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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 739 records · Page 41
All sourcesNASA NTRSDOE OSTI
DOE OSTI2019

Is There a Safety Concern for Drug-Coated Balloons in Peripheral Arterial Disease?

Purpose of Review: Drug-coated balloons (DEB) and drug-eluting stents (DES) emerged as a tool to aid in lowering the rates of neointimal hyperplasia and target lesion restenosis following endovascular peripheral arterial disease (PAD) interventions. Recent Findings: Although the initial trials comparing these devices with non-drug balloons and stents showed favorable results, more recent data raised concerns regarding the mid to long-term safety of these devices. Summary: In this review, we will discuss the evolution of endovascular therapy for PAD, with highlights regarding the recent debates on the long-term safety of the drug-coated devices for treatment of PAD.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Added prognostic value of left ventricular shape by gated SPECT imaging in patients with suspected coronary artery disease and normal myocardial perfusion

Background: Left ventricular (LV) remodeling is associated with adverse cardiovascular events. We evaluated the added prognostic value of LV shape index (SI) assessed by gated single-photon emission tomography (SPECT) in patients without known coronary artery disease (CAD). Methods and results: We studied 674 patients with normal myocardial perfusion and normal LV ejection fraction (EF) on stress gated SPECT imaging. An automated software program was used to calculate end-diastolic and end-systolic LVSI. An LVSI ≤ 0.54 at end-systole was considered normal. Follow-up was 96% complete with a median follow-up of 37 months. During follow-up, 25 events occurred (3.8% cumulative event rate). Event-free survival was lower in patients with abnormal end-systolic LVSI (P < .001). Age (P = .021), diabetes (P = .048), and end-systolic LVSI (P < .001) were independent predictors of events. LVSI added prognostic information increasing the global chi-square of the model including age and diabetes from 15.15 to 25.97 (P < .001). The effect of diabetes on hazard ratio increased with increasing values of end-systolic LVSI. The probability of events at 48 months predicted by Weibull analysis progressively increased with increasing values of end-systolic LVSI and was higher in patients with diabetes as compared to those without. Decision curve analyses indicate that the model including end-systolic LVSI resulted in an increased net benefit between 5% and 30% threshold probability, indicating superior estimation of outcomes at low threshold probability levels. Conclusions: The evaluation of LVSI may identify patients with early-stage LV remodeling and at higher risk of adverse cardiac events, even in the presence of normal myocardial perfusion.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

Global dynamics of a vector-borne disease model with infection ages and general incidence rates

A vector-borne disease model with general incidence rates is proposed and investigated in this paper, where both vector and host are stratied by infection ages in the form of a hyperbolic system of partial differential equations coupled with ordinary differential equations.The existence, uniqueness, nonnegativeness, and boundedness of solution of the model are studied for biologically reasonable purpose. Furthermore, a global threshold dynamics of the system is established by constructing suitable Lyapunov functionals, which is determined by the basic reproduction number R{sub 0}: the infection-free equilibrium is globally asymptotically stable when R{sub 0} < 1 while the endemic equilibrium is globally asymptotically stable when R{sub 0} > 1.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2013

Borna disease virus nucleoprotein inhibits type I interferon induction through the interferon regulatory factor 7 pathway

Highlights: •IRF7 nuclear localisation was inhibited by BDV persistently infected. •BDV N protein resistant to IFN induction both in BDV infected OL cell and N protein plasmid transfected OL cell. •BDV N protein is related to the inhibition of IRF7 nuclear localisation. -- Abstract: The expression of type I interferon (IFN) is one of the most potent innate defences against viral infection in higher vertebrates. Borna disease virus (BDV) establishes persistent, noncytolytic infections in animals and in cultured cells. Early studies have shown that the BDV phosphoprotein can inhibit the activation of type I IFN through the TBK1–IRF3 pathway. The function of the BDV nucleoprotein in the inhibition of IFN activity is not yet clear. In this study, we demonstrated IRF7 activation and increased IFN-α/β expression in a BDV-persistently infected human oligodendroglia cell line following RNA interference-mediated BDV nucleoprotein silencing. Furthermore, we showed that BDV nucleoprotein prevented the nuclear localisation of IRF7 and inhibited endogenous IFN induction by poly(I:C), coxsackie virus B3 and IFN-β. Our findings provide evidence for a previously undescribed mechanism by which the BDV nucleoprotein inhibits type I IFN expression by interfering with the IRF7 pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Tolerance induction between two different strains of parental mice prevents graft-versus-host disease in haploidentical hematopoietic stem cell transplantation to F1 mice

