ISSN 0253-2778

CN 34-1054/N

2008 Vol. 38, No. 8

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Original Paper
To die or not to die, for cell that is the question
WU Mian, YAO Zhan
2008, 38(8): 873-877.
Apoptosis, or the programmed cell death, is employed by eukaryotes to eliminate damaged or unwanted cells tomaintain homeostasis. Unlike necrosis, apoptosis is an active, genetically controlled sequence of events which involve the activation, expression and regulation of multiple genes. Apoptosis reflects a strategy of cells to adapt to a changing environment rather than passive self-damage under pathological conditions. Malfunction of apoptosis, either being “too much” or “too little”, has been implicated in various diseases, including tumorigenesis. Due to the critical roles apoptosis play in maintaining tissue homeostasis, pro- and anti-apoptotic signals are carefully balanced within cells. This balance is achieved through the products of a series of apoptosis-related genes, including the anti-apoptotic IAP (inhibitor of apoptosis protein) family, the pro-apoptotic caspase protease family, the p53 tumor suppressor as well as recently characterized non-coding RNAs such as microRNAs. Through directly or indirectly interacting with each other, these factors constitute a complex signaling network whose overall function determines the progress of apoptosis and ultimately, the fate of the cell. Defining the molecular mechanisms by which each factor contributes to apoptosis will not only deepen our understanding of cell physiology and the origin of life, but also enable a more rational approach to anticancer drug design and therapy.
Progress and perspective of cellular dynamics studies
YAO Xue-biao
2008, 38(8): 878-882.
The cell is a fundamental building block of life. Cellular dynamics and plasticity are essential for animal development, growth and reproduction. At the molecular level, cellular plasticity and dynamics are governed by genetic and epigenetic regulations. With the completion of animal genomes and elucidation biochemical characterization of macromolecule interactions, it is becoming increasingly important to delineate the spatiotemporal dynamics and regulation of key regulators underlying cellular dynamics such as cell division, which was the chief objective to build the Laboratory of Cellular Dynamics in the University of Science and Technology of China at the beginning of this Millennium. Using kinetochore assembly in mitosis as a model system, the Laboratory of Cellular Dynamics has successfully carried out molecular dissection of mammalian kinetochore composition, elucidated several important kinetochore interacting networks and illustrated the key regulator dynamics. Toward the completion of molecular delineation of mammalian kinetochore interactome and signaling cascades, the Lab aims to illuminate the molecular dynamics underlying kinetochore assembly at nano-scale. Successful accomplishment of their long-term objectives will enable us to consolidate dynamic protein-protein interactome into nano-scale physiology, which will provide a launch-pad for solving complex biological questions such as stem cell plasticity and for designing better anti-cancer drugs.
Aneuploidy: a destroyer of human reproduction health
SHI Qing-hua, XU Bo, YANG Qing-ling, CHEN Da-wei, HOU He-li, MA Tie-liang, ZHENG Yuan
2008, 38(8): 883-889.
Aneuploidy, a numerically chromosomal abnormality, is a major cause of infertility, spontaneous abortion or birth with defects. It occurs at the rate of approximately 5%~7%, 22%~90% and more than 50% in spermatozoa, eggs and early spontaneously aborted fetuses,respectively. The vast majority of frequently observed aneuploidy in humans results from eggs (mothers), and nondisjunction of homologous chromosomes in maternal meiosis I is accused of aneuploid eggs for most chromosomes, except chromosome 13 and 18. Maternal age is the only factor identified epidemically so far for the generation of aneuploid germ cells. Alterations in recombination frequency and location, establishment and maintenance of cohesion between sister chromatids are thought to be responsible for homologous chromosome nondisjunction during meiosis I. Sister chromatids cohesion is established during the last DNA replication before meiosis and homologous chromosomes recombination occurs during meiotic prophase I, both of which happen in fetal ovaries. However, most homologous chromosome nondisjunction takes place in women over the age of 35. This implies that mechanisms incorporating chromosome segregation with recombination and cohesion exist during meiosis, which could be abraded with women aging. Future studies should be focused on what the mechanisms are, and how they work to prevent chromosome missegregation during meiosis.
Alteration in meiotic recombination in human male infertility
2008, 38(8): 890-895.
