To address the growing need for new antimicrobial agents, we explored whether inhibition of bacterial signaling machinery could inhibit bacterial growth. Because bacteria rely on two-component signaling systems to respond to environmental changes, and because these systems are both highly conserved and mediated by histidine kinases, inhibiting histidine kinases may provide broad spectrum antimicrobial activity. The histidine kinase ATP binding domain is conserved with the ATPase domain of eukaryotic Hsp90 molecular chaperones. To find a chemical scaffold for compounds that target histidine kinases, we leveraged this conservation. We screened ATP competitive Hsp90 inhibitors against CckA, an essential histidine kinase in Caulobacter crescentus that controls cell growth, and showed that the diaryl pyrazole is a promising scaffold for histidine kinase inhibition. We synthesized a panel of derivatives and found that they inhibit the histidine kinases C. crescentus CckA and Salmonella PhoQ but not C. crescentus DivJ; and they inhibit bacterial growth in both Gram-negative and Gram-positive bacterial strains.

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Prof. Sylvester's Theory of Tatnisage. 85 the form considered in this memoir, in which (x = 0) is the determinate line passing through the cusp and the two points of osculation of the osculating conic. The general form of quartics, which are simply met by the .line at infinity in three coincident points and another point and which have a triple and a single asymptote (x 3 y-\-u s-\-u 2 = 0), is not here considered. [The assumed form KO S /3 = tt 2 , or, as this is afterwards written, 2Kx s y-ax l + 2bxy + cy i + 2ex + 2dy + \, is, I think, introduced without a proper explanation. Say, the form is xSj = z 2 (*j£aj, y, z) 2 , it ought to be shown how for a cuspidal quartic we arrive at this form; viz., taking the cusp to be at the point (x=0, z=0), z = 0 for the tangent at the cusp, and x-0 an arbitrary line through the cusp; then the line «=0 besides intersects the curve in a single point, and, if y = 0 is taken as the tangent at that point, the equation of the curve must, it can be seen, be of the form {x* + 0xh)y = z> (a, b;c,f, g, h%x, y, «)". The conic (a, b, c, / , g, h^x, y, z)* = 0 touches the quartic at each of the two intersections of the quartic with the arbitrary line # = 0 ; and we cannot, so long as the line remains arbitrary, find a conic which shall osculate the quartic at the two points in question; but, for the particular line x+±dz = 0, there exists such a conic, viz., writing x instead of x + \6z, the form is x*y = z 2 (a, &' , c',/', g, h'~Qx, y, z) 5 , and the new conic (a', ...Qx, y, a) 2 = 0 has the property in question. This is the adopted form, and it thus appears that in it the line x = 0 is a determinate line, viz., the line passing through the cusp and the two points of osculation of the osculating conic. It thus appears that in the assumed form the lines JC==O, y = 0, 8 = 0 are determinate lines.-A. C ] Note on an Excejitional Case in which the Fundamental Postulate of Professor Sylvester's Theory of Tamisage fails.

In "Threshold Concepts and Troublesome Knowledge," Jan Meyer and Ray Land (2006) explain that "interviews and wider discussions with practitioners in a range of disciplines and institutions" (6) led them to identify the characteristics associated with threshold concepts that have become familiar to researchers who have adopted or adapted this framework for thinking about learning and teaching. That is, threshold concepts are transformative, probably irreversible, integrative, potentially troublesome, and bounded. It's this latter idea that is significant for this chapter. Specifically, as Meyer and Land explain, threshold concepts are "possibly often (though not necessarily always) bounded in that any conceptual space will have terminal frontiers, bordering with thresholds into new conceptual areas. It might be that such boundedness in certain instances serves to constitute the demarcation between disciplinary areas, to define academic territories" (6). They follow this with two illustrations: one from a faculty member in cultural studies and one from veterinary sciences, both of whom explain the consequences for students of seeing through or seeing with threshold concepts from other disciplines, or of invoking ways of thinking and practicing (Hounsell and Anderson 2009) associated with operationalization of threshold concepts inconsistent with the threshold concepts of the discipline. The idea that threshold concepts serve as portals into disciplinary participation has become an important one for teachers, learners, and researchers working with the idea.