Latest Articles Include:
- Nature Medicine, reloaded
- Nature Medicine 16(1):1 (2010)
Molecular medicine has undergone profound changes since the publication of the first issue of Nature Medicine 15 years ago this month. To keep up with these changes, we strengthen our commitment to publishing the best research and the most topical newsand commentary on translational medicine by adding more pages to the journal. - Biomarkers still off the mark for detecting breast cancer
May M - Nature Medicine 16(1):3 (2010)
Fifty years ago, the radiologist Robert Egan developed the first easily reproducible mammogram. Yet the anniversary is hardly golden. - To boost breast cancer research, a center banks on healthy tissue
Scudellari M - Nature Medicine 16(1):4 (2010)
As the sun rose one Saturday morning last summer, 45 Hispanic women climbed aboard a bus in Evansville, Indiana, each with a nametag and pink satin flower pinned to her shirt. Many of the women worked weekends and had taken the day off to make the four-hour trip to Indianapolis, recalls oncologist Anna Maria Storniolo. - Embryonic stem cell lines given the go-ahead
Dolgin E - Nature Medicine 16(1):4 (2010)
Nine months after US President Barack Obama issued an executive order lifting restrictions on human embryonic stem cell (hESC) research in the United States, scientists can at last start to use taxpayer dollars to study newly added cell lines. In the first two weeks of December, National Institutes of Health (NIH) director Francis Collins approved no fewer than 40 new hESC lines for federal funding, although some carry caveats. - Better forecasting urged to avoid drug waste
Dolgin E - Nature Medicine 16(1):5 (2010)
Here's a predicament you don't hear about too often: in November, Dutch health officials found that they had too much flu vaccine on their hands. Early on in the swine flu pandemic, they had ordered two doses of the H1N1 vaccine for each of the country's 16. - Forecast calls for clouds over biological computing
May M - Nature Medicine 16(1):6 (2010)
The reams of genomic and proteomic data produced from high-throughput analyses promise to answer some of the toughest questions in medicine. But the flood of information from today's experiments might be too much of a good thing—most universities and biotech companies lack the necessary computing infrastructure to store and use it. - Top 10 pharma firings of 2009
- Nature Medicine 16(1):6 (2010)
Following three megamergers and a global recession, the axe came down hard on the pharmaceutical sector this past year. According to Chicago-based consulting firm Challenger, Gray & Christmas, 61,109 pharma and biotech jobs were cut through the end of November—18,000 more than were lost in all of 2008. - Algorithms aim to improve hunt for disease markers
Torres C - Nature Medicine 16(1):7 (2010)
Genome-wide association studies, also known as GWASs, have made headlines in recent years, touting risk markers for illness. The approach relies on a simple concept: compare the genomes of affected individuals with healthy controls and look at significant points of genetic variance between the two that could contribute to the illness. - Matchmaking service links up researchers to wallflower drugs
Schubert C - Nature Medicine 16(1):7 (2010)
The shelves of pharmaceutical companies are filled with drugs that didn't make the cut. These are the compounds that sickened experimental animals, failed to cure disease or otherwise faltered along the pipeline. - African networks launch to boost clinical trial capacity
Dolgin E - Nature Medicine 16(1):8 (2010)
African countries are hosting an increasing number of clinical trials to develop treatment against infectious diseases. But much of the continent lacks the basic infrastructure and know-how to conduct clinical trials that meet top international standards. - China offers billions in loans to boost health research in Africa
- Nature Medicine 16(1):8 (2010)
China's Prime Minister Wen Jiabao has announced his country's plans to offer more than $10 billion in preferential export credits and concessional foreign aid loans to African governments over the next three years.The loans, announced at the Forum on China-Africa Cooperation in Egypt in November, are part of a raft of eight new Chinese initiatives in Africa. - Pandemic blows lid off laws limiting mercury in vaccines
Schubert C - Nature Medicine 16(1):9 (2010)
As public health officials around the world scramble to protect their citizens from swine flu, some in the US are grappling with an additional issue: state laws that limit the use of a mercury preservative in vaccines.Between 2004 and 2006, six states—California, Delaware, Illinois, Missouri, New York and Washington—enacted laws limiting the use of the preservative, thimerosal, in flu vaccines and other shots given to children and pregnant women. - In prevention push, AIDS program prioritizes research
Willyard C - Nature Medicine 16(1):9 (2010)
In early December, the US President's Emergency Plan for AIDS Relief—better known as PEPFAR—released a new strategy that prioritizes HIV prevention, partnerships with national governments and operations research. The five-year strategy represents a major shift from PEPFAR's initial goal of getting millions of people on antiretroviral treatment. - Painkiller concerns grow ahead of new guidelines
Hutson S - Nature Medicine 16(1):10 (2010)
In 1887, German pharmacologist Joseph von Mering determined that a coal tar−derived chemical called paracetamol was potentially dangerous because it caused changes to hemoglobin in the blood that might deprive tissues of oxygen. Paracetamol (better known as acetaminophen in the US) spent the next six decades in pharmaceutical exile. - Caution urged on tobacco research
- Nature Medicine 16(1):10 (2010)
In June 2009, the US Food and Drug Administration (FDA) received the authority to regulate tobacco. The following month, the FDA asked for public comments on the new regulatory process, and, in December, the American Association for Cancer Research (AACR) responded with advice on expediting scientific research on tobacco. - To save lives, initiative pushes for standardized diagnostic tools
Hutson S - Nature Medicine 16(1):11 (2010)
Take your car into any repair shop and, chances are, the mechanics there have a computer that can interface with the vehicle's diagnostic system and pinpoint the problem."The question that the medical community should be asking is, 'why isn't there this level of compatibility among [diagnostic] devices used to save lives? - Penalty payouts from pharma rise
- Nature Medicine 16(1):11 (2010)
Last September, when Pfizer agreed to pay out a record $2.3 billion for illegally marketing the drug Bextra, the news made headlines around the world. - Institute of Medicine calls for savvier vaccine strategy
Schubert C - Nature Medicine 16(1):12 (2010)
As the vaccine campaign against the H1N1 swine flu ramped up last year, experts across government agencies scrambled to get safety testing and monitoring systems running smoothly. In the US, the jumble of data all funneled through one place: the National Vaccine Program Office (NVPO). - For cost effectiveness, real data trumps trial results
Torres C - Nature Medicine 16(1):12 (2010)
As healthcare systems look to save cash, many are turning to cost-effectiveness analyses that show which drugs make the most economical sense. But current methods for comparing the returns on medications might be trickier than previously thought, according to new research. - Bioethicists renew call for changes to prison research
Westly E - Nature Medicine 16(1):13 (2010)
In 2006, the Institute of Medicine (IOM), the health arm of the US National Academy of Sciences, released a special report on the ethics of conducting research on prison inmates. The report deemed existing guidelines convoluted and suggested updates to improve prisoners' ability to participate in trials. - Britain reevaluates taxes on patent income
Dolgin E - Nature Medicine 16(1):13 (2010)
In a move to make the UK more attractive as an innovation hub, the British government announced plans to ease the tax burden on revenue stemming from research-related patents. On 9 December, the Labour party unveiled its spending plans for the coming fiscal year with a prebudget report that included a lower rate of corporation tax on income from new intellectual property. - Exec salaries look up in life sciences
- Nature Medicine 16(1):13 (2010)
Although heads of technology companies probably saw their base salaries remain flat last year, life science leaders may have experienced a slight increase. According to a survey by the executive search firms J. - News in brief
- Nature Medicine 16(1):14-15 (2010)
Nov 16The European Society of Human Reproduction and Embryology released a statement opposing the European Commission's proposed screening for viruses—including HIV and hepatitis—among those interested in fertility treatment, on the grounds that the tests cost too much. - Straight talk with... Eric Green
Westly E - Nature Medicine 16(1):16-17 (2010)
Eric Green, the new head of the US National Human Genome Research Institute (NHGRI), has been involved with genomics since the term was first coined in the 1980s. He started at the US National Institutes of Health (NIH) as a postdoc and was a key contributor to the Human Genome Project. Nearly a decade ago, when Green was part of a team that produced one of the first human genome sequences, the potential for genomics-related medical applications seemed limitless. But most disorders have proved to be too complex to benefit from our current understanding of genomics, and some critics have argued that researchers have put too much emphasis on uncovering the genetic underpinnings of diseases. Recent demand for comparative effectiveness research in medicine has further complicated the debate, leading former head of NHGRI Francis Collins to worry that genomic differences could get "lost in the wash." Erica Westly spoke with Green about where he sees the genomics field he! ading and what role he thinks the NHGRI should have in the American health care system. - The saving switch
Willyard C - Nature Medicine 16(1):18-21 (2010)
