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Transplant arteriosclerosis is a leading cause of transplanted organ dysfunction. Human regulatory T cells expanded ex vivo can prevent transplant arteriosclerosis in a mouse model by preventing the immune infiltration of the graft.
In a mouse model of systemic autoimmunity, the damage-associated molecular pattern molecules Mrp8 and Mrp14 are essential for the induction of autoreactive CD8+ T cells and for disease development in a TLR4– and IL-17–dependent manner. A similar mechanism might be at play in people with cutaneous lupus erythematosus.
Individuals with obsessive-compulsive disorder (OCD) perform obsessive repetitive actions. Shahin Rafii and his colleagues show that mice lacking the gene Slitrk5 show OCD-like behavioral phenotypes and have deficits in corticostriatal communication in the brain.
Chromosomal translocations involving the gene encoding MOZ, a transcriptional regulator, can result in the production of fusion proteins that promote acute myeloid leukemia. In a mouse model of acute myeloid leukemia induced by a MOZ-containing fusion protein, Yukiko Aikawa et al. now identify a potential new therapeutic target, the cytokine receptor CSF1R, which is present on leukemia stem cells and is needed for leukemia induction and progression.
A three-gene expression signature can predict long-term prognosis in two autoimmune diseases, antineutrophil cytoplasmic antibody-associated vasculitis and systemic lupus erythematosus.
The omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid alleviate inflammatory pain in patients. Ru-Rong Ji and his colleagues find that the resolvins RvE1 and RvD1, which are derived from omega-3 fatty acids, potently reduce pain in a number of animal models of inflammatory pain. These effects are mediated by both peripheral and central mechanisms and suggest that resolvins may represent a new class of analgesics for inflammatory pain (pages 518–520).
A new transpeptidase that modifies the structure of the cell wall of Mycobacterium tuberculosis is important for bacterial virulence and could become the target of new antituberculosis agents.
Although the precipitating mechanisms of atrial fibrillation are not fully understood, atrial fibrosis is thought to set the stage for arrhythmia. Volker Rudolph et al. now show that the enzyme myeloperoxidase, released by inflammatory cells, is a key inducer of atrial fibrosis and arrhythmia in a mouse model of atrial fibrillation, and that myeloperoxidase levels are associated with atrial fibrillation in humans.
Despite highly active antiretroviral therapy, active replication persists and drives immune activation in some individuals with HIV. This activation is higher if therapy is intensified by additional antiretroviral drugs (pages 373–374).
Vaccine design is challenging when the infectious agent is genetically diverse. Polyvalent 'mosaic' antigens might be used to address this challenge, and these two studies show promising results in monkeys infected with HIV-1 (pages 268–270 and 324–328).
The concerted action of JNK and Pin1 on viral integrase regulate permissiveness of activated CD4+ T cells to HIV-1 infection, whereas lack of these modifications restricts viral infection in nonactivated lymphocytes.
Vaccine design is challenging when the infectious agent is genetically diverse. Polyvalent 'mosaic' antigens might be used to address this challenge, and these two studies show promising results in monkeys infected with HIV-1 (pages 268–270 and pages 319–323).
Defects in the ion transporter CFTR result in cystic fibrosis, which is marked by excessive mucous buildup in the lungs and colon and premature death. Christopher Glass and his colleagues now show that these aspects of the disease are associated with defects in PPAR-γ signaling in epithelial cells and that a synthetic agonist of this nuclear receptor is sufficient to partially normalize signaling and improve survival of a mouse model (pages 267–268).
Osteoporosis results from misregulation of bone catabolism and bone anabolism, resulting in severe bone loss. Most current therapies act by decreasing bone catabolism, but targeting bone anabolism is more desired, because once bone is lost, it is difficult to replace. In a new report by Gerard Karsenty and his colleagues, they show that orally delivered pharmacological targeting of serotonin synthesis in the gut is sufficient to increase bone anabolism and thus restore lost bone in rat and mouse models of well-established osteoporosis (pages 264–265).
Chikungunya virus (CHIKV) is an emerging infectious agent that can cause severe disease in humans and against which there is presently no vaccine. Akahata et al. now describe their development of a virus-like particle (VLP) vaccine that elicits neutralizing antibodies against CHIKV and can protect nonhuman primates from infection. Their VLP-based approach may facilitate development of a CHIKV vaccine for human use.
Two amplified genes from chromosome 8q22—YWHAZ and LAPTM4B—are associated with metastatic breast cancer recurrence by promoting resistance to anthracyclines. YWHAZ codes for an antiapoptotic protein and LAPTM4B encodes a previously undescribed lysosomal protein.
Jeffrey Weiser and his colleagues provide a mechanism for a beneficial effect from commensal bacteria that colonize the gut. They show that peptidoglycan from gut microbiota traverses the gut mucosa and boosts the systemic innate immune response by priming neutrophils in the bone marrow. Such priming requires the recognition of peptidoglycan by the intracellular receptor Nod-1 (pages 160–161).
Smallpox was eradicated by vaccination with a related poxvirus, vaccinia virus, which was applied to superficially injured skin in a process called scarification. Recombinant poxvirus–based vaccines are attractive candidates for protecting against a number of different infections, but they are nowadays usually administered intramuscularly. Thomas Kupper and his colleagues now show that the traditional route of administration, scarification, enables poxvirus-based vaccines to mediate more potent immunity compared with the intramuscular route. In particular, scarification with the poxvirus vaccines induced the sort of immune responses that are required for protection of distant tissues, including the lung mucosa.
Neutrophil elastase speeds up the progression of lung cancer by degrading insulin receptor substrate-1 and thereby phosphatidylinositol 3-kinase. This is the first description of a secreted proteinase gaining access to the inside of a cell to alter intracellular signaling (pages 161–163).