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Volume 18 Issue 12, December 2012

In this issue (p 1797), Val Sheffield and his colleagues identify a role for neural progenitor cells in the development of neonatal hydrocephalus. The cover shows ependymal motile cilia lining the cerebral ventricles. Image courtesy of Thomas Moninger and Calvin Carter (University of Iowa).

Editorial

  • In spite of years of effort, we still lack highly efficacious vaccines against HIV, tuberculosis, malaria and numerous other widespread pathogens. Two recent setbacks in vaccine trials suggest that it's time to rethink how new vaccines are developed and to investigate what can be learned from the existing armament of childhood vaccines.

    Editorial

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News

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Q&A

  • A year ago, Guido Rasi stepped into the role of executive director of the European Medicines Agency (EMA), becoming only the third person to fill that role since the inception of the continental drug advisory body, in 1995. He spoke with Roxanne Khamsi about how the EMA is working toward better safety guidance and improved transparency.

    Q&A
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News in Brief

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Correction

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News

  • This year has proven to be a veritable cliff-hanger for the world of biomedicine. At the same time that the US government stands poised on the brink of the so-called 'fiscal cliff', pharmaceutical companies are stumbling with the industry's 'patent cliff' and academic researchers face the looming 'funding cliff'. But not everything in 2012 was so dire, with dozens of new drugs to hit worldwide markets and countless discoveries made to enable the next generation of medicines. What follows are a set of 'Cliff's notes' to the year that was for the field.

    News
  • We list the key people who made headlines this year, either for public reports that overstretched their reach or for papers that almost never saw the light of day.

    News
  • From the microbiome to the microenvironment, certain areas of biomedicine saw fast-paced discovery this year. Here's a rundown of the papers that helped these fields advance quickly in 2012.

    News
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Opinion

  • In recent years, the pharmaceutical industry has struggled to deliver new therapies, especially for diseases that affect the most vulnerable in developing countries. The global health community can fill this vacuum by catalyzing innovative partnerships across academia, government and the private sector, fostering a more rigorous environment for scientific decision making and creating the tools and infrastructure to conduct effective translational research.

    • Trevor Mundel
    Opinion
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Correspondence

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News & Views

  • Many mechanisms can contribute to complex diseases such as metabolic diseases; thus, combination therapies may be required to target individual underlying pathological mechanisms. A new study combines glucagon-like peptide-1 (GLP1) and estrogen in a single molecule, allowing selective targeting of this conjugate to cells that express the GLP1 receptor. This strategy improves the metabolic profile of obese mice without the adverse side effects associated with estrogen therapy (pages 1847–1856).

    • Marcelo O Dietrich
    • Tamas L Horvath
    News & Views
  • There is a growing appreciation of the importance of circadian regulation in energy homeostasis, and the dysregulation of the circadian clock has been associated with obesity and metabolic abnormalities. A new study shows that adipocyte-specific deletion of a core circadian clock gene, Arntl (Bmal1), in mice shifts the timing of their feeding behavior, resulting in obesity (pages 1768–1777).

    • Ingrid Wernstedt Asterholm
    • Philipp E Scherer
    News & Views
  • Delayed blood count recovery is a major cause of morbidity and mortality in people undergoing stem cell transplantation or intensive chemotherapy. Treatment with hematopoietic growth factors can accelerate hematopoiesis, but prolonged cytopenias still occur. A new study shows that inhibition of dipeptidylpeptidase IV augments the activity of certain hematopoietic growth factors, providing a new approach to potentially treat cytopenias (pages 1786–1796).

    • Yen-Michael S Hsu
    • Daniel C Link
    News & Views
  • Hydrocephalus describes an expansion of the cerebral ventricles that is associated with decreased cerebral volume and compromised neurological function. Although hydrocephalus mostly occurs sporadically, it is frequently associated with diseases caused by defective cilia function, including Bardet–Biedl syndrome (BBS). A new study reveals that hydrocephalus in a mouse model of BBS is related to defective proliferation and apoptosis of neural progenitor cells (NPCs) and can be rescued with lithium treatment (pages 1797–1804).

    • Bethany N Sotak
    • Joseph G Gleeson
    News & Views
  • In neuroinflammatory diseases such as multiple sclerosis, ion channels may fan the embers of neurodegeneration. A new study shows that the cation channel TRPM4 (transient receptor potential melastatin 4) crucially contributes to axonal loss in an animal model of multiple sclerosis (pages 1805–1811).

    • Reinhard Hohlfeld
    News & Views
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Community Corner

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Between Bedside and Bench

  • Despite the irrefutable role of inflammation in psoriasis, a complete knowledge of what immune cells and cytokines are involved during initiation and progression of this skin disease is lacking. Moreover, the complexities of the immune cell network and potential differences between mice and humans have led to translational failures. It is therefore important that we acquire in-depth understanding of what inflammatory players, of the many involved, are crucial, if we wish to develop effective therapies. In 'Bedside to Bench', James Krueger discusses how a subset of T cells, TH17 cells, which release interleukin-17 in humans, seem to be essential for pathogenesis of psoriasis. The interplay between interleukin-17 and other cytokines that may potentially be involved in psoriasis also needs further investigation. Additionally, there are open questions as to what subset of T cells, other than TH17, also produce interleukin-17 and when. In 'Bench to Bedside', Burkhard Becher and Stanislav Pantelyushin examine this issue by looking at a mouse model of skin inflammation that resembles psoriasis in humans. A class of skin-invading innate immune cells called γδ T cells was shown to drive skin inflammation in this model, particularly during the early stages of the disease, suggesting that innate immunity plays an important part in the initiation of psoriasis.