Highlights: • Injection of UVB-irradiated iDCs induces alloantigen tolerance. • This alloantigen tolerance may be associated regulatory T cell induction. • Tolerant mice serve as bone marrow donors reduces GVHD to their F1 recipients in allo-HSCT. • Tolerance is maintained in F1 recipients for long time post HSCT. - Abstract: Haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) has been employed worldwide in recent years and led to favorable outcome in a group of patients who do not have human leukocyte antigen (HLA)-matched donors. However, the high incidence of severe graft-versus-host disease (GVHD) is a major problem for Haplo-HSCT. In the current study, we performed a proof of concept mouse study to test whether induction of allogeneic tolerance between two different parental strains was able to attenuate GVHD in Haplo-HSCT to the F1 mice. We induced alloantigen tolerance in C3H mice (H-2k) using ultraviolet B (UVB) irradiated immature dendritic cells (iDCs) derived from the cultures of Balb/c bone marrow cells. Then, we performed Haplo-HSCT using tolerant C3H mice as donors to F1 mice (C3H × Balb/c). The results demonstrated that this approach markedly reduced GVHD-associated death and significantly prolonged the survival of recipient mice in contrast to the groups with donors (C3H mice) that received infusion of non-UVB-irradiated DCs. Further studies showed that there were enhanced Tregs in the tolerant mice and alloantigen-specific T cell response was skewed to more IL-10-producing T cells, suggesting that these regulatory T cells might have contributed to the attenuation of GVHD. This study suggests that it is a feasible approach to preventing GVHD in Haplo-HSCT in children by pre-induction of alloantigen tolerance between the two parents. This concept may also lead to more opportunities in cell-based immunotherapy for GVHD post Haplo-HSCT.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

The Batten disease gene CLN3 confers resistance to endoplasmic reticulum stress induced by tunicamycin

Highlights: • The work reveals a protective properties of CLN3 towards TM-induced apoptosis. • CLN3 regulates expression of the GRP78 and the CHOP in response to the ER stress. • CLN3 plays a specific role in the ERS response. - Abstract: Mutations in CLN3 gene cause juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease), an early-onset neurodegenerative disorder that is characterized by the accumulation of ceroid lipofuscin within lysosomes. The function of the CLN3 protein remains unclear and is presumed to be related to Endoplasmic reticulum (ER) stress. To investigate the function of CLN3 in the ER stress signaling pathway, we measured proliferation and apoptosis in cells transfected with normal and mutant CLN3 after treatment with the ER stress inducer tunicamycin (TM). We found that overexpression of CLN3 was sufficient in conferring increased resistance to ER stress. Wild-type CLN3 protected cells from TM-induced apoptosis and increased cell proliferation. Overexpression of wild-type CLN3 enhanced expression of the ER chaperone protein, glucose-regulated protein 78 (GRP78), and reduced expression of the proapoptotic protein CCAAT/-enhancer-binding protein homologous protein (CHOP). In contrast, overexpression of mutant CLN3 or siRNA knockdown of CLN3 produced the opposite effect. Together, our data suggest that the lack of CLN3 function in cells leads to a failure of management in the response to ER stress and this may be the key deficit in JNCL that causes neuronal degeneration.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Mitochondrial impairment observed in fibroblasts from South African Parkinson’s disease patients with parkin mutations