ARTICLE NAVIGATION - ISSUE Previous January 2010, Volume 16 No 1 pp1-129 * Editorial * News * Correspondence * Book Review * News and Views * Community Corner * Between Bedside and Bench * Research Highlights * Brief Communication * Articles * Letters * Technical Reports * Corrigenda * ErrataAbout the cover Editorial Nature Medicine, reloaded - p1 doi:10.1038/nm0110-1 Molecular medicine has undergone profound changes since the publication of the first issue of Nature Medicine 15 years ago this month. To keep up with these changes, we strengthen our commitment to publishing the best research and the most topical newsand commentary on translational medicine by adding more pages to the journal. Abstract - | Full Text - Nature Medicine, reloaded | PDF (87 KB) - Nature Medicine, reloaded News Biomarkers still off the mark for detecting breast cancer - p3 Mike May doi:10.1038/nm0110-3 Full Text - Biomarkers still off the mark for detecting breast cancer | PDF (271 KB) - Biomarkers still off the mark for detecting breast cancer To boost breast cancer research, a center banks on healthy tissue - p4 Megan Scudellari doi:10.1038/nm0110-4a Full Text - To boost breast cancer research, a center banks on healthy tissue | PDF (69 KB) - To boost breast cancer research, a center banks on healthy tissue Embryonic stem cell lines given the go-ahead - p4 Elie Dolgin doi:10.1038/nm0110-4b Full Text - Embryonic stem cell lines given the go-ahead | PDF (69 KB) - Embryonic stem cell lines given the go-ahead Better forecasting urged to avoid drug waste - p5 Elie Dolgin doi:10.1038/nm0110-5 Full Text - Better forecasting urged to avoid drug waste | PDF (129 KB) - Better forecasting urged to avoid drug waste Forecast calls for clouds over biological computing - p6 Mike May doi:10.1038/nm0110-6a Full Text - Forecast calls for clouds over biological computing | PDF (304 KB) - Forecast calls for clouds over biological computing Top 10 pharma firings of 2009 - p6 doi:10.1038/nm0110-6b Full Text - Top 10 pharma firings of 2009 | PDF (304 KB) - Top 10 pharma firings of 2009 Algorithms aim to improve hunt for disease markers - p7 Christian Torres doi:10.1038/nm0110-7a Full Text - Algorithms aim to improve hunt for disease markers | PDF (128 KB) - Algorithms aim to improve hunt for disease markers Matchmaking service links up researchers to wallflower drugs - p7 Charlotte Schubert doi:10.1038/nm0110-7b Full Text - Matchmaking service links up researchers to wallflower drugs | PDF (128 KB) - Matchmaking service links up researchers to wallflower drugs African networks launch to boost clinical trial capacity - p8 Elie Dolgin doi:10.1038/nm0110-8a Full Text - African networks launch to boost clinical trial capacity | PDF (117 KB) - African networks launch to boost clinical trial capacity China offers billions in loans to boost health research in Africa - p8 Georgina Kenyon doi:10.1038/nm0110-8b Full Text - China offers billions in loans to boost health research in Africa | PDF (117 KB) - China offers billions in loans to boost health research in Africa Pandemic blows lid off laws limiting mercury in vaccines - p9 Charlotte Schubert doi:10.1038/nm0110-9a Full Text - Pandemic blows lid off laws limiting mercury in vaccines | PDF (69 KB) - Pandemic blows lid off laws limiting mercury in vaccines In prevention push, AIDS program prioritizes research - p9 Cassandra Willyard doi:10.1038/nm0110-9b Full Text - In prevention push, AIDS program prioritizes research | PDF (69 KB) - In prevention push, AIDS program prioritizes research Painkiller concerns grow ahead of new guidelines - p10 Stu Hutson doi:10.1038/nm0110-10a Full Text - Painkiller concerns grow ahead of new guidelines | PDF (125 KB) - Painkiller concerns grow ahead of new guidelines Caution urged on tobacco research - p10 Vicki Brower doi:10.1038/nm0110-10b Full Text - Caution urged on tobacco research | PDF (125 KB) - Caution urged on tobacco research To save lives, initiative pushes for standardized diagnostic tools - p11 Stu Hutson doi:10.1038/nm0110-11a Full Text - To save lives, initiative pushes for standardized diagnostic tools | PDF (184 KB) - To save lives, initiative pushes for standardized diagnostic tools Penalty payouts from pharma rise - p11 doi:10.1038/nm0110-11b Full Text - Penalty payouts from pharma rise | PDF (184 KB) - Penalty payouts from pharma rise Institute of Medicine calls for savvier vaccine strategy - p12 Charlotte Schubert doi:10.1038/nm0110-12a Full Text - Institute of Medicine calls for savvier vaccine strategy | PDF (68 KB) - Institute of Medicine calls for savvier vaccine strategy For cost effectiveness, real data trumps trial results - p12 Christian Torres doi:10.1038/nm0110-12b Full Text - For cost effectiveness, real data trumps trial results | PDF (68 KB) - For cost effectiveness, real data trumps trial results Bioethicists renew call for changes to prison research - p13 Erica Westly doi:10.1038/nm0110-13a Full Text - Bioethicists renew call for changes to prison research | PDF (113 KB) - Bioethicists renew call for changes to prison research Britain reevaluates taxes on patent income - p13 Elie Dolgin doi:10.1038/nm0110-13b Full Text - Britain reevaluates taxes on patent income | PDF (113 KB) - Britain reevaluates taxes on patent income Exec salaries look up in life sciences - p13 doi:10.1038/nm0110-13c Full Text - Exec salaries look up in life sciences | PDF (113 KB) - Exec salaries look up in life sciences News in brief - pp14 - 15 doi:10.1038/nm0110-14 Full Text - News in brief | PDF (714 KB) - News in brief Straight talk with... Eric Green - pp16 - 17 Erica Westly doi:10.1038/nm0110-16 Eric Green, the new head of the US National Human Genome Research Institute (NHGRI), has been involved with genomics since the term was first coined in the 1980s. spoke with Green about where he sees the genomics field heading and what role he thinks the NHGRI should have in the American health care system. Abstract - | Full Text - Straight talk with... Eric Green | PDF (316 KB) - Straight talk with... Eric Green The saving switch - pp18 - 21 Cassandra Willyard doi:10.1038/nm0110-18 The epigenome consists of a system of chemical tags that attach to our DNA and its associated molecules, switching genes on and off. But the system is not without glitches—and scientists think that the misplacement of these tags can cause disease. This idea has led to new drugs that aim to correct gene activity (and obliterate disease) by altering the proteins around which DNA winds. examines whether this approach will unlock the long-awaited promise of epigenetic therapy. Abstract - | Full Text - The saving switch | PDF (1,023 KB) - The saving switch Drug ads move online, creating a web of regulatory challenges - p22 Meredith Wadman doi:10.1038/nm0110-22 Full Text - Drug ads move online, creating a web of regulatory challenges | PDF (113 KB) - Drug ads move online, creating a web of regulatory challenges Correspondence Nicotinamide and neutrophilia - p23 Abram Hoffer doi:10.1038/nm0110-23a Full Text - Nicotinamide and neutrophilia | PDF (70 KB) - Nicotinamide and neutrophilia Reply to: "Nicotinamide and neutrophilia" - p23 Julia Skokowa & Karl Welte doi:10.1038/nm0110-23b Full Text - Reply to: "Nicotinamide and neutrophilia" | PDF (70 KB) - Reply to: "Nicotinamide and neutrophilia" Book Review Personalizing medicine - p24 Edison T Liu reviews The Language of Life: DNA and the Revolution in Personalized Medicine by Francis S. Collins doi:10.1038/nm0110-24 Full Text - Personalizing medicine | PDF (87 KB) - Personalizing medicine News and Views Cloaked virus slips between cells - pp25 - 27 Kathryn S Jones & Patrick L Green doi:10.1038/nm0110-25 A common retrovirus encases itself in an extracellular matrix, enabling its transfer between T4 cells. The discovery of this new mode of infectivity has the potential to lead to new ways to combat the virus, human T cell leukemia virus type 1 (HTLV-1), which is associated with cancers and inflammatory disorders (pages 83–89). Full Text - Cloaked virus slips between cells | PDF (602 KB) - Cloaked virus slips between cells See also:Article by Pais-Correia et al. Hypertension finds a new rhythm - pp27 - 28 Bernard C Rossier doi:10.1038/nm0110-27 Blood pressure oscillates with the circadian rhythm, and a molecular mechanism has now been discovered (pages 67–74). The results point to a new genetic risk factor for hypertension and to a potential new target against this condition. Full Text - Hypertension finds a new rhythm | PDF (277 KB) - Hypertension finds a new rhythm See also:Article by Doi et al. A NOD for autophagy - pp28 - 30 Mihai G Netea & Leo A B Joosten doi:10.1038/nm0110-28 Susceptibility to Crohn's disease has been linked to polymorphisms in genes involved in two pathophysiological pathways: autophagy and the recognition of bacterial peptidoglycan by nucleotide oligomerization domain-2 (NOD2), an intracellular receptor. Two studies link these pathways by showing that recognition of bacterial peptidoglycans by NOD2 induces autophagy and bacterial clearance. Full Text - A NOD for autophagy | PDF (968 KB) - A NOD for autophagy See also:Article by Cooney et al. Myelodysplasia: battle in the bone marrow - pp30 - 32 Yan Liu, Takashi Asai & Stephen D Nimer doi:10.1038/nm0110-30 Innate immune signals and p53 contribute to the 5q– myelodysplastic syndrome, an acquired bone marrow failure disorder (pages 49–58 and 59–66). Full Text - Myelodysplasia: battle in the bone marrow | PDF (815 KB) - Myelodysplasia: battle in the bone marrow See also:Article by Starczynowski et al. | Article by Barlow et al. Huntington's disease: tagged for clearance - pp32 - 33 Dimitri Krainc doi:10.1038/nm0110-32 The neuronal accumulation of mutant huntingtin is a hallmark of Huntington's disease. New research shows that post-translational modifications of the mutant protein promote its clearance, uncovering new therapeutic targets for this disorder. Full Text - Huntington's disease: tagged for clearance | PDF (621 KB) - Huntington's disease: tagged for clearance Vessel remodeling in the newborn: platelets fill the gap - pp33 - 35 Ronald Clyman & Sylvain Chemtob doi:10.1038/nm0110-33 In newborn infants, permanent closure of a major blood vessel connecting the main pulmonary artery to the aorta is essential to allow adequate circulation of blood to major organs. Platelet aggregation now emerges as a crucial step in this process in newborn mice and, possibly, in preterm infants (pages 75–82). Full Text - Vessel remodeling in the newborn: platelets fill the gap | PDF (1,738 KB) - Vessel remodeling in the newborn: platelets fill the gap See also:Article by Echtler et al. Migration or evasion - pp35 - 36 Cornelis Melief doi:10.1038/nm0110-35 Tumors use many strategies to evade the immune system. A new study adds a new trick to the list—inhibiting the migration of dendritic cells from tumors toward lymph nodes (pages 98–105). Full Text - Migration or evasion | PDF (1,583 KB) - Migration or evasion See also:Article by Villablanca et al. Community Corner Gene therapy tackles demyelinating disease - p37 doi:10.1038/nm0110-37 Full Text - Gene therapy tackles demyelinating disease | PDF (159 KB) - Gene therapy tackles demyelinating disease Between Bedside and Bench Kidney complications: Why don't statins always work? - pp38 - 40 S Ananth Karumanchi & Ravi Thadhani doi:10.1038/nm0110-38 The vasculature suffers damage as a result of diabetes, often leading to conditions such as kidney failure. In bench to bedside, Christian Rask-Madsen and George King examine endogenous factors that protect against damage of the vasculature, such as vascular-endothelial growth factor (VEGF). Recent studies report that VEGF is expressed by kidneys and fends off renal failure; such findings have implications for the development of treatments that harness endogenous factors and sound a note of caution for the therapeutic use of VEGF inhibitors. People with end-stage renal disease often die of cardiovascular complications and clinical studies have shown that one popular class of drugs, statins, does not work in this population. In bedside to bench, S. Ananth Karumanchi and Ravi Thadhani show how this clinical finding is spurring research into the biological mechanisms behind cardiovascular death in people with kidney disease. Abstract - | Full Text - Kidney complications: Why don't statins always work? | PDF (605 KB) - Kidney complications: Why don't statins always work? Kidney complications: Factors that protect the diabetic vasculature - pp40 - 41 Christian Rask-Madsen & George L King doi:10.1038/nm0110-40 Full Text - Kidney complications: Factors that protect the diabetic vasculature | PDF (181 KB) - Kidney complications: Factors that protect the diabetic vasculature Research Highlights Research Highlights - pp42 - 43 doi:10.1038/nm0110-42 Full Text - Research Highlights | PDF (110 KB) - Research Highlights Brief Communication Characterization of the human neutrophil alloantigen-3a - pp45 - 48 Andreas Greinacher, Jan Wesche, Elke Hammer, Birgitt Fürll, Uwe Völker, Angelika Reil & Jürgen Bux doi:10.1038/nm.2070 A serious complication of blood transfusions is transfusion-related acute lung injury, which can be caused by antibodies in the donor blood that recognize and activate