Li Lv

Decreased mitochondrial DNA copy number in the hippocampus and peripheral blood during opiate addiction is mediated by autophagy and can be salvaged by melatonin

Drug addiction is a chronic brain disease that is a serious social problem and causes enormous financial burden. Because mitochondrial abnormalities have been associated with opiate addiction, we examined the effect of morphine on mtDNA levels in rat and mouse models of addiction and in cultured cells. We found that mtDNA copy number was significantly reduced in the hippocampus and peripheral blood of morphine-addicted rats and mice compared with control animals. Concordantly, decreased mtDNA copy number and elevated mtDNA damage were observed in the peripheral blood from opiate-addicted patients, indicating detrimental effects of drug abuse and stress. In cultured rat pheochromocytoma (PC12) cells and mouse neurons, morphine treatment caused many mitochondrial defects, including a reduction in mtDNA copy number that was mediated by autophagy. Knockdown of the Atg7 gene was able to counteract the loss of mtDNA copy number induced by morphine. The mitochondria-targeted antioxidant melatonin restored mtDNA content and neuronal outgrowth and prevented the increase in autophagy upon morphine treatment. In mice, coadministration of melatonin with morphine ameliorated morphine-induced behavioral sensitization, analgesic tolerance and mtDNA content reduction. During drug withdrawal in opiate-addicted patients and improvement of protracted abstinence syndrome, we observed an increase of serum melatonin level. Taken together, our study indicates that opioid addiction is associated with mtDNA copy number reduction and neurostructural remodeling. These effects appear to be mediated by autophagy and can be salvaged by melatonin.

Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/α-synuclein aggregation

Autophagy is involved in the pathogenesis of neurodegenerative diseases including Parkinson disease (PD). However, little is known about the regulation of autophagy in neurodegenerative process. In this study, we characterized aberrant activation of autophagy induced by neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and demonstrated that melatonin has a protective effect on neurotoxicity. We found an excessive activation of autophagy in monkey brain tissues and C6 cells, induced by MPTP, which is mediated by CDK5 (cyclin-dependent kinase 5). MPTP treatment significantly reduced total dendritic length and dendritic complexity of cultured primary cortical neurons and melatonin could reverse this effect. Decreased TH (tyrosine hydroxylase)-positive cells and dendrites of dopaminergic neurons in the substantia nigra pars compacta (SNc) were observed in MPTP-treated monkeys and mice. Along with decreased TH protein level, we observed an upregulation of CDK5 and enhanced autophagic activity in the striatum of mice with MPTP injection. These changes could be salvaged by melatonin treatment or knockdown of CDK5. Importantly, melatonin or knockdown of CDK5 reduced MPTP-induced SNCA/α-synuclein aggregation in mice, which is widely thought to trigger the pathogenesis of PD. Finally, melatonin or knockdown of CDK5 counteracted the PD phenotype in mice induced by MPTP. Our findings uncover a potent role of CDK5-mediated autophagy in the pathogenesis of PD, and suggest that control of autophagic pathways may provide an important clue for exploring potential target for novel therapeutics of PD.

De Novo Design, Synthesis and Evaluation of Benzylpiperazine Derivatives as Highly Selective Binders of Mcl-1

Considerable efforts have been made to the development of small‐molecule inhibitors of antiapoptotic B‐cell lymphoma 2 (Bcl‐2) family proteins (such as Bcl‐2, Bcl‐xL, and Mcl‐1) as a new class of anticancer therapies. Unlike general inhibitors of the entire family, selective inhibitors of each member protein can hopefully reduce the adverse side effects in chemotherapy treatments of cancers overexpressing different Bcl‐2 family proteins. In this study, we designed four series of benzylpiperazine derivatives as plausible Bcl‐2 inhibitors based on the outcomes of a computational algorithm. A total of 81 compounds were synthesized, and their binding affinities to Bcl‐2, Bcl‐xL, and Mcl‐1 measured. Encouragingly, 22 compounds exhibited binding affinities in the micromolar range (Ki<20 μM) to at least one target protein. Moreover, some compounds were observed to be highly selective binders to Mcl‐1 with no detectable binding to Bcl‐2 or Bcl‐xL, among which the most potent one has a Ki value of 0.18 μM for Mcl‐1. Binding modes of four selected compounds to Mcl‐1 and Bcl‐xL were derived through molecular docking and molecular dynamics simulations. It seems that the binding affinity and selectivity of these compounds can be reasonably interpreted with these models. Our study demonstrated the possibility for obtaining selective Mcl‐1 inhibitors with relatively simple chemical scaffolds. The active compounds identified by us could be used as lead compounds for developing even more potent selective Mcl‐1 inhibitors with potential pharmaceutical applications.

