Morphogenesis of the Acanthocephala

Postzygotic development of acanthocephalans is described. The major conclusion that can be drawn is that there has been a great deal of speculation, and that there are still many questions left unanswered. For example, exactly when does the acanthor become a complete syncytium? Is the formulation of the central nuclear mass really homologous to gastrulation, and does this mass really represent endoderm? What is endoderm in an animal with no trace of a digestive system? What is the significance, if any, of the 90 degree change in polarity from the acanthor to the adult? How do a few giant nuclei determine the fate and function of a massive synctial body? These and other questions continue to intrigue and perplex the investigator. Perhaps by the time of ICOPA-VII we will have some of the answers.     

世界上已知维管植物有多少种? 基于多个全球植物数据库的整合

维管植物是地球上生物多样性的重要组成部分, 拥有超过200年的研究历史。然而, 世界上有多少种维管植物, 其中有多少种已被发现和描述等问题迄今仍未很好回答。本文整合分析了全球4个主要植物数据库, 以期回答全球已发现和描述了多少物种的问题。结果表明, 全球已发现和描述的维管植物有376,366种(包括自然杂交种)。排除自然杂交种后, 全球共包含369,054种维管植物, 其中广义蕨类植物13,810种, 裸子植物1,172种, 被子植物354,072种。我们的结果比已有的4个数据库中的任何一个的物种数都至少要多17,700种。     

The demoiselle of X-inactivation: 50 years old and as trendy and mesmerising as ever

In humans, sexual dimorphism is associated with the presence of two X chromosomes in the female, whereas males possess only one X and a small and largely degenerate Y chromosome. How do men cope with having only a single X chromosome given that virtually all other chromosomal monosomies are lethal? Ironically, or even typically many might say, women and more generally female mammals contribute most to the job by shutting down one of their two X chromosomes at random. This phenomenon, called X-inactivation, was originally described some 50 years ago by Mary Lyon and has captivated an increasing number of scientists ever since. The fascination arose in part from the realisation that the inactive X corresponded to a dense heterochromatin mass called the “Barr body” whose number varied with the number of Xs within the nucleus and from the many intellectual questions that this raised: How does the cell count the X chromosomes in the nucleus and inactivate all Xs except one? What kind of molecular mechanisms are able to trigger such a profound, chromosome-wide metamorphosis? When is X-inactivation initiated? How is it transmitted to daughter cells and how is it reset during gametogenesis? This review retraces some of the crucial findings, which have led to our current understanding of a biological process that was initially considered as an exception completely distinct from conventional regulatory systems but is now viewed as a paradigm “par excellence” for epigenetic regulation.     

Endpiece: Three different talks

ObjectivesTo characterise the information needs of family doctors by collecting the questions they asked about patient care during consultations and to classify these in ways that would be useful to developers of knowledge bases.DesignObservational study in which investigators visited doctors for two half days and collected their questions. Taxonomies were developed to characterise the clinical topic and generic type of information sought for each question.SettingEastern Iowa.ParticipantsRandom sample of 103 family doctors.ResultsParticipants asked a total of 1101 questions. Questions about drug prescribing, obstetrics and gynaecology, and adult infectious disease were most common and comprised 36% of all questions. The taxonomy of generic questions included 69 categories; the three most common types, comprising 24% of all questions, were “What is the cause of symptom X?” “What is the dose of drug X?” and “How should I manage disease or finding X?” Answers to most questions (702, 64%) were not immediately pursued, but, of those pursued, most (318, 80%) were answered. Doctors spent an average of less than 2 minutes pursuing an answer, and they used readily available print and human resources. Only two questions led to a formal literature search.ConclusionsFamily doctors in this study did not pursue answers to most of their questions. Questions about patient care can be organised into a limited number of generic types, which could help guide the efforts of knowledge base developers.

Key messages

• Questions that doctors have about the care of their patients could help guide the content of medical information sources and medical training
• In this study of US family doctors, participants frequently had questions about patient care but did not pursue answers to most questions (64%)
• On average, participants spent less than 2 minutes seeking an answer to a question
• The most common resources used to answer questions included textbooks and colleagues; formal literature searches were rarely performed
• The most common generic questions were “What is the cause of symptom X?” “What is the dose of drug X?” and “How should I manage disease or finding X?”

     

Polypeptide translocation across the endoplasmic reticulum membrane.