During the prophase of meiosis I, homologous chromosomes pair, synapse and exchange genetic materials (recombination). Meiotic recombination plays a crucial role in the proper segregation of homologous chromosomes and normal gametogenesis. Altered recombination may lead to various sperm abnormalities, such as arrest in spermatogenesis or non-disjunction, which in turn contributes to infertility or aneuploidy. Infertility is a major health problem that affects 10%~15% of couples, about half of which being attributed to male factors in which the aetiology and mechanisms are unidentified. Despite the obvious clinical significance and high incidence of human male infertility, the mechanisms of spermatogenic failure caused by meiotic recombination errors in humans has been inadequately unclear. However, recently-developed immunofluorescence methods which can directly view meiotic recombination and associated important events during gametogenesis have revolutionized our understanding of human spermatogenesis. In this paper, the relationship between meiotic recombination and spermatogenesis is reviewed.
Innate recognition and immune regulation of NK
TIAN Zhi-gang, WEI Hai-ming, SUN Rui
2008, 38(8): 896-904.
Natural killer receptors (NKRs) and Toll-like receptors (TLRs) are the most important receptor supfamilies in innate immunity and act as first line of host defense against infection or transformed cells. These receptors exert peculiar recognition mechanisms to sense danger signals and distinguish infectious nonself from noninfectious self, and thereafter work as link molecules between innate and adaptive immunity. NK cells are the most important lymphocytes population, recognize infection and tumor at initial, and play a critical role in linking innate immunity with adaptive immunity. In this paper, we highlight the importance of recognition and interaction of those receptors via NK cells. The precise mechanisms can be harnessed to aid the rational design of therapy against infection, inflammation, cancer or autoimmune diseases.
Research and development of biotechnology and drugs
LIU Jing
2008, 38(8): 905-908.
As an example of R & D of Biotechnology and Drugs at USTC, several monoclonal antibodies (Abs) have been prepared for applications in industrial and medicinal applications. The Ab against human α-interferon (IFN) was used to prepare the IFN affinity chromatography gel which can provide efficient means for the manufacture of IFNs. It made this key technique for manufacturing IFNs no longer rely on input. Based on these, Anhui Anke High Biotechnology INC was founded in 1995. One of the Abs against oncoprotein p185erbB-2/HER-2 was developed for the diagnostic reagent of the cancers overexpressing oncoprotein p185 such as breast cancer and ovary cancer. This diagnostic reagent was proved by SFDA in 2004. Another Ab against p185 which can inhibit growth and proliferation of cancers overexpressing p185 is being developed into a therapeutic antibody drug. In addition, the fragments with anti-platelet aggregation activities have been developed for a potential anti-thrombus drug by a pharmaceutical company based on the research of the Labs in our school. More achievements are being made at USTC and will be applyied to biotech industries.
Structural biology of some snake venom protein families
NIU Li-wen, TENG Mai-kun, ZHU Zhong-liang, GAO Yong-xiang, ZHANG Ping
2008, 38(8): 909-922.
Following the clues from our groups characteristic investigations of five snake venom protein families, a short review was provided on some research conclusions, current opinions and latest advances from structural biology of snake venom protein families of serine proteases, metalloproteinase, CRISP, phospholipase A2 and neurotoxin as well. This review emphasized the importance of structural biology of snake venom glycoproteins, crystal structures at an ultrahigh resolution and the complex structure related to snake venom proteins in the field of snake venom proteins.
Structural basis for yeast pathway in response to oxidative stress
ZHOU Cong-zhao
2008, 38(8): 923-929.
The yeast Saccharomyces cerevisiae is a unicellular organism with the best research background. To date, there are 78 genes annotated to the term of response to oxidative stress in yeast. The encoded proteins of these genes could be classified into three groups, sensors, regulators and effectors. Taking advantage of the methodology of structural genomics, we started with all of the effectors and have solved all key effectors along the electron transfer pathway of thioredoxin and glutaredoxin systems. Moreover, a series of assays will be set up to identify the potential biochemical activities of the important effectors. Biochemical assays, in combination with protein-protein complex identification and structure solution, and the fast growing information in yeast databases, enable us to remodel a structure-based protein-protein interaction network of effectors in response to oxidative stress. These researches will provide us with some hints to design potential drugs for preventing oxidative stress-related diseases and aging.
The progress in exploring the structure and
RUAN Jian-bin, ZANG Jian-ye
2008, 38(8): 930-940.
