Volume 19 Issue 6, June 2013

The Center for Biosecurity of the University of Pittsburgh Medical Center (UPMC) was recently renamed the UPMC Center for Health Security. As director and chief executive officer for the past four years, Tom Inglesby has expanded the center’s focus toward preventing public health crises arising from infectious diseases, pandemics and major natural disasters, in addition to biological, chemical and nuclear accidents or threats. Inglesby spoke with Kevin Jiang about how responses to bioterrorism, pandemics and natural disasters aren’t all that different.

A new regulatory pathway established last year allows drugs with dramatic early clinical promise to be expedited to the market quicker than ever before. To date, most of these 'breakthrough' designations have gone to cancer agents, raising the prospect of faster access to the latest lifesaving therapies for the estimated 4,500 people newly diagnosed with cancer each day in the US. Elie Dolgin looks at what sets these breakthrough medicines apart.

Almost 50 years ago, the World Medical Association adopted the Declaration of Helsinki as an ethical guide for research involving human subjects. There are now proposed revisions under consideration that will provide additional protection for study participants as well as increased clarity regarding the responsibilities of those conducting the research. Making these changes is important in a complex environment where what is ethical is not always self-evident.

During resuscitation after cardiac arrest, a burst of reactive oxygen species (ROS) generated in mitochondria triggers a lethal cascade of events. Nitric oxide is known to be protective, but the mechanism is unknown. A new study shows that a mitochondria-targeted nitric oxide donor S-nitrosates the ND3 subunit of mitochondrial complex I, limiting its ability to generate ROS and protecting the heart against injury (pages 753–759).

Blockage of transforming growth factor-β (TGF-β) signaling in subchondral bone after acute injury in rodents prevents aberrant bone remodeling and cartilage degeneration, suggesting that TGF-β signaling in bone may initiate osteoarthritis in some cases (pages 704–712).

Anticancer cytotoxic drugs also kill normal progenitors found in rapidly regenerating tissues, resulting in prolonged hematopoietic insufficiency. Chemotherapy-induced toxicity of the nerves that regulate bone marrow niches required for regeneration of hematopoietic stem cells (HSCs) is involved in this insufficiency, which suggests that co-administration of neuroprotective agents may protect HSCs from the toxic effects of drugs such as cisplatin and vincristine (pages 695–703).

Liver steatosis is a characteristic feature of hepatitis C virus (HCV) infection, and the virus itself is known to alter the lipid metabolism of infected hepatocytes. A recent study shows that HCV co-opts the antiviral innate immune response to stimulate the production of hepatic fat droplets, which it can then use to complete its own life cycle and spread (pages 722–729).

Malaria remains the most deadly human parasitic disease. A new study finds that malaria parasites signal to mast cells to promote disease through the expansion of specialist dendritic cells and the subsequent activation of pathogenic CD8⁺ T cells (pages 730–738).

New insights into the actions of the hormone glucagon are provided by a recent study in rodents, which shows that glucagon can suppress hepatic glucose production by acting through the mediobasal hypothalamic region of the brain. This central regulatory mechanism is impaired in rats fed a high-fat diet, suggesting that hypothalamic glucagon resistance may be relevant to the hyperglycemia observed in obesity, diabetes or both (pages 766–772).

Using brain surgery, specific areas in the brain can be stimulated with electrical impulses to reversibly change their activity and alleviate symptoms related to mental illnesses. This so-called deep brain stimulation and other methodological advances that even more selectively activate specific groups of neurons can give us clues as to what neural circuitry is involved in a particular mental disorder and whether therapeutic activation of these brain areas and neurons may be effective. In 'Bedside to Bench', Eric Nestler discusses two trials of individuals with anorexia nervosa in which deep brain stimulation of different brain areas resulted in improvement of behavioral domains associated with the syndrome. The results and potential of this technique in animals and humans may bring us closer to understanding the neurobiology of anorexia nervosa, which still remains a mystery and poses a challenge for treatment. In 'Bench to Bedside', Jennifer Warner-Schmidt peruses recent findings that uncover the functional connectivity of brain regions involved in depression and how activation of cortical regions can result in antidepressant effects that can compensate for the malfunction of other brain circuits that results in depression.

Autism spectrum disorders (ASDs) are a clinically heterogeneous group of neurodevelopmental disorders characterized by social and communication deficits and repetitive behaviors. In a subset of individuals with ASD, mutations in genes involved in synaptic function have been identified, and this Perspective discusses the evidence from mouse models of ASD that synaptic deficits can be ameliorated in the mature brain. The authors also suggest a strategy for designing more informative clinical trials for ASD therapies that stratify patients according to their specific synaptic mutations.

