Viral Mediated Redirection of NEMO/IKKγ to Autophagosomes Curtails the Inflammatory Cascade

The early host response to viral infections involves transient activation of pattern recognition receptors leading to an induction of inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα). Subsequent activation of cytokine receptors in an autocrine and paracrine manner results in an inflammatory cascade. The precise mechanisms by which viruses avert an inflammatory cascade are incompletely understood. Nuclear factor (NF)-κB is a central regulator of the inflammatory signaling cascade that is controlled by inhibitor of NF-κB (IκB) proteins and the IκB kinase (IKK) complex. In this study we show that murine cytomegalovirus inhibits the inflammatory cascade by blocking Toll-like receptor (TLR) and IL-1 receptor-dependent NF-κB activation. Inhibition occurs through an interaction of the viral M45 protein with the NF-κB essential modulator (NEMO), the regulatory subunit of the IKK complex. M45 induces proteasome-independent degradation of NEMO by targeting NEMO to autophagosomes for subsequent degradation in lysosomes. We propose that the selective and irreversible degradation of a central regulatory protein by autophagy represents a new viral strategy to dampen the inflammatory response

Coherent oscillations in word-use data from 1700 to 2008

In written language, the choice of specific words is constrained by both grammatical requirements and the specific semantic context of the message to be transmitted. To a significant degree, the semantic context is in turn affected by a broad cultural and historical environment, which also influences matters of style and manners. Over time, those environmental factors leave an imprint in the statistics of language use, with some words becoming more common and other words being preferred less. Here we characterize the patterns of language use over time based on word statistics extracted from more than 4.5 million books written over a period of 308 years. We find evidence of novel systematic oscillatory patterns in word use with a consistent period narrowly distributed around 14 years. The specific phase relationships between different words show structure at two independent levels: first, there is a weak global phase modulation that is primarily linked to overall shifts in the vocabulary across time; and second, a stronger component dependent on well defined semantic relationships between words. In particular, complex network analysis reveals that semantically related words show strong phase coherence. Ultimately, these previously unknown patterns in the statistics of language may be a consequence of changes in the cultural framework that influences the thematic focus of writers