Many polypeptides have been postulated to play direct roles in secretory protein translocation based on genetic criteria, cross-linking, and antibody inhibition. Much of the excitement in the next few years will come from the resolution of current controversies. What is the nature of the ribosome receptor, and is it essential for translocation? Is BiP required for translocation in mammalian cells? Are all of the polypeptides of signal peptidase and oligosaccharyltransferase required for catalytic function, or do some of them mediate steps of protein translocation? One of the best ways to resolve these problems will be to determine the importance of each in reconstituted translocation reactions by fractionation or immunodepletion, or by analysis in a purified reaction. Another approach is to identify homologues of these molecules in S. cerevisiae and to assess their importance in in vivo translocation. Several mechanistic questions remain to be addressed as well. Does the protein translocation apparatus consist of protein, or lipid, or both? How are integral membrane proteins inserted? How is the translocon gated to admit only unfolded or partially folded secretory polypeptides and to exclude cytoplasmic molecules? The answers to these questions will illuminate a basic enigma in cell biology that has remained unanswered for many years.     

Redundancy or specificity? The role of the CDK Pho85 in cell cycle control

It is generally accepted that progression through the eukaryotic cell cycle is driven by cyclin-dependent kinases (CDKs), which are regulated by interaction with oscillatory expressed proteins called cyclins. CDKs may be separated into 2 categories: essential and non-essential. Understandably, more attention has been focused on essential CDKs because they are shown to control cell cycle progression to a greater degree. After clearly determining the basic and “core” mechanisms of essential CDKs, several questions arise. What role do non-essential CDKs play? Are these CDKs functionally redundant and do they serve as a mere backup? Or might they be responsible for some accessory tasks in cell cycle progression or control? In the present review we will try to answer these questions based on recent findings on the involvement of non-essential CDKs in cell cycle progression. We will analyse the most recent information with regard to these questions in the yeast Saccharomyces cerevisiae, a well-established eukaryotic model, and in its unique non-essential CDK involved in the cell cycle, Pho85. We will also briefly extend our discussion to higher eukaryotic systems.     

Gaia Pigino: Inside the cell

Gaia Pigino studies the molecular mechanisms and principles of self-organization in cilia using 3D cryo-EM.

