Table of contents



Reaction to retractions p1523


Retracting a paper is perhaps the most unpleasant task a journal has to face, particularly if the retraction involves scientific misconduct. With the number of retractions on the rise, an improved mechanism to deal with misconduct is necessary.



Trial networks move beyond single-disease strategies p1525

Elie Dolgin


New HCV drugs trigger race for more tolerable therapies p1526

Sarah C P Williams


Institutes unite to put New York on the biopharma map p1527

Hannah Waters


Genome center's location stuck in transit p1527

Hannah Waters


Four-in-one HIV pill may be exception among combination drugs pp1528 - 1529

Hannah Waters


Class of once-weekly diabetes drugs poised for approval p1528

Hannah Waters


Patent-sharing scheme for neglected diseases may have catch p1529

Hannah Waters


Corrections p1529


International coding upgrade affects clinical research and reviews p1530

Madhumita Venkataramanan


Databases aim to bridge the East-West divide of drug discovery p1531

Katharine Sanderson


Biostatisticians call for more scientifically rigorous pilot studies p1531

Cassandra Willyard


News in brief: Biomedical briefing pp1532 - 1533



Straight talk with... Amanda Glassman p1534

Elie Dolgin


Since its launch in 2001, the Center for Global Development (CGD) has been instrumental in convening working groups and issuing reports that shape the agenda for a range of topics that affect global poverty and people of the developing world. At the helm of its global health effort is Amanda Glassman. In recognition of CGD's ten-year anniversary last month, Elie Dolgin spoke to Glassman about how the think tank turns its words into actions.


Efficient drug approval and monitoring must rely on sound regulatory science p1535

Emma A Meagher & Garret A FitzGerald


The path to drug approval is long, hard and often perplexing. In recent months, the US Food and Drug Administration (FDA) has promised to bolster 'regulatory science', which aims to transform its decision-making process to be more efficient, transparent and accountable. However, diverse stakeholders, including patients, drug developers and the US Congress, will have to rise to the challenge of coordinating their priorities if this endeavor is to succeed.

News Features

Breaking the silence pp1536 - 1538

Alla Katsnelson


Scientists had long assumed that any genetic mutation that does not alter a protein sequence should have no impact on human health. But recent research has shown that such synonymous DNA changes can trigger disease in a number of ways. Alla Katsnelson talks to scientists and biotech companies who are speaking up about 'silent' mutations.

2011 in review p1539


The Yearbook p1539


We list key people who made headlines this year, either by standing up for what they saw as right or by stopping what they felt was wrong.

Notable advances 2011 pp1540 - 1541


We look back on some of the key insights into biomedicine published this year.

Drugs in traffic: the road to approval pp1542 - 1543


Here we present the in-gene-ious cancer drugs, sanguine blood thinners and others of 2011 as we look back on this year's major headlines related to medications.


Book Review

The history of hemophilia p1545

Katherine A. High reviews The Bleeding Disease: Hemophilia and the Unintended Consequences of Medical Progress by Stephen Pemberton




Mannose-binding lectin—the forgotten molecule? pp1547 - 1548

Michael Osthoff, George Trendelenburg, Damon P Eisen & Marten Trendelenburg


Reply to: Mannose-binding lectin—the forgotten molecule? p1548

Costantino Iadecola & Josef Anrather



News and Views

A gut triumvirate rules homeostasis pp1549 - 1550

Alejo Chorny & Andrea Cerutti


IgA regulates intestinal homeostasis by maintaining appropriate communities of bacteria within the gut. A new study shows that intestinal bacteria regulate metabolism via IgA (pages 1585–1593).

See also: Article by Shulzhenko et al.

A sweet T cell response pp1551 - 1552

Rino Rappuoli & Ennio De Gregorio


Although protein-polysaccharide conjugate vaccines provide notable clinical benefits, it is still not fully understood how they work. A new mechanism of action for these vaccines has been identified in which T cells can recognize sugar epitopes in the context of the major histocompatibility complex (MHC) provided they are bound to a protein 'anchor', which allows binding of the sugar epitope to the MHC (pages 1602–1609).

See also: Article by Avci et al.

Stressed tumor cell, chemosensitized cancer pp1552 - 1554

Erik A C Wiemer


miR-200 family expression results in highly proliferative ovarian cancer cells. Yet this expression is also linked to longer overall survival in women with ovarian cancer. A new study sheds light into this apparent paradox showing that two members of this family—miR-141 and miR-200a—not only boost tumor growth but also sensitize tumor cells to chemotherapy (pages 1627–1635).

See also: Article by Mateescu et al.

