Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases

Under normal physiological conditions the brain primarily utilizes glucose for ATP generation. However, in situations where glucose is sparse, e.g., during prolonged fasting, ketone bodies become an important energy source for the brain. The brain’s utilization of ketones seems to depend mainly on the concentration in the blood, thus many dietary approaches such as ketogenic diets, ingestion of ketogenic medium-chain fatty acids or exogenous ketones, facilitate significant changes in the brain’s metabolism. Therefore, these approaches may ameliorate the energy crisis in neurodegenerative diseases, which are characterized by a deterioration of the brain’s glucose metabolism, providing a therapeutic advantage in these diseases. Most clinical studies examining the neuroprotective role of ketone bodies have been conducted in patients with Alzheimer’s disease, where brain imaging studies support the notion of enhancing brain energy metabolism with ketones. Likewise, a few studies show modest functional improvements in patients with Parkinson’s disease and cognitive benefits in patients with—or at risk of—Alzheimer’s disease after ketogenic interventions. Here, we summarize current knowledge on how ketogenic interventions support brain metabolism and discuss the therapeutic role of ketones in neurodegenerative disease, emphasizing clinical data.     

Influence of geosynthetic reinforcement on the stability of an embankment with rigid columns embedded in an inclined underlying stratum

Incompressible dipping substrata are commonly encountered in engineering practice. Compared to horizontal underlying strata, the inclined underlying stratum increase the risk of collapse of embankments reinforced with columns because it weakens the restraint of the column base. The objective of this study is to investigate the effectiveness of geosynthetics on improving the embankment stability when the underlying stratum is inclined. The influence of geosynthetic tensile stiffness on the ultimate surcharge and failure mechanism is studied. A deep-seated failure with column tilting occurs when the geosynthetic tensile stiffness is low, whereas a lateral sliding occurs when the geosynthetic tensile stiffness is high. To illustrate the contribution of geosynthetics, the distribution of the lateral pressures acting on the columns is analyzed.     

Effect of Forming Pressure on the Internal Structure of Alumina Green Bodies Examined with Immersion Liquid Technique

Green bodies prepared by compaction of alumina granules were made transparent by an immersion liquid technique, and the internal structure was characterized with an optical microscope to study the effect of forming pressure on the internal structure. Clear images obtained by the technique provide more detailed information than other existing methods for structures ranging from one to tens of micrometers. Intergranular pores were present between unfractured granules. Their sizes and concentration tended to decrease with increasing forming pressure. However, pores were clearly present even in the green body prepared at 600 MPa. A rod- and needlelike feature was also found and was concluded to correspond to a high-density region. The significance of large pores and high-density regions on processing as well as the details of the technique is discussed.     

Purification and renaturation of recombinant human lymphotoxin (tumour necrosis factor beta) expressed in Escherichia coli as inclusion bodies

High level expression of recombinant human tumour necrosis factor β (rh TNF-β) in Escherichia coli results in the formation of two portions of protein, namely soluble active protein and insoluble protein which is inactive and aggregates in the form of inclusion bodies (IBs). In this study, a procedure for purification and renaturation of rh TNF-β from inclusion bodies has been designed and verified experimentally with a product purity of more than 90% and a recovery of about 30%. The procedure includes washing of IBs with specific wash buffer (Triton X-100/EDTA/lysozyme/PMSF), their solubilization with 8 mol dm^?3 alkaline urea, purification with ion-exchange columns, refolding with renaturation buffer and finally concentration and desalination with an ultrafiltration membrane. The characteristics of the renatured protein were identical with those of purified protein from the soluble fraction as demonstrated by (1) SDS-PAGE, (2) cytotoxic activity on mouse L929 cells, (3) N-terminal amino acid sequence, and (4) gel filtration chromatography.     

