Volume 17 Issue 1, January 2011

Late last year, Phil Willis stepped into the role of chairman of the Association of Medical Research Charities (AMRC) in the UK. He spoke with Asher Mullard about his plans to drive the medical research sector forward through tough economic times.

For most people, a single bite from a parasite-infected tsetse fly can trigger a slow, agonizing and sometimes fatal disease known as African sleeping sickness. But new research shows that some people, as well as baboons and other great apes, are naturally resistant to infection. Cassandra Willyard awakens to the possibility of using existing immunity to engineer new therapies and transgenic livestock.

Collagen may be the darling of the beauty world for its purported antiwrinkle function, but too much of the protein can have ugly—even deadly—consequences. Measuring and treating this overabundance, known as fibrosis, presents a seemingly impossible challenge. Thomas Hayden visits a company in California offering a weighty solution.

This century will bring exciting biomedical advances thanks to stem cells and genetic engineering. If scientists want the public to grasp the meaning of these developments, they need to start getting personally involved in improving the education system.

The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell survival. A new study now shows that these beneficial effects of adiponectin are dependent on sphingolipid metabolism (pages 55–63).

Adenosine therapy for sickle cell disease has been proposed to improve blood flow, mediate cytoprotection and inhibit natural killer cell activity. Complicating this approach, adenosine signaling also induces hemoglobin S polymerization, promoting 'sickling', vasoocclusion, hemolysis and organ damage (pages 79–86).

The antiplatelet drug clopidogrel helps prevent stent-associated thrombosis, but the antiplatelet effects are quite variable and the clinical consequences can be serious. New findings show that the variability in clopidogrel efficacy is affected by the enzyme paraoxonase-1 (PON1), which is required for clopidogrel bioactivation (pages 110–116).

Histamine produced by immature myeloid cells restricts the expression of inflammatory mediators and regulates leukocyte recruitment to sites of tissue stress. Unexpectedly, cancer susceptibility is increased in mice lacking histamine, thus revealing a previously unknown mechanism whereby immature myeloid cells contribute to cancer development (pages 87–95).

Loss of kidney filter function during nephrotic syndrome results in loss of protein from the blood into the urine (proteinuria). A new study mechanistically links proteinuria to dysregulated expression and post-transcriptional modification of the secreted glycoprotein angiopoietin-like-4 in kidney glomerular podocytes (pages 117–122).

The pathogen causing malaria, Plasmodium, is a perfect escapist that causes millions of infections and deaths—mostly in endemic areas plagued with poverty and lack of resources. Efforts in developing vaccines against the parasite focus on several immunological strategies, but they still fail to control it. In 'Bedside to Bench', Pedro Alonso and Quique Bassat examine recent observational studies where Plasmodium vivax was associated with severe malaria—usually linked to Plasmodium falciparum—in non-African endemic areas. Understanding what factors add to this morbidity and how this species severely sickens children and adults may help pave the way to eradicate malaria worldwide. In 'Bench to Bedside', Michael Good and Christian Engwerda discuss how a CD8⁺ T cell–mediated strategy may be useful in a vaccine to tackle the blood-stage parasite. Stimulation of these immune cells with the correct vaccination approach could open new doors to prevent disease in people infected with malaria.

The protein hormone adiponectin is known to have many beneficial systemic effects, including promoting cell survival, anti-inflammation and insulin sensitivity. Phil Scherer and his colleagues have found that these pleiotropic effects are mediated by a ceramidase activity associated with the two known isoforms of the adiponectin receptor.

Expression of miR-124, a microglial microRNA, reduces disease in a mouse model of multiple sclerosis by inhibiting the transcription factor C/EBP-α and its downstream target PU.1.

Jian-Xun Wang et al. show that mitochondrial fission, which occurs during cell death, is regulated in cardiomyocytes by the microRNA miR-499 through a mechanism involving the phosphatase calcineurin and its substrate Drp1. Overexpression of miR-499 was able to reduce mitochondrial fission and apoptosis in the hearts of mice or rats injured by ischemia-reperfusion and to improve heart function, suggesting new therapeutic approaches for myocardial injury.

Yujin Zhang et al. discovered that the concentration of adenosine in the blood is increased both in a mouse model of sickle cell disease and in humans with this disease. Adenosine seems to have a pathological role in this disease, as it induced sickling of human erythrocytes through a mechanism involving activation of the A_2B adenosine receptor. Treatment of the mouse model of sickle cell disease with an agent to lower adenosine levels or with an A_2B adenosine receptor antagonist had beneficial effects, pointing to new therapeutic strategies for this disease.

Histidine decarboxylase (Hdc) is required for the endogenous production of histamine, but its role in tumorigenesis is unclear. Yang et al. now report that Hdc-deficient mice develop more tumors in models of chemically induced carcinogenesis, associated with an increased recruitment of immature myeloid cells to the tumors and higher amounts of interleukin-6. The authors further show that Hdc deficiency inhibits myeloid cell maturation and that exogenous histamine promotes monocyte differentiation and suppresses tumor growth.

A subset of series B adenoviruses binds epithelial cells via a previously unknown receptor. Wang et al. now identify this receptor as desmoglein-2 (DSG-2), which has a role in intercellular adhesion. Binding of group B Ad3 to DSG-2 triggered an epithelial to mesenchymal transition, opened intercellular junctions and increased access to junction-localized proteins, which together may contribute to the spread of these viruses though epithelial tissues.

Adenovirus type 37 (Ad37) causes epidemic keratoconjunctivitis, a highly contagious disease for which there is no specific antiviral therapy. The receptor for Ad37 infection was previously unidentified, but known to contain sialic acid. Nilsson et al. report here that Ad37 binds to the GD1a glycan motif of the GD1a ganglioside. This finding may facilitate the development of antiviral agents targeting Ad37-associated disease.

The antithrombotic drug clopidogrel, widely prescribed after heart attacks, is a prodrug and must be metabolically activated. The efficiency of this activation step varies among individuals and is thought to account for clopidogrel's variable clinical efficacy, a major drawback to its use. Heleen Bouman et al. provide biochemical, clinical and epidemiological evidence to show that a common polymorphism in the gene encoding paraoxonase-1 is largely responsible for this variability. Paraoxonase-1 genotyping might identify those individuals unlikely to benefit from clopidogrel treatment.

Proteinuria results from defects in glomerular filtration, often as a result of kidney injury or inflammation. Sumant Chugh and his colleagues now show that the glycoprotein Angptl4 is highly upregulated in minimal change disease, a type of human proteinuria, and that genetic deletion protects against experimentally induced proteinuria in mice.

Bhang and colleagues have developed a tumor-specific imaging strategy that uses the progression elevated gene-3 (PEG-3) promoter, known to be specifically associated with malignant transformation, to selectively drive the expression of luciferase or herpes simplex virus 1 thymidine kinase reporters. Systemic delivery of PEG-3 promoter–driven constructs using a nonviral gene delivery vehicle allowed detection of both primary tumors and micrometastatic disease in mouse models of human melanoma and breast cancer.

A major problem in the clinical management of patients with brain tumors is distinguishing tumor recurrence from radiation-induced necrosis after brain tumor therapy. Zhou et al. use an MRI technique called amide proton transfer imaging to noninvasively differentiate between these two pathologies. The approach is successfully evaluated by comparing two orthotopic glioma models with a radiation necrosis model in rats.