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AIMBN RESEARCH Research Highlights Collection SUPPORTED BY Editorial Board Kenichi Arai Yoshito Kaziro Peng Li John Mattick University of Tokyo, Japan Kyoto University Graduate School of Medicine, Japan Tsinghua University, China Institute for Molecular Bioscience, University of Queensland, Australia Amit Sharma James Shen Chris Tan Jeongbin Yim International Centre for Genetic Engineering and Biotechnology, India Academia Sinica, Taiwan Institute of Molecuar and Cell Biology, Singapore Seoul National University, Korea Advisory Board Shigetaka Asano Department of Chemistry and Biochemistry, Waseda University, Japan Virander Chauhan ICGEB New Delhi, India Pham Thi Tran Chau ProteinEnzyme Laboratory, Vietnam National University, Vietnam Robert Gallo Institute of Human Virology, USA Frank Gannon Queensland Institute of Medical Research, Australia Benjamin Geiger Weizmann Institute of Science, Israel Yoram Groner Weizmann Institute of Science, Israel Yi Guan Department of Microbiology, University of Hong Kong, China Wanjin Hong Institute of Molecular and Cell Biology, Singapore Robert Huber MaxPlanckInstitut fr Biochemie, Germany JohE Ikeda Department of Molecular Life Sciences, Tokai University School of Medicine, Japan Nancy Ip School of Science, Hong Kong University of Science amp Technology, China Yoshiaki Ito Department of Medicine, National University of Singapore, Singapore Kanyawim Kirtikara National Center for Genetic Engineering and Biotechnology, Thailand Kiyoshi Kita School of International Health/Global Health Sciences, University of Tokyo, Japan Kiyoshi Kurokawa National Graduate Institute for Policy Studies, Japan Michael Lai Academia Sinica, Taiwan Kong Peng Lam Institute of Molecular and Cell Biology, Singapore Yong Jun Liu MD Anderson, USA Peter Lobie Liggins Institute, New Zealand Nor Muhammad Mahadi Malaysia Genome Institute, Malaysia Barry Marshall Atsushi Miyajima Yoshikazu Nakamura Yusuke Nakamura Filipinas Natividad Nicos Nicola Rofina Yasmin Othman Gang Pei Sang Ki Rhee Yijun Ruan Jeongsun Seo Jinho Seo Rho Hyun Seong HeeSup Shin Obaid Siddiqi Richard Simpson Jisnuson Svasti Axel Ullrich Andrew Wang Sumiko Watanabe John Wong Zhicheng Xiao Ook Joon Yoo University of Western Australia, Australia Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan Institute of Medical Science, University of Tokyo, Japan Institute of Medical Science, University of Tokyo, Japan St Lukes Medical Center, Philippines Walter and Eliza Hall Institute, Australia University of Malaya, Malaysia Shanghai Institute for Biological Sciences, Institute of Biochemistry and Cell Biology, China College of Medical Sciences, Soon Chun Hyang University, Korea Genome Institute of Singapore, ASTAR, Singapore College of Medicine, Seoul National University, Korea Department of Agricultural Biotechnology, Seoul National University, Korea College of Biological Sciences, Seoul National University, Korea Korea Institute of Science and Technology, Korea National Centre for Biological Sciences, India Ludwig Institute for Cancer Research, Australia Mahidol University, Thailand MaxPlanckInstitut fr Biochemie, Germany Academia Sinica, Taiwan Institute of Medical Science, University of Tokyo, Japan National University Health System, Singapore Innovative Research, GSK, China Korea Advanced Institute of Science and Technology, Korea AIMBN RESEARCH In association with the AsiaPacific International Molecular Biology Network AIMBN www.natureasia.com/AIMBN AIMBN Research is published by Nature Publishing Group NPG, a division of Macmillan Publishers Ltd, in association with the AsiaPacific International Molecular Biology Network AIMBN. The AIMBN Research website is updated every two weeks with concise, highquality research highlights of papers published by AsiaPacificbased researchers in molecular biology in leading international research journals. COPYRIGHT. Nature Japan K.K. NPG Nature AsiaPacific is a trading name of Nature Japan K.K. This publication may be reproduced in its original form for personal use only. Modification or commercial use without prior permission from the copyright holder is prohibited. AIMBN EDITORIAL Asia Pacific International Molecular Biology Network AIMBN Seoul National University BioMAX Institute BK Grad School Research Bldg F Seoul, Korea NPG EDITORIAL NPG Nature AsiaPacific Chiyoda Building, Ichigayatamachi Shinjukuku, Tokyo , Japan T F Editor online Editor print Production Managers EditorinChief Founding Editor Executive Editor Managing Editor Editorial Assistants Jeongbin Yim KenIchi Arai Sumiko Watanabe Kevin Yoon Kiyoung Kim Heejong Kim Production Controller Copy Editor Editorial Assistant PUBLISHING NPG Nature AsiaPacific Linda Worland Matthew Salter Chris Gilloch Sou Nakamura Brett Davis Brett Davis Kazuho Fujine Managing Director Publisher AsiaPacific Sales Director Marketing Manager Web Production Manager Web Production Executive Operations Director David Swinbanks Matthew Salter Kate Yoneyama Masahiro Yamashita Bob Edenbach Naomi Nakahara Hiroshi Minemura ISTO TO/SEB CKPHO ASTIAn KA ulITzKI IS TOCKPHOTO/ HEnrIK JOnSSOn ISTOCKPHOTO/SEBASTIAn KAulITzKI ISTOCKPHOTO/MArTIn MCCA rTHy ISTOC KPHOTO/ HEnrIK JOnSSO n Table of Contents Cell biology A TALL tale Divide and conquer Better feed at lower cost Nutrition makes the cell cycle go round Confining cancer Following new instructions Stem cell shortcuts Stem cells on steroids When the time is right Seeing itoI Cellcycle blockers Fitting the profile Lipids trapped within a SNARE The acid advantage Tracking cellular hunger pangs Reciprocal connections Profiling cell death perpetrators The missing link Pinpointing a missing link Maintaining stem cell identity AIDing our understanding of cancer Identifying a cancerspreading culprit The accomplice to viral entry Route of entry Dissecting cellular crisis management Frontline healer Thank you for not smoking Lung cancer link Extremophiles Cold complexity Mountains that make the people Combining forces to combat cancer Filling the gaps of a genome map Pinpointing inflammatory genomic changes Keeping track of changes Pinpointing genetic susceptibility to Parkinsons disease Asian genomes point the way Different strokes, different genes Casting wide yields aneurysm suspects Plant fungis jump on pathogenicity Sprouting information Transcending ethnic differences Linking more suspects to bowel disease Getting at the roots of cancer risk Diversity in the genome Stopping the cancer spreading Binding and gagging tumors Tying up loose ends Putting injured cells to sleep Compatible partners All mixed up Cellular stress protection Tracking transcriptional traffic Unraveling the roles of multitasking enzymes Working with a silent partner Spotlighting single DNA molecules Making the right connections Bacterial chaperonin a trick of the tail Immunology amp Therapeutics Taking a shot at pandemic flu Last line of defense Curtailing cholera Slow and steady Fighting the flu virus Flu fighter The good without the bad Poisoning the well of cancer Collaborating with the enemy Dialing up diabetes Unmasking bacterial saboteurs Pathways of presentation Unlikely allies against infection Infectionproofing by the gut When antibiotics backfire Fate director Immune response linked to early arrival Building a better booster Single protein seeks mature partner Protective markings neuroscience amp Developmental Biology Muscling in on receptor clusters A model of dementia Benefitting from mixed messages Sniffing out the olfactory code Shaping blood vessel formation Accelerating synapse formation Keeping genes in their place First instructions for male mice A green light for growth Genetics Knockout resource for yeast biologists Looking out for number one Exploring the genetic generation gap Evolution through , generations Structural amp Molecular biology Getting in the blood Making the cut Maintaining the silence Amplifying the silence AIMBN RESEARCH Research Highlight Collection INTRODUCTION AIMBN RESEARCH Welcome to the AIMBN Research Collection e at NPG Nature AsiaPacific in partnership with the AsiaPacific International Molecular Biology Network AIMBN are delighted to present this collection of research highlights published on the AIMBN Research website in . AIMBN Research covers some of the best research in molecular biology and biotechnology from the AsiaPacific region, and the everexpanding showcase of highquality research that can be found on the website is a testament to the growing strength of life science research in this part of the world. The website provides a remarkable overview of the efforts being made by the top scientists in the region and draws attention to many of the key AsiaPacific institutions that are publishing worldclass research in this field. NPG Nature AsiaPacific would like to take this opportunity to thank the organizations that have supported the AIMBN Research project through financial sponsorship of the journal website. The year saw the inclusion of four new sponsors, including the projects new gold sponsor, the Life Science Network Asia LSNA supported by the Japanese government. The research highlights presented in this collection are only a snapshot of what is being published on the website every month. To read the very latest highlights of top research published by AsiaPacific scientists in the best international journals, be sure to visit the AIMBN Research website www.natureasia.com/AIMBN. We encourage you to alert your colleagues to the website and register for email alerts of each new update. With the continued support of our readers and members, AIMBN Research will become a hub that can foster a thriving network of molecular biology research in the AsiaPacific region. W David Swinbanks, PhD Managing Director Asia and Australasia amp Medical and Scientific Communications Nature Publishing Group www.natureasia.com/AIMBN AIMBN RESEARCH INTRODUCTION have great pride in welcoming you to this, the latest collection of research highlights from AIMBN Research, the webbased journal of the AsiaPacific International Molecular Biology Network AIMBN. Since its founding in , the mission of the AIMBN has been to raise the international profile of molecular biology and related disciplines emerging in the AsiaPacific region and to aid its development. The AIMBN is active in a variety of areas, including the provision of training courses and practical workshops as well as advancing its fellowship program throughout Asia by sponsoring annual conferences. Modern molecular, cell and computational biology along with bioinformatics and other related disciplines have spawned an incredible wealth of new biotechnologies that offer great promise for the development of the agriculture and health sectors, all of which are of particular interest to many AsiaPacific countries. These activities can be made even more effective by the development of a forum for crossfertilization of ideas and assistance in publishing highquality research in highimpact journals. The AIMBN has an important role to play in assisting in this process and the AIMBN Research website is a valuable tool for promoting the very best of published research in molecular biology from the AsiaPacific region in a timely and accessible manner. To date, close to original research papers originally published in top international journals such as Nature, Cell, Science and PNAS have been highlighted on the website. AIMBN Research is only made possible by the financial support of sponsors from around the AsiaPacific region, all of whom are acknowledged on the website and in the pages of this magazine. In , we welcomed four new supporting organizations including a new gold sponsor the Life Science Network Asia LSNA. These join the existing sponsors who find AIMBN Research an effective means of introducing their research activities to the global scientific community. With the support of our sponsors and the commitment of our members, I see a great future for AIMBN Research and commend it to the readership. I Jeongbin Yim, PhD Professor, Seoul National University President, AIMBN RESEARCH HIGHLIGHT COLLECTION Gold sponsor Sponsor Information Life Science Network Asia Institute of Medical Science, The University of Tokyo Shirokanedai Minatokuku, Tokyo , Japan Silver sponsors AsiaPacific International Molecular Biology Network AIMBN BioMax Institute Seoul National University Seoul , Korea www.aimbn.org Academia Sinica Academia Road Section , Nankang Taipei , Taiwan www.sinica.edu.tw/maine.shtml Electronic International Molecular Biology Laboratory eIMBL eIMBL Secretariat BioMAX Institute Seoul National University Seoul , Korea www.eimbl.org BioMax Institute International Vaccine Institute IVI Seoul National University Research Park San , Bongcheon dong Gwanakgu, Seoul , Korea www.biomax.org National Taiwan University School of Medicine NTU No. , Section , Renai Rd Taipei , Taiwan www.med.ntu.edu.tw Universiti Sains Malaysia USM Persiaran Seksyen / Bandar Putra Bertam Kepala Batas Pulau Pinang, Malaysia www.amdi.usm.edu.my Korea National Institute of Health KNIH , TongilLo EunpyungGu Seoul , Korea www.cdc.go.kr/eng/english/knih.htm Korea Research Institute of Bioscience and Biotechnology KRIBB Gwahangno, Yuseonggu Daejeon , Korea www.kribb.re.kr/eng Institute of Biochemistry and Cell Biology SIBCB Chinese Academy of Sciences Yue Yang Road Shanghai , China www.sibcb.ac.cn/eindex Bronze sponsor National Center for Genetic Engineering and Biotechnology BIOTEC Thailand Science Park Phahonyothin Road Klong , Klong Luang Pathumthani , Thailand www.biotec.or.th/biotechnologyen ISTOCKPHOTO/SeBASTIAN KAulITzKI Cell Biology CELL BIOLOGY AIMBN RESEARCH Published in Science A TAll tale Cell fate mapping and genetic analysis reveals how a T cell cancercausing gene gives rise to leukemia ISTOCKPHOTO/eRAXION T cell acute lymphoblastic leukemia TALL is marked by hyperproliferation of T cells in the blood system and if left untreated results in rapid death. The hyperproliferating T cells, which Published in Proceedings of the National Academy of Sciences USA Divide and conquer Insights provided by a gene expression signature signal the effects of a gene mutation on breast cancer prognosis Understanding how breast cancers differ from each other at the molecular level can allow for targeted therapy against these molecules and lead to greater success at fighting the cancer. Now, an international team of researchers has identified a gene expression profile in breast cancer samples from human patients that can flag whether the tumors contain a mutation in the cell signaling gene PIKCA. In cancer patients whose tumor expressed the estrogen receptor protein, the gene signature also could identify patients who were likely to have a better outcome. This association of the mutant PIKCA gene expression profile with good outcome was surprising, according to lead author Sherene Loi from the Peter MacCallum Cancer Centre, Australia, because these mutations Loi, S. et al. PIKCA mutations associated with gene signature of low mTORC signaling and better outcomes in estrogen receptorpositive breast cancer. Proceedings of the National Academy of Sciences USA , . are thought to induce tumor formation. However, the researchers found that the mutant gene signature actually demonstrated very low activation of downstream signaling. This means that drugs that are being developed to block this signaling cascade are unlikely to work in patients with the mutant PIKCA gene expression profile. While the mechanisms that mediate the effects of the mutations on tumor outcome remain to be determined, parsing out the differences in signaling between breast cancer subtypes could pave the way for therapy tailored for each individual breast cancer patient in the future. overrun normal T cells, arise from a single leukemiainitiating cell LIC that commonly harbors an activating mutation in a cancercausing gene called an oncogene. Now, Matthew McCormack from Royal Melbourne Hospital, Australia, and colleagues from the Walter and Eliza Hall Institute of Medical Research and other institutions in Australia and the UK have provided mechanistic insights on how the activation of the oncogene Lmo an important transcription factor in blood cell development leads to TALL. After genetically labeling cells in a mouse model of TALL, the researchers found that the LIC appeared in the thymus, the source of T cells, months before the onset of disease. This indicates that Lmo activation alone does not cause leukemia per se. Rather, they found that Lmo inhibits T cell maturation while also initiating a genetic program that induces a stem celllike behavior. Hence, the LIC undergoes continuous selfrenewal, which allows secondary mutations to accumulate that in turn cause TALL. These new insights may lead to therapeutics that target the LIC rather than just the hyperproliferating leukemia cells, thus preventing the relapse that often occurs in the clinic. McCormack, M. P. et al. The Lmo oncogene initiates leukemia in mice by inducing thymocyte selfrenewal. Science , . www.natureasia.com/AIMBN AIMBN RESEARCH CELL BIOLOGY Published in FEMS Microbiology Letters Better feed at lower cost A yeast supplement that exploits a cellsurface enzyme could provide a more costeffective method for producing animal feed Genetically engineered yeast cells that release nutrients from plantbased foods could be used to produce cheap and highly nutritious animal feed, researchers at the National Center for Genetic Engineering and Biotechnology have shown. Inorganic phosphorous in plantbased feedstuff is stored largely in the form of phytic acid. Most animals cannot absorb this, so feed is normally treated with phytase, an enzyme that releases the phosphorous. However, using phytase is costly and timeconsuming, as it involves collecting and concentrating the enzyme from the microorganisms that produce it. Piyanun Harnpicharnchai and her colleagues engineered Pichia pastoris yeast cells that express phytase and display it on their surface. The researchers found that their cellsurface enzyme was stable at high temperatures and under acidic and alkaline conditions. It also released phosphorous from feedstuff as efficiently as commercially available phytase. When added to feed, the modified yeast provided biotin, niacin and proteins, increasing its nutritional value. The researchers are currently developing yeast cells that codisplay phytase with other enzymes that are often added to animal feed. Yeast engineered in this way could be used as an animal feed supplement. As well as being cheaper to produce, feed containing such a supplement would require fewer ingredients but would also be more nutritious, Harnpicharnchai notes. RESEARCH HIGHLIGHT COLLECTION Harnpicharnchai, P., Sornlake, W., Tang, K., Eurwilaichitr, L. amp Tanapongpipat, S. Cellsurface phytase on Pichia pastoris cell wall offers great potential as a feed supplement. FEMS Microbiology Letters , . Published in Proceedings of the National Academy of Sciences USA nutrition makes the cell cycle go round A landscape model shows how cells remain stable under changing chemical conditions Jin Wang and colleagues from the Chinese Academy of Sciences and the State University of New York have developed an energybased, threedimensional landscape model of the cycle of growth, development and reproduction in budding yeast cells. Their work helps explain how networks of chemical reactions give rise to such a stable, functioning system. The model revealed that the progress of yeast around the cell cycle is driven by increasing mass and energy through nutrition. The researchers found that changing the rates and numbers of chemical interactions does not necessarily weaken the stability of the cycle. The cell cycle is generally thought to have four phases G or first gap where the cell grows, S or Wang, J., Li, C. amp Wang, E. Potential and flux landscapes quantify the stability and robustness of budding yeast cell cycle network. Proceedings of the National Academy of Sciences USA , . synthesis when it duplicates its chromosomes, G, another growth phase to prepare for division, and M or mitosis when it divides. The landscape picture, predicted from the modeling results, develops as the mass of an individual cell increases. The cell moves from one phase of the cell cycle to the next like a ball rolling between holes or depressions of lower energy separated by barriers of higher energy. Its energy pathway, as it proceeds around the cell cycle, eventually traces a ring. The same methods can be applied to other complicated networks, the researchers say. ISTOCKPHOTO/KNORRe CELL BIOLOGY AIMBN RESEARCH Published in Proceedings of the National Academy of Sciences USA Confining cancer Treatments that stop lung cancer cells from invading other tissues could stem from the recent identification of a critical signaling pathway ISTOCKPHOTO/WIllSIe Researchers from the Chinese Academy of Sciences, along with colleagues from other institutes in China and the US, have deciphered Published in The Journal of Clinical Investigation Following new instructions Overexpression of a cellular protein helps clear the way for lung cancer by switching off genes that restrain cell growth Enzymes such as DNA methyltransferase I DNMT routinely downregulate expression of genes by masking specific stretches of DNA with chemical modifications, but some cancers exploit this activity to block production of factors that suppress tumor growth. A new study from a team led by LiJung Juan at Taiwans Academia Sinica has revealed a cofactor that facilitates this process in lung cancer. Although previous data linking the hNaap protein to tumorigenesis have been somewhat ambiguous, Juan and coworkers demonstrate that hNaap helps to recruit DNMT to specific sites in the genome and facilitates the silencing of cancerrelated genes. Ecadherin, a known tumor suppressor, is among the targets inactivated by hNaap and DNMT, and the researchers Lee, C.F. et al. hNaap contributes to tumorigenesis by facilitating DNMTmediated tumor suppressor gene silencing. The Journal of Clinical Investigation , . found that the interaction of these two factors significantly promoted transformation and cell proliferation in cultured lung cancer cells. Clinical data showing elevated