Gaia Pigino was only 3 yr old when she became fascinated with nature in the beautiful countryside of Siena, Italy, where she grew up. The neighbor’s daughter showed her a hen in the chicken coop, and they caught it in the act of laying an egg. Gaia remembers, “This was for me almost a shock, as my experience about eggs was that they come directly out of paper boxes!” Her father was also an important part of awakening Gaia’s curiosity for the amazing things in nature. He used to bring home the award-winning magazine Airone, the Italian equivalent of National Geographic. Gaia never missed an issue; even before learning to read, she could spend hours looking at the captivating photos of the wildlife. She wanted to understand what she was seeing, and maybe because of that, she was determined to do science.Gaia Pigino. Photo courtesy of Human Technopole.Gaia took her first “scientific” steps with Professor Fabio Bernini and Professor Claudio Leonzio at the University of Siena, where she studied bioindicators of soil contamination and detoxification strategies of soil arthropods as part of her PhD project. But it was later, when she joined the laboratory of Professor Pietro Lupetti and met Professor Joel Rosenbaum, a pioneer of cilia research, that Gaia discovered the world of 3D EM and felt her place was “inside a single cell.” She solidified her interest in the structure of protein complexes of cilia and flagella and boosted her passion for cryo-electron tomography (ET) in the laboratory of Professor Takashi Ishikawa, first at the ETH Zurich and then at the Paul Scherrer Institut in Switzerland. In 2012, Gaia started her own laboratory at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, with the vision of creating a truly interdisciplinary laboratory. Her team combines techniques from different fields such as biophysics, cell biology, and structural biology to answer open questions in the cilia field. Gaia recently moved countries again—this time to take over the position of Associate Head of the Structural Biology Research Centre, at the Human Technopole, Milan, Italy.We reached out to Gaia to learn more about her scientific journey and future research directions.What interested you about cilia?The first thing that attracted me toward cilia and flagella were some EM micrographs, by Professor Romano Dallai in Siena, that showed the beautiful geometrical microtubular structures of sperm flagella. I was intrigued by the apparent perfection of these organelles that clearly showed me that a cell is a coordinated system of complex molecular machines, the mechanism of many of which we do not understand. Soon after, Professor Joel Rosenbaum introduced me to the bidirectional transport of components inside cilia, which, he explained to me, is required for both assembly and function of virtually all cilia and flagella, from the motile cilia in our lungs to the primary cilium in our kidneys. He called it intraflagellar transport (IFT) and compared it to a Paternoster elevator, where the individual cabins were what we now call IFT trains. I was completely fascinated by the IFT system, the structure, the function, the dynamics, and the mechanism of which were still largely unknown. Quickly, I realized that in addition to IFT, cilia represent a virtually infinite source of open biological questions waiting to be solved, from the mechanics and regulation of the beating to the sensory function of primary cilia, and their importance for human health.What are some of the scientific questions currently of interest in your laboratory?In the past few years, we have made substantial contributions to the current understanding of the structure and the mechanism of the IFT (1, 2, 3). Currently, we are investigating how the structure of IFT trains relates to their functions by looking, in cryo-electron tomography, at how anterograde trains transform into retrograde trains and at how different ciliary cargoes are loaded on the trains. Beside this more classical line of research, we are exploring other approaches to study IFT, for instance we have developed a method to reactivate IFT trains in vitro on reconstituted microtubules. We want to use this approach to investigate the behavior of IFT trains, and their motors, in experimentally controllable conditions, e.g., in the presence of only certain tubulin posttranslational modifications. We have also made interesting discoveries about the distribution of tubulin posttranslational modifications on the microtubule doublets of the axoneme and how this spatially defined tubulin code affects the function of different ciliary components. We hope we will be able to share these new “stories” with the structural and cell biology community very soon!What kind of approach do you bring to your work?I believe that the main reason for why science became an integral, and dominant, part of my life is because it provides infinite riddles and continuous challenges. I have always been curious about how things work in nature, but I quickly realized that learning from books didn’t satisfy me. My desire was to be at the frontline, to be among the ones that see things happening in front of their eyes, at the microscope, for the first time. I wanted to be among the ones that make the discoveries that students read about in textbooks. Thus, what I bring to my work is an endless desire of solving biological riddles, curiosity, creativity, determination, and energy, with which I hope to inspire the members of my team. My laboratory uses an interdisciplinary approach; we use whatever method, technique or technology is needed to reach our goal, from the most basic tool to the most sophisticated cryo-electron microscope. And if the method we need does not yet exist, we try to invent it.A young Gaia Pigino (3 yr old) the day she discovered how eggs are made. Photo courtesy of Giancarlo Pigino.Could you tell us a bit about the Structural Biology Research Centre at the Human Technopole (HT)?At the HT Structural Biology Centre, we are working to create a vibrant and interdisciplinary scientific environment that will attract molecular, structural, cell, and computational biologists from all over the world. We are creating fantastic facilities, including one of the most well equipped and advanced electron microscopy facilities in Europe—and likely the world—headed by Paolo Swuec. My team, together with the teams of my colleague Alessandro Vannini and the research group leaders Ana Casañal, Francesca Coscia, and Philipp Erdmann, already cover a vast range of competences and know-how from classical molecular and structural biology approaches, such as crystallography and protein biophysics, to cryo-CLEM, cryo-FIB SEM and cryo-ET, all of which allow us to address questions in cell biology. Our goal is to create a scientific infrastructure and culture that will enable biologists to obtain a continuum of structural and functional information across scales.What did you learn during your PhD and postdoc that helped prepare you for being a group leader? What were you unprepared for?I learned that everyday research is mostly made of failures, but that with the right amount of obsession, persistence, curiosity, and creativity, it is always possible to succeed and discover new things. Being given the freedom to develop your own ideas and your own project very early in your career is a treat; science is not only about having good ideas! One needs to follow up on these ideas with intense work and troubleshooting to make them reality. In addition, I realized that being fearless and attempting what is considered too difficult by others, despite challenges, can turn into a worthy learning experience. Also, how you present your work to the scientific community matters for swinging the odds of success in your favor. Different places might work in very different ways, and conducting good science does not only depend on you, but also on the possibilities given to you by your environment.What was I unprepared for?—I guess several things, but one comes immediately to mind: I underestimated how much being responsible not only for my own life and career, but also the career of students, postdocs, and others in the laboratory, would affect me personally.Structure of the 96-nm axonemal repeat reconstructed by cryo-ET and subtomogram averaging. Image courtesy of Gonzalo Alvarez Viar, Pigino Lab.What has been the biggest accomplishment in your career so far?This is a tricky question for me... I tend to look into the future more than celebrating the past. I fight to succeed in something, but as soon as I conquer it, I find it less of an achievement than the thing I could conquer next. Nevertheless, I am happy about the discoveries and the papers published together with my students and postdocs (1, 2, 3, 4, 5). I am extremely excited about the fact that after many years of work I am now leading an interdisciplinary laboratory, where we combine techniques from different fields. I am also happy that three times my husband and I were able to move from one world class academic institution to the another to start exciting and fitting jobs and could still live together in the same place. We worked hard for this, but we also got lucky.What has been the biggest challenge in your career so far?I studied French in school; I had almost no exposure to spoken English until the end of my PhD. To avoid having to show my English insufficiencies, I did hide beside the board of my poster at the first international conference I attended in 2004! It took me a while to overcome this barrier and feel confident to express my thoughts and ideas in English.What do you think you would be if you were not a scientist?I had been a good fencer during my youth. I was a member of the Italian National Team between ages 14 and 19 and saw quite a bit of the world, which was cool! When my sporting career failed, due to diabetes, I was torn between art and science. I guess that in a parallel universe, I am a wildlife photographer and a potter specialized in wood kiln firing. [Gaia confesses that she misses “the amazing and addictive adrenaline rush of a good fencing match!”]Any tips for a successful research career?Do not compare your performances to the ones of the people at your career stage; compare yourself with people that are already successful one level higher than you currently are at. For example, if you are a PhD student, ask yourself what in your current performance separates you from being a good postdoc—once a postdoc, what is missing to be a good PI.     

