The assembly of primary cilia is dependant on intraflagellar transport (IFT), which mediates the bidirectional movement of proteins between the base and tip of the cilium. In mice, congenic mutations ...disrupting genes required for IFT (e.g., Tg737 or the IFT kinesin Kif3a) are embryonic lethal, whereas kidney-specific disruption of IFT results in severe, rapidly progressing cystic pathology 1–3. Although the function of primary cilia in most tissues is unknown, in the kidney they are mechanosenstive organelles that detect fluid flow through the tubule lumen 4. The loss of this flow-induced signaling pathway is thought to be a major contributing factor to cyst formation 5–7. Recent data also suggest that there is a connection between ciliary dysfunction and obesity as evidenced by the discovery that proteins associated with human obesity syndromes such as Alström and Bardet-Biedl localize to this organelle 8. To more directly assess the importance of cilia in postnatal life, we utilized conditional alleles of two ciliogenic genes (Tg737 and Kif3a) to systemically induce cilia loss in adults. Surprisingly, the cystic kidney pathology in these mutants is dependent on the time at which cilia loss was induced, suggesting that cyst formation is not simply caused by impaired mechanosensation. In addition to the cystic pathology, the conditional cilia mutant mice become obese, are hyperphagic, and have elevated levels of serum insulin, glucose, and leptin. We further defined where in the body cilia are required for normal energy homeostasis by disrupting cilia on neurons throughout the central nervous system and on pro-opiomelanocortin-expressing cells in the hypothalamus, both of which resulted in obesity. These data establish that neuronal cilia function in a pathway regulating satiety responses.
Experimental characterization of the damage induced to SiC power MOSFETs by heavy-ion irradiation is presented as a premise to a finite element simulation study aimed at gaining an insight into the ...physics of damage formation. Thanks to the new experimental setup, which is capable of accurately measuring the time evolution of the gate and drain leakage currents during irradiation, we herein demonstrate that the gate of a SiC power MOSFET is damaged by heavy-ion irradiation at biasing drain voltages lower than 100 V, which is less than 10% of the nominal blocking voltage of the tested devices. The evolution of the gate and drain leakage currents during irradiation is explained considering that localized resistive paths due to damage sites are formed across the gate oxide. The results presented herein indicate the strong sensitivity of SiC power MOSFETs to gate rupture even if the main concern in the literature addressed so far is the rupture of the drain structure due to single-event burnout.
Taurine is an abundant, free amino acid found in mammalian cells that contributes to many physiologic functions from that of a simple cell osmolyte to a programmer of adult health and disease. ...Taurine’s contribution extends from conception throughout life, but its most critical exposure period is during perinatal life. In adults, taurine supplementation prevents or alleviates cardiovascular disease and related complications. In contrast, low taurine consumption coincides with increased risk of cardiovascular disease, obesity and type II diabetes. This review focuses on the effects that altered perinatal taurine exposure has on long-term mechanisms that control adult arterial blood pressure and could thereby contribute to arterial hypertension through its ability to program these cardiovascular regulatory mechanisms very early in life. The modifications of these mechanisms can last a lifetime and transfer to the next generation, suggesting that epigenetic mechanisms underlie the changes. The ability of perinatal taurine exposure to influence arterial pressure control mechanisms and hypertension in adult life appears to involve the regulation of growth and development, the central and autonomic nervous system, the renin–angiotensin system, glucose–insulin interaction and changes to heart, blood vessels and kidney function.
The incidence of type 2 diabetes and metabolic disease is rapidly increasing, but effective therapies for their prevention and treatment have been poorly tolerated or minimally effective. In this ...study, chronic administration of kudzu root extract (8 months, 0.2%, w/w, in diet) decreased baseline fasting plasma glucose (183±14 vs. 148±11mg/dl) and improved glucose and insulin tolerance in C57BL/6J ob/ob mice (1.67±0.17ng/ml kudzu treated vs. 2.35±0.63ng/ml control), but such treatment did not alter these parameters in lean control mice. Among the mice on the kudzu supplementation, plasma levels of isoflavone metabolites were significantly higher in ob/ob versus lean control mice, and unmetabolized puerarin (11.50±5.63ng/g) was found in adipose tissue only in the treated mice. Together, these data demonstrate that a puerarin containing kudzu diet improves glucose and insulin responsiveness in ob/ob mice, suggesting that puerarin may be a beneficial adjuvant for treating metabolic disease.
This article presents the results of a 2-D finite element simulation study of the gate damages induced by heavy-ion irradiation in SiC power metal-oxide-semiconductor field-effect transistors ...(MOSFETs). The time evolution of the electric field in the gate oxide is studied. Two effects are investigated: the first is associated with the charge deposition in the SiC portion of the MOSFET, with the time evolution studied using the 2-D finite element simulator; the second one results from holes generated during the ion transit, trapped in the gate oxide after the fast electrons have been quickly swept away by the electric field. Two different techniques have been combined for estimating the hole concentration in the gate oxide: the well-known recombination rate was modified to consider the trapped charge yield, as was recently done to better interpret single event gate rupture (SEGR) failure of silicon power MOSFETs. Under ion irradiation test conditions at which the gate damage experimentally starts to be observed, we demonstrate that, because of the ion impact, regardless of the ion linear energy transfer (LET), the peak value of the electric field in the gate oxide becomes practically equal to the oxide breakdown field (~12-15 MV/cm). Moreover, we show that simulations can be used to predict the test conditions at which gate damage starts to appear as a function of LET and the range of heavy ions used in the irradiation experiments.
