'If I had a hedge fund, I would cure diabetes': endogenous mechanisms for creating public goods.

We consider the problem of organizing capital to produce public goods with broad societal value. We review why market corrections via government subsidies or philanthropic initiatives are inadequate, in addition to considering the paradox of patents. Our proposed mechanism (an Ever-growing Prize and a Patent Repository) directs capital towards two innovation problems routinely overlooked: (1) problems for which the reward is insufficient even with established mechanisms (e.g. patents or academic prestige), and (2) problems for which the reward is large, but the effort risk is incalculable. The proposed hedge fund mechanism facilitates crowdsourcing, addressing the challenge of determining problems with broad societal interest; the ever-growing prize allows for an emergent rather than predetermined reward; the patent repository turns private intellectual property into a public good for target problems while circumventing the inventors' threat of patent expiration. We guide this discussion by considering two problems: treating Cystic Fibrosis and curing Diabetes.

PineSAP--sequence alignment and SNP identification pipeline.

UNLABELLED: The Pine Alignment and SNP Identification Pipeline (PineSAP) provides a high-throughput solution to single nucleotide polymorphism (SNP) prediction using multiple sequence alignments from re-sequencing data. This pipeline integrates a hybrid of customized scripting, existing utilities and machine learning in order to increase the speed and accuracy of SNP calls. The implementation of this pipeline results in significantly improved multiple sequence alignments and SNP identifications when compared with existing solutions. The use of machine learning in the SNP identifications extends the pipeline's application to any eukaryotic species where full genome sequence information is unavailable. AVAILABILITY: All code used for this pipeline is freely available at the Dendrome project website (http://dendrome.ucdavis.edu/adept2/resequencing.html)

Attention switching during scene perception: how goals influence the time course of eye movements across advertisements.

Eye movements across advertisements express a temporal pattern of bursts of respectively relatively short and long saccades, and this pattern is systematically influenced by activated scene perception goals. This was revealed by a continuous-time hidden Markov model applied to eye movements of 220 participants exposed to 17 ads under a free-viewing condition, and a scene-learning goal (ad memorization), a scene-evaluation goal (ad appreciation), a target-learning goal (product learning), or a target-evaluation goal (product evaluation). The model reflects how attention switches between two states--local and global--expressed in saccades of shorter and longer amplitude on a spatial grid with 48 cells overlaid on the ads. During the 5- to 6-s duration of self-controlled exposure to ads in the magazine context, attention predominantly started in the local state and ended in the global state, and rapidly switched about 5 times between states. The duration of the local attention state was much longer than the duration of the global state. Goals affected the frequency of switching between attention states and the duration of the local, but not of the global, state.

Caring for those without words: a perspective on aphasia.

A technical grasp of a medical condition does not always give a person a sense of the emotions behind the disease. Medical professionals, of course, cannot afford to be emotionally invested in every illness they see. Some amount of distance is needed for them to maintain their own emotional health and to give good care to patients. However, emotional or psychological struggles are a large component of a patient's suffering. If these realities are ignored, a medical professional will be much less effective on any level.

Loss and hope: strategies for coping with aphasia.

Speaking from almost 30 years of experience living with aphasia, the author offers suggestions for health care professionals who relate to persons with this disorder. Persons with aphasia should be involved in meaningful activities, learn to accept limitations, build trusting relationships, strengthen social support, and find tools that facilitate communication.

The sounds of silence: relating to people with aphasia.

For people with aphasia, the struggle to communicate creates powerful emotions, such as anger and frustration, and feelings of isolation and depression. The author, who has had aphasia for more than 25 years, calls on health care professionals to relate to people with aphasia with patience, active listening, and motivation for success.

Automated Factor Slice Sampling.