host neutrophils. Andreas Greinacher and his colleagues now determine the molecular identity of the antigen recognized by one of these antibodies, termed human neutrophil alloantigen-3a, as a variant of the choline transporter-like protein-2. This finding opens the door to systematic screening of blood donors and recipients. Abstract - | Full Text - Characterization of the human neutrophil alloantigen-3a | PDF (723 KB) - Characterization of the human neutrophil alloantigen-3a | Supplementary information Articles Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype - pp49 - 58 Daniel T Starczynowski, Florian Kuchenbauer, Bob Argiropoulos, Sandy Sung, Ryan Morin, Andrew Muranyi, Martin Hirst, Donna Hogge, Marco Marra, Richard A Wells, Rena Buckstein, Wan Lam, R Keith Humphries & Aly Karsan doi:10.1038/nm.2054 For myelodysplastic syndromes caused by deletion of chromosome 5q, Daniel Starczynowski et al. provide evidence that decreased expression of two miRNAs in this region—miR-145 and miR-146a—contributes to abnormal megakaryocyte differentiation and platelet production and progression of the disease to either bone marrow failure or leukemia. The authors also provide a mechanistic explanation for these effects by which loss of these two miRNAs leads to derepression of innate immune signaling. Abstract - | Full Text - Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype | PDF (1,134 KB) - Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype | Supplementary information See also:News and Views by Liu et al. | Article by Barlow et al. A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome - pp59 - 66 Jillian L Barlow, Lesley F Drynan, Duncan R Hewett, Luke R Holmes, Silvia Lorenzo-Abalde, Alison L Lane, Helen E Jolin, Richard Pannell, Angela J Middleton, See Heng Wong, Alan J Warren, James S Wainscoat, Jacqueline Boultwood & Andrew N J McKenzie doi:10.1038/nm.2063 In individuals with 5q– syndrome, deletion within chromosome 5q is associated with hematological abnormalities. Jillian Barlow et al. now create an animal model of the disease using chromosomal engineering to remove a corresponding region of the mouse genome. The resulting hematological abnormalities resemble those in the human disease, and the authors provide genetic evidence that p53 activation contributes to the disease process. Abstract - | Full Text - A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome | PDF (1,234 KB) - A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome | Supplementary information See also:News and Views by Liu et al. | Article by Starczynowski et al. Salt-sensitive hypertension in circadian clock–deficient Cry-null mice involves dysregulated adrenal Hsd3b6 - pp67 - 74 Masao Doi, Yukari Takahashi, Rie Komatsu, Fumiyoshi Yamazaki, Hiroyuki Yamada, Shogo Haraguchi, Noriaki Emoto, Yasushi Okuno, Gozoh Tsujimoto, Akihiro Kanematsu, Osamu Ogawa, Takeshi Todo, Kazuyoshi Tsutsui, Gijsbertus T J van der Horst & Hitoshi Okamura doi:10.1038/nm.2061 The circadian clock controls many aspects of human physiology, and disturbances in circadian rhythms have been linked to cardiovascular disease. Masao Doi et al. now delineate a new pathway by which the circadian clock influences hormone production and blood pressure in mice—clock genes control expression of an aldosterone biosynthetic enzyme, such that increased activity of this enzyme in mice with a disrupted circadian clock may account for the increased aldosterone levels and salt-sensitive hypertension seen in these mice. Abstract - | Full Text - Salt-sensitive hypertension in circadian clock–deficient Cry-null mice involves dysregulated adrenal Hsd3b6 | PDF (1,398 KB) - Salt-sensitive hypertension in circadian clock–deficient Cry-null mice involves dysregulated adrenal Hsd3b6 | Supplementary information See also:News and Views by Rossier Platelets contribute to postnatal occlusion of the ductus arteriosus - pp75 - 82 Katrin Echtler, Konstantin Stark, Michael Lorenz, Sandra Kerstan, Axel Walch, Luise Jennen, Martina Rudelius, Stefan Seidl, Elisabeth Kremmer, Nikla R Emambokus, Marie-Luise von Bruehl, Jon Frampton, Berend Isermann, Orsolya Genzel-Boroviczény, Christian Schreiber, Julinda Mehilli, Adnan Kastrati, Markus Schwaiger, Ramesh A Shivdasani & Steffen Massberg doi:10.1038/nm.2060 Premature infants can suffer from an anatomical defect in which the ductus arteriosus, a blood vessel that connects the pulmonary artery and the aorta during fetal development, fails to close at birth. Katrin Echtler et al. now show that platelets are needed for closure in mice and that reduced platelet function may be clinically relevant: in a retrospective study of preterm human infants, low platelet counts were associated with the presence of an unclosed ductus arteriosus. Abstract - | Full Text - Platelets contribute to postnatal occlusion of the ductus arteriosus | PDF (1,328 KB) - Platelets contribute to postnatal occlusion of the ductus arteriosus | Supplementary information See also:News and Views by Clyman & Chemtob Biofilm-like extracellular viral assemblies mediate HTLV-1 cell-to-cell transmission at virological synapses - pp83 - 89 Ana-Monica Pais-Correia, Martin Sachse, Stéphanie Guadagnini, Valentina Robbiati, Rémi Lasserre, Antoine Gessain, Olivier Gout, Andrés Alcover & Maria-Isabel Thoulouze doi:10.1038/nm.2065 The virus HTLV-1 is thought to pass between cells through synapses formed when infected lymphocytes make contact with other T cells. Isabelle Thoulouze and her colleagues uncover an alternative mechanism for the cell-to-cell transmission of this virus. They show that HTLV-1 virions bud at the plasma membrane and are held at the cell surface in structures reminiscent of bacterial biofilms. When infected lymphocytes make contacts with other cells, the adhesive viral assemblies are rapidly transferred to to the surface of the new lymphocyte, from which the virions mediate a new round of infection. Abstract - | Full Text - Biofilm-like extracellular viral assemblies mediate HTLV-1 cell-to-cell transmission at virological synapses | PDF (1,551 KB) - Biofilm-like extracellular viral assemblies mediate HTLV-1 cell-to-cell transmission at virological synapses | Supplementary information See also:News and Views by Jones & Green NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation - pp90 - 97 Rachel Cooney, John Baker, Oliver Brain, Benedicte Danis, Tica Pichulik, Philip Allan, David J P Ferguson, Barry J Campbell, Derek Jewell & Alison Simmons doi:10.1038/nm.2069 Mutations in NOD2—a bacterial sensor in dendritic cells—and mutations in genes related to autophagosome function have been linked to Crohn's disease. Alison Simmons and her colleagues link these susceptibility genes in a single functional pathway. They show that triggering of NOD2 induces autophagy, resulting in increased bacterial antigen presentation on the surface of the dendritic cell. They also show that this process goes awry in dendritic cells expressing the susceptibility variants from individuals with Crohn's disease. Abstract - | Full Text - NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation | PDF (1,033 KB) - NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation | Supplementary information See also:News and Views by Netea & Joosten Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses - pp98 - 105 Eduardo J Villablanca, Laura Raccosta, Dan Zhou, Raffaella Fontana, Daniela Maggioni, Aurora Negro, Francesca Sanvito, Maurilio Ponzoni, Barbara Valentinis, Marco Bregni, Alessandro Prinetti, Knut R Steffensen, Sandro Sonnino, Jan-Ake Gustafsson, Claudio Doglioni, Claudio Bordignon, Catia Traversari & Vincenzo Russo doi:10.1038/nm.2074 Sterol metabolism modulates immune responses through liver X receptor activation. Tumors harness this signaling pathway and can escape immunosurveillance by inhibiting dendritic cell migration to tumor-draining lymph nodes. Abstract - | Full Text - Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses | PDF (885 KB) - Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses | Supplementary information See also:News and Views by Melief Letters A mitotic transcriptional switch in polycystic kidney disease - pp106 - 110 Francisco Verdeguer, Stephanie Le Corre, Evelyne Fischer, Celine Callens, Serge Garbay, Antonia Doyen, Peter Igarashi, Fabiola Terzi & Marco Pontoglio doi:10.1038/nm.2068 Deficiency of the transcription factor HNF-1β results in kidney cyst formation. Marco Pontoglio and his colleagues now show that HNF-1β normally remains bound to condensed chromatin during mitosis to facilitate the rapid expression of key genes involved in cell quiescence post-mitosis. In the absence of HNF-1β, these genes fail to express, and the kidney epithelial cells continue to proliferate, resulting in cysts. Abstract - | Full Text - A mitotic transcriptional switch in polycystic kidney disease | PDF (617 KB) - A mitotic transcriptional switch in polycystic kidney disease | Supplementary information A key role for orexin in panic anxiety - pp111 - 115 Philip L Johnson, William Truitt, Stephanie D Fitz, Pamela E Minick, Amy Dietrich, Sonal Sanghani, Lil Träskman-Bendz, Andrew W Goddard, Lena Brundin & Anantha Shekhar doi:10.1038/nm.2075 Orexin, a neuropeptide best known for its role in arousal and its absence in people with narcolepsy, is also involved in the pathophysiology of panic anxiety disorder. First Paragraph - | Full Text - A key role for orexin in panic anxiety | PDF (600 KB) - A key role for orexin in panic anxiety | Supplementary information Technical Reports Real-time imaging reveals the single steps of brain metastasis formation - pp116 - 122 Yvonne Kienast, Louisa von Baumgarten, Martin Fuhrmann, Wolfgang E F Klinkert, Roland Goldbrunner, Jochen Herms & Frank Winkler doi:10.1038/nm.2072 One of the major challenges of metastasis research is being able to track the fate of individual metastasizing cancer cells over time. Here, Kienast et al. describe an animal model in which multiphoton laser scanning microscopy is used to image the steps involved in the establishment of brain metastasis in vivo. The movement of systemically injected, red fluorescent protein–labeled tumor cells is monitored over several weeks, revealing potential targets for therapy. Abstract - | Full Text - Real-time imaging reveals the single steps of brain metastasis formation | PDF (1,615 KB) - Real-time imaging reveals the single steps of brain metastasis formation | Supplementary information Generation of stable monoclonal antibody–producing B cell receptor–positive human memory B cells by genetic programming - pp123 - 128 Mark J Kwakkenbos, Sean A Diehl, Etsuko Yasuda, Arjen Q Bakker, Caroline M M van Geelen, Michaël V Lukens, Grada M van Bleek, Myra N Widjojoatmodjo, Willy M J M Bogers, Henrik Mei, Andreas Radbruch, Ferenc A Scheeren, Hergen Spits & Tim Beaumont doi:10.1038/nm.2071 Kwakkenbos et al. describe an in vitro method to generate antibody-secreting B cell lines from human peripheral blood memory B cells by transducing them with retroviral vectors encoding Bcl-6 and Bcl-xL. The approach can be used to stably and simultaneously produce high levels of B cell receptor (BCR) on the cell surface and secreted immunoglobulins, useful for studying BCR signaling and producing antigen-specific antibodies. Abstract - | Full Text - Generation of stable monoclonal antibody–producing B cell receptor–positive human memory B cells by genetic programming | PDF (852 KB) - Generation of stable monoclonal antibody–producing B cell receptor–positive human memory B cells by genetic programming | Supplementary information Corrigenda Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells - p129 Keisuke Ito, Atsushi Hirao, Fumio Arai, Keiyo Takubo, Sahoko Matsuoka, Kana Miyamoto, Masako Ohmura, Kazuhito Naka, Kentaro Hosokawa, Yasuo Ikeda & Toshio Suda doi:10.1038/nm0110-129a Full Text - Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells | PDF (53 KB) - Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells Modulating hedgehog signaling can attenuate the severity of osteoarthritis - p129 Alvin C Lin, Brian L Seeto, Justyna M Bartoszko, Michael A Khoury, Heather Whetstone, Louisa Ho, Claire Hsu, Amanda S Ali & Benjamin A Alman doi:10.1038/nm0110-129b Full Text - Modulating hedgehog signaling can attenuate the severity of osteoarthritis | PDF (53 KB) - Modulating hedgehog signaling can attenuate the severity of osteoarthritis Errata Drugs in the headlines - p129 Victoria Aranda doi:10.1038/nm0110-129c Full Text - Drugs in the headlines | PDF (53 KB) - Drugs in the headlines Drugs in the headlines - p129 Victoria Aranda doi:10.1038/nm0110-129d Full Text - Drugs in the headlines | PDF (53 KB) - Drugs in the headlines - Drug ads move online, creating a web of regulatory challenges
