Tribute to John Pickering

This is my homage to John. I ask you to summon up in your imagination today a grand circus, a sort of Cirque du Soleil of lawyers: full of shining talents performing legal feats of wonder, but presided over by a grand ringmaster. This ringmaster knows his performers very well. He knows how to train and stroke them to high achievement. He knows how to groom the younger workers. He can keep his stars in check. He knows when to sit back with a smile, letting his charges perform and claim the applause, even when the applause rightfully belongs to him. When his performers bicker, as they often do, he cajoles them back into their act. When they sulk, he cheers them up. John Pickering is this ringmaster. In my judgment, he was the but-for cause of the firm\u27s great success. Without John, I do not think the firm could have made it past its heady early days. He embodied the firm\u27s conscience, and I hope he still does. Even far beyond the firm, John stood as a model for all lawyers to emulate. I hope he still does

Enterobactin-Mediated Delivery of β-Lactam Antibiotics Enhances Antibacterial Activity against Pathogenic Escherichia coli

The design, synthesis, and characterization of enterobactin–antibiotic conjugates, hereafter Ent-Amp/Amx, where the β-lactam antibiotics ampicillin (Amp) and amoxicillin (Amx) are linked to a monofunctionalized enterobactin scaffold via a stable poly(ethylene glycol) linker are reported. Under conditions of iron limitation, these siderophore-modified antibiotics provide enhanced antibacterial activity against Escherichia coli strains, including uropathogenic E. coli CFT073 and UTI89, enterohemorrhagic E. coli O157:H7, and enterotoxigenic E. coli O78:H11, compared to the parent β-lactams. Studies with E. coli K-12 derivatives defective in ferric enterobactin transport reveal that the enhanced antibacterial activity observed for this strain requires the outer membrane ferric enterobactin transporter FepA. A remarkable 1000-fold decrease in minimum inhibitory concentration (MIC) value is observed for uropathogenic E. coli CFT073 relative to Amp/Amx, and time-kill kinetic studies demonstrate that Ent-Amp/Amx kill this strain more rapidly at 10-fold lower concentrations than the parent antibiotics. Moreover, Ent-Amp and Ent-Amx selectively kill E. coli CFT073 co-cultured with other bacterial species such as Staphylococcus aureus, and Ent-Amp exhibits low cytotoxicity against human T84 intestinal cells in both the apo and iron-bound forms. These studies demonstrate that the native enterobactin platform provides a means to effectively deliver antibacterial cargo across the outer membrane permeability barrier of Gram-negative pathogens utilizing enterobactin for iron acquisition.Pacific Southwest Regional Center of Excellence for Biodefense and Emerging Infectious DiseaseKinship Foundation. Searle Scholars ProgramMassachusetts Institute of Technology. Department of Chemistr

Tribute to John Pickering

This is my homage to John. I ask you to summon up in your imagination today a grand circus, a sort of Cirque du Soleil of lawyers: full of shining talents performing legal feats of wonder, but presided over by a grand ringmaster. This ringmaster knows his performers very well. He knows how to train and stroke them to high achievement. He knows how to groom the younger workers. He can keep his stars in check. He knows when to sit back with a smile, letting his charges perform and claim the applause, even when the applause rightfully belongs to him. When his performers bicker, as they often do, he cajoles them back into their act. When they sulk, he cheers them up. John Pickering is this ringmaster. In my judgment, he was the but-for cause of the firm\u27s great success. Without John, I do not think the firm could have made it past its heady early days. He embodied the firm\u27s conscience, and I hope he still does. Even far beyond the firm, John stood as a model for all lawyers to emulate. I hope he still does

Tracing historical introductions in the Mediterranean Basin: the success story of the common genet (Genetta genetta) in Europe

The successful introduction of the common genet (Genetta genetta) into Europe has been traditionally associated to the Muslim invasion of Iberia, although diverse evidence suggested an earlier arrival. In this study, we assessed genetic variation at 11 microsatellite loci in 199 individuals from the Mediterranean Basin and used approximate Bayesian computation (ABC) combining genotypes and published mitochondrial sequences. Our objectives were to (1) test alternative scenarios of introduction of the species in Europe, (2) re-assess the mitochondrial signatures of ‘introduction hotspots’ in Iberia, and (3) evaluate how post-introduction demographic processes have shaped genetic structure in the invaded range. ABC estimates favored a scenario of independent introductions from Maghreb into the Balearic Isl. and Iberia; the latter was dated between the Upper Palaeolithic and the end of Phoenicians’ influence. Patterns of genotypic diversity broadened the Andalusian introduction hotspot to the antique Tartessos Kingdom and suggested multiple introductions and/or long-term genetic drift. The best fit ABC scenario implied a natural spread from Iberia to France, but was in potential conflict with our delimitation of two genetic clusters (France and Iberia) in continental Europe. In fact, southwestern France populations showed a fair proportion of alleles shared with Maghreb and low levels of heterozygosity that may reflect subsequent introduction from Iberia, in line with the high error rates in favor of this alternative scenario. Significant patterns of isolation-by-distance among individuals within both genetic clusters are suggestive of natural dispersal from both Iberian and French introduction sites resulting in a secondary contact zone in northern Iberia. Overall, our study strongly suggests that the common genet was intentionally introduced in southern Iberia at a time antedating the Muslim invasion, possibly via Phoenicians’ commercial routes. Subsequent introduction in France, long-term genetic drift and admixture likely shaped the species genetic variation currently observed in continental Europe