Which Single Intervention Would Do the Most to Improve the Health of Those Living on Less Than $1 Per Day?

Background to the debate: PLoS Medicine is participating in the Council of Science Editors'' global theme issue on poverty and human development on October 22, 2007 (http://www.councilscienceeditors.org/globalthemeissue.cfm). Over 200 scientific and medical journals are taking part. For our theme issue, we asked a wide variety of commentators worldwide—including clinicians, medical researchers, health reporters, policy makers, health activists, and development experts—to name the single intervention that they think would improve the health of those living in poverty. We also asked four individuals living in poor, rural agricultural communities in the Santillana district, province of Huanta, Ayacucho, Peru to give us their response to the question, “What do you think would do the most to improve your health and the health of your family?” (The four community members were Severino Rojas Poma, Mercedes Vargas Soto, Julián De La Cruz Chahua, and Martín Rojas Poma). Our October 2007 Editorial discusses this debate further.     

Biosafety in DIY‐bio laboratories: from hype to policy: Discussions about regulating DIY biology tend to ignore the extent of self‐regulation and oversight of DIY laboratories

Policymakers should treat DIY‐biology laboratories as legitimate parts of the scientific enterprise and pay attention to the role of community norms. Subject Categories: Synthetic Biology & Biotechnology, S&S: Economics & Business, S&S: Ethics

DIY biology – very broadly construed as the practice of biological experiments outside of traditional research environments such as universities, research institutes or companies – has, during the past decade, gained much prominence. This increased attention has raised a number of questions about biosafety and biosecurity, both in the media and by policy makers who are concerned about safety and security lapses in “garage biology”. There are a number of challenges here though when it comes to policies to regulate DIY biology. For a start, the term itself escapes easy definition: synonyms or related terms abound, including garage biotechnology, bio‐hacking, self‐modification/grinding, citizen science, bio‐tinkering, bio‐punk, even transhumanism. Some accounts even use ‘DIY‐bio’ interchangeably with synthetic biology, even though these terms refer to different emerging trends in biology. Some of these terms are more charged than others but each carries its own connotations with regard to practice, norms and legality. As such, conversations about the risk, safety and regulation of DIY‐bio can be fraught.

Synonyms or related terms abound, including garage biotechnology, bio‐hacking, self‐modification/grinding, citizen science, bio‐tinkering, bio‐punk, even transhumanism.

