Abnormal oxygen homeostasis in the nucleus tractus solitarius of the spontaneously hypertensive rat

The effects of arterial hypertension on cerebral blood flow remain poorly understood. Hemodynamic responses within the somatosensory cortex have been shown to be impaired in the spontaneously hypertensive rat (SHR) model. However, it is unknown whether arterial hypertension affects oxygen homeostasis in vital brainstem areas that control cardiovascular reflexes. In this study, we assessed vagus nerve stimulation-induced changes in local tissue PO2 (Pt O2 ) in the caudal nucleus tractus solitarius (cNTS) of SHRs and normotensive Wistar rats. Pt O2 measurements were performed using a novel application of fast cyclic voltammetry, which allows higher temporal resolution of O2 changes than traditional optical fluorescence techniques. Electrical stimulation of the central-cut end of the vagus nerve (ESVN) caused profound arterial blood pressure decreases along with biphasic Pt O2 changes in the cNTS, characterised by a rapid decrease in Pt O2 ("initial dip") followed by a post-stimulus overshoot above baseline. The initial dip was found to be significantly smaller in SHRs compared to normotensive Wistar rats even after ganglionic blockade. Post-ESVN overshoot was similar in both groups but was reduced in Wistar rats after ganglionic blockade. In conclusion, neural activity-dependent changes in tissue oxygen in brainstem cardiovascular autonomic centres are significantly impaired in animals with arterial hypertension

Adrenal insufficiency

This issue of eMedRef provides information to clinicians on the pathophysiology, diagnosis, and therapeutics of adrenal insufficiency

Where and Why Do Coastal Retrogressive Thaw Slumps Develop?

Retrogressive thaw slumps (RTSs) are among the most active landforms in the Arctic; their number has increased tremendously over the past decades. While processes initiating discrete RTSs are well defined, little research has been done on a regional scale to reveal the major terrain controls on their development. Our research provides new insights into the dynamics of coastal RTSs. We reveal the main geomorphic factors determining the development of RTSs along a 238 km coastal segment of the Yukon Coastal Plain, Canada. We 1) show the current extent of RTSs, 2) ascertain the factors controlling their activity and initiation, and 3) explain the differences in density and coverage of RTSs. We mapped and classified the RTSs based on high-resolution satellite images acquired in 2011. We derived the terrain characteristics for each RTS and highlighted the main terrain controls over their development using univariate regression trees. We tested the response variables (RTSs activity, initiation, density and coverage) against 16 environmental variables. We detected 287 coastal RTSs in the study area. Both the activity and the initiation of the RTSs were influenced by coastal geomorphology: active RTSs and new RTSs occurred primarily on terrain with slope angles greater than 3.9° and 5.9°, respectively. The density and coverage of RTSs within each coastal segment were constrained by the volume and thickness of massive ice bodies. Coastal erosion appears to have only an indirect effect on the development of RTSs by maintaining the best conditions for RTSs to reactivate

RNAseq reveals hydrophobins that are involved in the adaptation of aspergillus nidulans to lignocellulose

Background Sugarcane is one of the world’s most profitable crops. Waste steam-exploded sugarcane bagasse (SEB) is a cheap, abundant, and renewable lignocellulosic feedstock for the next-generation biofuels. In nature, fungi seldom exist as planktonic cells, similar to those found in the nutrient-rich environment created within an industrial fermenter. Instead, fungi predominantly form biofilms that allow them to thrive in hostile environments. Results In turn, we adopted an RNA-sequencing approach to interrogate how the model fungus, Aspergillus nidulans, adapts to SEB, revealing the induction of carbon starvation responses and the lignocellulolytic machinery, in addition to morphological adaptations. Genetic analyses showed the importance of hydrophobins for growth on SEB. The major hydrophobin, RodA, was retained within the fungal biofilm on SEB fibres. The StuA transcription factor that regulates fungal morphology was up-regulated during growth on SEB and controlled hydrophobin gene induction. The absence of the RodA or DewC hydrophobins reduced biofilm formation. The loss of a RodA or a functional StuA reduced the retention of the hydrolytic enzymes within the vicinity of the fungus. Hence, hydrophobins promote biofilm formation on SEB, and may enhance lignocellulose utilisation via promoting a compact substrate-enzyme-fungus structure. Conclusion This novel study highlights the importance of hydrophobins to the formation of biofilms and the efficient deconstruction of lignocellulose

