Volume 20 Issue 1, January 2014

On 27 January, the US National Institute on Alcohol Abuse and Alcoholism (NIAAA) will welcome George Koob as its new permanent head. A neurobiologist at the Scripps Research Institute in La Jolla, California, for the past 30 years, Koob, 66, made his name both in the study of alcoholism and in addiction to other substances. His work has long been funded by both NIAAA and NIDA. Elie Dolgin spoke with Koob about what he thinks sets alcohol research apart.

Insulin-producing islet cells could hold the secret to curing type 1 diabetes—if only scientists could figure out a way to encapsulate and transplant them into the body. But first, the right biocompatible material must be found to hold these precious cells. A team of bioengineers thinks it has discovered one. Elie Dolgin reports.

The problem of inequity in international research is perpetuated by policies that enable scientists to conduct research in lower-resourced areas of the world without partnering with local researchers. The World Health Organization (WHO) needs to lead in solving this problem by working with research institutions, journal editors and funding agencies to document the degree of inequity and to impose penalties for failures to collaborate.

Many tumors display a hierarchical organization that is maintained by a self-renewing 'cancer stem cell' population. A new study in mice shows that targeting the self-renewal regulator BMI-1 abrogates the tumorigenic capacity of colon cancer stem cells, providing a new therapeutic strategy (pages 29–36).

Under most circumstances, Foxp3⁺ regulatory T (T_reg) cells are a stable T cell population essential for maintaining self-tolerance. A study now shows that the inflammatory environment in autoimmune arthritis induces conversion of a subset of Foxp3⁺ T cells into interleukin-17–producing cells that contribute to disease pathogenesis (pages 62–68).

Liver-stage Plasmodium infection triggers a type I interferon transcriptional program in hepatocytes that amplifies an innate immune response within hepatic myeloid cells. This minimizes liver parasite load and delays the release of disease-causing parasites into the bloodstream (pages 47–53).

The concordant epidemics of asthma and obesity are both associated with inflammation, and obesity has been shown to be an independent risk factor for asthma. A new study in mice indicates that part of the immunological connection between obesity and asthma involves inflammasome activation and production of the cytokine interleukin-17 by innate lymphoid cells in the lung (pages 54–61).

Metabolic regulators that permit adaptation to changes in caloric intake have been shown to be needed to protect from age-related disorders. Sirtuins play a crucial part in this program, impinging on not only aging but also other diseases. New findings are uncovering the multifaceted activity of sirtuins in living organisms and their effects on healthspan. In 'Bedside to Bench', Leonard Guarente discusses how different sirtuins are hindering cancer metabolism through suppression of the Warburg effect. The apparent antitumor effects of several sirtuins through their regulation of different metabolic pathways suggest therapeutic approaches to induce sirtuin function or that of downstream targets may block cancer growth. In 'Bench to Bedside', Eric Verdin peruses a few studies in different animal models showing that increased amounts of nicotinamide adenine dinucleotide (NAD), a cofactor of sirtuins, may have a positive effect in longevity and span of healthy life, or healthspan, by increasing sirtuin enzymatic activity. Whether harnessing NAD therapeutically is a potential way to extend lifespan and ameliorate diseases is still open to debate.

Cancer stem cells are thought to be resistant to anticancer therapies and are able to repopulate tumors and sustain tumor growth. The authors establish BMI-1 as a crucial regulator of cancer cell stemness in colorectal tumors and develop a chemical inhibitor that targets cancer stem cell renewal by reducing the levels of BMI-1. This strategy affords antitumor effects in vitro and in vivo and may pave the way for the precise targeting of elusive cancer stem cells.

Nephrotic syndrome is marked by excess of both protein in the urine (proteinuria) and triglycerides in the blood (hypertriglyceridemia). Sumant Chugh and his colleagues now explain these linked pathologies while also suggesting a possible new therapy to treat the proteinuria without aggravating the hypertriglyceridemia.