    • Burkhard Becher
    • Stanislav Pantelyushin
    Between Bedside and Bench
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Research Highlights

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Review Article

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Article

  • A molecular mechanism in the brain and individual tissues allows mammals to adapt to a 24-hour clock. Garret FitzGerald and colleagues now show that genetic deletion of one member of this pathway specifically in the fat of mice results in acutely altered lipid profiles that, in turn, result in increased feeding and obesity. This could explain why human night-shift workers are at an increased risk for obesity and metabolic disease.

    • Georgios K Paschos
    • Salam Ibrahim
    • Garret A FitzGerald
    Article
  • Hematopoietic stem cells are difficult to maintain in vitro, hampering their clinical use. Jian Huang et al. show that mouse and human hematopoietic stem cells can be maintained in culture in the absence of exogenous cytokines by combined treatment with agents that activate Wnt and inhibit mTOR signaling, two major signaling pathways implicated in stem cell homeostasis. Moreover, treatment with two such compounds used clinically increases the number of hematopoietic stem cells in mice in vivo.

    • Jian Huang
    • Michelle Nguyen-McCarty
    • Peter S Klein
    Article
  • The peptidase DPP4 has a wide variety of target proteins, including the chemokine SDF-1 and the hormone GLP-1. Hal Broxmeyer and his coworkers now identify colony-stimulating factors as a new class of DPP4 substrates, including GM-CSF, G-CSF, IL-3 and erythropoietin. Treatment of mice with a clinically approved, orally available DPP4 inhibitor improved hematopoietic recovery after radiation or chemotherapeutic drug administration, pointing to potential clinical applications of these findings.

    • Hal E Broxmeyer
    • Jonathan Hoggatt
    • Timothy B Campbell
    Article
  • Hydrocephalus is a neurological disorder characterized by expansion of the ventricles. In a mouse model, the authors identified a role for neural progenitors and for platelet-derived growth factor signaling in the pathogenesis of neonatal hydrocephalus. Targeting this pathway reduced ventricular volume, pointing to a new therapeutic target for this condition.

    • Calvin S Carter
    • Timothy W Vogel
    • Val C Sheffield
    Article
  • Axonal and neuronal damage are commonly seen in patients with multiple sclerosis. Manuel A. Friese and his colleagues now report that the cation channel transient receptor potential melastatin 4 (TRPM4) is upregulated in multiple sclerosis lesions in patients and contributes to disease in vivo. Genetic deletion or pharmacological inhibition of TRPM4 in a mouse model of multiple sclerosis reduces clinical scores and is neuroprotective, suggesting this may represent a novel therapeutic target.

    • Benjamin Schattling
    • Karin Steinbach
    • Manuel A Friese
    Article
  • Proinflammatory cytokine expression increases as a result of amyloid deposition in Alzheimer's disease. Frank L. Heppner and colleagues show that genetic and pharmacological inhibition of IL-12 and IL-23 signaling reduces plaque load and improves cognitive deficits in mouse models of Alzheimer's disease. As the concentration of p40 is also increased in the cerebrospinal fluid of individuals with Alzheimer's disease, this suggests that this pathway may be targeted therapeutically in patients.

    • Johannes vom Berg
    • Stefan Prokop
    • Frank L Heppner
    Article
  • Attenuated viruses can be highly effective vaccines. In this issue, Ralph Baric and colleagues report that inactivating mutations in the exonuclease ExoN of a mouse-adapted SARS coronavirus impair replication fidelity and cause a mutator phenotype. The resulting attenuated virus protected mice against a lethal coronavirus challenge.

    • Rachel L Graham
    • Michelle M Becker
    • Ralph S Baric
    Article
  • Oncolytic virotherapy has been tested in cancer patients, but its efficacy is uncertain. Alvarez-Breckenridge et al. now report that in mouse models of glioblastoma, an antiviral response mediated by natural killer (NK) cells may impair the anticancer efficacy of oncolytic virotherapy. Their findings suggest that limiting the cytolytic activity of NK cells might enhance replication of oncolytic viruses and increase tumor cell killing.

    • Christopher A Alvarez-Breckenridge
    • Jianhua Yu
    • E Antonio Chiocca
    Article
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Technical Report

  • Cancer cells shed large numbers of small, membrane-bound microvesicles (MVs) into the circulation, which have diagnostic potential but have proved difficult to analyze in a point-of-care setting. Huilin Shao and colleagues have developed a microfluidic chip with an integrated NMR detection system for the rapid profiling of circulating MVs directly from blood samples of patients with glioblastoma. The system was used to distinguish cancer cell–derived MVs from host cell–derived MVs and to measure treatment effects in vivo.

    • Huilin Shao
    • Jaehoon Chung
    • Hakho Lee
    Technical Report
  • Currently there is no single imaging system that can offer adequate spatial and temporal resolution to accurately assess many of the important factors involved in peripheral arterial diseases. Here, an epifluorescence imaging approach is offered that overcomes many of the current limitations and uses the near-infrared fluorescence of single-walled carbon nanotubes as fluorophores in the second near-infrared window (beyond 1,000 nm). Its use is demonstrated for imaging blood vessels in mouse hindlimb vasculatures millimeters deep in vivo.

    • Guosong Hong
    • Jerry C Lee
    • Hongjie Dai
    Technical Report
  • Estrogen is beneficial for obesity and type 2 diabetes, though its use is limited by important side effects. In a new study, Matthias Tschöp and colleagues avoid this issue by chemically linking estrogen to the hormone GLP-1 to selectively target metabolically relevant tissue and show that the conjugated compound corrects obesity, hyperglycemia and dyslipidemia in mice. This approach could be used for other hormone pairs to treat other diseases.

    • Brian Finan
    • Bin Yang
    • Matthias H Tschöp
    Technical Report
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Corrigendum

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