Articles in 2011

Fragile X mental retardation is caused by mutations in the FMRP gene. Now, Xinyu Zhao and her colleagues show that deletion of Fmrp specifically in adult neural progenitor cells is sufficient to induce learning deficits in mice, whereas restoration of Fmrp only in neural progenitor cells in Fmrp-deficient mice restores learning.

Inflammatory cell recruitment to injured tissues is needed for repair, but an excessive inflammatory response can exacerbate injury. Tibor Kempf et al. now identify the cytokine GDF-15 as a new anti-inflammatory factor that dampens leukocyte recruitment in the setting of myocardial infarction in mice, thereby preventing cardiac rupture. GDF-15 blocks leukocyte extravasation from the blood into injured tissue by inhibiting the activation of cell surface integrin receptors.

By studying the effects of salt intake in mice and rats, ShengYu Mu et al. unravel the mechanisms by which dietary salt contributes to hypertension. Salt's prohypertensive effect required the activity of the glucocorticoid receptor in the kidney, which together with sympathetic nervous system activation led to decreased expression of the protein kinase WNK4, a key regulator of sodium channels that regulate blood pressure, via epigenetic regulation.

Edgar Engleman and his colleagues show that B cell production of pathogenic IgG antibodies is involved in obesity-induced insulin resistance. They also show that B cell depletion in obese mice ameliorates metabolic disease, and that obese, insulin-resistant humans have a unique profile of IgG autoantibodies. These results suggest a possible new therapeutic target to treat insulin resistance.

ADHD is characterized by hyperactivity and deficits in learning and memory. Now, Eunjoon Kim and colleagues report that a polymorphism in the gene that encodes the adaptor protein GIT1 is linked to ADHD in humans. This polymorphism reduces GIT1 expression, and GIT1-deficient mice show ADHD-like behaviors that can be alleviated with the psychostimulant drugs used to treat human ADHD.

Chronic inflammation of the airways is associated with remodeling and fibrosis, leading to a progressive decline in lung function in people with severe asthma. Michael Croft and his colleagues report that in mouse models of allergic lung inflammation expression of the TNF family member LIGHT is induced. Blockade of LIGHT prevents remodeling, providing a therapeutic strategy to prevent asthmatic airway remodeling.

Heterotopic ossification is the conversion of soft tissue into bone, usually after surgery or trauma but also as a result of the genetic disease fibrodysplasia ossificans progressiva. Masahiro Iwamoto and his colleagues have now shown that retinoic receptor-γ agonists ameliorate this condition in mouse models.

Schizophrenia has been associated with overactive neuregulin signaling and with glutamatergic synaptic hypoactivity. Now, in brain slice culture experiments, Michael Salter and his colleagues show that neuregulin signaling interferes with Src-induced activation of glutamatergic synaptic activity.

Amino acid profiles could aid in diabetes risk assessment, as a five-amino-acid signature had highly significant associations with the development of future diabetes in two large, independent cohorts.

Repulsive guidance molecule-a (RGMa) is an axon guidance molecule that is involved in retinal development and neural tube closure. Toshihide Yamashita and colleagues describe a previously unrecognized role for RGMa in the immune system. Blockade of RGMa attenuates clinical symptoms of experimental autoimmune encephalomyelitis and reduces T cell proliferation and cytokine release. These results suggest a possible new therapeutic target for multiple sclerosis.

Alum has long been used as a vaccine adjuvant, yet the mechanisms by which it increases antigen-specific immune responses remain unclear. Flach et al. now report that alum interacts with lipids in the plasma membrane of dendritic cells, resulting in nonphagocytic uptake of antigen and increased association with CD4⁺ T cells. These results suggest that, at least for dendritic cells, lipids rather than proteins may sense alum and trigger downstream signaling events that lead to enhanced T cell responses.

This report uncovers that activation of Src lies downstream of multiple trastuzumab-resistance–driving pathways. The authors show that Src, a major mediator of PI3K and IGFR resistance pathways, also drives resistance caused by PTEN loss, revealing that Src is directly dephosphorylated by PTEN. Src inhibition can overcome de novo and acquired trastuzumab resistance, suggesting a potential therapeutic strategy broadly applicable in breast cancer.

The STEP HIV-1 vaccine trial failed to protect volunteers from infection, but whether vaccine-driven immune responses affected the profile of viral variants in infected individuals was unknown. By analyzing nucleotide sequences and predicted T cell epitopes in viruses from newly infected trial participants, Rolland et al. now report that the degree of viral divergence from vaccine-encoded inserts suggests that vaccine-induced T cell responses indeed influenced the viral repertoire, a finding that might be harnessed in future vaccine design.

Polyubiquitination of the tumor suppressor p53 (encoded by TP53) regulates its stability by targeting it for degradation. Wu et al. now report that UBE4B, an E3 and E4 ligase, is a key enzyme in this process and that overexpression of UBE4B in some brain tumors is associated with reduced p53 abundance, suggesting a previously unknown mechanism blocking p53 function in cancer.

Insulin dials down endogenous hepatic glucose production after a meal by deactivating the transcription factor FoxO1. In a mouse model of insulin resistance, Umut Ozcan and his colleagues now show that hepatic overexpression of Xbp-1s, a factor involved in the cell stress response, leads to the protein degradation of FoxO1, thus reducing serum glucose levels. These results suggest a way to bypass one aspect of insulin resistance.

Mice lacking kinase suppressor of Ras-1 (Ksr1) are highly susceptible to Pseudomonas aeruginosa, a bacterium that often causes infections in people with cystic fibrosis. Ksr1 recruits inducible nitric oxide synthase and heat shock protein-90 to release nitric oxide upon infection, enhancing bactericidal activity.

There is an essential need for vaccines that can prevent primary infection by Mycobacterium tuberculosis and control its reactivation in individuals with latent disease. Claus Aagaard et al. now report the development of a dual-function vaccine that shows protective efficacy in mice by both inhibiting infection upon initial pathogen exposure and by impairing reactivation of latent infection with M. tuberculosis.

Obesity is generally considered an inflammatory state. Vishwa Dixit and his colleagues have now shown that excess dietary lipids leads to the activation of the Nlrp3 inflammasome, a sensor of the innate immune system, and that its genetic deficiency results in decreased inflammation and improved insulin sensitivity. These results suggest a possible new therapeutic avenue to treat the effects of obesity.