Regulation of autophagy,mitochondrial dynamics,and cellular bioenergetics by 4-hydroxynonenal in primary neurons

The production of reactive species contributes to the age-dependent accumulation of dysfunctional mitochondria and protein aggregates, all of which are associated with neurodegeneration. A putative mediator of these effects is the lipid peroxidation product 4-hydroxynonenal (4-HNE), which has been shown to inhibit mitochondrial function, and accumulate in the postmortem brains of patients with neurodegenerative diseases. This deterioration in mitochondrial quality could be due to direct effects on mitochondrial proteins, or through perturbation of the macroautophagy/autophagy pathway, which plays an essential role in removing damaged mitochondria. Here, we use a click chemistry-based approach to demonstrate that alkyne-4-HNE can adduct to specific mitochondrial and autophagy-related proteins. Furthermore, we found that at lower concentrations (5–10 μM), 4-HNE activates autophagy, whereas at higher concentrations (15 μM), autophagic flux is inhibited, correlating with the modification of key autophagy proteins at higher concentrations of alkyne-4-HNE. Increasing concentrations of 4-HNE also cause mitochondrial dysfunction by targeting complex V (the ATP synthase) in the electron transport chain, and induce significant changes in mitochondrial fission and fusion protein levels, which results in alterations to mitochondrial network length. Finally, inhibition of autophagy initiation using 3-methyladenine (3MA) also results in a significant decrease in mitochondrial function and network length. These data show that both the mitochondria and autophagy are critical targets of 4-HNE, and that the proteins targeted by 4-HNE may change based on its concentration, persistently driving cellular dysfunction.     

Design and synthesis of novel PRMT1 inhibitors and investigation of their binding preferences using molecular modelling

Protein arginine methyltransferase 1 (PRMT1) catalyses the methylation of substrate arginine by transferring the methyl group from SAM (S-adenosyl-l-methionine), which leads to the formation of S-adenosyl homocysteine (SAH) and methylated arginine. We have shown previously that the Asp84 on PRMT1 could be a potential inhibitor binding site. In the current study, 28 compounds were designed and synthesized that were predicted to bind the Asp84 and substrate arginine sites together. Among them, 6 compounds were identified as potential PRMT1 inhibitors, and showed strong inhibitory effects on cancer cell lines, especially HepG2. The most potent PRMT1 inhibitor, compound 13d, was selected for molecular dynamic simulations to investigate binding poses. Based on the free energy calculations and structural analysis, we predicted that the ethylenediamine group would tightly bind to Asp84, and the trifluoromethyl group should occupy part of substrate arginine binding site, which is consistent with our original goal. Our results show for the first time that PRMT1 inhibitors can target the Asp84 binding site, which will be helpful for future drug discovery studies.     

Systems model-guided rice yield improvements based on genes controlling source,sink, and flow

A large number of genes related to source, sink,and flow have been identified after decades of research in plant genetics. Unfortunately, these genes have not been effectively utilized in modern crop breeding. This perspective paper aims to examine the reasons behind such a phenomenon and propose a strategy to resolve this situation. Specifically, we first systematically survey the currently cloned genes related to source, sink, and flow;then we discuss three factors hindering effective application of these identified genes, which include the lack of effective methods to identify limiting or critical steps in a signaling network, the misplacement of emphasis on properties, at the leaf, instead of the whole canopy level,and the non-linear complex interaction between source,sink, and flow. Finally, we propose the development of systems models of source, sink and flow, together with a detailed simulation of interactions between them and their surrounding environments, to guide effective use of the identified elements in modern rice breeding. These systems models will contribute directly to the definition of crop ideotype and also identification of critical features and parameters that limit the yield potential in current cultivars.     

我国葫芦科植物离体培养研究进展

葫芦科植物包括多种瓜类蔬菜,对其进行离体培养研究具有重要的理论和实践意义。综述了国内在葫芦科植物器官培养、体细胞胚胎发生、花药培养、原生质体培养和体细胞杂交及离体遗传转化等方面取得的研究进展,并对葫芦科植物离体培养、遗传转化与育种的前景作了展望。     

Recent developments of enantioseparation techniques for adrenergic drugs using liquid chromatography and capillary electrophoresis: a review

This review provides the achievements of enantioseparation of adrenergic drugs and application of these methods in clinical and pharmaceutical analysis. The adrenergic agonist and antagonist drugs are analyzed in the direct and indirect modes by liquid chromatography (LC) and capillary electrophoresis (CE). Other chromatographic enantioseparation methods including super- and sub-critical fluid chromatography (SFC), and capillary electrochromatography (CEC) are presented likewise to analyse the cited compounds. The different separation processes for these drugs are briefly discussed and some applications are presented.     