NF-κB in DCs: it takes effort to be immature pp1554 - 1556

Rémi J Creusot


The nuclear factor-κB (NF-κB) family of regulators is well known for mediating dendritic cell (DC) maturation—that is, the acquisition of the functions required for full activation of T cells. Paradoxically, a key member of this family, NF-κB1, is now also implicated in maintaining DCs in an immature state (pages 1663–1667).

See also: Letter by Dissanayake et al.

Nitrite-NO bailout for a NOS complex too big to fail pp1556 - 1557

Mark T Gladwin & Jesús Tejero


Cellular production of nitric oxide (NO) by nitric oxide synthase (NOS) in the face of limiting pools of arginine requires the intracellular citrulline-to-NO pathway, catalyzed by the enzyme argininosuccinate lyase (ASL). People with the urea cycle disorder argininosuccinic aciduria, caused by a deficiency of ASL, have systemic NO deficiency, which can be rescued by the use of an alternative, NOS-independent, nitrite-to-NO pathway.

See also: Article by Erez et al.

Diagnosis in a dish: your skin can help your brain pp1558 - 1559

Anita Huttner & Pasko Rakic


The discovery that skin cells from an adult human can be reprogrammed back to their embryonic stage and then differentiated to produce neuron-like cells in culture opens an opportunity to study disease pathogenesis and screen potential therapeutic drugs. A new study provides an example of this approach for the neuropsychiatric disorder Timothy syndrome (pages 1657–1662).

See also: Letter by Paşca et al.


Community Corner

Mixed results for a malaria vaccine pp1560 - 1561



Between Bedside and Bench

Fruitful progress to fertility: Preserving oocytes from chemodestruction pp1562 - 1563

Min Xu, Mary Ellen Pavone & Teresa Woodruff


Chemotherapy can save the lives of many individuals with cancer. Unfortunately, it usually causes infertility after treatment, posing a concern for these people who will face a lifetime condition that considerably limits the quality of their lives. Advances in the field of oncofertility have brought hope to cancer survivors who long to plan a family; however, standard approaches only rely on cryopreservation of sperms and eggs before treatment and do not prevent infertility. In 'Bedside to Bench', Min Xu, Mary Ellen Pavone and Teresa Woodruff examine a study where individuals treated with gonadotropin-releasing hormone (GnRH) agonists before cancer therapy showed a decreased risk of infertility. How these agonists work to suppress and protect ovarian function and increase fertility in women after treatment is still unclear and begs further investigation at the bench. In 'Bench to Bedside', Amander Clark, Bart Phillips and Kyle Orwig discuss potential experimental options to preserve and restore male fertility after chemotherapy. These approaches will shed light into mechanisms of male fertility and spermatogenesis and may be the alternative to sperm freezing, which is not suitable for prepubertal boys and men unable to make sperm.

Fruitful progress to fertility: Male fertility in the test tube pp1564 - 1565

Amander T Clark, Bart T Phillips & Kyle E Orwig




Improving the efficacy of translational medicine by optimally integrating health care, academia and industry pp1567 - 1569

Stefan R Bornstein & Julio Licinio




Diseases in a dish: modeling human genetic disorders using induced pluripotent cells pp1570 - 1576

Gustavo Tiscornia, Erica Lorenzo Vivas & Juan Carlos Izpisúa Belmonte


This review provides a guide to the conceptual and practical issues to consider when trying to generate an iPSc model that accurately recapitulates the features of a human genetic disease. The authors highlight recent successes in modeling genetic diseases using iPSCs and offers a perspective on the next steps that will be needed to improve current iPSC-based disease models.



A hepatocyte growth factor receptor (Met)−insulin receptor hybrid governs hepatic glucose metabolism pp1577 - 1584

Arlee Fafalios, Jihong Ma, Xinping Tan, John Stoops, Jianhua Luo, Marie C DeFrances & Reza Zarnegar


It is well regarded that insulin receptor signaling in the liver is key to proper metabolic control. Reza Zarnegar and his colleagues now show that the hepatocyte growth factor receptor, Met, physically interacts with the insulin receptor signaling complex, potentiating the latter's signaling. They also show that Met signaling restores insulin responsiveness in a mouse model of insulin resistance, suggesting a potentially new therapeutic avenue to treat prediabetes.

Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut pp1585 - 1593

Natalia Shulzhenko, Andrey Morgun, William Hsiao, Michele Battle, Michael Yao, Oksana Gavrilova, Marlene Orandle, Lloyd Mayer, Andrew J Macpherson, Kathy D McCoy, Claire Fraser-Liggett & Polly Matzinger


Polly Matzinger and her colleagues have shown that in the absence of B cells, and in the presence of the microbiota, the intestinal epithelium launches its own immune defense mechanisms. However, this comes at the expense of metabolic programs involved in fat absorption by the gut. These results could explain the lipid malabsorption often seen in humans with common variable immunodeficiency or with HIV infection.

See also: News and Views by Chorny & Cerutti

Mesenchymal stem cell–based tissue regeneration is governed by recipient T lymphocytes via IFN-γ and TNF-α pp1594 - 1601

Yi Liu, Lei Wang, Takashi Kikuiri, Kentaro Akiyama, Chider Chen, Xingtian Xu, Ruili Yang, WanJun Chen, Songlin Wang & Songtao Shi


Bone marrow-derived mesenchymal stem cells (BMMSCs) have so far failed to live up to their potential as a treatment for the repair of large bone defects. Songtao Shi and his colleagues now show that this may be due to their apoptosis mediated by resident T cells in the wound as a result of excess IFN-γ and TNF-α signaling. They show that reducing the levels of these cytokines, including through the local administration of aspirin, markedly increases the survival of implanted BMMSCs and improves bone wound healing in a mouse model.

A mechanism for glycoconjugate vaccine activation of the adaptive immune system and its implications for vaccine design pp1602 - 1609

Fikri Y Avci, Xiangming Li, Moriya Tsuji & Dennis L Kasper


Glycoconjugate vaccines—such as those targeting some bacteria—couple a glycan to a protein to provide T cell help to B cells and induce polysaccharide-specific IgGs. T cell help has been thought to be conferred by recognition of the protein portion by T cells. Dennis Kasper and his colleagues now report that a glycan-peptide conjugate can induce T cells specific for the glycan moiety, which could help inform future glycoconjugate vaccine development.

See also: News and Views by Rappuoli & De Gregorio

Oxidation of CaMKII determines the cardiotoxic effects of aldosterone pp1610 - 1618

B Julie He, Mei-ling A Joiner, Madhu V Singh, Elizabeth D Luczak, Paari Dominic Swaminathan, Olha M Koval, William Kutschke, Chantal Allamargot, Jinying Yang, Xiaoqun Guan, Kathy Zimmerman, Isabella M Grumbach, Robert M Weiss, Douglas R Spitz, Curt D Sigmund, W Matthijs Blankesteijn, Stephane Heymans, Peter J Mohler & Mark E Anderson


The hormone aldosterone can damage the heart after myocardial infarction, such that drugs that inhibit its action are often prescribed. B. Julie He et al. now uncover a new pathway underlying the detrimental effects of aldosterone action: oxidation of the enzyme Ca2+/calmodulin-dependent protein kinase II leads to its activation and increased expression of the metalloprotease MMP9 in cardiac muscle cells, thereby promoting cardiac rupture.

Requirement of argininosuccinate lyase for systemic nitric oxide production pp1619 - 1626

Ayelet Erez, Sandesh C S Nagamani, Oleg A Shchelochkov, Muralidhar H Premkumar, Philippe M Campeau, Yuqing Chen, Harsha K Garg, Li Li, Asad Mian, Terry K Bertin, Jennifer O Black, Heng Zeng, Yaoping Tang, Anilkumar K Reddy, Marshall Summar, William E O'Brien, David G Harrison, William E Mitch, Juan C Marini, Judy L Aschner, Nathan S Bryan & Brendan Lee


The enzyme argininosuccinate lyase (ASL) generates the amino acid arginine, the precursor to both urea and nitric oxide. However, arginine supplementation is not sufficient to correct all of the symptoms of individuals with a congenital deficiency of this enzyme. Ayelet Erez et al. explain this paradox by showing that ASL has a role in nitric oxide synthesis that is independent of its catalytic activity and provide evidence that therapy with agents boosting nitric oxide levels might be beneficial in ASL-deficient individuals.

See also: News and Views by Gladwin & Tejero

miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response pp1627 - 1635

Bogdan Mateescu, Luciana Batista, Melissa Cardon, Tina Gruosso, Yvan de Feraudy, Odette Mariani, André Nicolas, Jean-Philippe Meyniel, Paul Cottu, Xavier Sastre-Garau & Fatima Mechta-Grigoriou


This report identifies a new contribution of members of the miR-200 family to tumorigenesis. miR-200a and miR-141 specifically regulate p38α, contributing to the cellular modulation of oxidative stress responses. In this role, the miRs can accelerate ovarian tumorigenesis but also endow cancer cells with increased sensitivity to ROS-inducing chemotherapy. This two-part effect is reflected on the distinct association of the miRs with patient survival and may be informative for treatment decisions.