Astrocytes modulate baroreflex sensitivity at the level of the nucleus of the solitary tract

Maintenance of cardiorespiratory homeostasis depends on autonomic reflexes controlled by neuronal circuits of the brainstem. The neurophysiology and neuroanatomy of these reflex pathways are well understood, however, the mechanisms and functional significance of autonomic circuit modulation by glial cells remain largely unknown. In experiments conducted in male laboratory rats we show that astrocytes of the nucleus tractus solitarii (NTS), the brain area that receives and integrates sensory information from the heart and blood vessels, respond to incoming afferent inputs with [Ca2+]i elevations. Astroglial [Ca2+]i responses are triggered by transmitters released by vagal afferents, glutamate acting at AMPA receptors and 5-HT acting at 5-HT2A receptors. In conscious freely behaving animals blockade of Ca2+-dependent vesicular mechanisms in NTS astrocytes by virally driven expression of a dominant-negative SNARE protein (dnSNARE) increased baroreflex sensitivity by 70% (p<0.001). The effect of compromised astroglial function was specific to the NTS as expression of dnSNARE in astrocytes of the ventrolateral brainstem had no effect. ATP considered the principle gliotransmitter and is released by vesicular mechanisms affected by dnSNARE expression. Consistent with this hypothesis, in anesthetized rats, activation P2Y1 purinoceptors in the NTS decreased baroreflex gain by 40% (p=0.031), while blockade of P2Y1 receptors increased baroreflex gain by 57% (p=0.018). These results suggest that glutamate and 5-HT released by NTS afferent terminals trigger Ca2+-dependent astroglial release of ATP to modulate baroreflex sensitivity via P2Y1 receptors. These data add to the growing body of evidence supporting an active role of astrocytes in the brain information processing

Where and Why Do Retrogressive Thaw Slumps Occur?

Retrogressive thaw slumps (RTSs) are among the most active landforms in the Arctic; their number has increased tremendously over the past decades. While processes initiating discrete RTSs are well defined, little research has been done on a regional scale to reveal the major terrain controls on their development. Our research provides new insights into the dynamics of coastal RTSs. We reveal the main geomorphic factors determining the development of RTSs along a 238 km coastal segment of the Yukon Coastal Plain, Canada. We 1) show the current extent of RTSs, 2) ascertain the factors controlling their activity and initiation, and 3) explain the differences in density and coverage of RTSs. We mapped and classified the RTSs based on high-resolution satellite images acquired in 2011. We derived the terrain characteristics for each RTS and highlighted the main terrain controls over their development using univariate regression trees. We tested the response variables (RTSs activity, initiation, density and coverage) against 16 environmental variables. We detected 287 coastal RTSs in the study area. Both the activity and the initiation of the RTSs were influenced by coastal geomorphology: active RTSs and new RTSs occurred primarily on terrain with slope angles greater than 3.9° and 5.9°, respectively. The density and coverage of RTSs within each coastal segment were constrained by the volume and thickness of massive ice bodies. Coastal erosion appears to have only an indirect effect on the development of RTSs by maintaining the best conditions for RTSs to reactivate

The novel mTOR inhibitor RAD001 (Everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells

Background/Aim: Tumors exhibiting constitutively activated PI(3) K/Akt/mTOR signaling are hypersensitive to mTOR inhibitors such as RAD001 (everolimus) which is presently being investigated in clinical phase II trials in various tumor entities, including neuroendocrine tumors (NETs). However, no preclinical data about the effects of RAD001 on NET cells have been published. In this study, we aimed to evaluate the effects of RAD001 on BON cells, a human pancreatic NET cell line that exhibits constitutively activated PI(3) K/Akt/mTOR signaling. Methods: BON cells were treated with different concentrations of RAD001 to analyze its effect on cell growth using proliferation assays. Apoptosis was examined by Western blot analysis of caspase-3/PARP cleavage and by FACS analysis of DNA fragmentation. Results: RAD001 potently inhibited BON cell growth in a dose-dependent manner which was dependent on the serum concentration in the medium. RAD001-induced growth inhibition involved G0/G1-phase arrest as well as induction of apoptosis. Conclusion: In summary, our data demonstrate antiproliferative and apoptotic effects of RAD001 in NET cells in vitro supporting its clinical use in current phase II trials in NET patients. Copyright (c) 2007 S. Karger AG, Basel

Dispersion as an Important Step in the Candida albicans Biofilm Developmental Cycle

Biofilms are dynamic microbial communities in which transitions between planktonic and sessile modes of growth occur interchangeably in response to different environmental cues. In the last decade, early events associated with C. albicans biofilm formation have received considerable attention. However, very little is known about C. albicans biofilm dispersion or the mechanisms and signals that trigger it. This is important because it is precisely C. albicans cells dispersed from biofilms that are the main culprits associated with candidemia and establishment of disseminated invasive disease, two of the gravest forms of candidiasis. Using a simple flow biofilm model recently developed by our group, we have performed initial investigations into the phenomenon of C. albicans biofilm dispersion, as well as the phenotypic characteristics associated with dispersed cells. Our results indicate that C. albicans biofilm dispersion is dependent on growing conditions, including carbon source and pH of the media used for biofilm development. C. albicans dispersed cells are mostly in the yeast form and display distinct phenotypic properties compared to their planktonic counterparts, including enhanced adherence, filamentation, biofilm formation and, perhaps most importantly, increased pathogenicity in a murine model of hematogenously disseminated candidiasis, thus indicating that dispersed cells are armed with a complete arsenal of “virulence factors” important for seeding and establishing new foci of infection. In addition, utilizing genetically engineered strains of C. albicans (tetO-UME6 and tetO-PES1) we demonstrate that C. albicans biofilm dispersion can be regulated by manipulating levels of expression of these key genes, further supporting the evidence for a strong link between biofilms and morphogenetic conversions at different stages of the C. albicans biofilm developmental cycle. Overall, our results offer novel and important insight into the phenomenon of C. albicans biofilm dispersion, a key part of the biofilm developmental cycle, and provide the basis for its more detailed analysis

Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet

Glucocorticoid hormones are critical to respond and adapt to stress. Genetic variations in the glucocorticoid receptor (GR) gene alter hypothalamic-pituitary-adrenal (HPA) axis activity and associate with hypertension and susceptibility to metabolic disease. Here we test the hypothesis that reduced GR density alters blood pressure and glucose and lipid homeostasis and limits adaption to obesogenic diet. Heterozygous GR βgeo/+ mice were generated from embryonic stem (ES) cells with a gene trap integration of a β-galactosidase-neomycin phosphotransferase (βgeo) cassette into the GR gene creating a transcriptionally inactive GR fusion protein. Although GRβgeo/+ mice have 50% less functional GR, they have normal lipid and glucose homeostasis due to compensatory HPA axis activation but are hypertensive due to activation of the renin-angiotensin- aldosterone system (RAAS). When challenged with a high-fat diet, weight gain, adiposity, and glucose intolerance were similarly increased in control and GRβgeo/+ mice, suggesting preserved control of intermediary metabolism and energy balance. However, whereas a high-fat diet caused HPA activation and increased blood pressure in control mice, these adaptions were attenuated or abolished in GRβgeo/+ mice. Thus, reduced GR density balanced by HPA activation leaves glucocorticoid functions unaffected but mineralocorticoid functions increased, causing hypertension. Importantly, reduced GR limits HPA and blood pressure adaptions to obesogenic diet