Articles in 2014

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.

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).

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.

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.

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).

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.

The work of Michael Angelo and colleagues uses multiplexed ion beam imaging (MIBI) to localize and visualize protein expression in a manner analogous to immunohistochemistry (IHC) while circumventing some of the limitations of conventional IHC with clinical samples. MIBI uses secondary ion mass spectrometry to image antibodies tagged with isotopically pure elemental metal reporters, expanding the number of targets that can be analyzed simultaneously to about 100. The approach, used here to image breast tumor tissue sections, offers over a five-log dynamic range and compatibility with standard formalin-fixed, paraffin-embedded tissue sections.

Obesity is marked by a state of low-grade inflammation, including the accumulation of macrophages in the adipose tissue, which results in insulin resistance. Kathryn Moore and her colleagues now show that the neuronal guidance molecule, netrin-1, is upregulated in fat cells during obesity and leads to the retention of macrophages in this tissue. They also show that its genetic deletion in mice prevents the development of insulin resistance by a high-fat diet.

Atherosclerotic lesions develop preferentially at sites of disturbed blood flow. As shown by Christian Weber and his coworkers, this predilection stems from effects of disturbed blood flow on endothelial expression of the microRNA miR-126-5p, which maintains the proliferative reserve of endothelial cells through repression of the Notch pathway inhibitor Dlk1.

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 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.

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.

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.