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"Fleming, Thomas J"
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The intimate lives of the founding fathers
A look at the founding fathers--Washington, Franklin, Adams, Jefferson, Hamilton, and Madison--and the women who played essential roles in their lives.
Book
Mechanical properties of hydroxyapatite–zirconia compacts sintered by two different sintering methods
Microwave sintering is traditionally employed to reduce the sintering temperature required to densify powder compacts. The effect of microwave heating on hydroxyapatite (HA)–zirconia (ZrO
2
) green bodies has been investigated in order to understand how microwave energy may affect the physical and mechanical properties of the resultant densified composites. Laboratory synthesised nano-sized HA and a commercial nano-sized ZrO
2
powder have been ball milled to create mixtures containing 0–5 wt% ZrO
2
loadings. Compacts were microwave sintered at either 700, 1000 or 1200°C with a 1 h hold time. Comparative firings were also performed in a resistive element furnace using the same heating profile in order to assess the differences between conventional and microwave heating on the physical, mechanical and microstructural properties of the composites. Samples sintered at 700°C show little sign of densification with open porosities of approximately 50%. Composites conventionally sintered at 1000°C were between 65 and 75% dense, whereas the samples microwave sintered at this temperature were between 55 and 65% dense. Samples sintered at 1200°C showed the greatest degree of densification (>80%) with a corresponding reduction in open porosities. TCP generation occurred as a consequence of sintering at 1200°C, even with 0 wt% ZrO
2
, and increased degradation of the HA phase to form significant amounts of TCP occurred with increasing additions of ZrO
2
, along with increasing open porosity. Nanosized ZrO
2
prevents the densification of the HA matrix by effectively pinning grain boundaries and this effect is more pronounced in the MS materials. Similar strengths are achieved between the microwave and conventionally sintered samples. Greater amount of open porosity and pore interconnectivity are seen in the MS samples, which are considered to be useful for biomedical applications as they can promote osteo-integration.
Journal Article
The Glyoxalase System—New Insights into an Ancient Metabolism
The glyoxalase system was discovered over a hundred years ago and since then it has been claimed to provide the role of an indispensable enzyme system in order to protect cells from a toxic byproduct of glycolysis. This review gives a broad overview of what has been postulated in the last 30 years of glyoxalase research, but within this context it also challenges the concept that the glyoxalase system is an exclusive tool of detoxification and that its substrate, methylglyoxal, is solely a detrimental burden for every living cell due to its toxicity. An overview of consequences of a complete loss of the glyoxalase system in various model organisms is presented with an emphasis on the role of alternative detoxification pathways of methylglyoxal. Furthermore, this review focuses on the overlooked posttranslational modification of Glyoxalase 1 and its possible implications for cellular maintenance under various (patho-)physiological conditions. As a final note, an intriguing point of view for the substrate methylglyoxal is offered, the concept of methylglyoxal (MG)-mediated hormesis.
Journal Article
CNDP1 knockout in zebrafish alters the amino acid metabolism, restrains weight gain, but does not protect from diabetic complications
The gene CNDP1 was associated with the development of diabetic nephropathy. Its enzyme carnosinase 1 (CN1) primarily hydrolyzes the histidine-containing dipeptide carnosine but other organ and metabolic functions are mainly unknown. In our study we generated CNDP1 knockout zebrafish, which showed strongly decreased CN1 activity and increased intracellular carnosine levels. Vasculature and kidneys of CNDP1−/− zebrafish were not affected, except for a transient glomerular alteration. Amino acid profiling showed a decrease of certain amino acids in CNDP1−/− zebrafish, suggesting a specific function for CN1 in the amino acid metabolisms. Indeed, we identified a CN1 activity for Ala–His and Ser–His. Under diabetic conditions increased carnosine levels in CNDP1−/− embryos could not protect from respective organ alterations. Although, weight gain through overfeeding was restrained by CNDP1 loss. Together, zebrafish exhibits CN1 functions, while CNDP1 knockout alters the amino acid metabolism, attenuates weight gain but cannot protect organs from diabetic complications.
