Functions of ULK1 in autophagy and non-autophagy pathways and its implications in human physiology and disease

ULK1 (unc-51 like autophagy activating kinase 1), a mammalian serine/threonine kinase, is a key component of autophagy initiation complex and helps to induce all types of autophagy. Canonical autophagy is a process in which, through the interactions of a series of autophagy-related proteins, damaged organelles or misfolded proteins are engulfed by autophagosomes and then merged with lysosomes to be degraded. Thus, canonical autophagy is an important constituent part of the cellular “quality control.” Besides, accumulating evidence indicates that ULK1 exerts autophagy-independent effects in a cell-specific manner. For example, ULK1 facilitates neurite elongation through the regulation of endoplasmic reticulum (ER)–Golgi trafficking in neurons, stimulates phosphopentose pathway to help NADPH (nicotinamide adenine dinucleotide phosphate hydrogen) production, and acts as a duplex regulator in type I IFN (type I interferon) induced innate immune response. Considering the importance and diversity of ULK1 in various biological processes, this review aims to present a comprehensive overview of autophagy and non-autophagy related functions of ULK1 in a variety of human physiological, pathological, and disease processes.     

Lack of de-epoxidation of type B trichothecenes in incubates with human faeces

The ability of human gastrointestinal organisms to transform the trichothecenes 3-acetyldeoxynivalenol and nivalenol was investigated. Samples of human faeces were incubated under anaerobic conditions for 48 h with the toxins. They were then extracted and analysed for trichothecenes and metabolites. 3-Acetyldeoxynivalenol was metabolized to deoxynivalenol during the incubation period. In contrast to what has been reported for other species such as rats, mice and pigs, no de-epoxidated metabolites were detected in the faecal incubates. The toxicological significance of the difference in the intestinal ability to transform trichothecenes between species is unknown.     

Analysis of cell aggregation in the culturing of cerebellar granule neurons

We have proposed previously that an increased concentration of growth factor secreted by neurons themselves has a direct effect on survival of the neurons, and thereby cell density serves as a regulator of survival of neurons. In this study, the same idea was used to analyze the aggregation of cerebellar granule neurons in culture experimentally and theoretically. Assuming the transport of growth factor and substrate within an aggregate is by molecular diffusion, the metabolic efficiency of neurons, on the basis of an autocatalytic phenomenon, was increased within an aggregate compared to an identical quantity of dispersed cells. A good agreement in the size of neuronal aggregate between the theoretical prediction and the experimental result was found. This illustrates that growth factors produced by neurons acting in either an autocrine or paracrine manner play an important role during the development of cultured neurons.     

How crystals that sense and respond to their environments could evolve

An enduring mystery in biology is how a physical entity simple enough to have arisen spontaneously could have evolved into the complex life seen on Earth today. Cairns-Smith has proposed that life might have originated in clays which stored genomes consisting of an arrangement of crystal monomers that was replicated during growth. While a clay genome is simple enough to have conceivably arisen spontaneously, it is not obvious how it might have produced more complex forms as a result of evolution. Here, we examine this possibility in the tile assembly model, a generalized model of crystal growth that has been used to study the self-assembly of DNA tiles. We describe hypothetical crystals for which evolution of complex crystal sequences is driven by the scarceness of resources required for growth. We show how, under certain circumstances, crystal growth that performs computation can predict which resources are abundant. In such cases, crystals executing programs that make these predictions most accurately will grow fastest. Since crystals can perform universal computation, the complexity of computation that can be used to optimize growth is unbounded. To the extent that lessons derived from the tile assembly model might be applicable to mineral crystals, our results suggest that resource scarcity could conceivably have provided the evolutionary pressures necessary to produce complex clay genomes that sense and respond to changes in their environment.

Sources and Bioactive Properties of Conjugated Dietary Fatty Acids

The group of conjugated fatty acids known as conjugated linoleic acid (CLA) isomers have been extensively studied with regard to their bioactive potential in treating some of the most prominent human health malignancies. However, CLA isomers are not the only group of potentially bioactive conjugated fatty acids currently undergoing study. In this regard, isomers of conjugated α‐linolenic acid, conjugated nonadecadienoic acid and conjugated eicosapentaenoic acid, to name but a few, have undergone experimental assessment. These studies have indicated many of these conjugated fatty acid isomers commonly possess anti‐carcinogenic, anti‐adipogenic, anti‐inflammatory and immune modulating properties, a number of which will be discussed in this review. The mechanisms through which these bioactivities are mediated have not yet been fully elucidated. However, existing evidence indicates that these fatty acids may play a role in modulating the expression of several oncogenes, cell cycle regulators, and genes associated with energy metabolism. Despite such bioactive potential, interest in these conjugated fatty acids has remained low relative to the CLA isomers. This may be partly attributed to the relatively recent emergence of these fatty acids as bioactives, but also due to a lack of awareness regarding sources from which they can be produced. In this review, we will also highlight the common sources of these conjugated fatty acids, including plants, algae, microbes and chemosynthesis.     

