Volume 18 Issue 11, November 2012

In late September, the Association of University Research Parks announced that David Baker would serve as president of the organization’s board of directors for the next year and help guide its strategic goals for the next five years. Baker spoke with Roxanne Khamsi about how the organization hopes to branch out and transform these workplaces.

The most common genetic killer of infants, a disease known as spinal muscular atrophy, is caused by mutations in a single gene. The human genome contains its own backup system—near-identical copies of the defective gene—yet these secondary sequences rarely get used correctly. As Elie Dolgin finds out, drug companies hope to change that, with the first wave of targeted therapies that reboot the body's backup system now entering clinical trials.

Clinical trials typically address more than one question. But in attempting to protect against misleading results that are due to chance when multiple interrelated tests are run simultaneously, researchers sometimes apply overly strict statistical devices that mask true effects. They should give more consideration to choosing the type of statistical analysis that fits best.

Angiogenesis is a key feature of central nervous system injury. A neovessel-derived signal mediated by prostacyclin triggers axonal sprouting and functional recovery in a mouse model of inflammatory spinal cord injury (pages 1658–1664). Are such angiocrine signals relevant to neurovascular remodeling and recovery in other neurological contexts?

A long-standing question in the HIV field is why HIV-1 fails to replicate in resting CD4⁺ T cells. A new study shows that host deoxynucleoside triphosphate triphosphohydrolase (dNTPase) sterile α motif and histidine/aspartic domain–containing protein 1 (SAMHD1), previously shown to block HIV infection in myeloid cells, also restricts HIV replication in resting CD4⁺ T cells by hydrolyzing dNTPs, which are needed for reverse transcription of the virus (pages 1682–1687).

Two anatomical niches for hematopoietic stem cells (HSCs) have been reported in the bone marrow, but a distinct function for each of these niches has remained unclear. A new role in stem cell proliferation has now been identified for the adhesion molecule E-selectin expressed by bone marrow endothelial cells at the vascular niche (pages 1651–1657).

A new study provides mechanistic insights into how live attenuated simian immunodeficiency virus (SIV) vaccines (LAVs) can protect monkeys from infection with pathogenic SIV. The authors show that replicating LAVs stimulate a protective immune response from a safe haven in the germinal centers of lymph nodes (pages 1673–1681).

The production of cross-reactive neutralizing antibodies is the ultimate goal in HIV vaccine development, but no immunogen other than HIV itself has been able to elicit this type of humoral immunity. In natural HIV infections, these antibodies take several years to develop. A new study sheds light on what may be causing this delay in neutralizing antibody development (pages 1688–1692).

The sirtuins (SIRTs) have gained preeminence for their roles in the response to caloric restriction and the regulation of aging and lifespan. A new study now identifies gene promoters that bind the transcription factor AP1 as targets for silencing by SIRT6, providing possible links between SIRT6 deficiency and dysregulation of insulin-like growth factor signaling, hypertrophic cardiomyopathy and heart failure (pages 1643–1650).

An imaging technique adapted to differentiate between chronic obstructive pulmonary disease phenotypes can identify small-airway pathophysiology, locate the disease and potentially track disease progression. This approach may be used as a biomarker to identify the small-airway lesion in chronic obstructive pulmonary disease, at an individual level in the clinic (pages 1711–1715).

There is increasing interest in understanding how epilepsy initiates and how to thwart the establishment of the disease. Many questions remain open as to what targets may the best for preventing epilepsy and whether any common triggering pathway exists to treat this complex malady. In 'Bedside to Bench', Rod C. Scott and Gregory Holmes discuss alternative therapies to treat neonatal seizures to prevent chronic cognitive impairment and brain developmental problems, which can lead to epilepsy later in life. Increasing inhibitory signals in the developing brain may be useful in dampening brain hyperexcitability—and enhanced susceptibility for seizures—and blocking epilepsy development in children. In 'Bench to Bedside', Annamaria Vezzani argues how the mTOR pathway may be a potential target for blocking epileptogenesis. The role of mTOR in seizures in early life and progression of established disease raises the possibility that mTOR could be a common mediator involved in epilepsy at different stages of disease initiation and progression. Given the lack of current antiepileptic drugs to prevent seizures in children and to block epileptogenesis, developing new disease-modifying therapies remains a priority.

Large-scale sequencing has recently revealed the presence of highly complex, localized chromosomal rearrangements in cancer genomes. The authors discuss the evidence that such rearrangements can occur through at least two mechanisms: chromosomal shattering (chromothripsis) and template switching initiated by local defective DNA replication (chromoanasynthesis). They propose use of the term chromoanagenesis to describe this class of rearrangements, regardless of the initiating mechanism.