Journal Article
Comparison of Microwave and Conventionally Sintered Yttria Doped Zirconia Ceramics and Hydroxyapatite‐Zirconia Nanocomposites
This chapter contains sections titled:
Introduction
Experimental Procedure
Results and Discussion
Comparison Of Microwave And Conventional Sintering Of Zirconia
Comparison Of Microwave And Conventional Sintering Of Hydroxyapatite‐Zirconia Composites
Conclusions
Acknowledgements
Book Chapter
Carnosine metabolism in diabetes is altered by reactive metabolites
Carnosinase 1 (CN1) contributes to diabetic nephropathy by cleaving histidine-dipeptides which scavenge reactive oxygen and carbonyl species and increase nitric oxide (NO) production. In diabetic mice renal CN1 activity is increased, the regulatory mechanisms are unknown. We therefore analysed the in vitro and in vivo regulation of CN1 activity using recombinant and human CN1, and the db/db mouse model of diabetes. Glucose, leptin and insulin did not modify recombinant and human CN1 activity in vitro, glucose did not alter renal CN1 activity of WT or db/db mice ex vivo. Reactive metabolite methylglyoxal and Fenton reagent carbonylated recombinant CN1 and doubled CN1 efficiency. NO S-nitrosylated CN1 and decreased CN1 efficiency for carnosine by 70 % (p < 0.01), but not for anserine. Both CN1 cysteine residues were nitrosylated, the cysteine at position 102 but not at position 229 regulated CN1 activities. In db/db mice, renal CN1 mRNA and protein levels were similar as in non-diabetic controls, CN1 efficiency 1.9 and 1.6 fold higher for carnosine and anserine. Renal carbonyl stress was strongly increased and NO production halved, CN1 highly carbonylated and less S-nitrosylated compared to WT mice. GSH and NO₂/₃ concentrations were reduced and inversely related with carnosine degradation rate (r = −0.82/−0.85). Thus, reactive metabolites of diabetes upregulate CN1 activity by post-translational modifications, and thus decrease the availability of reactive metabolite-scavenging histidine dipeptides in the kidney in a positive feedback loop. Interference with this vicious circle may represent a new therapeutic target for mitigation of DN.
Journal Article
Sensitive mass spectrometric assay for determination of 15-deoxy-Δ12,14-prostaglandin J2 and its application in human plasma samples of patients with diabetes
The determination of individual prostaglandins (PG) in humans is mainly performed in urine samples. The quantification of PGs in human plasma could improve the understanding of particular PG species under various physiological and pathological conditions. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a dehydrated downstream product of PGD2 and is of high interest due to its recently discovered anti-inflammatory effects. Increasing availability of highly sensitive mass spectrometry allows the quantification of low abundant biomarkers like 15d-PGJ2 in human plasma samples. Herein, a sensitive LC-MS/MS method for the determination of 15d-PGJ2 was established. The method was validated according to the guidance of the American Food and Drug Administration and tested in plasma samples from patients with poorly controlled diabetes, considered to be a pro-inflammatory condition. Extraction of 15d-PGJ2 was achieved with an easy-to-use liquid-liquid extraction by ethyl acetate following a methanol precipitation. The lower limit of quantification was 2.5 pg mL−1 and linearity (R2 = 0.998) was guaranteed between 2.5 and 500 pg mL−1 for 15d-PGJ2. Selectivity was assured by the use of two individual mass transitions (qualifier and quantifier). Precision and accuracy were validated in an inter- and intraday assay with a coefficient of variation below 11.8% (intraday) and 14.7% (interday). In diabetic patients with an HbA1C > 9%, increased plasma concentrations of 15d-PGJ2 compared to control plasma were measured. 15d-PGJ2 correlated negatively with the inflammation marker C-reactive protein. The developed LC-MS/MS method represents a new possibility to quantify 15d-PGJ2 with high specificity in human plasma samples. This may contribute to a better understanding of the potential anti-inflammatory effects of 15d-PGJ2 in severe long-term pro-inflammatory disorders like diabetes, cancer, or cardiovascular disease.
Journal Article
Protective Effects of Transient Glucose Exposure in Adult C. elegans
C. elegans are used to study molecular pathways, linking high glucose levels (HG) to diabetic complications. Persistent exposure of C. elegans to a HG environment induces the mitochondrial formation of reactive oxygen species (ROS) and advanced glycation endproducts (AGEs), leading to neuronal damage and decreased lifespan. Studies suggest that transient high glucose exposure (TGE) exerts different effects than persistent exposure. Thus, the effects of TGE on ROS, AGE-formation and life span were studied in C. elegans. Four-day TGE (400 mM) as compared to controls (0mM) showed a persistent increase of ROS (4-days 286 ± 40 RLUs vs. control 187 ± 23 RLUs) without increased formation of AGEs. TGE increased body motility (1-day 0.14 ± 0.02; 4-days 0.15 ± 0.01; 6-days 0.16 ± 0.02 vs. control 0.10 ± 0.02 in mm/s), and bending angle (1-day 17.7 ± 1.55; 3-days 18.7 ± 1.39; 6-days 20.3 ± 0.61 vs. control 15.3 ± 1.63 in degree/s) as signs of neuronal damage. Lifespan was increased by 27% (21 ± 2.4 days) after one-day TGE, 34% (22 ± 1.2 days) after four-days TGE, and 26% (21 ± 1.4 days) after six-days TGE vs. control (16 ± 1.3 days). These experiments suggest that TGE in C. elegans has positive effects on life span and neuronal function, associated with mildly increased ROS-formation. From the perspective of metabolic memory, hormetic effects outweighed the detrimental effects of a HG environment.
Journal Article
