Month: September 2020

Human self-reports of stress during pregnancy are associated with increased circulating cortisol, but only 10–20% of maternal cortisol passes to the fetus. This barrier function of the placenta is achieved through the actions of the enzyme 11b-hydroxysteroid dehydrogenase type 2, which converts the glucocorticoids cortisol/corticosterone into the inactive metabolites cortisone/11b-dehydrocorticosterone, thus preventing the activation of glucocorticoid receptors. In contrast, the enzyme 11ß–HSD1 converts inactive glucocorticoids to cortisol/corticosterone. Targeted gene deletion and pharmacological studies suggest a functional consequence of 11ß–HSD for the development of the hypothalamicpituitary adrenal response to stress. In mice, mutation of the HSD11B2 gene leads to hypertension, excess mineralocorticoid activity, and increased anxiety-like behavior in adulthood whereas HSD11B1 mutation leads to attenuated negative-feedback of the HPA response to stress and improved cognitive performance in aging. Pharmacological inhibition of 11ß–HSD2 during pregnancy or administration of dexamethasone, a synthetic glucocorticoid that is not metabolized by 11ß–HSD2, leads to molecular and neurobiological changes within the HPA axis associated with increased stress responsivity and anxiety-like behavior in adulthood. These glucocorticoid programming effects may also be evident in humans, consequent to prenatal betamethasone exposure or inhibition of 11ß–HSD2 through elevated glycyrrhizin consumption during pregnancy. These studies suggest that the regulation of placental 11ß–HSD2 levels may be a mechanistic link between the experience of maternal gestational stress and long-term health outcomes in offspring. There is increasing evidence that maternal adversity during pregnancy may lead to a down-regulation of 11ß–HSD2. In rats, chronic restraint stress during gestational days 11–20 was found to decrease placental 11ß–HSD2 enzymatic activity and decrease mRNA levels of this gene. Similarly, rat dams that are food restricted from gestational days 10–20, a manipulation that increases maternal plasma corticosterone and induces similar phenotypes to those observed following prenatal stress, have reduced placental protein levels of 11ß–HSD2. In humans, Nutlin-3 heightened maternal anxiety was found to be negatively correlated with placental HSD11B2 mRNA levels. Reduced placental HSD11B2 mRNA levels have also been found associated with intrauterine growth retardation and pre-term birth, suggesting that the transcriptional activity of this enzyme may be predicted by maternal adversity and predictive of high risk birth outcomes. Regulation of gene expression through epigenetic mechanisms – factors that alter gene transcription without altering DNA sequence – is being increasingly explored within the context of environmentally-induced changes in neurobiology, metabolism, and disease risk.

To this end, available treatments in stroke focus on improving brain tissue perfusion. Targeting vascular injury/BBB dysfunction or immune response within the peri-ischemic region is not yet a treatment option. Thus, intravenous recombinant tissue plasminogen activator and mechanical recanalization remain the only approved treatments for stroke. The fundamental limitation of these therapies is the short treatment window. Moreover, symptomatic hemorrhagic transformation of the infarct associated with the administration of IV r-tPA remains a primary concern. In the USA, for example, only about 4% of ischemic stroke patients are treated with IV r-tPA. Hence, there is substantial interest in developing novel therapeutics for the treatment of acute cerebral ischemia. The aims of the present study were to use imaging methods to test directly the effect of SPG stimulation on vascular diameter and permeability, rCBF, infarct size and neuronal network activity in the acutely ischemic cortex. A better insight into the mechanisms underlying the effects of SPG may improve patient selection and follow-up, and improve the use of SPG stimulation as a new therapeutic modality for brain disorders. In the present study, we examined – for the first time– the effect of SPG stimulation on the diameter and blood flow in surface cortical vessels in healthy and ischemic brains. We further tested the effect of repetitive SPG stimulation on cortical electrophysiology within the peri-infarct region in the photothrombosis model. The main findings of this study were: SPG stimulation led to intensity- and pulse width dependent vasodilation and increased rCBF; SPG-induced vasodilation facilitated partial reperfusion of occluded vessels in the phothrombosis RB model; the periischemic zone showed increased permeability of the BBB, which was reduced in size both immediate and delayed stimulation of the SPG; the necrotic core lesion was smaller following SPG treatment; fast cortical electrical activity and seizure-like events were prominent from day 3 after photothrombosis and reduced to control levels in SPG treated animals. A milder effect on rCBF was reported by Henninger and Fisher in rats, when isoflurane anesthesia was used, perhaps because of the vasodilating effect of isoflurane. While previous studies in monkeys demonstrated that SPG stimulation induces dilatation of constricted large vessels, in a sub-arachnoid hemorrhage model, our study shows that similar dilation occurs in small surface arterioles of the healthy brain. EX 527 Recently, similar protocol has been shown to increase perfusion in MRI scans of rats following MCAO occlusion, suggesting that the vasodilation we observed in superficial vessels reflects a general response of both superficial and deep vessels to stimulation of the parasympathetic fibers of the greater superficial petrosal nerves. Notably, using the direct imaging approach we show for the first time in a stroke model, that SPGinduced vasodilation may result in immediate reperfusion of the ischemic core.

