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In this issue (p 159), Benjamin Marsland and his colleagues show that the gut microbiota can influence allergic airway disease through the metabolism of dietary fiber. Cover image: Tim Gainey / Alamy.
The important gains in supporting local biomedical science made by South Africa's Medical Research Council in recent years may be lost unless the country continues to fund and grow this important institution.
In October, Jeremy Farrar took the helm of the UK-based Wellcome Trust, the second largest nongovernmental funder of biomedical research in the world. The Wellcome Trust, with its £16 billion endowment, is far more than just an enabler of biomedical research. It is also a key player in wider science policy debates. Farrar sat down with Daniel Cressey to discuss his Trust issues.
After decades of decline, South Africa's Medical Research Council has undergone a dramatic turnaround in recent years, with a more than 50% increase in government funding. But as the leader credited with this turnaround prepares to step down at the end of next month, onlookers worry about what lies ahead for the institute. Linda Nordling reports.
The European Medicines Agency requires that drug developers submit a 'pediatric investigational plan' to ensure that there is adequate information about how children fare on experimental medication for many indications before they go to market. But this requirement places an undue constraint on the makers of new hemophilia drugs and threatens to create an unreasonable delay in access to these therapies among adults with this disorder in the EU.
A new study in mice provides a link between dietary fiber intake, amounts of intestinal and systemic short-chain fatty acids, changes in the microbiome and allergic responses in the airways. The findings support the growing appreciation of a potential therapeutic role of diet in treating allergic diseases (pages 159–166).
Modification of a natural product with antibiotic properties to block its efflux from Mycobacterium tuberculosis results in a new drug candidate for tuberculosis with a promising therapeutic profile in mice (pages 152–158).
Retinoic acid and arsenic trioxide cure individuals with acute promyelocytic leukemia (APL). In mouse models, these drugs eradicate tumor cells by activating the tumor suppressors p53 and PML to induce senescence of cancer cells (pages 167–174).
Numerous neurodegenerative diseases show deposition of protein aggregates, which are thought to cause neuronal damage. This Review discusses how cell-to-cell transmission of these pathogenic misfolded proteins is involved in initiation and progression of the disease and examines the clinical relevance of different strains in the heterogeneity of neurodegenerative disorders.
Understanding how and where HIV-1 infection persists in the body is crucial for efforts to eradicate the viral reservoir. Now Mathias Lichterfeld and his colleagues report that HIV-1 can infect CD4+ T memory stem cells (TSCM cells) and that infected TSCM cells constitute a stable component of the viral reservoir in individuals treated with antiretroviral therapy.
Monoclonal antibodies (mAbs) that bind the stalk domain of the influenza hemagglutinin glycoprotein have been shown to have broadly neutralizing activity against diverse influenza subtypes. In this study, DiLillo et al. report that, unlike strain-specific anti–hemagglutinin head domain mAbs, anti-stalk mAbs can mediate antibody-dependent cell cytotoxicity and require interactions with Fc receptors for their in vivo neutralizing activity.
New antibiotics are needed to treat drug-resistant Mycobacterium tuberculosis infections. Richard Lee and his colleagues now report a new series of semisynthetic spectinomycin analogs that show promise as potentially safe and effective antitubercular drug candidates.
Dietary fibers are metabolized by the gut microbiota into short-chain fatty acids (SCFAs) and have protective effects in inflammatory bowel disease. Here Benjamin J Marsland and colleagues report that mice fed a high-fiber diet have an altered microbiota and are protected from allergic airway inflammation. The SCFA propionate regulated allergic inflammation, bone marrow hematopoiesis and dendritic cell function. Taken together, these findings suggest that metabolites produced by the gut microbiota can influence hematopoiesis and immune responses in the lung.
Retinoic acid and arsenic therapies have shown considerable efficacy in patients with acute promyelocytic leukemia, but their exact mechanism of action remains unclear. Here, Hugues de Thé and colleagues uncover a therapeutic effect mediated by nuclear body reformation and p53 activation that involves the induction of a senescence transcriptional program. These data suggest that redifferentiation and apoptosis induction may not be sufficient for the effect of these agents in patients and uncover alternative therapeutic routes that could be applied to other tumor and treatment types.
In a new study by Kamran Atabai and colleagues, the milk fat globule protein, Mfge8, is found to promote the uptake of dietary fat and the absorption of fatty acids by peripheral organs via activation of integrin signaling and the expression of fatty acid transporters. They also found that genetic deletion of Mfge8 protected mice from diet-induced obesity and insulin resistance.
In heart muscle cells, sarcoplasmic reticulum calcium overload leads to spontaneous calcium waves that can cause arrhythmias and sudden cardiac death. S.R. Wayne Chen and his colleagues now detail the molecular mechanism by which intra–sarcoplasmic reticulum calcium ions interact with the gate of the calcium release channel RyR2, explaining how calcium waves are initiated and thereby contribute to calcium-triggered arrhythmias.
Although numerous studies have demonstrated anti-atherosclerotic effects of high-density lipoprotein (HDL), drugs that elevate HDL cholesterol levels have failed in the clinic. Stanley Hazen and colleagues provide a potential explanation for this paradox by showing that within human atherosclerotic plaques and plasma of individuals with coronary artery disease, apoA1—the major apolipoprotein present in HDL—is modified by oxidation of a specific tryptophan residue, impairing the anti-atherosclerotic function of apoA1 and HDL.
Gaucher's disease is a lysosomal storage disease caused by mutations in the glucocerebrosidase gene. Now, Anthony Futerman and his colleagues report that the expression of proteins linked to a form of cell death called necroptosis is increased in Gaucher's disease and that blocking these proteins can improve disease in a mouse model.
The measurement of metabolites such as creatine, which are involved in the tissue creatine kinase reaction, enable the study of the effects of energy deprivation on the heart. Haris and colleagues introduce a new magnetic resonance imaging technique that maps the distribution of creatine in the heart that does not use radiation or exogenous contrast agents and offers higher sensitivity compared to proton (1H) magnetic resonance spectroscopy methods. Feasibility is demonstrated in vivo in infarcted swine myocardium using a standard clinical MRI scanner.
PET imaging using 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) has been widely used for the detection of plaque inflammation. Here, however, Nobuhiro Tahara and colleagues explore the possibility of using 18F-labeled mannose (2-deoxy-2-[18F]fluoro-d-mannose, [18F]FDM), a structural analog to FDG, as an alternative and potentially more specific PET tracer than FDG for assessing the risk of acute vascular events in patients. The approach targets the mannose receptor–bearing macrophages that are abundant in high-risk atherosclerotic plaques, with feasibility demonstrated in a rabbit model of atherosclerosis.