Given the increasing policy discussions about DIY‐bio, it is crucial to consider prevailing practice thoughtfully, and accurately. Key questions that researchers, policy makers and the public need to contemplate include the following: “How do different DIY‐bio spaces exist within regulatory frameworks, and enact cultures of (bio)safety?”, “How are these influenced by norms and governance structures?”, “If something is unregulated, must it follow that it is unsafe?” and “What about the reverse: does regulatory oversight necessarily lead to safer practice?”.The DIY‐bio movement emerged from the convergence of two trends in science and technology. The first one is synthetic biology, which can broadly be defined as a conception of genetic engineering as systematic, modular and programmable. While engineering living organisms is obviously a complex endeavour, synthetic biology has sought to re‐frame it by treating genetic components as inherently modular pieces to be assembled, through rational design processes, into complex but predictable systems. This has prompted many “LEGO” metaphors and a widespread sense of democratisation, making genetic engineering accessible not only to trained geneticists, but also to anyone with an “engineering mindset”.The second, much older, trend stems from hacker‐ and makerspaces, which are – usually not‐for‐profit – community organisations that enable groups of enthusiasts to share expensive or technically complex infrastructure, such as 3D printers or woodworking tools, for their projects. These provide a model of community‐led initiatives based on the sharing of infrastructure, equipment and knowledge. Underpinning these two trends is an economic aspect. Many of the tools of synthetic biology – notably DNA sequencing and synthesis – have seen a dramatic drop in cost, and much of the necessary physical apparatus is available for purchase, often second‐hand, through auction sites.DIY‐bio labs are often set‐up under widely varying management schemes. While some present themselves as community outreach labs focusing on amateur users, others cater specifically to semi‐ or professional members with advanced degrees in the biosciences. Other such spaces act as incubators for biotech startups with an explicitly entrepreneurial culture. Membership agreements, IP arrangements, fees, access and the types of project that are encouraged in each of these spaces can have a profound effect on the science being done.     

RNA silencing and antiviral defense in plants

Much progress has been made recently in identifying the molecular components of RNA silencing in plants, and in understanding their roles in the biogenesis of small interfering RNAs and microRNAs, in RNA-directed DNA methylation, and in RNA-mediated antiviral defense. However, many crucial questions remain unanswered. What are the molecular bases of sense and antisense transgene-mediated silencing? Why does silencing only appear to spread through transgenes? Plant viruses encode silencing suppressors to counteract host RNA silencing, and some of these suppressors affect microRNA accumulation and function and hence normal plant development. Is viral pathogenicity determined, partly or entirely, by their silencing suppressor activity?     

Physiology and biophysics of chloride and cation cotransport across cell membranes

Many important questions remain to be answered about the mechanism that mediates coupled Na,K,Cl cotransport. We still do not know what the ATP requirement involves. Is ATP the direct energy source? Such an energy source does not seem to be necessary, inasmuch as the net free energy in the combined transmembrane chemical gradients of Na, K, and Cl is quite sufficient to maintain the observed high Cl(i). Could a protein kinase-mediated mechanism be responsible for the ATP requirement? How does reducing Cl(i) stimulate the transporter? What are the kinetic relationships for the co-ions at the outward- and inward-facing transport sites? Are they symmetrical? Can the squid axon regulate its cell volume? If so, is the Na,K,Cl transporter directly involved? Thus, the squid axon remains a fruitful preparation to study a transport mechanism similar to that found in a variety of cells. Its large size confers unique experimental advantages that should help us in our quest to understand this widely distributed transport mechanism.     

In conversation with the Chief Editor

An interview with Facundo D Batista, The EMBO Journal new Editor‐in‐Chief.