See also: News and Views by Wiemer



Inhibition of proteasome deubiquitinating activity as a new cancer therapy pp1636 - 1640

Pádraig D'Arcy, Slavica Brnjic, Maria Hägg Olofsson, Mårten Fryknäs, Kristina Lindsten, Michelandrea De Cesare, Paola Perego, Behnam Sadeghi, Moustapha Hassan, Rolf Larsson & Stig Linder


b-AP15 is a novel inhibitor of proteasome activity, with a different mechanism of action than the available and widely used proteasome inhibitors such as bortezomib. b-AP15 inhibits the deubiquitinating activity of the regulatory subunit of the proteasome, necessary for protein degradation, and induces cytotoxicity impairing tumor growth in mouse models. The compound may represent an alternative therapeutic approach with a broader spectrum of applicability than current proteasome inhibitors.

A MEK-independent role for CRAF in mitosis and tumor progression pp1641 - 1645

Ainhoa Mielgo, Laetitia Seguin, Miller Huang, Maria Fernanda Camargo, Sudarshan Anand, Aleksandra Franovic, Sara M Weis, Sunil J Advani, Eric A Murphy & David A Cheresh


Raf kinase activity is deregulated in cancers and is thought to promote tumor growth by inducing proliferation signaling through MEK/Erk. This report identifies a new role for c-Raf independent of MEK/Erk and relying on phosphorylation of Ser338. Phospho–C-Raf interacts with the mitotic kinases Aurora-A and Plk1, activating the latter to promote mitotic progression and increase cell division, and this pathway is a crucial mediator for the protumorigenic effect of c-Raf in vivo.

Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer pp1646 - 1651

Dan R Robinson, Shanker Kalyana-Sundaram, Yi-Mi Wu, Sunita Shankar, Xuhong Cao, Bushra Ateeq, Irfan A Asangani, Matthew Iyer, Christopher A Maher, Catherine S Grasso, Robert J Lonigro, Michael Quist, Javed Siddiqui, Rohit Mehra, Xiaojun Jing, Thomas J Giordano, Michael S Sabel, Celina G Kleer, Nallasivam Palanisamy, Rachael Natrajan, Maryou B Lambros, Jorge S Reis-Filho, Chandan Kumar-Sinha & Arul M Chinnaiyan


This report identifies oncogenic fusions in individuals with breast cancer involving the genes encoding NOTCH and MAST, recurring in approximately 5–7% of studied cases. The fusions show growth-promoting properties that suggest that they may represent targetable events in a subset of people with breast cancer.

The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis pp1652 - 1656

Merit Cudkowicz, Michael E Bozik, Evan W Ingersoll, Robert Miller, Hiroshi Mitsumoto, Jeremy Shefner, Dan H Moore, David Schoenfeld, James L Mather, Donald Archibald, Mary Sullivan, Craig Amburgey, Juliet Moritz & Valentin K Gribkoff


Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons. Now, Valentin Gribkoff and his colleagues show some preliminary evidence that the drug dexpramipexole may have clinical activity in a small placebo-controlled trial in patients with ALS.

Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome pp1657 - 1662

Sergiu P Paşca, Thomas Portmann, Irina Voineagu, Masayuki Yazawa, Aleksandr Shcheglovitov, Anca M Paşca, Branden Cord, Theo D Palmer, Sachiko Chikahisa, Seiji Nishino, Jonathan A Bernstein, Joachim Hallmayer, Daniel H Geschwind & Ricardo E Dolmetsch


Timothy syndrome is a neurodevelopmental disease that includes autism-like features. Using iPS-derived neurons from individuals with Timothy syndrome, Ricardo Dolmetsch and his colleagues identify changes in cortical neuron fate and neurotransmitter expression that may begin to explain the neural mechanisms that underlie this disorder.

See also: News and Views by Huttner & Rakic

Nuclear factor-κB1 controls the functional maturation of dendritic cells and prevents the activation of autoreactive T cells pp1663 - 1667

Dilan Dissanayake, Håkan Hall, Nancy Berg-Brown, Alisha R Elford, Sara R Hamilton, Kiichi Murakami, Leslie Summers Deluca, Jennifer L Gommerman & Pamela S Ohashi


Although maturation of dendritic cells can drive autoimmune responses in mice, it remains unclear whether intrinsic factors hold dendritic cells in a resting state. Pamela Ohashi and her colleagues identify a repressive mechanism requiring expression of nuclear factor-κB1 in dendritic cells. Loss of nuclear factor-κB1 results in CD8+ T cell activation, TNF-α production and autoimmune diabetes in mice.

