Reviews & Analysis

In this Review, David L. Thomas discusses how recent therapeutic and diagnostic advances could be implemented in public health strategies to prevent viral hepatitis infections and treat existing infected patients. Despite the still increasing incidence and prevalence of hepatitis C infection, available tools may bring viral eradication a step closer toward becoming a reality.

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).

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).

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).

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).

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).

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).

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.

Although it is now accepted that adult humans possess active brown adipose tissue, it has been questioned whether this is genuine classical brown adipose tissue. Two new studies provide evidence that humans, both as babies and adults, do have classical brown tissue and also indicate that there is heterogeneity in the composition of brown fat depots in humans, as in mice (pages 631–634 and 635–639).

The RAS-RAF-MEK-ERK signaling kinase pathway has been the focus of intense cancer drug development efforts because of its central role in tumor cell proliferation and survival. Although inhibitors of RAF and MEK provide therapeutic validation, tumor resistance challenges their effectiveness. Targeting scaffolding proteins such as IQGAP1 may be a new approach (pages 626–630).

It has long been unknown how activation of resident macrophages in the brain, or microglia, is regulated during the inflammatory pathogenesis of multiple sclerosis. Work in a mouse model of human multiple sclerosis identifies the E3 ubiquitin ligase Peli1 as a new crucial regulator of microglia activation (pages 595–602).

L-Carnitine is a common food supplement and naturally occurs in red meat. This nutrient is metabolized into trimethyl metabolites by the gut microbiota and is associated with an elevated risk for cardiovascular disease. A recent study provides new insights into this link by exploring how the gut microbiota generates proatherogenic metabolites from L-carnitine and how the microbiota is altered in response to an omnivorous diet (pages 576–585).

A study now links platelet generation and cholesterol metabolism, providing new understanding of the mechanisms involved in thrombocytosis and atherogenesis. The authors show that the cholesterol transporter ABCG4 is highly expressed in bone marrow megakaryocyte progenitors, and in its absence, these cells have defective cholesterol efflux and increased proliferation, leading to increased megakaryocyte production, thrombocytosis and accelerated atherogenesis in atherosclerosis-prone mice (pages 586–594).

A new study establishes a link between glucagon-like peptide-1 (GLP-1) release from the gut and the cardiac hormone atrial natriuretic peptide, which lowers blood pressure. As GLP-1 receptor agonists are used to control glycemia in patients with type 2 diabetes, this new gut-heart axis suggests a role of these agents in overall cardiovascular homeostasis (pages 567–575).

This Review discusses recent developments in understanding the immune processes that occur at the fetomaternal interface to ensure fetal tolerance during pregnancy, including the roles of fetal trophoblasts, epigenetically modified decidual stromal cells and maternal innate and adaptive immune cells. The authors also explain how impairments in the maternal immune adaptation to pregnancy might influence pregnancy complication,s such as spontaneous miscarriage, as well as postnatal health of the child.

Thiazolidinediones (TZDs), which act through the nuclear receptor peroxisome proliferator activated receptor-γ (PPARγ), are a widely prescribed class of drugs for type 2 diabetes; however, their use has been challenged by a number of side effects. Here the authors outline recent advances in our understanding of the modulation of the PPARγ pathway in metabolism and discuss how these insights might be used to explain the adverse side effects of TZD therapy and develop a new generation of safer PPARγ-targeting drugs.

Although cancer vaccines can induce tumor-specific cytotoxic CD8⁺ T cells, tumors treated by vaccination often fail to regress. A study in mice provides a potential explanation for this phenomenon by showing that a peptide vaccine in a water-oil adjuvant leads to the trapping of tumor-specific CD8⁺ T cells at the vaccination site, instead of promoting an effective T cell response at the tumor site (pages 465–472).

Trisomy 21 triggers multiple potential routes to intellectual disability in Down's syndrome. A new study suggests that aberrant endosomal function may contribute to the neuronal deficits behind learning and memory impairments in affected individuals (pages 473–480).

Two new studies suggest a crucial role for macrophages in boosting the number of red blood cells produced in vivo during stress, with translational implications for disease states such as β-thalassemia and polycythemia vera (pages 429–436 and 437–445).

Many HIV-infected people show impaired humoral immune responses, but it is unclear why. A new view into this conundrum may be provided with the recent discovery of altered interactions between follicular helper T (T_FH) cells and germinal center B cells from HIV-infected individuals. This leads to inadequate T_FH cell help for germinal center B cells and decreased B cell antibody responses (pages 494–499).