1、新視野系列研究生課程：科技論文的構(gòu)思、撰寫和發(fā)表,生物醫(yī)學(xué)世紀(jì)講壇,特邀報(bào)告：,How to Publish Your Papers in the Top Scientific Journals,魯白教授,What Is a First-Class Paper?,Major advance in a classic field 干細(xì)胞是如何分化成特定組織細(xì)胞的，膽固醇在人體的正常功用 New techniques and methods that can be widely used 人類基因組研究中的自動(dòng)測序技術(shù) , PCR, Patch clamp Discoveries with obv

2、ious practical implications AIDS virus receptor 的發(fā)現(xiàn), 老年癡呆癥基因的發(fā)現(xiàn) Conceptual breakthrough, novel ideas 神經(jīng)營養(yǎng)因子可以促進(jìn)學(xué)習(xí)記憶 Challenge to traditional views, break dogma 腦內(nèi)有可分裂的神經(jīng)干細(xì)胞，打破了傳統(tǒng)觀念 opening up new area, cross board “細(xì)胞凋亡”現(xiàn)象的發(fā)現(xiàn), 開辟了新的科研領(lǐng)域,What Is a Mediocre Paper?,Horizontal growth I made the discover

3、y 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, “me too” EGF-R

4、 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 and why? What

5、 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, appreciative,Articl

6、es,An RNA Thermosensor Controls Expression of Virulence Genes in Listeria monocytogenesJrgen Johansson, Pierre Mandin, Adriana Renzoni, Claude Chiaruttini, Mathias Springer, and Pascale Cossart,Single-Stranded Antisense siRNAs Guide Target RNA Cleavage in RNAiJavier Martinez, Agnieszka Patkaniowska,

7、 Henning Urlaub, Reinhard Lhrmann, and Thomas Tuschl,OcaB Is Required for Normal Transcription and V(D)J Recombination of a Subset of Immunoglobulin gene Rafael Casellas, Mila Jankovic, Gesa Meyer, Anna Gazumyan, Yan Luo, Robert G. Roeder, and Michel C. Nussenzweig,Cell,September 6, 2002: 110 (5),A

8、Structural Mechanism of Integrin IIb3 Inside-Out Activation as Regulated by Its Cytoplasmic Face Olga Vinogradova, Algirdas Velyvis, Asta Velyviene, Bin Hu, Thomas A. Haas, Edward F. Plow, and Jun Qin,Global Conformational Rearrangements in Integrin Extracellular Domains in Outside-In and Inside-Out

9、 SignalingJunichi Takagi, Benjamin M. Petre, Thomas Walz, and Timothy A. Springer,AppA Is a Blue Light Photoreceptor that Antirepresses Photosynthesis Gene Expression in Rhodobacter sphaeroidesShinji Masuda and Carl E. Bauer,What Makes Good Science?,Important and significant Original and innovative

10、Solid and rigorous Unique and unusual,Novelty is essential,Editorial Policies of Different Journals,Cell/Neuron/Immunity Editorial board does a lot of reviews. Editors discuss and decide Nature sister journals Editors discuss and decide Science Space meeting, editorial board PNAS Communicate, contri

11、bute, Track C Others,Procedures for High Profile Journals,Pre-submission inquiry Submit/cover letter Initial screen 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

12、 friends may not always support you “not to review” always honored “soft” and “harsh” reviewers,Selection of reviewers,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 GDN

13、F Acutely Modulates Neuronal Excitability and A-type Potassium Channels in Midbrain Dopaminergic Neurons, which 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

14、degenerated in Parkinsons disease. In this paper, we report an unexpected, acute effect of GDNF on A-type potassium 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+ chann

15、els through a mechanism that involves activation of MAP kinase. Thus, this study has revealed, for the first time, 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 norma

16、l function of GDNF is to regulate neuronal excitability, and consequently dopamine release. These results may 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 co

17、nsidered as reviewers. With thanks for your consideration, I am Sincerely yours,Dear Editor, We would like to 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 publica

18、tion in Neuron. We believe that two aspects of this manuscript will make it interesting to general readers of 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 t

19、his new family of neurotrophic factors in functional synaptic transmission. Second, we show that the GDNF effect 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