hNaap expression in more than half of all lung cancer specimens examined further supported these findings. This overexpression was generally associated with downregulation of Ecadherin and other tumor suppressor genes, as well as poor overall patient prognosis. However, the researchers also note that some previous studies have found that hNaap may inhibit growth in breast cancers, and conclude that this proteins function may vary considerably depending on the tumor context. Gao, Y. et al. LKB inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling. Proceedings of the National Academy of Sciences USA , . the molecular mechanism by which a tumor suppressor gene called LKB inhibits lung cancer progression. Mutations in the LKB gene are observed in up to of human lung adenocarcinomas and contribute significantly to cancer progression, but little was known about the underlying mechanisms. Hongbin Ji, in collaboration with Gaoxiang Ge and colleagues, found that the enzyme called lysyl oxidase LOX is inhibited by the LKB protein through the signaling pathway known as mTORHIF, which mediates metastasis of lung tumors lacking the LKB gene. They also found that the elevated LOX expression in LKBdeficient lung tumors ultimately resulted in excessive deposition of collagen, which in turn activated signaling by integrin and promoted cancer cell invasion. Then, in mice with Lkbdeficient lung tumors, they showed that treatment with a pharmacological inhibitor of LOX dramatically alleviated malignancy progression. The researchers work links the microenvironment of cells to enhanced lung cancer progression and metastasis induced by the loss of LKB. They also identified LOX as a potential therapeutic target for metastatic cancer treatment, and observed that LOX may serve as an important biomarker for lung cancer prognosis. www.natureasia.com/AIMBN AIMBN RESEARCH CELL BIOLOGY Published in Nature Stem cell shortcuts Refinement of a powerful cellular reprogramming technique could represent important progress in the development of viable alternatives to embryonic stem cells PlOS BIOlOgy VOl. //, e Embryonic stem cells ESCs retain the capacity to develop into any cell type from the body, a property known as pluripotency but their tantalizing clinical potential is countered by the strict regulatory environment surrounding work in this area. Adult cells that have been reprogrammed into a pluripotent state by the activation of selected genes could offer a practical alternative, but these induced pluripotent stem cells iPSCs can vary widely in their resemblance to true ESCs. In an effort to identify factors that could boost reprogramming, Genome Institute of Singapore researcher Bing Lim and colleagues looked for genes whose activity is modulated by known pluripotency regulators Nanog and Tcf, identifying transcription factor Tbx as a promising candidate. Lim and colleagues observed faster and more efficient iPSC formation when the Tbx gene was introduced into mouse fibroblasts alongside a combination of three other reprogramming genes. Importantly, these cells expressed other key pluripotency genes at levels equivalent to ESCs, and proved significantly more effective than standard cell preparations for the experimental generation of purely iPSCderived animals. The authors note that cellular reprogramming is hypothesized to occur via multiple developmental routes, yielding cells with varying degrees of pluripotency, and conclude that Tbx expression may help steer iPSC production down a more efficient path. RESEARCH HIGHLIGHT COLLECTION Han, J. et al. Tbx improves the germline competency of induced pluripotent stem cells. Nature , . Published in Nature Stem cells on steroids estrogen and progesterone increase mammary stem cell number and enhance their potential for outgrowth in breast tissue The risk for breast cancer increases after prolonged exposure to the ovarian steroid hormones estrogen and progesterone, such as during pregnancy. Now, researchers in Australia and Japan have a plausible explanation exposure to these hormones enhances the growth capacity of mammary stem cells MaSCs potential seeds of breast cancer. When the researchers transplanted MaSCs from mice lacking ovaries into breast tissue of normal mice, they found that the cells could not populate the tissue as well as MaSCs from mice with ovaries. The data indicated that MaSCs from the mice lacking ovaries had trouble completing the cell cycle normally. After administering estrogen and progesterone to mice, the researchers noted that MaSC number increased. MaSCs also increased during pregnancy, when estrogen and progesterone levels are high. Drugs that blocked these hormones reduced MaSC counts, and mice lacking the genes involved in the synthesis of these hormones also had fewer MaSCs than normal mice. MaSCs do not express the receptors for these hormones, so the researchers realized that mature cells in the breast responded to the hormones, and these mature cells then secreted a protein called RANKL onto the MaSCs, which in turn affected their growth potential. These findings could explain why ovary removal or antiestrogens reduce breast cancer risk, the team suggests. AsselinLabat, M.L. et al. Control of mammary stem cell function by steroid hormone signalling. Nature , . CELL BIOLOGY AIMBN RESEARCH Published in Proceedings of the National Academy of Sciences USA When the time is right One protein acts as a gatekeeper that regulates the activation of key genes involved in blood cell maturation ISTOCKPHOTO/AlXPIN The development of red blood cells, also known as erythrocytes, depends on the properly timed activation of a subset of genes involved in Published in Blood Seeing itoI Different classes of blood cells use a common mechanism to undergo changes associated with maturation Blood cells display diverse antigen molecules on their surface, including chains of Nacetyllactosamine carbohydrates. These can manifest in a linear i form or branched I form the i variant is most prevalent during early development in human red blood cells, but by the age of months these cells predominantly display the I antigen. Previous research from LungChih Yu of the National Taiwan University has highlighted a key role for the transcriptional regulator C/EBP in regulating genes that facilitate this itoI transition in red blood cells. However, C/EBP also contributes to development of white blood cells known as granulocytes, and Yu and coworkers have now determined that these cells employ a similar mechanism for I antigen production. Twu, Y.C. et al. Phosphorylation status of transcription factor C/EBP determines cell surface polyLacNAc branching I antigen formation in erythropoiesis and granulopoiesis. Blood , . C/EBP activity is modulated by the addition of phosphate molecules to specific amino acids, and the researchers identified a single phosphorylation site at serine that appears to act as a direct switch for triggering I antigen expression. Working with cells that can differentiate into either red blood cells or granulocytes, they demonstrated that I production is directly correlated with removal of phosphorylation from this C/EBP residue in blood cells from both lineages, suggesting that this may represent a common pathway for driving this antigenic transition in diverse cell types. differentiation. In undifferentiated erythroid precursors, many of these genes are maintained in an inactive state by the inhibitory Bach/Maf protein complex, which associates with a regulatory DNA sequence known as the Maf recognition element MARE. Activation in turn depends on the substitution of Bach with p, although it has remained unclear how cells maintain appropriate control over this latter protein. However, new research from a team led by CheKun James Shen of the Academia Sinica in Taiwan has provided insights into the regulatory mechanisms that ensure that p is only present at the right time and place. Shen and coworkers determined that p is normally marked for destruction through chemical modifications introduced by the JNK enzyme, but can be stabilized via the inactivation of JNK in the earliest stages of erythrocyte differentiation. The resulting increase in p levels initiates a chain of events that lead to Bach release and degradation, so that MARE elements are instead bound by geneactivating p/Maf complexes. Based on these findings, the authors conclude that JNKmediated regulation of p likely represents a vital, toplevel checkpoint governing the onset of blood cell maturation. Lee, T.L. et al. JNKmediated turnover and stabilization of the transcription factor p/NFE during differentiation of murine erythroleukemia cells. Proceedings of the National Academy of Sciences USA , . www.natureasia.com/AIMBN AIMBN RESEARCH CELL BIOLOGY Published in Science Cellcycle blockers The mechanism used by two pathogenic bacterial species to block the division of their host cells is no longer a mystery The bacteria Burkholderia pseudomallei and Escherichia coli cause the human condition melioidosis and diarrheal disease, respectively. By injecting virulence factors called effectors, they curtail the division of host cells, which then fuse allowing the bacteria to spread from cell to cell. Now, a team led by Feng Shao of the Chinese National Institute of Biological Sciences in Beijing has revealed the mechanism by which these effectors block the cell cycle. Escherichia coli produces an effector called cycle inhibiting factor Cif , whereas B.pseudomallei produces the related protein CHBP. Both Cif and CHBP can block the normal cycle of cell division, when injected into host cells. Shao and his collaborators showed that Cif and CHBP directly interfere with the ubiquitinproteasome system, which normally drives the cell cycle by degrading key regulatory proteins at the appropriate times. When no longer needed, these cellcycle regulators are tagged with a small protein called ubiquitin. This directs them to a structure called the proteasome where they are broken down for recycling. The researchers revealed that CHBP and Cif interfere with ubiquitination by chemically altering and thereby inactivating ubiquitin and/or the ubiquitinlike protein NEDD. Because ubiquitination is involved in many cellular processes, they suggest that these effectors probably play a range of roles in bacterial pathogenesis. RESEARCH HIGHLIGHT COLLECTION Cui, J. et al. Glutamine deamidation and dysfunction of ubiquitin/NEDD induced by a bacterial effector family. Science , . Published in Proceedings of the National Academy of Sciences USA Fitting the profile Variations in surface proteins may help researchers to reliably isolate and track cells with potential value for studying blood cell development Characterizing the differentiation of hematopoietic stem cells HSCs into mature blood cells in vivo poses a serious challenge, and researchers have begun to seek cell preparations with HSClike characteristics that might prove more practical for experimental use. Recent work from a team led by Donald Metcalf at Australias Walter and Eliza Hall Institute of Medical Research demonstrated how mouse bone marrow cells could be chemically induced to yield two subtypes of socalled blast colonyforming cells. These multicentric and dispersed blast cells differ in their capacity for differentiation into mature blood cells, but both could represent useful HSC alternatives for certain applications. Metcalf and colleagues have since investigated the composition of these two cell preparations in greater detail. They found they could enrich either type of blast cell from initial cultures with reasonable efficiency based on differential expression of cellsurface proteins, although they noted considerably more heterogeneity than expected in these preparations. The researchers observed clear differences in the marker surface proteins displayed by multicentric and dispersed colonies, as well as between the various blood cell types these two colonies yield. They conclude that these findings should provide useful guidelines for more effectively identifying and observing maturation of these two blast cell types in future work. Metcalf, D. et al. Murine hematopoietic blast colonyforming cells and their progeny have distinctive membrane marker profiles. Proceedings of the National Academy of Sciences USA , . ISTOCKPHOTO/JARROD CELL BIOLOGY AIMBN RESEARCH Published in Molecular Cell lipids trapped within a SnArE An unusual regulatory mechanism provides tight control over intracellular transport of molecules ISTOCKPHOTO/ eRAXION Within every eukaryotic cell is a constant flow of molecular traffic, with various cargos being shipped from one place to another in membranebased bubbles known as vesicles. Published in Proceedings of the National Academy of Sciences USA The acid advantage An acidsensing receptor protein on the surface of tumor cells enhances their ability to survive and grow Cancerous cells often reside in an acidic environment which would kill normal cells. Now, a team of researchers in Japan describe how tumor cell expression of a protein that signals in response to acid can confer a selective advantage to cancer cells. The researchers expressed the protein, Tcell deathassociated gene TDAG, in lung cancer cells that are normally free of the protein, and transplanted them into mice. These TDAGexpressing cells formed more and larger tumors than normal cells lacking TDAG. Mutating the portions of TDAG that allow it to sense acid reduced the ability of the protein to drive tumor formation in the animals. In tissue culture experiments, the researchers found that lung cancer cells expressing TDAG survived Ihara, Y. et al. The G proteincoupled receptor Tcell deathassociated gene TDAG facilitates tumor development by serving as an extracellular pH sensor. Proceedings of the National Academy of Sciences USA , . better and proliferated faster in acidic conditions than did cells lacking TDAG. They also observed that reducing expression of TDAG in lung cancer cells, which normally expressed the protein, reduced cell survival in acidic conditions and reduced tumor formation in animals. TDAG seemed to activate signaling molecules inside the cancer cell, including various kinase enzymes that add phosphate groups to other proteins. Blocking these kinases decreased the ability of TDAG to drive proliferation in tissue culture. The findings suggest that targeting TDAG signaling could be a therapeutic approach to fight cancer. Each is addressed to a particular destination via membraneanchored Nethylmaleimidesensitive factor attachment protein receptors SNAREs, which allow vesicles to recognize the membranes of target organelles. Most SNAREs are permanently membranebound, but the essential vesicletargeting protein Ykt appears to exist in an inactive soluble form that can be induced to undergo rearrangements that enable membrane insertion. A team led by Mingjie Zhang of the Hong Kong University of Science and Technology has now provided direct experimental confirmation for this atypical activation model. Ykt is typically modified with a farnesyl lipid group, and Zhang and coworkers determined that this farnesyl group preferentially sequesters itself within a pocket formed by various protein domains. As a result, Ykt is stably maintained in a compact soluble conformation, where it is incapable of binding other SNAREs or interacting with membranes. The authors hypothesize that subsequent addition of a palmitoyl lipid group shifts Ykt into an open arrangement that leaves the farnesyl group exposed and capable of membrane insertion. Importantly, this palmitoylation is reversible, thus providing cells with a useful means to regulate Ykt activity. Wen, W. et al. Lipidinduced conformation switch controls fusion activity of longin domain SNARE Ykt. Molecular Cell , . www.natureasia.com/AIMBN AIMBN RESEARCH CELL BIOLOGY Published in Nature Structural and Molecular Biology Tracking cellular hunger pangs Animal cells have retained components of an essential bacterial signaling mechanism for coping with starvation When external nutrient supplies run dry, bacteria and plant cells produce a warning signal that halts cell growth while ramping up the activity of cellular processes that might help to rectify the shortage. Levels of this alarmone, guanosine ,diphosphate ppGpp, are governed by two enzymes RelA, which synthesizes ppGpp, and SpoT, which breaks it down. Until recently, neither enzyme had been observed in animal cells, but new work from a team led by Jongkyeong Chung at Seoul National University in Korea and Young Ho Jeon at the Korea Basic Science Institute has now identified homologs of SpoT in diverse animal species. Both the human and fruit fly homologs, which the researchers termed metazoan SpoT homolog Mesh, showed remarkable structural similarity to their bacterial counterparts and proved equally capable of the specific processing of ppGpp molecules. Escherichia coli bacteria lacking the gene encoding SpoT normally accumulate ppGpp under nutrientpoor conditions and subsequently undergo growth arrest, but this condition could be effectively reversed by inducing these cells to express human or fly Mesh. As this enzyme apparently plays an equivalent role in flies, regulating both cell growth and responses to nutrient deprivation, these findings shed light on a highly important but previously uncharacterized environmentalsensing pathway in animal cells. RESEARCH HIGHLIGHT COLLECTION Sun, D. et al. A metazoan ortholog of SpoT hydrolyzes ppGpp and functions in starvation responses. Nature Structural and Molecular Biology , . Published in Neuron reciprocal connections Odor responses in the fruit fly brain are modulated by an exchange of excitatory signals between two specific neuron populations Researchers in China have found how neuronal populations in the antennal lobe of the fruit fly brain communicate with each other to encode olfactory information. The flys response to olfactory information is critical, particularly in the search for food. The findings have been published in the journal Neuron. The researchers stimulated neurons in flies that expressed a fluorescent protein in a population of excitatory interneurons in the antennal lobe of the brain. They recorded the response in projection neurons that send olfactory information to higher brain centers. Stimulating the excitatory interneurons activated the projection neurons, and stimulating projection neurons activated the excitatory interneurons. These two neuronal populations seemed to be connected to each other through direct gap junction coupling, allowing for rapid communication between them. Certain odors triggered stronger responses than others in the excitatory interneurons, the researchers observed. They also found that switching an odor on or off in the flies environment could preferentially activate these neurons. The specificity of these interneuron responses, and their reciprocal excitation of the projection neurons, suggested to the researchers that these excitatory interneurons might amplify the response of the olfactory neuronal circuit to low concentrations of odors in the environment. Huang, J., Zhang, W., Qiao, W., Hu, A. amp Wang, Z. Functional connectivity and selective odor responses of excitatory local interneurons in Drosophila antennal lobe. Neuron , . ISTOCKPHOTO/ARlINDO CELL BIOLOGY AIMBN RESEARCH Published in Cell Death and Differentiation Profiling cell death perpetrators genetic deletion reveals the individual and overlapping roles of two key instigators of programmed cell death in various cell types Safeguarding against tumor formation and other diseases hinges on programmed cell death, or apoptosis, for the removal of redundant and defective cells. Two important factors Published in The EMBO Journal The missing link A commonly used anticancer therapeutic helps to preserve the activity of a protein that causes tumor cells to commit suicide Many cancer patients benefit from treatment with cellular signaling molecules known as interferons IFNs, which eliminate tumor cells by triggering cellular selfdestruct mechanisms via their influence on proteins such as deathassociated protein kinase DAPK. Until recently, the molecular details of this response were poorly understood, but a team led by RueyHwa Chen at Academia Sinica in Taiwan has revealed valuable details about how IFN helps promote the activity of this cell death initiator. Cellular pathways are often switched off via a process known as ubiquitination, which marks specific proteins for destruction by a complex known as the proteasome. Accordingly, Chen and coworkers discovered that the KLHL protein acts as an adapter that selectively Lee, Y. R. et al. The Cullin substrate adaptor KLHL mediates DAPK ubiquitination to control interferon responses. The EMBO Journal , . facilitates DAPK degradation by tethering it to proteins that help direct it to the proteasome. However, they observed that cells treated with IFN or exhibit dramatically altered localization of KLHL, with much of this protein segregated within the nucleus as opposed to its typical distribution throughout the cytoplasm. This nuclear segregation essentially eliminates the bridge that links DAPK to the ubiquitination pathway, thereby extending the proteins lifespan and promoting the onset of cell death. Chen and coworkers suggest that malfunctions in this process could underlie emergence of interferon resistance in certain cancer patients. in apoptosis induction are the proteins Bim and Bad. By genetically engineering mice to lack one or both of these proteins, Andreas Strasser and his colleagues from the Walter and Eliza Hall Institute of Medical Research in Australia have characterized how Bim and Bad work together to trigger apoptosis in various cell types. The researchers found that loss of Bad extended the life span of platelets, whereas loss of Bim reduced the production of these cells, possibly because a Bimdependent, apoptosislike, process may be critical for platelet shedding. In mice lacking both Bim and Bad, they recorded a normal number of platelets, likely because the effects of these proteins on these cells counterbalance each other. Strasser and colleagues also found that loss of Bim in thymocytes, and of Bad in their support cells, helped nurture their sustained survival upon