Nanopatterned acellular valve conduits drive the commitment of blood-derived multipotent cells

Considerable progress has been made in recent years toward elucidating the correlation among nanoscale topography, mechanical properties, and biological behavior of cardiac valve substitutes. Porcine TriCol scaffolds are promising valve tissue engineering matrices with demonstrated self-repopulation potentiality. In order to define an in vitro model for investigating the influence of extracellular matrix signaling on the growth pattern of colonizing blood-derived cells, we cultured circulating multipotent cells (CMC) on acellular aortic (AVL) and pulmonary (PVL) valve conduits prepared with TriCol method and under no-flow condition. Isolated by our group from Vietnamese pigs before heart valve prosthetic implantation, porcine CMC revealed high proliferative abilities, three-lineage differentiative potential, and distinct hematopoietic/endothelial and mesenchymal properties. Their interaction with valve extracellular matrix nanostructures boosted differential messenger RNA expression pattern and morphologic features on AVL compared to PVL, while promoting on both matrices the commitment to valvular and endothelial cell-like phenotypes. Based on their origin from peripheral blood, porcine CMC are hypothesized in vivo to exert a pivotal role to homeostatically replenish valve cells and contribute to hetero- or allograft colonization. Furthermore, due to their high responsivity to extracellular matrix nanostructure signaling, porcine CMC could be useful for a preliminary evaluation of heart valve prosthetic functionality

Differential Enzymatic Activity of Rat ADAR2 Splicing Variants Is Due to Altered Capability to Interact with RNA in the Deaminase Domain

In mammals, adenosine (A) to inosine (I) RNA editing is performed by adenosine deaminases acting on RNA (ADAR), ADAR1 and ADAR2 enzymes, encoded by mRNAs that might undergo splicing process. In rat, two splicing events produce several isoforms of ADAR2, called ADAR2a, ADAR2b, ADAR2e, and ADAR2f, but only ADAR2a and ADAR2b are translated into an active protein. In particular, they differ for ten amino acids located in the catalytic domain of ADAR2b. Here, we focused on these two isoforms, analyzing the splicing pattern and their different function during rat neuronal maturation. We found an increase of editing levels in cortical neurons overexpressing ADAR2a compared to those overexpressing ADAR2b. These results indicate ADAR2a isoform as the most active one, as reported for the homologous human short variant. Furthermore, we showed that the differential editing activity is not due to a different dimerization of the two isoforms; it seems to be linked to the ten amino acids loop of ADAR2b that might interfere with RNA binding, occupying the space volume in which the RNA should be present in case of binding. These data might shed light on the complexity of ADAR2 regulations

Early raise of BDNF in hippocampus suggests induction of posttranscriptional mechanisms by antidepressants

<p>Abstract</p> <p>Background</p> <p>The neurotrophin BDNF has been implicated in the regulation of neuroplasticity, gene expression, and synaptic function in the adult brain, as well as in the pathophysiology of neuropsychiatric disorders and the mechanism of action of antidepressants. Antidepressant treatments have been shown to increase the expression of BDNF mRNA, although the changes measured were found to be different depending on various factors. A few studies only have measured levels of BDNF protein after antidepressant treatments, and poor correlation was found between mRNA and protein changes. We studied the time course of expression of BDNF mRNA and protein during drug treatments, in order to elucidate the temporal profile of regulation of this effector and whether mRNA and protein levels correlate. Rat groups were treated for 1, 2 or 3 weeks with fluoxetine or reboxetine; in additional groups drug treatment was followed by a washout week (3+1). Total BDNF mRNA was measured by Real Time PCR, pro- and mature BDNF proteins were measured by Western blot.</p> <p>Results</p> <p>We found that mature BDNF protein is induced more rapidly than mRNA, by both drugs in hippocampus (weeks 1–2) and by reboxetine in prefrontal/frontal cortex (week 1). The temporal profile of BDNF protein expression was largely inconsistent with that of mRNA, which followed the protein induction and reached a peak at week 3.</p> <p>Conclusion</p> <p>These results suggest that BDNF protein is rapidly elevated by antidepressant treatments by posttranscriptional mechanisms, and that induction of BDNF mRNA is a slower process.</p

Human Mutated MYOT and CRYAB Genes Cause a Myopathic Phenotype in Zebrafish

Myofibrillar myopathies (MFMs) are a group of hereditary neuromuscular disorders sharing common histological features, such as myofibrillar derangement, Z-disk disintegration, and accumulation of degradation products into protein aggregates. They are caused by mutations in several genes that encode either structural proteins or molecular chaperones. Nevertheless, the mechanisms by which mutated genes result in protein aggregation are still unknown. To unveil the role of myotilin and αB-crystallin in the pathogenesis of MFM, we injected zebrafish fertilized eggs at one-cell stage with expression plasmids harboring cDNA sequences of human wildtype or mutated MYOT (p.Ser95Ile) and human wildtype or mutated CRYAB (p.Gly154Ser). We evaluated the effects on fish survival, motor behavior, muscle structure and development. We found that transgenic zebrafish showed morphological defects that were more severe in those overexpressing mutant genes which developed a myopathic phenotype consistent with that of human myofibrillar myopathy including the formation of protein aggregates. Results indicate that pathogenic mutations in myotilin and αB-crystallin genes associated with MFM cause a structural and functional impairment of the skeletal muscle in zebrafish, thereby making this non-mammalian organism a powerful model to dissect disease pathogenesis and find possible druggable targets

