Volume 20 Issue 3, March 2014

On 29 January, Johnson & Johnson announced that it will make all of its clinical trial data available through an academic clearinghouse for scientific information known as the Yale University Open Data Access (YODA) project. At the helm of YODA is Harlan Krumholz, a physician-scientist who for almost two decades has led the Yale-New Haven Hospital Center for Outcomes Research and Evaluation. Krumholz spoke with Roxanne Khamsi about how greater access to data is a boon for medicine.

In the era of big data, biomedical databases are brimming with protein structures, image collections and genomic sequences. As the data mount, new 'cave automatic virtual environments', or CAVEs, are being built to help researchers pick through the files. Dyani Lewis meets the pioneers behind these large-scale visualization labs to see whether immersive virtual worlds can cut through the complexity.

A growing number of participants in clinical trials are sharing information about their health online. It's time that the drug development community starts to examine how this social media use might compromise the integrity of research studies and how it might also offer new opportunities.

Decreased muscle stem cell function in aging has long been shown to depend on altered environmental cues, whereas the contribution of intrinsic mechanisms remained less clear. Two new studies now reveal that cell-autonomous changes in the p38 mitogen-activated protein kinase pathway are major phenotype determinants of aged muscles stem cells (pages 255–271).

Interferon-β (IFN-β) is widely used to treat multiple sclerosis (MS), but its mechanism of protection remains obscure. A new study shows that IFN-β induces FoxA1⁺ regulatory T cells, a new regulatory T cell population, which suppress conventional T cells via programmed cell death 1 ligand 1. This cell subset limits disease in a mouse model of MS and was found in patients with MS who responded to IFN-β therapy (pages 272–282).

The cure and elimination of malaria caused by Plasmodium vivax is hindered by the threat of relapse infections from undetectable dormant forms of the parasite in the liver. In a new breakthrough, using a related parasite, Plasmodium cynomolgi, it has been shown that the small nongrowing forms of the parasite, termed hypnozoites, can be reactivated in primary simian hepatocytes that have been infected and maintained in culture for 40 days, providing a system to study this parasite form with the development of potential new antihypnozoite drugs in mind (pages 307–312).

Neural circuits are able to modulate immune responses by detecting inflammatory mediators and relaying signals back to the immune system. Here, in a mouse model of sepsis, the authors show that the immune responses can be modulated by electroacupuncture, which stimulates a neural circuit that results in the release of dopamine. The mechanism, like the inflammatory reflex, is neither sympathetic nor parasympathetic. Their results show a potential way forward in developing therapies for sepsis in dopamine agonists (pages 291–295).

The expression of antibodies to protect against an infectious disease can be achieved by the injection into the host of vectors carrying the gene to the relevant antibodies. Here the authors demonstrate the applicability of this technique to protection from HIV in a humanized mouse model, showing this to be a valid route to pursue in vaccine development for humans (pages 296–300).

Despite the existence of numerous antibiotics, recurrence of certain infections, such as those caused by Clostridium difficile, remains a clinical challenge. The root of the problem is the detrimental effect of antibiotics on the function and composition of intestinal commensals. To tackle C. difficile refractoriness to treatment and infection recurrence, scientists are trying to understand how a healthy microbiota may keep this pathogen at bay to identify the microbial contributors of protection and to develop targeted probiotic-based therapies. In 'Bedside to Bench', Ying Taur and Eric Pamer discuss the potential of fecal microbiota transplantation (FMT) and peruse mechanisms to explain its efficacy. Alteration of bile salts, which are involved in germination of C. difficile spores, by the healthy microbiota may explain why microbiome depletion upon antibiotic treatment can lead to pathogen overgrowth. In 'Bench to Bedside', Ruth Ley peruses a recent study suggesting that sialic acids increasingly released by gut commensals after antibiotic treatment may play a crucial part in boosting C. difficile growth. Starving the pathogen of this carbohydrate in the gut by FMT or, more specifically, with engineered probiotics that can outcompete the pathogen for sialic acids may prove effective to treat or even prevent C. difficile infection.