radiation treatment. Accordingly, they observed an acceleration of radiationinduced lymphoma development when both factors were lacking. Since Bim and Bad play interacting roles in apoptosis the team suggests that pharmacologically activating both might assist with the treatment of certain types of lymphomas. Kelly, P. N. et al. Individual and overlapping roles of BHonly proteins Bim and Bad in apoptosis of lymphocytes and platelets and in suppression of thymic lymphoma development. Cell Death and Differentiation , . NIeHS/NIH www.natureasia.com/AIMBN AIMBN RESEARCH CELL BIOLOGY Published in Proceedings of the National Academy of Sciences USA Pinpointing a missing link The discovery of the protein Stk will help facilitate full use of embryonic stem cells in regenerative medicine A research team led by Ying Jin of the Chinese Academy of Sciences has identified a key protein, Stk, involved in embryonic stem cell ESC differentiation. ESCs derived from earlystage embryos renew themselves through cell division. Their capacity to differentiate into a diverse range of specialized cells makes them attractive candidates for use in regenerative medicine. However, factors controlling renewal and differentiation need to be better understood before the full therapeutic potential of ESCs can be realized. The researchers identified Stk as a target gene of Oct, the master regulator of gene expression maintaining ESCs in an undifferentiated state. They showed that Stk cooperates with a calciumbinding protein, Rcn, to activate a previously characterized Erk/MAPK signaling pathway already known to be crucial for ESC differentiation. However, the exact mechanism by which these proteins activate signaling remains to be established. Experiments with mouse embryos revealed that signaling triggered by Stk induces ESC differentiation specifically into extraembryonic endoderm. In mammals, cells from this lineage form yolk sacs, which nourish the developing embryo, and also orchestrate patterning of later developmental structures. The researchers concluded that Oct maintains ESCs in an undifferentiated state by suppressing Stk expression, thereby blocking signals that would otherwise lead to differentiation. RESEARCH HIGHLIGHT COLLECTION Li, L. et al. Stk links the pluripotency factor Oct to the Erk/MAPK pathway and controls extraembryonic endoderm differentiation. Proceedings of the National Academy of Sciences USA , . Published in Nature Maintaining stem cell identity Identification of the genes that keep embryonic stem cells in an undifferentiated state is an important step forward Researchers from the ASTAR Genome Institute of Singapore have identified the genes that make human embryonic stem cells ESCs remain in the pluripotent, undifferentiated state, which enables them to generate the multiple cell types in the body. HuckHui Ng and his colleagues performed a genomewide screen to pinpoint the genes that specify ESC identity by regulating the selfrenewing and pluripotency properties of the cells. They used genetic engineering to fuse green fluorescent protein to the regulatory region of the POUF gene, which is critical for ESC selfrenewal. This enabled them to identify the genes that interact with and control POUF expression. They established that one of the genes identified, PRDM, directly controls the expression of the OCT gene, which is a key regulator of ESC pluripotency. Furthermore, inserting PRDM into cultured cells called fibroblasts pushed them towards a pluripotent state by activating these genes, enabling more efficient reprogramming of the cells. Conversely, reducing PRDM levels led to a reduction in ESCassociated genes in three different stem cell lines, causing them to express celltype specific genes and to undergo morphological changes characteristic of differentiation. We are currently studying the novel regulators identified in the screen, says Ng. It is likely that many will play unexpected roles in human embryonic stem cells. Chia, N.Y. et al. A genomewide RNAi screen reveals determinants of human embryonic stem cell identity. Nature , . ISTOCKPHOTO/luISMMOlINA CELL BIOLOGY AIMBN RESEARCH Published in Leukemia AIDing our understanding of cancer ISTOCKPHOTO/ DAVIDBgRAy A different approach in modeling AIDinduced immunecell cancers reveals new insights into their development Mutations introduced in the DNA of immune cells by the enzyme called activationinduced cytidine deaminase Published in Cell Stem Cell Identifying a cancerspreading culprit The protein CD defines a population of cancer stem cells that can spread human colorectal cancer to other organs Cancer researchers believe that tumors harbor a relatively small number of longlived cells, dubbed cancer stem cells CSCs, which are the mutant cells that initially gave rise to the tumor. CSCs have been identified in human tumors and shown to initiate tumor development when injected into mice. Benjamin Wong and his colleagues from the University of Hong Kong have now identified the cell surface protein CD as a marker of a subpopulation of CSCs that also give rise to secondary tumors metastases. Using cells collected from human colorectal cancers, the researchers found that a population of CSCs expressing CD within these samples can initiate cancer metastasis when injected into mice. They also observed Pang, R. et al. A subpopulation of CD cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell , . that these cells displayed enhanced tissue invasiveness and resistance to chemotherapeutic agents. Wong and colleagues noted that at the beginning of a study of colorectal cancer patients without metastasis but with CSCs not expressing CD of individuals did not develop secondary tumors. However, of colorectal patients . with CDpositive cells eventually developed secondary tumors. These results suggest that CDexpressing CSCs may be the source of metastases in colorectal cancer and may also have prognostic value in the clinic for this disease. AID lead to the diversification of these cells. However, misregulation of AID can inappropriately introduce mutations in the genes that regulate cancer, resulting in the hyperproliferation of B cells and consequently tumors of the lymph socalled Bcell lymphomas. Surprisingly, modeling this disease by genetic overexpression of AID in mice had resulted only in Tcell lymphomas. Toshio Kitamura from the University of Tokyo and his colleagues have now found that bone marrow cells transduced with AID and injected into normal mice can cause T and Bcell lymphomas and Bcell leukemia. None of the recipient mice, however, developed myeloid leukemias even when the team injected mice with purified precursors of these blood cells that were transduced with AID. The team speculates that AID induces leukemia/lymphoma in one subset of immune cells but not another because myeloid cells have a more efficient DNArepair process than T or B cells. Kitamura and colleagues also identified mutations in several key genes regulating Tcell and Bcell proliferation and differentiation in the mice that developed cancer, thus offering a possible molecular mechanism by which AID can induce such cancers in humans. Komeno, Y. et al. AIDinduced Tlymphoma or Bleukemia/lymphoma in a mouse BMT model. Leukemia , . www.natureasia.com/AIMBN AIMBN RESEARCH CELL BIOLOGY Published in Proceedings of the National Academy of Sciences USA The accomplice to viral entry Researchers identify the cell surface receptor that effectively opens the door to the nervous system for herpes virus infection The molecular mechanism by which varicella zoster and related viruses gain entry into host cells has been revealed by researchers in Japan. Varicella zoster virus VZV is a herpes virus that targets primary sensory neurons, leading to chicken pox in children and shingles in immunocompromised and elderly adults. During infection, virus envelope glycoproteins bind to receptors on the host cell surface, causing the envelope to fuse with the cell membrane and enabling the virus to gain entry into its host. The cell surface receptor which mediates this process was, however, unknown. Tadahiro Suenaga of Osaka University and colleagues in Japan have identified the host receptor as myelinassociated glycoprotein MAG, a cellsurface protein expressed predominantly by glial cells in the nervous system, which is known to be important for axonal outgrowth during neural development. The researchers transfected a human kidney cell line with MAG and then cocultured them with cells transfected with VZV glycoproteins B, E, H or L. In all but the cocultures containing gE, they observed many fused cells see image. They also found that human oligodendrocytes transfected with MAG were susceptible to VZV infection. These findings demonstrate that cell cell fusion is mediated by an interaction between MAG and VZV glycoproteins B, H and L, but not glycoprotein E. Suenaga, T., Satoh, T., Somboonthum, P., Kawaguchi, Y. amp Mori, Y. Myelinassociated glycoprotein mediates membrane fusion and entry of neurotropic herpesviruses. Proceedings of the National Academy of Sciences USA , . Published in Nature route of entry The herpes virus enters host cells by binding to a myosin protein found on the cell surface The point of entry of the herpes virus to human host cells has been identified by researchers in Japan and the US. The herpes virus glycoprotein B gB binds to a cell surface protein called nonmuscle myosin heavy chain IIA NMHCIIA, which allows it to invade host cells. The researchers focused on NMHCIIA by isolating and sequencing host cell surface proteins that interacted with herpes virus expressing gB. They found that human leukemia cells that were relatively resistant to herpes virus infection became highly susceptible to viral infection when they overexpressed NMHCIIA. Kidney epithelial cells that are usually susceptible to herpes infection became resistant when the researchers reduced their expression of NMHCIIA. Arii, J. et al. Nonmuscle myosin IIA is a functional entry receptor for herpes simplex virus. Nature , . Since a drug called ML that blocks the ability of NMHCIIA to reach the cell surface could prevent herpes virus infection in kidney cells, NMHCIIA could represent a new target for drug development against herpes virus infections. Infection with herpes virus can cause death in mice. The researchers found that ML could enhance the survival of mice exposed to the herpes virus. The teams discovery could assist development of drugs against human herpes virus infection, which can cause blistering of the skin, mouth and genitalia, and, in some cases, damage to nerves. RESEARCH HIGHLIGHT COLLECTION PNAS CELL BIOLOGY AIMBN RESEARCH Published in Molecular Cell Dissecting cellular crisis management ISTOCKPHOTO/ ISTACKPHOTONS Cells rely on a complex, multistep signal transduction pathway to coordinate their response to DNA damage Serious DNA damage triggers cellular survival responses mediated by transcription factor NFB, which some cancer cells exploit to evade destruction Published in Developmental Cell Frontline healer Repair of physical damage to body tissues is coordinated by one of the protein that helps epithelial cells stay in layers Many tissues in the body are composed of sheets of tightly connected epithelial cells. When these tissues suffer damage, epithelial cells respond by migrating towards wounds in order to initiate healing. For this process to succeed, epithelial cells need a good sense of direction, which is established by socalled polarity complexes such as ParaPKC and ParaPKC. Zhengjun Chen and colleagues at Chinas Shanghai Institutes for Biological Sciences have now revealed that this orientation depends on the participation of occludin, one of the proteins that helps epithelial sheets maintain their cohesion. Working with kidney epithelial cells, the researchers showed that occludin rapidly localizes to the leading edge of epithelial cells near the wound essentially the front Du, D. et al. The tight junction protein, occludin, regulates the directional migration of epithelial cells. Developmental Cell , . line of the healing process. Occludin subsequently recruits ParaPKC, and thereby establishes directionality for cell migration on the other hand, artificially induced downregulation of occludin prevented the cells from undergoing cytoskeletal rearrangements that are an essential prelude to migration. Likewise, Chens team also demonstrated that occludin is needed to localize and activate PIK, an important cellular signaling factor, at the leading edge, where it triggers formation of cellular projections that help pull epithelial cells into motion. Depletion of occludin sabotages this process, further highlighting the apparently critical role of this protein in wound healing. by radiation or chemotherapy. The ATM protein coordinates a parallel response to these toxic stimuli, and although there is evidence for an intersection between these two pathways, the details remain murky. ZhaoHui Wu from the University of Tennessee Health Science Center and colleagues including Ee Tsin Wong and Vinay Tergaonka of the ASTAR Institute of Molecular and Cell Biology have filled in some of those blanks. They identified a key role for the ELKS protein, which gets modified via the addition of chains of ubiquitin molecules. This modification enables ELKS interaction with downstream elements of the NFB activation pathway. Ubiquitination of ELKS is driven in response to DNA damage by the cooperative action of ATM and a second protein, NEMO. Interestingly, NEMO also participates in a late stage of NFB activation, indicating a key role for this factor at both ends of this particular pathway. Numerous other stimuli can activate NFB, including cellular signaling factors like cytokine TNF. However, Wu and colleagues found evidence that the interaction between NEMOATM and ELKS plays a minimal role in the TNF response, suggesting that the mechanism they uncovered represents a specific response to DNA damage. Wu, Z.H. et al. ATM and NEMOdependent ELKS ubiquitination coordinates TAKmediated IKK activation in response to genotoxic stress. Molecular Cell , . www.natureasia.com/AIMBN ISTOCKPHOTO/HeNRIK JONSSON Genetics GENETICS AIMBN RESEARCH Published in Nature Biotechnology Knockout resource for yeast biologists A genomewide deletion collection for fission yeast provides an invaluable new tool for biotechnology and biomedical research ISTOCKPHOTO/MKuCOVA Scientists led by KwangLae Hoe of the Korea Research Institute of Bioscience and Biotechnology have ascertained which genes are dispensable Published in Proceedings of the National Academy of Sciences USA looking out for number one A mathematical analysis suggests that parasitic genetic elements need not perish from their singular selfishness Most genes contribute to the survival of the organism within whose genome they reside, but some are less beneficial. For example, homing endonuclease genes HEGs act only to ensure their own duplication. When one member of a chromosome pair contains an HEG but the other does not, the enzyme it encodes selectively cleaves the empty chromosome at the appropriate site the cellular DNA repair machinery then copies the HEGcontaining chromosome to fill in the resulting break. Scientists have assumed that once HEGs are established in a population, they must be transmitted horizontally to another population or species to avoid extinction due to accumulation of inactivating mutations over time. However, new mathematical models from University of Tokyo Yahara, K., Fukuyo, M., Sasaki, A. amp Kobayashi, I. Evolutionary maintenance of selfish homing endonuclease genes in the absence of horizontal transfer. Proceedings of the National Academy of Sciences USA , . researcher Ichizo Kobayashi and his colleagues at Kurume University and the Graduate University for Advanced Studies, Japan, suggest otherwise. Mutation of the HEG locus to an inactive but also uncleavable pseudogene sometimes carries a cost to the host organisms reproductive fitness, and they identified this as a key consideration in determining the mechanism of HEG persistence. But regardless of whether or not this cost becomes significant, Kobayashis team could identify multiple scenarios that would enable these genes and, potentially, other selfish genetic elements to survive over long periods of time within isolated populations. and which are essential in fission yeast Schizosaccharomyces pombe, a model for studying basic biological processes in eukaryotes, a group of organisms that includes humans. The researchers systematically knocked out some , genes covering more than the fission yeast genome, and replaced each one with a marker gene flanked by unique molecular bar codes. This allowed them to assess experimentally which genes were needed for viability, growth and reproduction in the laboratory. By comparing their results with previous findings from budding yeast Saccharomyces cerevisiae used in baking and brewing, they found that fission yeast has more essential genes than budding yeast despite having fewer genes in total. They also found that essential genes tend to be present as singlecopy, evolutionarily conserved genes, often interrupted by noncoding DNA sequences called introns, possibly reflecting aspects of their regulation and/or ancient origin. In contrast, nonessential genes are more often duplicated in the genome, and less likely to contain introns or to be present in both species. The researchers believe that their genomewide fissionyeast deletion library will facilitate the identification of eukaryotic molecular pathways and networks, benefiting both biotechnology and biomedical research. Kim, D.U. et al. Analysis of a genomewide set of gene deletions in the fission yeast Schizosaccharomyces pombe. Nature Biotechnology , . www.natureasia.com/AIMBN AIMBN RESEARCH GENETICS Published in PLoS Biology Exploring the genetic generation gap The emergence of functional mismatches between genes in the nucleus and the mitochondria accelerates the evolutionary process As new species emerge over the course of evolution, they lose the capacity to generate fertile progeny with members of their parent species. In many cases, such reproductive isolation is presumed to occur via accumulation of mutations that disrupt interactions between each species complement of genes. JunYi Leu and colleagues at Academia Sinica have explored an alternative mechanism for reproductive isolation in yeast, driven by the emergence of incompatibilities between the nuclear genome and mitochondria, an essential metabolic organelle with its own discrete set of genes. The researchers established a multistage breeding scheme for generating crosses between yeast species and identifying pairs for which this cytonuclear incompatibility was a primary obstacle to offspring fertility. Leu and colleagues were subsequently able to identify genes responsible for this incompatibility by screening genomic libraries for sequences that restored the mitochondrial function of the various infertile hybrids. Their data revealed two genes, MRS and AIM, which appear to contribute to cytonuclear incompatibility via distinct biological mechanisms. Strikingly, the patterns of emergence for these mutations directly correlated with known evolutionary history of the various species, and the authors conclude that genomic changes associated with cytonuclear incompatibility may represent important early drivers of the speciation process. RESEARCH HIGHLIGHT COLLECTION Chou, J.Y., Hung, Y.S., Lin, K.H., Lee, H.Y. amp Leu, J.Y. Multiple molecular mechanisms cause reproductive isolation between three yeast species. PLoS Biology , e . ISTOCKPHOTO/TePIC Published in the Journal of Molecular Biology Evolution through , generations Tracking longterm evolution in bacteria reveals that genome change and adaptation are linked in highly complex ways In addition to showing that relationships between genomic change and adaptation are complex, the results of an extensive analysis of the evolution of a population of bacteria over , generations have revealed that the pace of genome evolution is not directly coupled to improvement in fitness. The international study, involving the Korea Research Institute of Bioscience and Biotechnology KRIBB, does, however, clearly demonstrate the validity of Darwins theory of evolution by natural selection. The researchers believe that their work can be applied to bettering the performance of industrial strains of bacteria, as well as contributing to understanding the tempo and mode of evolution. In , researchers from Michigan State University led by Richard Lenski began to grow Escherichia coli in the laboratory at a constant rate of six or more generations a day. Samples were frozen for future analysis. A team led by Jihyun F. Kim at KRIBB sequenced and compared bacterial genomes from samples taken at ,, ,, ,, ,, , and , generations, after determining the complete genome sequence of the ancestral strain. In addition, Dominique Schneiders group in Grenoble, France, measured the fitness of each population, in part by moving mutations back to ancestral populations and observing their impact. Barrick, J. E. et al. Genome evolution and adaptation in a longterm experiment with Escherichia coli. Nature , Jeong, H. et al. Genome sequences of Escherichia coli B strains REL and BLDE. Journal of Molecular Biology , . GENETICS AIMBN RESEARCH Published in Acta Pharmacologica Sinica Thank you for not smoking gender differences in the frequency of a cancerassociated mutation among Chinese patients may arise from differences in smoking behavior ISTOCKPHOTO/MAC Patients diagnosed with lung adenocarcinoma, the most common of all lung cancers, can often benefit from treatment with drugs such as Iressa Published in Nature Genetics lung cancer link A newly identified genetic variant is associated with increased lung cancer risk in east Asian Lung cancer is a leading cause of death worldwide, but little is known about the genetic factors that confer susceptibility to it. Yataro Daigo of the University of Tokyo and Shiga University of Medical Science, and his colleagues have now identified a gene variant in the Japanese and Korean populations that is associated with increased risk of the disease. The researchers performed a genomewide association study that