Editors' Picks

        Signals from unanchored chains

        Cytosolic receptors, such as retinoic-acid-inducible gene-I (RIG-I), trigger signal transduction cascades that stimulate the immune system and result in the production of interferons and other molecules that suppress viral replication. Polyubiquitination, which has been implicated in a diverse array of signaling pathways, is important in the RIG-I pathway. Zeng and colleagues established a cell-free system that mimics viral infection in intact cells. In this system, molecules that mimic viral DNA (5-pppRNA and dsRNA) activated the entire RIG-I signaling cascade and subsequently activated the downstream transcription factors NF-κB and IRF3. Importantly, incubation with RNA and unanchored K63-polyubiquitin (polyUb) chains induced activation of RIG-I and dimerization of IRF3. Specifically, the N-terminus of RIG-I, which contains tandem caspase recruitment domains, binds to these polyUb chains (required for RIG-I activation). In addition, these polyUb chains activate RIG-I in human cells. Unanchored K63-polyUb chains are a novel and potent intracellular signaling molecule that activates the RIG-1 pathway. (Cell 141:315-30, 2010)

        Bone marrow replacement of collagen

        Because current patient care for the inherited blistering disease recessive dystrophic epidermolysis bullosa has been palliative and restricted to individual wounds, new treatment strategies for improving the quality of life in these patients are warranted. This disease is caused by loss-of-function mutations in the collagen type VII (C7) gene, and Wagner and colleagues performed a phase I–phase II clinical trial of bone marrow transplantation for collagen replacement in treating this disease. Infusion of unfiltered allogeneic bone marrow cells into six affected children partially corrected the C7 deficiency and resulted in improved skin and mucosal integrity. In agreement with previous reports, partial C7 correction was associated with clinical benefit. Interestingly, a substantial proportion of donor cells was detected in the skin and mucosa after treatment. This new treatment approach carries significant risk to the patient; the utility of such a treatment for a systemic disease warrants follow-up. (N Engl J Med 363:629-39, 2010)

        Essential selenium

        Antioxidant substances and enzymes often require trace elements such as dietary selenium to combat reactive oxygen species, which are implicated in skin disorders, including skin cancer. Selenium protects the skin and other organs via selenoproteins, which contain selenium in the form of selenocysteine (Sec). To examine the effects of selenoproteins in skin cells, the Sec tRNA, which governs the expression of all selenoproteins, was knocked out specifically in the epidermis of mice. These mice exhibited altered morphogenesis in the skin and hair follicles within days after birth and died prematurely. The results of this study revealed an essential protective role for selenium in the skin and provided evidence that deficiencies in selenoproteins result in the abnormalities observed in selenium-deficient human skin. Taken together, these findings highlight the importance of selenoproteins in cutaneous function and development. (PLoS ONE 5:e12249, 2010)

        Reversing muscle loss

        In an attempt to understand the underlying mechanisms of cancer cachexia and muscle wasting, which account for nearly 30% of cancer-related deaths, Zhou and colleagues examined the effects of an antagonist of ActRIIB, a high-affinity activin type 2 receptor with ligands that have been implicated in regulating muscle mass. This antagonist not only prevented further muscle wasting in mouse cancer models but also actually fully reversed skeletal muscle loss and heart atrophy without any concomitant effects on tumor growth, fat levels, or inflammatory cytokine expression. Functionally, these effects resulted in a prolonged survival of tumor-bearing animals. Administration of the antagonist blocked the ubiquitin–proteasome system and stimulated muscle satellite cell growth. Ultimately, development of antiactivin therapies may enhance the quality and length of life of cancer patients and may combat muscle loss under other catabolic conditions. (Cell 142:531-43, 2010)

        Speedy delivery

        Transepidermal drug delivery (TDD) has been used for addiction treatment, although current mechanisms for TDD cannot provide variable drug delivery rates, which are critical for successful drug withdrawal treatment. Wu and colleagues employed carbon nanotube (CNT) membranes, which allow highly efficient electrophoretic pumping, to control the delivery rates of nicotine in a programmable smoking cessation treatment device. Examination of these CNT membranes showed the membrane to be the rate-limiting component and the flux values to be based on simple diffusion. Importantly, a common watch battery was sufficient to power the CNT membrane for 12 days. The steady-state flux of nicotine was sufficient for a therapeutic smoking cessation treatment device. These programmable TDD devices, which can be adapted for the delivery of various agents and which caused minimal skin irritation, will improve the delivery of drugs used in substance abuse treatment programs. (PNAS 107:11698-702, 2010)