Articles in 2013

Nan Wang and colleagues uncover a new function for HDL that may contribute to its anti-atherosclerotic effects. In the bone marrow, HDL removes cholesterol from megakaryocyte progenitor cells in a process requiring the cholesterol transporter ABCG4, thereby dampening megakaryocyte and platelet production.

The long-noted association of red meat with an increased risk of cardiovascular disease may be due to ingestion of a specific compound found in red meat, l-carnitine. The ability of this compound to promote atherosclerosis in mice requires that it be further metabolized by the gut microbiota. In humans, omnivores but not vegans or vegetarians metabolize l-carnitine in this manner, a difference which may be explained by effects of diet on the presence of specific types of bacteria in the gut.

The peptide hormone GLP-1 has both antidiabetic and antihypertensive effects. Daniel Drucker and his colleagues now show that GLP-1 lowers blood pressure through indirect mechanisms involving the heart: GLP-1 acts on its receptor in atrial cardiomyocytes to stimulate secretion of the peptide hormone ANP, which in turn lowers blood pressure through direct effects on the vasculature and kidney.

Understanding how adenoviruses transduce cells is important for their use and development as vaccine vectors. Adenovirus type 5 (Ad5) is known to bind coagulation factor X (FX), and FX is thought to act as a bridge between the virus and its receptor on hepatocytes. Andrew Byrnes and his colleagues now report that the major role of FX binding to Ad5 is actually to protect Ad5 from neutralization by complement and natural antibodies, and in the absence of B cells, Ad5 does not require FX binding for effective liver transduction.

Synaptic abnormalities and learning dysfunction are prominent characteristics of Down's syndrome. Now Huaxi Xu and colleagues show that expression of the protein SNX27 is reduced in Down's syndrome brains and that restoring its expression can ameliorate learning dysfunction in a mouse model of the disease.

Focal and segmental glomerulosclerosis, or renal scarring, is a debilitating disease. The identification of the molecular mechanisms of its initiation and progression has been limited, thus hampering the development of proper animal models. Dontscho Kerjaschki and his colleagues now report that microRNA-193a is elevated in human cases of the disease and that transgenic expression in mice is sufficient to cause the condition.

Ramos et al. report a crucial role for macrophages in erythroblast development in mice. Under conditions that induce new red blood cell formation, macrophage depletion impaired red blood cell recovery. Conversely, macrophage depletion normalized red blood cell counts in mouse models of polycythemia vera and ®-thalassemia, pointing to a potential new therapeutic strategy for these diseases. Findings similar to these are reported in an accompanying paper by Chow et al.

Chow et al. report a crucial role for macrophages in erythroblast development in mice. Under conditions that induce new red blood cell formation, macrophage depletion impaired red blood cell recovery. Conversely, macrophage depletion normalized red blood cell counts in a mouse model of polycythemia vera, pointing to a potential new therapeutic strategy for this disease. Findings similar to these are reported in an accompanying paper by Ramos et al.

Ulcerations of the oral cavity, or oral mucositis, often occur during radiation treatment for cancers of the head or neck or during bone marrow transplantation. Xiao-Jing Wang and colleagues now show that in a mouse model, Smad7 is an effective treatment for this condition, offering more hope for its clinical management.

Cancer vaccines have had limited success in eliminating tumors in patients. Here Willem Overwijk and colleagues report that one reason for the failure of peptide-based vaccines may be their formulation. Their research shows that peptides formulated in incomplete Freund's adjuvant sequester CD8+ T cells at the site of injection, leading to T cell dysfunction and eventual apoptosis. A peptide and adjuvant formulation that did not persist long term at the injection site showed superior ability to induce a functional antitumor T cell response.

Coagulation factor Xa is targeted by a new generation of antithrombotic drugs such as rivaroxaban. However, as excessive factor Xa inhibition can cause bleeding, the clinical use of factor Xa inhibitors would be enhanced by the availability of a specific antidote. Uma Sinha and her colleagues devise such an antidote, an inactive form of recombinant factor Xa that can bind to and neutralize factor Xa inhibitors, and demonstrate its efficacy in animal models.