compared the entire genomes of , lung cancer patients with those of , healthy controls. They found that a variant of the TP gene is strongly associated with increased susceptibility for lung adenocarcinoma, which accounts for approximately of all lung cancer cases, and whose prevalence is increasing among East Asians and Western Europeans. Miki, D. et al. Variation in TP is associated with lung adenocarcinoma susceptibility in Japanese and Korean populations. Nature Genetics , . TP belongs to a family of genes whose members are involved in development, differentiation and cellular responses to stress, and are known to function as tumor suppressors. The newly identified genetic variation in TP may play a role in regulating TP expression, but further research is needed to establish exactly how it influences susceptibility to lung adenocarcinoma. We are continuing further functional studies to clarify the mechanisms of TP on lung adenocarcinoma susceptibility, says Daigo, as well as additional studies on other ethnic populations. and Tarceva, which inhibit certain signaling enzymes known as kinases. These compounds are most effective in patients with mutations in the gene encoding one particular kinase, the epidermal growth factor receptor EGFR. Previous studies have suggested that females in general, and males and females who have never smoked are especially likely to acquire such EGFR mutations, but new findings from a team led by Hongbin Ji at the Shanghai Institutes for Biological Sciences suggest that for some populations, this gender effect may simply be an artifact of lifestyle differences. Chinese women are considerably less likely to smoke than their male counterparts, a trend that Ji and coworkers clearly observed in their analysis of adenocarcinoma tissue samples from Chinese patients. When they independently considered only those individuals who had never smoked, they were surprised to note that EGFR mutations occurred with essentially the same frequency among both women and men . versus .. These findings suggest that a history of smoking is a more important consideration than gender in determining whether Chinese patients diagnosed with adenocarcinoma are likely to benefit from kinase inhibitor treatment. Sun, Y. H. et al. Comparable rate of EGFR kinase domain mutation in lung adenocarcinomas from Chinese male and female neversmokers. Acta Pharmacologica Sinica , . www.natureasia.com/AIMBN AIMBN RESEARCH GENETICS Published in Proceedings of the National Academy of Sciences USA Extremophiles Cold complexity An impressive variety of microbes can survive in the polar deserts of Antarctica The McMurdo Dry Valleys, an extremely cold, dry desert region representing the largest icefree area in Antarctica, support a higher variety of life than scientists once believed. During a recent study of permafrost in the high inland McKelvey Valley, Steve Pointing and colleagues at the University of Hong Kong, along with Roberta Farrell at the University of Waikato, New Zealand, and coworkers in the USA, discovered previously unreported bacteria and fungi existing in highly specialized microbial communities. The researchers used molecular techniques to assess the relative abundance of different microbes and identify variations in community structure. They found socalled endolithic and chasmolithic cyanobacteria, which are capable of photosynthesis and occupy ecological niches in the pores and cracks in sandstone outcrops. The surrounding soil, however, contained very few organisms except on scattered quartz rocks. Our data counters the viewthat cyanobacteria are restricted to wetter, more productive polar locations, the researchers note in their publication. The data also showed that the abundance of microbes in some areas may occasionally increase due to moisture input from melting snow. However, they found no significant difference in the biodiversity of communities at different locations probably because only a few resilient species can survive in such an extreme environment. RESEARCH HIGHLIGHT COLLECTION Pointing, S. B. et al. Highly specialized microbial diversity in hyperarid polar desert. Proceedings of the National Academy of Sciences USA , . Published in the Journal of Human Genetics Mountains that make the people Culture is geographically defined by the Himalayas, and DNA fingerprinting shows that these mountains also impede gene flow The genetic structure of the peoples of Tibet is consistent with the geographical barriers and the languages they speak, a study led by researchers from Fudan University in Shanghai has shown. The researchers found Tibetans are relatively similar to north Asians, but the small Deng minority in the Himalayan Mountains of southeast Tibet is unique. The Deng people are most closely related to a neighboring minority, the Luoba/Adi. The two are genetically more similar to each other than to any other ethnic group in East Asia. And although the Deng and Luoba/Adi live in isolated valleys on the southern side of the Himalayas, the researchers found no detectable genetic link with Indian peoples. These assessments were made on the basis of the analysis of different regions of short tandem repeats STRs from Deng, central Tibetans and eastern Tibetans. STRs are groups of repeated sequences of DNA code between two and units long, often used in DNA fingerprinting. The numbers of repeats varies in different individuals but the more closely people are related, the more similar the pattern of repeats. There was not enough evidence to reconstruct a more detailed history of the settlement of Tibet, the researchers say. Kang, L. et al. Genetic structures of the Tibetans and the Deng people in the Himalayas viewed from autosomal STRs. Journal of Human Genetics , . ISTOCKPHOTO/ gOINyK GENETICS AIMBN RESEARCH Published in the British Journal of Cancer Combining forces to combat cancer ISTOCKPHOTO/BeHOlDINgeye Research into colorectal cancer genetics gets a largescale boost from the establishment of a multinational research consortium The COGENT COlorectal cancer GENeTics consortium, comprised of some twenty research groups, including the Human Genome Research Center at the University of Tokyo, has been established to study genetic predisposition to colorectal cancer. Colorectal cancer is the fourth most common form of cancer in the United States, and causes more than , deaths worldwide annually. Although inherited susceptibility underlies approximately of genetic variance in colorectal cancer, highrisk mutations account for less than of cases. The goal of the COGENT consortium is therefore to identify and characterize socalled lowpenetrance genetic variants. The risk of colorectal cancer associated with each of these is modest, but they occur with high frequency in the population, and may significantly affect an individuals risk when acting together. Very few of these variants have been identified to date, because of small sample sizes and the limitations of early genetic testing methods. COGENT overcomes these limitations by enrolling researchers who are conducting studies involving a minimum of patients and controls. Collectively, the studies performed by researchers in the consortium have included , cases and , controls. Pooling these data provides a costeffective means of performing powerful statistical analyses that could not be achieved from an individual study. Tomlinson, I. P. M. et al. COGENT Colorectal cancer GENeTics an international consortium to study the role of polymorphic variation on the risk of colorectal cancer. British Journal of Cancer , . Published in Cell Research Filling the gaps of a genome map Application of a proteomic technique allows better annotation of the genome reported for the pathogenic bacterium leptospira interrogans The Genomic Age has allowed scientists to quickly sequence the complete genomes of several species, including important human pathogens. Rong Zeng and colleagues in Shanghai have now used a proteomics technique to provide the information needed to more accurately map the genome of Leptospira interrogans, a freeliving pathogenic spirochete that causes leptospirosis, a dangerous malady marked by sever fever and muscle ache. The genome of this bacterium was sequenced in . Fully annotating the sequenced genome of a species involves identifying all of its genes and the proteins that they encode. Identifying all the posttranslational modifications of these proteins is also useful as they are important regulators. Cao, X.J. et al. Highcoverage proteome analysis reveals the first insight of protein modification systems in the pathogenic spirochete Leptospira interrogans. Cell Research , . Zengs group used a computational algorithm that predicts the existence of genes from known sequence data while also performing mass spectrometry on cell extracts to physically identify expressed proteins. These two approaches allowed the team to identify novel genes in the bacteriums genome, better define the start site of several other genes and identify the posttranslational modifications of a large percentage of its proteome. This annotation of L.interrogans may eventually allow for the identification of gene products needed for its survival and thus the development of new antibiotics. www.natureasia.com/AIMBN AIMBN RESEARCH GENETICS Published in Nature Genetics Pinpointing inflammatory genomic changes The effects of a subtle sequence variation in an immunityrelated gene may predispose individuals to rheumatoid arthritis and other inflammatory diseases Over the course of rheumatoid arthritis, the immune system mobilizes T cells against tissues within the joints to produce debilitating pain and inflammation. Genetic factors contribute to the onset and severity of this disorder. A team of researchers from several Japanese research institutes recently surveyed the genomes of more than , Japanese patients and controls and revealed a twonucleotide sequence variant that has an apparently strong role in conferring vulnerability to rheumatoid arthritis. The research team, which was led by Yuta Kochi and Kazuhiko Yamamoto of the RIKEN Center for Genomic Medicine in Yokohama, identified these changes within the CCR gene, which encodes a receptor for signals that promote activation of the immune system. Intriguingly, CCR expression is generally associated with Th cells, a subclass of helper T cells that is poorly understood but has been tentatively linked with rheumatoid arthritis pathology. The investigators noted that these sequence changes dramatically affected CCR expression levels in patients, and that individuals with the highest CCR levels were also significantly more likely to exhibit increased production of certain proinflammatory signals. Their data also offer compelling evidence that the gene variant may also predispose some individuals to Graves disease and Crohns disease, two other common autoimmune inflammatory disorders. RESEARCH HIGHLIGHT COLLECTION Kochi, Y. et al. A regulatory variant in CCR is associated with rheumatoid arthritis susceptibility. Nature Genetics , . ISTOCKPHOTO/SueMACK Published in Proceedings of the National Academy of Sciences USA Keeping track of changes Coordination between two important pathways for the chemical modification of chromosomes leads to finetuned regulation of gene expression Gene activity levels depend heavily on socalled epigenetic modifications, such as the targeted addition of methyl chemical groups to individual cytosine nucleotides or to the histone proteins around which genomic DNA is wrapped. Scientists have proposed that these two processes are closely linked, with the methylation state of the tail domain of histone H directly affecting cytosine methylation within individual genes, and a new study from a team led by JinQiu Zhou and GuoLiang Xu at the Shanghai Institutes for Biological Sciences offers strong support for this model. The researchers introduced mouse genes encoding DNA methyltransferase enzymes into yeast, which lack this pathway but retain an innate capacity for histone methylation, and noted that the activity of these enzymes was apparently blocked by methylation of a key lysine residue in the H tail, HK. In fact, DNA methylation was consistently absent at the actively transcribed gene loci where HK methylation was markedly enriched disruption of the histone methylation pathway in turn led to DNA methylation at previously unmarked sites. They found that DNA modification is dependent on the capacity of DNA methyltransferases to bind directly to the H tail, and hypothesize that HK modification helps activate genes by masking this binding site and thereby preventing DNA methylationmediated repression. Hu, J.L. et al. The Nterminus of histone H is required for de novo DNA methylation in chromatin. Proceedings of the National Academy of Sciences USA , . GENETICS AIMBN RESEARCH Published in Nature Genetics Pinpointing genetic susceptibility to Parkinsons disease ISTOCKPHOTO/BANKSPHOTOS A largescale genomic study reveals two previously unidentified genetic risk factors for Parkinsons disease A consortium led by Wataru Satake of Kobe University Graduate School of Medicine, including researchers from the RIKEN Center for Genomic Medicine and the RIKEN Brain Science Institute, Japan, has identified two previously unknown genetic variants associated with increased susceptibility to Parkinsons disease PD. PD is a progressive neurodegenerative disorder caused by death of dopamineproducing midbrain neurons and characterized by tremor, rigidity and slow movements. In a genomewide association study GWAS, the researchers compared the entire genomes of , Japanese PD patients with those of , healthy controls. One of the variants identified lies within the PARK region and encodes a magnesium transporter. The other is in BST, which encodes an enzyme that catalyses formation of cyclic ADPribose, which releases calcium from intracellular stores. Magnesium deficiency has been implicated in PD and other neurodegenerative diseases disrupted calcium homeostasis is thought to compromise dopaminergic neurons. The researchers compared these results with those of a European GWAS. They found the BST variant only in Japanese patients, whereas a variant of the MAPT gene was found only in Europeans. The PARK variants, and previously identified variants in the SCNA and LRRK genes, were common to both populations. Although most cases of PD are sporadic, identification of these variants and others will improve understanding of PD. Satake, W. et al. Genomewide association study identifies common variants at four loci as genetic risk factors for Parkinsons disease. Nature Genetics , . Published in Nature Genetics Asian genomes point the way Personalized medicine takes a step closer to reality with a new technique for analyzing genomic variation An international team of molecular geneticists has developed a highly sensitive technique for detecting the differences between human genomes known as copy number variants CNVs. The researchers used their new technique, which provides finer resolution than previously possible, on individuals each of Korean, Chinese and Japanese origin, and found CNVs of which , were distinctively Asian. Humans ordinarily have two copies of each region of DNA, one from each parent. The ability to sequence whole genomes, however, has shown widespread variation in the number of copies between different individuals and ethnic groups. The CNVs are the result of rearrangements such as deletions and duplications. Led by JeongSun Seo of Seoul National University, the researchers Park, H. et al. Discovery of common Asian copy number variants using integrated highresolution array CGH and massively parallel DNA sequencing. Nature Genetics , . developed a strategy combining array comparative genomic hybridization aCGH with whole genome sequencing data. Initially, the researchers used socalled millionprobe aCGH technology to assess the relative differences in copy number between test and reference genomes for regions as short as base pairs. The sequencing data then allowed the relative copy numbers to be turned into absolute numbers. Our results provide guidance for future studies in genomic medicine in Asian populations, especially those that identify ethnic differences in predisposition to disease and drug response, the team says. www.natureasia.com/AIMBN AIMBN RESEARCH GENETICS Published in the Journal of Human Genetics Different strokes, different genes Two genetic variants that predispose Caucasians to stroke are also found in the Japanese population ISTOCKPHOTO/PHIlARTPHACe Stroke affects millions of people every year and is a leading cause of death, but very little is known about its genetic predisposition factors. Comparing the entire genomes of healthy and diseased individuals in genomewide association studies GWASs is a powerful way of identifying diseaserelated genes. Last year, an international team of researchers identified two genetic variants on chromosome that are associated with increased risk of stroke in Caucasians in a GWAS. Now, Tomonaga Matsushita of the RIKEN Center for Genomic Medicine, Japan, and his colleagues have reported that one of these variants is also associated with susceptibility to stroke in the Japanese population. The researchers replicated the earlier GWAS using Japanese instead of Caucasian participants, and analyzed the genomes of , patients who had suffered different types of stroke and , healthy controls. They found that the two previously identified variants are also present in the Japanese, and are most closely associated with atherothrombitic stroke, in which a large artery to the brain or smaller blood vessel is blocked by a clot. Stroke is a heterogeneous disease that comprises several subtypes, says Matsushita, and very few associated genetic variants have been identified. We now know of five, three of which appear to be specific to Asian populations. RESEARCH HIGHLIGHT COLLECTION Matsushita, T. et al. Association study of the polymorphisms on chromosome p with atherothrombotic stroke in the Japanese population. Journal of Human Genetics , . Published in Nature Genetics Casting wide yields aneurysm suspects Balloonlike dilations of arteries in the brain, called secular intracranial aneurysms, can cause severe neurological damage and death. They are the most common type of brain aneurysm, affecting approximately of the population. Richard Lifton of Yale University School of Medicine, USA, in collaboration with a large team of international researchers, including three from the University of Tokyos Institute of Sciences, have identified three gene variants associated with increased risk for intracranial aneurysms. The researchers performed a genomewide association study GWAS comparing the genomes of healthy and diseased individuals from Europe and Japan. By combining the data with those from a previous GWAS, they analyzed a A largescale genetic study identifies three genes associated with increased risk of brain aneurysm total of , aneurysm patients and , controls. Their analysis not only confirmed the three gene variants identified in the previous study, but also identified three more hitherto unidentified variants that are associated with increased risk for intracranial aneurysm. Based on their chromosomal positions, the researchers speculate that the newly identified gene variants are likely to play a role in cell division, and in maintaining the stem cells that are responsible for the formation and repair of blood vessels. The team writes that these data could contribute to the preclinical identification of individuals at high risk of developing intracranial aneurysms. Yasuno, K. et al. Genomewide association study of intracranial aneurysm identifies three new risk loci. Nature Genetics , . GENETICS AIMBN RESEARCH Published in Nature Plant fungis jump on pathogenicity genome study reveals horizontal gene transfer as a driver of rapid adaptation in diseasecausing plant fungi ISTOCKPHOTO/lIeNKIe An international genome consortium including researchers from Seoul National University in Korea has found evidence that socalled jumping Published in DNA Research Sprouting information Comparisons of the mungbean chloroplast genome reveal evolutionary relationships and will help genetically improve crop species Photosynthesis occurs in chloroplasts, organlike structures within the cells of green plant tissues. Chloroplasts are believed to have evolved from bacteria and have their own genomes. A team led by Sithichoke Tangphatsornruang of the National Center for Genetic Engineering and Biotechnology in Thailand has sequenced the chloroplast genome of mungbean Vigna radiata. Mungbean belongs to the family Fabaceae, which contains some , species, and is an economically important legume with proteinrich seeds. As in other higher plants, the mungbean chloroplast genome is a circular molecule of doublestranded DNA. The researchers found that it is also of a similar size to those of other flowering plants, and that it contains a pair of inverted repeats of nucleotide sequences separated by two singlecopy regions. Tangphatsornruang, S. et al. The chloroplast genome sequence of mungbean Vigna radiata determined by highthroughput pyrosequencing structural organization and phylogenetic relationships. DNA Research , . DNA sequencing revealed genes, including genes duplicated in the inverted repeat, while nearly a half of the genome is noncoding, as in other sequenced chloroplast genomes. Although chloroplast structure and gene content is generally conserved, the researchers did find a relatively large amount of genome rearrangement, as reported for other legumes. Comparison with the previously sequenced chloroplast genomes of other members of the Fabaceae and other plants allowed the researchers to reconstruct evolutionary relationships. Future studies should facilitate genetic engineering of agriculturally important legume species. genes segments of DNA that move location in the genome facilitate rapid adaptation of important fungal pathogens to new plant hosts. Species of fungi belonging to the genus Fusarium cause economically significant damage to crops around the world through blights, root rots and wilts. Some Fusarium species are host specific, while others have broad host ranges. Fusarium oxysporum, for example, infects