Wadman M - Nature Medicine 16(1):22 (2010)
Not too many months ago, a person who entered "multiple sclerosis medication" into Google would find, at or near the top of the list of retrieved links, the following one, paid for by the drug's maker: "Multiple Sclerosis? Satisfied with your MS Medication or Looking for Something Different? - Nicotinamide and neutrophilia
Hoffer A - Nature Medicine 16(1):23 (2010)
The authors of an article appearing in the February 2009 issue of Nature Medicine reporting that nicotinamide induces neutrophilia in humans1 should have acknowledged that this observation is not new. The marked neutrophilia induced by nicotinamide was previously reported by me in a larger and more detailed clinical study2 than the one reported in Nature Medicine. - Reply to: "Nicotinamide and neutrophilia"
- Nature Medicine 16(1):23 (2010)
When we performed our experiments and wrote our manuscript1, we were not aware of the papers published by Hoffer and his colleagues2, 3, 4 that he mentions in his correspondence5. Indeed, according to the ISI Web of Knowledge, none of these three papers, published in 1956 or 1959, seems to have been previously cited in the biomedical literature. - Personalizing medicine
- Nature Medicine 16(1):24 (2010)
Books about science for the general public have several purposes. They may argue the case for a new idea or expound on a fresh conceptual synthesis of existing knowledge, such as the case with Jared Diamond's Guns, Germs and Steel. - Cloaked virus slips between cells
Jones KS Green PL - Nature Medicine 16(1):25-27 (2010)
The epigenome consists of a system of chemical tags that attach to our DNA and its associated molecules, switching genes on and off. But the system is not without glitches—and scientists think that the misplacement of these tags can cause disease. This idea has led to new drugs that aim to correct gene activity (and obliterate disease) by altering the proteins around which DNA winds. Cassandra Willyard examines whether this approach will unlock the long-awaited promise of epigenetic therapy. - Hypertension finds a new rhythm
Rossier BC - Nature Medicine 16(1):27-28 (2010)
Human T cell leukemia virus type 1 (HTLV-1) is a lymphotropic retrovirus whose cell-to-cell transmission requires cell contacts. HTLV-1–infected T lymphocytes form 'virological synapses', but the mechanism of HTLV-1 transmission remains poorly understood. We show here that HTLV-1–infected T lymphocytes transiently store viral particles as carbohydrate-rich extracellular assemblies that are held together and attached to the cell surface by virally-induced extracellular matrix components, including collagen and agrin, and cellular linker proteins, such as tetherin and galectin-3. Extracellular viral assemblies rapidly adhere to other cells upon cell contact, allowing virus spread and infection of target cells. Their removal strongly reduces the ability of HTLV-1–producing cells to infect target cells. Our findings unveil a novel virus transmission mechanism based on the generation of extracellular viral particle assemblies whose structure, composition and function ! resemble those of bacterial biofilms. HTLV-1 biofilm-like structures represent a major route for virus transmission from cell to cell. - A NOD for autophagy
Netea MG Joosten LA - Nature Medicine 16(1):28-30 (2010)
From the following article Biofilm-like extracellular viral assemblies mediate HTLV-1 cell-to-cell transmission at virological synapses Ana-Monica Pais-Correia, Martin Sachse, Stéphanie Guadagnini, Valentina Robbiati, Rémi Lasserre, Antoine Gessain, Olivier Gout, Andrés Alcover & Maria-Isabel Thoulouze Nature Medicine 16, 83 - 89 (2010) Published online: 20 December 2009 doi:10.1038/nm.2065 BACK TO ARTICLE Download plugins and applications Supplementary Text and Figures Supplementary Figures 1–8 and Supplementary Methods Supplementary Text and Figures - Download PDF file (3MB) BACK TO ARTICLE DOWNLOAD PLUGINS FOR YOUR BROWSER Movie files * QuickTime Player (PC or Mac) * Realplayer (PC or Mac) * Windows Media player (PC only) PDF documents * Adobe Acrobat Reader (PC or Mac) Text documents * Textpad (PC only) * SimpleText (Mac only) PostScript documents * GhostView (Mac and PC) Flash movies * Macromedia Flash Player Audio files * Apple iTunes (PC or Mac) * QuickTime Player (PC or Mac) * Realplayer (PC or Mac) * Windows Media player (PC only) Chemical structures * MDL Chime Mathematica * Mathematica Player Microarray * Treeview Compressed Stuff files * StuffIt Expander Compressed Zip files * WinZip (PC only) Systems Biology Markup Language files (SBML) * More information about SMBL Chemical Markup language files (CML) * More information about CML BACK TO ARTICLE - Myelodysplasia: battle in the bone marrow
Liu Y Asai T Nimer SD - Nature Medicine 16(1):30-32 (2010)
ARTICLE NAVIGATION - ISSUE Previous January 2010, Volume 16 No 1 pp1-129 * Editorial * News * Correspondence * Book Review * News and Views * Community Corner * Between Bedside and Bench * Research Highlights * Brief Communication * Articles * Letters * Technical Reports * Corrigenda * ErrataAbout the cover Editorial Nature Medicine, reloaded - p1 doi:10.1038/nm0110-1 Molecular medicine has undergone profound changes since the publication of the first issue of Nature Medicine 15 years ago this month. To keep up with these changes, we strengthen our commitment to publishing the best research and the most topical newsand commentary on translational medicine by adding more pages to the journal. Abstract - | Full Text - Nature Medicine, reloaded | PDF (87 KB) - Nature Medicine, reloaded News Biomarkers still off the mark for detecting breast cancer - p3 Mike May doi:10.1038/nm0110-3 Full Text - Biomarkers still off the mark for detecting breast cancer | PDF (271 KB) - Biomarkers still off the mark for detecting breast cancer To boost breast cancer research, a center banks on healthy tissue - p4 Megan Scudellari doi:10.1038/nm0110-4a Full Text - To boost breast cancer research, a center banks on healthy tissue | PDF (69 KB) - To boost breast cancer research, a center banks on healthy tissue Embryonic stem cell lines given the go-ahead - p4 Elie Dolgin doi:10.1038/nm0110-4b Full Text - Embryonic stem cell lines given the go-ahead | PDF (69 KB) - Embryonic stem cell lines given the go-ahead Better forecasting urged to avoid drug waste - p5 Elie Dolgin doi:10.1038/nm0110-5 Full Text - Better forecasting urged to avoid drug waste | PDF (129 KB) - Better forecasting urged to avoid drug waste Forecast calls for clouds over biological computing - p6 Mike May doi:10.1038/nm0110-6a Full Text - Forecast calls for clouds over biological computing | PDF (304 KB) - Forecast calls for clouds over biological computing Top 10 pharma firings of 2009 - p6 doi:10.1038/nm0110-6b Full Text - Top 10 pharma firings of 2009 | PDF (304 KB) - Top 10 pharma firings of 2009 Algorithms aim to improve hunt for disease markers - p7 Christian Torres doi:10.1038/nm0110-7a Full Text - Algorithms aim to improve hunt for disease markers | PDF (128 KB) - Algorithms aim to improve hunt for disease markers Matchmaking service links up researchers to wallflower drugs - p7 Charlotte Schubert doi:10.1038/nm0110-7b Full Text - Matchmaking service links up researchers to wallflower drugs | PDF (128 KB) - Matchmaking service links up researchers to wallflower drugs African networks launch to boost clinical trial capacity - p8 Elie Dolgin doi:10.1038/nm0110-8a Full Text - African networks launch to boost clinical trial capacity | PDF (117 KB) - African networks launch to boost clinical trial capacity China offers billions in loans to boost health research in Africa - p8 Georgina Kenyon doi:10.1038/nm0110-8b Full Text - China offers billions in loans to boost health research in Africa | PDF (117 KB) - China offers billions in loans to boost health research in Africa Pandemic blows lid off laws limiting mercury in vaccines - p9 Charlotte Schubert doi:10.1038/nm0110-9a Full Text - Pandemic blows lid off laws limiting mercury in vaccines | PDF (69 KB) - Pandemic blows lid off laws limiting mercury in vaccines In prevention push, AIDS program prioritizes research - p9 Cassandra Willyard doi:10.1038/nm0110-9b Full Text - In prevention push, AIDS program prioritizes research | PDF (69 KB) - In prevention push, AIDS program prioritizes research Painkiller concerns grow ahead of new guidelines - p10 Stu Hutson doi:10.1038/nm0110-10a Full Text - Painkiller concerns grow ahead of new guidelines | PDF (125 KB) - Painkiller concerns grow ahead of new guidelines Caution urged on tobacco research - p10 Vicki Brower doi:10.1038/nm0110-10b Full Text - Caution urged on tobacco research | PDF (125 KB) - Caution urged on tobacco research To save lives, initiative pushes for standardized diagnostic tools - p11 Stu Hutson doi:10.1038/nm0110-11a Full Text - To save lives, initiative pushes for standardized diagnostic tools | PDF (184 KB) - To save lives, initiative pushes for standardized diagnostic tools Penalty payouts from pharma rise - p11 doi:10.1038/nm0110-11b Full Text - Penalty payouts from pharma rise | PDF (184 KB) - Penalty payouts from pharma rise Institute of Medicine calls for savvier vaccine strategy - p12 Charlotte Schubert doi:10.1038/nm0110-12a Full Text - Institute of Medicine calls for savvier vaccine strategy | PDF (68 KB) - Institute of Medicine calls for savvier vaccine strategy For cost effectiveness, real data trumps trial results - p12 Christian Torres doi:10.1038/nm0110-12b Full Text - For cost effectiveness, real data trumps trial results | PDF (68 KB) - For cost effectiveness, real data trumps trial results Bioethicists renew call for changes to prison research - p13 Erica Westly doi:10.1038/nm0110-13a Full Text - Bioethicists renew call for changes to prison research | PDF (113 KB) - Bioethicists renew call for changes to prison research Britain reevaluates taxes on patent income - p13 Elie Dolgin doi:10.1038/nm0110-13b Full Text - Britain reevaluates taxes on patent income | PDF (113 KB) - Britain reevaluates taxes on patent income Exec salaries look up in life sciences - p13 doi:10.1038/nm0110-13c Full Text - Exec salaries look up in life sciences | PDF (113 KB) - Exec salaries look up in life sciences News in brief - pp14 - 15 doi:10.1038/nm0110-14 Full Text - News in brief | PDF (714 KB) - News in brief Straight talk with... Eric Green - pp16 - 17 Erica Westly doi:10.1038/nm0110-16 Eric Green, the new head of the US National Human Genome Research Institute (NHGRI), has been involved with genomics since the term was first coined in the 1980s. spoke with Green about where he sees the genomics field heading and what role he thinks the NHGRI