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By immunizing mice with a small synthetic metal-baring complex mimicking the active site of matrix metalloproteinases (MMPs), the authors have generated antibodies that bind and inhibit activated MMP2 and MMP9 in a manner analogous to the mechanism of action of tissue inhibitors of metalloproteinases. Targeting the active conformation of these MMPs is therapeutically effective in mouse models of inflammatory bowel disease.
Ali Ertürk and colleagues present a novel tetrahydrofuran-based histological tissue clearing procedure that renders fixed and unsectioned adult CNS tissue (spinal cord and brainstem) transparent and, as such, fully amenable to a range of different optical imaging techniques. This three-dimensional imaging method can be used for studying axon regeneration and glial reactions.
Sepsis is associated with a hyperinduction of proinflammatory cytokines. ATF3, a transcription factor, is induced in macrophages under conditions of endotoxic shock and downregulates expression of cytokines, including interleukin-6 (IL-6). Although ATF3 may thereby mitigate the severity of sepsis, Hoetzenecker et al. now show that endotoxin-induced ATF3 increases the susceptibility of mice to secondary pathogenic infections due to suppression of IL-6. Their findings suggest that temporal modulation of ATF3 may be important for the successful resolution of sepsis and the ensuing sepsis-associated immunosuppression.
Huntington's disease is a neurodegenerative disease caused by the accumulation of mutant HTT protein. Now, two groups led by Dimitri Krainc and Wenzhen Duan report that mutant HTT binds and inactivates the deacetylase enzyme SIRT1 and that SIRT1 overexpression is protective in Huntington's disease mouse models.
Salmonella infection is a common complication in people with malaria. Here the authors show that induction of heme oxygenase-1, a mechanism of tolerance to malaria, impairs resistance to Salmonella infection by limiting production of bactericidal reactive oxygen species.
Huntington's disease is a neurodegenerative disease caused by the accumulation of mutant htt protein. Now, two groups led by Dimitri Krainc and Wenzhen Duan report that mutant htt binds and inactivates the deacetylase enzyme SIRT1 and that SIRT1 overexpression is protective in Huntington's disease mouse models.
Congenital disorder of glycosylation-Ia in humans is a multisystemic disease marked by severe neurological deficits and results from deficient glycoprotein processing during development. Christian Körner and his colleagues now show that orally supplying mannose to pregnant dams in a mouse model of the disease is sufficient to ameliorate disease symptoms and early lethality, suggesting a possible therapy to treat this devastating condition.
A major issue in the clinic is excessive, or hypertrophic, scarring of the skin after injury. Geoffrey Gurtner and his colleagues have now shown that mechanical forces during such injury upregulates focal adhesion kinase (FAK), which in turn leads to the release of a cytokine that promotes inflammation and fibrosis. They also show that genetic deletion of FAK or its pharmacological inhibition results in minimal scarring in a mouse model.
The authors identify a set of microRNAs regulated by EGFR and MET that are involved in the oncogenic signaling exerted by these receptors and also modulate the response of tumors to targeted EGFR inhibition. These results shed light on the known contribution of MET to therapy resistance and suggest that MET-regulated microRNAs can be key mediators of its effects and potential markers of clinical utility.
The authors find a reciprocal negative regulation loop between TCTP and P53. TCTP modulates P53 by competing with NUMB for MDM2 binding and increasing MDM2-mediated degradation of P53. This is reciprocated by p53's direct transcriptional repression of TCTP. Some human breast tumors have increased amounts of TCTP, which only in some cases correlateswith decreased P53 activity, and elevated TCTP is associated with poor prognosis and may influence P53-regulated stemness of tumor cells.