a wide range of plants as well as humans with compromised immune systems. The researchers sequenced the genomes of the maize pathogen F.verticillioides, the toxins of which contaminate grain, and a strain of F.oxysporum that causes tomato wilt. By comparing these genomes and that of the previously sequenced cereal pathogen F.graminearum, they identified lineagespecific genomic regions of F.oxysporum rich in jumping genes and other evolutionarily distinct genes encoding virulence factors. By simple coincubation, they were able experimentally to transfer lineagespecific chromosomes between strains, conferring an otherwise nonpathogenic strain with the ability to cause tomato wilt. The researchers propose that horizontal transfer of virulence genes between strains may mediate the rapid emergence of new pathogenic lineages, with important implications for the management of crop diseases. Ma, L.J. et al. Comparative genomics reveals mobile pathogenicity chromosomes in Fusarium. Nature , . www.natureasia.com/AIMBN AIMBN RESEARCH GENETICS Published in Nature Genetics Transcending ethnic differences A genomewide analysis of the gene variants associated with blood and enzyme traits reveals similarities and differences between the Japanese and europeans Sixty single nucleotide polymorphisms SNPs, or DNA variations, associated with differing characteristics of blood, and a further associated with biochemical traits, have been uncovered in genomewide studies of some , individuals whose genetic material is stored in Japans Biobank. Of these associations, just over half were reported for the first time. The work was completed by researchers from the University of Tokyo and RIKEN in Japan. When the researchers compared their Japanese results with previous studies in European populations, the vast majority of the associations found among Europeans were replicated. A significant advantage of the Japanese work is that the array of data available on donor individuals allows for adjustment for factors which can potentially bias results. The research reveals genetic associations with differences in hemoglobin concentrations and platelet, white and red blood cell counts, as well as levels of lipids, proteins, albumin, blood urea nitrogen and several enzymes. Knowledge of the genes involved in some of the bloodrelated associations gives rise to plausible explanations for the observed impacts of the SNPs. Often these genes are related to cell division. Most of the differences found between ethnic groups involve SNPs at low frequency in one or other of the populations. Kamatani, Y. et al. Genomewide association study of hematological and biochemical traits in a Japanese population. Nature Genetics , . Published in Nature Genetics linking more suspects to bowel disease Across Asia, the prevalence of ulcerative colitis, a type of inflammatory bowel disease, is rising. Now, as reported in the journal Nature Genetics, Japanese researchers have identified two genes that are associated with this disease in the Japanese population SLCA and FCGRA. The SLCA protein is involved in ion transport in intestinal cells, and its expression is reduced in individuals with ulcerative colitis. Near, but not within, the coding region for this protein, the researchers discovered changes or polymorphisms in the genomic DNA that they had established is linked to the disease. They therefore propose that these polymorphisms may act to regulate the levels of SLCA gene expression. FCGRA encodes a receptor that binds to antibodies and drives the A largescale genetic study identifies three genes associated with increased risk of brain aneurysm immune response. In individuals with ulcerative colitis, the researchers found a polymorphism that enhances the affinity of the receptor for antibodies, making it easier for immune cells to be activated. Interestingly, an opposing polymorphism that reduces the receptors affinity for antibodies has previously been linked to autoimmune diseases like lupus. Another area of the genome that the scientists associated with increased disease risk did not contain any known genes. More research must be done to determine whether or not this region is involved in regulating the expression of other genes. Asano, K. et al. A genomewide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. Nature Genetics , . RESEARCH HIGHLIGHT COLLECTION ISTOCKPHOTO/TOMMl GENETICS AIMBN RESEARCH Published in Nature Genetics Getting at the roots of cancer risk genomic analysis reveals novel risk factors for a throat cancer with elevated prevalence throughout much of Asia AFIP/PeIR.NeT Relative to the general population, individuals in south China or Southeast Asia are at considerably greater risk of Published in Nature Genetics Diversity in the genome The first Japanese genome reveals the extent of human genetic variation The first whole genome sequence of a Japanese individual reveals that the human genome contains considerable and as yet undiscovered variation. Tatsuhiko Tsunoda of the RIKEN Center for Genomic Medicine and his colleagues used sophisticated DNA sequencing technology and analysis methods to analyze rare variations that are not normally targeted by previous methods. They sequenced the whole genome of a Japanese male comprehensively, covering . of the entire sequence times. They then compared the sequence with six other previously sequenced human genomes from nonJapanese populations. Their analysis revealed numerous variations in the Japanese individuals genome, many of which have not been reported. These included more than . million single nucleotide Fujimoto, A. et al. Wholegenome sequencing and comprehensive variant analysis of a Japanese individual using massively parallel sequencing. Nature Genetics , . variations, over , deletions, duplicated chromosomal regions and variations in the number of copies of certain genes. Functionally important variations were more enriched in rare ones than in common ones. The results suggest that a considerable number of rare variations, particularly those associated with disease, may still be undiscovered. They also show that wholegenome sequencing can be used to identify such variations, and that it will eventually be valuable for personalized medicine. We want to expand our scope to study diseases caused by multiple variants, says Tsunoda, and highthroughput sequencing technologies will greatly help such analyses. developing nasopharyngeal carcinoma pictured, a tumor of the upper throat. Environmental factors are partly to blame, including smoking or exposure to infection by EpsteinBarr virus. However, there is also clear evidence for genetic risk factors. A recent study, led by YiXin Zeng of Chinas Sun YatSen University Cancer Center and Jianjun Liu of the Genome Institute of Singapore, has uncovered several such candidate loci based on their analyses of large cohorts of southern Chinese individuals. Zeng, Liu and their colleagues performed a genomewide association study that assessed the distribution of tiny DNA sequence variations within these individuals. Their goal was to zoom in on variants with a statistically robust correlation with the onset of nasopharyngeal carcinoma. Some of these hits provided strong additional support for previous findings suggesting a meaningful connection with the HLA genes, which contribute to immune system function. However, Liu and Zeng also identified entirely novel risk factors, including a trio of genetic loci that have already been associated with leukemia and lymphoma. Such blood disorders are often associated with nasopharyngeal carcinoma, and the researchers intend to investigate the interconnections between these risk factors in future studies. Bei, J.X. et al. A genomewide association study of nasopharyngeal carcinoma identifies three new susceptibility loci. Nature Genetics , . www.natureasia.com/AIMBN neuroscience amp Developmental Biology ISTOCKPHOTO/SeBASTIAN KAulITzKI NEUROSCIENCE amp DEVELOPMENTAL BIOLOGY AIMBN RESEARCH Published in Neuron Muscling in on receptor clusters A protein that organizes receptors at cell membranes is essential for development of the neuromuscular junction Efficient signaling at the neuromuscular junction the interface between nerves and muscles requires precise alignment of synaptic vesicles at the nerve Published in The Journal of Experimental Medicine A model of dementia Transgenic mice reveal the cause of a common neurodegenerative disease A common form of dementia called frontotemporal lobar degeneration with ubiquitinpositive inclusions FTLDU is associated with insoluble protein clumps, containing TDP, which accumulate within neurons. CheKun James Shen from Academia Sinica, Taiwan, and his colleagues created genetically engineered mice overexpressing TDP in the forebrain and hippocampus, and found that this protein accumulated within neurons, causing severe learning and memory defects. The mice could not remember the location of a hidden platform in a water maze, and failed to associate a location in their housing chamber with electric shocks. Additional behavioral tests showed that TDP overexpression affected the animals motor functions, with coordination, balance and grasping reflex severely Tsai, K.J. et al. Elevated expression of TDP in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLDU. The Journal of Experimental Medicine , . impaired by six months of age. The memory defects were caused by altered levels of memoryassociated proteins in the hippocampus. This led to impaired longterm potentiation, the process by which neuronal connections are strengthened, and which is widely believed to underlie memory formation. The mice also exhibited characteristic FTLDU neuropathologies, which developed as in humans with the disease, and had shorter lifespans than normal animals. We have used these mice to test the therapeutic effects of a few drugs, says Shen, and are now analyzing the defects of neuronal development, neuron structure, gene expression, and protein metabolism misregulation in this FTLDU mouse model. terminal with acetylcholine receptors AChRs in the muscle cell membrane. During development, AChR clusters are transformed from a simple ovalshaped structure to a complex pretzelshaped one that is perfectly aligned with the motor neuron nerve terminal. This involves disassembling certain regions of the AChR clusters, but the underlying molecular mechanisms are unknown. A research team led by Nancy Ip of Hong Kong University of Science and Technology has now shown that the protein ephexin is essential for AChR cluster maturation. Ephexin was previously known to interact with EphA, a receptor tyrosine kinase involved in gene transcription at the neuromuscular junction, but the role of ephexin was unclear. The researchers found that mice lacking the ephexin gene exhibit severe muscle weakness and impaired nervemuscle signaling, because the neuromuscular junction does not mature properly, and the pretzelshaped structure fails to form. Experiments in cultured muscle cells revealed that ephexin regulates AChR cluster stability by activating the enzyme RhoA GTPase, which induces reorganization of the actin cytoskeleton. This raises the possibility that introducing ephexin might be a potential therapeutic approach for neuromuscular diseases such as myasthenia gravis, says Ip. Shi, L. et al. Ephexin is required for structural maturation and neurotransmission at the neuromuscular junction. Neuron , . elSeVIeR www.natureasia.com/AIMBN AIMBN RESEARCH NEUROSCIENCE amp DEVELOPMENTAL BIOLOGY Published in Proceedings of the National Academy of Sciences USA Benefitting from mixed messages Crosstalk between two signaling pathways ensures proper development of the nervous system within a developing embryo The transition from a simple ball of cells into a properly formed embryo depends on the coordinated interplay of numerous signal transduction pathways. By modulating each others activity, each signaling factors effects are constrained to ensure appropriate body patterning of the developing organism. A team led by Naihe Jing of the Shanghai Institutes for Biological Sciences, China, has provided a novel example of such regulatory crosstalk during the formation of the central nervous system. This process is directed in part by bone morphogenetic protein BMP signaling, which coordinates dorsalventral patterning, and retinoic acid RA signaling, which contributes to anteriorposterior patterning. Jing and colleagues demonstrated that RA gradually inhibits BMP activity in cultured mouse cells, an effect mediated by the accelerated degradation of Smad, a key downstream effector of BMP signaling. The same effect was also observed in vivo in chicken embryos. BMP signaling is typically observed in the dorsal region of the neural tube, the precursor to the mature central nervous system, but this activity could be restricted by RA signaling. Likewise, inappropriate BMP activity in embryos can markedly disrupt normal neural development, but the researchers showed that these perturbations could be mitigated through the effects of RA, highlighting the crucial interplay between these two networks. RESEARCH HIGHLIGHT COLLECTION Sheng, N. et al. Retinoic acid regulates bone morphogenic protein signal duration by promoting the degradation of phosphorylated Smad. Proceedings of the National Academy of Sciences USA , . ISTOCKPHOTO/HeRBAP Published in Neuron Sniffing out the olfactory code genetically engineered mice provide fresh insights into how mammalian neuronal circuits process odor information Odors are detected by olfactory sensory neurons OSNs that express olfactory receptors and form connections with mitral/tufted M/T cells in the main olfactory bulb, which sends the information to the brain. Understanding how odor information is processed involves comparing OSN responses with those of their corresponding M/T cells. This is possible in fruit flies, but is technically challenging in the more complex olfactory system of mammals. To overcome this, Minmin Luo of Chinas National Institute of Biological Sciences and his colleagues examined genetically engineered mice with OSNs expressing a specific olfactory receptor labeled with green fluorescent protein. This enabled them to record the electrical activity of specified OSNs and their corresponding M/T cells in response to various odors. Tan, J., Savigner, A., Ma, M. amp Luo, M. Odor information processing by the olfactory bulb analyzed in genetargeted mice. Neuron , . Their analysis revealed that M/T cells respond selectively to the odors detected by their corresponding OSNs, but also respond weakly to additional, noncorresponding odors at higher concentrations. In fruit flies, olfactory information is encoded differently, with projection neurons responding broadly to odors detected by many different OSNs. Further experiments revealed an important role for inhibitory neurons in the olfactory bulb. Blocking interneuron activity reduced the selectivity of M/T cells at high odorant concentrations, suggesting that they normally finetune M/T cell responses by suppressing the weak responses to noncorresponding odors. NEUROSCIENCE amp DEVELOPMENTAL BIOLOGY AIMBN RESEARCH Published in Proceedings of the National Academy of Sciences USA Shaping blood vessel formation early development of the circulatory system is regulated by an enzyme that induces chemical modification of chromosomes Chromosomal DNA is wound around scaffolds composed of histone proteins, and gene expression levels are profoundly affected by the extent to which Published in Nature Neuroscience Accelerating synapse formation An interaction between a scaffold protein and a membrane protein helps neurons form communication junctions Thrombospondin TSP, a scaffold protein critical for blood clotting, also plays a role in the formation of synapses between brain cells, according to a new study by researchers from the Hong Kong University of Science and Technology. TSP, which is secreted by various cell types including astrocytes in the brain, was already known to promote formation of synapses in retinal ganglion cells, but whether it does so in neurons from the brain has been unclear. Junyu Xu and Nan Xiao, led by neuroscientist Jun Xia, studied TSPs effect by applying TSP to cultured rat hippocampal neurons. By staining for synapsin and PSD, proteins enriched in the pre and postsynaptic membranes of Xu, J., Xiao, N. amp Xia, J. Thrombospondin accelerates synaptogenesis in hippocampal neurons through neuroligin . Nature Neuroscience , . excitatory synapses, respectively, they found that TSP increases the number of synapse in the earlier stages of neurons, but not in late stage mature neurons. This indicates that TSP accelerates the formation of synapses in neurons from the brain. The researchers also found that TSP binds the membrane protein neuroligin NL, and that reducing NL levels blocked TSPinduced synaptogenesis. This indicates that the effect of TSP is mediated by an interaction with NL. The effect in retinal ganglion cells is bigger, so may involve a different mechanism. specific DNA sequences are exposed to or masked from regulatory factors. Certain enzymes can modulate gene expression by introducing chemical modifications to histones that help regulate the arrangement of these proteins on chromosomal DNA. Now, new work from a team led by QiuHua Huang, SaiJuan Chen and Zhu Chen at Chinas Shanghai Jiao Tong University School of Medicine has revealed an important role for one such enzyme, the histone methyltransferase Hypb, in blood vessel development. The authors observed that mice lacking Hypb expression see image perish during embryonic development, with profound physical defects that include a relatively primitive and disorganized circulatory network. Compared with wildtype embryos, yolk sacs of Hypbdeficient mutants showed limited capacity for formation of both capillaries and larger blood vessels, and gene expression data revealed that loss of Hypb leads to misregulation of dozens of genes involved in vascular development. Accordingly, targeted inactivation of HYPB in cultured human endothelial cells impaired their innate capacity to selforganize and assemble into tightly interconnected capillarylike structures, further supporting a role for this enzyme in the direct regulation of genes that govern maturation of the vascular network. Hu, M. et al. Histone H lysine methyltransferase Hypb/Setd is required for embryonic vascular remodeling. Proceedings of the National Academy of Sciences USA , . PNAS www.natureasia.com/AIMBN AIMBN RESEARCH NEUROSCIENCE amp DEVELOPMENTAL BIOLOGY Published in Developmental Cell Keeping genes in their place expression of key developmental genes is restricted to certain embryonic regions via activitymodulating chemical modifications to chromosomal proteins ISTOCKPHOTO/HeNRIK Embryonic segmentation is a key component of development, wherein the body is divided into discrete zones whose maturation informs appropriate formation of the skeleton, nervous system and other tissues. These segments are established by the action of numerous Hox genes, whose activity is believed to be partly regulated by the chemical modification of histones proteins that provide a structural scaffold for the chromosomal DNA containing these genes. New work from a team at Australias Walter and Eliza Hall Institute of Medical Research, led by Anne Voss and Tim Thomas, has provided experimental support for this model, identifying histonemodifying enzyme Moz as an important regulator of anterior embryonic development in mice. This protein directly contributes to the introduction of acetyl groups at key points on histones associated with Hox gene clusters, and thereby helps govern their activation. In the absence of Moz, expression of the majority of Hox genes are shifted toward the posterior of the embryo, resulting in marked developmental defects in the spinal column and nervous system. Importantly, these developmental problems can be rescued by treatment with retinoic acid, a compound known to induce Hox gene activation. The authors conclude that Moz directly contributes to the segmentation process via its regulation of spatiallyappropriate expression of key Hox genes. RESEARCH HIGHLIGHT COLLECTION Voss, A. K., Collin, C., Dixon, M. P. amp Thomas, R. Moz and retinoic acid coordinately regulate HK acetylation, Hox gene expression, and segment identity. Developmental Cell , . Published in Developmental Cell First instructions for male mice The fate of male sex cells is determined by a molecule produced in the fetal testis A protein called fibroblast growth factor FGF directs germ cells to differentiate into sperm, researchers led by Peter Koopman from the University of Queensland, Australia, have found. The finding finally explains how a germ cell becomes either a sperm or an egg after being generated by meiosis, a form of cell division. Koopman and his colleagues performed cell culture experiments and examined mutant mice lacking either the Fgf gene or the gene encoding the enzyme CYPB. This enzyme is normally expressed in the testes and breaks down a molecule called retinoic acid RA, which drives egg specification by increasing expression of the Stra gene. The researchers found that germ cells in the testes of mice lacking CYPB did not differentiate into eggs, suggesting that a signal other than RA controls male sex cell determination. They then showed that FGF receptors are expressed on the surface of germ cells in the testes, and that Fgf acts directly on the cells to alter gene expression patterns. The team therefore concludes that high FGF levels in the testes promote male sex cell fate by reducing expression of Stra and inducing expression of male sex cell genes and is investigating how these findings relate to human infertility syndromes and testicular germ cell cancers. Bowles, J. et al. FGF suppresses meiosis and promotes male germ cell fate in mice. Developmental Cell , . NEUROSCIENCE amp DEVELOPMENTAL BIOLOGY AIMBN RESEARCH Published in Cell A green light for growth A small RNA molecule helps to stimulate body growth by removing obstacles to cell division ISTOCKPHOTO/JANeFF Proper body development requires careful regulation to ensure that the mature animal is neither excessively big nor small, as either outcome could have serious