should have in the American health care system. Abstract - | Full Text - Straight talk with... Eric Green | PDF (316 KB) - Straight talk with... Eric Green The saving switch - pp18 - 21 Cassandra Willyard doi:10.1038/nm0110-18 The epigenome consists of a system of chemical tags that attach to our DNA and its associated molecules, switching genes on and off. But the system is not without glitches—and scientists think that the misplacement of these tags can cause disease. This idea has led to new drugs that aim to correct gene activity (and obliterate disease) by altering the proteins around which DNA winds. examines whether this approach will unlock the long-awaited promise of epigenetic therapy. Abstract - | Full Text - The saving switch | PDF (1,023 KB) - The saving switch Drug ads move online, creating a web of regulatory challenges - p22 Meredith Wadman doi:10.1038/nm0110-22 Full Text - Drug ads move online, creating a web of regulatory challenges | PDF (113 KB) - Drug ads move online, creating a web of regulatory challenges Correspondence Nicotinamide and neutrophilia - p23 Abram Hoffer doi:10.1038/nm0110-23a Full Text - Nicotinamide and neutrophilia | PDF (70 KB) - Nicotinamide and neutrophilia Reply to: "Nicotinamide and neutrophilia" - p23 Julia Skokowa & Karl Welte doi:10.1038/nm0110-23b Full Text - Reply to: "Nicotinamide and neutrophilia" | PDF (70 KB) - Reply to: "Nicotinamide and neutrophilia" Book Review Personalizing medicine - p24 Edison T Liu reviews The Language of Life: DNA and the Revolution in Personalized Medicine by Francis S. Collins doi:10.1038/nm0110-24 Full Text - Personalizing medicine | PDF (87 KB) - Personalizing medicine News and Views Cloaked virus slips between cells - pp25 - 27 Kathryn S Jones & Patrick L Green doi:10.1038/nm0110-25 A common retrovirus encases itself in an extracellular matrix, enabling its transfer between T4 cells. The discovery of this new mode of infectivity has the potential to lead to new ways to combat the virus, human T cell leukemia virus type 1 (HTLV-1), which is associated with cancers and inflammatory disorders (pages 83–89). Full Text - Cloaked virus slips between cells | PDF (602 KB) - Cloaked virus slips between cells See also:Article by Pais-Correia et al. Hypertension finds a new rhythm - pp27 - 28 Bernard C Rossier doi:10.1038/nm0110-27 Blood pressure oscillates with the circadian rhythm, and a molecular mechanism has now been discovered (pages 67–74). The results point to a new genetic risk factor for hypertension and to a potential new target against this condition. Full Text - Hypertension finds a new rhythm | PDF (277 KB) - Hypertension finds a new rhythm See also:Article by Doi et al. A NOD for autophagy - pp28 - 30 Mihai G Netea & Leo A B Joosten doi:10.1038/nm0110-28 Susceptibility to Crohn's disease has been linked to polymorphisms in genes involved in two pathophysiological pathways: autophagy and the recognition of bacterial peptidoglycan by nucleotide oligomerization domain-2 (NOD2), an intracellular receptor. Two studies link these pathways by showing that recognition of bacterial peptidoglycans by NOD2 induces autophagy and bacterial clearance. Full Text - A NOD for autophagy | PDF (968 KB) - A NOD for autophagy See also:Article by Cooney et al. Myelodysplasia: battle in the bone marrow - pp30 - 32 Yan Liu, Takashi Asai & Stephen D Nimer doi:10.1038/nm0110-30 Innate immune signals and p53 contribute to the 5q– myelodysplastic syndrome, an acquired bone marrow failure disorder (pages 49–58 and 59–66). Full Text - Myelodysplasia: battle in the bone marrow | PDF (815 KB) - Myelodysplasia: battle in the bone marrow See also:Article by Starczynowski et al. | Article by Barlow et al. Huntington's disease: tagged for clearance - pp32 - 33 Dimitri Krainc doi:10.1038/nm0110-32 The neuronal accumulation of mutant huntingtin is a hallmark of Huntington's disease. New research shows that post-translational modifications of the mutant protein promote its clearance, uncovering new therapeutic targets for this disorder. Full Text - Huntington's disease: tagged for clearance | PDF (621 KB) - Huntington's disease: tagged for clearance Vessel remodeling in the newborn: platelets fill the gap - pp33 - 35 Ronald Clyman & Sylvain Chemtob doi:10.1038/nm0110-33 In newborn infants, permanent closure of a major blood vessel connecting the main pulmonary artery to the aorta is essential to allow adequate circulation of blood to major organs. Platelet aggregation now emerges as a crucial step in this process in newborn mice and, possibly, in preterm infants (pages 75–82). Full Text - Vessel remodeling in the newborn: platelets fill the gap | PDF (1,738 KB) - Vessel remodeling in the newborn: platelets fill the gap See also:Article by Echtler et al. Migration or evasion - pp35 - 36 Cornelis Melief doi:10.1038/nm0110-35 Tumors use many strategies to evade the immune system. A new study adds a new trick to the list—inhibiting the migration of dendritic cells from tumors toward lymph nodes (pages 98–105). Full Text - Migration or evasion | PDF (1,583 KB) - Migration or evasion See also:Article by Villablanca et al. Community Corner Gene therapy tackles demyelinating disease - p37 doi:10.1038/nm0110-37 Full Text - Gene therapy tackles demyelinating disease | PDF (159 KB) - Gene therapy tackles demyelinating disease Between Bedside and Bench Kidney complications: Why don't statins always work? - pp38 - 40 S Ananth Karumanchi & Ravi Thadhani doi:10.1038/nm0110-38 The vasculature suffers damage as a result of diabetes, often leading to conditions such as kidney failure. In bench to bedside, Christian Rask-Madsen and George King examine endogenous factors that protect against damage of the vasculature, such as vascular-endothelial growth factor (VEGF). Recent studies report that VEGF is expressed by kidneys and fends off renal failure; such findings have implications for the development of treatments that harness endogenous factors and sound a note of caution for the therapeutic use of VEGF inhibitors. People with end-stage renal disease often die of cardiovascular complications and clinical studies have shown that one popular class of drugs, statins, does not work in this population. In bedside to bench, S. Ananth Karumanchi and Ravi Thadhani show how this clinical finding is spurring research into the biological mechanisms behind cardiovascular death in people with kidney disease. Abstract - | Full Text - Kidney complications: Why don't statins always work? | PDF (605 KB) - Kidney complications: Why don't statins always work? Kidney complications: Factors that protect the diabetic vasculature - pp40 - 41 Christian Rask-Madsen & George L King doi:10.1038/nm0110-40 Full Text - Kidney complications: Factors that protect the diabetic vasculature | PDF (181 KB) - Kidney complications: Factors that protect the diabetic vasculature Research Highlights Research Highlights - pp42 - 43 doi:10.1038/nm0110-42 Full Text - Research Highlights | PDF (110 KB) - Research Highlights Brief Communication Characterization of the human neutrophil alloantigen-3a - pp45 - 48 Andreas Greinacher, Jan Wesche, Elke Hammer, Birgitt Fürll, Uwe Völker, Angelika Reil & Jürgen Bux doi:10.1038/nm.2070 A serious complication of blood transfusions is transfusion-related acute lung injury, which can be caused by antibodies in the donor blood that recognize and activate host neutrophils. Andreas Greinacher and his colleagues now determine the molecular identity of the antigen recognized by one of these antibodies, termed human neutrophil alloantigen-3a, as a variant of the choline transporter-like protein-2. This finding opens the door to systematic screening of blood donors and recipients. Abstract - | Full Text - Characterization of the human neutrophil alloantigen-3a | PDF (723 KB) - Characterization of the human neutrophil alloantigen-3a | Supplementary information Articles Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype - pp49 - 58 Daniel T Starczynowski, Florian Kuchenbauer, Bob Argiropoulos, Sandy Sung, Ryan Morin, Andrew Muranyi, Martin Hirst, Donna Hogge, Marco Marra, Richard A Wells, Rena Buckstein, Wan Lam, R Keith Humphries & Aly Karsan doi:10.1038/nm.2054 For myelodysplastic syndromes caused by deletion of chromosome 5q, Daniel Starczynowski et al. provide evidence that decreased expression of two miRNAs in this region—miR-145 and miR-146a—contributes to abnormal megakaryocyte differentiation and platelet production and progression of the disease to either bone marrow failure or leukemia. The authors also provide a mechanistic explanation for these effects by which loss of these two miRNAs leads to derepression of innate immune signaling. Abstract - | Full Text - Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype | PDF (1,134 KB) - Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype | Supplementary information See also:News and Views by Liu et al. | Article by Barlow et al. A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome - pp59 - 66 Jillian L Barlow, Lesley F Drynan, Duncan R Hewett, Luke R Holmes, Silvia Lorenzo-Abalde, Alison L Lane, Helen E Jolin, Richard Pannell, Angela J Middleton, See Heng Wong, Alan J Warren, James S Wainscoat, Jacqueline Boultwood & Andrew N J McKenzie doi:10.1038/nm.2063 In individuals with 5q– syndrome, deletion within chromosome 5q is associated with hematological abnormalities. Jillian Barlow et al. now create an animal model of the disease using chromosomal engineering to remove a corresponding region of the mouse genome. The resulting hematological abnormalities resemble those in the human disease, and the authors provide genetic evidence that p53 activation contributes to the disease process. Abstract - | Full Text - A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome | PDF (1,234 KB) - A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome | Supplementary information See also:News and Views by Liu et al. | Article by Starczynowski et al. Salt-sensitive hypertension in circadian clock–deficient Cry-null mice involves dysregulated adrenal Hsd3b6 - pp67 - 74 Masao Doi, Yukari Takahashi, Rie Komatsu, Fumiyoshi Yamazaki, Hiroyuki Yamada, Shogo Haraguchi, Noriaki Emoto, Yasushi Okuno, Gozoh Tsujimoto, Akihiro Kanematsu, Osamu Ogawa, Takeshi Todo, Kazuyoshi Tsutsui, Gijsbertus T J van der Horst & Hitoshi Okamura doi:10.1038/nm.2061 The circadian clock controls many aspects of human physiology, and disturbances in circadian rhythms have been linked to cardiovascular disease. Masao Doi et al. now delineate a new pathway by which the circadian clock influences hormone production and blood pressure in mice—clock genes control expression of an aldosterone biosynthetic enzyme, such that increased activity of this enzyme in mice with a disrupted circadian clock may account for the increased aldosterone levels and salt-sensitive hypertension seen in these mice. Abstract - | Full Text - Salt-sensitive hypertension in circadian clock–deficient Cry-null mice involves dysregulated adrenal Hsd3b6 | PDF (1,398 KB) - Salt-sensitive hypertension in circadian clock–deficient Cry-null mice involves dysregulated adrenal Hsd3b6 | Supplementary information See also:News and Views by Rossier Platelets contribute to postnatal occlusion of the ductus arteriosus - pp75 - 82 Katrin Echtler, Konstantin Stark, Michael Lorenz, Sandra Kerstan, Axel Walch, Luise Jennen, Martina Rudelius, Stefan Seidl, Elisabeth Kremmer, Nikla R Emambokus, Marie-Luise von Bruehl, Jon Frampton, Berend Isermann, Orsolya Genzel-Boroviczény, Christian Schreiber, Julinda Mehilli, Adnan Kastrati, Markus Schwaiger, Ramesh A Shivdasani & Steffen Massberg doi:10.1038/nm.2060 Premature infants can suffer from an anatomical defect in which the