An interview with Facundo D. Batista, The EMBO Journal new Chief Editor. Facundo D. Batista has shaped our understanding of the molecular and cellular biology of B‐cell activation. In 2016, he relocated his lab to Massachusetts General Hospital/M.I.T./Harvard’s Ragon Institute to explore the translational potential of two decades of basic research in B‐cell biology. The interview was conducted by Thiago Carvalho. Thiago Carvalho (TC): What inspired you to pursue a career in science? Facundo D Batista (FDB): I was very inspired by my undergraduate course on molecular biology at the University of Buenos Aires. The course was given for the first time, and we were taught the basic techniques of handling DNA, producing insulin, and so forth. Two professors in the course, Daniel Goldstein and Alberto Kornblihtt, really primed us to open our horizons and encouraged training in centers of excellence abroad. I did not speak any English at all, and applying to graduate school in the United States and doing the GRE was impossible for me. I would not have passed. Then, an opportunity to go to Italy and get experience in institutes that could provide me with better training came up. If I recall correctly, we were the first generation of Argentinian biology graduates—myself, Pablo Pomposiello, and many others—that left Argentina looking for a PhD. In general, people would try for a postdoc.I applied to a PhD program in Italy. I went with an open ticket for a year. If I had not passed the ICGEB/SISSA (Trieste) examination, I had three thousand dollars to travel around, and then I would go back to Argentina. I had never been in Europe before. So, for me it was an experience. What happened was that I was very lucky to be admitted in probably the first generation of this new institution, the International Centre for Genetic Engineering and Biotechnology in Italy. In three years, I finished my PhD, and then, to be honest, as an Argentinian in Europe, I did not have many postdoctoral funding opportunities either. TC: How did you move from Trieste to Cambridge’s Laboratory of Molecular Biology? FDB: I found Michael Neuberger’s laboratory to be very appealing, and I wrote to Michael. He replied to me, in a letter that I still keep, that—if I was able to obtain a fellowship—he would take me in his laboratory. A wonderful thing about EMBO was that it would recognize the country where you did your PhD when considering postdoctoral fellowship applications, giving me access to this important funding support. ¹ It was the very early days of diversity—the notion that people could be eligible for support based not only on their nationality, but also on their “scientific nationality”. It gave me a unique opportunity. TC: It was also an opportunity to meet another source of inspiration for you, César Milstein FDB: César was not well at the time, he had heart problems. But I met him, and I felt very close because Michael was working with César, and he worked next door. For me, walking in those corridors with César Milstein and several other Nobel Prize winners—you know, Aaron Klug and Max Perutz—it was a dream. I could not believe that you could have lunch with these wonderful people, and they would come and talk to you, not as Dr. Klug or Dr. Milstein, but they would be César, Aaron, and Max. That for me was totally mind‐changing, together with my relationship with Michael, whom I love. They completely changed my perspective on science. TC: What do you remember most about Michael Neuberger as a mentor? FDB: What was incredible about Michael was his clarity. You would present any biological problem to him, and he would crystallize in one sentence what the real question behind it was. He was amazing. Michael would enter into a state of thinking where he would stop looking at you and would start looking up at a wall and would start to concentrate for those 10, 20 minutes that you’d explain the problem. Then, he would come up with critical questions and he would be critical to the bones. I think that that is something that science has lost these days. I think that this notion of going deep into critically asking the right scientific questions has been lost as a tradition. It is something that I try to transmit to my postdocs and PhD students: Scientific criticism is not about personal or emotional evaluation. It is really about trying to nail down what the question is and how a project develops. I think that is what I remember most of Michael, his commitment to the people that worked with him and who surrounded him and that deep thinking and constant challenging about what is the next step. TC: In 2002, you started your laboratory at the London Research Institute FDB: I was at one stage considering staying at the LMB with my independent lab, and César and Michael were very supportive of that. But then came the opportunity to join the LRI—which at the time was still the ICRF. I was the last employee recruited (to the ICRF), and it was wonderful. The notion of changing environments again, changing colleagues. The LMB was not an immunology institute. It was a general research institute and the ICRF at that time was similar, with very little immunology. I have always valued the whole spectrum of biology from mathematical modeling to quantitative biology to biochemistry to technological inputs, to development, and so forth. TC: Your LRI laboratory revealed entirely new aspects of the molecular and cellular biology of B lymphocytes—one was the existence of organized membrane structures reminiscent of the immunological synapse first described in T cells that were crucial for activation. What are the implications of the immunological synapse for B‐cell function? FDB: It was a concept that was resisted by the B‐cell field. The notion at the time was that B cells would get activated by soluble antigens. But if you think about it, that does not make any sense. You will never reach a physiological concentration of a ligand that will allow you to engage a receptor in vivo at a low affinity. So in order to reach that concentration, you need to aggregate antigen on the surface of other cells first. And that makes the whole process much more efficient. It not only localizes the process into lymph nodes or spleens, but it also allows focusing the response into what the arrangement of a membrane is. I was not the first—the notion that antigens are on follicular dendritic cells was well‐established by early experiments. But I think our work transformed the field. A lot of laboratories have incorporated the notion that stimulating cells at the level of membranes changes the way that receptors perceive signals. This does not apply only to the B‐cell receptor, it applies to chemokines too, many of them are also coating the surface of other cells and that helps guide the signals that cells receive.I think that it is an important concept that is likely to be applicable to vaccines. There are several papers now showing that helping to aggregate antigens on the surface of macrophages or dendritic cells makes antigens more potent by driving them more efficiently into where they are used in follicles and lymph nodes. TC: What prompted your pivot to translational research? FDB: I had learned a lot about basic principles of B‐cell biology and antibody responses, but on model antigens. I felt at the time that translating that into humans and trying to understand how vaccines could be improved was an important step. I always like to recognize mentors or people who influenced me and one person who really influenced me in this thinking was Dennis Burton at Scripps. He was very early to incorporate into his HIV vaccine and antibody research people like me or Michelle Nussenzweig that were coming from basic B‐cell immunology to try to help to think about how vaccines can be improved. I decided to take a risk. I left a tenured, core‐funded position at the best institution in Europe to lead the Ragon Institute with Bruce Walker—I am the Associate Director and he is the Director—and brought my years of expertise at the ICGEB, LMB, LRI, and CRICK to a unique environment that is based on translational research. There is the incredible ecosystem of Harvard, MIT, and MGH, and the notion is to incorporate technologies and to incorporate immunology to tackle incredible challenges, like COVID‐19 is today. TC: Are there any major initiatives that you plan to focus on at The EMBO Journal? FDB: One of the things that I would really like to do is to involve the younger generations in the journal. I think that we have an opportunity for direct “translation”. I mean, EMBO has EMBO postdoctoral fellowships and EMBO young investigators, involving early career European scientists, but also scientists across the globe. We are discussing initiatives like, for example, inviting postdocs from different laboratories to present at the editorial meetings. The EMBO Journal has an open‐door policy in terms of people wanting to participate in the editorial meetings.I think that we have amazing scientists around the world that can really bring new views as to where the journal should be going. I feel strongly about that and about keeping a real sense of diversity in the journal, in terms of fields, in terms of gender, in terms of race, in getting people involved from Brazil, getting people involved from China, getting people involved from Japan, from across the globe. EMBO is no longer a European journal. EMBO is a journal whose office faces Europe, but it has a global outlook. TC: Early in their career, many researchers do not feel comfortable engaging with editors FDB: I sent one of my first papers as an independent P.I. to EMBO. That paper was editorially rejected. I replied to that rejection, saying that EMBO should stop publishing just biochemistry, and that they needed to appreciate the importance of quantitative cell biology. The paper was ultimately sent to review and accepted. What was also very positive was that a later review of the scope of The EMBO Journal came to a similar conclusion. That resulted in my appointment to the editorial advisory board of The EMBO Journal (I was not an EMBO member at the time). The positive message is that the journal very much welcomed receiving feedback. That was what made me like the journal. I felt that the journal was ready to listen, to change.This is not my journal. It is the community’s journal. I am just playing a role, putting in some time and effort. There are a lot of things that I do not see and other young people could see, and I am looking for inspiration there, to listen and translate those things into good policies for the journal. I think that this is important and I think that this is at the basis of what I want to be as a chief editor.     

