Hot off the presses! Sep 01 Nat Med

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Latest Articles Include:

• In the land of the monolingual
  - Nat Med 15(9):975 (2009)
  Translating a basic finding into a new therapy requires us to speak many languages—scientific, clinical, legal and financial. Yet most of us are hopelessly 'monolingual', a limitation that substantially slows translational research. Steps have been taken to address this problem, but a lot remains to be done.
• A change is in the wind as 'adaptive' clinical trials catch on
  - Nat Med 15(9):977 (2009)
  In 2003, researchers stopped the ASTIN study, a clinical trial of a drug suspected to help stroke victims, because the drug was found to be ineffective. Of course, the fact that it was stopped isn't wholly remarkable: more than 80% of drugs that enter clinical trials fail, according to estimates by the Center for Drug Evaluation and Research of the US Food and Drug Administration (FDA).
• Pandemic vaccine enters clinical trials
  - Nat Med 15(9):978 (2009)
  The majority of the seasonal flu vaccine has already been shipped ahead of flu season in the Northern Hemisphere, but candidate vaccines against pandemic H1N1—which had killed nearly 1,800 people as of August—are just entering clinical trials. Health officials predict that the first doses should be available, at the earliest, in September.
• New plan seeks to accelerate African diagnostic capacity
  - Nat Med 15(9):978 (2009)
  Africa is home to 60% of the world's HIV/AIDS burden, 90% of its malaria cases and nearly a quarter of the globe's tuberculosis sufferers, but only a handful of clinical laboratories can properly identify and treat patients. That could soon change, however, thanks to an ambitious accreditation initiative unveiled on 27 July that seeks to double Africa's diagnostic laboratory capacity over the next two years.
• Sealants get specific
  - Nat Med 15(9):978 (2009)
  Researchers from the Massachusetts Institute of Techology say they have new insights into how a glue-like material might be tailored to work with specific tissues and organs. The authors of the paper, published online this summer, think that the current surgical sealants used to repair wounds have not reached their true potential.
• New technologies promise safer sex for women
  - Nat Med 15(9):979 (2009)
  With nearly 7,000 people being infected with HIV every day, societies around the world need new techniques to keep sex safe. Currently, condoms provide the highest protection against HIV infection during intercourse.
• Growing pains plague children's health study
  - Nat Med 15(9):979 (2009)
  The congressionally mandated National Children's Study (NCS), the largest long-term study of environmental and genetic effects on child health in the US to date, experienced some growing pains this month. A US Senate committee released a report on 4 August stating that it will reevaluate NCS funding after its 18-month pilot phase finishes in 2010, raising questions about whether the full study will move forward as planned.
• News in brief
  - Nat Med 15(9):980-981 (2009)
  Jul 22A report from the US National Academies, including the Institute of Medicine, urged researchers to do a better job of divulging the data behind their study results, as well as the computer programs used to analyze the raw data. Some experts, however, criticized the report for failing to outline detailed rules about such data sharing.
• Straight talk with...Ian Lipkin
  - Nat Med 15(9):982-983 (2009)
  How do you sequence a virus that no one has identified before? With the right technology, it's not as difficult a task as it might seem, says Ian Lipkin, director of the Center for Infection and Immunity at Columbia University's Mailman School of Public Health. Lipkin has been working on the technology involved with viral discovery since the late 1980s, when he became the first researcher to identify a microbe using only molecular tools. He and the Center's team of about 50 researchers have identified close to 200 new viruses so far. Most recently, Lipkin and his colleague Thomas Briese identified a new hemorrhagic fever virus that killed several patients in southern Africa last year. Now, in addition to processing samples from around the world, Lipkin has been working to export his sequencing technology—and the expertise needed to use it—to the developing world. Erica Westly spoke with Lipkin about how the viral discovery techniques he uses could help prevent futu! re viral disease outbreaks, from swine flu to the unknown.
