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1、,许田教授：How to Give Oral Presentations,11月9日（星期日）,11月3日（星期一）,顾玉东院士： 怎样做临床科研,11月10日（星期一）,袁钧瑛教授：科研与合作,8:50（306教室）邯郸校区正门内8:00有车前来 韩启德院士：漫谈研究生的成长问题,1:30 pm（12-30）教室,新视野系列研究生课程：科技论文的构思、撰写和发表,生物医学世纪讲坛,How to Publish Your Papers in the Top Scientific Journals,鲁白 教授,鲁白教授,1957年12月生于上海市。1982年获上海华东师范大学学士学位。1990年
2、获康乃尔大学博士学位后，在洛克菲勒大学和哥伦比亚大学从事博士后研究,导师为Paul Greengard和蒲慕明教授。1993年加入罗氏分子生物学研究所，并任哥伦比亚大学助理教授。1996年加入NIH儿童健康和人类发育研究所，任突触发育和可塑性研究室主任。 主要研究神经营养因子在突触发育和可塑性中的作用。他的研究室是最早提出并发现神经营养因子对神经系统突触传递、突触发育可塑性有调控作用的实验室之一，与几个著名实验室一起开创了神经营养因子的突触调控这一新领域。,M. F. Egan, M. Kojima, J. H. Callicott, T. E. Goldberg, B. S. Kolacha
3、na, E. Zaistev, A. Bertolino, B. Gold, D. Goldman, M. Dean, B. Lu, (co-corresponding author) and D. R. Weinberger. (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112, 257-269. L. Ma, Y. -Z. Huang, J. Valtschanoff, L.
4、 Feng, B. Lu, W. Xiong, R. Weinberg, L. Mei. (2003) Ligand-dependent recruitment of the neuregulin signaling complex into neuronal lipid rafts. J. Neurosci. 23, 3164-3175. J. Wang, C. -Q. Chen, B. Lu, and C. -P. Wu. (2003) GDNF acutely potentiates Ca2+ channels and excitatory synaptic transmission i
5、n midbrain dopaminergic neurons. NeuroSignals 12, 78-88. M. Miura, S. Gronthos, M. Zhao, B. Lu, L. W. Fisher, P. G. Robey, and S. Shi (2003) SHED: Stem cells from human exfoliated deciduous teeth. Proc. Natl. Acad. Sci. USA 100, 5807-5812. Y. X. Zhou, M. Zhao, K. Shimazu, K. Sakata, D. Li, C. -X. De
6、ng, B. Lu. (2003) Impairments in cerebellum Purkinje cells and motor function in mice lacking Smad4 in the central nervous system. J. Biol. Chem. 278, 42313 - 42320. J. Du, L. Feng, E. Zaitsev, H. S. Je, X. Liu, and B. Lu. (2003) Activity- and tyrosine kinase-dependent facilitation of TrkB receptor
7、internalization in hippocampal neurons. J Cell Biol. In press. Z. G. Luo, H. -S. Je, F. Yang, W. C. Xiong, B. Lu, and L. Mei (2003) Activation of geranylgenanyltransferase is essential for Agrin-induced AChR clustering. Neuron In press. S. X. Bamji, K. Shimazu, N. Kimes, J. Huelsken, W. Birchmeier,
8、B. Lu, L. F. Reichardt. (2003) Regulation of presynaptic assembly and maintenance by -catenin. Neuron In Press. F. Yang, X. He, J. Russell, and B. Lu. (2003) Ca2+ influx independent transmitter release mediated by mitochondrial Na+-Ca2+ exchanger and protein kinase C. J. Cell Biol. In press.,2003 re
9、search articles,What Is the Purpose of Doing Research?,It is not about the number of papers It is not about the impact factor of the papers It is not about the Nobel Prize,Publish or perish 1 Nature = 10 JBC,Basic Elements for Basic Research,Passion,6 Sigma,Silver bullet test,Good Research Is the Ke
10、y,My English is not good They are biased against Chinese (foreigners),What Is a First-Class Paper/Research?,Major advance in a classic field 干细胞是如何分化成特定组织细胞的，胆固醇在人体的正常功用 New techniques and methods that can be widely used 人类基因组研究中的自动测序技术 , PCR, Patch clamp, Ca2+ Imaging, GFP Discoveries with obvious
11、practical implications AIDS virus receptor 的发现, 老年痴呆症基因的发现 Conceptual breakthrough, novel ideas 神经营养因子可以促进学习记忆, RNA干扰现象 Challenge to traditional views, break dogma 脑内有可分裂的神经干细胞，打破了传统观念 Opening up new area, cross board “细胞凋亡”现象的发现, 开辟了新的科研领域,What Is a Mediocre Paper/Research?,Horizontal growth I made
12、 the discovery in rats, you find the same in cat. Filling gaps EGF activates JNK which is known to induce c-Jun expression. You show that EFG enhances c-Jun expression. Working out details I found NO induces the production of cGMP, you work out dose response and time course. Support existing idea, “
13、me too” EGF-R endocytosis requires dynamin, PDGF-R too. Follow up CREB binds to CRE. Working out CRE sequence. Incomplete study, preliminary,How to Read Scientific Papers?,The Gilbert way Keep these in mind when you read What is the major question addressed in this paper? Is this question important
14、and why? What are the approaches used in this paper, and whether they are adequate for the questions? What are the novel idea or using innovative approaches? What is the concept coming out of this paper? Do the results presented support this new concept? Weekly reading of CNS titles Critical, apprec
15、iative,What Makes Good Science?,Important and significant Original and innovative Solid and rigorous Unique and unusual,Novelty is essential,语不惊人誓不休,The evaluation process,Editorial staff Board of Reviewing Editors,20-30%,REJECT,REVIEW,REJECT,70%,ACCEPT (10%),70%,20%,6%,4%,Should your paper go to CN
16、S?,Is it your best ever? Will it have a big impact? Does it interest scientists in other fields? Does it overturn conventional wisdom? Work that represents a large step forward solution to long-standing problem different way of thinking broad implications,What helps:,Convincing data Appropriate cont
17、rols Careful presentation Consideration of all viable alternatives,What doesnt help,The minimal publishable unit. Excessive or unfounded speculation Repeat examples of a known phenomenon Insufficient advance over previously published work,Editorial Policies of Different Journals,Cell/Neuron/Immunity