negative consequences. AIMBN RESEARCH SUPPORTED BY Molecular biology from an Asian perspective BioMAX Institute National Taiwan University School of Medicine Hyun, S. et al. Conserved microRNA miR/miR and its target USH/FOG control growth by regulating PIK. Cell , . Signaling pathways triggered by insulin play an important role in this process, but many gaps remain in the current understanding of growth control mechanisms. Seoul National University researcher V. Narry Kim and colleagues recently uncovered an important component of this process while looking for microRNAs small RNA molecules that inhibit expression of selected target genes that affect human cell proliferation. Her team observed strong effects from the various miR RNAs, and decided to further investigate their function by characterizing their fruit fly counterpart, miR. Flies with reduced miR levels were considerably smaller than normal due to reduced levels of cell division, but Kims team noted that proper growth could be fully rescued by selective expression of this microRNA in the fat body, a structure associated with metabolic regulation. They subsequently identified the Ush gene as a key target for downregulation by miR, and showed that both factors directly participate in regulation of insulin signaling. Since both miR and Ush have highly conserved human counterparts, the investigators hypothesize that this pathway could contribute to growth and, if misregulated, tumorigenesis in higher organisms. www.natureasia.com/AIMBN www.natureasia.com/AIMBN Structural amp Molecular Biology ISTOCKPHOTO/MARTIN MCCARTHy STRUCTURAL amp MOLECULAR BIOLOGY AIMBN RESEARCH Published in Proceedings of the National Academy of Sciences USA Getting in the blood Increased understanding of how malaria parasites gain entry to red blood cells should aid vaccine development A team led by Alan Cowman of the Walter and Eliza Hall Institute of Medical Research in Australia has made a significant breakthrough Published in Nature Making the cut The malarial enzyme plasmepsin V mediates the entry of malarial proteins into host red blood cells Symptoms of malaria, such as coma, can occur when the Plasmodium falciparum parasite infects red blood cells and exports its proteins into the host cell. This results in changing some of the properties of red blood cells including how readily it sticks to receptors on endothelial cells and other blood cells causing dysfunction in the body. Now, researchers in Australia have identified plasmepsinV PMV as the protease the proteincutting enzyme that is involved in this export process. Before being exported into red blood cells, malaria proteins need to be cleaved at an amino acid sequence called the Plasmodium export element PEXEL. The researchers honed in on PMV owing to its expression at the right time and place during the P.falciparum Boddey, J. A. et al. An aspartyl protease directs malaria effector proteins to the host cell. Nature , . life cycle, and because the PEXEL sequence showed similarities to protein sequences cleaved by HIV proteases, which are targeted by HIV protease inhibitor drugs. The researchers found that incubating PMV with PEXELcontaining peptides caused cleavage of the peptides, but this could be blocked by mutating the PEXEL. In addition, parasites expressing inactive PMV could not cleave these substrates. Importantly, PMV binds to exported proteins, and seems to be involved in directing them to be exported into the host blood cell. Developing drugs against PMV could become a novel therapeutic strategy against malaria. in understanding how malaria parasites invade human red blood cells erythrocytes. Malaria is a major killer in the tropics. Humans can become infected when bitten by mosquitoes carrying the malaria parasite. But to survive within the human host, the parasite must successfully invade erythrocytes see image. Cowmans team studied erythrocyte invasion by Plasmodium falciparum, which is responsible for the most severe form of human malaria. Invasion involves the binding of molecular ligands expressed by the parasite to receptor proteins on the erythrocyte surface. Some of these receptors contain sialic acid, whereas others do not. By expressing different ligands, P.falciparum can switch between sialic aciddependent and independent invasion pathways, helping it to evade the hosts immune system. Cowman and his collaborators showed that a known protein called Complement receptor CR is the erythrocyte receptor for PfRh, a major P.falciparum ligand essential for sialic acidindependent invasion. This is especially important because only ligandreceptor pairs involved in sialic aciddependent invasion had been identified previously. The researchers hope that their discovery will lead to the development of a vaccine capable of blocking erythrocyte invasion by malaria parasites. Tham, W.H. et al. Complement receptor is the host erythrocyte receptor for Plasmodium falciparum PfRh invasion ligand. Proceedings of the National Academy of Sciences USA , . CDC/MelVIN www.natureasia.com/AIMBN AIMBN RESEARCH STRUCTURAL amp MOLECULAR BIOLOGY Published in Nature Maintaining the silence The enzyme eSeT prevents the expression of endogenous retroviruses to preserve the integrity of the mammalian genome Uncontrolled dispersal of endogenous retroviral ERV sequences throughout the mammalian genome during early development can be harmful. The protein ESET can effectively silence ERV sequences in embryonic stem ES cells, but not more mature cells, researchers from Japan and Canada have found. ESET is a histone methyltransferase an enzyme that transfers methyl groups onto histone proteins around which genomic DNA is wrapped. Methylation of histone proteins or of the DNA itself can repress gene expression. Previous reports had shown that DNA methylation plays a key role in ERV silencing in some cell types, including germ cells, but another silencing pathway separate from DNA methylation operates in ES cells. The research team, including Yoichi Shinkai from Kyoto University, found the ESET protein localizes near genomic regions of DNA that contained ERV sequences in ES cells. In ES cells lacking ESET, the researchers found that transcription of three different ERVs was induced, and this was independent of DNA methylation. Because they did not see this same activation of ERVs in more mature fibroblasts lacking ESET, they concluded that ESET was only able to inhibit ERV expression in immature cells. The findings suggest that ESET silences ERVs during early development when DNA methylation is dynamically reprogrammed to maintain the integrity of the genome. RESEARCH HIGHLIGHT COLLECTION Matsui, T. et al. Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. Nature , . Published in Proceedings of the National Academy of Sciences USA Amplifying the silence gene silencing in plants is affected by the length of RNA molecules A plants development and defense against pathogen attack depends on its ability to silence certain genes. Now, a research team from Taiwan and the UK has confirmed that the power of gene silencing activity in plants is increased by microRNA molecules that are one nucleotide longer than the norm of nucleotides. MicroRNAs are small molecules that interfere with gene expression by instigating RNA cleavage. MicroRNAs can trigger the breakup of target messenger RNA mRNA into secondary, small interfering RNA molecules siRNAs, which further obstructs gene expression. The teams research clarifies why most microRNAmRNA interactions fail to produce secondary siRNAs. Led by ShuHsing Wu, the researchers found that both natural and engineered microRNA molecules containing nucleotides can direct cleavage of target mRNA and trigger the formation of secondary siRNA in the model plant Arabidopsis. They also confirmed experimentally that the length, not the composition of the nucleotide sequence, is the primary feature of microRNAs that initiates secondary siRNA production. In the future, the researchers will examine how the subtle increase in size affects microRNAmRNA interactions during RNA cleavage. Amplification in gene silencing could benefit scientists working not only to develop technologies for disease resistance in plants but also to manipulate gene expression in biotechnological applications. Chen, H.M. et al. nucleotide RNAs trigger secondary siRNA biogenesis in plants. Proceedings of the National Academy of Sciences USA , . CCASA/ zePHyRIS STRUCTURAL amp MOLECULAR BIOLOGY AIMBN RESEARCH Published in Cancer Cell Stopping the cancer spreading The identification of a new molecular player advances the quest to stop cancer in its tracks A team led by Qi Zeng of the ASTAR Institute of Molecular and Cell Biology, Singapore, has discovered that a protein called PCPB helps protect Published in Cell Research Binding and gagging tumors A newly identified molecular mechanism prevents cancerous cells from breaking off from tumors and spreading Researchers in China have found that a transcription factor called FOXA prevents tumors from spreading by inhibiting a process called the epithelialtomesenchymal transition EMT. EMT is characterized by loss of cell adhesion and increased cell movement. It is therefore critical for cancer progression, as it enables cancerous cells to break off from a tumor, enter the bloodstream and invade other organs. Jianguo Song and his colleagues from the Shanghai Institutes of Biological Sciences made the discovery by examining FOXA expression in several human lung cancer cell lines. They found that reducing FOXA levels induced EMT and promoted cell migration, whereas overexpressing the protein inhibited EMT and migration. Tang, Y., Shu, G., Yuan, X., Jing, N. amp Song, J. FOXA functions as a suppressor of tumor metastasis by inhibition of epithelialtomesenchymal transition in human lung cancers. Cell Research , Further investigation revealed that FOXA inhibits expression of a protein called slug, which normally promotes cell migration by reducing the expression of cell adhesion molecules in lung cancer cells. Others have previously shown that FOXA regulates the spread of colorectal cancer to the liver. This study now implicates FOXA in lung tumors, and suggests that it is a possible new drug target for lung cancer treatment. Our study also implies that cells with high FOXA levels are less malignant than cells with a low level, says Song, suggesting that FOXA is an important marker for judging the stages of lung cancer. against metastasis the spread of cancer around the body by suppressing translation of the metastasisassociated protein PRL phosphatase. Abnormally high levels of PRL phosphatase found in diverse human tumors are associated with metastasis and poor prognosis. Zeng and her collaborators analyzed over , human tumor samples and found that that PRL protein levels were elevated in nearly a quarter of them. PRL protein levels were not directly related to PRL gene expression, suggesting regulation at the level of messenger RNA mRNA translation. The researchers identified sequence motifs in the nonproteincoding region of PRL mRNA that are important for regulating translation efficiency in colon cancer cell lines. Further experiments revealed that a known RNAbinding protein, PCBP, suppressed PRL translation by specifically binding to these regulatory motifs, and that low levels of PCBP were associated with high levels of PRL in primary human cancers. In addition, experiments with mice showed that PCBP could suppress tumor development by limiting PRL protein levels and downstream signaling. The researchers hope that the identification of PCBP as a translational regulator of PRL will eventually lead to new anticancer drugs. Wang, H. et al. PCBP suppresses the translation of metastasisassociated PRL phosphatase. Cancer Cell , . www.natureasia.com/AIMBN AIMBN RESEARCH STRUCTURAL amp MOLECULAR BIOLOGY Published in Nature Structural and Molecular Biology Tying up loose ends A component of the telomerase complex folds DNA into a conformation that directly facilitates that enzymes chromosomeprotecting activity NIH/PADIllANASH AND RIeD Every time a chromosome is copied for cell division, it ends up slightly shorter due to a quirk in the replication process. The risk of serious genetic damage from this shortening is ameliorated by the presence of telomeres caps composed of repetitive DNA sequences that are maintained at the ends of each chromosome see image by the telomerase enzyme complex. The singlestranded ends of telomeres are believed to form structures called Gquadruplexes, but their functional importance was unclear. New work from JinQiu Zhou and colleagues at the Shanghai Institutes for Biological Sciences in China has now shown that Gquadruplex formation is critical to telomere maintenance, and establishes an important role for telomerase subunit Estp in this process. Estp is known to facilitate telomerase recruitment to telomeres, but Zhous team was surprised to discover that this protein can directly convert singlestranded yeast telomeric DNA into Gquadruplexes via a magnesiumdependent mechanism. They subsequently showed that mutations in a magnesiumbinding domain of Estp essentially cripple telomere growth, bringing yeast cell division to a grinding halt. Zhou and colleagues hypothesize that Estpmediated quadruplex formation helps position the telomerase catalytic domain and potentially contributes to its translocation during telomere extension a mechanism that seems likely to be evolutionarily conserved in higher organisms as well. RESEARCH HIGHLIGHT COLLECTION Zhang, M.L. et al. Yeast telomerase subunit Estp has guanine quadruplexpromoting activity that is required for telomere elongation. Nature Structural and Molecular Biology , . Published in Nature Cell Biology Putting injured cells to sleep A DNA damage response pathway brings cell division to a halt by eliminating a protein that maintains chromosomal integrity Each time a cell divides, chromosome ends shorten owing to a quirk in the DNA replication process. Proteincapped repetitive sequences called telomeres provide an essential buffer against degradation of the chromosome ends. Telomeric uncapping causes cell division to shut down via a process known as senescence, which is mediated at least in part by the protein p. However, new findings from a team led by Curtis Harris at the US National Cancer Institute in Bethesda, Maryland have shown that p can also actively trigger this uncapping process in response to genetic damage. Exposure to DNAdamaging conditions stimulates production of p. Harris and colleagues found that this upregulation is associated with reduced levels of TRF, a key telomerebinding protein, in cultured Fujita, K. et al. Positive feedback between p and TRF during telomeredamage signalling and cellular senescence. Nature Cell Biology , . cells. Under these conditions, p also induces the expression of Siah this enzyme, ubiquitin ligase, selectively marks other proteins for rapid degradation TRF appears to be among its targets. Premalignant adenoma cells exhibiting passociated senescence also showed increased Siah and decreased TRF levels relative to healthy cells, indicating that this regulatory pathway is also active in the human body. The researchers conclude that this represents a potentially important feedback loop that drives rapid telomere uncapping in damaged cells, shunting them towards senescence as a protective measure against uncontrolled cancerous growth. STRUCTURAL amp MOLECULAR BIOLOGY AIMBN RESEARCH Published in Virus Research Compatible partners Optimal enzyme activity for viral replication of a pandemic swineflu virus hinges on the enzymes subunit origins CDC/gOlDSMITH AND ROllIN To replicate successfully, influenza viruses pictured require the activity of an RNA polymerase that consists of three subunits PB, PB and PA. Published in Science All mixed up Genetic reassortment of influenza strains within pigs could yield more virulent or vaccineresistant derivatives of the pandemiccausing strain The rapid emergence of the HN/ swine flu pandemic triggered global panic in , raising fears of a potential public health crisis on the scale of the devastating outbreak. The HN/ virus contains gene variants derived from a number of other influenza strains, and it remains an open question whether this strain might stably establish itself in pig populations to an extent that enables further interviral recombination. To address this question, Yi Guan and Malik Peiris at the University of Hong Kong characterized influenza variants isolated from swine at a Hong Kong abattoir in late and early . In January , they isolated one novel HN variant termed Vijaykrishna, D. et al. Reassortment of pandemic HN/ influenza A virus in swine. Science , . swine/HK//, which appears to be an amalgam of genes from three other strains. Importantly, the gene encoding one major viral surface protein, neuraminidase, appears to have originated from HN/, while the other, hemagglutinin, is derived from a different strain as a result, the HN/ vaccine is ineffective at blocking swine/HK// infection. Based on these findings, Guan and Peiris caution that further viral genome reorganization could give rise to a more virulent influenza strain in the near future, and advocate more aggressive swine surveillance to identify and intercept these variants as they emerge. Now, researchers at the National Center for Genetic Engineering and Biotechnology in Thailand have found that mixing subunits from different influenza viral strains reduces the activity of this enzyme and renders it less able to replicate virus in cell culture experiments. The PA protein of the pandemic swineorigin influenza virus SOIV of contains the amino acid serine at position . Older swine flu strains and human and avian flu viruses, however, contain the amino acid glycine at this position. When the researchers switched this serine in SOIV PA to glycine, the function of the SOIV RNA polymerase was reduced. They also found that switching the glycine at position in an older swine flu strain to a serine enhanced the activity of an RNA polymerase that was also composed of PB and PB from the SOIV strain. The findings suggest to the researchers that SIOV is unlikely to mix, or reassort, with other strains to create new viral strains. The results also provide insight into how the enzyme subunits work together to drive RNA polymerase activity. Further, targeting amino acid may be efficacious in fighting viral growth. Wanitchang, A., Jengarn, J. amp Jongkaewwattana, A. The N terminus of PA polymerase of swineorigin influenza virus HN determines its compatibility with PB and PB subunits through a strainspecific amino acid serine . Virus Research , . www.natureasia.com/AIMBN AIMBN RESEARCH STRUCTURAL amp MOLECULAR BIOLOGY Published in Human Molecular Genetics Cellular stress protection Insights into the physiological function of a membrane transport protein may explain the mechanism underpinning a human vascular disease A research team based in Taiwan has revealed the mechanism by which mutations in a membranebound protein called glucose transporter GLUT, which actually transports solutes, can lead to the vascular disease called arterial tortuosity syndrome ATS. Lax skin and joints, as well as twisting of the major arteries, which can cause aneurysms and strokes, are hallmarks of patients with ATS. Building on earlier work by other researchers who identified GLUT deficiency as the cause of ATS, the research team, led by YanTsong Chen of Taiwans Academia Sinica, showed that GLUT is expressed in the mitochondria of smooth muscle cells of mice. The team also showed that, in contrast to similar forms of this protein that transport glucose, GLUT actually delivers dehydroascorbic acid DHA the oxidized form of vitamin C. Once in the mitochondria, DHA protects the cell from the ravages of reactive oxygen species, a common byproduct of mitochondrial function. The researchers conclude that when mutations stop GLUT from functioning, ATS results from excessive oxidative stress in smooth muscle cells, which leads to distorted and misshapen arteries. They also note that their findings underline the importance of a derivative of vitamin C and reactive oxygen species in degenerative diseases. dehydroascorbic acid import and protects cells against oxidative stress mechanistic insight into arterial tortuosity syndrome. Human Molecular Genetics , . Published in Proceedings of the National Academy of Sciences USA Tracking transcriptional traffic Detailed maps capture the starts and stops of the machinery at the core of gene expression Lee, Y.C., Huang, H.Y., Chang, C.J., Cheng, C.H. amp Chen, Y.T. Mitochondrial GLUT facilitates RESEARCH HIGHLIGHT COLLECTION Although the RNA polymerase complex Pol II hypothetically travels in a straight line as it transcribes gene sequences into messenger RNA, its actual journey is less straightforward. Transcription proceeds in fits and starts, and is coupled to other complex processes such as splicing, in which nonproteincoding intron sequences are neatly excised from the rough draft RNA transcript. To chart the dynamic behavior of Pol II during transcription, a team led by Tatsuhiko Kodama and Sigeo Ihara of the University of Tokyo, Japan, and Peter Cook at the University of Oxford, UK, performed an elaborate series of timecourse experiments to track RNA production from five large genes. All five are activated by a common factor, tumor Wada, Y. et al. A wave of nascent transcription on activated human genes. Proceedings of the National Academy of Sciences USA , . necrosis factor, which enabled the researchers to turn on and track each gene simultaneously. They observed that each rough transcript is produced in a fastmoving initial wave during this period, additional waves start but do not progress, and latearriving Pol II complexes produce only short, abortive transcripts. Pol II doesnt appear to brake for splicing, with introns trimmed almost as quickly as they can be transcribed. However, the complex does stall at sites where DNAinteracting proteins RAD and CTCF are bound. The authors speculate that these may act as physical roadblocks to Pol IImediated elongation. ISTOCKPHOTO/KATIV STRUCTURAL amp MOLECULAR BIOLOGY AIMBN RESEARCH Published in Genes amp Development unraveling the roles of multitasking