News & Views in 2014

Diamond-Blackfan anemia (DBA) is an inherited hypoplastic anemia characterized by impaired production of erythroid cells, and it is caused by inactivating mutations in ribosomal protein genes in more than half of all cases. A new study in human cells demonstrates that reduced translation of the transcription factor GATA1, as a consequence of ribosomal protein haploinsufficiency, is a crucial factor in mediating the erythroid defect found in DBA (pages 748–753).

Stress has long been thought to be a major contributing factor to cardiovascular disease, although little is known about the underlying cellular mechanisms. A new study in humans and mice suggests that chronic stress promotes hematopoietic stem cell proliferation in bone marrow, leading to increased leukocyte production, circulation and recruitment to the vasculature (pages 754–758).

Leptin deficiency, which is associated with type 1 diabetes, is a critical factor in the pathophysiology of this disease, a new study in rats shows. The lack of this hormone triggers a cascade of neuroendocrine events that affect adipose tissue and the liver, resulting in hyperglycemia and ketoacidosis (pages 759–763).

Barth syndrome is a rare X-linked genetic disorder caused by mutations in the tafazzin (TAZ) gene that result in dilated cardiomyopathy, skeletal myopathy and neutropenia. Tafazzin has a mitochondrial function, and a new study using cardiomyocytes derived from induced pluripotent stem cells (iPSCs) from humans with Barth syndrome identifies increased mitochondrial reactive oxygen species (ROS) production as a key intermediate causing cardiac contractile dysfunction (pages 616–623).

Regulatory B cells exert an immunosuppressive role by secreting the cytokine interleukin-10 (IL-10). Two studies have now identified B cell–derived IL-35 as both an inducer and a mediator of regulatory B cell function. IL-35 switched off inflammation in mouse models of autoimmunity, whereas its absence in B cells in mice enhanced survival after Salmonella enterica serovar Typhimurium infection. IL-35 could therefore be targeted for treating human autoimmune and infectious disease.

A new study in infants shows that broadly neutralizing antibodies (bNAbs) against HIV can be found early in life, demonstrating for the first time that these antibodies can be induced by the infant immune system.

Although hematological cancers are genomically unstable, the mechanisms by which they evade DNA damage–induced cell death are largely unknown. A current study has revealed that the Hippo signaling pathway transcriptional regulator YAP1 activates an ABL1/p73-mediated proapoptotic effect in response to DNA damage, suggesting that YAP1 has a tumor suppressor function and that the Hippo pathway is a potential therapeutic target in human cancers.

Age-related cognitive decline occurs in many mammals, including humans, resulting from a decline in hippocampal function, and it is associated with reduced synaptic plasticity in hippocampal circuits. In this issue of Nature Medicine, a new study shows that cognitive impairment observed in aged mice is largely reversible following exposure to the blood of young mice.

The function of the innate immune system is suppressed in patients with acutely decompensated cirrhosis and predisposes these patients to bacterial infections. A new study shows that increased synthesis of the immunosuppressive prostaglandin PGE₂ by circulating monocytes and resident macrophages and impaired hepatic synthesis of human serum albumin (HSA) are major contributors to immune suppression in cirrhosis (pages 518–523). The authors' data suggests a new avenue for therapy in acute decompensation of cirrhosis.

A new antiviral capacity for matrix metalloproteinase 12 (MMP-12) adds to our expanding understanding of matrix metalloproteinase biology, from matrix remodeling to host defense, in this issue of Nature Medicine (pages 493–502). Marchant et al. show that following viral infection, macrophages secrete MMP-12, which regulates antiviral immunity both as a transcription factor for IκBα, leading to interferon-α (IFN-α) secretion, and later by degrading extracellular IFN-α, resolving inflammation.

Central nervous system (CNS) control of systemic nutrient homeostasis is a crucial but poorly understood metabolic regulatory axis. A new study (484–492) shows that rat insulin promoter (RIP)-expressing neurons in the hypothalamus regulate peripheral metabolic responses to both normal and high-fat diets through anti-inflammatory effects mediated by vagal innervation of the spleen.

As babies leave their mothers' wombs, they are colonized by commensal bacteria. A new study shows that these microbes in a newborn's gut can promote an increase in circulating neutrophils that can guard the body from infections. Altering a neonate's gut microbiota with perinatal antibiotic treatment can impair neutrophils, leaving the newborn vulnerable to attack by harmful bacteria (pages 524–530).

DNA that is shed by dead tumor cells into the blood, termed circulating tumor DNA (ctDNA), is a rich resource that could potentially be used for cancer diagnostics and monitoring. A new study describes a sequencing-based method that improves upon the sensitivity and specificity achieved by past techniques for detecting ctDNA and that can be used for monitoring of disease burden in patients with non–small-cell lung cancer (pages 548–554).

Anemia is a debilitating condition that can be complicated by ineffective erythropoiesis. Two new studies identify GDF11 as a regulator of erythropoiesis and show that its inhibition in mouse models of anemia with ineffective erythropoiesis restores normal erythropoietic differentiation and alleviates anemia (pages 398–407 and 408–414).

Pharmacologic modulation of iron metabolism may be a potential strategy to control infection caused by the intracellular bacteria Salmonella enterica var. Typhimurium (S. typhimurium) (pages 419–424). The molecular mechanism involves the estrogen-related receptor γ (ERRγ) in the liver, which can be targeted with an inverse agonist to improve survival of infected animals.

In the mammary gland, the stiffness of extracellular matrix (ECM) collagen is thought to influence tumor progression and clinical outcome. A new mechanism orchestrated by a microRNA circuit is shown to mediate the physical effects of the microenvironment on tumor cell progression. The findings may explain how increased breast matrix stiffness is associated with poor survival and could help identify women with aggressive breast cancer (pages 360–367).

Bariatric surgery reduces the weight of morbidly obese individuals and exerts beneficial effects on associated metabolic disorders such as type 2 diabetes. However, despite growing traction in this area of metabolic research, questions remain as to the mechanisms that lead to these benefits. New findings propose that the bile acid–activated nuclear receptor FXR mediates the metabolic improvement seen after one particular bariatric surgery approach and that this may involve alterations in the microbiome.

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).

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).