However, we do identify several CpG sites within the placenta at which an individual’s DNA methylation levels do significantly predict those observed in the fetal cortex, raising the intriguing possibility of using the epigenetic status of placenta to predict corresponding changes in the brain. Overall, these findings provide novel evidence for the epigenetic regulation of HSD11B2 as a potential mechanism linking maternal stress during gestation, dysregulation of placental gene expression, and neurodevelopmental outcomes in offspring. Though placental 11ß-HSD2 can function as an enzymatic buffer against the deleterious effects of exposure to maternal glucocorticoids, it is clear that this enzyme can be down-regulated by adverse prenatal experiences, thus limiting its capacity to protect the developing fetus. However, the nature and timing of these experiences is an important consideration in predicting the direction of the effects on 11ß-HSD2. For example, acute stress in pregnant rats has been found to increase the activity of placental 11ß-HSD2 and similarly in humans, betamethasone treatment within 72 hours of parturition leads to increased 11ß-HSD2 enzymatic activity. Up-regulation of placental 11ß-HSD2 may thus be an adaptive response to elevated maternal glucocorticoids. In contrast, chronic exposure to maternal glucocorticoids may lead to reduced placental 11ß-HSD2, increased exposure of fetal tissues to glucocorticoids, and neurodevelopmental and metabolic phenotypes associated with glucocorticoid programming. BAY 73-4506 Heightened glucocorticoid exposure during fetal development may promote lung development and thus increase survival following pre-term birth – an obstetric outcome predicted by maternal stress. Thus, though heightened anxiety and HPA activity may be considered maladaptive, these outcomes may be the cost of promoting survival amongst the offspring of gestationally stressed females. One possible strategy to buffer the brain against these neurodevelopmental consequences would be to increase 11ß-HSD2 within the brain. Though we do not find an increase in hypothalamic or cortical HSD11B2 mRNA levels, the stress-induced DNA hypomethylation of this gene that we observe in hypothalamic tissue may be an epigenetic precursor to these buffering effects. Time course analysis of HSD11B2 gene expression and DNA methylation throughout the prenatal stress exposure and into the postnatal period may thus be a key strategy for determining the dynamics of glucocorticoid programming mechanisms. Investigation of the epigenetic regulation of HSD11B2 has previously been explored outside the context of studies on maternal stress. In humans and in rats, the promoter and first exon of the HSD11B2 gene are rich in CpG sites and DNA methylation levels at CpG sites within this region are related to the expression of this gene. Pharmacological hypomethylation of HSD11B2 through in vitro or in vivo treatment with the DNA methyltransferase inhibitor 5-aza29-deoxycytidine has been found to increase HSD11B2 expression.

