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Lissencephaly is a developmental brain disorder caused by mutations in LIS1 and characterized by impaired neuronal migration. Inhibiting calpain prevents LIS1 degradation in heterozygous mice and rescues the defective neuronal migration in utero.
A role for cell senescence and p53 in the development of insulin resistance (or prediabetes) has been obscure. Issei Komuro and colleagues now show that premature cell senescence occurs in the adipose tissue of obese mice and humans and that genetic deficiency of p53 is sufficient to prevent insulin resistance in mouse models of obesity, suggesting a new target to treat diabetes.
Canonical Wnt signaling is known to be crucial in embryonic organ development. Joseph Gleeson and his colleagues now report that it is also important in the adult homeostasis of the kidney, especially after injury, and that disruption of this signaling pathway results in cystic kidney disease.
Ischemia causes pericytes on brain microvessels to contract, obstructing erythrocyte transit even after blood flow is restored. This contraction, which depends on the production of oxygen and nitrogen radicals, represents a novel pathophysiological mechanism in stroke.
Dysregulation of osteoclasts, the cells that chew up bone, can lead to severe bone loss. Although many positive regulators of the differentiation of this cell type have been identified, few negative regulators have. Now, Masamichi Takami and colleagues have identified IRF-8 as an inhibitor of osteoclast formation and explore its role in disease.
These two studies show that primary cilia can either mediate or suppress tumorigenesis in models of basal cell carcinoma and medulloblastoma, respectively, depending on the nature of the initial oncogenic event (pages 994–996) and (pages 1055–1061).
The mechanisms that lead to idiopathic pulmonary fibrosis, or lung scarring, is not clear. Victor Thannickal and his colleagues have now provided further insight by showing that induction of NOX4, an enzyme that creates reactive oxygen species, is required for the progression of the disease. Their findings suggest NOX4 as a potential target to treat this common ailment that currently has no proven treatment options.
Enterotoxigenic Bacteroides fragilis, a bacterium from the intestinal flora, may promote colon tumor formation through a pathway that involves Stat3 expression and T helper type 17 immune responses.
These two studies show that primary cilia can either mediate or suppress tumorigenesis in models of basal cell carcinoma and medulloblastoma, respectively, depending on the nature of the initial oncogenic event (pages 994–996) and (pages 1062–1065).
Giovanni Monteleone and his colleagues show that the T cell-derived cytokine interleukin-21 is a new potential therapeutic target for psoriasis. Interleukin-21 seems to act directly on keratinocytes, stimulating them to proliferate and causing epidermal hyperplasia.
Jin and colleagues introduce a new chip-based system for the rapid identification and isolation of single antigen-specific antibody–secreting cells from human peripheral blood lymphocytes. The approach can be used to detect antibody-secreting cells for multiple antigens on the same chip and should have advantages over current technologies for isolating and producing human monoclonal antibodies of clinical significance.
The degenerative joint disease osteoarthritis is known to involve the activation of the protease ADAMTS-5. Now, Frank Echtermeyer and his colleagues have shown that the transmembrane proteoglycan syndecan-4 is responsible for this activation. They also show that genetic deletion of syndecan-4, or inhibition with a blocking antibody, reduces disease progression in a mouse model.
Although endogenous inhibitors of blood vessel growth have been studied extensively, specific inhibitors of lymphatic vessel growth have not been identified. Albuquerque et al. now identify truncated, secreted versions of mouse and human VEGFR-2 receptors generated by alternative splicing. The mouse protein acts as an endogenous inhibitor of lymphatic vessel growth in the cornea and skin, and its administration had therapeutic effects in mouse models of corneal injury and transplantation.
Suppression of the immune system could block autoimmune disease pathogenesis. Here Jacques Galipeau and his colleagues report that a fusion protein of two cytokines can induce immunosuppressive regulatory B cells. Transferring these cells into a mouse model of multiple sclerosis reduces disease in the mice.
There are three established HIV-1 lineages, M, N and O, which arose after cross-species transmission of simian immunodeficiency virus circulating in chimpanzees. An unusual variant of HIV-1 has now been identified that seems to be the prototype of a new lineage derived from gorillas.
Inflammatory cells invade the brain after stroke, but their role in disease has been unclear. Now, Akihiko Yoshimura and colleagues report that a particular population of T cells that express the inflammatory cytokine IL-17 plays a key role in stroke progression: depletion of these cells—even as late as 1 day after stroke—can alleviate brain injury in mice pages 844–846).
Contrary to the belief that basal-like breast cancers develop from mammary stem cells in BRCA1 mutation carriers, an aberrant luminal progenitor population might be the target for transformation in basal tumors in these individuals (pages 842–844).
Infection with HSV-2 increases the likelihood of HIV acquisition, but suppression of HSV-2 reactivation with antiviral drugs does not seem to reduce the acquisition of HIV. Laurence Corey and colleagues provide a potential mechanism underlying this observation, showing that even after acyclovir treatment for the HSV-2 infection, many inflammatory and immune cells possessing the receptors required for HIV infection persist in the mucosa, making the initial 'spark' of infection more likely.