The two-player Iterated Prisoner’s Dilemma game is a model for both sentient and evolutionary behaviors, especially including the emergence of cooperation. It is generally assumed that there exists ...no simple ultimatum strategy whereby one player can enforce a unilateral claim to an unfair share of rewards. Here, we show that such strategies unexpectedly do exist. In particular, a player X who is witting of these strategies can (i) deterministically set her opponent Y’s score, independently of his strategy or response, or (ii) enforce an extortionate linear relation between her and his scores. Against such a player, an evolutionary player’s best response is to accede to the extortion. Only a player with a theory of mind about his opponent can do better, in which case Iterated Prisoner’s Dilemma is an Ultimatum Game.
Ribosome profiling produces snapshots of the locations of actively translating ribosomes on messenger RNAs. These snapshots can be used to make inferences about translation dynamics. Recent ribosome ...profiling studies in yeast, however, have reached contradictory conclusions regarding the average translation rate of each codon. Some experiments have used cycloheximide (CHX) to stabilize ribosomes before measuring their positions, and these studies all counterintuitively report a weak negative correlation between the translation rate of a codon and the abundance of its cognate tRNA. In contrast, some experiments performed without CHX report strong positive correlations. To explain this contradiction, we identify unexpected patterns in ribosome density downstream of each type of codon in experiments that use CHX. These patterns are evidence that elongation continues to occur in the presence of CHX but with dramatically altered codon-specific elongation rates. The measured positions of ribosomes in these experiments therefore do not reflect the amounts of time ribosomes spend at each position in vivo. These results suggest that conclusions from experiments in yeast using CHX may need reexamination. In particular, we show that in all such experiments, codons decoded by less abundant tRNAs were in fact being translated more slowly before the addition of CHX disrupted these dynamics.
As electronic medical records enable increasingly ambitious studies of treatment outcomes, ethical issues previously important only to limited clinical trials become relevant to unlimited whole ...populations. For randomized clinical trials, adaptive assignment strategies are known to expose substantially fewer patients to avoidable treatment failures than strategies with fixed assignments (e.g., equal sample sizes). An idealized adaptive case--the two-armed Bernoulli bandit problem--can be exactly optimized for a variety of ethically motivated cost functions that embody principles of duty-to-patient, but the solutions have been thought computationally infeasible when the numbers of patients in the study (the "horizon") is large. We report numerical experiments that yield a heuristic approximation that applies even to very large horizons, and we propose a near-optimal strategy that remains valid even when the horizon is unknown or unbounded, thus applicable to comparative effectiveness studies on large populations or to standard-of-care recommendations. For the case in which the economic cost of treatment is a parameter, we give a heuristic, near-optimal strategy for determining the superior treatment (whether more or less costly) while minimizing resources wasted on any inferior, more expensive, treatment. Key features of our heuristics can be generalized to more complicated protocols.
A major limitation of high-throughput DNA sequencing is the high rate of erroneous base calls produced. For instance, Illumina sequencing machines produce errors at a rate of ∼0.1–1 × 10−2 per base ...sequenced. These technologies typically produce billions of base calls per experiment, translating to millions of errors. We have developed a unique library preparation strategy, "circle sequencing," which allows for robust downstream computational correction of these errors. In this strategy, DNA templates are circularized, copied multiple times in tandem with a rolling circle polymerase, and then sequenced on any high-throughput sequencing machine. Each read produced is computationally processed to obtain a consensus sequence of all linked copies of the original molecule. Physically linking the copies ensures that each copy is independently derived from the original molecule and allows for efficient formation of consensus sequences. The circle-sequencing protocol precedes standard library preparations and is therefore suitable for a broad range of sequencing applications. We tested our method using the Illumina MiSeq platform and obtained errors in our processed sequencing reads at a rate as low as 7.6 × 10−6 per base sequenced, dramatically improving the error rate of Illumina sequencing and putting error on par with low-throughput, but highly accurate, Sanger sequencing. Circle sequencing also had substantially higher efficiency and lower cost than existing barcode-based schemes for correcting sequencing errors.
Schlafen11 (encoded by the SLFN11 gene) has been shown to inhibit the accumulation of HIV-1 proteins. We show that the SLFN11 gene is under positive selection in simian primates and is ...species-specific in its activity against HIV-1. The activity of human Schlafen11 is relatively weak compared to that of some other primate versions of this protein, with the versions encoded by chimpanzee, orangutan, gibbon, and marmoset being particularly potent inhibitors of HIV-1 protein production. Interestingly, we find that Schlafen11 is functional in the absence of infection and reduces protein production from certain non-viral (GFP) and even host (Vinculin and GAPDH) transcripts. This suggests that Schlafen11 may just generally block protein production from non-codon optimized transcripts. Because Schlafen11 is an interferon-stimulated gene with a broad ability to inhibit protein production from many host and viral transcripts, its role may be to create a general antiviral state in the cell. Interestingly, the strong inhibitors such as marmoset Schlafen11 consistently block protein production better than weak primate Schlafen11 proteins, regardless of the virus or host target being analyzed. Further, we show that the residues to which species-specific differences in Schlafen11 potency map are distinct from residues that have been targeted by positive selection. We speculate that the positive selection of SLFN11 could have been driven by a number of different factors, including interaction with one or more viral antagonists that have yet to be identified.