ductus arteriosus, a blood vessel that connects the pulmonary artery and the aorta during fetal development, fails to close at birth. Katrin Echtler et al. now show that platelets are needed for closure in mice and that reduced platelet function may be clinically relevant: in a retrospective study of preterm human infants, low platelet counts were associated with the presence of an unclosed ductus arteriosus. Abstract - | Full Text - Platelets contribute to postnatal occlusion of the ductus arteriosus | PDF (1,328 KB) - Platelets contribute to postnatal occlusion of the ductus arteriosus | Supplementary information See also:News and Views by Clyman & Chemtob Biofilm-like extracellular viral assemblies mediate HTLV-1 cell-to-cell transmission at virological synapses - pp83 - 89 Ana-Monica Pais-Correia, Martin Sachse, Stéphanie Guadagnini, Valentina Robbiati, Rémi Lasserre, Antoine Gessain, Olivier Gout, Andrés Alcover & Maria-Isabel Thoulouze doi:10.1038/nm.2065 The virus HTLV-1 is thought to pass between cells through synapses formed when infected lymphocytes make contact with other T cells. Isabelle Thoulouze and her colleagues uncover an alternative mechanism for the cell-to-cell transmission of this virus. They show that HTLV-1 virions bud at the plasma membrane and are held at the cell surface in structures reminiscent of bacterial biofilms. When infected lymphocytes make contacts with other cells, the adhesive viral assemblies are rapidly transferred to to the surface of the new lymphocyte, from which the virions mediate a new round of infection. Abstract - | Full Text - Biofilm-like extracellular viral assemblies mediate HTLV-1 cell-to-cell transmission at virological synapses | PDF (1,551 KB) - Biofilm-like extracellular viral assemblies mediate HTLV-1 cell-to-cell transmission at virological synapses | Supplementary information See also:News and Views by Jones & Green NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation - pp90 - 97 Rachel Cooney, John Baker, Oliver Brain, Benedicte Danis, Tica Pichulik, Philip Allan, David J P Ferguson, Barry J Campbell, Derek Jewell & Alison Simmons doi:10.1038/nm.2069 Mutations in NOD2—a bacterial sensor in dendritic cells—and mutations in genes related to autophagosome function have been linked to Crohn's disease. Alison Simmons and her colleagues link these susceptibility genes in a single functional pathway. They show that triggering of NOD2 induces autophagy, resulting in increased bacterial antigen presentation on the surface of the dendritic cell. They also show that this process goes awry in dendritic cells expressing the susceptibility variants from individuals with Crohn's disease. Abstract - | Full Text - NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation | PDF (1,033 KB) - NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation | Supplementary information See also:News and Views by Netea & Joosten Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses - pp98 - 105 Eduardo J Villablanca, Laura Raccosta, Dan Zhou, Raffaella Fontana, Daniela Maggioni, Aurora Negro, Francesca Sanvito, Maurilio Ponzoni, Barbara Valentinis, Marco Bregni, Alessandro Prinetti, Knut R Steffensen, Sandro Sonnino, Jan-Ake Gustafsson, Claudio Doglioni, Claudio Bordignon, Catia Traversari & Vincenzo Russo doi:10.1038/nm.2074 Sterol metabolism modulates immune responses through liver X receptor activation. Tumors harness this signaling pathway and can escape immunosurveillance by inhibiting dendritic cell migration to tumor-draining lymph nodes. Abstract - | Full Text - Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses | PDF (885 KB) - Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses | Supplementary information See also:News and Views by Melief Letters A mitotic transcriptional switch in polycystic kidney disease - pp106 - 110 Francisco Verdeguer, Stephanie Le Corre, Evelyne Fischer, Celine Callens, Serge Garbay, Antonia Doyen, Peter Igarashi, Fabiola Terzi & Marco Pontoglio doi:10.1038/nm.2068 Deficiency of the transcription factor HNF-1β results in kidney cyst formation. Marco Pontoglio and his colleagues now show that HNF-1β normally remains bound to condensed chromatin during mitosis to facilitate the rapid expression of key genes involved in cell quiescence post-mitosis. In the absence of HNF-1β, these genes fail to express, and the kidney epithelial cells continue to proliferate, resulting in cysts. Abstract - | Full Text - A mitotic transcriptional switch in polycystic kidney disease | PDF (617 KB) - A mitotic transcriptional switch in polycystic kidney disease | Supplementary information A key role for orexin in panic anxiety - pp111 - 115 Philip L Johnson, William Truitt, Stephanie D Fitz, Pamela E Minick, Amy Dietrich, Sonal Sanghani, Lil Träskman-Bendz, Andrew W Goddard, Lena Brundin & Anantha Shekhar doi:10.1038/nm.2075 Orexin, a neuropeptide best known for its role in arousal and its absence in people with narcolepsy, is also involved in the pathophysiology of panic anxiety disorder. First Paragraph - | Full Text - A key role for orexin in panic anxiety | PDF (600 KB) - A key role for orexin in panic anxiety | Supplementary information Technical Reports Real-time imaging reveals the single steps of brain metastasis formation - pp116 - 122 Yvonne Kienast, Louisa von Baumgarten, Martin Fuhrmann, Wolfgang E F Klinkert, Roland Goldbrunner, Jochen Herms & Frank Winkler doi:10.1038/nm.2072 One of the major challenges of metastasis research is being able to track the fate of individual metastasizing cancer cells over time. Here, Kienast et al. describe an animal model in which multiphoton laser scanning microscopy is used to image the steps involved in the establishment of brain metastasis in vivo. The movement of systemically injected, red fluorescent protein–labeled tumor cells is monitored over several weeks, revealing potential targets for therapy. Abstract - | Full Text - Real-time imaging reveals the single steps of brain metastasis formation | PDF (1,615 KB) - Real-time imaging reveals the single steps of brain metastasis formation | Supplementary information Generation of stable monoclonal antibody–producing B cell receptor–positive human memory B cells by genetic programming - pp123 - 128 Mark J Kwakkenbos, Sean A Diehl, Etsuko Yasuda, Arjen Q Bakker, Caroline M M van Geelen, Michaël V Lukens, Grada M van Bleek, Myra N Widjojoatmodjo, Willy M J M Bogers, Henrik Mei, Andreas Radbruch, Ferenc A Scheeren, Hergen Spits & Tim Beaumont doi:10.1038/nm.2071 Kwakkenbos et al. describe an in vitro method to generate antibody-secreting B cell lines from human peripheral blood memory B cells by transducing them with retroviral vectors encoding Bcl-6 and Bcl-xL. The approach can be used to stably and simultaneously produce high levels of B cell receptor (BCR) on the cell surface and secreted immunoglobulins, useful for studying BCR signaling and producing antigen-specific antibodies. Abstract - | Full Text - Generation of stable monoclonal antibody–producing B cell receptor–positive human memory B cells by genetic programming | PDF (852 KB) - Generation of stable monoclonal antibody–producing B cell receptor–positive human memory B cells by genetic programming | Supplementary information Corrigenda Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells - p129 Keisuke Ito, Atsushi Hirao, Fumio Arai, Keiyo Takubo, Sahoko Matsuoka, Kana Miyamoto, Masako Ohmura, Kazuhito Naka, Kentaro Hosokawa, Yasuo Ikeda & Toshio Suda doi:10.1038/nm0110-129a Full Text - Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells | PDF (53 KB) - Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells Modulating hedgehog signaling can attenuate the severity of osteoarthritis - p129 Alvin C Lin, Brian L Seeto, Justyna M Bartoszko, Michael A Khoury, Heather Whetstone, Louisa Ho, Claire Hsu, Amanda S Ali & Benjamin A Alman doi:10.1038/nm0110-129b Full Text - Modulating hedgehog signaling can attenuate the severity of osteoarthritis | PDF (53 KB) - Modulating hedgehog signaling can attenuate the severity of osteoarthritis Errata Drugs in the headlines - p129 Victoria Aranda doi:10.1038/nm0110-129c Full Text - Drugs in the headlines | PDF (53 KB) - Drugs in the headlines Drugs in the headlines - p129 Victoria Aranda doi:10.1038/nm0110-129d Full Text - Drugs in the headlines | PDF (53 KB) - Drugs in the headlines - Huntington's disease: tagged for clearance
Krainc D - Nature Medicine 16(1):32-33 (2010)
Susceptibility to Crohn's disease has been linked to polymorphisms in genes involved in two pathophysiological pathways: autophagy and the recognition of bacterial peptidoglycan by nucleotide oligomerization domain-2 (NOD2), an intracellular receptor. Two studies link these pathways by showing that recognition of bacterial peptidoglycans by NOD2 induces autophagy and bacterial clearance. - Vessel remodeling in the newborn: platelets fill the gap
Clyman R Chemtob S - Nature Medicine 16(1):33-35 (2010)
5q– syndrome is a subtype of myelodysplastic syndrome characterized by severe anemia and variable neutropenia but normal or high platelet counts with dysplastic megakaryocytes. We examined expression of microRNAs (miRNAs) encoded on chromosome 5q as a possible cause of haploinsufficiency. We show that deletion of chromosome 5q correlates with loss of two miRNAs that are abundant in hematopoietic stem/progenitor cells (HSPCs), miR-145 and miR-146a, and we identify Toll–interleukin-1 receptor domain–containing adaptor protein (TIRAP) and tumor necrosis factor receptor–associated factor-6 (TRAF6) as respective targets of these miRNAs. TIRAP is known to lie upstream of TRAF6 in innate immune signaling. Knockdown of miR-145 and miR-146a together or enforced expression of TRAF6 in mouse HSPCs resulted in thrombocytosis, mild neutropenia and megakaryocytic dysplasia. A subset of mice transplanted with TRAF6-expressing marrow progressed either to marrow failure or acut! e myeloid leukemia. Thus, inappropriate activation of innate immune signals in HSPCs phenocopies several clinical features of 5q– syndrome. - Migration or evasion
Melief C - Nature Medicine 16(1):35-36 (2010)
The ductus arteriosus (DA) is a fetal shunt vessel between the pulmonary artery and the aorta that closes promptly after birth. Failure of postnatal DA closure is a major cause of morbidity and mortality particularly in preterm neonates. The events leading to DA closure are incompletely understood. Here we show that platelets have an essential role in DA closure. Using intravital microscopy of neonatal mice, we observed that platelets are recruited to the luminal aspect of the DA during closure. DA closure is impaired in neonates with malfunctioning platelet adhesion or aggregation or with defective platelet biogenesis. Defective DA closure resulted in a left-to-right shunt with increased pulmonary perfusion, pulmonary vascular remodeling and right ventricular hypertrophy. Our findings indicate that platelets are crucial for DA closure by promoting thrombotic sealing of the constricted DA and by supporting luminal remodeling. A retrospective clinical study revealed tha! t thrombocytopenia is an independent predictor for failure of DA closure in preterm human newborns, indicating that platelets are likely to contribute to DA closure in humans. - Gene therapy tackles demyelinating disease
- Nature Medicine 16(1):37 (2010)
Gene therapy researchers have treated two boys with X-linked adrenoleukodystrophy (X-ALD), a demyelinating disease highlighted in the movie "Lorenzo's Oil." Such individuals are normally treated with allogeneic hematopoietic stem cell (HSC) transplantation, which results in donor-derived microglia in the brain. - Kidney complications: Why don't statins always work?