Markov chain Monte Carlo (MCMC) algorithms offer a very general approach for sampling from arbitrary distributions. However, designing and tuning MCMC algorithms for each new distribution, can be challenging and time consuming. It is particularly difficult to create an efficient sampler when there is strong dependence among the variables in a multivariate distribution. We describe a two-pronged approach for constructing efficient, automated MCMC algorithms: (1) we propose the "factor slice sampler", a generalization of the univariate slice sampler where we treat the selection of a coordinate basis (factors) as an additional tuning parameter, and (2) we develop an approach for automatically selecting tuning parameters in order to construct an efficient factor slice sampler. In addition to automating the factor slice sampler, our tuning approach also applies to the standard univariate slice samplers. We demonstrate the efficiency and general applicability of our automated MCMC algorithm with a number of illustrative examples.

Unique features of the loblolly pine (Pinus taeda L.) megagenome revealed through sequence annotation.

The largest genus in the conifer family Pinaceae is Pinus, with over 100 species. The size and complexity of their genomes (∼20-40 Gb, 2n = 24) have delayed the arrival of a well-annotated reference sequence. In this study, we present the annotation of the first whole-genome shotgun assembly of loblolly pine (Pinus taeda L.), which comprises 20.1 Gb of sequence. The MAKER-P annotation pipeline combined evidence-based alignments and ab initio predictions to generate 50,172 gene models, of which 15,653 are classified as high confidence. Clustering these gene models with 13 other plant species resulted in 20,646 gene families, of which 1554 are predicted to be unique to conifers. Among the conifer gene families, 159 are composed exclusively of loblolly pine members. The gene models for loblolly pine have the highest median and mean intron lengths of 24 fully sequenced plant genomes. Conifer genomes are full of repetitive DNA, with the most significant contributions from long-terminal-repeat retrotransposons. In depth analysis of the tandem and interspersed repetitive content yielded a combined estimate of 82%.

Decoding the massive genome of loblolly pine using haploid DNA and novel assembly strategies.

BACKGROUND: The size and complexity of conifer genomes has, until now, prevented full genome sequencing and assembly. The large research community and economic importance of loblolly pine, Pinus taeda L., made it an early candidate for reference sequence determination. RESULTS: We develop a novel strategy to sequence the genome of loblolly pine that combines unique aspects of pine reproductive biology and genome assembly methodology. We use a whole genome shotgun approach relying primarily on next generation sequence generated from a single haploid seed megagametophyte from a loblolly pine tree, 20-1010, that has been used in industrial forest tree breeding. The resulting sequence and assembly was used to generate a draft genome spanning 23.2 Gbp and containing 20.1 Gbp with an N50 scaffold size of 66.9 kbp, making it a significant improvement over available conifer genomes. The long scaffold lengths allow the annotation of 50,172 gene models with intron lengths averaging over 2.7 kbp and sometimes exceeding 100 kbp in length. Analysis of orthologous gene sets identifies gene families that may be unique to conifers. We further characterize and expand the existing repeat library based on the de novo analysis of the repetitive content, estimated to encompass 82% of the genome. CONCLUSIONS: In addition to its value as a resource for researchers and breeders, the loblolly pine genome sequence and assembly reported here demonstrates a novel approach to sequencing the large and complex genomes of this important group of plants that can now be widely applied.

The evolutionary genetics of the genes underlying phenotypic associations for loblolly pine (Pinus taeda, Pinaceae).

A primary goal of evolutionary genetics is to discover and explain the genetic basis of fitness-related traits and how this genetic basis evolves within natural populations. Unprecedented technological advances have fueled the discovery of genetic variants associated with ecologically relevant phenotypes in many different life forms, as well as the ability to scan genomes for deviations from selectively neutral models of evolution. Theoretically, the degree of overlap between lists of genomic regions identified using each approach is related to the genetic architecture of fitness-related traits and the strength and type of natural selection molding variation at these traits within natural populations. Here we address for the first time in a plant the degree of overlap between these lists, using patterns of nucleotide diversity and divergence for >7000 unique amplicons described from the extensive expressed sequence tag libraries generated for loblolly pine (Pinus taeda L.) in combination with the >1000 published genetic associations. We show that loci associated with phenotypic traits are distinct with regard to neutral expectations. Phenotypes measured at the whole plant level (e.g., disease resistance) exhibit an approximately twofold increase in the proportion of adaptive nonsynonymous substitutions over the genome-wide average. As expected for polygenic traits, these signals were apparent only when loci were considered at the level of functional sets. The ramifications of this result are discussed in light of the continued efforts to dissect the genetic basis of quantitative traits.