Cost-Benefit Analysis of Fruit Tree Based Agro-Forestry Systems: The Case of The Htee Pu Climate-Smart Village, Nyaung-U Township, Central Dry Zone, Myanmar

Htee Pu is a farming village located in the Central Dry Zone of Myanmar, where drought, high atmospheric temperature, and infertile and degraded soils are constraints to sustaining and increasing agricultural productivity and farm income. Dryland fruit-tree-based agroforestry and the raising of goats were the prominent CSA options introduced to supplement the risk-prone prevalent annual cropping systems. This study was conducted to measure the financial benefits of introducing dryland-appropriate fruit trees (with one group having an additional complementary goat component) to Htee Pu households. The Cost and Return Analysis, Payback Period for Investment Analysis, and Household Liquidity Analysis were the analytical methods that were used in the study. Estimating the Net Value generated from potential fruit harvests showed that planting fruit trees on farms or homesteads can be highly profitable. Adding the financial benefits from fruit trees to the households’ farm and off-farm income resulted in improvements in the liquidity condition of a number of households. While the Cost-Benefit Analysis results were less impressive than the fruit tree project, the longer-term outcomes would improve once all the female goat breeders had reached their reproductive age. Goats would be significant additional sources of income and food for home consumption, thus a relevant CSA option as well

Transcriptional Profiling of Rat Prefrontal Cortex after Acute Inescapable Footshock Stress

Stress is a primary risk factor for psychiatric disorders such as Major Depressive Disorder (MDD) and Post Traumatic Stress Disorder (PTSD). The response to stress involves the regulation of transcriptional programs, which is supposed to play a role in coping with stress. To evaluate transcriptional processes implemented after exposure to unavoidable traumatic stress, we applied microarray expression analysis to the PFC of rats exposed to acute footshock (FS) stress that were sacrificed immediately after the 40 min session or 2 h or 24 h after. While no substantial changes were observed at the single gene level immediately after the stress session, gene set enrichment analysis showed alterations in neuronal pathways associated with glia development, glia-neuron networking, and synaptic function. Furthermore, we found alterations in the expression of gene sets regulated by specific transcription factors that could represent master regulators of the acute stress response. Of note, these pathways and transcriptional programs are activated during the early stress response (immediately after FS) and are already turned off after 2 h-while at 24 h, the transcriptional profile is largely unaffected. Overall, our analysis provided a transcriptional landscape of the early changes triggered by acute unavoidable FS stress in the PFC of rats, suggesting that the transcriptional wave is fast and mild, but probably enough to activate a cellular response to acute stress

Whole Blood Transcriptome Characterization of 3xTg-AD Mouse and Its Modulation by Transcranial Direct Current Stimulation (tDCS)

The 3xTg-AD mouse is a widely used model in the study of Alzheimer’s Disease (AD). It has been extensively characterized from both the anatomical and behavioral point of view, but poorly studied at the transcriptomic level. For the first time, we characterize the whole blood transcriptome of the 3xTg-AD mouse at three and six months of age and evaluate how its gene expression is modulated by transcranial direct current stimulation (tDCS). RNA-seq analysis revealed 183 differentially expressed genes (DEGs) that represent a direct signature of the genetic background of the mouse. Moreover, in the 6-month-old 3xTg-AD mice, we observed a high number of DEGs that could represent good peripheral biomarkers of AD symptomatology onset. Finally, tDCS was associated with gene expression changes in the 3xTg-AD, but not in the control mice. In conclusion, this study provides an in-depth molecular characterization of the 3xTg-AD mouse and suggests that blood gene expression can be used to identify new biomarkers of AD progression and treatment effects

Higgs mass implications on the stability of the electroweak vacuum

We update instability and metastability bounds of the Standard Model electroweak vacuum in view of the recent ATLAS and CMS Higgs results. For a Higgs mass in the range 124--126 GeV, and for the current central values of the top mass and strong coupling constant, the Higgs potential develops an instability around $10^{11}$ GeV, with a lifetime much longer than the age of the Universe. However, taking into account theoretical and experimental errors, stability up to the Planck scale cannot be excluded. Stability at finite temperature implies an upper bound on the reheat temperature after inflation, which depends critically on the precise values of the Higgs and top masses. A Higgs mass in the range 124--126 GeV is compatible with very high values of the reheating temperature, without conflict with mechanisms of baryogenesis such as leptogenesis. We derive an upper bound on the mass of heavy right-handed neutrinos by requiring that their Yukawa couplings do not destabilize the Higgs potential.Comment: 14 pages, 8 figure