Twenty-five years of natural coordinates

In the early eighties, the author and co-workers created and further developed the natural coordinates to describe the motion of 2-D and 3-D multibody systems. Natural coordinates do not need angles or angular parameters to define orientation, leading to constant inertia matrices and to the simplest form of the constraint equations. Natural coordinates are composed by the Cartesian coordinates of some points and the Cartesian components of some unit vectors distributed on the different bodies of the system. The points and vectors can be located in the joints, being shared by contiguous bodies, decreasing or even eliminating the need to set joint constraints and reducing the total number of variables. However, other authors prefer not to share variables in order to get even simpler equations and to keep a bigger decoupling of equations, which is preferable in some cases. In this paper the history of natural coordinates is reviewed, as well as the main contributions coming from other research groups. In the second part of the paper some application areas in which natural coordinates can be particularly advantageous are examined. Commemorative Contribution.     

考虑材料参数的刚粘塑性有限元初始速度场自动生成方法

本文采用一种包含材料硬化指数ｎ和速率敏感性指数ｍ的刚粘塑性有限元模型，阶段硬化处理考虑到等效应力公与应变率有关，依据线粘性材料假设，提出了考虑材料参数ｎ、ｍ影响的刚粘塑性有限元初始速度场自动生成方法，改进了文献［３］方法。数值模拟结果与有关文献的计算和实验结果进行了比较，表明本文方法是有效的。     

圆柱体平板镦粗应力场的有限元分析

应用刚粘塑性有限元法对圆柱体在两平板间镦粗时的应力场进行了分析 ,给出了毛坯在不同初始高径比时的心部应力随压下量的变化曲线。由此得出 :在变形过程中 ,圆柱体心部存在两向拉应力 ;并且在墩粗过程中 ,当瞬时高径比约为 1 .0时 ,心部σθ、σr 由拉应力转变为压应力。     

Genetic Architecture and Molecular,Imaging and Prodromic Markers in Dementia with Lewy Bodies: State of the Art,Opportunities and Challenges

Dementia with Lewy bodies (DLB) is one of the most common causes of dementia and belongs to the group of α-synucleinopathies. Due to its clinical overlap with other neurodegenerative disorders and its high clinical heterogeneity, the clinical differential diagnosis of DLB from other similar disorders is often difficult and it is frequently underdiagnosed. Moreover, its genetic etiology has been studied only recently due to the unavailability of large cohorts with a certain diagnosis and shows genetic heterogeneity with a rare contribution of pathogenic mutations and relatively common risk factors. The rapid increase in the reported cases of DLB highlights the need for an easy, efficient and accurate diagnosis of the disease in its initial stages in order to halt or delay the progression. The currently used diagnostic methods proposed by the International DLB consortium rely on a list of criteria that comprises both clinical observations and the use of biomarkers. Herein, we summarize the up-to-now reported knowledge on the genetic architecture of DLB and discuss the use of prodromal biomarkers as well as recent promising candidates from alternative body fluids and new imaging techniques.     

Validation of a Gas Chromatography-Mass Spectrometry Method for the Measurement of the Redox State Metabolic Ratios Lactate/Pyruvate and β-Hydroxybutyrate/Acetoacetate in Biological Samples

The metabolic ratios lactate/pyruvate and β-hydroxybutyrate/acetoacetate are considered valuable tools to evaluate the in vivo redox cellular state by estimating the free NAD+/NADH in cytoplasm and mitochondria, respectively. The aim of the current study was to validate a gas-chromatography mass spectrometry method for simultaneous determination of the four metabolites in plasma and liver tissue. The procedure included an o-phenylenediamine microwave-assisted derivatization, followed by liquid-liquid extraction with ethyl acetate and silylation with bis(trimethylsilyl)trifluoroacetamide:trimethylchlorosilane 99:1. The calibration curves presented acceptable linearity, with a limit of quantification of 0.001 mM for pyruvate, β-hydroxybutyrate and acetoacetate and of 0.01 mM for lactate. The intra-day and inter-day accuracy and precision were within the European Medicines Agency’s Guideline specifications. No significant differences were observed in the slope coefficient of three-point standard metabolite-spiked curves in plasma or liver and water, and acceptable recoveries were obtained in the metabolite-spiked samples. Applicability of the method was tested in precision-cut liver rat slices and also in HepG2 cells incubated under different experimental conditions challenging the redox state. In conclusion, the validated method presented good sensitivity, specificity and reproducibility in the quantification of lactate/pyruvate and β-hydroxybutyrate/acetate metabolites and may be useful in the evaluation of in vivo redox states.