Our algorithm then checks the clique size in descending order, until size two. For a clique size k, if there is no clique with the same size, it can still be merged into a community if at least 70% of the nodes are members of the community. The overlapping communities can thus be generated through this backward clique percolation algorithm. For the percolation steps in our algorithm, the runtime is linear in terms of the number of cliques, as shown in. For the community merging steps, the worse-case runtime is quadratic in terms of the number of communities, which is usually a much smaller number than the number of nodes or cliques. Note that SECOM predicts the conserved regions of the domains instead of estimating the exact boundaries of the domains. To predict the boundaries, one can apply the widely used method in local Temozolomide alignment algorithms, which extends the aligned conserved regions in both directions until the alignment score is lower than a certain threshold. Biological features can also be extracted to enhance the prediction accuracy for boundaries. Since these are not the main focus of the paper, we leave it as a user option. Regulated insulin secretion from pancreatic beta-cells is required for normal glucose homeostasis. However, the molecular pathways underlying glucose-stimulated insulin secretion are complex and remain incompletely understood. In order to secrete insulin in response to glucose, beta-cells must sense a rise in extracellular glucose which in turn leads to a stimulus-secretion coupling cascade that triggers insulin granule exocytosis. Glucose is ‘sensed’ via an increase in the ATP to ADP ratio. Glucose enters the beta-cell via facilitative glucose transporters, and is then metabolised via the glycolytic pathway, Krebs cycle and the electron transport chain to generate 34–36 molecules of ATP per molecule of metabolised glucose. Increased ATP:ADP closes K channels, leading to membrane depolarisation; this in turn leads to the opening of voltage-dependent calcium channels in the cell membranes, facilitating calcium influx into the beta-cell. Insulin granule trafficking and insulin exocytosis in beta-cells are ATP and calcium dependent processes. Gem belongs to the RGK family of Ras-related GTPases, which includes Rad, Rem, and Rem2. While relatively little is known about the physiological roles of RGK family members, all RGK proteins are known to be capable of modulating VDCC function, with Gem and Rad also able to regulate cytoskeletal dynamics. The conserved ability of all RGK proteins to potently inhibit VDCCs, suggests that tissue-specific patterns of expression contribute to the functional differences between family members. Previous studies reported expression of Gem and Rem2 in rodent pancreatic beta-cells. Analysis of human islets indicate that multiple RGK family members are expressed in betacells, but further expression studies are required to focus specifically on beta-cells within the islet. The genes encoding detoxification enzymes belong to supergene families which have evolved predominantly by gene duplication and functional diversification.

The sum of estimated annual payments per person for inpatient hospital admissions, annual payments per person for outpatient services, annual payments per person for medicines, and annual payments per person for glucose-testing supplies. To avoid doublecounting, because self-reported payments for OPVs and admissions included payments for medicines, the study team subtracted from the grand total payments for medicines and strips that were purchased from hospitals during visits and admissions. To calculate the amount to subtract, the team first estimated the mean “as-used” supply of medicines, including aspirin and other over-the-counter products, when purchased from hospital pharmacies. Based on patient self-report, we then calculated the proportion of hospital clinic OPVs during which medicines were purchased. Because the interview schedule did not ask subjects which medicines they purchased at OPVs, we assumed that one refill of every current medicine was purchased at every OPV. To make use of these data, comparative analysis has often been used to induce meaningful hypotheses through discovery of conserved sequences with regulatory functions and novel genes. Each protein contains domains that have unique functions and can evolve independently of the rest of the protein chain. A domain is generally considered as a compact and semi-independent unit that can fold into a PB 203580 cost stable, three-dimensional structure. Such evolutionary relationships between closely related species can be revealed by comparative analysis of their domains. The prediction of protein domains has long been considered one of the most fundamental steps in deciphering the evolution and functions of proteins as well as species. Domain detection is often closely related to the determination of discrete structural folding units. Various domain prediction methods have been reported in the literature. The existing methods can be classified into two main categories, namely template-based methods and de novo methods. The template-based methods identify the similarities between a target sequence and the template sequences in a protein structure database such as Protein Data Bank. However, the accuracy of the template-based methods is highly dependent on the quality of the template structures. Therefore, such methods should not be assumed to work well for proteins containing novel domains, especially when they are from less characterized species. On the other hand, the ab-initio methods can predict protein domains by taking advantage of various sequence-based features, including sequence profiles, secondary structure predictions, and correlated mutations. Those methods use computational tools, such as neural networks, support vector machines, and hidden Markov models. However, the accuracy of ab-initio domain prediction methods on multidomain proteins is still very low. All these methods have either a well-defined structural database or structure-related features as their foundations. However, structural information is available for only a very tiny fraction of the entire set of proteins.