Mutations inactivating ARID1A, a subunit of the chromatin remodeling SWI/SNF complex, have been identified in some human cancers. This study reveals that cancer cells with mutated ARID1A are dependent on the residual activity of the complex for proliferation and that even if concomitant alterations in the ARID1A homolog ARID1B can occur, loss of ARID1B activity confers a specific vulnerability to ARID1A-mutant cells that may in the future be explored for targeting purposes.

In two new studies, Helen Blau and Bradley Olwin and their colleagues show that muscle stem cells in aged mice have an intrinsic defect in their stem cell capacity, contributing to age-related sarcopenia. They also provide mechanistic insight to explain this phenomenon and show that biochemical and biophysical manipulations can overcome the defect, suggesting a possible future route of therapy.

In two new studies, Helen Blau and Bradley Olwin and their colleagues show that muscle stem cells in aged mice have an intrinsic defect in their stem cell capacity, contributing to age-related sarcopenia. They also provide mechanistic insight to explain this phenomenon and show that biochemical and biophysical manipulations can overcome the defect, suggesting a possible future route of therapy.

Shohreh Issazadeh-Navikas and colleagues report on a previously undescribed population of regulatory T (Treg) cells that accumulate in the CNS in response to autoimmune inflammation and are induced by interferon-β (IFN-β). These cells, termed FoxA1+ Treg cells, express the transcription factor FoxA1+, which is required for their development and function. Individuals with multiple sclerosis that respond to IFN-β have an increased frequency of FoxA1+ Treg cells, suggesting that the induction of these cells may account for some of the protective effects of IFN-β.

Immune surveillance has been proposed to eliminate transformed cells and thereby limit tumor formation. Axel Kallies and colleagues now report that spontaneous B cell lymphoma development in Blimp1-deficient or Bcl6-overexpressing mice is accelerated by T cell deficiency and identify the Fas-Fas ligand pathway as a crucial mediator of T cell control of lymphoma growth.

In sepsis, systemic inflammation leads to multiple organ failure and death. Now, Luis Ulloa and colleagues show that electroacupuncture can rescue mice from sepsis by causing the adrenal medulla to produce dopamine.

Delivery of HIV-specific neutralizing antibodies by adeno-associated virus vectors—termed vectored immunoprophylaxis (VIP)—has been shown to protect mice or macaques from intravenous infection by HIV or SIV, respectively. David Baltimore and colleagues now report that VIP is also effective at preventing HIV infection after vaginal challenge in humanized mice, suggesting that the approach might limit mucosal transmission between humans.

Diagnosis of bacterial infections is largely based on nonspecific criteria, with definitive diagnoses made only after biopsy or culture. Frank Hernandez and his colleagues demonstrate noninvasive imaging of Staphylococcus aureus infections in mice with an activatable fluorescent molecular imaging probe. The approach exploits the properties of micrococcal nuclease and uses short, synthetic oligonucleotides that are highly sensitive to micrococcal nuclease but are rendered resistant to mammalian serum nucleases by chemical modifications.

Relapses in malaria are caused by hypnozoites, the latent hepatic stage formed by species such as Plasmodium vivax and Plasmodium ovale. Drug discovery programs have been severely hampered by a lack of in vitro cultivation methods for malarial hypnozoites. Only one drug, primaquine, is currently available, but its use is limited in people with glucose-6-phosphate dehydrogenase deficiency. Here, Laurent Dembélé and colleagues offer a system that can be used to monitor the growth and development of Plasmodium cynomologi liver-stage forms, a model for P. vivax, for up to 40 d.

The use of antibodies against tumour necrosis factor (TNF) has markedly improved the treatment of Crohn's disease, but only certain patients respond to therapy. Here, Raja Atreya and colleagues have developed an approach using topical fluorescent antibodies to TNF and confocal laser endomicroscopy to evaluate the expression of transmembrane TNF (mTNF) in the intestinal mucosa of patients with active Crohn's disease in order to identify patients likely to respond to subsequent treatment with the anti-TNF therapy, adalimumab.