The University of Alabama at Birmingham (UAB) began as a medical school that evolved into a comprehensive university where over $600 million per year of extramural funding enables its investigators ...to conduct cutting-edge research in medicine, engineering, and other fields. Here, Genau and Wyss discuss the UAB's Center for Community OutReach Development.
Early‐life stress (ELS) can alter neurodevelopment in variable ways, ranging from producing deleterious outcomes to stress resilience. While most ELS studies focus on its harmful effects, recent work ...by our laboratory and others shows that ELS elicits positive effects in certain individuals. We exposed Wistar Kyoto (WKY) rats, known for a stress reactive, anxiety/depression‐like phenotype, to maternal separation (MS), a model of ELS. MS exposure elicited anxiolytic and antidepressant behavioral effects as well as improved cardiovascular function in adult WKY offspring. This study interrogates an epigenetic mechanism (DNA methylation) that may confer the adaptive effects of MS in WKY offspring. We quantified global genome methylation levels in limbic brain regions of adult WKYs exposed to daily 180‐min MS or neonatal handling from postnatal day 1–14. MS exposure triggered dramatic DNA hypermethylation specifically in the hippocampus. Next‐generation sequencing methylome profiling revealed reduced methylation at intragenic sites within two key nodes of insulin signaling pathways: the insulin receptor and one of its major downstream targets, mitogen‐activated protein kinase kinase kinase 5 (Map3k5). We then tested the hypothesis that enhancing DNA methylation in WKY rats would elicit adaptive changes akin to the effects of MS. Dietary methyl donor supplementation improved WKY rats’ anxiety/depression‐like behaviors and also improved cardiovascular measures, similar to previous observations following MS. Overall, these data suggest a potential molecular mechanism that mediates a predicted adaptive response, whereby ELS induces DNA methylation changes in the brain that may contribute to successful stress coping and adaptive physiological changes in adulthood.
Maternal separation stress improves Wistar Kyoto rats’ anxiety and depression – like behavior. Our data here suggest these adaptive behavioral effects are mediated, in part, via changes in hippocampal DNA methylation. Maternal separation triggered lasting increases in hippocampal DNA methylation, including methylation changes within molecules involved in insulin signaling. Increasing dietary methyl donor content lead to similar improvements in Wistar Kyoto rats’ anxiety/depression?like behavior.
Proanthocyanidin rich plant extracts derived from grape seed extract (GSE), hawthorn and cranberry are on markets for their preventive effects against cardiovascular diseases and uroinfections in ...woman. However, the importance of these health beneficial effects of these botanicals remains elusive due to incomplete understanding of uptake, metabolism and bioavailability of proanthocyanidins
in vivo. In the present study rats were given GSE orally (300
mg/kg, twice a day) and blood and urine were collected over a 24
h period. Monomeric catechins and their methylated metabolites, and proanthocyanidins up to trimers were detected in blood samples treated with GSE using LC-MS/MS operating in the multiple reaction monitoring (MRM) mode. A new tetramethylated metabolite of dimeric proanthocyanidin (
m/z 633) in GSE-treated urine was tentatively identified. Using LC-MS/MS, (+)-catechin and (−)-epicatechin were identified in the brain conclusively. These data suggested that GSE catechins cross the blood brain barrier and may be responsible for the neuroprotective effects of GSE.
This study tests the hypothesis that perinatal taurine imbalance impairs renal function in adult female rats via alterations in estrogen activity. Female Sprague-Dawley rats were fed normal rat chow ...and water containing 3% beta-alanine (TD), 3% taurine (TS) or water alone (C) from conception until weaning. Then, female offspring received normal rat chow and water with (CG, TDG, TSG) or without (CW, TDW, TSW) 5% glucose. At 7-8 weeks of age, renal function at rest and after acute saline load was tested in conscious, restrained female rats treated with non-selective estrogen receptor blocker tamoxifen for a week. Compared to control, TD or TS did not affect mean arterial pressure (MAP). Tamoxifen significantly increased resting MAP only in TDG compared to TDW groups. Although renal blood flow did not significantly differ among the groups, renal vascular resistance increased in TSG compared to CW, CG, and TSW groups. Glomerular filtration rate and water and sodium excretion were not significantly different among the groups. Compared to CW, saline load significantly depressed fractional water excretion in CG, TDW, TDG, and TSW, and fractional sodium excretion in CG, TDW, TDG, TSW, and the TSG groups. Potassium excretion was not significantly different among the corresponding groups. Fractional potassium excretion significantly increased in TDW compared to CG and in TSG compared to CG and TSW groups. These differences were abolished by tamoxifen treatment. These data indicate that in adult female rats, perinatal taurine imbalance, particularly followed by high sugar intake, alters renal function via an estrogenic mechanism.
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