The discovery of histone demethylase LSD1 is an important progress in the field of epigenetics, indicating that histone lysine methylation is a reversible and dynamic process like other covalent histone modifications such as acetylation, phosphorylation and ubiquitylation.Structural and functional research results demonstrate that LSD1 regulates the activation and silencing of gene transcription and the function of p53. LSD1 plays a significant role in the development of several cancers and is a potential target protein for developing anti-cancer drugs.
Protein structure and function studied by NMR
SHI Yun-yu, WU Ji-hui
2008, 38(8): 941-949.
More than 10 years of research in the Laboratory of Nuclear Magnetic Resonance (NMR) at the School of Life Science, University of Science and Technology of China is reviewed. Our researches have focused on two systems: proteins related to the regulation of gene expression in humans and other eukaryotes, and proteins existing in the cell junction in humans. The majority of proteins selected from these two systems are related to human health and diseases, and some are potential drug targets. We were interested in using NMR to study structural basis of protein-protein interactions. NMR was highly suited for investigating molecular interactions under approximately physiological conditions and was particularly suited for the study of low-affinity, transient complexes. It can provide information of protein interaction surface, complex structure, and dynamic properties during protein recognition. Several examples were given in this paper. NMR was also used to study dynamic properties of protein both in pico-second to nano-second and in micro-second to mili-second time scales. We have studied protein folding and unfolding by NMR together with fluorescence and circular dichroism experiments. Proteins in unfolded states were characterized in detail by NMR. The last example of NMR application is the identification of a novel inhibitor of a human dual-specific phosphatase and the cellular effects of this compound were also studied. Our results demonstrate that our screening strategy, which combines both virtual and NMR-based methods, is feasible and might be employed in the early stage of drug discovery.
Progress of membrane protein structural studies
SHI Pan, TIAN Chang-lin
2008, 38(8): 950-960.
Membrane proteins play vital roles in maintaining cells proper function, but structural studies of membrane proteins lag far behind water soluble proteins. Because it is unnecessary to prepare crystals of membrane proteins, nuclear magnetic resonance (NMR) is coming to play an increasingly important role in membrane protein structural studies. Several NMR methods can be applied for different states of membrane protein samples. Solution NMR is used to study membrane protein in detergent micelles or in low q bicelles, and several membrane proteins structures have been solved using solution NMR. Static oriented solid state NMR can be applied for uniformly oriented membrane proteins in high q bicelles or in lipid bilayers. Methods of magic angle spinning (MAS) solid state NMR are also under development to solve membrane protein structures in lipid bilayers.
Computer simulation of protein structure and dynamics:
LIU Hai-yan
2008, 38(8): 961-966.
Computer simulation has been developed into an important tool for the elucidation of biological functions from the atomic level structures and dynamics of biomolecules. Compared with current experimental techniques probing atomic level structures, simulations provide not only averages, but also distributions. Besides structures, biological functions often rely on sophisticatedly controlled dynamics of biomolecules, such as the allosteric effects in enzyme catalysis or the effects of ligand-receptor binding in signal transduction. To help understand and eventually control such processes, simulations can be used to reconstruct conformational pathways, identifying intermediates and transition states. This report highlights our recent work in this field. One focus of our research is on developing, testing and refining energy functions for protein simulations, including pure molecular mechanical models for modeling conformational dynamics and hybrid quantum mechanical/molecular mechanical models for modeling enzyme catalysis. Another focus is on developing methods for efficient sampling in the conformational space and for mapping conformational pathways.
The regulation of hypothalamic corticotropin releasing
ZHOU Jiang-ning, YAN Xue-bo
2008, 38(8): 967-977.
Our recent studies reported that the expression of estrogen receptor (ER) and androgen receptor (AR) in corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of hypothalamus increases in depressed patients. Estrogen and androgen can modulate the transcription activity of CRH by binding ER or AR, which act on the estrogen response elements (EREs) and androgen response elements (AREs) on the human CRH gene promoter respectively. Androgen inhibits the activity of the CRH gene promoter while estrogen activates CRH gene expression. In addition to ER and AR, multiple receptors in the hypothalamus which regulate the activity of CRH neurons show a disturbed balance in depressed patients. Drug targeting to glucocorticoid receptors and sex hormone receptors might be useful for improving depressive behavior by modulating the neurons of different areas in the hippocampus. Based on these findings, we proposed the hypothesis that imbalances of multiple receptors in the hypothalamus may contribute to depression.