History of the clinical use of umbilical cord blood hematopoietic cells

The first cord blood (CB) transplant was performed in 1988 in a patient with Fanconi anemia. The donor was his HLA-identical sister who was known by pre-natal diagnosis to be HLA identical and not affected by the Fanconi mutation. The CB was collected and cryopreserved at birth. The transplant was successful without GvHD and the patient is currently alive and free of disease more than 15 years after transplant, with full hematologic and immunologic donor reconstitution. At the time of the first transplant, little was known about the biologic properties of CB cells and it was thanks to the pioneering work of H. E. Broxmeyer and E. A. Boyse, who studied the progenitor cell content of CB, and of A. D. Auerbach, who realized the pre-natal diagnosis of Fanconi anemia, that this transplant was possible. Since this first transplant, many questions have been answered but others are still open for further research. For example: would a single CB unit contain enough stem cells to permanently engraft children and adults? Would maternal cell contamination in fetal blood engraft and give severe GvHD? What are the immunologic properties of CB cells? How does it interfere with GvHD, GvL and immune reconstitution? Is the immune immaturity of CB lymphocytes able to overcome the HLA barrier and authorize HLA-mismatched transplants? Is it possible to establish CB banks for unrelated and related transplants? What would be the criteria for collection, quality control and cryopreservation?     

Neural stem cells: From fly to vertebrates

Our goal in this review is to explore the relationship between Drosophila and vertebrate neural stem cell development by comparing progress in each system with the aim of answering several central questions in stem cell biology: (a) How are stem cells formed? (b) Do stem cells divide symmetrically or asymmetrically? (c) How is stem cell fate maintained? (d) How is stem cell differentiation initiated? (e) How are different stem cell fates determined? (f) How “plastic” are different neural stem cell fates? (g) How do neural stem cells produce different progeny? and (h) What regulates stem cell proliferation versus quiescence? Not surprisingly, research in Drosophila and vertebrate systems each have their own biases, strengths, and weaknesses; we hope that by directly comparing progress in each field, new experiments and interpretations in both vertebrate and Drosophila research will become apparent. It has become increasingly clear that vertebrates and Drosophila share many fundamental mechanisms of neurogenesis, validating a comparative approach. © 1998 John Wiley & Sons, Inc. J Neurobiol 36: 111–127, 1998     