18、 Editorial board does a lot of reviews. Editors discuss and decide Nature sister journals Editors discuss and decide Science Space meeting, board of review editors PNAS Communicate, contribute, Track C Others,Procedures for High Profile Journals,Pre-submission inquiry Submit/cover letter Initial scr
19、een Send out for reviews Reject/soft reject/revise Rebuttal Revise again Accept,significance/importance general interests unusual/surprise,Initial screening,suggest reviewers, may take one friends may not always support you “not to review” always honored “soft” and “harsh” reviewers,Selection of rev
20、iewers,You,Editors,Cover Letters,main findings significance suggested reviewers “not to review” list who have read,Dear Editor, We would like to submit the enclosed manuscript entitled “GDNF Acutely Modulates Neuronal Excitability and A-type Potassium Channels in Midbrain Dopaminergic Neurons“, whic
21、h we wish to be considered for publication in Nature Neuroscience. GDNF has long been thought to be a potent neurotrophic factor for the survival of midbrain dopaminergic neurons, which are degenerated in Parkinsons disease. In this paper, we report an unexpected, acute effect of GDNF on A-type pota
22、ssium channels, leading to a potentiation of neuronal excitability, in the dopaminergic neurons in culture as well as in adult brain slices. Further, we show that GDNF regulates the K+ channels through a mechanism that involves activation of MAP kinase. Thus, this study has revealed, for the first t
23、ime, an acute modulation of ion channels by GDNF. Our findings challenge the classic view of GDNF as a long-term survival factor for midbrain dopaminergic neurons, and suggest that the normal function of GDNF is to regulate neuronal excitability, and consequently dopamine release. These results may
24、also have implications in the treatment of Parkinsons disease. Due to a direct competition and conflict of interest, we request that Drs. XXX of Harvard Univ., and YY of Yale Univ. not be considered as reviewers. With thanks for your consideration, I am Sincerely yours,Dear Editor, We would like to
25、submit the enclosed manuscript entitled “Ca2+-binding protein frequenin mediates GDNF-induced potentiation of Ca2+ channels and transmitter release“, which we wish to be considered for publication in Neuron. We believe that two aspects of this manuscript will make it interesting to general readers o
26、f Neuron. First, we report that GDNF has a long-term regulatory effect on neurotransmitter release at the neuromuscular synapses. This provides the first physiological evidence for a role of this new family of neurotrophic factors in functional synaptic transmission. Second, we show that the GDNF ef
27、fect is mediated by enhancing the expression of the Ca2+-binding protein frequenin. Further, GDNF and frequenin facilitate synaptic transmission by enhancing Ca2+ channel activity, leading to an enhancement of Ca2+ influx. Thus, this study has identified, for the first time, a molecular target that
28、mediates the long-term, synaptic action of a neurotrophic factor. Our findings may also have general implications in the cell biology of neurotransmitter release.,Dear Editor: Enclosed are copies of a manuscript entitled “BDNF and NT-4/5 Promote the Development of Long-Term Potentiation in the Hippo
29、campus“, which we wish to be considered for publication in Nature. As you know, there is a great deal of interest and excitement recently in understanding the role of neurotrophins in synapse development and plasticity. Our manuscript provides, for the first time, the physiological evidence that neu
30、rotrophins regulate long-term potentiation (LTP). The main point of the paper is that the neurotrophins BDNF and NT-4 induce an earlier appearance of LTP in developing hippocampus. In contrast to recent Science article by XXs group, we (and several other LTP groups) did not see that BDNF enhance bas
31、al synaptic transmission in adullt hippocampus. However, we found that in adult hippocampus, inhibition of BDNF/TrkB activity attenuated LTP, and weak tetanus that normally cannot induce LTP produced enduring LTP. These findings may have implications in the basic mechanism for regulation of synapse
32、development and long-term modulation of synaptic efficacy. Because of the rather competitive nature of the field and the important implication of our findings, we have not yet presented this work in any public forum. However, confidential discussion with several prominent neuroscientists such as 111
33、 and 222 have generated tremendous excitement. Thus, we feel that this work is of general interest and is suitable for publication in Nature. We would like to suggest Drs. aaa of Yale Univ., bbb of Harvard Medical School, and ccc of Univ. of California-Berkeley, as reviewers for this manuscript. Due