enzymes ISTOCKPHOTO/DRASCHWARTz Studies of genetically engineered mice are uncovering subtle molecular mechanisms responsible for fine tuning protein expression in mammalian cells Over recent years, molecular biologists have increasingly recognized the functional importance of small RNA molecules called microRNAs that inhibit proteincoding messenger RNAs. A microRNA biosynthesis pathway known as the canonical pathway that has been described in fruit flies and nematodes requires two RNAprocessing enzymes Drosha and Dicer. A team led by Mark Chong of the Walter and Eliza Hall Institute of Medical Research in Australia has now determined the roles of these enzymes in mice. Chong and his collaborators confirmed that both enzymes are required for canonical microRNA biosynthesis in mice. However, they found different gene expression and protein profiles of mice deficient in Drosha or Dicer, suggesting their separate involvement in other processes. Further experiments revealed that Drosha directly cleaves many messenger RNAs in earlystage thymocytes, which eventually mature into the functional T cells of the immune system. The researchers also identified a number of unusual microRNAs generated by a Dicerdependent but Droshaindependent mechanism, demonstrating that Dicer is involved in generating different classes of microRNA in mammalian cells. However, these microRNAs were mostly distinct from mirtrons, a previously identified class of microRNAs in fruit flies and nematodes that are generated by messenger RNA splicing machinery. They hope now to elucidate the complex mechanistic details of microRNA pathways in mammals. Chong, M. M. W. et al. Canonical and alternate functions of the microRNA biogenesis machinery. Genes amp Development , . Published in The Plant Cell Working with a silent partner Proper functioning of a key plant enzyme depends on collaboration between a biologically active catalytic subunit and a passive regulator subunit Early stages in the production of the diverse family of biologically active molecules known as terpenes depend on the coordinated activity of various prenyltransferase PTS enzymes. The best characterized of these operate as homomeric complexes containing two copies of the same protein subunit. However, new work from a team led by TaoHsin Chang and Andrew H.J. Wang at the Academia Sinica in Taiwan has now revealed details of the workings of a more engimatic heteromeric PTS, CGPP synthase GPPS, from the mint plant Mentha piperita Mp. Mp GPPS contains two copies each of a large subunit LSU and a small subunit SSU. Although LSU closely resembles the subunits of homomeric PTS complexes, Chang Chang, T.H. et al. Structure of a heterotetrameric geranyl pyrophosphate synthase from mint Mentha piperita reveals intersubunit regulation. The Plant Cell , . and Wang found that it lacks catalytic activity on its own, and depends on interactions with SSU to achieve a stable, fully functional structure. Mp GPPS can synthesize two distinct terpene precursors of varying length, but synthesizes only the shorter of the two in vivo. Based on their crystal structure data the first ever obtained for a heteromeric PTS as well as a series of functional experiments, the researchers formulated a twochamber model in which the noncatalytic SSU acts as a regulator that physically constrains the length of molecules synthesized by the catalytic LSU. www.natureasia.com/AIMBN AIMBN RESEARCH STRUCTURAL amp MOLECULAR BIOLOGY Published in Nature Materials Spotlighting single DnA molecules Synthesis of lightactive nanostructures paves the way for detection of single DNA molecules A new approach for synthesizing lightactive nanostructured probes to detect single DNA molecules using the technique called surfaceenhanced Raman scattering SERS has been developed in Korea. Singlemolecule detection is expected to shed light on the behavior of biomolecules in living cells and clinical samples. Because SERSbased singlemolecule detection hinges on the probes nanoenvironment, reproducible synthesis of welldefined nanostructures is essential. The researchers, led by JwaMin Nam of Seoul National University and Yung Doug Suh of Korea Research Institute of Chemical Technology, combined DNA hybridization and magnetic nanoparticle separation to generate dumbbellshaped goldsilver nanostructures with a lightactive dye at the center pictured in high yield. First, the researchers synthesized two sets of DNAgold nanoparticle conjugates and tethered the dye to one of the DNA strands. After magnetic separation, they bridged the nanoparticles into dumbbells using a complementary singlestranded DNA. Finally, they deposited silver on the gold, creating nanometer shells around the gold nanoparticles. By controlling the silver deposition, the researchers could tune the nanometersize gap between the dye and metal nanoparticles. This strategy significantly enhanced the singlemolecule sensitivity of the nanostructures, allowing reproducible singleDNA detection. The team is currently investigating the potential implementation of their RESEARCH HIGHLIGHT COLLECTION nanostructures in fast, quantitative and multiplexed assays to detect infections. Lim, D.K., Jeon, K.S., Kim, H. M., Nam, J.M. amp Suh, Y. D. Nanogapengineerable Ramanactive nanodumbbells for singlemolecule detection. Nature Materials , . Published in Proceedings of the National Academy of Sciences USA Making the right connections An unusual partnership between proteins appears to underlie healthy development of the inner ear Harmonin and Sans are among the various proteins associated with Usher syndrome, a hereditary disorder characterized by congenital impairments in hearing and balance and a predisposition to blindness. These proteins form a complex that contributes directly to hair cell development within the ear. Now Mingjie Zhangs team at the Hong Kong University of Science and Technology has revealed important details about the basis for this interaction. Harmonin features multiple evolutionarily conserved PDZ domains, which mediate proteinprotein interactions. Zhang and coworkers observed that one PDZ domain combines with a nearby helical domain to form a Sansrecognizing supramodule. Although PDZ domains have been extensively studied, they were surprised to note that, in addition to the canonical PDZ binding behavior, the harmonin PDZ also associates with the SAM domain of Sans via a previously unidentified interaction mechanism. Many Usher syndrome patients express variants of these two proteins with mutations that directly affect PDZ or SAM. Cell culture experiments confirmed that these alterations can severely impair Sans and harmonin colocalization and complex formation. The authors conclude that their findings could not only help illuminate the molecular foundations of this debilitating disorder, but may also guide discovery of previously overlooked binding partners for some other PDZcontaining proteins in the human genome. Yan, J., Pan, L., Chen, X., Wu, L. amp Zhang, M. The structure of the harmonin/sans complex reveals an unexpected interaction mode of the two Usher syndrome proteins. Proceedings of the National Academy of Sciences USA , . STRUCTURAL amp MOLECULAR BIOLOGY AIMBN RESEARCH Published in Proceedings of the National Academy of Sciences USA Bacterial chaperonin a trick of the tail Discovery of a way to disrupt the structure of a key protein of the potentially pathogenic bacterium Heliobacter pylori could lead to new therapeutics ISTOCKPHOTO/SgAMe Shujian Cun and Hongzhe Sun of Hong Kong University may have discovered an Achilles heel of Heliobacter Founded in , the AsiaPacific International Molecular Biology Network AIMBN is an organization dedicated to bringing together leading researchers and institutions in Asia and the Pacific Rim to promote the development of scientific and technical excellence in molecular biology and genetic engineering research in the region. The AIMBN serves the scientific community through a range of activities including its fellowship program, technical workshops as well as regular scientific conferences. Further information about the work of the AIMBN including details of how to become a member can be found at www.aimbn.org pylori pictured, which can cause peptic ulcers and stomach cancer. In most organisms, the chaperonin proteins GroEL and GroES together protect cells from heat shock, which causes protein unfolding. GroES forms the lid of a molecular container composed of GroEL, inside which encapsulated proteins rapidly refold. Because GroES dysfunction is lethal, natural selection should tolerate few changes in the sequence of aminoacid building blocks. Cun and Sun studied HspA, a form of GroES found in H. pylori that, uniquely, has the amino acids histidine and cysteine at particular positions of its tail. Biochemical experiments showed that these amino acids form an oxidationsensitive zincbinding site. On infection, the hosts immune system releases zinc and reactive oxygen free radicals that damage bacteria. Supporting the idea that the unusual properties of HspA help counter these defenses, the researchers found that bismuth antiulcer drugs displace zinc from the metalbinding site, disrupting the proteins structure. Comparison with GroES proteins from other organisms suggested that the zincbinding site of HspA may have evolved as a result of negative selection against variation at neighboring sites. This discovery may lead to new drugs that can retard the emergence of drug resistance. Cun, S. amp Sun, H. A zincbinding site by negative selection induces metallodrug susceptibility in an essential chaperonin. Proceedings of the National Academy of Sciences USA , . www.natureasia.com/AIMBN ISTOCKPHOTO/HeNRIK JONSSON Immunology amp Therapeutics IMMUNOLOGY amp THERAPEUTICS AIMBN RESEARCH Published in The Lancet Taking a shot at pandemic flu A largescale clinical trial reveals the safest and most effective vaccine formulation to provide immunity to the pandemic influenza A HN virus ISTOCKPHOTO/MIKeKIeV Seasonal influenza vaccines help control the spread of specific influenza viruses by preparing the body to mount an immune response upon exposure to those viruses. After the pandemic Published in The EMBO Journal last line of defense Cellular enzymes keep influenza from running rampant by putting the brakes on viral replication For a virus, getting inside a cell is only half the job successful infection also requires the production of new viral particles, a process that is heavily dependent on factors found within the environment of the host cell. For example, recent studies have indicated that cellular enzymes may regulate the efficiency of influenza A replication by selectively tagging viral proteins with individual molecules of the small protein ubiquitin. New findings from Michael Lai and colleagues at Academia Sinica in Taiwan have now confirmed the importance of this modification. Based on a series of screening experiments, the researchers were able to determine that USP, a ubiquitinremoving enzyme, acts as an effective inhibitor of virus production in cells infected by influenza A. Liao, T.L., Wu, C.Y., Su, W.C., Jeng, K.S. amp Lai, M. M. C. Ubiquitination and deubiquitination of NP protein regulates influenza A virus RNA replication. The EMBO Journal , . Early in infection, the influenza genome is transcribed to produce proteins that include viral nucleoprotein and the components of the RNAdependent RNA polymerase complex, which subsequently combine to drive replication of the viral genome. Lai and colleagues demonstrated that nucleoprotein is a target of ubiquitination, and that this modification plays an important role in stabilizing its interaction with viral RNA. They hypothesize that by removing this individual ubiquitin molecule, USP prevents the replication complex from forming and thereby undermines the production of new virus particles. originating in Mexico in , there is a pressing need to develop safe and effective vaccines against the HN influenza viruses originating in swine. Now, researchers from China report a placebocontrolled clinical trial on an HN vaccine that has been produced in China, and tested in over , individuals. The researchers administered eight different vaccine formulations to determine which was the safest and most effective. For example, different antigen concentrations were included in the vaccine to ascertain how little antigen could be used to still obtain an effective immune response. This is an important question in the event of a pandemic and the need to vaccinate the population quickly with a limited antigen supply. The researchers also included formulations with or without aluminium adjuvant, a chemical that may boost the immune response to the vaccine. Interestingly, the formulations without adjuvant promoted a higher level of immunity, as assessed by antibody measurements against a viral antigen. The findings demonstrate the safety and efficacy of this vaccine, and will guide immunization parameters for patients. Liang, X.F. et al. Safety and immunogenicity of pandemic influenza A HN vaccines in China a multicentre, doubleblind, randomised, placebocontrolled trial. The Lancet , . www.natureasia.com/AIMBN AIMBN RESEARCH IMMUNOLOGY amp THERAPEUTICS Published in Proceedings of the National Academy of Sciences USA Curtailing cholera longterm immunity against cholera from a ricebased, oral vaccine takes a step forward A team led by Hiroshi Kiyono from the University of Tokyo, Japan, has developed a ricebased oral vaccine MucoRiceCTB that effectively induces neutralizing antibodies against the acute, and often fatal, disease cholera. MucoRiceCTB contains a component of cholera toxin CT produced by Vibrio cholerae, the bacterium responsible for cholera. The researchers previously showed that MucoRiceCTB protects against CTinduced diarrhea in mice and also induces CTneutralizing antibodies in monkeys. They have now shown that intestinal secretion of specific CTneutralizing IgA antibodies or secretory IgA SIgA following oral immunization with MucoRiceCTB is critical for protection against CTinduced diarrhea in mice. Immunized mice were protected up to six months after primary immunization and a further four months by a single booster immunization. MucoRiceCTB also protected mice against enterotoxigenic Escherichia coli ETEC, another major cause of human diarrheal disease, because CTneutralizing antibodies also recognize the heatlabile toxin of ETEC. MucoRiceCTB remained effective even after storage for three years at room temperature, suggesting that it could be distributed cheaply without refrigeration. Moreover, oral administration of the vaccine eliminates the need for needles and syringes. The findings confirmed the potential of MucoRiceCTB as a newgeneration oral vaccine. Clinical trials are now needed to show whether it is effective in preventing cholera and ETECinduced gastroenteritis in humans. RESEARCH HIGHLIGHT COLLECTION Published in Proceedings of the National Academy of Sciences USA Slow and steady A single injection of a large insulin aggregate into diabetic animals can allow for longterm regulation of their blood glucose levels A team of scientists from India has found that one injection of a specially formulated insulin aggregate into diabetic animals can lead to steady release of insulin into the blood for over days. If the findings can be extended into humans, this insulin aggregate formulation could revolutionize diabetes treatment by drastically reducing the number of insulin injections that diabetic patients need to administer. Current treatment calls for multiple daily injections of the hormone insulin, which is a high burden for patients to endure. The inability of diabetes patients to regulate their blood sugar levels can lead to complications such as nerve damage, kidney failure and cataracts. Gupta, S., Chattopadhyay, T., Singh, M. P. amp Surolia, S. Supramolecular insulin assembly II for a sustained treatment of type diabetes mellitus. Proceedings of the National Academy of Sciences USA , . Insulin is responsible for pulling glucose out of the blood and into all of the bodys cells. The insulin that is currently used for diabetes treatment is made up of single insulin peptides in solution. However, insulin peptides can aggregate into larger structures. The researchers thought that these larger aggregates could allow for slow and steady release of insulin peptides. When they injected the insulin aggregate into diabetic animals, this allowed for longterm control of blood glucose levels, and a decrease in the incidence of cataracts and other complications in the animals. ISTOCKPHOTO/yOuNgVeT Tokuhara, D. et al. Secretory IgAmediated protection against V. cholerae and heatlabile enterotoxinproducing enterotoxigenic Escherichia coli by ricebased vaccine. Proceedings of the National Academy of Sciences USA , . IMMUNOLOGY amp THERAPEUTICS AIMBN RESEARCH Published in Proceedings of the National Academy of Sciences USA Fighting the flu virus A campaign of very highthroughput screening for antiinfluenza compounds could lead to new treatments for flu Scientists in Taiwan have screened over . million chemicals to identify unique compounds that inhibit the replication of the influenza virus pictured. Published in Nature Biotechnology Flu fighter A drug that induces clumping of an influenza virus protein enhances the survival of mice that have been exposed to the flu A team of researchers from Hong Kong and Canada may have found a new treatment to combat influenza infections. The findings are timely because particular influenza virus strains that infect humans are now resistant to existing antiviral drugs. Led by KwokYung Yuen of the University of Hong Kong, the team revealed a molecule called nucleozin that causes aggregation of influenza virus nucleoprotein and reduces viral replication in cell culture experiments. The researchers identified nucleozin as a suitable drug candidate by screening a large chemical library of over , compounds. They found that nucleozin could protect a kidney cell line from viral toxicity. Nucleozin induced nucleoprotein aggregation in lung epithelial cells, Kao, R. Y. et al. Identification of influenza A nucleoprotein as an antiviral target. Nature Biotechnology , . which prevented nucleoprotein from moving into the nucleus and playing a role in replication of the virus. Nucleozin seemed to act directly on viral nucleoprotein alone, because of its nuclearexclusion of purified nucleoprotein protein, and because a single point mutation in nucleoprotein reduced the efficacy of nucleozin. Yuen and colleagues showed that nucleozin also had efficacy in animals it was able to enhance the survival of mice that were exposed to the influenza virus. If nucleozin has similar effects in humans, it may expand the current treatments for influenza infection. A few established pharmaceuticals that target the influenza enzyme neuraminidase are effective at inhibiting viral replication once an individual is infected. However, the rapid evolution of drugresistant influenza strains reduced the effectiveness of these drugs, highlighting the need to develop new antiinfluenza agents against different viral targets. Using very highthroughput screening methods, the researchers identified several new classes of antiinfluenza compound, including inhibitors of the viral RNA polymerase, which is essential for viral replication. One of these compounds, FA, is chemically similar to a recently reported influenza inhibitor called Nucleozin. They found that FA targets the polymerase subunit nucleoprotein, whereas a second chemical, called compound , targets a different polymerase subunit called PB. Further experiments revealed that FA potently inhibits the replication of several virulent influenza strains in cultured cells, and that it protects against lethal influenza infection in mice. The researchers used specific mutations in nucleoprotein and PB to confirm the selective targeting of compounds FA and . They believe that these new antiinfluenza compounds against different influenza RNA polymerase subunits could lead to new antiinfluenza drugs. CDC/MuRPHy Su, C.Y. et al. Highthroughput identification of compounds targeting influenza RNAdependent RNA polymerase activity. Proceedings of the National Academy of Sciences USA , . www.natureasia.com/AIMBN AIMBN RESEARCH IMMUNOLOGY amp THERAPEUTICS Published in Leukemia The good without the bad Stem cell transplants that fight leukemia could cause fewer side effects if patients are on the drug imatinib Some blood cancers can be cured with stem cell transplantation, but this can lead to graftversushost disease GVHD a side effect where the grafted cells mount an immune response against host organs, causing symptoms such as diarrhea, dry eyes and mouth, and skin rashes. Now, researchers collaborating across multiple institutions, hospitals and medical centers across Japan have discovered that the drug called imatinib could be used to prevent the onset of GVHD. Imatinib can be used to treat GVHD after onset, and is also used to prevent cancer recurrence. It inhibits signaling pathways that drive the pathological changes in organs that characterize GVHD, such as the formation of fibrous connective tissue where it does not belong. The researchers compared the medical records of patients who had been treated with imatinib after receiving their stem cell transplant, but before the development of GVHD, with those not treated with imatinib. They found that the imatinibtreated patients had decreased incidence and severity of GVHD, particularly of the gastrointestinal tractrelated symptoms such as diarrhea and dry mouth. Because the researchers based their analysis on existing medical records, they suggest that a clinical trial be initiated in leukemia patients after stem cell transplantation to test whether or not the beneficial effects of imatinib stand true in a large population. Nakasone, H. et al. Prophylactic impact of imatinib administration after allogeneic stem cell transplantation on the incidence of chronic graft versus host disease in patients with Philadelphia chromosomepositive leukemia. Leukemia , . Published in Science Poisoning the well of cancer Biochemical and biophysical analyses explain the ability of arsenic to promote the remission of leukemia Chromosomal