Highlights: • Mitochondrial dysfunction observed in patients with parkin-null mutations. • Mitochondrial ATP levels were decreased. • Electron-dense vacuoles were observed in the patients. • Mitochondria from muscle biopsies appeared within normal limits. • One patient did not show these defects possibly due to compensatory mechanisms. - Abstract: Parkinson’s disease (PD), defined as a neurodegenerative disorder, is characterized by the loss of dopaminergic neurons in the substantia nigra in the midbrain. Loss-of-function mutations in the parkin gene are a major cause of autosomal recessive, early-onset PD. Parkin has been implicated in the maintenance of healthy mitochondria, although previous studies show conflicting findings regarding mitochondrial abnormalities in fibroblasts from patients harboring parkin-null mutations. The aim of the present study was to determine whether South African PD patients with parkin mutations exhibit evidence for mitochondrial dysfunction. Fibroblasts were cultured from skin biopsies obtained from three patients with homozygous parkin-null mutations, two heterozygous mutation carriers and two wild-type controls. Muscle biopsies were obtained from two of the patients. The muscle fibers showed subtle abnormalities such as slightly swollen mitochondria in focal areas of the fibers and some folding of the sarcolemma. Although no differences in the degree of mitochondrial network branching were found in the fibroblasts, ultrastructural abnormalities were observed including the presence of electron-dense vacuoles. Moreover, decreased ATP levels which are consistent with mitochondrial dysfunction were observed in the patients’ fibroblasts compared to controls. Remarkably, these defects did not manifest in one patient, which may be due to possible compensatory mechanisms. These results suggest that parkin-null patients exhibit features of mitochondrial dysfunction. Involvement of mitochondria as a key role player in PD pathogenesis will have important implications for the design of new and more effective therapies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Protective effects of Sapindus mukorossi Gaertn against fatty liver disease induced by high fat diet in rats

Highlights: • AESM is able to prevent the elevation of ALT and AST, and to decreased LDL-C level. • AESM demonstrates the effects of down-regulating blood fat level and protecting liver. • AESM consistent with the efficacy of simvastatin in NAFLD. - Abstract: Objectives: Study the effects of alcohol extract of Sapindus mukorossi Gaertn (AESM) on the metabolism of blood fat, morphology of fenestrated liver sinusoidal endothelial cells (LSEC), and the ultrastructure of liver cells of the rats with non-alcoholic fatty liver disease (NAFLD). Methods: Divide SD rats into control group, model group, simvastatin (7.2 mg/kg) group, and S.mukorossi Gaertn group with high dosage (0.5 g/kg), moderate dosage (0.1 g/kg), and low dosage (0.05 g/kg). After feeding with fat-rich nutrients for 3 weeks and establishing the model of hepatic adipose, conduct intragastric administration and provide the rats with fat-rich nutrients at the same time. At the 43rd day, take blood sample and measure aminotransferase and different indexes of blood fat; take hepatic tissue for pathological section, and observe the hepatic morphological patterns under light microscope; obtain and fix the hepatic tissue after injecting perfusate into the body, and observe the changes of fenestrated LSEC under scanning electron microscope; observe the ultrastructure of liver cells under transmission electron microscope. Results: High-dosage alcohol extracts of S.mukorossi Gaertn can alleviate the AST, ALT, TC, TG, LDL, γ-GT, and ALP level, as well as raise the HDL and APN level in the serum of NAFLD-rat model. In addition, through the observation from light microscope and electron microscopes, the morphology of the hepatic tissue and liver cells as well as the recovery of the fenestrated LSEC in the treatment group has become normal. Conclusions: Alcohol extracts of S.mukorossi Gaertn can regulate the level of blood fat and improve the pathological changes of the hepatic tissues in NAFLD-rat model, which demonstrates the effects of down-regulating fat level and protecting liver.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