Preparation of α-alkyl-β-amino acids via β-alanine Ni(II) complex.

A new β-amino acrylic acid Ni(II) complex has been developed and used for the synthesis of α-alkyl-β-amino acids via alkylation with alkyl halides under operationally convenient conditions. The pivotal α-alkylated intermediate can be converted into the corresponding α-alkyl-β-amino acids via two steps with a wide range of substituents.

Room-temperature terahertz detection based on CVD graphene transistor

We report the fabrication and characterization of a single-layer graphene field-effect terahertz detector, which is coupled with dipole-like antennas based on the self-mixing detector model. The graphene is grown by chemical vapor deposition and then transferred onto an SiO2/Si substrate. We demonstrate room-temperature detection at 237 GHz. The detector could offer a voltage responsivity of 0.1 V/W and a noise equivalent power of 207 nW/Hz(1/2). Our modeling indicates that the observed photovoltage in the p-type gated channel can be well fit by the self-mixing theory. A different photoresponse other than self-mixing may apply for the n-type gated channel.

Superconducting phase qubits with shadow-evaporated Josephson junctions*

We develop a fabrication process for the superconducting phase qubits in which Josephson junctions for both the qubit and superconducting quantum interference device (SQUID) detector are prepared by shadow evaporation with a suspended bridge. Al junctions with areas as small as are fabricated for the qubit, in which the number of the decoherence-causing two-level systems (TLS) residing in the tunnel barrier and proportional to the junction area are greatly reduced. The measured energy spectrum shows no avoided crossing arising from coherent TLS in the experimentally reachable flux bias range of the phase qubit, which demonstrates the energy relaxation time T 1 and dephasing time on the order of 100 ns and 50 ns, respectively. We discuss several possible origins of decoherence from incoherent or weakly-coupled coherent TLS and further improvements of the qubit performance.

Characteristics and Mechanics Analysis of Debris Flow Disaster in Xinjiang Arid Area

Xinjiang arid area is characterized by low rainfall, strong evaporation capacity, sparse vegetation, intensive tectonic movement, and fragile ecological environment ; the rainfall-type debris flow in the arid area are obviously different from the same type debris flow in humid and subhumid area of China with conditions of rainfall excitation, watershed morphology, motion and deposition processes, material composition, active period and disaster mechanism. Investigations and analyses of characteristics of rainfall-type debris flow in the arid area will reveal the rule of the occurrence and development and explore the evolution trends, to establish reasonable disaster reduction measures. Qiaoquli gully located in Kashgar is a typical arid area rainfall debris flow gully. The 50-year frequency outbreak of debris flow in 2005 destroyed chinapakistan highway . Further investigation to this debris flow gully will contribute to our understanding of this kind of debris flow disaster characteristics and mechanism.

Quantitative Study for the Impact of Fines Content on Soil Surface Cracking

Cracking development in soils is of significance for their physical and mechanical properties. The fines content in soils is one of the most important factors in cracking development, leading to it being of great importance to quantitatively study how the cracking development is influenced by the fines content. In this paper, experimental simulations on soil surface cracking were first conducted in the lab with soil from Jiangjia Valley. Digital image processing technology was then applied to investigate cracking in soil with different fines content by describing the surface cracks with crack area density Ac (ratio of all cracks’ area to total surface area of the cracked soil) and crack line density Lc (ratio of all cracks’ perimeters to total surface area of the cracked soil). The conclusions are drawn as follows: 1) Surface cracks increase with fines content going up; specifically, when the soil mass with fines content ranging from 20% to 30%, there is a significant increase in cracks; There is no crack developed in the soil with no fines, comparing to the gradual increase in soils with other fines content. 2) With the loss of water content, Ac and Lc will increase until a constant value is reached. However, small cracks will be closed and big ones will evolve into smaller ones if enough water is added. 3) Soil mass with fines content less than 20% is inclined to have small cracks when it is drying and cracks will be closed if enough water is added; on the other hand, soil mass with fines content more than 20% is inclined to have bigger cracks and they will become smaller when submerged into water. 4) After times of wetting and drying cycles, soil mass shrinks and soil dry density increases, which leads to the decrease of Dc and Lc, which suggests soil with larger dry density will probably have fewer cracks.