20、an enhancement of Ca2+ influx. Thus, this study has identified, for the first time, a molecular target that 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 cop

21、ies of a manuscript entitled BDNF and NT-4/5 Promote the Development of Long-Term Potentiation in the Hippocampus, 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 de

22、velopment and plasticity. Our manuscript provides, for the first time, the physiological evidence that neurotrophins 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 t

23、o recent Science article by Erin Schumans group, we (and several other LTP groups) did not see that BDNF enhance basal 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 indu

24、ce LTP produced enduring LTP. These findings may have implications in the basic mechanism for regulation of synapse 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 presente

25、d this work in any public forum. However, confidential discussion with several prominent neuroscientists such as 111 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

26、Univ., bbb of Harvard Medical School, and ccc of Univ. of California-Berkeley, as reviewers for this manuscript. Due 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/significa

27、nt Unexpected/unusual Function Mechanisms Simple Straight forward Specific,Structure, mechanism, an regulation of the Neurospora plasma membrane H+,Modulation of postendocytic sorting of G-protein-coupled receptors,Distinct molecular mechanism for initiating TRAF6 signaling,Identification of; Role o

28、f; Involvement of,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 inh

29、ibitory 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 ve

30、ntricular 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 cellul

31、ar source 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 sugge

32、sts a possible copying mechanism for the genetic material. - J. D. Watson and F. H. C. Crick,MuSK plays an essential role in postsynaptic differentiation at the neuromuscular junction. However, the underlying mechanisms remained unclear. We demonstrate the interaction of MuSK with Dishevelled1 (Dvl1

33、) in muscle cells. The expression pattern of Dvl1 in developing and denervated muscle is similar to that of MuSK. Moreover, Dvl1 is enriched at the neuromuscular junction where MuSK is concentrated. Disruption of the interaction of MuSK with Dvl inhibits AChR clustering in muscle cells induced by ag

34、rin and motoneurons and attenuates the amplitude of spontaneous postsynaptic currents at the neuromuscular junction. In addition, Dvl1 interacts with PAK1 and mediates agrin-induced activation of PAK, which is required for AChR clustering. These results demonstrate essential roles of Dvl and PAK in

35、agrin-induced AChR clustering, revealing a signaling pathway that required the MuSK-Dvl-PAK complex.,An important aspect of synapse development is the clustering of neurotransmitter receptors in the postsynaptic membrane. Although MuSK is required for acetylcholine receptor (AChR) clustering at the

36、neuromuscular junction (NMJ), the underlying molecular mechanisms remain unclear. We report here that in muscle cells, MuSK interacts with Dishevelled (Dvl), a signaling molecule important for cell polarity. Dvl1 is localized at the neuromuscular synapses. Disruption of the MuSK-Dvl interaction inhi

37、bits Agrin-induced and neuron-induced AChR clustering. Expression of dominant negative Dvl1 in the postsynaptic muscle cells reduces the amplitude of spontaneous synaptic currents at the NMJ. Moreover, Dvl1 interacts with a downstream kinase PAK1. Agrin activates PAK, and this activation requires Dv

38、l. Inhibition of PAK1 activity attenuates AChR clustering. These results demonstrate important roles of Dvl and PAK in Agrin/MuSK-induced AChR clustering, and reveal a novel function of Dvl in synapse development.,Sequence of writing,Abstract Figure layout Figure legend Material and methods Results

39、Introduction Discussion,Introduction,What do we know about the subjects? Only relevant information should be provided; dont write a review What we dont know Rationale Why you want to do it? Dont repeat abstract Approaches How you are going to do it. Significance Make an appeal to general readers,In

40、this study we have examined the role of chromogranins CGA and CGB, in dense-core secretory granule biogenesis. We analyzed the effect of specific depletion of either CGA or CGB, using an antisense RNA strategy, on dense-core secretory granule formation in rat pheochromocytoma (PC12) cells, a model n

41、euroendocrine cell line. We also expressed CGA in a pituitary cell line (6T3) lacking the regulated secretory pathway and nonendocrine fibroblast cells to determine its effect on induction of dense-core secretory granule biogenesis and regulated secretion. Finally, we determined whether CGA could re