• Boosting our best shot
  - Nat Med 15(9):984-988 (2009)
  Vaccines work by training the immune system to target pathogens, but many types of shots need added substances called adjuvants to elicit a robust response. Despite the power of adjuvants, only one, called alum, is approved in the US. Charlotte Schubert looks at recent discoveries that could translate into a wider range of adjuvants and perhaps help provide future protection against diseases ranging from malaria to H1N1 'swine' flu.
• Illuminating alum
  - Nat Med 15(9):985 (2009)
  Alum, the world's most widely used adjuvant, got its start in the 1920s when vaccinologists found that mixing it into their preparations gave a boost to the diphtheria vaccine. Researchers then proposed that it worked by glomming onto vaccine components, causing them to be released slowly into the bloodstream.
• Swine flu agitates the adjuvant debate
  - Nat Med 15(9):986-987 (2009)
  US regulatory agencies will face a big decision, as early as this fall, as to whether to approve the use of adjuvants for pandemic H1N1 flu vaccine on an emergency basis.Adjuvants used in some seasonal flu vaccines in Europe have the potential to boost the effectiveness of pandemic H1N1 vaccine and also substantially reduce dosage—thereby stretching supplies.
• Mouse fertility is not dependent on the CREB coactivator Crtc1
  - Nat Med 15(9):989-990 (2009)
  Cyclic AMP response element–binding protein (CREB)-regulated transcription coactivators (Crtcs), also known as transducers of regulated CREB activity (TORCs), are coactivators that function as calcium- and cyclic AMP–sensitive coincidence detectors1, 2. Ubiquitously expressed Crtc2 is a key regulator of energy metabolism modulating gluconeogenesis and insulin signaling3, 4, 5.
• Reply to: "Mouse fertility is not dependent on the CREB coactivator Crtc1"
  - Nat Med 15(9):991 (2009)
  We find Cardinaux's correspondence1 quite interesting. Both laboratories used a practically identical approach to knock out the Crtc1 gene in similar genetic strains.
• Innovating for impact: The Affordable Medicines Facility-malaria (AMFm)
  - Nat Med 15(9):991 (2009)
  Your story1 on AMFm does not provide a balanced picture of the evidence pertaining to the proposed approach adopted by AMFm and the prevailing development approaches used to combat malaria.AMFm is an innovative financing mechanism to expand access to affordable artemisinin-based combination therapies (ACTs) for malaria, thereby saving lives and reducing the use of inappropriate treatments.
• The vaccine-autism controversy
  - Nat Med 15(9):992 (2009)
  Autism is a devastating developmental neuropsychiatric disorder whose symptoms emerge during the first three years of life. Although recent genetic studies have provided major advances in our understanding of autism's etiologies in up to 10% of cases, the causes of most cases are not known.
• Blocking the path of lymphatic vessels
  - Nat Med 15(9):993-994 (2009)
  Identification of an endogenous inhibitor of lymphatic vessel formation provides a glimpse at how lymphatic vessel growth is restrained (pages 1023–1030). The findings might be exploited to lower transplant rejection rates.
• Two sides to cilia in cancer
  - Nat Med 15(9):994-996 (2009)
  The primary cilium can keep cancer at bay, or it can instigate tumor development, according to studies in mice (pages 1055–1061 and 1062–1065). The outcome depends on the nature of the initiating event, which involves signaling through the Hedgehog pathway.
• Connecting obesity, aging and diabetes
  - Nat Med 15(9):996-997 (2009)
  Obesity accelerates the aging of adipose tissue, a process only now beginning to come to light at the molecular level. Experiments in mice suggest that obesity increases the formation of reactive oxygen species in fat cells, shortens telomeres—and ultimately results in activation of the p53 tumor suppressor, inflammation and the promotion of insulin resistance (pages 1082–1087).