Contrasting patterns of nucleotide diversity for four conifers of Alpine European forests.

A candidate gene approach was used to identify levels of nucleotide diversity and to identify genes departing from neutral expectations in coniferous species of the Alpine European forest. Twelve samples were collected from four species that dominate montane and subalpine forests throughout Europe: Abies alba Mill, Larix decidua Mill, Pinus cembra L., and Pinus mugo Turra. A total of 800 genes, originally resequenced in Pinus taeda L., were resequenced across 12 independent trees for each of the four species. Genes were assigned to two categories, candidate and control, defined through homology-based searches to Arabidopsis. Estimates of nucleotide diversity per site varied greatly between polymorphic candidate genes (range: 0.0004-0.1295) and among species (range: 0.0024-0.0082), but were within the previously established ranges for conifers. Tests of neutrality using stringent significance thresholds, performed under the standard neutral model, revealed one to seven outlier loci for each species. Some of these outliers encode proteins that are involved with plant stress responses and form the basis for further evolutionary enquiries.

DnaSAM: Software to perform neutrality testing for large datasets with complex null models.

Patterns of DNA sequence polymorphisms can be used to understand the processes of demography and adaptation within natural populations. High-throughput generation of DNA sequence data has historically been the bottleneck with respect to data processing and experimental inference. Advances in marker technologies have largely solved this problem. Currently, the limiting step is computational, with most molecular population genetic software allowing a gene-by-gene analysis through a graphical user interface. An easy-to-use analysis program that allows both high-throughput processing of multiple sequence alignments along with the flexibility to simulate data under complex demographic scenarios is currently lacking. We introduce a new program, named DnaSAM, which allows high-throughput estimation of DNA sequence diversity and neutrality statistics from experimental data along with the ability to test those statistics via Monte Carlo coalescent simulations. These simulations are conducted using the ms program, which is able to incorporate several genetic parameters (e.g. recombination) and demographic scenarios (e.g. population bottlenecks). The output is a set of diversity and neutrality statistics with associated probability values under a user-specified null model that are stored in easy to manipulate text file.

Multilocus patterns of nucleotide diversity and divergence reveal positive selection at candidate genes related to cold hardiness in coastal Douglas Fir (Pseudotsuga menziesii var. menziesii).

Forest trees exhibit remarkable adaptations to their environments. The genetic basis for phenotypic adaptation to climatic gradients has been established through a long history of common garden, provenance, and genecological studies. The identities of genes underlying these traits, however, have remained elusive and thus so have the patterns of adaptive molecular diversity in forest tree genomes. Here, we report an analysis of diversity and divergence for a set of 121 cold-hardiness candidate genes in coastal Douglas fir (Pseudotsuga menziesii var. menziesii). Application of several different tests for neutrality, including those that incorporated demographic models, revealed signatures of selection consistent with selective sweeps at three to eight loci, depending upon the severity of a bottleneck event and the method used to detect selection. Given the high levels of recombination, these candidate genes are likely to be closely linked to the target of selection if not the genes themselves. Putative homologs in Arabidopsis act primarily to stabilize the plasma membrane and protect against denaturation of proteins at freezing temperatures. These results indicate that surveys of nucleotide diversity and divergence, when framed within the context of further association mapping experiments, will come full circle with respect to their utility in the dissection of complex phenotypic traits into their genetic components.