171 research outputs found
Regulation of deoxynucleotide metabolism in cancer: novel mechanisms and therapeutic implications
Hyperphosphorylation and Cleavage at D421 Enhance Tau Secretion
It is well established that tau pathology propagates in a predictable manner in Alzheimer’s disease (AD). Moreover, tau accumulates in the cerebrospinal fluid (CSF) of AD’s patients. The mechanisms underlying the propagation of tau pathology and its accumulation in the CSF remain to be elucidated. Recent studies have reported that human tau was secreted by neurons and non-neuronal cells when it was overexpressed indicating that tau secretion could contribute to the spreading of tau pathology in the brain and could lead to its accumulation in the CSF. In the present study, we showed that the overexpression of human tau resulted in its secretion by Hela cells. The main form of tau secreted by these cells was cleaved at the C-terminal. Surprisingly, secreted tau was dephosphorylated at several sites in comparison to intracellular tau which presented a strong immunoreactivity to all phospho-dependent antibodies tested. Our data also revealed that phosphorylation and cleavage of tau favored its secretion by Hela cells. Indeed, the mimicking of phosphorylation at 12 sites known to be phosphorylated in AD enhanced tau secretion. A mutant form of tau truncated at D421, the preferential cleavage site of caspase-3, was also significantly more secreted than wild-type tau. Taken together, our results indicate that hyperphosphorylation and cleavage of tau by favoring its secretion could contribute to the propagation of tau pathology in the brain and its accumulation in the CSF
Variable tau accumulation in murine models with abnormal prion protein deposits
Rona Barron - ORCID: 0000-0003-4512-9177
https://orcid.org/0000-0003-4512-9177The conversion of cellular prion protein (PrP) into a misfolded isoform is central to the development of prion diseases. However, the heterogeneous phenotypes observed in prion disease may be linked with the presence of other misfolded proteins in the brain. While hyperphosphorylated tau (p.tau) is characteristic of Alzheimer's disease (AD), p.tau is also observed in human prion diseases. To explore this association in the absence of potential effects due to aging, drug treatment, agonal stage and postmortem delay we analyzed p.tau and PrP immunopositivity in mouse models. Analyses were performed on mice inoculated with prion agents, and mice with PrP amyloid in the absence of prion disease. We observed that p.tau was consistently present in animals with prion infectivity (models that transmit disease upon serial passage). In contrast, p.tau was very rarely observed or absent in mice with PrP amyloid plaques in the absence of prion replication. These data indicate that the formation of p.tau is not linked to deposition of misfolded PrP, but suggest that the interaction between replication of infectivity and host factors regulate the formation of p.tau and may contribute to the heterogeneous phenotype of prion diseases.https://doi.org/10.1016/j.jns.2017.10.040383pubpubDecember 201
SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia.
The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity-through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles-potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C-containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML
Tracking of Alzheimer's disease progression with cerebrospinal fluid tau protein phosphorylated at threonine 231
Ceramic heat recuperators for industrial heat recovery. Final report
Development of a GTE ceramic recuperator, designed for relatively small furnaces with firing rates of 0.3 to 0.6 MM Btu/h and with exhaust gas temperatures of 1500 to 2600 F, is described. The ceramic selected as the material of construction is cordierite, a magnesium aluminum silicate. Details of the ceramic recuperator design are presented in Chapter 2. Also results of tests and measurements, system economics, and cost performance analyses are presented. Five demonstration programs were performed to determine the heat transfer performance of the recuperator, establish the energy savings by recuperation, demonstrate minimum maintenance requirements in typical furnace operation, determine the durability of the ceramic core, determine the operating requirements of the burners and controls with recuperation, and establish the overall system costs and payback period. Demonstration programs and results of the Bliss Mill Furnace, Tungsten Reduction Furnace, Glass Tank, Pilot Plant US Smelting Furnace, and Rotary Calciner Furnace are given in Chapter 3. Chapter 4 develops the methodology and shows how an impact analysis may be performed. Industrial applications are implied and a process flow diagram for smelting and refining primary copper is shown. Concluding chapters present conclusions and recommendations, a bibliography, and additional information in appendices. (MCW
OSTEOGENIC ACTIVITY OF ACTIFUSE (TM) IS NOT ENHANCED BY PRE-ADSORBED BMP2
Meeting Abstrac
Studying Cancer Evolution and Therapeutic Responses in Different Organs: The Pros and Cons of a Broad Focus
Estimation of Fuel Savings by Recuperation of Furnace Exhausts to Preheat Combustion Air
The recovery of waste energy in furnace exhaust gases is gaining in importance as fuel costs continue to escalate. Installation of a recuperator in the furnace exhaust stream to preheat the combustion air can result in considerable savings in fuel usage. These savings are primarily the result of the sensible heat increase of the combustion air and, to some extent, improved combustion efficiency. The amount of fuel saved will depend on the exhaust gas temperature, amount of excess air used, the type of burner and the furnace control system. These fuel savings may be accurately measured by metering the energy consumption per unit of production before and after installation of the recuperator.
In the design of a waste heat recuperation system, it is necessary to be able to estimate the fuel saved by use of such a system. Standard industrial practice refers to the method described in the North American Combustion Handbook with its curves and tables that directly predict the percentage fuel savings. This paper analyzes the standard estimation technique and suggests a more realistic approach to calculation of percent fuel savings. Mass and enthalpy balances are provided for both methods and a typical furnace recuperation example is detailed to illustrate the differences in the two methods of calculating the percent energy saved
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