• Cardiovascular biomarker questioned
  - Nat Med 15(9):998 (2009)
  A study in the Journal of the American Medical Association addresses a long-standing controversy in cardiovascular medicine: does a protein in the bloodstream associated with cardiovascular disease, C-reactive protein (CRP), actually cause disease? The analysis, an amalgamation of data from 120,000 individuals, suggests that the answer is no1.
• A safer stem cell: on guard against cancer
  - Nat Med 15(9):999-1001 (2009)
  Before stem cell therapies become mainstream, several hurdles must be overcome. One challenge is developing air-tight approaches to assure that stem cell transplantation does not give rise to tumors. Another is finding safe ways to induce pluripotency in adult stem cells, which can then be used for transplantation. In Bedside to Bench, Evan Snyder and Rahul Jandial discuss the risks of tumorigenesis in stem cell therapies, and, in Bench to Bedside, Laura Clarke and Derek van der Kooy examine new ways to induce pluripotency.
• A safer stem cell: inducing pluripotency
  - Nat Med 15(9):1001-1002 (2009)
  The isolation of human embryonic stem cells1 (hESCs) theoretically gave scientists the starting material to produce any cell type in the body for use in regenerative medicine. One major obstacle to this approach has been the inevitable host immunological response to transplanted foreign tissue.
• Research Highlights
  - Nat Med 15(9):1004-1005 (2009)
  
• The advancement of translational medicine—from regional challenges to global solutions
  - Nat Med 15(9):1006-1009 (2009)
  Translating the progress in molecular medicine into new therapies has met with limited success; the route from idea to drug has many hurdles and is a very fragmented process. This fragmentation is evident at all levels—academia, industry and governments—and across geographic boundaries.
• Cancer stem cells: mirage or reality?
  - Nat Med 15(9):1010-1012 (2009)
  The similarities and differences between normal tissue stem cells and cancer stem cells (CSCs) have been the source of much contention, with some recent studies calling into question the very existence of CSCs. An examination of the literature indicates, however, that the CSC model rests on firm experimental foundations and that differences in the observed frequencies of CSCs within tumors reflect the various cancer types and hosts used to assay these cells. Studies of stem cells and the differentiation program termed the epithelial-mesenchymal transition (EMT) point to the possible existence of plasticity between stem cells and their more differentiated derivatives. If present, such plasticity would have major implications for the CSC model and for future therapeutic approaches.
• Involvement of interleukin-21 in the epidermal hyperplasia of psoriasis
  - Nat Med 15(9):1013-1015 (2009)
  T cells are crucial mediators of the skin damage in psoriasis. We here show that interleukin-21 (IL-21), a T cell–derived cytokine, is highly expressed in the skin of individuals with psoriasis, stimulates human keratinocytes to proliferate and causes epidermal hyperplasia when injected intradermally into mice. In the human psoriasis xenograft mouse model, blockade of IL-21 activity resolves inflammation and reduces keratinocyte proliferation. Blocking IL-21 may represent a new therapeutic strategy in psoriasis.
• A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses
  - Nat Med 15(9):1016-1022 (2009)
  The intestinal flora may promote colon tumor formation. Here we explore immunologic mechanisms of colonic carcinogenesis by a human colonic bacterium, enterotoxigenic Bacteroides fragilis (ETBF). ETBF that secretes B. fragilis toxin (BFT) causes human inflammatory diarrhea but also asymptomatically colonizes a proportion of the human population. Our results indicate that whereas both ETBF and nontoxigenic B. fragilis (NTBF) chronically colonize mice, only ETBF triggers colitis and strongly induces colonic tumors in multiple intestinal neoplasia (Min) mice. ETBF induces robust, selective colonic signal transducer and activator of transcription-3 (Stat3) activation with colitis characterized by a selective T helper type 17 (TH17) response distributed between CD4+ T cell receptor- (TCR)+ and CD4–8–TCR+ T cells. Antibody-mediated blockade of interleukin-17 (IL-17) as well as the receptor for IL-23, a key cytokine amplifying TH17 responses, inhibits ETBF-induced colitis! , colonic hyperplasia and tumor formation. These results show a Stat3- and TH17-dependent pathway for inflammation-induced cancer by a common human commensal bacterium, providing new mechanistic insight into human colon carcinogenesis.
• Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth
  - Nat Med 15(9):1023-1030 (2009)
  Disruption of the precise balance of positive and negative molecular regulators of blood and lymphatic vessel growth can lead to myriad diseases. Although dozens of natural inhibitors of hemangiogenesis have been identified, an endogenous selective inhibitor of lymphatic vessel growth has not to our knowledge been previously described. We report the existence of a splice variant of the gene encoding vascular endothelial growth factor receptor-2 (Vegfr-2) that encodes a secreted form of the protein, designated soluble Vegfr-2 (sVegfr-2), that inhibits developmental and reparative lymphangiogenesis by blocking Vegf-c function. Tissue-specific loss of sVegfr-2 in mice induced, at birth, spontaneous lymphatic invasion of the normally alymphatic cornea and hyperplasia of skin lymphatics without affecting blood vasculature. Administration of sVegfr-2 inhibited lymphangiogenesis but not hemangiogenesis induced by corneal suture injury or transplantation, enhanced corneal allo! graft survival and suppressed lymphangioma cellular proliferation. Naturally occurring sVegfr-2 thus acts as a molecular uncoupler of blood and lymphatic vessels; modulation of sVegfr-2 might have therapeutic effects in treating lymphatic vascular malformations, transplantation rejection and, potentially, tumor lymphangiogenesis and lymphedema (pages 993–994)
• Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery
  - Nat Med 15(9):1031-1037 (2009)
  Here we show that ischemia induces sustained contraction of pericytes on microvessels in the intact mouse brain. Pericytes remain contracted despite successful reopening of the middle cerebral artery after 2 h of ischemia. Pericyte contraction causes capillary constriction and obstructs erythrocyte flow. Suppression of oxidative-nitrative stress relieves pericyte contraction, reduces erythrocyte entrapment and restores microvascular patency; hence, tissue survival improves. In contrast, peroxynitrite application causes pericyte contraction. We also show that the microvessel wall is the major source of oxygen and nitrogen radicals causing ischemia and reperfusion–induced microvascular dysfunction. These findings point to a major but previously not recognized pathophysiological mechanism; ischemia and reperfusion-induced injury to pericytes may impair microcirculatory reflow and negatively affect survival by limiting substrate and drug delivery to tissue already under ! metabolic stress, despite recanalization of an occluded artery. Agents that can restore pericyte dysfunction and microvascular patency may increase the success of thrombolytic and neuroprotective treatments.
• A granulocyte-macrophage colony–stimulating factor and interleukin-15 fusokine induces a regulatory B cell population with immune suppressive properties
  - Nat Med 15(9):1038-1045 (2009)
  We have previously shown that a granulocyte-macrophage colony–stimulating factor (GM-CSF) and interleukin-15 (IL-15) 'fusokine' (GIFT15) exerts immune suppression via aberrant signaling through the IL-15 receptor on lymphomyeloid cells. We show here that ex vivo GIFT15 treatment of mouse splenocytes generates suppressive regulatory cells of B cell ontogeny (hereafter called GIFT15 Breg cells). Arising from CD19+ B cells, GIFT15 Breg cells express major histocompatibility complex class I (MHCI) and MHCII, surface IgM and IgD, and secrete IL-10, akin to previously described B10 and T2-MZP Breg cells, but lose expression of the transcription factor PAX5, coupled to upregulation of CD138 and reciprocal suppression of CD19. Mice with experimental autoimmune encephalomyelitis went into complete remission after intravenous infusion of GIFT15 Breg cells paralleled by suppressed neuroinflammation. The clinical effect was abolished when GIFT15 Breg cells were derived from mMT ! (lacking B cells), MHCII-knockout, signal transducer and activator of transcription-6 (STAT-6)-knockout, IL-10–knockout or allogeneic splenocytes, consistent with a pivotal role for MHCII and IL-10 by sygeneic B cells for the observed therapeutic effect. We propose that autologous GIFT15 Breg cells may serve as a new treatment for autoimmune ailments.