34、 to a direct competition and conflict of interest, we request that Dr. XX and YY. not be considered as reviewers. Thank you very much for your consideration.,Titles,Important/significant Unexpected/unusual Function Mechanisms Simple Straight forward Specific,Structure, mechanism, an regulation of th
35、e Neurospora plasma membrane H+,Modulation of postendocytic sorting of G-protein-coupled receptors,Distinct molecular mechanism for initiating TRAF6 signaling,Identification of; Role of; Involvement of,Sequence of writing,Abstract Figure layout Figure legend Material and methods Results Introduction
36、 Discussion,Abstract,Rationale “remain unknown”; “To determine” Summary statement “Here we show” Body Dont go into details; dont use many special terms Significance Must point out, but dont claim too much,Formation of the normal mammalian cerebral cortex requires the migration of GABAergic inhibitor
37、y interneurons from an extracortical origin, the lateral ganglionic eminence (LGE). Mechanisms guiding the migratory direction of these neurons, or other neurons in the neocortex, are not well understood. We have used an explant assay to study GABAergic neuronal migration and found that the ventricu
38、lar zone (VZ) of the LGE is repulsive to GABAergic neurons. Furthermore, the secreted protein Slit is a chemorepellent guiding the migratory direction of GABAergic neurons, and blockade of endogenous Slit signaling inhibits the repulsive activity in the VZ. These results have revealed a cellular sou
39、rce of guidance for GABAergic neurons, demonstrated a molecular cue important for cortical development, and suggested a guidance mechanism for the migration of extracortical neurons into the neocortex.,It has not escaped our notice that the specific pairing we have postulated immediately suggests a
40、possible copying mechanism for the genetic material. - J. D. Watson and F. H. C. Crick,Neuronal responses to brain-derived neurotrophic factor (BDNF) are initiated by the activation of the receptor TrkB tyrosine kinase (1). In this study we examined whether cholesterol- and glycolipid-rich microdoma
41、ins, lipid rafts, provide a functional platform for BDNF-dependent signal transduction (2). Using primary culture of cortical neurons, we demonstrated that TrkB was dramatically translocated into lipid rafts in BDNF-dependent manner (3). This translocation was blocked by the pharmacological effect o
42、f general Trk inhibitors, indicating that TrkB activation is required for the translocation mechanism. We also showed that BDNF and TrkB-FL were both concentrated in lipid rafts during development of cerebral cortex, concomitant with that of synaptic vesicle proteins, including soluble N-ethylmaleim
43、ide-sensitive factor attachment protein receptor (SNARE) proteins and synaptophysin (4). This result, together with the findings that BDNF stimulation caused translocation of synaptophysin into lipid rafts (5) and that BDNF-enhanced glutamate release and exocytosis were both attenuated by depletion
44、of cholesterol from the cell surface with methyl-beta-cyclodextrin (MCD), indicates that lipid rafts are essential for BDNF regulation of neurotransmitter release (6).,Brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity but the underlying signaling mechanisms rema
45、in unknown. Here we show that BDNF rapidly recruits full-length TrkB (TrkB-FL) receptor into cholesterol-rich lipid rafts from non-raft regions of neuronal plasma membranes. Truncated TrkB lacking the intracellular kinase domain was not translocated, and the translocation of TrkB-FL was blocked by T
46、rk inhibitors, suggesting a role for TrkB tyrosine kinase in the translocation. Disruption of lipid rafts by depleting cholesterol from the cell surface blocked BDNF-dependent TrkB translocation. Disruption of rafts also prevented the potentiating effect of BDNF on transmitter release in cultured ne
47、urons, as well as that on synaptic response to tetanus in hippocampal slices. In contrast, lipid rafts are not required for BDNF regulation of neuronal survival. Thus, ligand-induced TrkB translocation into lipid rafts may represent a selective signaling mechanism for synaptic modulation by BDNF in
48、the CNS.,A calcium-independent but voltage-dependent secretion (CIVDS) coexists with the calcium dependent exocytosis in dorsal root ganglion (DRG) neurons (1). Here we have investigated the CIVDS-coupled endocytosis (2). Using optical and membrane capacitance measurements, we show that, in calcium-
49、free medium, either step depolarization or a train of action-potential-like stimulation induce a novel form of rapid endocytosis, which occurs immediately after the CIVDS. Surprisingly, this calcium-independent endocytosis is strongly dependent on the stimulation frequency (3). H7 suppress the endocytosis, while PKA agonists enhance it (4). Biochemical experiments show that membrane depolarization directly up-regulate PKA in DRG neurons. Our experiments also showed that the frequency dependency of CIVDS-RE is dynamin-independent (5). Thus, our data indicat