Post-translational modifications of neurodegenerative disease proteins
FEI Er-kang, FAN Jun, WANG Hong-feng, ZHANG Tao, WANG Guang-hui
2008, 38(8): 978-985.
Post-translational modifications of target proteins are important for these proteins to execute their cellular functions and enable cells to respond to stimuli. There are phosphorylation, acetylation, methylation, ubiquitination, SUMOylation and other modifications to modify target proteins. In the research of neurodegenerative diseases, post-translational modifications participate in the process and pathogenesis of the diseases attracting increasing attention. In this review, we discuss the relationship between neurodegenerative diseases and phosphorylation, ubiquitination or SUMOylation and introduce our laboratorys work.
Neural mechanisms underlying tinnitus induced by sodium salicylate
CHEN Lin, WANG Hai-tao, LU Yun-gang, LUO Bin
2008, 38(8): 986-995.
Sodium salicylate (NaSal) is the metabolite and active component of aspirin. NaSal is often used for tinnitus research because it can reliably induce a tinnitus-like behavior in animals at a high dose. Given that NaSal can reach a high concentration in the cerebrospinal fluid, we propose that NaSal induces tinnitus by changing the balance between excitation and inhibition in the central auditory system. In order to test this hypothesis, a series of studies were conducted to investigate the effects of NaSal on the neuronal responses and synaptic transmissions in the central auditory region with whole-cell patch-clamp techniques. It has been found that NaSal significantly suppresses the functional activity of GABA neurons, suggesting that NalSal raises excitability in the central auditory system to induce tinnitus.
The history and current status of vision research laboratory at USTC
ZHOU Yi-feng, SHOU Tian-de
2008, 38(8): 996-1000.
In 1982, the Vision Research Laboratory in USTC was founded by Prof. Tiande Shou, whose research was focused on visual information processing in the central nervous system. In 1997, Dr. Yifeng Zhou was appointed Director of the Vision Research Lab after Prof. Shou left for Fudan University. The Vision Research Lab has undertaken more than 30 research projects since 1982, with the total grant support exceeding 8 million yuan. More than 60 papers were published in international journals, with more than 400 citations. A paper published in Neurobiology of Aging was selected as one of Chinas 100 Most Influential International Research Papers in 2007 by the Institute of Science and Technology Information of China. Members of the Lab have won many national awards, including Second Awards of Science of the Chinese Academy of Sciences. The Vision Research Lab has wide collaborations with other labs in the world: ① a joint research project with Professor Zhonglin Lu from University of South California on the mechanism of amblyopia resulted in a paper published in PNAS in 2008; ② collaboration with Professor Audie Leventhal from University of Utah on the mechanisms of aging in the mammalian visual system. The project was funded by a NIH subcontract and the Natural Science Foundation of China, and the result was published in Science in 2003. Furthermore, members of the Lab opened five courses; one of which won a course award from USTC. The Lab has supervised more than 50 Bachelors theses, 20 Master theses, and 21 PhD dissertations.
Cognitive neuroscience studies of memory and
ZHANG Da-ren
2008, 38(8): 1001-1006.
University of Science and Technology of China set up a Joint Laboratory for Brain Function and Medical Imaging in 1999. The main study interests are high level cognitive functions (e.g., working memory, selective attention, executive control and decision making), and related cognitive impairment and mental health (e.g., working memory in aging and neuroendocrinological disorders, e-game addiction) with cognitive behavioral and neuroimaging (ERP and fMRI) approaches. Many experiments have been completed and significant results have been obtained in these fields. The important topics in positive psychology such as neural correlates of emotion and well-being would be our further focus.
Lead-induced impairment of learning and memory in the nervous
RUAN Di-yun
2008, 38(8): 1007-1016.
The advances made in lead-induced impairment of learning and memory in the nervous system and mechanisms of pharmacals repair in Neurotoxicolog Lab in University of Science and Technology of China were described. They include: ①the effect of lead on synaptic plasticity in hippocampus; ②the mechanism of effect of lead on ion channels; ③lead-induced impairment of NMDA receptor, non NMDA receptors and receptor channels; ④the interaction between lead and neurotransmitters; ⑤the effect of lead on gene regulation; ⑥the repair mechanism of pharmacals (Taurine, Ganglioside, antioxidants, etc.) on lead-induced impairment.