• Impaired Wnt–-catenin signaling disrupts adult renal homeostasis and leads to cystic kidney ciliopathy
  - Nat Med 15(9):1046-1054 (2009)
  Cystic kidney disease represents a major cause of end-stage renal disease, yet the molecular mechanisms of pathogenesis remain largely unclear. Recent emphasis has been placed on a potential role for canonical Wnt signaling, but investigation of this pathway in adult renal homeostasis is lacking. Here we provide evidence of a previously unidentified canonical Wnt activity in adult mammalian kidney homeostasis, the loss of which leads to cystic kidney disease. Loss of the Jouberin (Jbn) protein in mouse leads to the cystic kidney disease nephronophthisis, owing to an unexpected decrease in endogenous Wnt activity. Jbn interacts with and facilitates -catenin nuclear accumulation, resulting in positive modulation of downstream transcription. Finally, we show that Jbn is required in vivo for a Wnt response to injury and renal tubule repair, the absence of which triggers cystogenesis.
• Primary cilia can both mediate and suppress Hedgehog pathway–dependent tumorigenesis
  - Nat Med 15(9):1055-1061 (2009)
  Primary cilia are present on most mammalian cells and are implicated in transducing Hedgehog (Hh) signals during development; however, the prevalence of cilia on human tumors remains unclear, and the role of cilia in cancer has not been examined. Here we show that human basal cell carcinomas (BCCs) are frequently ciliated, and we test the role of cilia in BCC by conditionally deleting Kif3a (encoding kinesin family member 3A) or Ift88 (encoding intraflagellar transport protein 88), genes required for ciliogenesis, in two Hh pathway–dependent mouse tumor models. Ciliary ablation strongly inhibited BCC-like tumors induced by an activated form of Smoothened. In contrast, removal of cilia accelerated tumors induced by activated Gli2, a transcriptional effector of Hh signaling. These seemingly paradoxical effects are consistent with a dual role for cilia in mediating both the activation and the repression of the Hh signaling pathway. Our findings demonstrate that cilia fu! nction as unique signaling organelles that can either mediate or suppress tumorigenesis depending on the nature of the oncogenic initiating event.
• Dual and opposing roles of primary cilia in medulloblastoma development
  - Nat Med 15(9):1062-1065 (2009)
  Recent work has shown that primary cilia are essential for Hedgehog (Hh) signaling during mammalian development1, 2, 3, 4, 5, 6, 7, 8, 9. It is also known that aberrant Hh signaling can lead to cancer10, but the role of primary cilia in oncogenesis is not known. Cerebellar granule neuron precursors (GNPs) can give rise to medulloblastomas, the most common malignant brain tumor in children11, 12. The primary cilium and Hh signaling are required for GNP proliferation8, 12, 13, 14, 15. We asked whether primary cilia in GNPs have a role in medulloblastoma growth in mice. Genetic ablation of primary cilia blocked medulloblastoma formation when this tumor was driven by a constitutively active Smoothened protein (Smo), an upstream activator of Hh signaling. In contrast, removal of cilia was required for medulloblastoma growth by a constitutively active glioma-associated oncogene family zinc finger-2 (GLI2), a downstream transcription factor. Thus, primary cilia are either req! uired for or inhibit medulloblastoma formation, depending on the initiating oncogenic event. Remarkably, the presence or absence of cilia was associated with specific variants of human medulloblastomas; primary cilia were found in medulloblastomas with activation in HH or WNT signaling but not in most medulloblastomas in other distinct molecular subgroups. Primary cilia could serve as a diagnostic tool and provide new insights into the mechanism of tumorigenesis.