abnormalities, such as those that stem from ionizing radiation or exposure to chemical mutagens, can lead to a fusion of genes that results in the expression of a novel, cancercausing protein. This often occurs in leukemias, including acute promyelocytic leukemia APL. Therapeutically targeting these unique fusion proteins is of high interest as they represent a way to specifically target cancer cells without harming genetically normal, healthy cells. The drug arsenic trioxide has already proved effective in inducing durable remission of APL. Zhu Chen and his colleagues in Shanghai and elsewhere in China and France have now revealed the molecular mechanism that underlies this therapeutic effect of arsenic. Zhang, X.W. et al. Arsenic trioxide controls the fate of the PMLRAR oncoprotein by directly binding PML. Science , . Using biochemical, genetic and biophysical techniques the team showed that arsenic binds to the cysteine residues of one portion of the fusion protein that causes APL. This binding induces a conformational change in the protein such that it forms aggregates, which increases its recognition by the components of the cellular machinery that lead to protein degradation. Reduction in the levels of the cancerpromoting fusion protein explains the ability of arsenic to promote remission of APL. With the molecular mechanism now identified, further refinement of arsenic therapy can now be developed. RESEARCH HIGHLIGHT COLLECTION ISTOCKPHOTO/THelINKe IMMUNOLOGY amp THERAPEUTICS AIMBN RESEARCH Published in Proceedings of the National Academy of Sciences USA Collaborating with the enemy An inflammatory signaling protein switches off essential immune surveillance systems that help keep tumor growth in check ISTOCKPHOTO/eRAXION Cellular signaling factor interleukin IL induces an inflammatory response that is believed to be conducive to accelerated tumor growth. IL Published in Nature Immunology Dialing up diabetes Discovery of a mechanism that triggers inflammation in patients with type diabetes could lead to a new type of treatment An international team of researchers from Ireland, the US and Japan has identified the protein islet amyloid polypeptide IAPP, which is found in abnormal clumps in the pancreas of diabetic patients, as the cause of an increase of a regulator of the immune system that plays an important role in inducing diabetes. The regulator, proinflammatory cytokine interleukin IL, increased when the team stimulated pancreatic immune cells with IAPP. The team found that mice that were expressing high levels of IAPP and on a highfat diet a significant risk factor for the development of diabetes in humans also exhibited elevated levels of IL. The researchers showed that the clumps of IAPP are engulfed by Masters, S. L. et al. Activation of the NLRP inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL in type diabetes. Nature Immunology , . the immune cells of the pancreas. This led to activation of a protein complex called the inflammasome, which was already known to be involved in the generation of IL. In cells lacking portions of the inflammasome complex, they found that IAPP was unable to alter IL protein levels. Interestingly, a drug currently used to treat diabetes also inhibited IL production that was induced by IAPP in the immune cells. The research team argues that reducing IAPPinduced activation of the inflammasome may be a new way to treat diabetes. also drives the proliferation of a specific subset of helper T cells Th that secrete another proinflammatory factor, interleukinA ILA, although it remains controversial whether ILA is also involved in cancer progression. A research team led by Mark Smyth at the Peter MacCallum Cancer Centre in Australia has helped to clarify this situation, using a variety of mouse tumor models to characterize the growthpromoting or inhibitory effects of these two interleukins. In virtually every case examined, production of IL was directly associated with tumor growth and metastatic spread, and even undermined the effectiveness of treatment strategies known to reduce formation of lung metastases. In comparison, the researchers observed no significant contribution from ILA to ILmediated acceleration of progression in any of these cancer models. The researchers note that IL appears to act by thwarting the activation of natural killer cells, which aggressively target cancer cells for destruction, although the detailed mechanism of this immunosuppression remains unclear. Nevertheless, Smyth and colleagues hypothesize that antibodies or other drugs that selectively target IL have the potential to boost the effectiveness of existing cancer therapeutic strategies. Teng, M. W. L. et al. IL suppresses innate immune response independently of ILA during carcinogenesis and metastasis. Proceedings of the National Academy of the Sciences USA , . www.natureasia.com/AIMBN AIMBN RESEARCH IMMUNOLOGY amp THERAPEUTICS Published in Nature Cell Biology unmasking bacterial saboteurs A bacterial protein helps eliminate a key component of the bodys defense mechanisms against infection Bacteria produce molecules that set off immune system alarms, but many have also developed strategies that enable them to directly counter the bodys defensive response by blocking immune signaling cascades. A team led by University of Tokyo researcher Chihiro Sasakawa has now revealed how one of these factors, the protein IpaH. in the Shigella bacterium pictured, achieves its sabotage of the host inflammatory response. IpaH. acts as an E ubiquitin ligase, an enzyme that marks other proteins for rapid destruction by tagging them with ubiquitin molecules, although its specific targets have remained a mystery. Sasakawas team found that this protein inhibits the activity of NFB, a transcription factor that activates numerous genes involved in triggering inflammation. Screening experiments subsequently confirmed that IpaH. binds to NEMO, an upstream activator of NFB, and ABIN, a protein that normally inhibits this activation. Interestingly, ABIN appears to directly facilitate the action of IpaH., enhancing binding to and subsequent ubiquitination of NEMO. Mice infected with Shigella lacking functional IpaH. exhibited more protracted inflammatory responses and reduced numbers of bacteria in their lung tissue. The authors conclude that the accelerated degradation of NEMO induced by this effector keeps the inflammatory response in check and thereby clears the way for infection. RESEARCH HIGHLIGHT COLLECTION Ashida, H. et al. A bacterial E ubiquitin ligase IpaH. targets NEMO/IKK to dampen the host NFBmediated inflammatory response. Nature Cell Biology , . Published in Proceedings of the National Academy of Sciences USA Pathways of presentation Specialized subsets of immune cells use separate cellular pathways to display antigen on their cell surface When fighting infection, T cell response is driven by antigens presented on the surface of immune cells called dendritic cells DCs. Typically, before being presented at the cell surface, DCs must degrade the antigen and load the processed version of it onto specialized molecules. Now, a team of researchers from Australia and France report different mechanisms by which different kinds of DCs in the spleen present antigens. When the researchers obtained DCs from the spleen of animals that had abdominal inflammation, they found that these inflammatory DCs use the mannose receptor protein to send antigen to a cellular compartment called the endosome. There, the inflammatory DCs use an enzyme called insulinregulated aminopeptidase IRAP to cleave the antigen and load it onto the specialized antigen presentation machinery. The researchers observed that inflammatory DCs lacking the mannose receptor or IRAP exhibited decreased antigen presentation. However, CD DCs derived from the spleen of healthy animals did not use these proteins to present antigen. Additional studies are needed to characterize how CD DCs process antigen for display on their surface. Nevertheless, the findings have important implications for vaccine development, since targeting antigen to specific types of DCs can elicit a more efficacious T cell response to antigen. Segura, E., Albiston, A. L., Wicks, I. P., Chai, S. Y. amp Villadangos, J. A. Different crosspresentation pathways in steadystate and inflammatory dendritic cells. Proceedings of the National Academy of Sciences USA , . CDC IMMUNOLOGY amp THERAPEUTICS AIMBN RESEARCH Published in Proceedings of the National Academy of Sciences USA unlikely allies against infection Intestinal bacteria help out their hosts by strengthening immune protection against other, less benevolent microbes Multitudes of bacteria make themselves a happy home within the mammalian small intestine. However, these residents are not merely freeloaders, but instead earn their keep by facilitating host digestion and metabolism, among other functions. New findings from a research team led by Hiroshi Kiyono of the University of Tokyo, Japan, now offer important insights into another important function of these gut flora pictured, revealing how the bacteria residing within clumps of immune cells known as Peyers patches PPs contribute to host defense against pathogenic microbes. Kiyono and colleagues determined that the interior of mouse PPs is largely populated by Alcaligenes, a common opportunistic bacterium. Its presence appears to trigger a highly localized immune response, characterized by elevated levels of IgA antibodies within the gut, without inducing a strong systemic reaction. These antibodies appear to directly contribute to stable internalization of Alcaligenes within PPs. They also found that this bacterium is in turn important to proper development and function of the mucosal immune system without Alcaligenes, mice generate considerably fewer mature IgAsecreting cells. This bacterium also resides within primate and human PPs, and the authors conclude that these and other findings from their study may hint at contributions of other bacterial species to immune system development at the wholebody level. Obata, T. et al. Indigenous opportunistic bacteria inhabit mammalian gutassociated lymphoid tissues and share a mucosal antibodymediated symbiosis. Proceedings of the National Academy of Sciences USA , . CDC Published in Nature Infectionproofing by the gut Clarification of the details of the molecular mechanism of the intestinal immune system may lead to new oral vaccines An international research team has unraveled the molecular details of a key mechanism of the largest segment of the immune system, the lining of the gut. The work opens the way to developing versatile, inexpensive vaccines that are imbibed, rather than injected. In an investigation that employed the latest techniques of microdissection, microarray analysis, staining, microscopy and molecular genetics, Hiroshi Ohno and colleagues from the RIKEN Research Center for Allergy and Immunology, Yokohama, working with biologists from several Japanese universities and Stanford University in the US, have uncovered a receptor molecule, glycoprotein GP, on specialized microfold or M cells of the gut lining. M cells are Hase, K. et al. Uptake through glycoprotein of FimH bacteria by M cells initiates mucosal immune response. Nature , . involved in moving antigens from the gut cavity to immune system cells beneath. GP stimulates this immune response by binding to a protein on the hairlike projections or pili of bacteria such as Escherichia coli and Salmonella. Ohno and colleagues experimented with mixing GP with E.coli, and found that it linked to the protein FimH on the type pili of bacteria. In fact, GP binds only to bacteria that carry FimH, and not to those without. The researchers found the immune process was severely hampered in Salmonella lacking FimH and in mice lacking GP. www.natureasia.com/AIMBN AIMBN RESEARCH IMMUNOLOGY amp THERAPEUTICS Published in Proceedings of the National Academy of Sciences USA When antibiotics backfire Antibiotic compounds directly initiate a defense mechanism in certain highly pathogenic bacteria that greatly undermines their effectiveness as drugs ISTOCKPHOTO/ VISuAlFIelD Staphylococcal bacteria represent a serious health concern, in part because of their remarkable capacity to protect themselves. For example, individual Staphylococcus epidermidis cells can respond to treatment with antibiotics by banding together to form biofilms that are resistant to both pharmaceuticals and host immune cells. Initiation of biofilm formation depends on production of polysaccharide intercellular adhesin PIA molecules. New research from a team led by Andrew Wang at the Academia Sinica in Taiwan has revealed a mechanism by which commonly used antibiotics actually promote drug resistance by activating the Ica genes that govern PIA synthesis. The S.epidermidis protein TcaR is a known regulator of the Ica gene cluster, and the researchers were able to determine how interacting pairs of TcaR molecules bind to specific DNA sequence elements, physically obstructing gene expression and thus repressing PIA production. However, TcaR is also capable of binding to a diverse array of antibiotics, including penicillin, kanamycin and chloramphenicol. The researchers revealed that these various molecules introduce structural alterations in TcaR that interfere with its capacity to bind DNA. As a result, these drugs effectively alleviate Ica repression and actively promote biofilm formation. Wang and coworkers conclude that the discovery of molecules that target this regulatory pathway could help thwart staphylococcal drug resistance. RESEARCH HIGHLIGHT COLLECTION Chang, Y.M. et al. Structural study of TcaR and its complexes with multiple antibiotics from Staphylococcus epidermidis. Proceedings of the National Academy of Sciences USA , . Published in Nature Immunology Fate director understanding the development of allergic inflammation advances from the identification of a crucial protein Allergic responses can be triggered by the inflammatory cytokine interleukin IL, which is secreted by a recently identified subset of T cells called TH cells. Now, a team of researchs from the US and Australia, led by Mark Kaplan from the Indiana University School of Medicine, has identified that a transcription factor protein called PU. is needed for the development of these cells. The researchers found that T cells from PU.deficient mice secreted less IL than T cells from normal mice. When they forced expression of PU. in T cells in cell culture, they noted an increase in IL expression. PU. seemed to act by binding directly to the IL gene in the genomic DNA, and inducing the expression of IL. In PU.deficient mice, the researchers observed less allergic airway inflammation in response to antigen exposure, and this correlated with less IL expression in their T cells. Alterations in levels of IL also seemed to affect allergic responses in humans in young children with allergies, the researchers found increased expression of IL, which may have come from TH cells. Moreover, blocking PU. expression in human T cells decreased IL production. Blocking production of PU. and IL may provide therapies to prevent or treat allergic responses, the team suggests. Chang, H. et al. The transcription factor PU. is required for the development of ILproducing T cells and allergic inflammation. Nature Immunology , . IMMUNOLOGY amp THERAPEUTICS AIMBN RESEARCH Published in Modern Pathology Immune response linked to early arrival Chronic inflammation of the placental membranes surrounding the fetus is linked to spontaneous preterm birth in humans ISTOCKPHOTO/ANDyl Babies born prematurely have an increased risk for developing cerebral palsy and other chronic illnesses. Understanding why preterm birth Published in Proceedings of the National Academy of Sciences USA Building a better booster Stronger protective immune responses from vaccines could now be possible from a modification made to a modulator of immune cells Vaccine efficacy can be improved by adding chemicals called adjuvants that boost the immune system, but finding the right molecule for the job can require iterations of modification. In phase I clinical trials using the molecule galactosylceramide GalCer to activate immune cells and modulate the immune response to a foreign antigen, researchers recorded limited biological activity. Now, a team of researchers from the US and Taiwan has designed a molecule called DW, a modification of GalCer, which can serve as a powerful adjuvant in mouse models, and so could be promising in humans. The team found that DW was more effective than GalCer at inducing inflammatory cytokine secretion from human immune cells. Li, X. et al. Design of a potent CDdbinding NKT cell ligand as a vaccine adjuvant. Proceedings of the National Academy of Sciences USA , . DW also bound more tightly than GalCer to protein receptors on both mouse and human immune cells that are critical for modulating immune responses. The immune systems of mice seemed to react more strongly to malaria and HIV vaccines when DW was coadministered as the immuneboosting adjuvant than when GalCer was coadministered, and the mice were better able to fight infection if they had received vaccine with the DW adjuvant. The researchers contend that DW may be a new and efficacious adjuvant to use in human vaccine clinical trials in the future. occurs is the first step toward developing appropriate interventions to prevent it. Now, researchers in the US and Korea have found that chronic inflammation of the membranes around the fetus called chronic chorioamnionitis is prevalent in patients who experienced spontaneous preterm birth. The researchers examined microscopic sections of placental tissue including the fetal membranes from women who had given birth. They found that the women who went into labor spontaneously before their due date had a much higher rate of chronic chorioamnionitis than women who delivered fullterm babies. The team found that expression of inflammatory chemokines that induce immune cell recruitment was increased in the fetal membranes in patients with chronic chorioamnionitis. They therefore think that chronic chorioamnionitis may be caused by inflammatory processes that occur because of a reaction of the mothers immune system against the fetus. The preterm births that were associated with chronic chorioamnionitis occurred later in pregnancy than preterm births linked to acute chorioamnionitis, which is caused by bacterial infections. The research team therefore suggests that chronic chorioamnionitis may explain nearterm preterm births. Kim, C. J. et al. The frequency, clinical significance, and pathological features of chronic chorioamnionitis a lesion associated with spontaneous preterm birth. Modern Pathology , . www.natureasia.com/AIMBN AIMBN RESEARCH IMMUNOLOGY amp THERAPEUTICS Published in Nature Single protein seeks mature partner Structural analysis reveals details of an important safeguard mechanism for proper immune system development Within the mammalian thymus, a sophisticated DNA recombination process ensures the production of a diverse array of T cell receptor TCR protein complexes. This heterogeneity is essential, as TCRs play a pivotal role in recognizing potential threats from foreign molecules within the body. The preTCR, which consists of an chain preT and a successfully recombined TCR chain, helps drive maturation of TCRexpressing cells. Now, new findings from a team led by James McCluskey at the University of Melbourne and Jamie Rossjohn at Monash University, Australia, have revealed how preT molecules selectively associate with mature chains to move this process forward. Both proteins are membranebound see image, and the researchers began by collecting structural data for the segments that project from the cell membrane. They found that when these two molecules are bound together, the recombined variable region of the chain remains unpaired. Based on the chemical composition of the exposed regions, one might predict this to be an unstable arrangement. Rossjohn and McCluskey determined, however, that these complexes actually pairoff in dimers, with a headtotail arrangement that shields the exposed residues. This mode of interaction can only occur with mature, processed chains, such that this highly stable arrangement also serves as a sensor for the production of fully functional TCR components. RESEARCH HIGHLIGHT COLLECTION Pang, S. S. et al. The structural basis for autonomous dimerization of the preTcell antigen receptor. Nature , . Published in Proceedings of the National Academy of Sciences USA Protective markings Rapid antiviral response depends on enzymatic modification of a protein that helps activate the immune system For many proteins, getting tagged with molecules of ubiquitin is a sentence of death via enzymatic destruction, while other proteins depend on ubiquitination to successfully execute their functions in the cell. A recent study from a team led by Kunitada Shimotohno at Japans Chiba Institute of Technology has added the NEMO protein to this latter list. NEMO is known to be an important middle man in the innate immune response, which represents the first line of defense against viral infection, although the details of its involvement have been unclear. Shimotohno and colleagues demonstrated that NEMO interacts with enzyme TRIM, which modifies at least five different sites on the protein by appending multiple molecules of ubiquitin arranged in a highly atypical chain configuration. A number of genes that are typically activated in response to viral infection showed reduced activity in cells subjected to TRIM depletion, and these cells also showed an impaired capacity to produce signaling factors that promote the innate immune response. These various antiviral responses appear to be directly dependent on TRIMmediated multisite ubiquitination of NEMO. As this pathway is triggered in response to a broad variety of viruses, the authors suggest that it may prove worthwhile to develop therapeutic strategies that specifically stimulate TRIM activity. Ariomoto, K. et al. Polyubiquitin conjugation to NEMO by triparite motif protein TRIM is critical in antiviral defense. Proceedings of the National Academy of Sciences USA , . NPg SUPPORTED BY www.natureasia.com/AIMBN
