Poliovirus mutant that contains a cold-sensitive defect in viral RNA synthesis

By manipulating an infectious cDNA clone of poliovirus, we have introduced a single-codon insertion into the 3A region of the viral genome which has been proposed to encode a functional precursor of the virion-linked protein VPg. The resulting mutant was cold sensitive in monkey kidney cells. Viral RNA synthesis was poor at 32.5 degrees C, although no other function of the virus was obviously affected. The synthesis of both positive and negative strands was severely depressed. Temperature shift experiments suggest that a normal level of production of the affected function was required only during the early (exponential) phase of RNA synthesis. Analysis of viral polyprotein processing at the nonpermissive temperature revealed that some of the normal cleavages were not made, most likely as a consequence of the defect in RNA synthesis or as a result of the concomitant reduction in the level of virally encoded proteases

Quantifying biosynthetic network robustness across the human oral microbiome

Metabolic interactions, such as cross-feeding, play a prominent role in microbial communitystructure. For example, they may underlie the ubiquity of uncultivated microorganisms. We investigated this phenomenon in the human oral microbiome, by analyzing microbial metabolic networks derived from sequenced genomes. Specifically, we devised a probabilistic biosynthetic network robustness metric that describes the chance that an organism could produce a given metabolite, and used it to assemble a comprehensive atlas of biosynthetic capabilities for 88 metabolites across 456 human oral microbiome strains. A cluster of organisms characterized by reduced biosynthetic capabilities stood out within this atlas. This cluster included several uncultivated taxa and three recently co-cultured Saccharibacteria (TM7) phylum species. Comparison across strains also allowed us to systematically identify specific putative metabolic interdependences between organisms. Our method, which provides a new way of converting annotated genomes into metabolic predictions, is easily extendible to other microbial communities and metabolic products.https://www.biorxiv.org/content/10.1101/392621v1First author draf

Do Endowments Predict the Location of Production? Evidence from National and International Data

Examining the relationship between factor endowments and production patterns using international and Japanese regional data, we provide the first empirical confirmation of Ethier's correlation approach to the Rybczynski theorem. Moreover, we find evidence of substantial production indeterminacy. Prediction errors are six to thirty times larger for goods traded relatively freely. A compelling explanation of this phenomenon is the existence of more goods than factors in the presence of trade costs. This result implies that regressions of trade or output on endowments have weak theoretical foundations. Furthermore, since errors are largest in data sets where trade costs are small, we explain why the common methodology of imputing trade barriers from regression residuals often leads to backwards results.

Implications and Policy Options of California's Reliance on Natural Gas

Examines existing and currently anticipated infrastructure, rising gas prices, and recurring supply problems, and looks at options to alleviate the problem. Part of a series of research reports that examines energy issues facing California

Metabolic network percolation quantifies biosynthetic capabilities across the human oral microbiome

The biosynthetic capabilities of microbes underlie their growth and interactions, playing a prominent role in microbial community structure. For large, diverse microbial communities, prediction of these capabilities is limited by uncertainty about metabolic functions and environmental conditions. To address this challenge, we propose a probabilistic method, inspired by percolation theory, to computationally quantify how robustly a genome-derived metabolic network produces a given set of metabolites under an ensemble of variable environments. We used this method to compile an atlas of predicted biosynthetic capabilities for 97 metabolites across 456 human oral microbes. This atlas captures taxonomically-related trends in biomass composition, and makes it possible to estimate inter-microbial metabolic distances that correlate with microbial co-occurrences. We also found a distinct cluster of fastidious/uncultivated taxa, including several Saccharibacteria (TM7) species, characterized by their abundant metabolic deficiencies. By embracing uncertainty, our approach can be broadly applied to understanding metabolic interactions in complex microbial ecosystems.T32GM008764 - NIGMS NIH HHS; T32 GM008764 - NIGMS NIH HHS; R01 DE024468 - NIDCR NIH HHS; R01 GM121950 - NIGMS NIH HHS; DE-SC0012627 - Biological and Environmental Research; RGP0020/2016 - Human Frontier Science Program; NSFOCE-BSF 1635070 - National Science Foundation; HR0011-15-C-0091 - Defense Advanced Research Projects Agency; R37DE016937 - NIDCR NIH HHS; R37 DE016937 - NIDCR NIH HHS; R01GM121950 - NIGMS NIH HHS; R01DE024468 - NIDCR NIH HHS; 1457695 - National Science FoundationPublished versio

Wicked Problems and Gnarly Results: Reflecting on Design and Evaluation Methods for Idiosyncratic Personal Information Management Tasks

This paper is a case study of an artifact design and evaluation process; it is a reflection on how right thinking about design methods may at times result in sub-optimal results. Our goal has been to assess our decision making process throughout the design and evaluation stages for a software prototype in order to consider where design methodology may need to be tuned to be more sensitive to the domain of practice, in this case software evaluation in personal information management. In particular, we reflect on design methods around (1) scale of prototype, (2) prototyping and design process, (3) study design, and (4) study population

Learning the Wrong Lessons from An American Tragedy

This paper is a critique of Margaret Berger and Aaron Twerski, “Uncertainty and Informed Choice: Unmasking Daubert,” forthcoming in the Michigan Law Review. Berger and Twerski propose that courts recognize a cause of action that would allow plaintiffs who claim injury from pharmaceutical products, but who do not have sufficient evidence to prove causation, to recover damages for deprivation of informed choice. Berger and Twerski claim inspiration from the litigation over allegations that the morning sickness drug Bendectin caused birth defects. Considering the criteria Berger and Twerski suggest for their proposed cause of action in the context of Bendectin, it appears that a pharmaceutical manufacturer could be held liable for failure to provide informed choice: (a) even when there was never any sound scientific evidence suggesting that the product caused the harm at issue, and there was an unbroken consensus among leading experts in the field that the product did not cause such harm; (b) when the product prevented serious harm to a significant number of patients, and prevented substantial discomfort to a much greater number, even when there were no available alternative products; (c) when a plaintiff claims that she would not have taken the product had she been informed of an incredibly remote and completely unproven risk; and (d) when the defendant is unable to prove a negative - that the product in question definitely did not cause the claimed injury. No rational legal system would allow such a tort. Putting the Bendectin example aside, the informed choice proposal has the following additional weaknesses: (1) it invites reliance on unreliable junk science testimony; (2) it ignores the fact that juries are not competent to resolve subtle risk assessment issues; (3) it reflects an unwarranted belief in the ability of juries to both follow limiting instructions and ignore their emotions; (4) it ignores the problems inherent to multiple trials - even if defendants were to win most informed choice cases, safe products could still be driven off the market by a minority of contrary verdicts; (5) it ignores the inevitable costs to medical innovation as pharmaceutical companies scale back on researching product categories that would be particularly prone to litigation; (6) to preempt litigation, pharmaceutical companies would overwarn, rendering more significant warnings less useful; and (7) FDA labeling requirements would arguably preempt the proposed cause of action