Karumanchi SA Thadhani R - Nature Medicine 16(1):38-40 (2010)
Sterol metabolism has recently been linked to innate and adaptive immune responses through liver X receptor (LXR) signaling. Whether products of sterol metabolism interfere with antitumor responses is currently unknown. Dendritic cells (DCs) initiate immune responses, including antitumor activity after their CC chemokine receptor-7 (CCR7)-dependent migration to lymphoid organs. Here we report that human and mouse tumors produce LXR ligands that inhibit CCR7 expression on maturing DCs and, therefore, their migration to lymphoid organs. In agreement with this observation, we detected CD83+CCR7− DCs within human tumors. Mice injected with tumors expressing the LXR ligand–inactivating enzyme sulfotransferase 2B1b (SULT2B1b) successfully controlled tumor growth by regaining DC migration to tumor-draining lymph nodes and by developing overt inflammation within tumors. The control of tumor growth was also observed in chimeric mice transplanted with bone marrow from mice l! acking the gene encoding LXR-α (Nr1h3−/− mice) Thus, we show a new mechanism of tumor immunoescape involving products of cholesterol metabolism. The manipulation of this pathway could restore antitumor immunity in individuals with cancer. - Kidney complications: Factors that protect the diabetic vasculature
Rask-Madsen C King GL - Nature Medicine 16(1):40-41 (2010)
Diabetes can wreak havoc on the vasculature, leading to renal failure, blindness and cardiovascular disease. Such conditions are ultimately the result of reduced insulin production or insulin action, leading to increased concentrations of glucose and free fatty acids and abnormal concentration of lipoproteins in the blood. - Research Highlights
- Nature Medicine 16(1):42-43 (2010)
- Characterization of the human neutrophil alloantigen-3a
Greinacher A Wesche J Hammer E Fürll B Völker U Reil A Bux J - Nature Medicine 16(1):45-48 (2010)
The vasculature suffers damage as a result of diabetes, often leading to conditions such as kidney failure. In bench to bedside, Christian Rask-Madsen and George King examine endogenous factors that protect against damage of the vasculature, such as vascular-endothelial growth factor (VEGF). Recent studies report that VEGF is expressed by kidneys and fends off renal failure; such findings have implications for the development of treatments that harness endogenous factors and sound a note of caution for the therapeutic use of VEGF inhibitors. People with end-stage renal disease often die of cardiovascular complications and clinical studies have shown that one popular class of drugs, statins, does not work in this population. In bedside to bench, S. Ananth Karumanchi and Ravi Thadhani show how this clinical finding is spurring research into the biological mechanisms behind cardiovascular death in people with kidney disease. - Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype
Starczynowski DT Kuchenbauer F Argiropoulos B Sung S Morin R Muranyi A Hirst M Hogge D Marra M Wells RA Buckstein R Lam W Humphries RK Karsan A - Nature Medicine 16(1):49-58 (2010)
From the following article Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses Eduardo J Villablanca, Laura Raccosta, Dan Zhou, Raffaella Fontana, Daniela Maggioni, Aurora Negro, Francesca Sanvito, Maurilio Ponzoni, Barbara Valentinis, Marco Bregni, Alessandro Prinetti, Knut R Steffensen, Sandro Sonnino, Jan-Ake Gustafsson, Claudio Doglioni, Claudio Bordignon, Catia Traversari & Vincenzo Russo Nature Medicine 16, 98 - 105 (2010) Published online: 27 December 2009 doi:10.1038/nm.2074 BACK TO ARTICLE Download plugins and applications Supplementary Text and Figures Supplementary Figures 1–8, Supplementary Table 1 and Supplementary Methods Supplementary Text and Figures - Download PDF file (2MB) BACK TO ARTICLE DOWNLOAD PLUGINS FOR YOUR BROWSER Movie files * QuickTime Player (PC or Mac) * Realplayer (PC or Mac) * Windows Media player (PC only) PDF documents * Adobe Acrobat Reader (PC or Mac) Text documents * Textpad (PC only) * SimpleText (Mac only) PostScript documents * GhostView (Mac and PC) Flash movies * Macromedia Flash Player Audio files * Apple iTunes (PC or Mac) * QuickTime Player (PC or Mac) * Realplayer (PC or Mac) * Windows Media player (PC only) Chemical structures * MDL Chime Mathematica * Mathematica Player Microarray * Treeview Compressed Stuff files * StuffIt Expander Compressed Zip files * WinZip (PC only) Systems Biology Markup Language files (SBML) * More information about SMBL Chemical Markup language files (CML) * More information about CML BACK TO ARTICLE - A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome
Barlow JL Drynan LF Hewett DR Holmes LR Lorenzo-Abalde S Lane AL Jolin HE Pannell R Middleton AJ Wong SH Warren AJ Wainscoat JS Boultwood J McKenzie AN - Nature Medicine 16(1):59-66 (2010)
Transfusion-related acute lung injury (TRALI) is a frequent cause of transfusion-associated morbidity and mortality. Severe TRALI is often due to antibodies in blood components directed against the human neutrophil alloantigen-3a (HNA-3a). We show here that the HNA-3a antigen arises from a nucleotide polymorphism in the choline transporter-like protein-2 gene (SLC44A2), with the resulting variation at amino acid position 154 determining the reactivity of the protein with HNA-3a–specific antibodies; the variant with an arginine at this position, rather than a glutamine, constitutes the HNA-3a antigen. The molecular identification of this antigen should facilitate the development of assays for blood donor screening to lower the risk of TRALI. - Salt-sensitive hypertension in circadian clock–deficient Cry-null mice involves dysregulated adrenal Hsd3b6
Doi M Takahashi Y Komatsu R Yamazaki F Yamada H Haraguchi S Emoto N Okuno Y Tsujimoto G Kanematsu A Ogawa O Todo T Tsutsui K van der Horst GT Okamura H - Nature Medicine 16(1):67-74 (2010)
The identification of the genes associated with chromosomal translocation breakpoints has fundamentally changed understanding of the molecular basis of hematological malignancies. By contrast, the study of chromosomal deletions has been hampered by the large number of genes deleted and the complexity of their analysis. We report the generation of a mouse model for human 5q– syndrome using large-scale chromosomal engineering. Haploinsufficiency of the Cd74–Nid67 interval (containing Rps14, encoding the ribosomal protein S14) caused macrocytic anemia, prominent erythroid dysplasia and monolobulated megakaryocytes in the bone marrow. These effects were associated with defective bone marrow progenitor development, the appearance of bone marrow cells expressing high amounts of the tumor suppressor p53 and increased bone marrow cell apoptosis. Notably, intercrossing with p53-deficient mice completely rescued the progenitor cell defect, restoring common myeloid progenitor! and megakaryocytic-erythroid progenitor, granulocyte-monocyte progenitor and hematopoietic stem cell bone marrow populations. This mouse model suggests that a p53-dependent mechanism underlies the pathophysiology of the 5q– syndrome. - Platelets contribute to postnatal occlusion of the ductus arteriosus
Echtler K Stark K Lorenz M Kerstan S Walch A Jennen L Rudelius M Seidl S Kremmer E Emambokus NR von Bruehl ML Frampton J Isermann B Genzel-Boroviczény O Schreiber C Mehilli J Kastrati A Schwaiger M Shivdasani RA Massberg S - Nature Medicine 16(1):75-82 (2010)
Malfunction of the circadian clock has been linked to the pathogenesis of a variety of diseases. We show that mice lacking the core clock components Cryptochrome-1 (Cry1) and Cryptochrome-2 (Cry2) (Cry-null mice) show salt-sensitive hypertension due to abnormally high synthesis of the mineralocorticoid aldosterone by the adrenal gland. An extensive search for the underlying cause led us to identify type VI 3β-hydroxyl-steroid dehydrogenase (Hsd3b6) as a new hypertension risk factor in mice. Hsd3b6 is expressed exclusively in aldosterone-producing cells and is under transcriptional control of the circadian clock. In Cry-null mice, Hsd3b6 messenger RNA and protein levels are constitutively high, leading to a marked increase in 3β-hydroxysteroid dehydrogenase-isomerase (3β-HSD) enzymatic activity and, as a consequence, enhanced aldosterone production. These data place Hsd3b6 in a pivotal position through which circadian clock malfunction is coupled to the development o! f hypertension. Translation of these findings to humans will require clinical examination of human HSD3B1 gene, which we found to be functionally similar to mouse Hsd3b6. - Biofilm-like extracellular viral assemblies mediate HTLV-1 cell-to-cell transmission at virological synapses
Pais-Correia AM Sachse M Guadagnini S Robbiati V Lasserre R Gessain A Gout O Alcover A Thoulouze MI - Nature Medicine 16(1):83-89 (2010)
The ductus arteriosus (DA) is a fetal shunt vessel between the pulmonary artery and the aorta that closes promptly after birth. Failure of postnatal DA closure is a major cause of morbidity and mortality particularly in preterm neonates. The events leading to DA closure are incompletely understood. Here we show that platelets have an essential role in DA closure. Using intravital microscopy of neonatal mice, we observed that platelets are recruited to the luminal aspect of the DA during closure. DA closure is impaired in neonates with malfunctioning platelet adhesion or aggregation or with defective platelet biogenesis. Defective DA closure resulted in a left-to-right shunt with increased pulmonary perfusion, pulmonary vascular remodeling and right ventricular hypertrophy. Our findings indicate that platelets are crucial for DA closure by promoting thrombotic sealing of the constricted DA and by supporting luminal remodeling. A retrospective clinical study revealed tha! t thrombocytopenia is an independent predictor for failure of DA closure in preterm human newborns, indicating that platelets are likely to contribute to DA closure in humans. - NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation
Cooney R Baker J Brain O Danis B Pichulik T Allan P Ferguson DJ Campbell BJ Jewell D Simmons A - Nature Medicine 16(1):90-97 (2010)
From the following article Salt-sensitive hypertension in circadian clock–deficient Cry-null mice involves dysregulated adrenal Hsd3b6 Masao Doi, Yukari Takahashi, Rie Komatsu, Fumiyoshi Yamazaki, Hiroyuki Yamada, Shogo Haraguchi, Noriaki Emoto, Yasushi Okuno, Gozoh Tsujimoto, Akihiro Kanematsu, Osamu Ogawa, Takeshi Todo, Kazuyoshi Tsutsui, Gijsbertus T J van der Horst & Hitoshi Okamura Nature Medicine 16, 67 - 74 (2010) Published online: 13 December 2009 doi:10.1038/nm.2061 BACK TO ARTICLE Download plugins and applications Supplementary Text and Figures Supplementary Figures 1–7, Supplementary Tables 1–3 and Supplementary Methods Supplementary Text and Figures - Download PDF file (2MB) BACK TO ARTICLE DOWNLOAD PLUGINS FOR YOUR BROWSER Movie files * QuickTime Player (PC or Mac) * Realplayer (PC or Mac) * Windows Media player (PC only) PDF documents * Adobe Acrobat Reader (PC or Mac) Text documents * Textpad (PC only) * SimpleText (Mac only) PostScript documents * GhostView (Mac and PC) Flash movies * Macromedia Flash Player Audio files * Apple iTunes (PC or Mac) * QuickTime Player (PC or Mac) * Realplayer (PC or Mac) * Windows Media player (PC only) Chemical structures * MDL Chime Mathematica * Mathematica Player Microarray * Treeview Compressed Stuff files * StuffIt Expander Compressed Zip files * WinZip (PC only) Systems Biology Markup Language files (SBML) * More information about SMBL Chemical Markup language files (CML) * More information about CML BACK TO ARTICLE - Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses
Villablanca EJ Raccosta L Zhou D Fontana R Maggioni D Negro A Sanvito F Ponzoni M Valentinis B Bregni M Prinetti A Steffensen KR Sonnino S Gustafsson JA Doglioni C Bordignon C Traversari C Russo V - Nature Medicine 16(1):98-105 (2010)
Human T cell leukemia virus type 1 (HTLV-1) is a lymphotropic retrovirus whose cell-to-cell transmission requires cell contacts. HTLV-1–infected T lymphocytes form 'virological synapses', but the mechanism of HTLV-1 transmission remains poorly understood. We show here that HTLV-1–infected T lymphocytes transiently store viral particles as carbohydrate-rich extracellular assemblies that are held together and attached to the cell surface by virally-induced extracellular matrix components, including collagen and agrin, and cellular linker proteins, such as tetherin and galectin-3. Extracellular viral assemblies rapidly adhere to other cells upon cell contact, allowing virus spread and infection of target cells. Their removal strongly reduces the ability of HTLV-1–producing cells to infect target cells. Our findings unveil a novel virus transmission mechanism based on the generation of extracellular viral particle assemblies whose structure, composition and function ! resemble those of bacterial biofilms. HTLV-1 biofilm-like structures represent a major route for virus transmission from cell to cell. - A mitotic transcriptional switch in polycystic kidney disease
Verdeguer F Le Corre S Fischer E Callens C Garbay S Doyen A Igarashi P Terzi F Pontoglio M - Nature Medicine 16(1):106-110 (2010)
Nucleotide-binding oligomerization domain–containing-2 (NOD2) acts as a bacterial sensor in dendritic cells (DCs), but it is not clear how bacterial recognition links with antigen presentation after NOD2 stimulation. NOD2 variants are associated with Crohn's disease, where breakdown in self-recognition of commensal bacteria leads to gastrointestinal inflammation. Here we show NOD2 triggering by muramyldipeptide induces autophagy in DCs. This effect requires receptor-interacting serine-threonine kinase-2 (RIPK-2), autophagy-related protein-5 (ATG5), ATG7 and ATG16L1 but not NLR family, pyrin domain containing-3 (NALP3).We show that NOD2-mediated autophagy is required for both bacterial handling and generation of major histocompatibility complex (MHC) class II antigen-specific CD4+ T cell responses in DCs. DCs from individuals with Crohn's disease expressing Crohn's disease—associated NOD2 or ATG16L1 risk variants are defective in autophagy induction, bacterial traff! icking and antigen presentation. Our findings link two Crohn's disease–associated susceptibility genes in a single functional pathway and reveal defects in this pathway in Crohn's disease DCs that could lead to bacterial persistence via impaired lysosomal destruction and immune mediated clearance. - A key role for orexin in panic anxiety
Johnson PL Truitt W Fitz SD Minick PE Dietrich A Sanghani S Träskman-Bendz L Goddard AW Brundin L Shekhar A - Nature Medicine 16(1):111-115 (2010)
Hepatocyte nuclear factor-1β (HNF-1β) is a transcription factor required for the expression of several renal cystic genes and whose prenatal deletion leads to polycystic kidney disease (PKD)1. We show here that inactivation of Hnf1b from postnatal day 10 onward does not elicit cystic dilations in tubules after their proliferative morphogenetic elongation is over. Cystogenic resistance is intrinsically linked to the quiescent state of cells. In fact, when Hnf1b deficient quiescent cells are forced to proliferate by an ischemia-reperfusion injury, they give rise to cysts, owing to loss of oriented cell division. Remarkably, in quiescent cells, the transcription of crucial cystogenic target genes is maintained even in the absence of HNF-1β. However, their expression is lost as soon as cells proliferate and the chromatin of target genes acquires heterochromatin marks. These results unveil a previously undescribed aspect of gene regulation. It is well established that tr! anscription is shut off during the mitotic condensation of chromatin2, 3. We propose that transcription factors such as HNF-1β might be involved in reprogramming gene expression after transcriptional silencing is induced by mitotic chromatin condensation. Notably, HNF-1β remains associated with the mitotically condensed chromosomal barrels. This association suggests that HNF-1β is a bookmarking factor that is necessary for reopening the chromatin of target genes after mitotic silencing. - Real-time imaging reveals the single steps of brain metastasis formation
Kienast Y von Baumgarten L Fuhrmann M Klinkert WE Goldbrunner R Herms J Winkler F - Nature Medicine 16(1):116-122 (2010)
Panic disorder is a severe anxiety disorder with recurrent, debilitating panic attacks. In individuals with panic disorder there is evidence of decreased central γ-aminobutyric acid (GABA) activity as well as marked increases in autonomic and respiratory responses after intravenous infusions of hypertonic sodium lactate1, 2, 3. In a rat model of panic disorder, chronic inhibition of GABA synthesis in the dorsomedial-perifornical hypothalamus of rats produces anxiety-like states and a similar vulnerability to sodium lactate–induced cardioexcitatory responses4, 5, 6, 7, 8, 9. The dorsomedial-perifornical hypothalamus is enriched in neurons containing orexin (ORX, also known as hypocretin)10, which have a crucial role in arousal10, 11, vigilance10 and central autonomic mobilization12, all of which are key components of panic. Here we show that activation of ORX-synthesizing neurons is necessary for developing a panic-prone state in the rat panic model, and either silen! cing of the hypothalamic gene encoding ORX (Hcrt) with RNAi or systemic ORX-1 receptor antagonists blocks the panic responses. Moreover, we show that human subjects with panic anxiety have elevated levels of ORX in the cerebrospinal fluid compared to subjects without panic anxiety. Taken together, our results suggest that the ORX system may be involved in the pathophysiology of panic anxiety and that ORX antagonists constitute a potential new treatment strategy for panic disorder. - Generation of stable monoclonal antibody–producing B cell receptor–positive human memory B cells by genetic programming
Kwakkenbos MJ Diehl SA Yasuda E Bakker AQ van Geelen CM Lukens MV van Bleek GM Widjojoatmodjo MN Bogers WM Mei H Radbruch A Scheeren FA Spits H Beaumont T - Nature Medicine 16(1):123-128 (2010)
Brain metastasis frequently occurs in individuals with cancer and is often fatal. We used multiphoton laser scanning microscopy to image the single steps of metastasis formation in real time. Thus, it was possible to track the fate of individual metastasizing cancer cells in vivo in relation to blood vessels deep in the mouse brain over minutes to months. The essential steps in this model were arrest at vascular branch points, early extravasation, persistent close contacts to microvessels and perivascular growth by vessel cooption (melanoma) or early angiogenesis (lung cancer). Inefficient steps differed between the tumor types. Long-term dormancy was only observed for single perivascular cancer cells, some of which moved continuously. Vascular endothelial growth factor-A (VEGF-A) inhibition induced long-term dormancy of lung cancer micrometastases by preventing angiogenic growth to macrometastases. The ability to image the establishment of brain metastases in vivo pro! vides new insights into their evolution and response to therapies. - Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells
- Nature Medicine 16(1):129 (2010)
Introduction Nat. Med. 12, 446–451 (2006); published online 26 March 2006; corrected after print 7 January 2010 In the version of this article initially published, two micrographs in Figure 2c, corresponding to the conditions BSO(−) Lineage− and BSO(+) Lineage−, were incorrect. These micrographs have been replaced with the correct micrographs in the HTML and PDF versions of the article. - Modulating hedgehog signaling can attenuate the severity of osteoarthritis
- Nature Medicine 16(1):129 (2010)
Introduction Nat. Med. 15, 1421–1425 (2009); published online 15 November 2009; corrected after print 7 January 2010 In the version of this article initially published, the author name Amanda S. Ali was incorrect. The correct name is S. Amanda Ali. The error has been corrected in the HTML and PDF versions of the article. - Drugs in the headlines
- Nature Medicine 16(1):129 (2010)
Introduction Nat. Med. 15, 1353 (2009); published online 4 December 2009; corrected after print 8 December 2009 In the version of this article initially published, the sentence "However, it failed in trials against early-stage colon cancers, and reports suggested that it might promote cancer metastasis in certain circumstances" was incorrect. Although it has been suggested that other strategies targeting blood vessel growth factors might promote tumor growth, this has not been specifically shown for Avastin. The text should read "However, it failed in trials against early-stage colon cancers. Reports have also suggested that targeting blood vessel growth factors might promote cancer metastasis in certain circumstances." The error has been corrected in the HTML and PDF versions of the article. - Drugs in the headlines
- Nature Medicine 16(1):129 (2010)
Introduction Nat. Med. 15, 1353 (2009); published online 4 December 2009; corrected after print 8 December 2009; corrected after print 11 December 2009 In the version of this article initially published, it was stated that Denosumab had gained approval for use in osteoporosis treatment, when in fact it had only been recommended for approval. Additionally, the approval of its preventive use was recommended against until further data are available. The text should read "Several clinical trials tested this antibody, which counteracts bone loss. Although a US Food and Drug Administration committee recommended its approval for osteoporosis treatment, it recommended against approval of its preventive use—and its use to treat bone loss in certain cancer cases—until more data are available." The error has been corrected in the HTML and PDF versions of the article.
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