NHE1 deficiency in liver: Implications for non-alcoholic fatty liver disease

Highlights: • FXR, PGC1α and PPARγ levels are upregulated in NHE1 deficient livers. • NHE1 deficiency downregulates expression of pro-lipogenic genes in liver. • Chronic exposure to high-fat diet upregulates hepatic NHE1 expression. • Loss of NHE1 better preserves hepatic insulin signaling in high-fat diet-fed mice. - Abstract: Non-alcoholic fatty liver disease NAFLD is closely associated with the dysregulation of lipid homeostasis. Diet-induced hepatic steatosis, which can initiate NAFLD progression, has been shown to be dramatically reduced in mice lacking the electroneutral Na{sup +}/H{sup +} exchanger NHE1 (Slc9a1). In this study, we investigated if NHE1 deficiency had effects in liver that could contribute to the apparent protection against aberrant lipid accumulation. RT-PCR and immunoblot analyses of wild-type and NHE1-null livers revealed an expression profile that strongly suggested attenuation of both de novo lipogenesis and hepatic stellate cell activation, which is implicated in liver fibrosis. This included upregulation of the farnesoid X receptor FXR, peroxisome proliferator-activated receptor PPARγ, its co-activator PGC1α, and sestrin 2, an antioxidant protein involved in hepatic metabolic homeostasis. Furthermore, expression levels of the pro-lipogenic liver X receptor LXRα, and acetyl CoA carboxylases 1 and 2 were downregulated. These changes were associated with evidence of reduced cellular stress, which persisted even upon exposure to a high-fat diet, and the better preservation of insulin signaling, as evidenced by protein kinase B/Akt phosphorylation (Ser473). These results indicate that NHE1 deficiency may protect against NAFLD pathogenesis, which is significant given the availability of highly specific NHE1 inhibitors.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Placental growth factor enhances angiogenesis in human intestinal microvascular endothelial cells via PI3K/Akt pathway: Potential implications of inflammation bowel disease

Background: Angiogenesis plays a major role in the pathogenesis of inflammatory bowel disease (IBD). Placental growth factor (PlGF) is a specific regulator of pathological angiogenesis and is upregulated in the sera of IBD patients. Therefore, the role of PlGF in IBD angiogenesis was investigated here using HIMECs. Methods: The expression of PlGF and its receptors in human intestinal microvascular endothelial cells (HIMECs) and inflamed mucosa of IBD patients were examined using quantitative PCR and western blot analysis and the role of PlGF in IBD HIMECs was further explored using small interfering RNA (siRNA). The induction of pro-inflammatory cytokine by PlGF in HIMECs was confirmed by ELISA. The capacity of PlGF to induce angiogenesis in HIMECs was tested through proliferation, cell-migration, matrigel tubule-formation assays and its underlying signaling pathway were explored by western blot analysis of ERK1/2 and PI3K/Akt phosphorylation. Results: mRNA and protein expression of PlGF and its receptor NRP-1 were significantly increased in IBD HIMECs. Inflamed mucosa of IBD patients also displayed higher expression of PIGF. The production of IL-6 and TNF-α in culture supernatant of HIMECs treated with exogenous recombinant human PlGF-1 (rhPlGF-1) were increased. Furthermore, rhPlGF-1 significantly induced HIMECs migration and tube formation in a dose-dependent manner and knockdown of endogenous PlGF in IBD HIMECs using siRNA substantially reduced these angiogenesis activities. PlGF induced PI3K/Akt phosphorylation in HIMECs and pretreatment of PlGF-stimulated HIMECs with PI3K inhibitor (LY294002) significantly inhibited the PlGF-induced cell migration and tube formation. Conclusion: Our results demonstrated the pro-inflammatory and angiogenic effects of PlGF on HIMECs in IBD through activation of PI3K/Akt signaling pathway. PlGF/PI3K/Akt signaling may serve as a potential therapeutic target for IBD. - Highlights: • Expression of PlGF and its receptor NRP-1 were significantly increased in IBD HIMECs. • Exogenous rhPlGF-1 treatment significantly induced HIMECs migration and tube formation. • Knockdown of endogenous PlGF in IBD HIMECs using siRNA substantially reduced cell angiogenesis activities. • PlGF induced PI3K/Akt phosphorylation in HIMECs which is required for PIGF-induced cell migration and tube formation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Metabolic biomarkers for non-alcoholic fatty liver disease induced by high-fat diet: In vivo magnetic resonance spectroscopy of hyperpolarized [1-{sup 13}C] pyruvate