• Interferon regulatory factor-8 regulates bone metabolism by suppressing osteoclastogenesis
  - Nat Med 15(9):1066-1071 (2009)
  Bone metabolism results from a balance between osteoclast-driven bone resorption and osteoblast-mediated bone formation. Diseases such as periodontitis and rheumatoid arthritis are characterized by increased bone destruction due to enhanced osteoclastogenesis1, 2. Here we report that interferon regulatory factor-8 (IRF-8), a transcription factor expressed in immune cells, is a key regulatory molecule for osteoclastogenesis. IRF-8 expression in osteoclast precursors was downregulated during the initial phase of osteoclast differentiation induced by receptor activator of nuclear factor-B ligand (RANKL), which is encoded by the Tnfsf11 gene. Mice deficient in Irf8 showed severe osteoporosis, owing to increased numbers of osteoclasts, and also showed enhanced bone destruction after lipopolysaccharide (LPS) administration. Irf8-/- osteoclast precursors underwent increased osteoclastogenesis in response to RANKL and tumor necrosis factor- (TNF-). IRF-8 suppressed osteoclasto! genesis by inhibiting the function and expression of nuclear factor of activated T cells c1 (NFATc1). Our results show that IRF-8 inhibits osteoclast formation under physiological and pathological conditions and suggest a model where downregulation of inhibitory factors such as IRF-8 contributes to RANKL-mediated osteoclastogenesis.
• Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis
  - Nat Med 15(9):1072-1076 (2009)
  Aggrecan cleavage by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 5 (ADAMTS-5) is crucial for the breakdown of cartilage matrix during osteoarthritis1, 2, a degenerative joint disease that leads to the progressive destruction of articular structures. The mechanisms of ADAMTS-5 activation and their links to the pathogenesis of osteoarthritis remain poorly understood, but syndecans have been shown to be involved in the activation of ADAMTS-4 (ref. 3). Here we show that syndecan-4 is specifically induced in type X collagen–producing chondrocytes both in human osteoarthritis and in murine models of the disease. The loss of syndecan-4 in genetically modified mice and intra-articular injections of syndecan-4–specific antibodies into wild-type mice protect from proteoglycan loss and thereby prevent osteoarthritic cartilage damage in a surgically induced model of osteoarthritis. The occurrence of less severe osteoarthritis-like cartilage d! estruction in both syndecan-4–deficient mice and syndecan-4–specific antibody–treated wild-type mice results from a marked decrease in ADAMTS-5 activity. Syndecan-4 controls the activation of ADAMTS-5 through direct interaction with the protease and through regulating mitogen-activated protein kinase (MAPK)-dependent synthesis of matrix metalloproteinase-3 (MMP-3). Our data suggest that strategies aimed at the inhibition of syndecan-4 will be of great value for the treatment of cartilage damage in osteoarthritis.
• NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury
  - Nat Med 15(9):1077-1081 (2009)
  Members of the NADPH oxidase (NOX) family of enzymes, which catalyze the reduction of O2 to reactive oxygen species, have increased in number during eukaryotic evolution1, 2. Seven isoforms of the NOX gene family have been identified in mammals; however, specific roles of NOX enzymes in mammalian physiology and pathophysiology have not been fully elucidated3, 4. The best established physiological role of NOX enzymes is in host defense against pathogen invasion in diverse species, including plants5, 6. The prototypical member of this family, NOX-2 (gp91phox), is expressed in phagocytic cells and mediates microbicidal activities7, 8. Here we report a role for the NOX4 isoform in tissue repair functions of myofibroblasts and fibrogenesis. Transforming growth factor-1 (TGF-1) induces NOX-4 expression in lung mesenchymal cells via SMAD-3, a receptor-regulated protein that modulates gene transcription. NOX-4–dependent generation of hydrogen peroxide (H2O2) is required for ! TGF-1–induced myofibroblast differentiation, extracellular matrix (ECM) production and contractility. NOX-4 is upregulated in lungs of mice subjected to noninfectious injury and in cases of human idiopathic pulmonary fibrosis (IPF). Genetic or pharmacologic targeting of NOX-4 abrogates fibrogenesis in two murine models of lung injury. These studies support a function for NOX4 in tissue fibrogenesis and provide proof of concept for therapeutic targeting of NOX-4 in recalcitrant fibrotic disorders.