After mosquito bite, the malaria parasite first infects the liver, where it is thought to be undetected by the host immune system as it develops into the blood-stage pathogen. Maria Mota and her colleagues now report that Plasmodium RNA is detected by hepatocytes, triggering an interferon response that controls the parasite burden in the liver and blood of infected mice.

The mechanisms underlying the association between obesity and the development of asthma remain incompletely understood. Dale T. Umetsu and his colleagues report that the number of IL-17A⁺ type 3 innate lymphoid cells (ILCs) is increased in the lungs of mice fed a high-fat diet. Activation of the NLRP3 inflammasome in lung macrophages promotes IL-1β production and ILC development, and blockade of IL-1 signaling inhibits airway hyperreactivity in obese mice. As these ILCs are also found in the lungs of individuals with asthma, these results suggest that this pathway may be targeted in asthma.

Regulatory T (T_reg) cells exhibit substantial phenotypic and functional plasticity. Hiroshi Takayanagi and his colleagues report that in autoimmune arthritis, a subset of T_reg cells can lose Foxp3 expression and convert into T_H17 cells. This conversion is mediated by synovial fibroblast-derived IL-6, and in vivo, these cells are osteoclastogenic and exacerbate arthritis. These findings suggest that a proportion of pathogenic T_H17 cells in autoimmune disease may be derived from T_reg cells.

The suppressive function and number of regulatory T cells (T_reg cells) is reduced in autoimmune disease. Here, Giuseppe Matarese and colleagues report that T_reg cell proliferation is reduced in subjects with relapsing-remitting multiple sclerosis. As disease severity increases, T_reg cell proliferation progressively decreases and is associated with impaired IL-2 release and IL-2 receptor and mTOR signaling.

Understanding how Mycobacterium tuberculosis is controlled by the body, leading to active disease in only a small fraction of infected individuals, is important for developing medical interventions to prevent and manage disease. Lin et al. now show that infected macaques with active tuberculosis have some sterile granulomas, suggesting immune-mediated control at certain sites of infection. Insight into the mechanisms underlying the heterogeneity of mycobacterial killing may inform vaccine development.

Bao-Liang Song and colleagues report that the clathrin adaptor Numb recognizes a peptide motif within the cholesterol transporter NPC1L1 upon cholesterol binding and thus facilitates dietary cholesterol uptake into the gut. Inhibition of this Numb-NPC1L1 interaction in mice reduces serum cholesterol levels and thus may be a therapeutic target to treat hypercholesterolemia in the clinic.

A screen for compounds that may inhibit the growth of hematological malignancies reveals the specific dependence of some mantle cell lymphoma (MCL) cell lines on canonical or alternative NF-κB signaling. As also seen in patients, genetic alterations affecting alternative NF-κB signaling confer insensibility to ibrutinib, a compound that was recently approved for MCL treatment. This alternative signaling pathway underscores the need to tailor treatments to the specific driving pathways in each patient group.

One of the most likely substrates for metabolic imaging of response to treatment in cancer is glucose, but until now, using hyperpolarized 13C-labelled glucose has been problematic because of the short lifetime of the hyperpolarization in this molecule. Using [U-¹³C, U-²H]glucose, Tiago Rodrigues et al. now show that they are able to image its glycolytic conversion to lactate in two mouse tumor models in vivo, and that in one model, flux is markedly reduced after treatment with the chemotherapeutic drug etoposide.

There are currently a paucity of approaches for the direct in vivo assessment of rates of hepatic mitochondrial oxidation and anaplerotic flux in humans. With this in mind, Douglas Befroy and colleagues have developed a new ¹³C-labeling strategy that they use in combination with ¹³C magnetic resonance spectroscopy, which should prove useful in determining the potential role of changes in hepatic mitochondrial fat oxidation in diseases such as nonalcoholic fatty liver disease and type 2 diabetes.