Hyperpolarized {sup 13}C magnetic resonance spectroscopy (MRS) to assess hepatic metabolism in non-alcoholic fatty liver disease (NAFLD) has not been reported. This study searched for cellular metabolism-based biomarkers for NAFLD induced by a high-fat diet (HFD) in rats. Also, correlations of the biomarkers with enzyme levels and histopathology were identified during a 6-week follow-up. Six rats were fed a control diet (CD) and seven rats were fed the HFD for 6 weeks. Hyperpolarized {sup 13}C dynamic MRS was performed on rat liver following an injection of hyperpolarized [1-{sup 13}C] pyruvate. Compared with CD-fed rats, HFD-fed rats showed significant increases in the levels of serum alanine aminotransferase and low-density lipoprotein cholesterol at weeks 4 and 6 of follow-up. After the 6-week HFD, the ratios of [1-{sup 13}C] alanine/pyruvate and [1-{sup 13}C] lactate/pyruvate were significantly increased, as were the levels of alanine aminotransferase and lactate dehydrogenase, which are potentially associated with hepatosteatosis. The results implicate [1-{sup 13}C] alanine and [1-{sup 13}C] lactate as potentially useful noninvasive biomarkers of hepatosteatosis occurring in NAFLD. - Highlights: • Hyperpolarized {sup 13}C-alanine and lactate are noninvasive biomarkers on hepatosteatosis. • During the course of HFD feeding, {sup 13}C-alanine and lactate were increased in HFD-rats. • Hyperpolarized {sup 13}C dynamic MRS will be helpful to monitor the progression of NAFLD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Treatment of Parkinson's disease in rats by Nrf2 transfection using MRI-guided focused ultrasound delivery of nanomicrobubbles

Parkinson's disease (PD) is a very common neurological disorder. However, effective therapy is lacking. Although the blood-brain-barrier (BBB) protects the brain, it prevents the delivery of about 90% of drugs and nucleotides into the brain, thereby hindering the development of gene therapy for PD. Magnetic resonance imaging (MRI)-guided focused ultrasound delivery of microbubbles enhances the delivery of gene therapy vectors across the BBB and improves transfection efficiency. In the present study, we delivered nuclear factor E2-related factor 2 (Nrf2, NFE2L2) contained in nanomicrobubbles into the substantia nigra of PD rats by MRI-guided focused ultrasound, and we examined the effect of Nrf2 over-expression in this animal model of PD. The rat model of PD was established by injecting 6-OHDA in the right substantia nigra stereotactically. Plasmids (pDC315 or pDC315/Nrf2) were loaded onto nanomicrobubbles, and then injected through the tail vein with the assistance of MRI-guided focused ultrasound. MRI-guided focused ultrasound delivery of nanomicrobubbles increased gene transfection efficiency. Furthermore, Nrf2 gene transfection reduced reactive oxygen species levels, thereby protecting neurons in the target region. - Highlights: • MRI-guided focused ultrasound enhances gene transfection into the brain of rats. • Increased Nrf2 expression protects neurons in the rat model of PD. • Nrf2 protects neurons in PD by inhibiting ROS production.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Nurr1 overexpression exerts neuroprotective and anti-inflammatory roles via down-regulating CCL2 expression in both in vivo and in vitro Parkinson's disease models