Quantification of 1,8‐cineole and of its metabolites in humans using stable isotope dilution assays

The metabolism of 1,8‐cineole after ingestion of sage tea was studied. After application of the tea, the metabolites 2‐hydroxy‐1,8‐cineole, 3‐hydroxy‐1,8‐cineole, 9‐hydroxy‐1,8‐cineole and, for the first time in humans, 7‐hydroxy‐1,8‐cineole were identified in plasma and urine of one volunteer. For quantitation of these metabolites and the parent compound, stable isotope dilution assays were developed after synthesis of [²H₃]‐1,8‐cineole, [9/10‐²H₃]‐2‐hydroxy‐1,8‐cineole and [¹³C,²H₂]‐9‐hydroxy‐1,8‐cineole as internal standards. Using these standards, we quantified 1,8‐cineole by solid phase microextraction GC‐MS and the hydroxyl‐1,8‐cineoles by LC‐MS/MS after deconjugation in blood and urine of the volunteer. After consumption of 1.02 mg 1,8‐cineole (19 μg/kg bw), the hydroxycineoles along with their parent compound were detectable in the blood plasma of the volunteer under study after liberation from their glucuronides with 2‐hydroxycineole being the predominant metabolite at a maximum plasma concentration of 86 nmol/L followed by the 9‐hydroxy isomer at a maximum plasma concentration of 33 nmol/L. The parent compound 1,8‐cineole showed a low maximum plasma concentration of 19 nmol/L. In urine, 2‐hydroxycineole also showed highest contents followed by its 9‐isomer. Summing up the urinary excretion over 10 h, 2‐hydroxycineole, the 9‐isomer, the 3‐isomer and the 7‐isomer accounted for 20.9, 17.2, 10.6 and 3.8% of the cineole dose, respectively.     

从本土到全球——日本新陈代谢派的演进与传播探究

20世纪60年代日本新陈代谢派以唯一非西方前卫的现代主义建筑思潮的形式出现使其在全球瞩目,通过几十年的进展,日本新陈代谢派的思想已不仅仅局限在日本而在全球范围内都得以传播.该文试对新陈代谢派的成员在他国的建筑实践和雷姆·库哈斯对新陈代谢派的研究来探讨新陈代谢派的全球化演进.     

Metformin Reduces Lipogenesis Markers in Obese Mice Fed a Low-Carbohydrate and High-Fat Diet

Lipogenesis is the process by which fatty acids are synthesized. In metabolic syndrome, an insulin resistant state along with high plasma levels of free fatty acids (FFA) and hyperglycemia may contribute to the lipogenic process. The aim of the present study was to investigate the effects of oral administration of metformin on the expression of lipogenic genes and glycemic profile in mice fed with low‐carbohydrate high‐fat diet by evaluating their metabolic profile. SWISS male mice were divided into 4 groups (N = 7) that were fed with standard (ST), standard plus metformin (ST + MET), low‐carbohydrate high‐fat diet (LCHFD) and low‐carbohydrate high‐fat diet plus metformin (LCHFD + MET) (100 mg kg^?1 diet) diets respectively. Food intake, body weight and blood parameters, such as glucose tolerance, insulin sensitivity, glucose, HDL‐c, total cholesterol, triglycerides, ASL and ALT levels were assessed. Histological analyses were performed on hematoxylin and eosin‐stained epididymal adipose tissue histological specimens. The expression levels of peroxisome proliferator‐activated receptor (PPARγ), sterol regulatory element‐binding protein 1 (SREBP1), fatty acid synthase (FAS) and acetyl‐CoA carboxylase (ACC), were assessed by RT‐PCR. This study showed that metformin decreased adipocyte area, body weight and food consumption in obese animals when compared to the standard group. Furthermore, the expression of lipogenic markers in adipose tissue were diminished in obese animals treated with metformin. This data showed that oral administration of metformin improved glucose and lipid metabolic parameters in white adipose tissue by reducing the expression of lipogenesis markers, suggesting an important clinical application of MET in treating obesity‐related diseases in metabolic syndrome.     

Dietary Alcohol and Fat Differentially Affect Plasma Cholesteryl Ester Transfer Activity and Triglycerides in Normo- and Hypertriglyceridemic Subjects

Moderate alcohol consumption is associated with increased plasma high-density lipoprotein (HDL)-cholesterol concentrations and reduced risk for cardiovascular disease. Plasma cholesteryl ester transfer activity (CETA) mediates the exchange of HDL-cholesteryl ester (CE) for the triacylglycerol (TAG) of very-low-density lipoproteins. We compared the effects of oral challenges of Alcohol, saturated fat (SAT), and (Alcohol + SAT) on plasma CETA, cholesterol, nonesterified fatty acids (NEFA), and TAG among normo-triglyceridemic (NTG) and mildly hypertriglyceridemic (HTG) volunteers having a range of plasma TAG concentrations. The major changes were (1) CETA increased more after ingestion of SAT and (Alcohol + SAT) in the HTG group versus the NTG group; (2) after all three challenges, elevation of plasma TAG concentration persisted longer in the HTG versus NTG group. Plasma cholesterol was not affected by the three dietary challenges, while Alcohol increased NEFA more in the HTG group than the NTG group. Plasma TAG best predicted plasma CETA, suggesting that intestinally derived lipoproteins are acceptors of HDL-CE. Unexpectedly, ingestion of (Alcohol + SAT) reduced the strength of the correlation between plasma TAG and CETA, that is the effects of (SAT and Alcohol) on plasma CETA are not synergistic nor additive but rather mutually suppressive. The alcohol-mediated inhibition of CE-transfer to chylomicrons maintains a higher plasma HDL-cholesterol concentration, which is athero-protective, although the suppressive metabolite underlying this correlation could be acetate, the terminal alcohol metabolite, other factors, including CETA inhibitors, are also likely important.