See also: News and Views by Creusot

Stimulating healthy tissue regeneration by targeting the 5-HT2B receptor in chronic liver disease pp1668 - 1673

Mohammad R Ebrahimkhani, Fiona Oakley, Lindsay B Murphy, Jelena Mann, Anna Moles, Maria J Perugorria, Elizabeth Ellis, Anne F Lakey, Alastair D Burt, Angela Douglass, Matthew C Wright, Steven A White, Fabrice Jaffré, Luc Maroteaux & Derek A Mann


Wound healing involves a transient regeneration of tissue, but, if this process continues unabated, pathology occurs in the form of fibrosis, which can prevent normal organ function and even death. Derek Mann and his colleagues have found that serotonin-responsive profibrogenic hepatic stellate cells inhibit the growth of neighboring liver cells during the termination phase of liver injury. They also found that inhibiting serotonin signaling during established disease improved liver fibrosis in various mouse models of liver injury.

Identification of a central role for complement in osteoarthritis pp1674 - 1679

Qian Wang, Andrew L Rozelle, Christin M Lepus, Carla R Scanzello, Jason J Song, D Meegan Larsen, James F Crish, Gurkan Bebek, Susan Y Ritter, Tamsin M Lindstrom, Inyong Hwang, Heidi H Wong, Leonardo Punzi, Angelo Encarnacion, Mehrdad Shamloo, Stuart B Goodman, Tony Wyss-Coray, Steven R Goldring, Nirmal K Banda, Joshua M Thurman, Reuben Gobezie, Mary K Crow, V Michael Holers, David M Lee & William H Robinson


Osteoarthritis, the breakdown of cartilage in synovial joints, has long been viewed as the result of 'wear and tear', but this report shows that dysregulation of the complement system has an active role in the pathogenesis of this disease.


Technical Reports

Intra-arterial catheter for simultaneous microstructural and molecular imaging in vivo pp1680 - 1684

Hongki Yoo, Jin Won Kim, Milen Shishkov, Eman Namati, Theodore Morse, Roman Shubochkin, Jason R McCarthy, Vasilis Ntziachristos, Brett E Bouma, Farouc A Jaffer & Guillermo J Tearney


The future of imaging is the integration of function and anatomy. Hongki Yoo et al. have successfully done just that by combining two existing intravascular imaging techniques into a single catheter-based system. Their dual-modality intra-arterial catheter uses a combination of optical frequency domain imaging and near-infrared fluorescence imaging to simultaneously provide molecular information in the context of the surrounding three-dimensional microanatomy of the artery wall.

Cancer cell–selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules pp1685 - 1691

Makoto Mitsunaga, Mikako Ogawa, Nobuyuki Kosaka, Lauren T Rosenblum, Peter L Choyke & Hisataka Kobayashi


Makoto Mitsunaga et al. have developed a new form of molecular-targeted cancer therapy that provides an alternative to current photodynamic approaches where damage to surrounding healthy cells and tissues can be a problem. They use a target-specific photosensitizer based on a near-infrared phthalocyanine dye, which is conjugated to monoclonal antibodies targeting human epidermal growth factor receptors (HER1 and HER2). Selective treatment using this approach was shown in vivo in subcutaneous cancer xenografts in mice.



Addendum: Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge p1692

Scott G Hansen, Cassandra Vieville, Nathan Whizin, Lia Coyne-Johnson, Don C Siess, Derek D Drummond, Alfred W Legasse, Michael K Axthelm, Kelli Oswald, Charles M Trubey, Michael Piatak Jr, Jeffrey D Lifson, Jay A Nelson, Michael A Jarvis & Louis J Picker


Addendum: The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2 p1693

Baofeng Yang, Huixian Lin, Jiening Xiao, Yanjie Lu, Xiaobin Luo, Baoxin Li, Ying Zhang, Chaoqian Xu, Yunlong Bai, Huizhen Wang, Guohao Chen & Zhiguo Wang




Corrigendum: The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2 p1693

Baofeng Yang, Huixian Lin, Jiening Xiao, Yanjie Lu, Xiaobin Luo, Baoxin Li, Ying Zhang, Chaoqian Xu, Yunlong Bai, Huizhen Wang, Guohao Chen & Zhiguo Wang


Corrigendum: Targeting osteoclast-osteoblast communication p1693

Xu Cao


Corrigendum: Resolving controversies on the path to Alzheimer's therapeutics p1693

Dennis J Selkoe



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