Doxorubicin, which induces tumor cell death through effects on topoisomerase-II, is a commonly used chemotherapeutic agent but has the substantial drawback of causing cardiotoxicity. Edward T.H.Yeh and his colleagues now show that doxorubicin-induced cardiotoxicity in mice is due to the deleterious effects of doxorubicin on topoisomerase-IIβ in cardiomyocytes, leading to alterations in gene expression, mitochondrial dysfunction and cell death.

The chromatin-modifying protein SIRT6 has previously been shown to have anti-aging properties. Sundaresan et al. now show that SIRT6 expression is low in failing human hearts and SIRT6 in mice protects the heart by suppressing the activity of the c-Jun transcription factor, which acts as a global regulator of genes encoding components of the IGF-Akt signaling pathway.

The self renewal of hematopoietic stem cells is regulated by the bone marrow microenvironment. Whereas previous studies have focused on the role of osteoblasts, Ingrid Winkler et al. now show that bone marrow endothelial cells in the so-called 'vascular niche' contribute to this regulation by directly inducing HSC proliferation. In mice, deficiency or antagonism of the endothelial-specific adhesion protein E-selectin promotes HSC quiescence and self renewal. These findings may point to a new treatment strategy for preserving HSC function in patients undergoing chemotherapy.

Angiogenesis is induced in response to central nervous system (CNS) injury and inflammation. Toshihide Yamashita and colleagues show that in a mouse model of multiple sclerosis, new vessels form around inflammatory lesions and promote neuronal remodeling, rewiring of the corticospinal tract, and recovery of motor function in these mice. Prostacyclin is released from these vessels and promotes neuronal outgrowth by signaling through the IP receptor on neurons.

Obesity is often marked by chronic, low-grade inflammation, which is believed to contribute to metabolic disturbances associated with this condition. Chih-Hao Lee and colleagues show that injection of a known immunomodulatory glycan, one found in mother's milk and in S. mansoni egg extract, results in improved metabolic function of the adipose tissue and liver in a mouse dietary-mediated obesity model.

Live attenuated SIV vaccines protect nonhuman primates from infection with pathogenic wild-type SIV, but the crucial mechanisms have not been clear. In this issue, Louis Picker and colleagues show that protection by live attenuated vaccines against intravenous SIV challenge in rhesus macaques is associated with SIV-specific T cell response in the lymph nodes, and not the blood, and persistent SIV replication in lymph node follicular T helper cells.

Resting CD4⁺ T cells are resistant to HIV-1 infection, but the underlying reasons for this lack of permissiveness have not been clear. Oliver Fackler and colleagues now report that SAMHD1, the deoxynucleoside triphosphate triphosphohydrolase responsible for restriction of HIV-1 infection in myeloid cells, also restricts infection of resting CD4⁺ T cells. The findings shed new light on the mechanisms of cellular and molecular regulation of HIV-1 infection.

A minority of HIV-1–infected individuals develop broadly neutralizing antibodies, which are considered an important goal of many HIV vaccine strategies. Moore et al. now report their study of the evolution of a broadly neutralizing antibody response targeting a glycan on the viral envelope in two HIV-1–infected individuals. Their findings show that the targeted glycan is absent early in acute infection but develops over time as the virus escapes initial antibody-mediated pressure.

The authors uncover a new mechanism for the regulation of the activity of leukemia-initiating cells in T-ALL. A subpopulation of stem cells with low amounts of reactive oxygen species (ROS) is enriched in their ability to reconstitute disease in mouse models, and this effect is regulated by repression of PKC-θ, which increases ROS production. Moreover, oncogenic NOTCH, a common T-ALL–driving alteration, regulates stem cell activity by increasing RUNX3 expression, which represses RUNX1, a PCK-θ activator, a pathway that is conserved in human patients.

Anaplastic large cell lymphomas (ALCL) often express the oncoprotein NPM-ALK. This study shows that the activator protein 1 family members JUN and JUNB promote lymphoma development through platelet-derived growth factor receptor-β (PDGFRB). Inhibition of PDGFRB prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor against transplanted NPM-ALK tumors. Inhibition of PDGFR in a patient with ALCL also resulted in rapid, complete and sustained remission.

House dust promotes allergic responses to inhaled allergens, but it remains unclear what microbial components in dust are required for this activity. Donald N. Cook and his colleagues show that the bacterial protein flagellin stimulates allergic airway responses, and its receptor, Toll-like receptor 5, is required to elicit airway eosinophilia and hyperreactivity in response to dust. Individuals with asthma have higher serum antibody titers to flagellin, suggesting exposure to flagellin is associated with allergic airway disease.

Chronic obstructive pulmonary disease (COPD) is now known to be a heterogeneous disorder, hence the pressing need to develop imaging biomarkers to differentiate between the broad range of COPD phenotypes–all of which require different treatments. Here, Craig Galban and his colleagues have adapted the parametric response map technique for the voxel-by-voxel classification analysis of CT lung images taken from a national COPD trial, providing a more objective characterization of the phenotypic contributions of functional small airways disease and emphysema in COPD.