Cathelicidin is a “fire alarm”, generating protective NLRP3-dependent airway epithelial cell inflammatory responses during infection with Pseudomonas aeruginosa

<div><p>Pulmonary infections are a major global cause of morbidity, exacerbated by an increasing threat from antibiotic-resistant pathogens. In this context, therapeutic interventions aimed at protectively modulating host responses, to enhance defence against infection, take on ever greater significance. <i>Pseudomonas aeruginosa</i> is an important multidrug-resistant, opportunistic respiratory pathogen, the clearance of which can be enhanced <i>in vivo</i> by the innate immune modulatory properties of antimicrobial host defence peptides from the cathelicidin family, including human LL-37. Initially described primarily as bactericidal agents, cathelicidins are now recognised as multifunctional antimicrobial immunomodulators, modifying host responses to pathogens, but the key mechanisms involved in these protective functions are not yet defined. We demonstrate that <i>P</i>. <i>aeruginosa</i> infection of airway epithelial cells promotes extensive infected cell internalisation of LL-37, in a manner that is dependent upon epithelial cell interaction with live bacteria, but does not require bacterial Type 3 Secretion System (T3SS). Internalised LL-37 acts as a second signal to induce inflammasome activation in airway epithelial cells, which, in contrast to myeloid cells, are relatively unresponsive to <i>P</i>. <i>aeruginosa</i>. We demonstrate that this is mechanistically dependent upon cathepsin B release, and NLRP3-dependent activation of caspase 1. These result in LL-37-mediated release of IL-1β and IL-18 in a manner that is synergistic with <i>P</i>. <i>aeruginosa</i> infection, and can induce caspase 1-dependent death of infected epithelial cells, and promote neutrophil chemotaxis. We propose that cathelicidin can therefore act as a second signal, required by <i>P</i>. <i>aeruginosa</i> infected epithelial cells to promote an inflammasome-mediated altruistic cell death of infection-compromised epithelial cells and act as a “fire alarm” to enhance rapid escalation of protective inflammatory responses to an uncontrolled infection. Understanding this novel modulatory role for cathelicidins, has the potential to inform development of novel therapeutic strategies to antibiotic-resistant pathogens, harnessing innate immunity as a complementation or alternative to current interventions.</p></div

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Western Woburn Greenway Study

In spring 2010, the Department of Landscape Architecture and Regional Planning at the University of Massachusetts Amherst was asked to complete a landscape planning study, the “Western Woburn Greenway Study” for the City of Woburn, MA. The study was undertaken by a team of graduate students, supervised by Professor Jack Ahern. The goals of that study are as follows. The City of Woburn currently has two large parcel groups of undeveloped land, Whispering Hill (the north focus area) and Winning/Shannon Farms (the south focus area) that are, or may become, available for acquisition (see “Scope of Project” below). The first goal of the study was to analyze these focus areas and conduct suitability assessments for potential land uses that meet the needs of the residents of Woburn, as well as meet the goals specified by the town’s 2004 Open Space and Recreation Plan. The analysis and land use recommendations could be used by the city in current and future land acquisition decisions. The second goal of the study was to evaluate strategies and actions for connecting these focus areas with linkages to each other, to other existing open spaces in Woburn, and to other green spaces in neighboring towns. These linkages could be obtained with Green Streets an