CRISPR-Cas nucleoproteins target foreign DNA via base pairing with a crRNA. However, a quantitative description of protein binding and nuclease activation at off-target DNA sequences remains elusive. ...Here, we describe a chip-hybridized association-mapping platform (CHAMP) that repurposes next-generation sequencing chips to simultaneously measure the interactions between proteins and ∼107 unique DNA sequences. Using CHAMP, we provide the first comprehensive survey of DNA recognition by a type I-E CRISPR-Cas (Cascade) complex and Cas3 nuclease. Analysis of mutated target sequences and human genomic DNA reveal that Cascade recognizes an extended protospacer adjacent motif (PAM). Cascade recognizes DNA with a surprising 3-nt periodicity. The identity of the PAM and the PAM-proximal nucleotides control Cas3 recruitment by releasing the Cse1 subunit. These findings are used to develop a model for the biophysical constraints governing off-target DNA binding. CHAMP provides a framework for high-throughput, quantitative analysis of protein-DNA interactions on synthetic and genomic DNA.
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•CHAMP enables massively parallel profiling of protein-nucleic acid interactions•CHAMP was used to measure off-target DNA binding by a CRISPR-Cas complex•Cascade decodes extended PAMs and binds DNA with a 3-nt periodicity•Cas3 binding is dependent on the PAM and PAM-proximal crRNA-DNA mismatches
Discarded next-gen sequencing chips provide a platform for analyzing protein-DNA interactions that reveals a novel proofreading mechanism used by the Cascade/Cas3 complex.
The use of profiling by ethnicity or nationality to trigger secondary security screening is a controversial social and political issue. Overlooked is the question of whether such actuarial methods ...are in fact mathematically justified, even under the most idealized assumptions of completely accurate prior probabilities, and secondary screenings concentrated on the highest-probablity individuals. We show here that strong profiling (defined as screening at least in proportion to prior probability) is no more efficient than uniform random sampling of the entire population, because resources are wasted on the repeated screening of higher probability, but innocent, individuals. A mathematically optimal strategy would be "square-root biased sampling," the geometric mean between strong profiling and uniform sampling, with secondary screenings distributed broadly, although not uniformly, over the population. Square-root biased sampling is a general idea that can be applied whenever a "bell-ringer" event must be found by sampling with replacement, but can be recognized (either with certainty, or with some probability) when seen.
Götz, Druckmüller, and, independently, Brady have defined a discrete Radon transform (DRT) that sums an image's pixel values along a set of aptly chosen discrete lines, complete in slope and ...intercept. The transform is fast, O(N²log N) for an N x N image; it uses only addition, not multiplication or interpolation, and it admits a fast, exact algorithm for the adjoint operation, namely backprojection. This paper shows that the transform additionally has a fast, exact (although iterative) inverse. The inverse reproduces to machine accuracy the pixel-by-pixel values of the original image from its DRT, without artifacts or a finite point-spread function. Fourier or fast Fourier transform methods are not used. The inverse can also be calculated from sampled sinograms and is well conditioned in the presence of noise. Also introduced are generalizations of the DRT that combine pixel values along lines by operations other than addition. For example, there is a fast transform that calculates median values along all discrete lines and is able to detect linear features at low signal-to-noise ratios in the presence of pointlike clutter features of arbitrarily large amplitude.
While investigating microRNA targets, we have found that human genes divide into two roughly equal populations, based on the fraction of A plus T bases in their 3' UTRs. Using the Gene Ontology ...database, we find significant functional differences between the two gene populations, with AT-rich genes implicated in transcription and translation processes, and GC-rich genes implicated in signal transduction and posttranslational protein modification. Better understanding of the background distribution of nucleotides in 3' UTRs may allow improved prediction of microRNA-targeted genes in humans. We predict at least 1,200 KnownGene transcripts to be regulated by microRNAs. The large majority of these microRNA targets are in the AT-rich 3' UTR population. However, notwithstanding this preference for AT-rich targets, microRNA targets are found preferentially to be regulatory genes themselves, including both transcription factors and posttranslational modifiers. These results suggest that some processes involving mRNA, of which microRNA regulation may be just one, require AT-richness of 3' UTRs for functionality. A relationship, not simply one-to-one, between these 3' UTR populations and large-scale genomic isochores is described.
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