Many chemotherapy drugs cause sensory nerve damage as well as long-lasting damage to hematopoietic regeneration in the bone marrow. Paul Frenette and his colleagues show that this hematopoietic damage is caused by injury to bone marrow sympathetic nerve fibers, disrupting the hematopoietic stem cell niche. These findings point to the potential of neuroprotective agents in preserving hematopoietic function in chemotherapy-treated patients with cancer.

Osteoarthritis has been believed to be caused by improper mechanical function of articular joints. Xu Cao and his colleagues now show that this mechanical process leads to upregulation of transforming growth factor β1 activity in mesenchymal stem cells of subchondral bone, resulting in aberrant bone formation, further destabilization of the joint and ultimately the onset of the disease.

Monocytes play an important part in the clearance of pathogens during infection. Yasmine Belkaid and her colleagues now report that inflammatory monocytes can also have a regulatory role. Specifically, these cells can mitigate the tissue damage induced by neutrophils during infection of mice with Toxoplasma gondii by releasing prostaglandin E2 in response to commensal bacteria.

Lipid droplets have a key role in the assembly of hepatitis C virus (HCV) particles in liver cells. Jake Liang and colleagues now report that a host factor, IκB kinase-α is required for efficient production of HCV by increasing cellular lipid droplet content through its regulation of lipogenic genes in infected cells. The findings provide insight into some of the metabolic changes induced by HCV infection and may offer a new potential therapeutic target.

Pierre Guermonprez and colleagues have worked out how a subset of dendritic cells expands in individuals with severe malaria. Plasmodium infection causes an accumulation of xanthine in infected red blood cells. The researchers found that type I interferon triggers an increase in the enzyme that metabolizes xanthine to uric acid. Uric acid then acts on mast cells to release Flt3 ligand, an important regulator of dendritic cells, which in turn stimulate T cells to respond to the infection.

Type 1 regulatory (Tr1) T cells are characterized by their immunosuppressive activity and cytokine secretion profile; however, their isolation and enumeration are limited by the absence of specific markers. Here Richard Flavell, Maria-Grazia Roncarolo and colleagues report that CD49b and LAG-3 are coexpressed by human and mouse Tr1 cells. These markers can be used to isolate Tr1 cells in vitro and in vivo and can be used to quantify Tr1 cells in tolerant subjects.

Identifying tumor-associated T cell epitopes can be laborious. Robbins et al. now report that they used whole-exome sequence data to identify mutated peptides from tumor antigens that are recognized by tumor-infiltrating T cells from patients with melanoma who experienced therapy-associated tumor regressions. The method will contribute to the identification of new tumor-specific epitopes that may further the development of effective T cell therapies for the treatment of patients with melanoma as well as a variety of additional malignancies.

Nitric oxide donors protect from myocardial ischemia-reperfusion injury, but the underlying mechanisms have been unclear. Edward T Chouchani et al. uncover the molecular target of such donors, a cysteine residue in a subunit of complex I of the mitochondrial respiratory chain, and suggest that this cysteine residue has a general role in regulating complex I activity and modulating ischemia-reperfusion injury.

Abnormalities in how pulmonary veins connect to the heart underlie a type of congenital heart disease. Jonathan Epstein and his colleagues show that this condition, termed anomalous pulmonary venous connections, can be caused by mutation of the gene encoding the guidance protein semaphorin 3d and show how this protein acts in the embryo to pattern the developing pulmonary veins.

Glucagon has traditionally been thought to act exclusively on the liver to promote endogenous glucose production in that organ. Tony Lam and his colleagues now show that it also acts on the hypothalamus to inhibit glucose production through a neural relay to the liver and that under high fat–fed conditions in rats this pathway is inhibited. This resistance may further explain the hyperglycemia that exists during obesity and diabetes.

Astrocytic dysfunction is a common feature in the brains of depressed subjects. Now, Xin-Hong Zhu and colleagues show that astrocytic release of ATP is reduced in the brains of stressed mice and that restoring brain ATP levels can rapidly reverse depressed behaviors in mice.

Marsilius Mues et al. have overcome previous obstacles precluding the expression of genetically encoded calcium indicators (GECIs) in immune cells by developing a new fluorescence resonance energy transfer–based GECI for the functional calcium imaging of T cells in vivo. Using two-photon imaging, the group traced the real-time activation of T cells in peripheral lymph nodes after antigen application, as well as in the CNS during experimental autoimmune encephalomyelitis.

The work of Dmitri Lodygin and his colleagues focuses on the important issue of when and where autoaggressive T cells are activated within their target organ to trigger autoimmune disease. Using intravital two-photon imaging and a new molecular sensor—a genetically encoded fluorescent sensor of nuclear factor of activated T cells (NFAT) combined with a fluorescently tagged version of nuclear histone protein H2B—the group was able to pinpoint key T cell activation events in experimental autoimmune encephalomyelitis, a model for multiple sclerosis.