The abnormality of nuclear receptor-related protein 1 (Nurr1) in expression and function can contribute to neurodegeneration of dopaminergic neurons and occurrence of Parkinson's disease (PD). However, its related mechanism in PD is still unknown. In this study, we found that Nurr1 was down-regulated and CCL2 was up-regulated in PD patients and PD mice. CCL2 promoted apoptosis and secretion of TNF-α and IL-1β in SH-SY5Y cells and inhibited cell viability while knockdown of CCL2 exerted the opposite effects. Nurr1 overexpression inhibited apoptosis, the release of TNF-α and IL-1β and promoted viability in α-Syn-treated SH-SY5Y cells, which was markedly promoted by CCL2 antibody and dramatically reversed by CCL2. Nurr1 overexpression negatively regulated CCL2 expression in vivo and in vitro. Furthermore, Nurr1 overexpression remarkably relieved MPTP-induced movement disorder and spatial memory deficits and played neuroprotective and anti-inflammatory roles in MPTP-induced PD mice by down-regulating CCL2 in vivo. In conclusion, Nurr1 overexpression exerts neuroprotective and anti-inflammatory roles via down-regulating CCL2 in both in vivo and in vitro PD models, contributing to developing mechanism-based and neuroprotective strategies against PD. - Highlights: • Nurr1 was down-regulated and CCL2 was up-regulated in PD patients and PD mice. • Nurr1 overexpression inhibited apoptosis, release of TNF-α and IL-1β and promoted viability in α-Syn-treated SH-SY5Y cells. • CCL2 reversed the effect of Nurr1 overexpression on apoptosis, inflammatory cytokines secretion and viability. • Nurr1 overexpression negatively regulated CCL2 expression in vivo and in vitro. • Nurr1 overexpression remarkably relieved MPTP-induced movement disorder and spatial memory deficits.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

The changes in glucose metabolism and cell proliferation in the kidneys of polycystic kidney disease mini-pig models

The pathogenic mechanism of polycystic kidney disease (PKD) is unclear. Abnormal glucose metabolism is maybe involved in hyper-proliferation of renal cyst epithelial cells. Mini-pigs are more similar to humans than rodents and therefore, are an ideal large animal model. In this study, for the first time, we systematically investigated the changes in glucose metabolism and cell proliferation signaling pathways in the kidney tissues of chronic progressive PKD mini-pig models created by knock-outing PKD1gene. The results showed that in the kidneys of PKD mini-pigs, the glycolysis is increased and the expressions of key oxidative phosphorylation enzymes Complexes I and IV significantly decreased. The activities of mitochondrial respiration chain Complexes I and IV significantly decreased; the phosphorylation level of key metabolism-modulating molecule AMP-activated protein kinase (AMPK) significantly decreased; and the mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK) signaling pathway are activated obviously. This study showed that in the kidneys of PKD mini-pigs, the level of glycolysis significantly increased, oxidative phosphorylation significantly decreased, and cell proliferation signaling pathways significantly activated, suggesting that metabolic changes in PKD may result in the occurrence and development of PKD through the activation of proliferation signaling pathways. - Highlights: • Mini-pigs are more similar to humans than rodents and are an ideal animal model. • The study was first performed in chronic model created by knock-outing PKD1gene. • We investigated the changes in glucose metabolism and cell proliferation. • The glycolysis was significantly increased in the kidneys of PKD mini-pigs. • The mTOR and ERK signaling pathway are activated obviously in PKD mini-pigs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

LncRNA NEAT1 promotes autophagy in MPTP-induced Parkinson's disease through stabilizing PINK1 protein

Highlights: • LncRNA NEAT1 was first observed to significantly up-regulate in the midbrain of PD mice in present study. • NEAT1 stabilizes PINK1 protein through direct binding. • NEAT1 promotes the MPTP-induced autophagy in SH-SY5Y cells via stabilizing PINK1 protein. Long non-coding RNA nuclear paraspeckle assembly transcript 1 (lncRNA NEAT1) was found to be closely related to the pathological changes in brain and nervous system. However, the role of NEAT1 and its potential mechanism in Parkinson's disease (PD) largely remain uncharacterized.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