• A crucial role for adipose tissue p53 in the regulation of insulin resistance
  - Nat Med 15(9):1082-1087 (2009)
  Various stimuli, such as telomere dysfunction and oxidative stress, can induce irreversible cell growth arrest, which is termed 'cellular senescence'1, 2. This response is controlled by tumor suppressor proteins such as p53 and pRb. There is also evidence that senescent cells promote changes related to aging or age-related diseases3, 4, 5, 6. Here we show that p53 expression in adipose tissue is crucially involved in the development of insulin resistance, which underlies age-related cardiovascular and metabolic disorders. We found that excessive calorie intake led to the accumulation of oxidative stress in the adipose tissue of mice with type 2 diabetes–like disease and promoted senescence-like changes, such as increased activity of senescence-associated -galactosidase, increased expression of p53 and increased production of proinflammatory cytokines. Inhibition of p53 activity in adipose tissue markedly ameliorated these senescence-like changes, decreased the expres! sion of proinflammatory cytokines and improved insulin resistance in mice with type 2 diabetes–like disease. Conversely, upregulation of p53 in adipose tissue caused an inflammatory response that led to insulin resistance. Adipose tissue from individuals with diabetes also showed senescence-like features. Our results show a previously unappreciated role of adipose tissue p53 expression in the regulation of insulin resistance and suggest that cellular aging signals in adipose tissue could be a new target for the treatment of diabetes (pages 996–967).
• A rapid and efficient single-cell manipulation method for screening antigen-specific antibody–secreting cells from human peripheral blood
  - Nat Med 15(9):1088-1092 (2009)
  Antigen-specific human monoclonal antibodies (mAbs) are key candidates for therapeutic agents. However, the availability of a suitable screening system for antigen-specific antibody–secreting cells (ASCs) is limited in humans. Here we present a unique method for detecting individual ASCs using microwell array chips, which enables the analysis of live cells on a single-cell basis and offers a rapid, efficient and high-throughput (up to 234,000 individual cells) system for identifying and recovering objective ASCs. We applied the system to detect and retrieve ASCs for hepatitis B virus and influenza viruses from human peripheral blood lymphocytes and produced human mAbs with virus-neutralizing activities within a week. Furthermore, we show that the system is useful for detecting ASCs for multiple antigens as well as for selection of ASCs secreting high-affinity antibodies on a chip. Our method can open the way for the generation of therapeutic antibodies for individual! patients.
• Erratum: GOAT links dietary lipids with the endocrine control of energy balance
  - Nat Med 15(9):1093 (2009)
  Introduction Nat. Med. 15, 741–745 (2009); published online 5 June; corrected after print 4 September 2009 In the version of this article initially published, the fourth condition from the top in the key to the bar graphs in Figure 2c was mislabeled as 'mC8'. The correct label is 'hC8'. The error has been corrected in the HTML and PDF versions of the article.
• Corrigendum: Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity
  - Nat Med 15(9):1093 (2009)
  Introduction Nat. Med. 13, 189–197 (2007); published online 4 February 2007; corrected after print 4 September 2009 In the version of this article initially published, the number of one of the grants listed in the Acknowledgments was incorrect; 'HL55993' should have been 'P01 HL81587'. The error has been corrected in the HTML and PDF versions of the article.