42、gulate the level of other secretory granule proteins in neuroendocrine and endocrine cells, PC12 and 6T3. These studies identified CGA as a key regulator of dense-core secretory granule biogenesis and storage of other granule proteins in endocrine cells.,Results,Logic Need to explain the rationales

43、in the beginning Connections between paragraphs Dont jump,Previous studies have shown that membrane depolarization-triggered Ca2+ influx through L-type VSCCs induces an increase in BDNF mRNA expression in cultured neurons (Zafra et al., 1990 ; Ghosh et al., 1994 ). This increase in BDNF mRNA could b

44、e the result of increased transcription initiation, or increased BDNF mRNA stability, or both. To determine if membrane depolarization stimulates BDNF transcription, we.,Given the finding that Ca2+ influx through L-type VSCCs induces BDNF transcription, experiments were carried out to determine whic

45、h of the four BDNF promoters is capable of mediating a Ca2+ response. As described above, the rat BDNF gene consists of four distinct 5 exons each driven by a specific promoter and each spliced to a common 3 exon that encodes the BDNF protein. Since each of the four primary BDNF transcripts can be p

46、olyadenylated at one of two sites, a total of eight BDNF transcripts are generated. In principle, the eight transcripts can be distinguished by Northern blotting using 5exonspecific probes, since each of the four 5 exon probes should detect a short and a long BDNF transcript. By identifying the spec

47、ific BDNF mRNAs induced upon Ca2+ influx through L-type VSCCs, it should be possible to identify which of the four BDNF promoters is Ca2+ responsive, since the Ca2+-responsive promoter(s) would be expected to be located just 5 of the initiation site of BDNF mRNA synthesis.,Discussion,Summary of main

48、 findings Papers that support you, but dont downgrade your novelty Pitfalls and why Significance. Dont speculate too much,The results in the present study may have a number of implications in the cell biology of tyrosine kinase receptors. First, we report the . To our knowledge, this is the first de

49、monstration for . Thus, our results suggest a cross-talk between Ca2+ and tyrosine kinase signaling pathways. Second, the present study reveals an important regulatory effect of . It will be interesting to determine whether . Finally, we show that . Xxx . Taken together, these results suggest a gene

50、ral role of tyrosine kinase in the endocytosis of growth factor receptors.,There are three main findings in the present study. First, we report a GDNF-induced long-term facilitation of neurotransmitter release at the neuromuscular synapses. Second, we show that the effect of GDNF on synaptic transmi

51、ssion is mediated by an increase in the expression of the Ca2+-binding protein frequenin. Finally, we demonstrate that GDNF and frequenin facilitate synaptic transmission by enhancing N-type Ca2+ channel activation, leading to an enhancement of Ca2+ influx. Thus, this study has identified, for the f

52、irst time, a molecular target that mediates the long-term, synaptic action of a neurotrophic factor. Our findings may also provide new insights into the regulatory mechanisms of neurotransmitter release.,Revise your paper,Be calm about reviewers criticisms. Always make editor your friend Never argue

53、 with reviewers Try to do everything that reviewers ask Seize the opportunity when reviewers make mistakes,When your paper gets rejected without review,Dear Editor, I would appreciate if you could reconsider to review our manuscript, “111. We feel strongly that this is an important subject that touc

54、hes one of the central dogmas in neuroscience: xxx. It is also very timely, given the publication of the paper by X and Y entitled “222” in the latest issue of Nature Neuroscience. In this paper, the authors xxx. They claimed that xxx. When a paper this provocative has been published by a high profi

55、le journal like Nature Neuroscience, we believe that it is worth giving a benefit of doubts. It will be helpful if there are papers that consider other alternative interpretations, or attempt to replicate in the same or different systems. We have observed similar xxx, but we have a completely differ

56、ent interpretation. We found that 1) xxx 2) xxx; 3) xxx. Thus, our paper raises the possibility that xxx reported by X and Y were due to xxx. Specifically, we would like you to consider the following two issues: First, X and Y used aaa, while we used bbb. sssssssss. Second, ccc used by X and Y may not be so specific. In addition to the drastically different opinions regarding xxx, we feel that our findings on xxx is also sig