Finding multiple target optimal intervention in disease‐related molecular network

Drugs against multiple targets may overcome the many limitations of single targets and achieve a more effective and safer control of the disease. Numerous high‐throughput experiments have been performed in this emerging field. However, systematic identification of multiple drug targets and their best intervention requires knowledge of the underlying disease network and calls for innovative computational methods that exploit the network structure and dynamics. Here, we develop a robust computational algorithm for finding multiple target optimal intervention (MTOI) solutions in a disease network. MTOI identifies potential drug targets and suggests optimal combinations of the target intervention that best restore the network to a normal state, which can be customer designed. We applied MTOI to an inflammation‐related network. The well‐known side effects of the traditional non‐steriodal anti‐inflammatory drugs and the recently recalled Vioxx were correctly accounted for in our network model. A number of promising MTOI solutions were found to be both effective and safer.     

Water sources of dominant species in three alpine ecosystems on the Tibetan Plateau, China

Plant water sources were estimated by two or three compartment linear mixing models using hydrogen and oxygen isotope （δD and δ^18O） values of different components such as plant xylem water, precipitation and river water as well as soil water on the Tibetan Plateau in the summer of 2005. Four dominant species （Quercus aquifolioides, Pinus tabulaeformis, Salix rehderiana and Nitraria tangutorum） in three typical ecosystems （forest, shrub and desert） were investigated in this study. Stable isotope ratios of the summer precipitations and the soil water presented variations in spatial and temporal scales. δ^18O values of N. tangutorum xylem water were constant in the whole growth season and very similar to those of deep soil water. Water sources for all of the plants came from both precipitations and soil water. Plants switched rapidly among different water sources when environmental water conditions changed. Rainwater had different contributions to the plants, which was influenced by amounts of precipitation. The percentage of plant xylem water derived from rainwater rose with an increase in precipitation. Water sources for broad-leaved and coniferous species were different although they grew in the same environmental conditions. For example, the broad-leaved species Q. aquifolioides used mainly the water from deep soil, while 92.5% of xylem water of the coniferous species P. tabulaeformis was derived from rainwater during the growth season. The study will be helpful for us to fully understand responses of species on the Tibetan Plateau to changes in precipitation patterns, and to assess accurately changes of vegetation distribution in the future.     

Identification of major histocompatibility complex class I alleles in Chinese rhesus macaques

Major histocompatibility complex (MHC) class I information is vital for understanding variance of immune responses in HIV vaccination and biomedical models. In this study, 9 Mamu-A and 13 Mamu-B alleles were identified from the cDNA products of 10 Chinese-origin rhesus macaques. Except for two alleles that had been reported by others, eight were novel and twelve extended the partial sequences that are available in GenBank. The additional information of MHC class I antigens might be beneficial to the availability of Chinese macaques in human disease studies. Furthermore, the polymorphism of leading peptides and the natural killer receptor recognition motifs in alpha1 domain both implies that Mamu-A and Mamu-B molecules might play key roles in innate immune responses of natural killer cells.     

In vitro expansion of DNA triplet repeats with bulge binders and different DNA polymerases

The expansion of DNA repeat sequences is associated with many genetic diseases in humans. Simple bulge DNA structures have been implicated as intermediates in DNA slippage within the DNA repeat regions. To probe the possible role of bulged structures in DNA slippage, we designed and synthesized a pair of simple chiral spirocyclic compounds [Xi Z, Ouyang D & Mu HT (2006) Bioorg Med Chem Lett 16, 1180-1184], DDI-1A and DDI-1B, which mimic the molecular architecture of the enediyne antitumor antibiotic neocarzinostatin chromophore. Both compounds strongly stimulated slippage in various DNA repeats in vitro. Enhanced slippage synthesis was found to be synchronous for primer and template. CD spectra and UV thermal stability studies supported the idea that DDI-1A and DDI-1B exhibited selective binding to the DNA bulge and induced a significant conformational change in bulge DNA. The proposed mechanism for the observed in vitro expansion of long DNA is discussed.     

Primary evaluation of carbon sequestration potential of wetlands in China

As one of the important ecosystem services of wetlands, carbon sequestration potential of lakes and swamps in China were investigated. Significant differences were found among the carbon sequestration potential of various lakes, determined by natural conditions and human disturbance. In this study, swamps had a carbon sequestration potential of 4.90 TgC, much higher than lakes in China. Mangrove and coastal marsh have the highest carbon sediment rate among swamps. Carbon sequestration potential in returning farms to lakes and swamps was 30.26 and 0.22 GgC. … a^?1, respectively. Under the ongoing national wetland conservation action plan in China, the carbon sequestration potential of wetland restoration was 6.57 GgC. … a^?1. Protection and restoration measurements can improve carbon sequestration potential of wetlands.