glycoprotein genes from an H9N2 virus and the six internal genes of a human H3N2 virus, showed enhanced replication and efficient transmission to direct contacts. Although no aerosol transmission was observed, the virus replicated in multiple respiratory tissues and induced clinical signs similar to those observed with the parental human H3N2 virus. Our results suggest that the establishment and prevalence of H9N2 viruses in poultry pose a significant threat for humans

Vascular Endothelial Growth Factor Receptor-2 Couples Cyclo-Oxygenase-2 with Pro-Angiogenic Actions of Leptin on Human Endothelial Cells

The adipocyte-derived hormone leptin influences the behaviour of a wide range of cell types and is now recognised as a pro-angiogenic and pro-inflammatory factor. In the vasculature, these effects are mediated in part through its direct leptin receptor (ObRb)-driven actions on endothelial cells (ECs) but the mechanisms responsible for these activities have not been established. In this study we sought to more fully define the molecular links between inflammatory and angiogenic responses of leptin-stimulated human ECs../Akt/COX-2 signalling axis is required for leptin's pro-angiogenic actions and that this is regulated upstream by ObRb-dependent activation of VEGFR2. These studies identify a new function for VEGFR2 as a mediator of leptin-stimulated COX-2 expression and angiogenesis and have implications for understanding leptin's regulation of the vasculature in both non-obese and obese individuals