Tribute to John Pickering

One of my colleagues asked me soon after John died, How could someone live to be eighty-nine years old and yet there is no one who had a bad word to say about him? This is an intriguing question. It is not because John Pickering did not have strongly held views about things. Anyone who ever tangled with John in crafting a brief knew how tenacious he was. John was direct and candid and you knew where he stood on any matter. It is not because John was easygoing. When he saw something that he wanted changed, he did not take no for an answer. He was relentless and tireless. It is not because he was not demanding. Working for John was hard work. He set high standards for himself and he expected you to work at the same level

Tribute to John Pickering

One of my colleagues asked me soon after John died, How could someone live to be eighty-nine years old and yet there is no one who had a bad word to say about him? This is an intriguing question. It is not because John Pickering did not have strongly held views about things. Anyone who ever tangled with John in crafting a brief knew how tenacious he was. John was direct and candid and you knew where he stood on any matter. It is not because John was easygoing. When he saw something that he wanted changed, he did not take no for an answer. He was relentless and tireless. It is not because he was not demanding. Working for John was hard work. He set high standards for himself and he expected you to work at the same level

Revealing Complex Traits with Small Molecules and Naturally Recombinant Yeast Strains

SummaryHere we demonstrate that natural variants of the yeast Saccharomyces cerevisiae are a model system for the systematic study of complex traits, specifically the response to small molecules. As a complement to artificial knockout collections of S. cerevisiae widely used to study individual gene function, we used 314- and 1932-member libraries of mutant strains generated by meiotic recombination to study the cumulative, quantitative effects of natural mutations on phenotypes induced by 23 small-molecule perturbagens (SMPs). This approach reveals synthetic lethality between SMPs, and genetic mapping studies confirm the involvement of multiple quantitative trait loci in the response to two SMPs that affect respiratory processes. The systematic combination of natural variants of yeast and small molecules that modulate evolutionarily conserved cellular processes can enable a better understanding of the general features of complex traits

Assist or accuse?: Identifying trends in crisis communication through a bibliometric literature review

Communication has always been key to crisis management research, but even more so in recent years, from multiple disciplinary angles. In this bibliometric study and review of the literature, we aim to identify different clusters of crisis communication research in the literature and whether and how much these crisis communication research clusters overlap. With different fields taking an interest in crisis communication, we ask ourselves where the interests of these fields overlap, and to what extent the different communities are aware of each other's work. Apart from offering an overview of topical clusters in crisis communication research and connections between those clusters of studies on crisis communication, we identify and explain two main approaches to crisis communication: a political or accusatory approach, and a functional or assistory approach. We conclude in our study and discussion that these approaches may need to broaden their research horizons to ensure the applicability of crisis communication strategies beyond the countries, media platforms, and audience orientations that have predominantly shaped the existing research landscapeSecurity and Global Affair

Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for the congenital disorder of glycosylation PMM2-CDG

Phosphomannomutase 2 deficiency, or PMM2-CDG, is the most common congenital disorder of glycosylation and affects over 1000 patients globally. There are no approved drugs that treat the symptoms or root cause of PMM2-CDG. To identify clinically actionable compounds that boost human PMM2 enzyme function, we performed a multispecies drug repurposing screen using a novel worm model of PMM2-CDG, followed by PMM2 enzyme functional studies in PMM2-CDG patient fibroblasts. Drug repurposing candidates from this study, and drug repurposing candidates from a previously published study using yeast models of PMM2-CDG, were tested for their effect on human PMM2 enzyme activity in PMM2-CDG fibroblasts. Of the 20 repurposing candidates discovered in the worm-based phenotypic screen, 12 were plant-based polyphenols. Insights from structure-activity relationships revealed epalrestat, the only antidiabetic aldose reductase inhibitor approved for use in humans, as a first-in-class PMM2 enzyme activator. Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S. PMM2 enzyme activity gains ranged from 30% to 400% over baseline, depending on genotype. Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homodimerization. Epalrestat is a safe, oral and brain penetrant drug that was approved 27 years ago in Japan to treat diabetic neuropathy in geriatric populations. We demonstrate that epalrestat is the first small molecule activator ofPMM2 enzyme activity with the potential to treat peripheral neuropathy and correct the underlying enzyme deficiency in a majority of pediatric and adult PMM2-CDG patients

Evolutionary rescue of phosphomannomutase deficiency in yeast models of human disease

The most common cause of human congenital disorders of glycosylation (CDG) are mutations in the phosphomannomutase gene PMM2, which affect protein N-linked glycosylation. The yeast gene SEC53 encodes a homolog of human PMM2. We evolved 384 populations of yeast harboring one of two human-disease-associated alleles, sec53-V238M and sec53-F126L, or wild-type SEC53. We find that after 1000 generations, most populations compensate for the slow-growth phenotype associated with the sec53 human-disease-associated alleles. Through whole-genome sequencing we identify compensatory mutations, including known SEC53 genetic interactors. We observe an enrichment of compensatory mutations in other genes whose human homologs are associated with Type 1 CDG, including PGM1, which encodes the minor isoform of phosphoglucomutase in yeast. By genetic reconstruction, we show that evolved pgm1 mutations are dominant and allele-specific genetic interactors that restore both protein glycosylation and growth of yeast harboring the sec53-V238M allele. Finally, we characterize the enzymatic activity of purified Pgm1 mutant proteins. We find that reduction, but not elimination, of Pgm1 activity best compensates for the deleterious phenotypes associated with the sec53-V238M allele. Broadly, our results demonstrate the power of experimental evolution as a tool for identifying genes and pathways that compensate for human-disease-associated alleles

The topology of connections between rat prefrontal, motor and sensory cortices

The connections of prefrontal cortex (PFC) were investigated in the rat brain to determine the order and location of input and output connections to motor and somatosensory cortex. Retrograde (100 nl Fluoro-Gold) and anterograde (100 nl Biotinylated Dextran Amines, BDA; Fluorescein and Texas Red) neuronanatomical tracers were injected into the subdivisions of the PFC (prelimbic, ventral orbital, ventrolateral orbital, dorsolateral orbital) and their projections studied. We found clear evidence for organized input projections from the motor and somatosensory cortices to the PFC, with distinct areas of motor and cingulate cortex projecting in an ordered arrangement to the subdivisions of PFC. As injection location of retrograde tracer was moved from medial to lateral in PFC, we observed an ordered arrangement of projections occurring in sensory-motor cortex. There was a significant effect of retrograde injection location on the position of labelled cells occurring in sensory-motor cortex (dorsoventral, anterior-posterior and mediolateral axes p < 0.001). The arrangement of output projections from PFC also displayed a significant ordered projection to sensory-motor cortex (dorsoventral p < 0.001, anterior-posterior p = 0.002 and mediolateral axes p < 0.001)

Baker Center Journal of Applied Public Policy - Vol. IV, No.II

This special edition includes articles from speakers at a 2010 conference - Howard H. Baker, Jr: A Life in Public Service and a special addendum including photographs and cartoons from Sen. Baker\u27s career