Volume 19 Issue 1, January 2013

In December 2011, Stephen O'Brien stepped down as head of the US National Cancer Institute's Laboratory of Genomic Diversity and took up a three-year, $5 million 'megagrant' in Russia through a program started a year earlier by the Russian Ministry of Education and Science. O'Brien used his money to help launch the Theodosius Dobzhansky Center for Genome Bioinformatics at Saint Petersburg State University. On a trip back to the US, O'Brien spoke with Elie Dolgin about his new Russian center.

Recent headlines have promised that a 'universal flu vaccine' may be within reach, pointing to antibodies that offer broad protection in animal studies. But the scientists behind this effort had to first overcome great skepticism from their peers—as well as an imperfect laboratory test. Hannah Hoag reports on one virologist's 20-year effort to challenge the tenets of the field.

India has become a hotbed of clinical trials, but recent reports of safety lapses have prompted calls for better regulation in this area. Currently, trial requirements can be relaxed if doing so is in the 'public interest', but a clearer definition of what this means is needed before this provision should be used.

Cells and tissues are often subjected to stressful environments that challenge homeostasis and can include oxidative, nutrient or metabolic stress. Cell survival requires the recruitment of stress pathways that 'defend' the internal homeostatic environment of the cell. Recent studies indicate that activation of some of these existing pathways is beneficial to whole-body metabolism. Now, mice with a muscle-specific autophagy deficiency are shown to adapt to stress through a newly discovered endocrine pathway involving fibroblast growth factor 21 (FGF21) (pages 83–92).

Several physiological and pathological events taking place postnatally in or around the pancreatic islets of Langerhans have been implicated in the initiation of type 1 diabetes. A new study highlights the contribution of neutrophils and how they, together with B1a cells and plasmacytoid dendritic cells (pDCs), may start the autoimmune process (pages 65–73).

The anticancer efficacy of conventional chemotherapies seems to be due, in part, to augmentation of the host immune reactivity. However, a new study reveals that two common chemotherapeutic agents, gemcitabine and 5-fluorouracil, can also activate immune regulatory cells, which stimulates the emergence of protumorigenic cytokines via inflammasome pathways, limiting the antitumor efficacy of the drugs (pages 57–64).

Production of the amyloid-β peptide in Alzheimer's disease by the γ-secretase complex can be regulated by certain G protein–coupled receptors. This regulation seems to be mediated by β-arrestin-2, whose expression was found to be elevated in Alzheimer's disease brains (pages 43–49).

Distinct roadblocks prevent translating basic findings in viral pathogenesis into therapies and implementing potential solutions in the clinic. An ongoing partnership between the Volkswagen Foundation and Nature Medicine resulted in an interactive meeting in 2012, as part of the “Herrenhausen Symposia” series. Current challenges for various fields of viral research were recognized and discussed with a goal in mind—to identify solutions and propose an agenda to address the translational barriers. Here, some of the researchers who participated at the meeting provide a concise outlook at the most pressing unmet research and clinical needs, identifying these key obstacles is a necessary step towards the prevention and cure of human viral diseases.

The term 'mesenchymal stem cells' is widely used, yet the capabilities and characteristics of these postnatal bone marrow stem cells still warrant further examination. A further understanding and clarification of the true potential of these mesenchymal stem cells is crucial for their appropriate exploitation in the clinic.

The mechanism whereby activation of G protein–coupled receptors (GPCRs) increase the production of amyloid-β (Aβ) peptide remains unclear. Here Bart De Strooper and colleagues show that the GPCR adaptor protein β-arrestin 2 promotes Aβ production by associating with APH-1A and increasing γ-secretase activity. Overexpression of β-arrestin 2 increases Aβ generation, whereas mice lacking β-arrestin 2 have reduced amyloid accumulation. Moreover, expression of β-arrestin 2 is elevated in individuals with Alzheimer's disease, suggesting a potential therapeutic target aimed at reducing amyloid production.

Whether the molecular drivers of tumor initiation are the same factors that promote metastasis during tumor progression is addressed in this report. In renal carcinoma, common primary driving alterations such as VHL loss do not necessarily correlate with outcome, and the authors show that additional epigenetic adaptations are required to unleash prometastatic behavior. Two important metastastic drivers, CXCR4 and CYTIP, are activated downstream of VHL loss through epigenetic reprogramming involving differential chromatin modification or DNA methylation, exemplifying the complex evolution of tumorigenic traits downstream of driving alterations.

Gemcitabine and 5-fluorouracil are two commonly used chemotherapeutic agents for the treatment of cancer. François Ghiringhelli and colleagues now report that the antitumor efficacy of these agents is mitigated by myeloid derived suppressor cells (MDSCs). The authors show that these drugs can activate the NLRP3 inflammasome, leading to increased secretion of IL-1β by MDSCs and IL-17 production by CD4⁺ T cells, which can promote tumor growth.

The early events in the pathogenesis of type 1 diabetes remain incompletely understood. Julien Diana et al. now show that in response to physiological beta cell death, innate immune cells including neutrophils and B1-a cells are recruited early on to pancreatic islets. These cells promote interferon-α production by plasmacytoid dendritic cells in the pancreas, promoting autoreactive T cell responses and autoimmunity.

Vascular homeostasis in the lung is disturbed in pulmonary arterial hypertension. Jongmin Kim et al. delineate a new signaling axis controlling endothelial cell proliferation and cytokine production that is dysregulated in pulmonary endothelial cells from individuals with this disease. In this axis, the peptide apelin controls expression of the cytokine FGF2, a mitogen for endothelial and vascular smooth-muscle cells, through effects on two microRNAs. The authors also demonstrated the functional importance of these miRNAs in rat models of pulmonary hypertension.

Defects in mitochondrial function have been believed to contribute to insulin resistance. Myung-Shik Lee and colleagues now show that mitochondrial dysfunction in muscle induced by tissue-specific deficiency of autophagy results in upregulation of Fgf21 and improved metabolism, suggesting that at least some mitochondrial dysfunction may actually be beneficial.

In a new study Yingxian Li and her colleagues show that the microRNA miR-214 targets ATF4 in osteoblasts to negatively regulate their activity. Manipulating miR-214 levels experimentally showed that its elevated expression is sufficient to induce bone loss in mice and that its therapeutic inhibition reduces bone loss in two mouse models.

Shin'ichi Takeda and colleagues show that loading of muscle results in nitric oxide creation and its conversion to peroxynitrite. The latter molecule then activates TRPV1 in the muscle, leading to increased cytoplasmic concentrations of calcium and activation of mTOR and, thus, muscle hypertrophy. They could replicate these effects without overload by treating mice with a TRPV1 agonist, suggesting a possible therapy for muscle wasting.

The glomerulus, unlike many capillary beds, readily supports leukocyte recruitment, but little is known about the actions of leukocytes upon recruitment to glomeruli. Devi and colleagues have addressed this issue with a multiphoton, confocal microscopy–based approach to shed light on glomerular inflammation. Induction of inflammation in mice did not increase the number of leukocytes recruited to glomeruli but prolonged the duration of leukocyte retention and migration.