“国际生物多样性观察年（IBOY）”核心项目——内容介绍及建议

生物多样性观察年（IBOY）的核心项目包括4个大的主题：1）全球生物多样性现状;2）生物多样性的变化方式;3）生物多样性对人类生活的价值;4）人类如何保护生物多样性。本文对这些主题内的不同课题进行了介绍,同时对我国生物多样性科学的发展提出了相应的建议。     

Outcomes for patients with the same disease treated inside and outside of randomized trials: a systematic review and meta-analysis

Background:

It is unclear whether participation in a randomized controlled trial (RCT), irrespective of assigned treatment, is harmful or beneficial to participants. We compared outcomes for patients with the same diagnoses who did (“insiders”) and did not (“outsiders”) enter RCTs, without regard to the specific therapies received for their respective diagnoses.

Methods:

By searching the MEDLINE (1966–2010), Embase (1980–2010), CENTRAL (1960–2010) and PsycINFO (1880–2010) databases, we identified 147 studies that reported the health outcomes of “insiders” and a group of parallel or consecutive “outsiders” within the same time period. We prepared a narrative review and, as appropriate, meta-analyses of patients’ outcomes.

Results:

We found no clinically or statistically significant differences in outcomes between “insiders” and “outsiders” in the 23 studies in which the experimental intervention was ineffective (standard mean difference in continuous outcomes −0.03, 95% confidence interval [CI] −0.1 to 0.04) or in the 7 studies in which the experimental intervention was effective and was received by both “insiders” and “outsiders” (mean difference 0.04, 95% CI −0.04 to 0.13). However, in 9 studies in which an effective intervention was received only by “insiders,” the “outsiders” experienced significantly worse health outcomes (mean difference −0.36, 95% CI −0.61 to −0.12).

Interpretation:

We found no evidence to support clinically important overall harm or benefit arising from participation in RCTs. This conclusion refutes earlier claims that trial participants are at increased risk of harm.When people are asked to participate in a randomized controlled trial (RCT), it is natural for them to ask several questions in return. How safe are these treatments? How many extra visits and tests must I undergo? Will the researchers keep my family doctor informed about what’s going on? What outcomes are to be measured, and do they include ones that are of interest to me as a patient?These multiple questions can be summarized as follows: Would I fare better being treated within the trial (as an “insider”) or in routine clinical care outside it (as an “outsider”)? Patients may ask this question in 1 of 2 ways. The first is highly specific: “Am I better off receiving this specific treatment as an insider or as an outsider?” Alternatively, they might ask a more general question: “Am I better off having my illness managed, regardless of the specific treatment I would receive, as an insider or as an outsider?” These questions are highly appropriate, and both deserve to be asked and answered,^1,2 especially given that nonsystematic reviews have suggested a possible “inclusion benefit” from participating in trials.³These 2 specific patient questions are analogous to those posed by researchers asking whether treatments do more good than harm when applied under “ideal” circumstances (in explanatory trials) or in the “real world” of routine health care (in pragmatic trials). Vist and colleagues answered the explanatory question when their earlier review⁴ found no advantage or disadvantage from receiving the same treatment inside or outside an RCT. Left unanswered, however, was the broader, more pragmatic question. In our experience, trial participants are often offered new, as-yet-untested treatments that would not be available to them outside the trial. This review looks at the dilemma faced by these patients, which needs to be addressed before general conclusions can be drawn about trial safety.     

Fitting curves to data using nonlinear regression: a practical and nonmathematical review

Many types of data are best analyzed by fitting a curve using nonlinear regression, and computer programs that perform these calculations are readily available. Like every scientific technique, however, a nonlinear regression program can produce misleading results when used inappropriately. This article reviews the use of nonlinear regression in a practical and nonmathematical manner to answer the following questions: Why is nonlinear regression superior to linear regression of transformed data? How does nonlinear regression differ from polynomial regression and cubic spline? How do nonlinear regression programs work? What choices must an investigator make before performing nonlinear regression? What do the final results mean? How can two sets of data or two fits to one set of data be compared? What problems can cause the results to be wrong? This review is designed to demystify nonlinear regression so that both its power and its limitations will be appreciated.