Different types of neurons are differentially susceptible to West Nile virus (WNV) infection. Michael Diamond and colleagues now show that cerebellar granule cell neurons (GCN) have a higher basal level of expression of type I interferon–inducible genes than cortical neurons, making GCN more resistant to infection by a variety of positive-stranded RNA viruses, including WNV.

Chronic stress and depression induce structural and functional plasticity; however, the mechanisms responsible for these alterations remain incompletely characterized. Here Scott J Russo and colleagues demonstrate that the Rac1 promoter is epigenetically modified, and its expression is reduced in the nucleus accumbens of mice after chronic defeat stress and in subjects with major depressive disorders. Reduced Rac1 expression is sufficient to induce depression-related behavior and stubby spine formation in mice.

The inability of the heart to efficiently relax as it beats, termed diastolic dysfunction, is a major underlying cause of heart disease. As a new strategy for treating diastolic dysfunction, Joseph Metzger and his colleagues engineered directed substitutions in the calcium-binding protein Parvalbumin to optimize its ability to promote cardiac myocyte relaxation. Gene transfer of this Parvalbumin variant promoted cardiac myocyte relaxation of rabbit and canine heart failure models in vitro and corrected heart function in two in vivo mouse models of diastolic dysfunction.

TNF-α suppresses regulatory T (T_reg) cell function, however the mechanism remains unclear. Here Jingwu Z Zhang and colleagues find that in activated T cells, phosphorylation of FOXP3 promotes its transcriptional activity. TNF-α induces protein phosphatase 1 expression, leading to dephosphorylation of FOXP3 and inhibition of T_reg cell function. In individuals with rheumatoid arthritis, TNF-α–specific antibody treatment restores T_reg cell activity and FOXP3 phosphorylation, suggesting that post-translational modifications, including phosphorylation, regulate FOXP3 activity and T_reg cell–mediated suppression.

Oncolytic viruses are under development for tumor treatment. David Kirn and colleagues now report their results of a randomized phase 2 dose-finding trial of JX-594, an oncolytic immunotherapeutic vaccinia virus, in patients with advanced hepatocellular carcinoma. The study shows that high-dose JX-594 was associated with significantly improved overall survival and induced radiographic responses and antitumor immunity.

Alan Saltiel and his colleagues report that the approved drug amlexanox, currently used to treat asthma and canker sores, is a relatively specific inhibitor of the noncanonical IκB kinases IKK-ɛ and TANK-binding kinase 1 (TBK1) and that it improves metabolic disease in mouse genetic and dietary models of obesity. These results suggest this drug may be repurposed to treat obesity and insulin resistance.

John Chute and his colleagues show that the cytokine EGF protects mouse bone marrow hematopoietic stem cells from radiation injury. EGF signaling in these cells inhibited cell death through repression of the proapoptotic protein PUMA. EGF administration rescued mice from death after total-body irradiation, suggesting a new therapeutic strategy for radioprotection.

The Notch signaling pathway has a key role in shaping the developing heart. Guillermo Luxán et al. identify two human mutations in the gene encoding the Notch pathway protein MIB1 that cause a type of cardiomyopathy, left ventricular noncompaction. The authors show that mice lacking Mib1 in the myocardium have a similar type of cardiomyopathy and analyze how MIB1 deficiency leads to defective ventricular development.

Inhibition of prosurvival proteins of the BCL family is a promising anticancer strategy; however, the similarities between the family members make the development of specific agents difficult. Current compounds have been designed to target BCL-2, which is frequently elevated in tumors and is an important prosurvival factor, but also inhibit BCL-X_L, which is required for the survival of platelets; thus, thrombocytopenia is a limiting toxic effect in patients. The authors have engineered anti-BCL drugs to generate a more BCL-2–specific compound that has less affinity for BCL-X_L and, therefore, reduced platelet toxicity. The compound is effective in several tumor models in vivo and had reduced toxicity in three patients with refractory leukemia, showing a promising activity and safety profile to refine and improve proapoptotic therapy in cancer.