FTO is involved in Alzheimer's disease by targeting TSC1-mTOR-Tau signaling

Diabetes and obesity are commonly associated with Alzheimer's disease (AD). Accumulating evidence show that insulin signaling defects are protentional upstream driver of AD. However, the mechanism by which diabetes and insulin signaling defects contribute to AD remains unknown. Here we show that Fat mass and obesity-associated protein (FTO) is involved the insulin defects-associated AD. Defective insulin signaling in diabetes and obesity in human and mice activated Fto in the brain tissues. Lentivirus-mediated knockdown of Fto reduced the phosphorylation of Tau protein whereas overexpression of FTO promoted the level of phosphorylated Tau in neurons. Mechanism study demonstrated that FTO activated the phosphorylation of Tau in a mTOR-dependent manner because FTO activated mTOR and its downstream signaling and rapamycin blocked FTO-mediated phosphorylation of Tau. FTO promoted the activation of mTOR by increasing the mRNA level of TSC1 but not TSC2, the upstream inhibitor of mTOR. Finally, we found that conditional knockout of Fto in the neurons reduced the cognitive deficits in 3xTg AD mice. Collectively, our evidence demonstrated that FTO is critically involved in insulin defects-related AD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Alteration of global protein SUMOylation in neurons and astrocytes in response to Alzheimer's disease-associated insults

Highlights: • The protein SUMOylation was not altered in the plaque-bearing AD model mouse brain. • Oxidative/excitotoxic stimuli reduced the SUMO1-modified protein levels in neurons. • SUMOylation prominently altered by cytotoxic stimuli in neurons than in astrocytes. SUMOylation, a post-translational modification of lysine residues by small ubiquitin-like modifier (SUMO) proteins, has been implicated in the pathogenesis of neurodegenerative disorders including Alzheimer's disease (AD), and in neuron- and astrocyte-specific physiological functions. Global SUMOylation is increased in the AD mouse brain in the pre-plaque-forming stage but returns to wild-type levels in the plaque-bearing stage. To clarify the reason for the transient change in SUMOylation, we analyzed the alteration of global SUMOylation induced by AD-associated cytotoxic stimuli in neurons and astrocytes individually. In neurons, amyloid β42 oligomers induced some but not significant increase in levels of SUMO1-modified proteins. Both hydrogen peroxide and glutamate significantly reduced SUMO1-modified protein levels. These changes were more prominent in neurons than in astrocytes. The opposite effect of Aβ and oxidative/excitotoxic stimuli on SUMO1 modification may cause the pathological stage-associated change in the level of SUMO-modified proteins in the AD mouse brain.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Virus-induced gene silencing (VIGS) of the NBS-LRR gene SLNLC1 compromises Sm-mediated disease resistance to Stemphylium lycopersici in tomato

Highlights: • Using the method of Virus-induced gene silencing verified the function of the SLNLC1gene. • DAB and NBT staining was applied to microscopic observation the production of H{sub 2}O{sub 2} or O{sub 2}-. • TB and AB staining was used for detecting the accumulation of lignin or callose. In a previous study, when resistant tomato plants (cv. Motelle) carrying the Sm gene were challenged with S. lycopersici, the SLNLC1 gene was significantly upregulated. In this study, to verify the function of the SLNLC1 gene response to disease resistance against S. lycopersici, virus-induced gene silencing (VIGS) was used to downregulate the expression level of the SLNLC1 gene in resistant tomato plants inoculated with S. lycopersici. After inoculation with S. lycopersici, a susceptible phenotype was observed in the silenced SLNLC1-resistant plants. Through microscopy, impaired hypersensitive response (HR) and decreased ROS accumulation were also observed in the silenced SLNLC1 plants. In addition, the production of lignin and callose were decreased in the silenced SLNLC1 plants. Taken together, these results indicated that silencing the SLNLC1 gene attenuated the resistance of tomato plants resistant to S. lycopersici.

60 APPLIED LIFE SCIENCES↗